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Guidelines for

Modern Radiation Oncology


Practice
Vol XIV
(Part A)

Editors
Dr. Umesh Mahantshetty
Professor, Radiation Oncology
Tata Memorial Hospital

Dr. Santam Chakraborty


Assistant Professor, Radiation Oncology
Tata Memorial Hospital

Dr. Shyamkishore Shrivastava


Professor & Head, Department of Radiation Oncology
Tata Memorial Hospital

Published by
Tata Memorial Centre
Mumbai

Tata Memorial Hospital


Dr. Ernest Borges Road, Parel
Mumbai 400 012. INDIA.
Tel.: +91-22-2417 7000
Fax: +91-22-2414 6937
Email: crs@tmc.gov.in
Website: http: //tmc.gov.in

Evidence Based Management of Cancers in India


Vol. XIV
Three Parts
Set ISBN: 978-93-82963-06-6
Guidelines for Modern Radiation Oncology Practice
Part A ISBN: 978-93-82963-07-3
Guidelines for Cytogenetic and Molecular Testing in
Myeloid Malignancies
Part B ISBN: 978-93-82963-08-0
Guidelines for Cardio Oncology
Part C ISBN: 978-93-82963-09-7

Published by the Tata Memorial Hospital, Mumbai


Printed at the Sundaram Art Printing Press, Mumbai
2015 Tata Memorial Hospital, Mumbai
All rights reserved.

Dedicated to
all our patients at
The Tata Memorial Hospital

Contributors

Dr. Jai Prakash Agarwal

Dr. Shirley Lewis

Dr. Ashwini Budrukkar

Dr. Umesh Mahantshetty

Dr. Naveen Balaiyya

Dr. Renuka Masodkar

Dr. Abhishek Chatterjee

Dr. Ashwathy Mathew

Dr. Sayan Das

Dr. Manu Mathew

Dr. Deepak D Deshpande

Dr. Vedang Murthy

Dr. Reena Engineer

Dr. Rima Pathak

Dr. Lavanya G

Dr. Abhishek Puri

Dr. Tejpal Gupta

Dr. Anupam Rishi

Dr. Rakesh Jalali

Dr. Rajiv Sarin

Ms. Swamidas V Jamema

Dr. Jayant Goda Sastri

Dr. Sangeeta Kakoti

Dr. Supriya Sastri

Dr. Chira Ranjan Khadanga

Dr. Shyamkishore Shrivastava

Dr. Nehal Khanna

Dr. Monali Swain

Dr. Rajesh Kinhikar

Dr. Anil Tibdewal

Dr. Siddhartha Laskar

Dr. Bhavin Visariya

Dr. Sarbani (Ghosh) Laskar

Dr. Tabassum Wadasadawala

Contents
1
2
3
4

Evolution of Newer Radiation Techniques


1
Brain tumors
18
Head and Neck Cancers
72
Thoracic tumors
Lung
122
Oesophagus
170
5 Breast Cancers
Newer XRT techniques
195
Brachytherapy
251
6 Gynaecological Cancers
External Radiation
276
Brachytherapy
300
7 Urology Cancers
Prostate Cancer
329
Bladder Cancer
356
8 Gastro-Intestinal Cancers
Stomach
368
Hepato-biliary tumors
376
Hepatocellular Cancers
390
Biliary Tract Cancers
400
Rectum Canal
406
Anal Canal
425
9 Hematolymphoid tumors
432
10 Pediatric Solid tumors
453
11 Bone &Soft Tissue Sarcomas
477

Preface
Practice of Evidence Based Medicine in Oncology allows
the clinician to make important clinical decisions for
improvement in cancer care. It integrates the best
medical research evidence with clinical expertise and
patient values.
Radiation Oncology specialty has evolved from radium
era to the state-of-the-art radiation technology today.
In last 2 decades, a revolution in radiation technology
has lead to a change in Radiation Oncology practice
today. The Modern Radiation Oncology practice
mandates the use of newer imaging modalities,
powerful treatment planning algorithms and
automated treatment delivery systems. The state-of-art
radiation technologies namely, Intensity Modulated
Radiation Therapy (IMRT), VMAT, Image Based
Brachytherapy etc. has been implemented in routine
clinical practice for past 10-15 years. There is a major
thrust and emphasis on the use of these newer radiation
techniques for better therapeutic ratio in terms of better
outcomes, minimizing toxicities and better quality of
life. With the advent of newer technology, stereotactic
radio-surgery / radiotherapy and hypo-fractionated
radiation for many cancers is being implemented. Also,
these modern radiation techniques have rekindled new
avenues for re-irradiation in some sites.

This is the 14th Volume on Evidence Based Management


Guidelines brought out by Tata Memorial Centre
represents the commitment of our institution to
implement uniform treatment strategies for cancer
across India. With an improvement in survival in most
cancers, the emphasis has now shifted to
individualization of treatment and reduction in
treatment related toxicities in this era of multidisciplinary approach. The current volume addresses the
best available evidence and potential research avenues
for Modern Radiation Oncology Practice for all cancer
sites. Each chapter is dedicated to a specific cancer site
and covers evolution of radiation technology to its
successful implementation in clinical practice and
generation of high level of current evidence. It also
includes in detail the hurdles in standardization of
various processes, evidence in terms of clinical outcome
and toxicities, caveats and research avenues for high
precision radiation techniques.
I hope this volume helps all the oncologists to
understand and adopt Modern Radiation Oncology
techniques in their routine clinical practice to achieve
excellent outcomes!

February 2015
Mumbai, India

R A Badwe
Director,
Director, Tata Memorial Centre

Evolution of High Precision


Radiation Technology

Introduction
Radiation therapy (RT) has advanced dramatically and
rapidly in the past few decades. From use of multileaf
collimators, CT imaging for planning, 3D Conformal
treatment, Intensity modulated treatment (IMRT), Image
guided treatment (IGRT), the list is endless. These advances
have lead to innovations in physics dosimetry as well.
Effectively it has resulted in precise dose delivery to the
target and better sparing of critical organs. The goal of
radiotherapy is to deliver maximum possible dose to the
tumour whilst sparing normal tissue. Technological
advances incorporating new imaging modalities, more
powerful computers and software, and new delivery
systems have helped to achieve this.

Paradigm Shift from 2D to 3DCRT


2D RT using rectangular fields based on plain X-ray imaging
has largely been replaced by 3D radiation therapy based
on computed tomography (CT) imaging which allows
volumetric delineation of the tumour and critical organ
structures for optimal beam placement and shielding. This
1

lead to more critical definitions of target volumes viz. gross


tumour volume (GTV), with a margin for microscopic
tumour extension called the clinical target volume (CTV),
and a further margin uncertainties from organ motion and
setup variations called the planning target volume (PTV)
etc.
Coupled with these developments, the advent of MLCS
has given a tool in hands of clinicians and physicists to
conform the dose to above target volumes. Many organs
are relatively sensitive to radiation damage (the spinal cord,
salivary glands, lungs, and the eyes are common examples)
and must be given special consideration during
radiotherapy treatment planning. Explicit field shaping of
the beam with MLCs has become possible to reduce the
amount of healthy tissue irradiated, and multiple beams
are used to lower the dose absorbed by tissue outside the
target volume. This form of treatment popularly known
as 3DCRT has been an important landmark in evolution of
precision therapy.

IMRT
IMRT allows creating irregular-shaped radiation fields that
conform to the target volume whilst simultaneously
avoiding critical organs. The critical organs are given
constraints to limit the dose through inverse planning.
This requires much advanced computer assisted treatment
planning systems. IMRT is made possible through:
a) inverse planning software and b) computer-controlled
intensity-modulation of multiple radiation beams during
treatment. IMRT can be delivered by linear accelerators
with static or dynamic multi-leaf collimators or
tomotherapy machines using binary MLCs.
2

IMRT has become treatment of choice for almost all sites


and there are many studies, which have established
superiority of IMRT against 3DCRT, mainly due to reduced
dose to critical organs.

Treatment planning algorithms


The smarter and faster algorithms with more capability
like auto-contouring, smart segmentation and improved
dose calculation have been developed. Algorithms for
registration to approach towards adaptive radiotherapy
and the dose calculation for accurate treatment delivery
are essential and desired features of TPS. The rigid
registration and deformable registrations play an important
role in 3D and 4D planning. Calculations greatly differ in
heterogeneous mediums or density changing zones.
TPS algorithms in computing volumetric doses
commercially available are: pencil beam convolution
(Eclipse PBC), analytical anisotropic algorithm (Eclipse
AAA), AcurosXB (Eclipse AXB), FFT convolution (XiO
Convolution), multigrid superposition (XiO Superposition),
Collapsed cone convolution (Tomotherapy) and Monte
Carlo photon (Monaco MC), etc.

SRS/SRT
Stereotactic radiotherapy/radiosurgery treatment are
mainly developed for brain cases. It employs small field
treatments with high dose per fraction in later case. SRS is
used mainly for AVMS with a single fraction high dose of
order of 12-18 Gy. A stereotactic invasive frame is used
for immobilization. The mechanical precision of the
machine is very crucial for accurate delivery of the
treatment. SRT uses non invasive specialised thermoplastic
3

immobilization and is fractionated treatment. The planning


system commissioning for small fields with miniature MLCs
or cones should be very accurate. The margin around PTV
with MLC is around 1-2 mm and same precision is expected
from the machine as well. The DICOM transfer of the plan
from treatment planning system to the machine needs
special attention from quality assurance point of view.
Generally other imaging modalities MRI and Angiography
are used in fusion with CT for better localization.
Nowadays, with use of frameless SRS/SRT, IGRT plays an
important role.

Hypofractionated Radiotherapy/SBRT
Stereotactic body radiation therapy (SBRT) involves the
delivery of a small/large number of ultra-high doses of
radiation with few fractions (usually 4-8) to a target volume
using very advanced technology and has emerged as a
novel treatment modality for cancer. The role of SBRT is
most important at two cancer stagesin early primary
cancer and in oligometastatic disease. This modality has
been used in the treatment of early-stage non-small-cell
lung cancer, prostate cancer, renal-cell carcinoma, liver
cancer, and in the treatment of oligometastases in the
lung, liver, and spine. The concept of delivering a single
high dose of radiation (as done with the Gamma Knife
technology for brain malignancies) rather than multiple
smaller doses can be especially useful for patients with
painful cancers metastatic to the spine. Immediate pain
relief is the goal and with the newer treatment planning
devices and treatment delivery machines it is possible to
give a large single dose successfully without damage to
the nearby spinal cord.
4

Image Guided Radiotherapy (IGRT):


IGRT is a technique, where, imaging is performed, within
the treatment room, prior to radiotherapy to improve the
geometric accuracy of the delivery of radiation beam. It is
a logical evolution arising from the ability to deliver highly
conformal dose through techniques such as IMRT, hypofractionated SRT, and charged particle therapy. These
conformal techniques would not be as effective if there
were significant uncertainties in daily patient position
verification. The combination of highly conformal dose
distribution, and accurate daily targeting of the tumor leads
to the possibility of dose escalation while reducing the
treatment related morbidity. Geometric and dosimetric
benefits of IGRT have been reported for a variety of disease
sites including the prostate, head and neck , lung and
liver.
Techniques of IGRT: Traditionally surface and skin marks
were used to direct the radiation beams, later on portal
imaging came into existence. However, with the
introduction of 3D imaging capability, there are a wide
range of techniques that are used for IGRT.
CBCT: The most commonly used IGRT technique is the
Cone-Beam Computed Tomography (CBCT) through
onboard kilovoltage systems on the currently available
linear accelerators. With improvements in flat-panel
technology, CBCT has been able to provide superior image
quality, and also allows for radiographic or fluoroscopic
monitoring throughout the treatment process. Typically,
cone beam CT acquires many projections over the entire
volume of interest in each projection. Using the
reconstruction algorithms, the 2D projections are
reconstructed into a 3D volume analogous to the CT
planning dataset.
5

MVCT: Megavoltage Cone Beam CT is a technique to use


megavoltage beam of accelerator for getting images just
before treatment. For getting better image however,
megavoltage energy is reduced for this purpose. It has
been used in earlier accelerator models and now used in
Tomotherapy. 3MV energy is used for getting MV images.
Ultrasound: US is useful for soft tissue visualization
especially in breast and prostate cancer patients.
Optical tracking: Optical tracking entails the use of a
camera to relay positional information of objects within
its inherent coordinate system by means of a subset of
the electromagnetic spectrum of wavelengths spanning
ultra-violet, visible, and infrared light. Optically tracked
tools are then used to identify the positions of patient
reference set-up points and these are compared to their
location within the planning CT coordinate system. A
computation based on least-squares methodology is
performed using these two sets of coordinates to
determine a treatment couch translation that will result in
the alignment of the patients planned isocenter with that
of the treatment set up.
MRI based IGRT systems: MRI-guided radiation therapy
enables clinicians to see a patients internal anatomy in
real-time using continual soft-tissue imaging and allows
them to keep the radiation beams on target when the
tumor moves during treatment.
Electromagnetic transponders: Electromagnetic
transponder serve exactly the same clinical function as CBCT
or kV X-ray, yet provide for a more temporally continuous
analysis of setup error analogous to that of the optical

tracking strategies although it is not an IGRT system per


se.

Correction Strategies
There are two basic correction strategies used while
determining the most beneficial patient position and beam
structure: on-line and off-line correction. Both serve their
purposes in the clinical setting, and have their own merits.
Generally, a combination of the both strategies is
employed. Often, a patient will receive corrections to their
treatment via on-line strategies during their first radiation
session, and subsequent adjustments off-line during check
film rounds.
On-line: The On-line strategy makes adjustment to patient
and beam position during the treatment process, based
on continuously updated information throughout the
procedure. The on-line approach requires a high-level of
integration of both software and hardware. The advantage
of this strategy is a reduction in both systematic and
random errors. Gold markers are implanted into the
prostate to provide a surrogate position of the gland. Prior
to each days treatment, portal imaging system results are
returned.
Off-line: The Off-line strategy determines the best patient
position through accumulated data gathered during
treatment sessions, almost always initial treatments. The
strategy requires greater coordination than on-line
strategies. However, the use of off-line strategies does
reduce the risk of systematic error. The risk of random
error may still persist.

Motion Management:
Radiotherapy in the presence of intra-fraction organ
motion causes blurring of the static dose distribution over
the path of the motion. This displacement results in a
deviation between the intended and delivered dose
distributions. The impact of target motion in the thoracic
and abdominal regions has been particularly important
due to the respiratory motion and many organs at risk in
these regions.
There are various methods to account for respiratory
motion in radiotherapy.




Slow CT acquisition,
Inhale and exhale breath-hold CT,
Four dimensional or respiration-correlated CT.

Respiratory gating methods:


The motion can be managed by means of gated delivery.
Respiratory gating involves the administration of radiation,
during both imaging and treatment delivery within a
particular portion of the patients breathing cycle. The
position and width of the gate within a respiratory cycle
are determined by monitoring the patients respiratory
motion, using either an external respiration signal or
internal fiducial markers. Since the beam is not
continuously delivered, gated procedures are longer than
non-gated procedures.
Gating using an external respiratory signal
This device uses external markers for gating the radiation
beam however, it has x-ray imaging capabilities for
determining the internal anatomy position and for verifying
8

the reproducibility of the internal anatomy during


treatment.

Gating using internal fiducial markers:


The fiducials are implanted in or near the tumour using a
percutaneous or bronchoscopic implanting technique.
Fiducial position is tracked in all three dimensions several
times a second using a pair of stereotactic kilovoltage
x-ray imaging systems in combination with automatic
detection software. When each fiducial is within an
acceptable range of the desired (simulation) position for
both stereotactic x-ray cameras, the linear accelerator
delivers radiation.
Gated IMRT:
In this method, an arc (conventional gantry system) or
continuous rotation (ring gantry system) is repeated while
gating the accelerator until the correct number of pulses
is delivered from each beam angle. The couch is stationary
until all beam pulses are delivered, then indexed to the
next position. The same technique can also be used with
helical delivery: the treatment helix would need to be
repeated until all of the pulses for each angle had been
delivered. The ability to quickly start and stop gantry
rotation or patient breathing irregularity and other
uncertainties are still to be resolved.

Volumetric Modulated Arc Therapy


(VMAT)
Despite the obvious benefits of IMRT, there are still some
disadvantages. IMRT plans use a larger number of monitor
units compared with conventional plans leading to an
9

increase in the amount of low dose radiation to the rest


of the body. The increase in MU and subsequent increase
in low dose radiation has led to concerns of increased risk
of secondary radiation-induced malignancies, which is of
particular relevance in paediatric patients or patients with
long life expectancies. VMAT is a new radiation technique
that combines the ability to achieve highly conformal dose
distributions with highly efficient treatment delivery. VMAT
was first introduced in 2007 and described as a novel
radiation technique that allowed the simultaneous
variation of three parameters during treatment delivery,
i.e. gantry rotation speed, treatment aperture shape via
movement of MLC leaves and dose rate. The basic concept
of VMAT is the delivery of radiation from a continuous
rotation of the radiation source and allows the patient to
be treated from a full 360 beam angle. The clinical
worldwide use of VMAT is increasing significantly. Currently
the majority of published data on VMAT are limited to
planning and feasibility studies, although there is emerging
clinical outcome data in several tumour sites.

Helical Tomotherapy (HT)


As a modality for delivering rotational therapy, HT offers
dosimetric advantages by combining a continuously
rotating gantry with a binary multileaf collimator. HT,
delivers intensity-modulated fan beams in a helical pattern
using binary multileaf collimator leaves while the couch is
translated through the gantry. Helical tomotherapy offers
the possibility of treating a variety of casesfrom simple
to complexwith improved target conformality and OAR
sparing compared with 3D or conventional static field IMRT
plans, thereby allowing biologically effective dose
10

escalation. For precise irradiation and possible treatment


adaptation, the fully integrated on-board image-guidance
system provides online volumetric images of patient
anatomy using 3.5-MV x-ray beams and the xenon
computed tomography detectors system.

CyberKnife:
The CyberKnife(CK) system uses the combination of a
robotics and image guidance to deliver concentrated and
accurate beams of radiation to intracranial and extracranial
targets, many of which are inoperable with sub- millimeter
accuracy. The robotic arm is highly flexible, allowing access
to tumors in difficult-to-reach locations. The CyberKnife,
unlike other stereotactic radiosurgery systems, is able to
locate and track the position of the tumor without the
use of an invasive stereotactic head frame or stereotactic
body frame. The system compensates for the patients
respirations and movement during treatment, constantly
ensuring accurate targeting for the delivery of radiation
beams. Unlike conventional SRT techniques, CK treats
tumours throughout the body including the head, spine,
lungs, prostate, liver, and pancreas. Current data have
validated that it is a highly efficient radiotherapeutic
modality for delivery of hypofractionated radiotherapy in
a variety of clinical scenarios and sites, especially for
palliation with superior normal tissue sparing. With
available evidence, this system offers an invaluable solution
to the treatment of selective tumours/lesions located close
to critical structures, salvage of recurrent and metastatic
lesions and potential of treatment of selective early stage
malignancies like the carcinoma prostate and lung.
However, it is still too premature, with insufficient follow
11

up data to advocate it as the treatment of choice in any


set up. There are several radiobiological issues that also
remain in the gray zone.

Flattening Filter Free (FFF) beams:


Flattening Filter Free (FFF) X-ray beam has been in clinical
use for quite some time. However, not until recently, these
FFF beams are used in limited, small field sizes, for example,
in Tomotherapy and CyberKnife machines, However, FFF
X-ray beams in conventional linacs have up to 40 X 40 cm
field sizes for both 6 and 10 MV X-rays. For large treatment
fields, the dose uniformity within an irradiated treatment
field will need to be modulated by MLC movements to
cut down the higher beam intensity near the central
portion of the FFF X-ray beam. Thus, larger MUs are
required compared with a conventional (flattened) X-ray
beam. Or, MLC movements (IMRT) are now being used to
flatten the FFF X-rays to provide dose uniformity within
those large PTVs. The high dose rates from the FFF X-rays
are now being off-set by the larger MUs requirements.
Therefore, FFF X-rays can bring clinical advantages over
conventional X-rays when used with small field sizes, such
as in SBRT and/or SRS applications. The primary purpose
of the FFF X-rays is to provide much higher dose rates
available for treatments. Commercially available FFF dose
rates are 1400 MU/minute for 6 MV X-rays and 2400 MU/
minutes for 10 MV X-rays. Higher dose rates have definite
clinical benefits in organ motion management. For
example, larger dose fractions can be delivered in a single
breath-hold or gated portion of a breathing cycle. In SRS
or SBRT treatments, large MUs are often required and FFF
X-ray beams can deliver these large MUs in much shorter
12

beam-on time. With shorten treatment time, these FFF


X-rays improve patient comfort and dose delivery accuracy.
FFF X-ray beams may become one of the necessary
equipment configurations for SBRT and/or SRS treatments,
in the future.

Brachytherapy:
The brachytherapy has evolved tremendously over past few
decades. In earlier days Radium needles/tubes were used
for implanting in tumour and the doses were calculated
by various systems like Manchester, Paris. Stockholm
derived from rich clinical experience and which were used
to deliver specified dose to the tumour fairly accurately in
absence of planning systems and any mode of visualization
of Implants & dose distributions. Later with development
of various manual and after-loaded applicators and
different Radium substitutes like Cs-137, Co-60, Ir-192
large potential of brachytherapy were evident. High Dose
Rate (HDR) remote after-loading coupled with advances
in treatment planning systems has ensured well defined
protocols and methods for brachytherapy dose analysis.
Recently use of imaging techniques for 3-D data acquisition
for brachytherapy application, contouring and treatment
planning has made significant contribution for precise
brachytherapy dose delivery.
Conventional Simulator radiographs had been basic tools
for TPS to input brachytherapy applicator & source data.
Recently CT-Simulator has been used to input the
applicator data and 3-D reconstruction through direct
images transfer by DICOM network. The CT & MRI are
also being used for contouring various volumes like target
& clinical organs which coupled with 3-D planning
13

algorithms gives direct doses to critical organs with volume


analysis. In case of intracavitary application MRI gives better
visualization of soft tissue so that we can more clearly see
the critical organs like bladder & rectum.
American Brachytherapy Society (ABS) Image guided
Brachytherapy working group (IGBWG) have provided
guidelines in reporting the image based brachytherapy,
which recommends the prescription of dose to a volume
rather than a point. Later GEC ESTRO published guidelines
for the practice and reporting of image based ICA, which
has been widely accepted so that a unified approach is
formed among the users of image based brachytherapy.

Hadron Therapy
The new and exciting development is use hadrons such as
protons and heavy ions (carbon) for radiotherapy. Proton
beam therapy has the advantage that the proton beam
gives up its maximum energy at end of its range in a small
area known as the Bragg peak. This has advantages in
terms of normal tissue sparing, better dose homogeneity.
The narrow brag peak is broadened by spreading it by
varying the energy of the beam to form a Spread Out
Bragg Peak (SOBP), which covers the target. The Carbon
ions have advantage of greater Relative Biological
Effectiveness (RBE), which is very important characteristics.
Intensity modulated proton therapy (IMPT) allows for the
modulation of the fluence and the position of the Bragg
peak, permitting three-dimensional dose distributions. So
it allows for the delivery of very high doses of radiation to
the tumor with minimal side effects.

14

Dosimetry and Quality Assurance


The advances in physics dosimetry include, advance
softwares in radiation field analyzers, detector arrays (ion
chamber based and diode based), in-vivo dosimetry
systems (diodes, MOSFETs, Gel dosimeters, optically
stimulated luminescence dosimeters (OSLD) etc). The
developments in film dosimetry led to more recent and
instant readout from the Radiochromic films, which does
not need development. Electronic portal imaging has
played its important role in IGRT and dosimetry as well.
EPID based dosimetry is used for patient specific dosimetry
in IMRT and volumetric modulated arcs.
In view of conforming targets and precise dose delivery
patient dose verification has assumed greater importance.
There are several national and international organizations
playing pivotal roles in patient dose verification. In United
States, Radiologic Physics Center (RPC, USA) and Regional
Calibration Laboratories (RCLs) provides phantoms and
TLDs with a benchmark case plan for advanced treatmentdelivery techniques to be delivered at hospital end and
compare with standard. Advanced Technology Integration
Committee (ATIC) and American Association of Physicists
in Medicine (AAPM) assist in standardizing the dosimetry
protocols through task group reports. Radiation Therapy
Oncology Group (RTOG) formulates clinical protocols for
newer treatment modalities and delivery techniques.
EQUAL-ESTRO in Europe also issues certificate after
intercomparison for particular clinical projects.
International Atomic Energy Agency (IAEA) conducts the
inter-institutional thermo-luminescent dosimeter (TLD)
comparison in order to facilitate the comparisons of
treatment protocols for better patient care. Bhabha Atomic
15

Research Center (BARC) in India is working towards the


same goal and conducts TLD intercomparison in the
country.

References:
1.

2.

3.

4.

5.

16

Purdie TG, Bissonnette JP, Franks K, et al. Cone-beam


computed tomography for on-line image guidance
of lung stereotactic radiotherapy: localization,
verification, and intrafraction tumor position. Int J
Radiat Oncol Biol Phys 2007;68:243252.
ICRU Repoat No. 50. Prescribing, recording and
reporting photon beam therapy In: Landberg T.,
Chavaudra J., Dobbs J., Hanks G., Johansson K.,
Mooller T., Purdy J. editors. International Commission
on Radiation Units and Measurements, 1993.
Lei Xing, Brian Thorndyke, Eduard Schreibmann,
et.al. Overview of image-guided radiation therapy.
Medical Dosimetry, Volume 31, Issue 2, Summer
2006, Pages 91112
Richard Potter, Christine Haie-Meder, Erik Van
Limbergen et al. Recommendations from
gynaecolgical (GYN) GEC ESTRO working group (II):
concepts and terms in 3D image based treatment
planning in cervix cancer brachytherapy-3D dose
volume parameters and aspects of 3D image based
anatomy, radiation physics, radiobiology.
Radiotherapy and Oncology, 78: 62-67, 2006.
Followill DS, Kry SF, Qin L, Lowenstein J, Molineu A,
Alvarez P, Aguirre JF, Ibbott GS.The Radiological Physics
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Erratum in: J Appl Clin Med Phys. 2014;15(2):4757.


PMID:22955664
6. Fanning B.CBCTthe justification process, audit
and review of the recent literature. J Ir Dent Assoc.
2011 Oct-Nov;57(5):256-61. Review. PMID:
22165476
7. Glide-Hurst CK, Chetty Improving radiotherapy
planning, delivery accuracy, and normal tissue sparing
using cutting edge technologies. IJ. J Thorac Dis. 2014
Apr;6(4):303-18. Review. PMID:24688775
8. Jaffray D, Kupelian P, Djemil T, Macklis RM. Review of
image-guided radiation therapy. Expert Rev Anticancer
Ther. 2007 ;7:89-103.
9. Teoh M1, Clark CH, Wood K, Whitaker S, Nisbet A.
Volumetric modulated arc therapy: a review of current
literature and clinical use in practice. See comment in
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967-96.
10. Sahani G, Sharma SD, Dash Sharma PK, Deshpande
DD, Negi PS, Sathianarayanan VK, et al. Acceptance
criteria for flattening filter-free photon beam from
standard medical electron linear accelerator: AERB task
group recommendations. J Med Phys 2014;39:
206-11.

17

BRAIN TUMORS

Introduction to Radiation therapy (RT) in


Neuro-Oncology:
Earch year 18,000 new brain tumor cases are registered
in India, accounting for 5% of all cancer cases in the
country(1).Recent advances in imaging modalities like
Magnetic Resonance Imaging (MRI), Magnetic Resonance
Spectroscopy (MRS), Perfusion, Bio-imaging and
simultaneous improvement in surgical techniques,
radiation therapy delivery techniques as well as discovery
of better chemotherapeutic drugs have led to improvement
in overall survival in these tumors. Brain tumors are broadly
classified into paediatric and adult tumors since prognosis
and management is different for these two groups. Till
the last decade adult high grade gliomas (HGM) were
considered to have poor clinical outcome. However, the
outcomes are now improving (2,3)not only due to the
above advances in the multimodal treatment approaches
but also due to the incorporation of molecular profiling in
the treatment algorithm(4).
Most paediatric brain tumors are low grade with good
local control and overall survival rates(5). Treating paediatric
tumors with good prognosis is especially challenging where
18

the long term treatment related toxicities can be


discouraging. Modern radiotherapy technology is focused
at achieving optimal therapeutic gain (6).
Surgery remains the mainstay of treatment for primary
brain tumors. However, adjuvant radiotherapy plays a
crucial role in improving local control, progression free
survival and overall survival rates for most intermediate to
high grade tumors. Following maximal safe resection,
adjuvant radiotherapy is indicated in all high-grade primary
brain tumors. Following complete excision of benign
tumors, like pituitary adenoma, Grade I meningiomas, low
grade gliomas (LGM) etc., currently, there is no evidence
for benefit with adjuvant radiotherapy. However, adjuvant
radiotherapy is indicated for macroscopic residual tumor,
recurrence or progression. For tumors in the eloquent
cortex where only a partial excision or biopsy is possible,
radical radiotherapy improves outcome.
With increasing overall survival (OS) there are concerns
regarding treatment related morbidity, which includes
neuropsychological impairment, endocrine dysfunction,
growth retardation, risk of second malignancy and
cerebrovascular events that can be attributed to both
treatment and tumour effects. Although the exact role of
radiotherapy in the causation of these sequelae is not yet
completely understood, it is fair to assume that
radiotherapy is at least partly responsible. Irradiated volume
is higher with conventional treatment portals which
potentially causes increased morbidity. Combined
approach of surgery and early chemotherapy, to delay or
avoid Radiotherapy (RT), reduction in RT doses with
concurrent chemotherapy have been tried in very young
children with mixed outcomes (5). Possibility of reducing
19

volume of normal tissue irradiation with advance RT


techniques have gained popularity due to their potential
to save critical normal structures without compromising
tumor control thereby reducing the long term sequelae (6)

Evolution of radiotherapy techniques in


Neuro Oncology
What is the need for changing radiotherapy
technique from 2D to 3D?

Two dimensional RT has been practised since the time
when x-rays were discovered and put to use in the
cancer therapy. It is still being extensively used in
majority of the centres across the world. However,
with the evolution in both imaging and radiotherapy
technology, there is a shift in practise from 2D RT to
3D-CRT.

3-Dimensional Conformal techniques (3DCRT/IMRT)
are capable of precisely targeting tumors while
avoiding normal structures. 3D planning and accurate
delivery of radiation dose to the target volume is
important for CNS tumours as it has been shown to
reduce late complications in long term survivors.
Requirements for radiotherapy planning and
delivery in brain tumours:

Positioning and Immobilization:

Immobilization devices have two fundamental
roles: to provide a reliable means of
reproducibility of the patient position during the
course of treatment and to immobilize the
patient during treatment to reduce motion.
Proper positioning and good immobilization is
20

an essential prerequisite for precision


radiotherapy for brain tumours in order to
achieve maximum benefit. Proper positioning
with different head support systems are required
for brain tumour radiotherapy delivery. For e.g,
Pituitary tumours, tumours in the frontal lobe
and temporal lobe are treated with full flexion
of the neck. Tumours in the high parietal region,
posterior fossa are treated with neutral neck
position.

Study from TMH between neck rest(NR) only and
neck rest with flexion(NRF) showed that errors
were significantly higher in the AP direction with
NRF when compared to NR-only (11).

For craniospinal irradiation (CSI) pts were
previously treated in prone position with
thermoplastic moulds to immobilize head and
neck. At present, with advanced techniques of
radiation delivery (IG-IMRT), supine position is
used as there is no difference in target coverage,
dose homogeneity and doses to OARs when
compaired with Vs prone position(12).
Target volume delineation by incorporation of
functional imaging:
11

C Methionine positron emission tomography
(MET-PET) has an improved specificity and
sensitivity for high-grade gliomas (9, 13).

Ga-DOTA TOC PET/CT shows increased sensitivity
in cranial meningioma when compared with
CE-MRI (14) and now this has been utilized in
target volume delineation for RT planning.
21

MET PET/MRI fusion demonstrates tumor infiltration better as compared to MRI shows grey
areas(15).

Radiation necrosis can be better differentiated
from actual tumor progression with a higher
accuracy(13).

Lee et al has shown association between high
areas of uptake and local failure (16).
Dose constraints:

Lt Temporal lobe 13 % of the volume should
receive less than 43.2 Gy (17).

Hippocampus: D median < 7.8 Gy, D100% < 10
Gy and Dmax < 15.3 Gy (18)

The Quantitative Analysis of Normal Tissue Effects
in the Clinic (QUANTEC) review has given
exhaustive normal tissue dose/volume tolerance
guidelines


22

Brainstem: Max dose should not go beyond


54 Gy & 1% volume <60Gy.

Optic chiasm & optic nerves: Max dose


should not go beyond 54 Gy. For SRS: <8Gy

Brain (whole) max dose should not go


beyond BED of 120 Gy (5% risk of radiation
necrosis)

Cochlear apparatus: <35Gy Dmax (<30Gy,


if possible),Mean cochlear dose: 45Gy. For
SRS: 12-14 Gy Max

Image guidance (IGRT): Image-guidance maximizes


the therapeutic index of brain irradiation by decreasing

setup uncertainty. The determination of the setup


uncertainty prior to the initiation of radiation plays
an important role in the treatment of CNS
malignancies. Daily setup variation may be under
recognized and may have an adverse impact,
including target under dose and normal structures
receiving a higher dose than anticipated.

Dose to critical structures can be affected by
patient motion during treatment and risk
volumes based on patient motion are
recommended to accurately ascertain the dose
administered to normal tissues (19).

Setup margin can be reduced using daily
localization based on cone beam CT and it further
helps in reducing normal tissue exposure to
radiation (20).

Evidence about the efficacy of Modern


Radiation Therapy Practice (General)
Early toxicity: 
RT is very well tolerated with modern conformal RT
for both localized fields and large fields such as CSI.
Also concurrent chemo RT quite feasible in routine
practice with minimal interruption in radiotherapy.

Modern conformal RT also gives an opportunity to
plan and deliver full RT doses in standard fractionation
even in elderly patient population with moderate
PS(ECOG2/3). This was not so much possible in 2D
era with cobalt 60 or in the era where WBRT was
commonly practiced.

23

24

Use of modern conformal techniques and precision


RT either with conventional IMRT or Tomotherapy in
patients with large field RT like CSI can be treated
with minimum interruptions or the need for growth
factors/platelets support.
Recent preliminary experiences in ultra high-precision
RT techniques of helical Tomotherapy and particle
therapy have shown promise in further minimizing
early RT induced toxicties. Many of the patients need
minimal or no dose of corticosteroids during RT for
most of the gliomas and other benign brain tumours
(21, 22).
Even large field RT like CSI- Minimum need to interrupt
RT or need for growth factors/platelets
50 pts of various histologies treated with vertebral
body sparing Proton CSI reported low incidence of
haematological and GI toxicity. 5 pts developed
grade 2 anorexia and 3 pts developed grade 3
cytopenias (22). This incidence is lower as compared
to conventional CSI technique.
In a retrospective review of acute toxicity of 40 pts
treated with conventional CSI and Proton CSI, Proton
CSI resulted in a significant reduction in weight loss,
grade II nausea and vomiting, oesophagitis, fewer
falls in blood counts (23).
Fatigue during radiation therapy is an important issue
which affects the quality of life of patients.
Compared to photon, fatigue is reduced with proton
and carbon ion (24).

Scalp sparing RT (Hair Loss) :



Roberge et al has shown in a dosimetric study
using IMRT that scalp sparing EBRT is feasible in
brain tumours (25).

With the evolution of radiation delivery
techniques like VMAT and helical tomotherapy
scalp sparing IMRT is achievable (26, 27).

Late Toxicity
Quality of life:

62 children of posterior fossa brain tumors
treated with conventional therapy and/or
chemotherapy were evaluated for QOL at a
median follow up of 5.2 yrs showed a correlation
between persistent hydrocephalus and large
ventricular size to be significantly associated with
reduction in QOL (28).

In a longitudinal phase II prospective trial using
proton beam therapy for LGG showed no
changes in QOL assessment over time (29).

Neurocognition:
Neurocognition is an important end point for
evaluation and formulation of treatment strategies
in brain tumours. The morbidity of neurocognitive
deficits is experienced with varying severity by all brain
tumor patients, but their impact is diluted in high
grade brain tumor with poor survival. Patients with
low grade gliomas or benign brain tumors have a
good overall survival and hence risk associated with
treatment related long term toxicities need to be
weighed against the benefit. Neurocognitive Function
25

(NCF) impairment is experienced due to a variety of


factors like the tumor itself, location of the tumor,
presenting symptoms like seizures, control of seizures
with anti- epileptic medication, surgical treatment and
its outcome on seizures, radiotherapy; its total dose,
fraction size, treatment volumes and technique (30).
Neurocognitive morbidity could be expressed in
diverse forms like lack of attention, executive
functioning, processing speed, working memory and
they collectively contribute to declines in intellectual
and academic abilities as reported by Linda et al in a
group of 65 patients of LGG (31). Not all patients
with brain tumors and especially children, with similar
diagnoses and treatment, have identical
neurocognitive outcomes. Reliable predictive markers
that indicate poor outcomes need to be recognized
and a risk-adapted strategy, to preserve neurocognitive function and QOL must be adopted.
Radiotherapy has shown to affect all the domains of
NCF. There are studies that have evaluated the impact
of early adjuvant RT Vs delayed RT (at progression)
after maximal safe resection in LGGs, the results differ.
However most studies conclude that the decision of
whether or not to irradiate should be individualized
and that whenever indicated early low dose RT is
recommended (32). Many studies have consistently
showed the impact of volume of irradiation on NCF
decline and hence it becomes important to use
modern RT techniques to spare as much normal brain
wherever possible (10). A new ongoing randomized
controlled trial ACNS 0331 is evaluating the impact
26

of reducing the treatment volume in CSI for


medulloblastoma.
A study by Raber et al suggested that the memory
component of NCF was affected by radiation to
hippocampus (33). Subsequently many studies
suggested that avoiding high doses to hippocampus
when delivering whole brain radiation was possible
using IMRT and that delayed recall was better in these
patients. Further prospective studies are needed to
establish the dose constraints for hippocampus for
whole brain and partial brain radiation.
Evidence for factors affecting neurocognition:

WBRT: In a study of acute lymphoblastic
leukaemia pts who received prophylactic cranial
irradiation to dose of 24 Gy or 18 Gy, demonstrated that pts who have received 18 Gy were
significantly better in FSIQ, Verbal IQ and
Performance IQ than 24 Gy and at same levels
as controls (34, 35)

In a multicentric phase III randomized controlled
trial of 1-3 brain metastasis treated by surgery/
radiosurgery was randomized between WBRT
30Gy/10# and observation. HRQOL scores were
worse in WBRT as compared to observation. The
difference between scores was more in early
follow up period (36).

Focal RT photons: Use of radiotherapy carries a
significant risk for intelligence and information
processing in a study of 50 pts treated with
conventional radiotherapy (37). Conformal
radiation therapy preserved neurocognition score
as compared to conventional RT(38).
27

28

Focal Proton therapy: 31 pts were prospectively


followed up after proton therapy, mean FSIQ at
BL and FU are 107 and 101, mean BL and FU
VIQ 110 and 109, PIQ 106 and 102. Processing
speed dropped from 99.5 at BL to 85.2 at FU
(p = 0.002)(39).
CSI: Neuropsychological evaluation of 31 pts of
PF were retrospectively reviewed and showed that
long term impairment occurred in most patents.
Significant correlation between the full-scale IQ
score (FSIQ) and the CSI dose was demonstrated.
Also marked drop in verbal comprehension scores
was noted in children who had received the
higher dose (40).
Dose per fraction: Higher dose per fraction size
of > 2Gy has detrimental effect on neurocognition(41), however even with 2 Gy/#
neurocognitive effects were seen (31)
Age: Young age at diagnosis of medulloblastoma
is the most significant predictor of worse
outcome despite reduction in dose and volume
(42,43).
Radiation volumes: In a study of 88 pts of
localized ependymoma, total brain volume and
supratentorial brain volume significantly
correlated with IQ (42).
Surgical complications: Young high risk children
of MB with posterior fossa syndrome have higher
and earlier onset of neuro cognition (43,44).

Hippocampal sparing:
Selective avoidance of hippocampus to avoid radiation
induced cognitive decline This is currently being tested in
a prospective fashion for patients with good prognosis in
brain metastases.


In a phase II (RTOG 0933)clinical trial of hippocampal


sparing treated with WBRT to dose of 30 Gy/10#,
LINAC based IMRT and IMRT tomotherapy plans were
generated and demonstrated that target coverage
and homogeneity was acceptable for both techniques.
Helical tomotherapy spared the hippocampus, with
a median and maximum dose of 5.5 Gy & 12.8 Gy
respectively while LINAC-based IMRT spared the
hippocampus, with a median and maximum dose of
7.8 Gy &15.3 Gy. Hippocampus volume was on an
average 2% of planned brain volume (18).
However, there is no current recommendation for
sparing in gliomas since it has not been tested in any
clinical trial; it can be problematic if the glioma is
close to hippocampal structure. Therefore there is a
strong case for inclusion of low grade gliomas.
Study investigating the role of treatment margins,
hippocampal avoidance and proton therapy in
reducing neurocognitive deficits in 17 paediatric
patients of MB, showed that largest risk reduction
was with hippocampus sparing proton therapy and
smallest boost margin. Based on this study
hippocampus avoidance was best with proton therapy
as compared to 3D CRT and IMRT(45).

29

30

Endocrine dysfunction:

Irradiation to HPA axis during craniospinal
irradiation can cause GH, ACTH and TSH
deficiencies which leads to morbidity that needs
prolonged hormonal replacement therapy (46).

Risk of hypothyroidism was similar in both 23.4
Gy and 36 Gy of CSI in MB. Young age and
chemotherapy correlated with higher incidence
of hypothyroidism (47).

Merchant et al has shown endocrinopathies were
present even before conformal radiation therapy
(GH-24%) and 10 yr cumulative incidence of GH,
thyroid hormone, ACTH and GnRH analog
replacement were 50%, 64%, 19.2% and 34.2%
respectively(10).

In a retrospective review of 24 pts of uncured
cushings disease treated with CRT, 15 patients
underwent remission, none of the patients had
recurrence. New onset endocrine deficiencies
were seen in 8 (40%) patients (48).
Ototoxicity :

In a prospective observational study of 23 pts of
medulloblastoma, the rate of high-grade
ototoxicity was low (5%) and the sensitivity to
low frequencies was preserved. These pts
received cisplatin to mean cumulative dose of
303mg/sq.m (49).

Increased dose to cochlea was significantly
associated with increasing ototoxicity and PF or
TB boost with 3D CRT and IMRT technique can
reduced the dose to cochlea and reduced the
incidence of grade 3 or 4 ototoxicity.

In a prospective study of 60 patients treated with


proton therapy, median dose to the cochlea was
29.5 CGE (Standard Risk) and 41.6 CGE (High
Risk). POG Grade 3 or 4 hearing deficit at base
line and follow up (mean 2.6 years) were 4.8%
ears and 16.7% ears, respectively (39).
Radiation Necrosis: 236 medulloblastoma pts were
reviewed for the incidence of necrosis and after a
median follow up of 56 months, cumulative incidence
of necrosis at 5 yrs was 3.7% 1.3% and 4.4%
1.5% for infratentorial tumor location. Volume of
infratentorial brain receiving > 50Gy was predictive
of necrosis (50).
Second Malignancy:

Packer et al reported estimated cumulative 10year incidence rate of secondary malignancies
of 4.2% (1.9%6.5%) in MB after a median
follow up of 5.8 years after diagnosis in which
majority were CNS tumours (5).

The use of proton radiation therapy was not
associated with a significantly increased risk of
secondary malignancies compared with photon
therapy (51).
Role of modern radiation delivery techniques for Reirradiation:

In a retrospective study of 18 pts of recurrent
ependymoma who received reirradiation with
conformal therapy (Radiosurgery and IMRT) to
dose of 54 Gy (focal/CSI), median duration
between first and second radiation was 2.2 years.
3yr OS rate was significantly better in reirradiated


31

32

Vs non-reirradiated (81% Vs 7%). Time to second


progression after reirradiation was significantly
longer than time to first progression(52).
In a single series of 172 pts of recurrent glioma
from Germany, fractionated stereotactic
reirradiation was given after a median duration
of 48 months for LGG to a median dose of 30
Gy. Median survival was 22 months for LGG after
reirradiation(53).
38 pts of ependymoma who relapsed after a
median time of 16 months treated with
reirradiation using different techniques(SRS, Focal
conformal RT & CSI) experience local tumor
control however remain at risk of metastasis (54).
Proton: Reirradiation for malignant brain tumors
has been tried with acceptable clinical outcomes
and toxicity (55).
SRS: In a retrospective review of 87 consecutive
pts of recurrent high grade gliomas treated with
radiosurgery. Dose of 18 Gy was delivered at
margins. Median survival after reirradiation was
10 months (56).
In a single institutional prospective study cohort
of 114 pts of recurrent glioma treated with SRS
using Gamma Knife to a dose of 16 Gy prescribed
to 50% isodose line. Median survival from time
of SRS was 26 months and 13 months for Gr III
and Gr IV gliomas respectively (57).

Modern radiation therapy practices w.r.t


to specific Brain Tumours
Adult Low grade Glioma (Grade I/II,
Oligoastrocytoma, Oligodendroglioma)

Although the role of RT is established in low grade
gliomas, its timing is quite debatable. Since the
survival in these patients is long, there is high chance
of development of late toxicities. Hence the role of
conformal techniques such as 3D CRT and IMRT is
essential to reduce late toxicities for e.g.
neurocognition. However there are no randomized
trials to compare the role of different conformal
techniques in terms of clinical outcome or late toxicity.

Clinical outcome

In a multicentric randomized controlled trial of
adult LGG pts (EORTC 22845) between no RT Vs
upfront RT (54Gy/30# arm),no significant
difference was seen in overall survival in both
the arms, however, progression free survival and
seizure control was better in the upfront RT
arm (58).

In a randomized controlled trial of adult LGG pts
between 45Gy Vs 59.4Gy (EORTC 22844) treated
with conventional/conformal techniques, no
difference in PFS (47% Vs 50%) and OS (58% Vs
59%) was found after a median follow up of 74
months (59).

33

Paediatric Low Grade Gliomas (Pilocytic


Astrocytoma, Ganglioglioma, DNET, PXA)

Clinical Outcome:

In a phase II trial of 78 paediatric pts treated
with 3D-CRT using 1 cm CTV margin and MRI
guidance demonstrated 87 % and 74% EFS rate
and OS rate of 98.5 % and 96 % at 5 and 10 yr
respectively(60).

Recent retrospective series of 39 paediatric pts
treated with IMRT after resection or at
progression reported 8 yr PFS and OS rate of 78.2
and 93.7 % respectively. This study used different
CTV margins to GTV and found CTV of 5 mm is
sufficient enough for achieving good outcomes.

In a prospective study of 50 pts of LGG treated
with SCRT at Dana Farber Cancer Institute, OS
rate of 97.8 % & 82 % and PFS rate of 82.5 % &
65 % at 5 yr and 8 yr respectively were reported
(62).

143 pts of grade II astrocytoma received FSRT
and after a median follow up of 44 months, an
actuarial OS rate of 58% and 50% at 5 and 8
years respectively and improvement in QOL (KPS
score) for 53% of pts were reported (63).

15 pts of optic pathway glioma reported by
Combs et al shows PFS rate of 92% and 72%
and OS rate of 100% and 90% respectively (64).

In a single arm prospective trial of proton therapy
of 20 pts, potential treatment toxicity and
progression-free survival was evaluated. After a

34

median follow up of 5.1 yrs intellectual


functioning remained stable over time. No overall
decline in cognitive functioning was seen over
time. The PFS rate at 3 years was 85%, but it
dropped to 40% at 5 years (29).
Late Toxicity:

Merchant et al studied 78 pts using conformal
therapy and has shown that cognition was
preserved without compromising overall survival
rate. Significant improvement in childs behavior
score and visual auditory learning were seen.
Decline in spelling scores was the only domain
which had statistical significance. Patients
younger than 5 yrs had greatest decline in
cognition (10).

In the same above study, cumulative incidence
of GH replacement and hearing loss at 10 yr was
48.9% and < 6%, however 24% of pts had GH
secretion abnormality before CRT.

In a prospective study of 32 children treated with
protons, it was observed that all the children had
preserved Full Scale Intelligent Quotient without
compromising PFS and OS.However, it was
observed that a subgroup of children <7 years
had a significant decline in the above
neurocognitive parameter as a result of
significant dose to left temporal lobe and
hippocampus (65).

35

Embryonal Tumours (MB, PNET, Germ Cell


Tumour)

Dosimetric data:

Sharma et al compared dosimetrically CSI plans
of 3DCRT, IMRT-LA and IMRT- Tomo and showed
that all plans achieved comparable DHI for PTV
brain and PTV spine, IMRT Tomo achieved the
highest mean DHI of 0.96. The IMRT Tomo plan
was superior in terms of reduction of maximum,
mean and integral doses to almost all organs at
risk (OARs) except low dose volume to OARs (66).

Dosimetrically proton beam when compared
with IMRT gives greatest reduction of dose to all
non-target areas at all dose levels (67,68).

Gupta et al studied translational displacement
of skull, upper spine and lower spine while
matching MVCT with planning CT on
tomotherapy for 33 pts and suggested that
smaller set-up margins maybe appropriate while
using daily image-guidance with an online
correction protocol as compared to margins
derived from strooms formula (69).

Clinical Outcome:

In a phase III trial of 421 pts of average risk
disease delivered CSI to dose of 23.4Gy/13#
followed by posterior fossa boost to dose of 32.4
Gy/18 # to a dose per fraction of 1.8 Gy/day for
5#/week. 10 yr EFS and OS were 75.8 % and
81.3% respectively (5).

36

Hyperfractionated Radiation Therapy (HFRT):



In a phase II trial, Carrie et al showed after a
median follow-up of 77.7 months, 6-year OS and
EFS rates of 78% and 75% respectively without
chemotherapy. Annual full scale IQ decline was
2 points over a 6-year period (70). Similarly,
Gupta et al after a median follow up of 33
months showed, 3-year relapse-free survival and
overall survival of 83.5% and 83.2%, respectively.
Cognitive functions tested for all domains were
preserved at 2 years post completion of HFRT
with no decline over time (7).

In a phase I/II study of 15 non metastatic pts
treated with HFRT and adjuvant chemotherapy,
95% PFS was demonstrated after a median
follow up of 6.5 yrs (71).
Hyperfractionated Accelerated Radiation therapy
(HART):

In a feasibility study of 34 metastatic
medulloblastoma pts, CSI was given to dose of
39.68 Gy/32#/ twice daily with minimum of 8 hr
interval between 2 fraction followed by 22.32 Gy
boost to the whole posterior fossa and 9.92 Gy
metastatic boosts. Dose per fraction is 1.24 Gy.
Median duration of HART was 34 days (range
3138). 3 yr EFS and OS rate of 59% and 71%
respectively was achieved after a median follow
up of 4.5 years (72).

In another study of metastatic medulloblastoma
of 33 pts pretreated with chemotherapy and then
with hyperfractionation to dose of 39Gy/30# @
37

1.3Gy/# b.d followed by posterior fossa boost


up to 60 Gy (1.5Gy/# b.d). Eight pts relapsed
after a median of 12 months and EFS, PFS and
OS at 5 yrs were 70%, 72%, and 73%
respectively(73).
IMRT in Medulloblastoma

Dosimetric data
IMRT for CSI gives better dose homogeneity in the
craniospinal field. Moreover, the use of tomotherapy based
IMRT can abrogate the requirement of field junction shifts.
There are no randomized studies comparing 2D RT vs IMRT
for CSI although there are small prospective dosimetric
studies showing excellent homogeneity in the craniospinal
region (74).
Clinical Outcome
There are no trials which have studied the clinical impact
of IMRT in CSI. However, numerous prospective studies
have tried to investigate the role of tumour bed IMRT.
These studies did not report any reduction in OS .Moreover
none of the studies have reported any increase in local
failure rates in the boost volumes (75).


38

Protons in Medulloblastoma
Protons for CSI is used only in limited centers which
have protons facility.In view of its physical attributes,
protons can give homogenous dose distribution with
excellent sparing of normal tissues.

In a phase II prospective trial of 60
medulloblastoma pts treated with proton RT. The
OS and PFS for the entire group is 87% and 81%.

3 yr OS and PFS for Standard risk was 90% and


83% and for HR is 82% and 76% respectively(39).

Jeminez et al reported outcome data of 15 pts
treated with proton and after a median follow
up of 39 months, 13 out of 15 were alive and
free of recurrence, one pt died of local failure
and one from non-disease related. 13% patients
developed grade 3 ototoxicity requiring hearing
aids and 20% had grade 2 neuroendocrinopathy. The IQ index remained stable
during follow-up testing in comparison to
baseline evaluation(76).
Toxicity data:
Conformal therapy in craniospinal irradiation using
IMRT either by conventional linacs or by tomotherapy
has led to reduction in radiation induced
complications.

Jose et al in a cohort of 18 pts treated with
Tomotherapy based IMRT did not report any
incidence of radiation pneumonitis even after a
median follow up of 16.5 months (21).

Huang et al retrospectively evaluated Pure Tone
Audiometry of 113 pts treated with either
conventional RT or IMRT. The reported incidence
of grade 3 or 4 hearing loss was 13 % in IMRT
group compared to 64% in the conventional RT
group.

Ependymoma

Dosimetry data:

In a prospective study of 17 pts of ependymoma,
dosimetric comparison was done between IMRT
39

40

with photons, 3D CRT with protons and IMRT


with protons. All normal structures doses were
less with protons when compared with photons
and IMPT further reduced doses to most
structures. Target volume coverage was
comparable with all 3 techniques (77).
Clinical Outcome:

There are no randomized trials comparing
different techniques of radiation in
ependymomas, however 3D CRT and IMRT have
shown improved overall survival and reduced
local recurrences (60,78,79).

A Phase II trial of 153 paediatric pts of localized
ependymoma treated with conformal radiation
therapy showed a 7 yr LC, EFS and OS rate of
83.7%, 69% and 81% after a median follow up
of 5.3 years. Mean scores of all neurocognitive
outcomes were stable when tested at or beyond
24 months (60,78).

In a retrospective study of 70 pts with localized
ependymoma treated with proton therapy, 3 year
LC, PFS and OS rate was 83 %, 76 % and 95 %
respectively. Mean Intelligence score and overall
adaptive skills remained stable and few pts
develop hormonal dysfunction (80).
Toxicity:

A cohort of 123 patients treated with 3D CRT or
IMRT at St jude hospital were assessed for IQ
and adaptive functioning till 5 yrs post treatment.
Stable IQ and adaptive functioning was found
for entire study period (81).

Hyper fractionation for Ependymoma



Hyperfractionation with or without
chemotherapy has also been tried to improve
local control in a study of 63 consecutive children.
5 yr OS and PFS for entire cohort was 75% &
56% and 82% & 65% for those who received
HFRT. This strategy did not improve local control
compared to historical series (82).

Benign Brain Tumours (Cranipharyngioma,


Meningioma, Pituitary, Acoustic Neuroma)

Dosimetric data:

A dosimetric comparison between three different
techniques, IMRT, 3D-PRT and IMPT was done
with dose prescription of 50.4 CGE at 1.8Gy/#
with PTV coverage of 95% or better. Adequate
PTV coverage was achieved by all modalities and
proton therapy compared with IMRT delivered
lower integral dose to hippocampus,
subventricular zone, dentate gyrus, vascular areas
and rest of the brain (83).

A dosimetric study of 14 patients compared IMRT,
Double scatter proton (DSP) and IMPT techniques
and found that conformity Index and optic nerve
dose of IMPT plans were significantly better than
those of the IMRT and DSP plans showed lower
cochlear, optic chiasm, brain, and scanned body
doses (84).

Clinical Outcome:

Craniopharyngioma:

In a retrospective study of 40 pts treated
with fractionated SCRT (FSRT), with a
41

median follow up of 98 months results


showed 100% local control and 89% OS at
10 years. Most pts were treated at
progression after surgery (85).

42

In another retrospective study of 55 pts


treated with FSRT, with a median follow up
of 128 months results showed LC and OS
at 20 yrs are 88.1% and 67.8% respectively.
No difference in LC and OS was found
between pts treated upfront or at
progression (86).

24 paediatric pts in a retrospective review


treated with IMRT to dose of 50.4 Gy,
demonstrates 5 and 10 yr OS of 96% and
83.8% and PFS of 65.8% & 60.7%
respectively (87).

Eighty eight children treated with CRT or


IMRT at St. Jude Hospital, after a median
follow up of 5 years demonstrate no
difference in PFS based on CTV margin of
5mm or >5mm (88).

137 pts of residual or recurrent


craniopharyngiomas treated with gamma
knife radiosurgery (GKS) to a median dose
of 12 Gy (range 9.5-16 Gy) at a median
isodose line of 55% (range 50%78%)
demonstrated after a median follow up of
45.7 months, tumor control rates of 72.7%,

73.9%, and 66.3% for the solid, cystic and


mixed tumors, respectively. Overall survival
rates at 5 and 10 yr of 91.5% and 83.9%
respectively (89).

46 pts of residual or recurrent


craniopharyngiomas treated with GKS to a
median dose of 13Gy and after a mean
follow up of 62 months reported 5 yr OS
and PFS rate of 97.1% and 91.6%
respectively (90).

Retrospective review of 52 children treated


with IMRT or Proton therapy showed 3 yr
OS of 96% and no difference in OS and local
control rates between treatment arms (91).

10 pts were treated with combined photon


and proton treatment with 2 fields by
photon and one or two field by proton per
day. Total dose prescribed ranged from 53.4
to 67.5 cobalt Gray equivalent (CGE) and
median proton dose as part of the total dose
was 26.9 CGE (47%). Actuarial 5 and 10
year local control rates were 93% and 85%,
respectively and actuarial 10-year survival
rate was 72%(92).

Meningioma:


In a retrospective review of 46 patients of


meningioma treated with IMRT, local
recurrence occurred in 8 patients with 2 and

43

3 year actuarial LC of 92% and 74%,


respectively. Results also showed low risk of
marginal failure with reduced margins
after IMRT treatment (93).


44

46 patients treated with combination of


protons and photons (59 CGE) at
Massachusetts General Hospital (MGH),
demonstrated overall survival of 95% and
77% at 5 years and 10 years and local
control of 100% and 88% at 5 and 10 years
respectively (94).

Pituitary:


51 patients treated with protons to dose of


60.6 CGE reported overall survival of 100%
and local control of 98% at 4 years. 2/51
patients developed Grade III toxicity and
unilateral hearing loss with complete
pituitary deficiency (95).

In a study of 47 pts treated with protons


(54 CGE) and had at least 6 months of follow
up showed 85% biochemical control rate
and 40% hormonal normalization rate
without significant morbidity (96).

In a randomized trial of proton Vs carbon ion of


260 pts of meningiomas, pituitary adenoma, LGG
and HGG after median follow up of 12 months,
no recurrences were found for meningiomas and
low grade gliomas. No severe late toxicities were

observed. Local recurrences were seen in high


grade tumours (97).
Late Toxicity:

In a prospective study of 22 pts, it was observed
that neuropsychological impairment and
Barthels index were low even before starting RT
and SCRT did not worsen it. It was concluded
from the study that the above parameters may
have been impaired due to surgical and tumour
related factors even before the start of RT (98).

In a single center randomized trial of 200 pts
conducted at TMH, investigating between
conventional RT and CRT using stereotactic
guidance, low intelligence score was present
before treatment only. Intelligence score are
better preserved in conformal arm at 2 yrs and 5
yrs post treatment. Verbal quotient and memory
quotient are also better preserved at 5 yrs in
conformal arm as compared to conventional arm
(6).

The observations of the study were as follows.


Mean full IQ scale at baseline remained


unchanged at 2 year follow up however one
third of patients did show a >10% decline
in FSIQ (99).

Patients aged <15 years had a significantly


higher chance of developing a >10% drop
in FSIQ than older patients (53% Vs.
10%)(100).

45

Dosimetric comparison in patients showing


a >10% decline Vs <10% decline in IQ
revealed that patients receiving >43.2 Gy
to >13% of volume left temporal lobe were
the ones to show a significant drop in FSIQ
(100).

Hormonal dysfunction was present at initial


diagnosis in 42% pts of craniopharyngiomas and
after surgical intervention in 74% prior to IMRT
indicating possible role of tumor and surgical
intervention(87).
In a study by Lee et al ,Gamma knife surgery was
done for craniopharyngiomas,new-onset or
worsened pituitary deficiencies was seen in 11
patients and smaller tumor volume was
significantly associated with good outcome with
SRS(89).

High Grade Gliomas (grade III, IV)


For primary high grade gliomas like anaplastic astrocytomas
and glioblastomas, the standard radiation technique is 3DCRT. The use of high precision techniques like IMRT is
generally avoided in view of the highly infiltrative nature
of these tumours as there is a higher chance of missing
the infiltrative component of the tumour.


46

Dosimetric data:

In a study of 58 patients of high grade gliomas
treated with IMRT technique, dosimetric IMRT
plans were compared with 3D-CRT plans. There
was no observed difference between IMRT and
3D-CRT in terms of target volume coverage and

this was irrespective of tumor location. However,


in terms of normal tissue sparing, IMRT was
better than 3D CRT especially in reducing the
maximum dose to the eyes, optic nerve and spinal
cord (101).
Clinical Outcome:

There are no randomized studies conducted till
date to compare the efficacy of IMRT over 3D
CRT in high grade gliomas especially for GBM.
However, the landmark randomized study of
stupp et al in which 573 patients of GBM were
enrolled compared the efficacy of conformal RT
Vs. Conformal RT+TMZ showed a clear
improvement in median OS in patients who have
been treated with concurrent RT+TMZ. The
median survival further improved in patients who
were MGMT gene promoter methylators (3). In
a retrospective study of 31 pts of GBM treated
with IMRT and concurrent TMZ was evaluated
and found median survival of 17.4 months for
pts receiving 60 Gy which concurs with the data
of 14.6 months of Stupp et al (8). Based on the
above studies, it is evident that the clinical
outcome is governed by the addition of TMZ to
RT rather than the RT technique in glioblastomas.
Hypofractionated RT in GBM

In a prospective study of 25 pts treated with
hypofractionated IMRT with helical Tomotherapy
along with TMZ in the radical setting, two dose
levels 54.4Gy/20# and 60Gy/22# were delivered.
Median OS and PFS were 15.6 and 6.7 months
respectively(102).
47

In a phase II trial of 24 pts treated with


hypofractionated course of radiation (60Gy/10#)
using IMRT along with concomitant and adjuvant
temozolomide and after a median follow up of
14.8 months, median overall survival was 16.6
months (103).
Dose escalation in high grade gliomas

RTOG 9803 was a phase I feasability study which
looked at radiation dose escalation along with
BCNU in GBM patients (n=209) using 3D CRT
and two PTVs. PTV1 (GTV+1.8 cm) received 46
Gy/23# and PTV2 (GTV+0.3 cm) received 4 dose
levels of 66, 72, 78 and 84 Gy. Patients were
divided into two groups based on the PTV
volumes. Group 1 consists of PTV 75 cc and
Group 2 PTV 75 cc. The final conclusion of the
study did not show any improvement in clinical
outcome in terms of OS with dose escalation.
Moreover, acute toxicities did not increase with
escalated doses, but late RT induced necrosis
increased with dose escalation although not
statistically significant (104).

Dose escalation with IMRT to dose of 66-81Gy
along with temozolomide was tried in 38 pts of
GBM. No late toxicity of radiation necrosis was
observed in pts receiving 75 Gy. Median OS and
PFS were 20 and 9 months respectively(105).

A randomized phase II study (CLEOPATRA),
evaluating role of carbon ion boost 18 CGE in 6
fractions at a single dose of 3 CGE) applied after
concurrent RT+ Temozolomide versus a proton


48

boost (10 CGE in 5 single fractions of 2) after


Concurrent RT+ Temozolomide in patients with
primary glioblastoma has been initiated. This is
the first such study which is looking at the role
of particle therapy in improving OS.The
secondary endpoint of the study are PFS, toxicity
and safety. Results are eagerly awaited.
Late Toxicity

In a prospective multi institutional trial of 252
pediatric HGGs(COGL991 study) 54 children
with long term follow up of 15 years were
retrospectively evaluated for neuropsychological,
behavioral and QOL. Intellectual functioning,
executive functioning and verbal memory were
within low average range. QOL was within or
above normal limits for both physical and
psychosocial domains in approximately 75% of
pts (106).

In EORTC trial, baseline HRQOL was comparable
between RT alone Vs RT+TMZ arm. At 1st follow
up, Social functioning score was better in RT
alone Vs TMZ arm (mean score 79 Vs 69.4). At
subsequent follow up, HRQOL was same
between treatment arms (107).

In a phase II trial of 34 patients of HGG treated
using conformal therapy, baseline and serial
evaluation of neurocognition were performed.
40% of patients had IQ score of less than 85
before CRT. Intelligence quotient decreased from
baseline to 6 months and then increased slightly
at 12 months. However adaptive functioning

49

50

decreased significantly from baseline till 12


months (108).
SRS and Brachytherapy in HGG

A randomized trial for malignant astrocytoma
between EBRT followed by brachytherapy boost
with temporary stereotactic Iodine125 implant
delivering dose upto 60Gy Vs EBRT 50Gy/25#
has shown no improvement in survival (109).

A prospective randomized study for GBM pts
(RTOG 9305) investigating the role of SRS
followed by EBRT+Carmustine Vs. EBRT+Carmustine failed to show any survival benefit. However,
one must keep in mind that the study was
conducted even before TMZ was introduced into
the clinics (110).

GiloSite involves the use of an expandable
balloon filled with radioactive I125 and is placed
during tumour debulking. Its an active area of
investigation by Brain Tumour Therapy Central
Nervous System Consortium that involves delivery
of 40-60Gy to the target volume in recurrent
disease.
IORT for HGG
IORT delivers high doses of electrons (Giordano FA)
or low energy X-rays to the tumor bed where
maximum recurrences are known.

INTRAGO is a phase I/II dose escalation study of
IORT delivered with low energy X rays by spherical
applicators. Primary end point is evaluation of
maximum tolerated dose and secondary
endpoint is PFS and OS.

Stem Cell Niches in GBM


Neural progenitor cells (stem cells) are thought to be
present in the subventricular zones (SVZ) that are
proposed to promote tumorigenesis. These cells can
migrate out through their niches leading to
progressive disease. It has been proposed that
irradiation of niches in the SVZ may influence survival
outcomes.

Gupta et al have analyzed dose-volume
parameters to the SVZ that correlate with survival
outcomes in GBM. Older age (>50 years), poor
RPA class, and higher than median of mean
contralateral SVZ dose were associated with
significantly worse PFS and OAS. Multivariate
analysis identified RPA class, KPS and mean
ipsilateral SVZ dose as independent predictors
of survival. The authors have observed that
increasing mean dose to the ipsilateral SVZ was
associated with significantly improved OAS(111).
How robust is the evidence for modern radiotherapy
techniques in Brain tumours.
In general the evidence for using IMRT in brain
tumours is at level II or III.
For benign tumourss, LGG and ependymoma a
single center large randomized trial from TMC,
Mumbai comparing efficacy of stereotactic
conformal radiotherapy (SCRT) versus
conventional RT in children and young adults
TMC ( SCRT trial: NCT00517959) is expected to
report its final results shortly.

51

For high grade gliomas: The role of using 3DCRT


is established. However the role of IMRT is
debatable with the evidence level at III/IV.

CONCLUSION:
Evidence supports a clear advantage of conformal
techniques like IMRT/IGRT in benign brain tumours, low
grade gliomas and in CSI in term of outcome and better
late profile (mainly late) translating into better QoL. Focal
conformal radiotherapy with 3D-CRT for high grade
gliomas is a standard practice all over the world, although
there is weak evidence for the usage of IMRT in high grade
gliomas and should be used with great caution due to
the infiltrative nature of these tumours. In the present
scenario, IMRT should always be complemented with
image guidance (IG-IMRT). Finally, practising high-precision
radiotherapy in brain tumours, needs a clear perspective
and rationale on the part of the treating clinician especially
in a country like India where the teledensity is quite low.

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71

HEAD AND NECK CANCERS

External beam radiation therapy with or without


chemotherapy has long been an important modality for
the treatment of head and neck cancer (HNC), and achieves
high rates of local tumor control of over 80% for stage 12 and 6070% for stage 3-4 [1]. Historically, conventional
radiotherapy involves the delivery of fractionated radiation,
i.e. 1.8 2 Gy per fraction, using a square or rectangle
portals. However, delivery is complicated by the close
proximity of tumour and normal tissue structures such as
the spinal cord, brain stem, parotid glands and optic
pathway structures, which are invariably irradiated to a
high dose leading to both acute and late toxicity.
Acute reaction in the form of radiation mucositis and
salivary changes, associated with pain and discomfort is
experienced by virtually all patients and is the major cause
of poor treatment compliance (1). Late radiation toxicities,
including xerostomia, persistent dysphagia, mucosal and
skin fibrosis, dental decay, osteonecrosis and persistent
dysgeusia, can occur in many patients with profound
effects on quality of life (2).
During the last two decades, the amalgamation of
advances in image acquisition, immobilization, planning,
set-up verification and treatment delivery have made it
72

possible to increase the therapeutic ratio, with a sizeable


impact in outcome with improved toxicity profile and
quality of life (QOL). However, all these technical
advancements should be dealt with caution for optimal
utilization and outcome, without jeopardizing the costbenefit ratio which is of importance in resource limited
countries. This chapter highlights advancements and
caveats in each step of HNC radiation treatment with
reference to available evidence.

Why we should move to 3D?


Historically, 2-dimensional RT has been used extensively,
and is still used in many centres and in different clinical
scenarios. However, it is fraught with several issues some
of which are summated below:
1.

2.

3.
4.

Uncertainties in delineation of true spatial extent of


disease especially in tumours not clinically
approachable e.g. nasopharynx, nasal cavity, paranasal sinuses (3).
Inadequate knowledge of exact shape and location
of normal structures - the distance between either
gross tumour volume (GTV) or areas at high risk for
microscopic disease (clinical target volume (CTV)) and
critical structures such as the optic nerve, spinal cord,
brainstem, salivary gland is no more than a few
millimeters. It is extremely difficult to deliver a high
radiation dose to the tumour while limiting the dose
to an organ at risk just a few millimeters away.
Lack of tools for efficient planning.
Limitations in customising the dose distributions to
match the tumour volume.
73

5.

Limited scope for dose escalation without


compromising doses to organs at risk (OAR).

These limitations results in


o
o

Incorporation of larger safety margins.


Tumor dose often has to be compromised to prevent
normal tissue complications leading to higher
probability of local failures.
3-Dimensional Conformal techniques (3DCRT/IMRT) are
capable of precisely targeting tumors while avoiding
normal structures and constitute the current standard of
care in the treatment of HNSCC. Three dimensional
planning assures that the desired high-dose distribution
matches the tumor/target in all physical dimensions.
Advances in computerized treatment planning systems
along with hardware improvisations including highresolution multi-leaf collimators have made this possible.
However, the success of such a highly conformal planning
process as IMRT is highly sensitive to two major factors:
(1) Delineation of tumor/target volume in 3 dimensions
by the clinician around which the high-dose
distribution is developed through conformal planning
(4), and
(2) Day-to-day variations in setup that could result in the
tumor sneaking outside of the high-dose
distribution (5).

POSITIONING AND IMMOBILISATION:


The success of radiotherapy depends mostly on the
accuracy and the reproducibility of daily treatment delivery.
Studies have shown that an effective immobilization system
74

can reduce positioning variations and improve the outcome


of radiotherapy treatment (6, 7).
Routinely patient lies supine with head straight and both
arms by the side and as flat as possible to maintain the
spinal cord parallel to the couch top.
Immobilization devices have two fundamental roles: to
provide a reliable means of reproducing the patient
position from during the course of treatment and to
immobilise the patient during treatment to dampen
motion.
Simple immobilisation devices restrict patient movement
to some extent and therefore patient movements will not
be entirely deterred, e.g. masking tape, plaster of Paris
cast or bite block. The use of a bite block has the benefit
of a reduced risk of skin toxicity, but requires that the
patient has some remaining teeth and that skin markers
be used, which may be a cosmetic problem. The traditional
bite block requires active patient cooperation, which may
affect the reproducibility, because the patient must
maintain bite compression throughout the treatment
session (8).
Newer complex immobilization devices restrict the patients
movement significantly, and ensure reproducibility in
positioning, e.g. thermoplastic masks along with a head
rest, shaped to fit snugly under the patients head and
neck area which in turn affixed to a base plate positioned
on the treatment couch. The thermoplastic masks have
been found to result in an accurate reproduction of the
treatment position (6) but they can also increase the risk
of radiation dermatitis, because of the reduction of the

75

skin-sparing effect (9). A tounge depressor / intra-oral


prosthesis can be used to push the hard palate away from
the treated volume in oral cavity tumours or to depress
the tongue when sino-nasal tissues are treated.
Newer immobilization devices like precut open-face
thermoplastic masks (with reinforced strips) are now
available with improved comfort and tolerability for
patients, particularly those with moderate claustrophobic
anxiety without any compromising the reproducibility (10).

IMAGE ACQUISITION:
Optimal delineation of the primary tumour and the
involved lymph nodes are a prerequisite for curative
radiotherapy in head and neck cancer, minimizing the risk
of geographical miss. Accurate target definition is therefore
one of the most critical steps towards improvement in
radiation therapy.
[A] CT Scan: Computed tomography CT is at present
routinely used for initial delineation of tumour
volumes. The use of iodinated contrast agents
increases sensitivity and reduces intra-observer
variation. CT scanning offers:

Inherent quantitative information on electron
density, used by algorithms to account for tissue
heterogeneities for dose calculation

Potential for rapid scanning,

4 -D imaging can be done, and

Universally available and inexpensive.

76

The disadvantages include:


Significant inter- and intra-observer variability in target
delineation (11).

Exposure to ionizing radiation.
Several groups have published elaborate guidelines on
nodal regions, based on CT images (12, 13) and there is
some literature providing direction for CTV generation for
the primary tumour (12). However, there still exists
controversy on the volume of the primary subsite to be
included in the CTV.


[B] Magnetic Resonance Imaging: MRI has several


potential advantages over CT, such as

Better discrimination between tumour and
normal tissues in several subsites within the head
and neck, especially the PNS, nasopharynx and
oropharynx.

MRI-derived GTVs are subject to lesser interobserver variation than CT-derived GTVs.

Multi-planar imaging and the superior soft tissue
contrast has led to its use in target delineation
in nasopharyngeal carcinoma (NPC), especially
with suspected intracranial infiltration and also
for detection of cranial nerves / pterygo-palatine
fossa involvement (14).

Currently, MRI is considered the imaging modality
of choice for tumours of the base of the tongue
and lesions arising at the base of the skull and
fusion of MRI and CT images is recommended in
treatment planning wherever feasible (15).

77

However the use of MRI in treatment planning might be


limited by:
The presence of geometrical distortions.
Electron density information necessary for treatment
dosimetry cannot be obtained from MRI at present.

The fusion of distortion-corrected MRI and CT images
could provide improvement in target delineation.
[C] Positron emission tomography (PET):
The impact of PET imaging on target delineation in
radiotherapy for HNC has recently been investigated. Most
commonly used biological marker in cancer diagnosis is 18F radionuclide attached to 2-fluoro-2 deoxy - D-glucose
(FDG). Historically PET had poor resolution, but the utility
of PET has been further improved by the introduction of
combination PET/CT scanners, which enables the collection
of both anatomical & biological information
simultaneously.



78

PET/CT has the ability to significantly increase interobserver agreement and improve the confidence in
disease localisation of FGD-avid lesions.
In addition the ability of PET-CT to detect occult
metastases has an impact on the management plan
& the ability to detect additional nodal metastases
has an impact on the volumes generated (16).
In general, all studies conclude that PET adds extra
information to both CT and MRI concerning target
delineation. However, we must keep in mind that the
majority of FDG PET findings lack corresponding
pathology data.

A number of hypoxia-related PET tracers such as 18F-MISO


and 18F-FAZA are available now, an effort to identify
hypoxic tumor sub-volumes (17, 18). Studying the
application of these tracers, it is necessary to image patients
at least after 2.5h, because of the slow improvement of
the contrast between hypoxic and normal tissues.
Compared to 18F-MISO, the clearance of 18F-FAZA from
blood and from non target tissues is faster and therefore
has a higher tumor to background ratio.

IMAGE SEGMENTATION / CONTOURING


Target Volume delineation:
GTV - The GTV is defined as the primary tumour (defined
by clinical examination, endoscopy and imaging) (19) and
any lymph nodes over 10 mm in short axis dimension or
smaller nodes with necrotic centres or rounded contours
are considered significant. If induction chemotherapy has
been used, the post-chemotherapy GTV is contoured, but
the pre-chemotherapy extent of tumour should be included
in the high risk CTV (20).
CTV The CTV is generated by growing the GTV by an
isotropic margin of 10 mm except where there are natural
tissue barriers. The CTV is then edited slice by slice to
subtract adjacent structures such as bone which are
definitely not involved. The CTV margin can be locally
expanded by more than 10 mm if local structures such as
mucosa, muscle or soft tissue are at risk of involvement.
However, it should be borne in mind that the CTV is an
anatomical/ biological volume and not a geometric one.
In the post-operative setting, it is more difficult to specify
guidance for CTV as the anatomy is distorted by the
79

resection and by the presence of any reconstructive


myocutaneous flaps. Radio-opaque clips used to mark
close or involved margins can be helpful but should not
be confused with vascular ligation clips which may be
distant to the original tumour.
For target volume delineation one can refer to site-specific
suggestions offered by Eisbruch and Liu (21, 22).
For CTV lymph node delineation, one has to take into
consideration the pattern and risk of lymphatic drainage
from different head and neck sites. For selection of neck
levels that should be included in the CTV for individual
primary tumor sites one can go through the suggestions
in the aforementioned article (21) as well as by Gregoire
et al (13).

Organ at Risk Delineation:


Depending on location of PTV the organs at risk that should
be contoured include Temporal lobes, Pitutary gland,
Brainstem, Spinal cord, Eyes, Optic nerves, Optic chiasm,
Cochlea, Parotid Glands, Mandible, Oral Cavity, Larynx,
Thyroid Gland, Pharyngeal Constrictor muscles,
Cricopharyngeus, Cervical Esophagus and Brachial Plexus.

TREATMENT DELIVERY TECHNIQUES:


IMRT
Intensity modulated radiotherapy (IMRT) is an advanced
approach to 3-D treatment planning and conformal
therapy. During IMRT, one can modulate the beams during
treatment so as to have a more accurate dose delivery
with steeper dose gradients around the target volume,
allowing a decrease of the dose to the surrounding organs
80

at risk while maintaining target coverage. In the head and


neck region, IMRT has a number of potential advantages:
(i)

Allows greater sparing of normal structures such as


salivary glands, optic nerves and chiasm, brain stem
and spinal cord (23, 24);
(ii) Allows treatment to be delivered in a single treatment
phase without the requirement for matching
additional fields to provide tumor boosts, and
eliminates the need for electron fields to the posterior
neck nodes; and
(iii) Offers the possibility of simultaneously delivering
higher radiation doses to regions of gross disease and
lower doses to areas of microscopic diseasethe socalled simultaneous integrated boost (SIB) IMRT (25).

ROLE OF IMRT IN HEAD AND NECK


CANCERS:
Parotid Sparing:
Radiation induced damage to the salivary glands - changes
the volume, consistency, and pH of secreted saliva from
thin secretions with a neutral pH to thick and tenacious
secretions with increased acidity. These patients have oral
discomfort, difficulty in speaking, chewing, swallowing
and run an increased risk of dental caries or oral infection.
Ultimately, these problems can lead to decreased
nutritional intake and weight loss (26).
Role of IMRT:
With IMRT, it is possible, in selected patients, to partly
spare at least one parotid gland, while still treating the
target volumes in the bilateral neck to the prescribed doses.
81

Sparing one parotid gland has been shown to be sufficient


to prevent permanent xerostomia (27).

Consensus and Caution:


Mean parotid dose 26 Gy (28). However, overzealous
sparing of parotids, may lead to loco-regional failure and
failure in intra-parotid nodes. Sparing of the ipsilateral
parotid glandi.e., on the side of the neck disease
should have low priority, especially if level II lymph nodes
are involved, otherwise this could result in avoidable
regional recurrences (4, 29). Thus dont spare parotids at
the cost of target!
Evidence:
There are adequate level I evidences in literature in head
and neck cancers to support the use of IMRT with
significant impact on parotid function sparing and its
consequent impact on the QOL of the treated patients
(30-34).
A recently published meta-analysis on five prospective
phase III randomized trials comparing IMRT with 2D-RT
or 3D-CRT concluded that IMRT reduces the incidence of
grade 2-4 xerostomia in patients with head and neck
cancers without compromising loco-regional control and
overall survival (35).
Submandibular gland sparing: The submandibular
glands are responsible for most saliva production in the
non-stimulated state and chiefly contribute to the patients
subjective sense of moisture. Studies have demonstrated
the role of contra-lateral submandibular gland-sparing
(Dmean <25 Gy) over parotid sparing in reducing observerrated xerostomia (36). However, meaningful reduction of
the mean dose to the submandibular gland is potentially
82

hazardous owing to its close proximity to the lower level II


nodes, which require the full prescribed radiation dose to
maximise regional tumour control (37). An alternative
technique is submandibular salivary gland transfer (38).
Reducing the dose to the oral cavity could have additional
benefits in terms of preventing taste dysfunction, as well
as mucosal fibrosis and atrophy (39).

Prevention of late dysphagia:


With conventional 2D radiotherapy, the peak incidence of
moderate to severe chronic dysphagia is around 35% (40)
which with IMRT has been brought down to around 2027% (41). A study by Eisbruch et al identified the anatomic
structures whose malfunction post-radiotherapy was likely
to cause dysphagia and aspiration these were termed as
dysphagia/aspiration-related structures (DARS) which
includes the pharyngeal constrictor muscles, supraglottic
and glottic larynx. This study also demonstrated that IMRT
was able to reduce the V50 (Gy) of the DARS (42). The
clinical relevance of DARS sparing was shown by Levendag
et al, who demonstrated a steep dose-effect relationship
between mean dose to constrictor muscles and severe
dysphagia and that, for each additional 10 Gy after 55
Gy, probability of dysphagia increases by 19% (43).
Dose volume constraints for anterior oral cavity (V30 <
65% and V35 < 35%) and high superior phayngeal
constrictor (V55 < 80% and V65 < 30%) were predictive
for swallowing dysfunction (44). The role of IMRT in
reducing late dysphagia is currently being investigated in
a number of trials (45-47).
The constrictors lie in close proximity to the parapharyngeal
spaces and cervical lymph node areas. Therefore,
83

constrictor sparing could result in a geographical miss.


Feng et al has demonstrated that demonstrated that IMRT
aiming at sparing the swallowing structures is feasible
without compromising locoregional control rates (46).
However, long-term data on locoregional recurrence are
required before the constrictor sparing approach can be
used in standard practice.

Voice/Speech Quality:
RT induced laryngeal edema can lead to voice change,
which have an impact on QoL. As pr QUANTEC, cut-off
for laryngeal edema is < 44Gy (Dmean) or V50 < 27%. In
the first prospective study to assess voice and speech
changes after IMRT in oropharyngeal cancer patients, it
was seen that radiation dose to the glottis is an
independent determinant of voice quality worsening and
speech impairment. Clinical studies have reported
dosimetric predictors of dysphonia identifying 50 Gy as
the mean larynx dose constraint required to minimize voice
changes (48), while dose > 66 Gy to the false vocal cords
and pharyngeal wall were associated with vocal
dysfunction (49), and that minimizing dose to the glottis
to as low as reasonably achievable is likely to optimize
voice quality outcomes (50).
Decreased risk of Hearing Loss:
By virtue of its ability to spare the cochlea, IMRT has the
potential to reduce the incidence of radiation-induced
hearing loss. Peng et al, in randomized phase III study of
616 patients treated for cancer of the nasopharynx,
showed that hearing loss occurred in 25.8% of patients
after IMRT versus 84.5 % patients after two-dimensional
radiotherapy (p <0.001) (33).
84

Reduction of Fibrosis and Trismus:


With regards to fibrosis and trismus, Gupta et al found a
significant improvement in fibrosis at 2 years after IMRT
compared to three-dimensional conformal radiotherapy
(p = 0.005) (30). Peng et al also showed that rate of
trismus and fibrosis were 3.3% and 2.3% after IMRT as
compared to 13.9% and 11.3% after two-dimensional
radiotherapy (p <0.001) (33).
Reduction of Osteoradionecrosis:
The incidence of osteoradionecrosis (ORN) following head
and neck radiotherapy is about 3% (51). By using IMRT,
the percent mandibular volume exposed to 50 Gy (V50)
may be minimized, thereby reducing the risk of ORN (52).
RT induced Hypothyroidism (clinical or subclinical):
It is an under-recognized entity but a significant
complication of head neck RT. The incidence of
hypothyroidism after radiation therapy varies between 19%
and 53%, with a peak incidence seen at 1 2 years (53).
It can occur as early as 3 months following RT. Radiationinduced hypothyroidism was not included in the
QUANTEC; however it is commonly seen following a dose
of 26 - 40 Gy to the whole neck. Thyroid volume receiving
> 30 Gy (V30) has been considered as a possible predictor
of hypothyroidism (53).
IMRT can reduce the dose to the thyroid gland when
identified as organ at risk and it can be limited to <40 Gy,
which may in future reduce the occurrence of
hypothyroidism. However, since it can be effectively treated
with hormone replacement, it is still counted as low in
constraints priority. In standard IMRT treatment planning,
85

the thyroid gland has not been defined as IMRT avoidance


structure. IMRT without constraints for the thyroid gland
dose results in a higher incidence and shorter latency time
of radiation-induced hypothyroidism compared to that
after 3D-CRT (53).
Aim should be to recognize hypothyroidism early and
treating it can prevent associated complications. Hence,
thyroid function tests should be made routine during
follow ups from as early as 3 months and carried out
lifelong.

Reduction of Xerophthalmia:
In paranasal sinus tumors, IMRT allows a significantly lower
incidence of complications such as xerophthalmia (7.7%
at 3 years with IMRT against 23.7% with 3DCRT) (54).
Impact on clinical outcomes:
Published results on tumor control outcomes in terms of
local control (LC), regional control (RC), and locoregional
control (LRC) and also on survival outcomes in terms of
overall survival (OS), distant metastasis-free survival (DMFS),
and disease-free survival (DFS) in head and neck cancers
showed equivalent results with conventional 2-3D RT or
IMRT. The mean 3-year overall survival for either IMRT or
2-3D RT was 89.5% (range: 64100%) and 82.7% (71
88%), respectively. The mean 3-year locoregional control
rates were 83.6% (range: 7097%) and 74.4 (range: 61
82%), respectively (55).
In 2012, results of a prospective randomized controlled
trial was published that showed IMRT resulted in better
local control (6.7%), regional control (7.7%) and overall
survival (12.5%) compared to conventional technique in
86

nasopharyngeal cancer patients, more so in late stage


patients (33).
A recent analysis of the Surveillance, Epidemiology, and
End Results (SEER) database, however, has demonstrated
that the use of IMRT was associated with a significant
improvement in cause-specific survival compared with nonIMRT techniques (56).
IMRT has the potential to take advantage of the steep
dose response relationship by making use of simultaneous
integrated boost technique and escalate radiation doses
to improve outcomes without increasing the normal tissue
toxicity in patients with locally advanced head and neck
cancers. The initial results from a phase I dose-escalation
study using IMRT with concomitant cisplatin in patients
with stage III and IV squamous cell carcinoma (SCC) of
the larynx/hypopharynx showed that dose escalation was
safe and tolerable. The 2-year loco-regional control was
higher for dose escalated patients without any significant
late toxicity (57).
VMAT: Volumetric intensity modulated arc therapy (VMAT)
is a newer technique of delivering IMRT. VMAT delivers
IMRT-like distributions in a single rotation of the gantry,
varying the gantry speed and dose rate during delivery in
contrast to standard IMRT, which uses fixed gantry beams.
Planning studies using VMAT demonstrate shorter
planning and treatment time, lesser monitor units for
treatment delivery and better dose homogeneity (58, 59).
Owing to the complexity of the target volumes in head
and neck radiotherapy, the general consensus is that more
than one arc is required to achieve an acceptable dose
distribution.
87

PLANNING AND DOSE PRESCRIPTION


(ICRU 83):
Important issues:

IMRT requires a detailed understanding of
radiographic anatomy as well as other developing 3and 4-D representations of the patient in order to
correctly delineate both tumor/target volume (s) and
organs at risk (critical structures). With IMRT using
inverse planning, the target must be outlined precisely
or it might not be treated to the prescribed dose.

If a critical structure is not outlined, it might not be
not spared.

Target volumes located near the skin surface may pose
problems with the inverse optimization process.

The expansion of target contours in three dimensions
to account for uncertainties in planning and delivery
may result in the intersection of two structures and
thereby create problems in inverse planning
optimization. Expansion into air or into the build-up
region may also cause problems.

IMRT dose distributions are often more
inhomogeneous within the target than traditional
conformal therapy. In general, dose inhomogeneity
increases as the required dose gradient between the
target and an adjacent critical structure increases, the
concavity of the required dose distribution increases,
the distance between the target and a critical structure
decreases, and the number of available beam
directions decreases. Under these conditions,
prescribing the dose to a single point becomes
unacceptable.
88

Isocenter Placement: At simulation the marked isocenter


is generally placed at a stable location somewhere near
the superior-inferior center of the area of interest and just
anterior to the vertebral body
Physicist should also create the following:
o

o
o
o

Planning Organ at Risk Volume (PORV) Spinal Cord


and Brain stem:

Cord expanded 5mm

Brainstem expanded 5mm
Parotid subs parotids without the CTV targets
External & external contracted 3mm - to ensure that
there is an adequate build-up region in place.
Shaving or cleaning-up PTV is sometimes required
to take the created PTV out of abutting critical
structures e.g. optic nerves, brain stem, spinal cord
or even air. However, ICRU recommends making of
PTV subvolumes and accepting underdose instead of
shaving / cleaning up.

Beams and Energy:



In IMRT planning for head and neck cancers, only
6MV photons are used.

If the PTV is symmetrical, the beams are usually
distributed symmetrically. If the PTV is placed to one
side of the head and neck region, one beam is placed
in an area in the middle of the PTV and the rest of
the beams are distributed at equal angles of 25 - 30.
There should not be any opposing beams (a minimum
of 5 from directly opposing beams is required).

The typical beam arrangement for bilateral cases
consists of 9 beams (40 degrees apart).
89

Unilateral cases - 7 beams



Left sided disease: 182, 350, 22, 54, 86, 118,
and 150 degrees.

Right sided disease: 210, 242, 274, 306, 338,
10 and 178 degrees.
An AP field is avoided to minimize dose to the lips
while a PA field is used to help reduce dose to the
spinal cord.

Simultaneous integrated Boost (SIB-IMRT):


Concept of SIB: As IMRT allows achieving a very sharp
dose fall-off while effectively sparing critical organs in close
proximity, one can possibly consider a modest escalation
of the dose per fraction to the tumor volume, without
jeopardizing nearby organs, especially late responding
tissues like the spinal cord.
IMRT with computer based optimisation also allows one
to deliver different doses to different target volumes while
keeping the overall number of fractions the same. This
concept is realized by means of the simultaneous
integrated boost (SIB) whereby a modestly escalated dose
per fraction (2.1 -2.2 Gy/fraction) is delivered to gross
disease, in the same number of fractions (30-33) as the
rest of the areas deemed at lower risk.
Advantage of SIB: Treatment is accelerated by reducing
overall treatment time by as much as one week, a factor
of utmost importance in high throughput centres with
resource constraints. This form of delivering radiotherapy
termed simultaneous modulated accelerated radiation
therapy (SMART) has been proven to be safely applicable
in clinical trials, where a dose of 60-66 Gy in 30 fractions
90

has been safely administered without increasing late


toxicities (32).

Dose Painting:
Imaging-based dose painting, the prescription and delivery
of a non-uniform dose to the clinical target volume (CTV)
is a novel paradigm for prescribing radiation therapy. The
volumes considered most frequently for selective dose
boosting are regions that display high metabolism,
increased tumour hypoxia, or increased cell proliferation
(60). Two prototypical strategies have been considered in
the literature: sub-volume boosting, where an imagingdefined discrete volume is given an additional boost
radiation dose (in which case the prescription function
takes only two discrete dose values) (61), or dose painting
by numbers, where a dose is prescribed at the voxel level,
and it is left for the dose plan optimizer to arrive at a
physically deliverable dose distribution that approximates
the desired dose distribution (62). Although feasibility
studies have been done that shows higher doses can be
delivered to subvolumes without increasing normal tissue
toxicity (63, 64), however, dose painting by numbers is
still considered experimental as major uncertainties about
volume definition, frequency and reposition (in)accuracy
have to be resolved.
HNSCC RT Dose Prescription followed by most centres
(including TMH):
1.
2.

Radical RT (conventional fractionation): 66 70 Gy/


33-35#/ 6.5 -7 weeks
Adjuvant RT (conventional fractionation): 56 - 60 Gy/
28-30#/ 5.5-6 weeks
91

3.
4.

5.

Hyperfractionated RT: 81.6 Gy/68#/7 weeks @ 1.2


Gy/#, twice daily(65)
Accelerated RT: 66-68 Gy/33-34#/6 weeks @ 2Gy/#
given 6 days in a week(66) or 72Gy/42#/6 weeks
which includes concomitant boost of 1.5Gy/# for the
last 12# (65)
IMRT using Simultaneous Integrated Boost: 66 Gy/
30#/6 weeks (nasopharyngeal carcinoma) or 70Gy/
33#/6.5 weeks to the high risk PTV, 60Gy/30#/6
weeks or 59.4/33#/6.5weeks to the intermediate risk
PTV, 54Gy/30#/6 weeks or 54Gy/33#/6.5 weeks to
the low risk PTV

PLAN EVALUATION:


Isodose line distributions:


o PTV - 95% coverage
o CTVs (subs) - 99 - 100% coverage
o Minimal overdose (volume receiving >105%).
o OARs dose
o Dose Volume Histograms (DVH) - Min / Max /
Mean

Dose Constraints in HNSCC:


The Quantitative Analysis of Normal Tissue Effects in the
Clinic (QUANTEC) review has given exhaustive normal tissue
dose/volume tolerance guidelines, which can be found
from the reference (67).
Suggested:
Cord: 45Gy max dose (Dmax) (<40Gy, if achievable)
Cord Expanded 5mm: 50Gy Dmax.
92

Brainstem: 54Gy max dose (typically <40Gy) (try for <30Gy


to posterior portion).
Brain: Tight 54Gy gradient
Parotids: <26Gy mean dose
Cochlea: <35Gy Dmax (<30Gy, if possible)
Optic Chiasm & Optic Nerves: < 54Gy Dmax
Mandible: <70 Dmax, no hot spots of > 105%
Oral cavity: ALARA
Larynx: ALARA
Esophagus: ALARA
Posterior Neck: <35Gy
Lens < 5Gy or <10 Gy if they are close to the target
Note: These are maximum dose limits with conventional
fractionation (1.8 2 Gy per faction), one should look to
achieve below these constraints, and should be more
conservative for hypo-fractionation or SIB-IMRT.

IMAGE GUIDED RADIOTHERAPY:


Why Image Guidance?
The success of IMRT is majorly due to setup reproducibility.
Due to the steep dose gradients that are achievable with
IMRT, the margin for setup error is small and the accuracy
of daily alignment and positioning becomes even more
important as there is an increased risk for a marginal
miss and under-dosing of the tumour as well as
unintended high doses to organs at risk.
93

Good Immobilization Do we still need Image


Guidance?
It is generally believed that this setup is stable with standard
thermoplastic mask for planning and treatment of HNSCC.
However, studies have reported considerable setup
variations with a standard mask immobilization (68). There
is significant random positional variation in the bony
anatomy that is skull, mandible and cervical spine despite
mask immobilization, with the effects most pronounced
for the mandible and lower cervical spine. The flexibility
of the neck and shoulders also leads to deformations with
setup errors.
Thus despite good immobilization, IGRT to verify patient
positioning ensures required accuracy to safely treat with
an IMRT plan.
EPID: The most basic and historical form of IGRT consisted
of two-dimensional (2D) portal images (megavoltage (MV)
or kilovoltage (KV) beam) acquired in perpendicular/
orthogonal planes to verify the position of the isocenter,
as well as the individual fields. Bony anatomical landmarks
are typically used as reference for alignment. These images
are obtained prior to treatment at our institution on the
first 3 days of treatment and thereafter once a week, but
other schedules have also been used.
Limitations poor image quality with MV imaging, and
difficult to appreciate small displacements.
Soft tissue alignment and deformations cannot be
appreciated with 2D imaging.
CBCT: Recent advances in 3-dimensional or volumetric
imaging have addressed some of these issues, and
94

integrated cone beam CT (CBCT) has emerged as an


efficient system for in-room localization. A scan can be
acquired quickly, generally in 1 to 2 minutes, just prior to
treatment with the patient in the treatment position. Both
KV and MV CBCT systems are available, but KV imaging
provides better image quality. The CBCT localization scan
is then superimposed on the treatment planning CT scan
utilizing software based registration algorithm to verify
the accuracy of setup, and any necessary shifts are made
to obtain an accurate match. Treatment planning target
volumes, organs at risk, and/or any user-defined regions
of interest (ROI) or structures may be visualized. Bony
misalignments are readily identified, rectified, and the
offsets are automatically recorded. In addition, soft tissue
deformations of tumor (e.g., due to regression), as well
as normal structures (e.g., due to weight loss) may be
identified, and it raises the possibility of adaptive
radiotherapy (ART) in response to these changes. CBCT
typically increased patient time on the table by no more
than 3 minutes.

What should we match for setup up in HNSCC?


Image registration should be performed at the level of the
primary tumour using a bony match.
Caveat: Anatomic displacements within the treatment
field at further location. For example, for tonsil cancer the
match is obtained at C2-3 vertebral bodies, but there could
be a mismatch in the low neck (required to electively treat
the level 4 lymph nodes). Reason: Random variation and
semi-independent rotational and translational movement
of the skull in relation to the lower cervical spine. Daily
CBCT have shown that maximum mobility was in the skull
and mandible relative to C4C6 (69).
95

Best Solution: Match to high neck anatomy at C1-C2, as


there are significant random setup errors in the low neck.
CTV to PTV Margin: In one of the largest prospective
series with daily pre-treatment CBCT-based IGRT in patients
undergoing head and neck IMRT by Den et al, the necessary
margin from CTV to PTV in order to account for daily setup
variation were found to be 3.9, 4.1, and 4.9mm in the
ML, CC, and AP dimensions, respectively, without CBCT to
account for systematic and random errors (70).
Thus, recommended CTV to PTV margin expansion:
-

Without IGRT = a minimum of 5mm,


With daily CBCT = Margins could potentially be
reduced to 2-3 mm.

Any impact on survival with 3 mm margin?


No randomized evidence so far. However, preliminary
clinical data based on 130 patients with HNSCC treated
with IMRT using a 3mm CTV to PTV expansion suggest
this is safe as they were compared with an earlier cohort
treated using a 5mm expansion (71). There was no
difference in two-year estimates of overall survival and
locoregional control, and there was no difference in the
incidence of marginal failures. Further follow-up and
additional studies will be required to confirm the safety of
margin reduction with IGRT.
Benefit of margin reduction?
1. A reduction in margin, if performed safely, could allow
for greater sparing of normal structures.
A PTV margin reduction from 6mm to 3mm resulted
in a 20% reduction in normal tissue complication
96

probability or about 1.3Gy mean parotid dose per


1mm (72).
2. Open the door for dose escalation.
However, extreme caution is necessary with these highly
conformal approaches given the close association of dose
and locoregional control in HNSCC.

Frequency of imaging an unresolved issue!



Ideal daily CBCT.

Logistic Solution: No imaging at initial fraction only,
followed by alternate day imaging.

Systematic setup errors are reduced with increasing
frequency of image guidance, but not random errors.
Daily CBCT for special cases
o Bulky Exophytic Tumor - to help guide the timing of
ART as they often experience significant tumor
regression during the course of treatment.
o Infrahyoid Primary Tumor - to ensure accurate
alignment with respect to the mid/lower cervical and
upper thoracic spine.
o Re-irradiation Given the elevated risk of normal tissue
complications
o Hypofractionated Regimens.
o Unstable setup and/or difficult verification
Adaptive Radiotherapy (ART):
It consists of the explicit inclusion of the temporal changes
in anatomy during the imaging, planning, and delivery of
RT.

97

Need for ART?


o To account for deformations of targets, normal
structures as well as patient anatomy during 6-7 week
course of radiotherapy, e.g. shrinkage of bulky
exophytic tumors (in particular oropharyngeal tumors
of HPV origin) and nasopharyngeal tumors, often
experience significant tumour regression, and medial
migration of parotid glands.
o Replanning adjusted for interval regression assures
to limit oral mucositis.
o It may be feasible to identify resistant tumors and
boost them to a higher dose.
o To account for changes in patient anatomy from
weight loss and tissue edema.
All these could have an impact on the dosimetric
parameters and potentially translate to a clinically
significant impact both on tumour coverage and normal
tissue toxicity.
Ideal platform for ART : IGRT with CBCT provides important
anatomic information during the course of treatment, and
can guide the need and timing of ART.
The optimal strategy, frequency, and clinical impact are
not well established, and at this point in time ART is
considered explorative.

IMAGE GUIDED BRACHYTHERAPY:


Image guidance has replaced geometric modelbased
brachytherapy prescription in most circumstances over the
last decade. With the integration of advance imaging
techniques [CT, magnetic resonance imaging (MRI),
98

intraoperative ultrasonography, positronemission


tomography, and functional imaging], the possibility of
accurate delineation of the target volumes and
optimization of dose distributions have made
brachytherapy much safer to patients and disease control
better (73). Although imaging for the purposes of dose
distribution was successfully achieved in the past using
two orthogonal fields, the use of 3D imaging such as CT
and/or MRI in head and neck brachytherapy to delineate
the GTV and CTV and the organs at risk (including the
mandible) makes it possible to obtain objective data on
dose volume histograms.
There is limited clinical evidence supporting the routine
use of CT image guidance for BT planning of interstitial
implants in the H&N region. Studies have shown that
Interstitial brachytherapy conferred more dose
homogeneity when compared with IMRT and lesser dose
to critical structures, limiting the risk of severe xerostomia
or trismus. (74).

CHARGED PARTICLE RADIOTHERAPY (CPR)


Radiobiological Rationale: Sharp dose fall-off in their
range due to the intrinsic physical principles underlying
their interactions with matter. They deposit little energy
until they near the end of their range at which point the
rate of energy loss increases resulting in what is termed a
Bragg peak.
HNSCCs are good test systems for CPR because of the
complex treatment volumes and close proximity of highrisk regions to critical avoidance organs at risk.

99

Relative Biological Effectiveness (RBE) 1.1 (for


practical clinical purposes, protons have the same
biological properties as photon beams) (75), except at
Braggs peak where increased linear energy transfer (LET)
lead to increase in RBE.

IMRT vs. CPR in HNSCC IMRT may produce good conformity, but at the cost of
large integral volume, thus irradiating larger volumes of
normal tissues to low-intermediate doses. As per the
ALARA (as low as reasonably achievable) principle it would
be desirable to reduce or eliminate radiation dose to
normal tissue. CPR has advantages in terms of normal tissue
sparing, better dose homogeneity and a reduced dose bath
effect (low radiation dose to normal tissue). Intensity
modulated proton therapy (IMPT) allows modulation of
the fluence and the position of the Bragg peak, permitting
three-dimensional dose distributions. There are no
randomised trials comparing IMPT with IMRT reported as
yet.
CPR in HNSCC Evidence and issues:
While there have been multiple treatment planning studies
showing the dose superiority of charged particle
radiotherapy to that of photon radiotherapy (76, 77), there
have not been many clinical reports on its utility for HNSCC.
In general, it is difficult to lower the Dmax to normal
structures (OARs) when they were in close proximity to
the high-dose regions. It was in the doses to OARs located
some distance away from the GTV where the CPR plans
showed a major advantage over photon radiotherapy. In
addition, the dose to the skin at the entry portal could be
higher than would be expected with IMRT.
100

Parvathaneni et al studied 10 cases of early stage tonsil


cancers treated with unilateral technique and compared
IMRT plans with Proton therapy and found that the
maximum dose to skin with proton plans was 66 Gy versus
58 Gy with IMRT. The volume of skin receiving 60 Gy and
above with protons was 11 cc versus 0.5 cc with IMRT (3).
While these skin doses are within generally tolerable limits,
it may not always be the case for larger portals or in
complex re-irradiation settings.
There are a small number of articles reporting clinical
outcome data for HNSCC patients treated with charged
particle radiotherapy. Admittedly these studies are often
not well controlled, and many patients were treated with
a combination of photons and protons rather than with
protons alone. This, coupled with the small patient
numbers, makes it difficult to draw meaningful conclusions
about the efficacy of the charged particle radiotherapy
component.
Demonstrating superior dose distributions in treatment
planning comparisons does not substitute for clinical trial
data in assessing the relative merits of charged particle
radiotherapy versus photon radiotherapy. In particular,
charged particle radiotherapy is often more sensitive to
daily setup variation and changes in patient anatomy
during treatment. Moreover, the range of ion beams can
be impacted by metal artefacts such as dental prostheses
and surgical reconstruction plates that are often found in
the head and neck cancer patient, something of lesser
concern in photon radiotherapy.

101

CPR in Skull Base Tumours:


One of the earliest clinical applications of proton therapy
was for the treatment of chordomas and chondrosarcomas
of the skull base. In 1999, Munzenrider et al presented
the first published series of patients with skull base
chordoma and chondrosarcoma treated with proton
therapy to doses of 66 to 83 cobalt-Gray equivalents (CGE,
currently known as Gy [RBE]) and the control rates were
much higher than those for historical control individuals
treated with photon therapy (78). Ares et al and Rombi et
al have published their experience with the use of IMPT to
deliver a median dose of 73.5 Gy (RBE) for chordomas
and 68.4 Gy (RBE) for chondrosarcomas with excellent
local control rates, perhaps because of the higher doses
that had been delivered (79, 80). As chordomas and
chondrosarcomas both have relatively high recurrence rates
after definitive treatment, need for salvage therapy is an
important issue. McDonald et al published their experience
using proton therapy in the reirradiation setting for
recurrent chordomas and has shown that it can be
effectively used to give good local control and survival
outcomes where few other salvage options exist (81).

TOXICITY AND QUALITY OF LIFE (QOL):


The evaluation of the quality of life (QOL) in patients with
head and neck cancer is integral to optimal patient care.
Various aspects of QOL in HNSCC:

102

Xerostomia
Swallowing Dysfunction , Dysphagia and Aspiration
Speech Dysfunction
Post Treatment Nutritional Intake
Depression

Precision Radiotherapy and QOL:


Greater avoidance of normal tissues by IMRT has
radiobiological advantages in reducing both acute and
late toxicities, and hence improving QOL Evidence has been
consistent with radiobiological predictions. Various studies
have shown that IMRT yields better QoL compared with
conventional or three-dimensional conformal radiotherapy
(82, 83).

CONCLUSION:
Evidence supports a clear advantage of IMRT / IGRT in
HNSCC, in term of outcome and better toxicity profile
(mainly late) translating into better QoL. By and large, IMRT
has established itself as the current standard of care in
the treatment of HNSCC. However, this success has not
come without a note of caution and a price-tag.
Practicing high-precision radiotherapy in HNSCC, needs a
clear perspective and rationale, as there is a greater chance
of missing the target due to uncertainties in target volume
definition by the clinician, as well as random and systematic
errors, which might lead to poor control considering a
clear dose response relationship in HNSCC. Unless a centre
and clinician meet this standard, we could be doing our
patients more harm than good, and would have been
better off treating with conventional techniques rather
than IMRT that may be less morbid but may not cure them.
When in doubt, use of IGRT ensures the level of accuracy
warranted to deliver a highly conformal treatment plan
and should be utilized with IMRT, wherever feasible. Finally
in developing countries with low teledensity and poor
affordability, the cost-benefit ratio and utility of high
precision techniques should be prioritised and utilised
judiciously.
103

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cancers. Brachytherapy. 2010 Jul-Sep;9(3):235-8.
PubMed PMID: 20116345.
Prescribing, recording, and reporting proton-beam
therapy: contents. Journal of the ICRU. 2007
Dec;7(2):NP. PubMed PMID: 24171099.
van de Water TA, Bijl HP, Schilstra C, Pijls-Johannesma
M, Langendijk JA. The potential benefit of
radiotherapy with protons in head and neck cancer
with respect to normal tissue sparing: a systematic
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PMCID: 3228110.
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77. Chera BS, Malyapa R, Louis D, Mendenhall WM, Li Z,


Lanza DC, et al. Proton therapy for maxillary sinus
carcinoma. American journal of clinical oncology.
2009 Jun;32(3):296-303. PubMed PMID: 19433966.
78. Munzenrider JE, Liebsch NJ. Proton therapy for tumors
of the skull base. Strahlentherapie und Onkologie :
Organ der Deutschen Rontgengesellschaft [et al].
1999 Jun;175 Suppl 2:57-63. PubMed PMID:
10394399.
79. Ares C, Hug EB, Lomax AJ, Bolsi A, Timmermann B,
Rutz HP, et al. Effectiveness and safety of spot
scanning proton radiation therapy for chordomas and
chondrosarcomas of the skull base: first long-term
report. International journal of radiation oncology,
biology, physics. 2009 Nov 15;75(4):1111-8. PubMed
PMID: 19386442.
80. Rombi B, Ares C, Hug EB, Schneider R, Goitein G,
Staab A, et al. Spot-scanning proton radiation therapy
for pediatric chordoma and chondrosarcoma: clinical
outcome of 26 patients treated at paul scherrer
institute. International journal of radiation oncology,
biology, physics. 2013 Jul 1;86(3):578-84. PubMed
PMID: 23582853.
81. McDonald MW, Linton OR, Shah MV. Proton therapy
for reirradiation of progressive or recurrent chordoma.
International journal of radiation oncology, biology,
physics. 2013 Dec 1;87(5):1107-14. PubMed PMID:
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83. Rathod S, Gupta T, Ghosh Laskar S. et al. Quality of


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PubMed PMID: 23562564.

121

THORACIC TUMORS

Advanced Radiotherapy Techniques


in Lung Cancer
INTRODUCTION
Despite being one of the most common cancers
worldwide, lung cancer has been characterized by poor
outcomes, with reported 5 year overall survival rates
hovering around 15% till the last decade. Recent advances
in understanding of the molecular biology of lung cancer
have resulted in small but incremental gains in the control
rates over the past decade. In parallel, improvements in
imaging and radiotherapy delivery technologies have
resulted in a continuous expansion in the role of
radiotherapy in the treatment of this cancer

HISTORY AND ROLE OF RT IN LUNG


CANCER
Radiotherapy in lung cancer has come a long way from 2dimensional conventional planning on X-rays to the present
era of image-guided stereotactic treatments. Limitations
of traditional 2 dimensional conventional planning
122

included excess normal tissue irradiation due to underlying


uncertainties arising from tumor motion, dose calculation
uncertainties due to tissue heterogeneity as well as
improper tumor localization with potential for geometric
miss. Advances in imaging technology and radiation dose
calculation algorithms have allowed increasingly accurate
volumetric dose calculation. Simultaneously advances in
managing tumor motion have allowed us to deliver highly
conformal radiotherapy with increasing accuracy.1, 2
Sharply conformal escalated dose treatments relying on
stereotactic imaging have become a potentially viable
alternative to surgery in early stage lung cancer.
Indications for Radiotherapy in Lung Cancer


In Early Stage NSCLC: Medically inoperable early stage


node negative NSCLC with tumor size 5 cm.
In Locally Advanced NSCLC: Definitive concurrent
cisplatin based chemoradiation is the current standard
of care. The standard dose prescription is 60 66 Gy
in 30 33 fractions delivered over 6 weeks .
In Limited Stage Small Cell Lung Cancer (SCLC): The
standard treatment is cisplatin based concurrent
chemoradiation followed by Prophylactic Cranial
Irradiation (PCI) in responders.
In Extensive Stage SCLC: Patients with good response
to chemotherapy, PCI may be offered to reduce the
risk of intracranial relapse.3
Palliative radiotherapy has an important role in
treating patients with Superior Vena Caval Obstruction
(SVCO), painful bone metastases, brain metastases.
Stereotactic radiotherapy may have a role in reirradiation in such settings.
123

Stereotactic radiotherapy is emerging as a viable


modality for response consolidation in patients with
oligometastatic lung cancer.

TOXICITIES WITH CONVENTIONAL


TREATMENTS


Radiation pneumonitis is considered as the dose


limiting toxicity for lung cancer irradiation. It occurs
in 1540% of patients receiving concurrent
chemoradiation for NSCLC 4. Mean Lung dose
20Gy 4, V 20 < 30-35 % 5 and V 30 <20-25% 6 are
recommended dose volume parameters when
conventional fractionation is used, with an observed
risk of severe radiation pneumonitis between
13-37%.7
Use of concurrent chemotherapy increases the risk of
radiation induced acute esophagitis. While no definite
dose volume constraints are available, mean doses
exceeding 28 Gy have been associated with an
increased risk of Grade 3 or more esophagitis.8

IMAGE ACQUISITION & BASICS OF


SIMULATION.
a.

124

Positioning: Patients should be simulated in a position


which is reproducible, stable and comfortable to the
patient.9 Most commonly patients are positioned
supine with arms overhead and various
immobilization devices are used to immobilize spine
and arms - Arm Rest and Knee rest, Vacuum cushions,
body frame (abdominal compression device and a
vacuum cushion) etc. Stereotactic body frame with
& without thermoplastic mask and Double vacuum

b.

c.

d.

system (BodyFix) are commonly used in SBRT


treatments. One randomized trial and one prospective
study have shown that use of a T bar / Wing board
(with arms above the head) allows more reproducible
setup as compared to no immobilization or a
customized foam based immobilization device.10,11
Three fiducials are placed over the chest wall at the
level of the nipple. Intravenous contrast is
administered and 5 mm CT cuts are taken from C2C3 upto L3-4. RTOG recommends that if contrast
produces clinically relevant density changes or artifacts
in the dose calculation volume, density overrides may
be performed.12
CECT : the conventional planning CT scan is a helical
CT scan which gives average image of tumour in all
phases of respiration but may also cause artefacts
related to respiratory movement resulting in distortion
of the shape and size of the gross tumour. Slow CT
scan is longer in duration than the average respiratory
cycle and hence gives an average image of the tumour
in all phases of respiration.Respiratory triggered CT
scanning will image the patient and tumour only in a
particular phase of respiration which is detected by
means of a surrogate. Use of a 4D CT over a
conventional CT results in an improvement in the
coverage for the target volume even when serial scans
are acquired independently over different phases of
respiration.13
4DCT: is used extensively in lung cancer radiotherapy
to image tumor motion. Tumour motion can occur
up to >3 cm in the cranio-caudal direction (max) and
min in the antero-posterior direction. Motion is most
125

e.

f.

126

evident for tumours that are unfixed and located close


to the diaphragm14,15. The primary range of motion
of tumours is in the superioreinferior direction due
to diaphragmatic motion, with less motion in the
anteroposterior and medio-lateral directions . For
most lung tumours, the range of motion is small (<1
cm), but can be as much as 2-3 cm. Tumour motion
is also variable-including variations in both motion
extent and trajectory pattern. Hysteresis describes the
phenomenon by which tumours can exhibit
paradoxical motion on inspiration and expiration.16
Nodal motion can be different from primary tumour
motion.17,18 Cardiac motion can influence left lower
lobe tumours motion.14
MRI: At present use of MRI in lung cancer radiotherapy
is still experimental, but 4-D dynamic MRI series has
the potential to be used for temporal and spatial
delineation of the moving target and replace 4-D CT.
MRI may also allow delineation of functional parts of
the lung through dynamic perfusion MRI.19 There have
been no definitive contouring studies comparing the
delineation of lung cancer on MRI versus CT or PET CT
scans.20 Continuous MRI guidance is available on the
commercially available ViewRay platform at present.
Linear Accelerators incorporating onboard MRI
scanning machines are currently under development
so IGRT based on MRI may become the modality of
choice in the future
PET-CT: 18-FDG PET-CT is used in radiotherapy
planning to correctly distinguish gross tumour from
atelectatic lung21,22 detect previously undetected
mediastinal /hilar nodal metastases23 and also detect

g.

previously undetected sites of distant metastases.


FDG-PET/CT improves staging accuracy, providing a
20-30% improvement in specificity and sensitivity over
CT scanning24,25. Inclusion of FDGPET reduces the
overall 3D inter-observer variation substantially, from
1.0 cm (1 SD) for CT alone to 0.4 cm (1 SD) for
FDGPET-CT 26. 4D-PET is possible but not very widely
used; as PET count acquisition times are very much
longer than the respiratory cycle, there is a blurring
of the image corresponding to the position
distribution of the PET positive volume over the entire
scan acquisition time.
Tumor Motion Management:
i. Tumor Tracking: Several tumor tracking
technologies are available most of which utilize
some form of surrogate markers (placed
externally or implanted in the tumor). Examples
including the Synchrony system of Cyberknife and
the Calypso system of Varian. The relationship
between surrogates and tumor motion may not
remain stable over time, with average variations
of 2.6 1.3 mm with respect to the GTV center.27
Hence repeated imaging is required, in order to
ensure that predicted models match the actual
models. Transcutaneous implantation may be
associated with pneumothorax and migration of
seeds. Vascular embolization coils may be better
retained as compared to fiducial seeds and be
associated
with
reduced
rates
of
pneumothorax.28
ii. Reducing the tumor motion: An alternative
strategy is reducing the tumor motion by using
127

h.

respiratory gating, deep inspiration breath hold,


abdominal compression devices or respiratory
coaching. Abdominal compression is not
universally applicable. It may be unusable in
patients with poor respiratory function ,
unsuitable for obese patients and for some the
compression may lend itself to more erratic
breathing, which can be counterproductive.
Although abdominal compression can enable a
reduction in treatment volumes, this may also
lead to a simultaneous reduction in lung volume.
This may not lead to improvements in mean lung
dose or V20 (percentage volume of lung receiving
>20 Gy) as the dose received by a given volume
remains stable.
Newer Imaging: FMISO-PET demonstrated the ability
to image and quantify hypoxia in NSCLC. High uptake
of FMISO correlated with greater risk of tumor
recurrence. A high ratio of uptake of FMISO by tumor
tissue compared to uptake by muscle tissue correlated
with a higher rate of tumor recurrence.29 FMISO-PET
allowed for the qualitative and quantitative definition
of hypoxic sub-areas that may correspond to the sites
of local recurrences. The degree of FMISO uptake may
predict response to radiotherapy and freedom from
disease, as well as overall survival.30

IMAGE SEGMENTATION / CONTOURING


Contouring should be done on planning CT sets based on
guidelines by the EORTC.9 Mediastinal setting- window
width of 400 and a level of +20 and Lung setting- with
a window width of 1600 and a level of 600 are used during
delineation.
128

a.

b.

c.

Site specific guidelines are available on the internet


in the RTOG contouring atlas for target delineation
on the RTOG website.31 The visual GTV contouring
incorporating PET-CT data at standardized window
settings is safest as PET co-registration with CT
datasets is not reliable.9
Nodal level contouring guidelines have been newly
revised using the new international lymph node map
used in the seventh edition of the TNM classification
for lung cancer.32 Nodes > 1 cm or with central
necrosis should be included in the GTV . FDG positive
nodes are recommended to be included in GTV even
if they are not enlarged in CT, if histologic examination
is not feasible to exclude false positive nodes.9 No
elective nodal irradiation is practiced as isolated nodal
failures are less than 5% in selective nodal irradiation.33
Guidelines for contouring of Organs at Risk are to be
done as per guidelines available on RTOG website.31
The lung dose limits are based on the DVHs of both
lungs, with exclusion of the target volume. However,
controversies exist regarding which target volume to
subtractthe GTV, CTV or PTV. Most of the currently
ongoing RTOG protocols consider Lung DVH as total
volume of both lungs minus the GTV12 although the
dose limits are based on total lung volume minus PTV.5

DOSE PRESCRIPTION
a.

Radical and post op doses: Definitive concurrent


chemoradiation of locally advanced lung cancer is still
prescribed at fixed doses (typically 6066 Gy in 30
33 fractions) for all patients. Only grossly involved
nodes are included in target volume - no elective nodal
129

b.

130

irradiation (standard fractionation). Doses in postoperative radiotherapy are typically restricted to 50Gy
in 25 fractions in margin-positive cases.
Hypo-fractionation: has been employed in the form
of stereotactic body radiotherapy incorporating image
guidance in the treatment of medically inoperable
early lung cancer. SBRT has increasingly become the
standard of care for inoperable Stage I peripheral
NSCLC patients in Europe over the last 5
years.9,34,35,36,37, (LEVEL II evidence). SBRT works on the
premise of highly conformal irradiation of a small
volume to tumoricidal doses using hypofractionation.
i. Eligibility criteria: T1 or T2 (<5 cm), N0 M0
tumours, NSCLC, located outside a 2 cm no-fly
zone around the proximal bronchial tree.
ii. Within the no-fly zone risk-adapted SBRT is
done by using less extreme fractionation
schedules.38,39,
iii. Dose- fractionation: different schedules have
been used but 1-5# @ 8-30 Gy/# for peripheral
tumours and 5-10# @ 5-7.5 Gy/# for central
tumours are described. The BED for tumour
control should be 100 Gy for survival outcomes
similar to surgery.
iv. No concurrent chemotherapy to be given with
SBRT, but role of adjuvant systemic therapy is
under investigation.
v. There are several prospective and retrospective
studies that support and further investigate the
role of SBRT. 40-47 These studies consistently show
local control rates of 8098% at 3 years and OS

5070% at 3 years, but distant metastasis of up


to 2530% at 3 years.
vi. Long term follow up of SBRT in a recent study
with over 600 patients has shown 5 year rates
of local, regional and distant recurrence of
10.5%, 12.7% and 19.9%, respectively.
vii. SBRT is well tolerated with low toxicity rates
allowing patients previously not considered
suitable for treatment, such as the elderly or
those with more comorbidities, to receive
potentially curative treatment. 48, 49 New evidence
has emerged that SBRT offers equivalent results
in patients who are medically inoperable and
patients who are surgically operable but who
wish to avoid surgery.50, 51
viii. Patient should be simulated supine with both
arms overhead with immoblisation device (either
simple T-bar devices with or without vacuum
mattresses) to achieve stable and reproducible
patient positioning during treatment planning
and delivery, especially in cases where prolonged
treatment duration will be required like
respiratory breath-hold techniques or respiratory
gated treatments. 52
c.

Altered fractionation: CHART, CHART-WEL [continous


Hyperfractionated Accelerated Radiation Therapy
Weekend Less] demonstrated overall survival benefit
at cost of increased normal tissue toxicity. Newer
studies are underway or planned.

d.

Dose Escalation: Radiation dose escalation may


improve LRC and OS in patients with stage III NSCLC.
131

Although results from several centers. 53,54, 55, 56 and


an RTOG secondary analysis57 demonstrated that highdose radiation may be associated with improved
outcomes, the randomized trial RTOG 0617
comparing chemo-radiation to 60 vs. 74 Gy, and with
or without Cetuximab (four arms) 58 actually
demonstrated an inferior median survival (19.5 vs.
28.7months, p=0.0007) and an increase in local
failure at 18months (34.3 vs. 25.1%, p=0.0319)in
the 74 Gy arm. The reasons for this result are unclear
but at present there is no evidence to support
escalation of dose beyond 60 Gy using 3-DCRT
techniques.
e.

How to prescribe if too near to critical structures:


Isotoxic radiotherapy is a novel concept of
personalized radiotherapy treatment allowing the
individualized administration of radiotherapy dose
based on predefined normal tissue constraints.59, 60,61
It ensures the delivery of the maximum achievable
BED for each patient whilst ensuring the safety of the
OARs. Considering that many patients are unsuitable
for concurrent treatment due to age, PS and
comorbidities, strategies such as individualised dose
escalation aiming to improve local control and survival
in the sequential setting are particularly attractive.

TREATMENT DELIVERY TECHNIQUES


a.

132

3D-CRT: is the standard of care in lung cancer


radiotherapy at conventional fractionation. Involves
the use of divergent customized blocks or multi-leaf
collimators to shield normal tissues such as normal
lung, esophagus, heart etc.

b.

IMRT: IMRT is also standard of care however there


exists concern regarding motion and irradiation of
larger volumes of lung to low doses.

No randomized controlled trials between 3-D
CRT and IMRT

Retrospective studies show equivalent outcomes
with 3-DCRT and IMRT but decreased esophageal
toxicity with IMRT.62,63,64,

In spite of lack of evidence, the use of IMRT in
lung cancer in the West has increased over the
past decade.65 A large retrospective analysis of
the prospectively maintained SEER database
showed recently that use of IMRT in Stage III
NSCLC has similar OS and CSS as 3-D CRT with
similar toxicity.66

As no cohort studies or RCTs are available, and
there is concern regarding the effects of low dose
RT received by the lung in IMRT, it is advisable to
use IMRT in cases where the tumor is in close
proximity to an organ at risk, where the target
volume includes a large volume of an organ at
risk, or in scenarios where dose escalation would
be potentially beneficial while minimising normal
tissue toxicity. Superior sulcus tumors are a
potential site where IMRT may be useful. Until
randomised data are available, future research
in IMRT for lung cancer should include a
comprehensive prospective assessment of the
relevant outcomes, including tumour control and
normal tissue toxicity.67

133

c.

d.

IGRT: Image guidance in lung cancer has evolved out


of the need to treat a target moving with respiration.
The concept of motion management arose in 1980s
and was aided by the technological advances in
imaging. By 1990s the respiratory motion
management was clinically implemented and by
2000, Varian had commercialized the gating solution.
4DCT was available in clinical practice in 2001-3.
Dynamic tumor tracking which is the most advanced
solution for respiratory motion management was
available in 2005. Motion management for lung
tumors incorporates five key components:
1. 4D imaging
2. Breath-hold techniques,
3. Abdominal compression,
4. Respiratory tracking
5. Respiratory gating
Motion management is not deemed applicable for
all patients. The AAPM Task Group 7668 recommended
consideration of motion management for tumours
with motion of >5 mm, whereas Korreman et al 69
and Guckenberger et al 70 advised that routine image
guidance should be used for lesions that move >8
mm with respiratory gating reserved for tumours with
magnitudes of >13 and >15 mm, respectively.

PLANNING
a.

134

Prescription: the dose in 3-DCRT technique is usually


prescribed to the isocentre of the PTV .

b.

c.

d.

Critical structures: include the normal surrounding


lung, spinal cord, esophagus, heart/pericardium and
brachial plexus for superiorly located tumors.
Dose Calculation Algorithms: Due to the significant
heterogeneity in the composition of tissues in the
thorax, dose calculation algorithms that account
correctly for lateral electron transport in tissues with
different densities is required. Dose algorithms
simulating Monte Carlo algorithms (which is the gold
standard) like analytical anisotropic algorithm (Eclipse,
Varian Medical Systems) and the collapsed cone
algorithm (Pinnacle, Philips Electronics) are better than
the traditional Pencil Beam Convolution Algorithm.
In treatment planning for targets in or near the lung,
this is an important issue, and it is especially crucial
for treatments with respiratory management in which
the lung tissue density (correlated to lung filling) is
an active planning variable. In particular, when deep
inhalation is used (very large lung filling with resulting
very small lung density), the errors can be large,
decreasing the target dose coverage by up to 20%71,
and should be explicitly considered when evaluating
dose to target and organs at risk.
Plan Evaluation
1. Target Coverage: At least 95% of the PTV should
receive the full prescription dose. The maximum
dose must not exceed 110% of the prescribed
dose and the high dose area should be located
within the PTV.
2. Critical Normal Tissues : Commonly used dose
limits for the OARs using conventional dose
fractionation are given below135

Lung (minus GTV)- Mean Lung Dose 20 Gy,


V20 35%, V5 65%
Heart- Max dose 70 Gy, Mean dose 30 Gy,
V30 50%, V40 35%
Esophagus- Max dose 74 Gy, Mean dose
34 Gy
Spinal Cord- Max dose 50 Gy, Brachial plexusMax dose 63 Gy
3.

e.

136

Dose constraints for Hypo-fractionation: In SBRT


using hypofractionated dose protocols the dose
limits for OARs differ.72,73
Lung V20 10%, 1500 cc < 12.5 Gy, 1000 cc
< 13.5 Gy
Heart- max dose 30 Gy
Esophagus- Max dose 27 Gy.
Spinal Cord- Max dose 18 Gy
Chest wall V 30 30 cm3 in 3-5 fractions

Adaptive planning.
1. Rationale: adaptation to the breathing related
movement is already widely implemented
through motion management techniques.
Adaptive management of anatomical and
biological response has large potential. More
data, however, are required before large-scale
clinical implementation. Robust quantification of
modes of tumor regression and validated
threshold to identify responders and
nonresponders are lacking.74

2.

Evidence: Most reports are retrospective studies


of isotoxic dose escalation by shrinking volumes
during RT. 75, 76Some institutions have reported
adapted treatments using inhouse 3-D portal
dosimetric measurements to detect variations in
tissue densities during treatment and dose
delivery variations due to it.77 No large-scale
clinical studies are available at present.

VERIFICATION
a.

b.

c.

Rules of Image verification: For the majority of radical


lung cancer treatments, volumetric CBCT or
megavoltage CT is recommended, whereas for more
hypofractionated regimens, such as SBRT, daily online
imaging is mandatory.78,79 The AAPM Task Group 7668
recommended consideration of motion management
for tumours with motion of >5 mm, whereas
Korreman et al.69 and Guckenberger et al. 70 advised
that routine image guidance should be used for
lesions that move >8 mm with respiratory gating
reserved for tumours with motion magnitudes of >13
and >15 mm, respectively.
Image verification may be done by EPID, Kilovoltage
or megavoltage fan or cone beam CT, orthogonal XRays (Cyberknife), and may be guided by internal or
external fiducials or surrogate markers.These IGRT
approaches can be used to account for variations in
the interfraction position of the tumour due to
breathing, tumour regression and patho-anatomical
changes, e.g. resolution of effusion/atelectasis.
Kilovoltage cone-beam CT (CBCT) is currently the gold
standard for IGRT in lung cancer radiotherapy.
137

d.

e.

138

Advantages include high spatial resolution and


imaging in the patients treatment position. The KV
CBCT comprises of a series of kilovoltage planar
images taken at regular intervals during gantry
rotation and combined together to create a volumetric
image. These images can then be compared with a
reference planning 4D-CT data set. It can therefore
be used to correct for positional changes and can
allow adaptation of treatment plans if there are
significant tumour-related changes. For the majority
of radical lung cancer treatments, volumetric CBCT
or megavoltage CT is recommended, whereas for
more hypofractionated regimens, such as SBRT, daily
online imaging is mandatory. 78,79
Despite the widespread uptake of many of these
techniques, there is a paucity of literature reporting
improved outcome in overall survival and local control
for patients whenever motion management
techniques are used. A recent study used
mathematical modeling of TCP/NTCP and showed
significant reduction in complication risk with 4DCT
planning compared with 3DCT planning, without any
reduction in modelled tumour control.80 Significant
dosimetric improvements in target volume coverage
were observed, as well as reductions in the dose to
OAR specifically Mean Lung Dose. 4D planning in this
study would allow, on average, an additional increase
in total dose by a factor of 1.19 compared with 3D
planned dose escalation.
Matching Technique: For advanced lung cancer, the
spine or carina can be used equally for CBCT image
registration without compromising target coverage.

The carina was more reproducible than the spine and


hence is used routinely after matching the spine to
confirm image verification. 81 Unresolved problems
include variable motion amplitude and trajectories for
nodes and primary tumor, variable nature of tumor
shrinkage during therapy as well as impact of adjacent
organ motion like cardiac motion on the overall
movement. However in SBRT treatments, in treatment
of tumours without lymph nodes CBCT matching on
tumour with an additional check on organs at risk is
better. Also for standard verification of soft tissue
(tumor) during RT and adaptive replanning, CBCT is
a must.

TOXICITY
a.

b.

c.

The reported rates of symptomatic pneumonitis after


RT for lung cancer is 5-50%82 and after SBRT ranges
from 9% to 28%83. The risk of developing radiation
pneumonitis is directly related to the volume of
irradiated lung, the amount of radiation given, and
the use of concurrent chemotherapy84. Additional risk
factors include comorbid lung disease, poor baseline
pulmonary function testing, and poor performance
status.85
Bronchial injury/stenosis, an unusual complication
with conventional doses, has been associated with
SBRT of perihilar/central tumors.7
RT induced esophagitis incidence is grade 2 in 32.2%,
grade 3 in 17.1%, and grade 4 in 0.9%.86 In SBRT of
peripheral tumours, esophagitis is generally not
encountered but in centrally located tumours,
incidence of grade 2 acute toxicity was 12%87
139

2.

3.

Quality of Life assessment: standard tools for


assessment include EORTC QLQ-30 with theQLQLC13 and FACT-L questionnaires. SBRT in early
stage medically inoperable lung cancer generally
improves or maintains the baseline quality of life
in this cohort of patients, but does not cause
deterioration.
Follow-Up: an FDG-PET scan to document
treatment response especially in patients treated
with chemoradiation is helpful at 2-3 months
after completion of RT. 88 89, Assesement of the
pulmonary function as well as rehabilitation are
important components of followup protocol.
Subsequently, 6 monthly CT scan as
recommended by ACCP for patients treated with
curative intent may be helpful. 90 History and
physical examination, chest X-ray and annual CT
are also appropriate tests, CT in particular for
earlier detection of a second primary tumour. 91

PROTON BEAM THERAPY


a.

140

Proton therapy is radiobiologically equivalent to


photons but have dosimetric advantages secondary
to the phenomenon of Braggs peak. Several planning
studies comparing the dose to the OARs between
proton and photon radiotherapy demonstrated
significantly reduced doses with proton treatment,
even compared to IMRT.92,93,94A range of phase I/II
studies and retrospective series showed that high-dose
proton treatment is feasible and safe in stage I
NSCLC, 95, 96, 97,98, 99 but its potential for a higher
therapeutic benefit over SBRT still remains uncertain.

b.

Two retrospective series in medically inoperable stage


IIIII patients who received proton therapy alone
noted satisfactory survival rates with minimal
pulmonary and oesophageal toxicity 100 , 101 .
Retrospective data evaluating proton radiotherapy
combined with concurrent platinum-based
chemotherapy demonstrated reduced rates of
pneumonitis and oesophagitis compared to lower
doses of either 3DCRT or IMRT (pneumonitis, 2%
versus 30% versus 9% respectively; oesophagitis, 5%
versus 18% versus 44% respectively; p for all
<0.001)102.
These findings were further supported by the
preliminary results of an ongoing phase II trial of
concurrent
proton
chemo-radiotherapy
(ClinicalTrials.gov Identifier: NCT00495170) which
reported a median survival of 24.9 months and low
rates of Grade 3 pneumonitis (2%) and oesophagitis
(11%)

TARGETED THERAPY


No agent has shown survival benefit when combined


with radiotherapy alone or with concurrent/sequential
chemo-radiotherapy including epidermal growth
factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)
(associated with severe pulmonary toxicity), EGFR
monoclonal antibodies, anti-angiogenic agents such
as bevacizumab (trials closed due to high
tracheooesophageal fistulation and pulmonary
haemorrhage), multi-targeted TKIs and thalidomide
(trials closed due to thromboembolic events)103,104,105.
The results from the low-dose arms of the RTOG 0617
141

trial are eagerly awaited to determine if the addition


of cetuximab to concurrent chemo-radiotherapy
improves outcomes in locally advanced NSCLC.

BRAIN METASTASIS
Lung cancer remains the most common tumor associated
with brain metastasis106, 107. Radiotherapy represents an
important palliative option for patients with brain
metastases by alleviating symptoms, decreasing the use
of corticosteroids needed to control tumor-associated
edema108, and potentially improving overall survival. 109
a.

b.

142

WBRT alone: In patients with multiple cerebral


metastases, WBRT is generally the treatment of choice,
as it addresses both macroscopic and microscopic
disease. Studies have shown an improvement in
symptoms in 64-83% of patients after treatment with
WBRT alone 110, and have also demonstrated an
increase in median overall survival from 1 month with
no treatment to 3-7 months following WBRT.109
Dose-fractionation of WBRT : The most common dose/
fractionation schedule used is 30 Gy delivered in 10
fractions over the course of 2 weeks110. Overall,
sufficient evidence is not currently available to suggest
superior efficacy or reduced toxicity of alternative
dosing schedules over the accepted and currently used
standard WBRT protocols . 111 The prognostic
significance of the RPA classification of patients of
lung cancer with brain metastases (Class II and III)
has been validated in our institution and a short course
course accelerated radiotherapy schedule (SCAR=
20Gy in 5 fractions) has been demonstrated to have
similar outcome as conventional fractionation in these

c.

d.

e.

classes. Hence use of this SCAR in RPA classes II and


III may be justified in resource-constrained, busy
setups in our country, while standard dose
fractionation may be reserved for RPA class I
patients.112
Localized RT alone: A recent trend in the field of
radiation oncology has been toward withholding
WBRT and proceeding with a localized approach in
the management of patients with brain metastases
using SRS. Two recent RCTs found an improvement
in local and regional control, measured as relapse at
2 years, with SRS and WBRT versus SRS alone113,114
while a third RCT actually demonstrated a detriment
in overall survival in patients undergoing WBRT.115 A
meta-analysis of the pooled results of the three
aforementioned studies found no difference in OS.111
Dose escalation by adding SRS to WBRT vs WBRT alone
was studied in a randomized trial by RTOG which
showed increase in local control. Further the study
found an increase in median survival time in patients
with single brain metastases but not in multiple
intracranial metastases.108 Also addition of SIB to
WBRT using helical tomotherapy has been reported.116
Decreasing the morbidity of WBRT: Use of
hippocampal sparing WBRT, limbic system sparing
WBRT and radioprotectors like Memantine have been
explored in Phase II and III RTOG trials with
preservation of memory and QOL as compared with
historical series and delayed time to cognitive decline
and reduced rate of decline in memory, executive
function, and processing speed in patients receiving
WBRT with memantine.117,118,119Results from the
143

RTOG phase II trial studying hippocampal sparing


whole brain radiotherapy indicate significantly lower
decline in Hopkins Verbal Learning TestRevised
Delayed Recall (HVLT-R DR) test as compared to
historical controls.120

BONE METASTASIS
a.

b.

c.

ASTRO guidelines suggest palliative radiotherapy to


the sites of bony metastases affords pain relief as well
as prevention of morbidity from uncomplicated bone
metastasis involving the spine or other critical
structures. 121The randomized controlled trial RTOG
97-14 proved that a dose of 8 Gy/single fraction
affords the same outcomes as 30 Gy in 10 fractions
although it may lead to higher incidence of retreatment 122
The same guidelines recommend that postoperative
RT be given to spinal bony metastases and preferably
should be fractionated- 30 Gy in 10 # as aim of
treatment is eradication of microscopic disease.
SBRT may have a role in the setting of reirradiation
for bone metastases especially in the case of vertebral
metastases. However further research is indicated
prior to widespread adoption.

OLIGOMETASTASES
a.

144

Multiple retrospective studies indicate benefit in


survival of surgical treatment of the lung primary in a
case with a single metastatic site in lung cancer. But
a single prospective non-randomised trial indicates
no benefit of addition of surgery to the systemic
therapy.123SBRT has a potential role in this setting as

a consolidation modality after chemotherapy


especially in view of its non invasive nature.
Rushthoven et al have calculated a potential PFS
benefit of 3 months with the use of SBRT as a
consolidation modality after first line chemotherapy
in metastatic lung cancers.124 In a recently reported
proof of concept phase II trial patients with stage IV
NSCLC who were on second / subsequent line of
treatment with Erlotinib and had 6 or less sites of
metastatic disease were treated with SBRT. The median
OS for the cohort was 20 months with only 3 of 47
leisons recurring within the irradiated field. These
results were obtained despite none of the patients
being tested positive for EGFR mutations. 125

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170

Esophageal Cancer
Esophageal cancers are divided into two distinct spectra
of disease , at one end is the squamous cell carcinomas
involving the cervical esophagus and upper, middle and
lower thoracic esophagus while at the other end is the
adenocarcinomas involving the lower thoracic esophagus
and gastro-esophageal junction. The incidence of the latter
has been persistently rising over the last decade in the
West.1 Radiotherapy forms an important component of
management of esophageal cancer both in the curative
as well as palliative intent of treatment.
Resectable cancer: as pre- operative concurrent
chemoradiotherapy, to improve local control; as postoperative radiotherapy in positive cut margins, nodal
positivity and presence of residual disease.

In patients with unresectable cancer, concurrent
chemoradiation is the current standard of care.2

In patients with metastatic disease, palliative
radiotherapy is offered either by external beam or
brachytherapy.
The standard of care for radiotherapy technique in
esophageal cancer was conventional 2-D treatment
planning till the 1990s.2,3. From 1990s 3-dimensional
conformal radiotherapy techniques gradually took over and
are the standard of care at present.4,5


Even with combined chemoradiotherapy the relapses are


local within the radiation field in a large majority of cases,
so future efforts at reducing these local in-field relapses
are needed in the form of dose escalation or selective
171

tumour sensitization.6 In the past two decades Intensity


Modulated Radiotherapy (IMRT)& Image- Guided
Radiotherapy (IGRT) techniques have been explored in
various studies in an effort to improve target dosage as
well as sparing of normal tissues. Inverse planning IMRT,
Volumetric modulated arc therapy (VMAT),IGRT including
respiratory gated treatments, Proton Beam therapy (PBT)
etc are the newer techniques. Dose escalation may be
facilitated by the use of advanced radiotherapy techniques
which better protect the normal tissues that are the dose
limiting constraints at present.

1. Image acquisition & Basics of


Simulation :
a.

172

Positioning, immobilization & image acquistion:


The patient is to be positioned in an
individualized
immobilization
device
(thermoplastic device, vacuum cushion) in a
reproducible position (supine/prone) which is
comfortable for the patient on a flat hard table.
The supine position is preferred. The position of
the arm at the time of image acquisition should
be recorded to ensure reproducibility during
treatment.
Previously, fluoroscopy was used for tumour
localization during simulation but the advent of
flexible endoscopy, endoscopic ultrasound
(EUS)and contrast enhanced Computed
Tomography (CT) scans has reduced the use of
fluoroscopy in radiotherapy planning. 7
The planning CT should encompass the entire
thoracic cavity and the abdomen to a level below

b.

c.

the bottom of the kidneys. A uniform 5 mm slice


thickness may be utilized.
Three fiducials are placed at the level of the
nipple. Esophageal contrast may be used during
simulation but is optional if a diagnostic CT scan
with contrast was performed.8Endoscopically
placed mucosal metal clips can aid field
simulation when planning radiation therapy in
patients with esophageal cancer.9However, the
presence of esophageal contrast and intra
tumoral markers, together may not provide any
benefit.
MRI: Delineation of the esophageal GTV may be
done with greater accuracy than CT or routine
MRI using Diffusion weighted MR images.10 No
studies clearly report on the role of Magnetic
Resonance Imaging (MRI) in real-time guidance
for radiotherapy so far.11 Some recent reports
suggest that Diffusion-weighted MRI may be
used to assess treatment response in esophageal
cancer as well as prognosis. 12, 13. Cine-MRI has
been used to quantify the movement
of esophageal tumors and visualize tumor
movement directly throughout multiple
breathing cycles.14
Positron Emission Tomography-Computed
Tomography (PET-CT): 18-FluoroDeoxyGlucose
(18-FDG) PET-CT is used in esophageal cancer as
a routine part of initial staging for detection of
distant metastases. Also, the use of PET-CT for
tumour delineation results in both decreases and
increases of the target volume when compared
173

to CT and EUS in 10-63% of patients.15The


discordance between CT and PET-CT was due
mainly to differences in defining the longitudinal
extent of disease in the oesophagus.16These
changes may ultimately allow for improvement
in coverage of the true malignant volume and
for relevant additional sparing of normal
surrounding tissues. However, studies
demonstrating the impact of such modifications
by PET-CT in terms of improved loco-regional
control or survival are limited.
There are contradictory findings regarding the
use of 18-FDG PET-CT in decreasing intra- and
inter-observer variability.
Therefore, standard implementation of PET-CT
in tumour delineation process for radiation
treatment planning remains a subject of debate
and requires further clinical validation.17
d.

174

4-Dimensional Computed Tomographic Scans


(4-D CT scans): As with other thoracic tumours,
the esophagus also moves with respiration and
due to cardiac motion. 18 This has been quantified
using 4-D CT and attempts have been made to
quantify the errors and generate appropriate
Internal Target Volume (ITV)margins. Motion was
greatest in the transverse(right-left)direction
above the carina. Coverage of 95% of esophageal
mobility requires 12mm left, 8mm right, 10mm
posterior, and 9mm anterior margins. For lower
esophageal tumours, a radial margin of 0.8 cm
and axial margin of 1.8 cm would provide

tumor motion coverage for 95% of cases.19


The Internal Target Volume (ITV) generated
directly from Maximum Intensity Projection (MIP)
underestimates
the
range
of
the
respiratory motion for esophageal cancer. The
ITV generated from 3 phases (ITV3) may be used
for regular breathers, whereas the ITV generated
from 4 phases (ITV4) or ITV3 plus a 1-mm
uniform margin may be applied for irregular
breathers.20
However there is no evidence available to
demonstrate the clinical benefit of using 4-DCT
in radiotherapy treatments.

2. Image Segmentation / Contouring


a.

Site specific guidelines Target volumes are


contoured on the planning CT scan as per
International Commission on Radiation Units and
Measurements (ICRU) Reports 50 and 62
recommendations using endoscopic findings,
endoscopic ultrasonography (EUS), and/or
barium swallow findings in addition to the
information from the diagnostic CT8.The Clinical
Target Volume (CTV) is created by a 3 cm
expansion superiorly and inferiorly along the
length of the esophagus and cardia and a 1.01.5 cm radial expansion plus the grossly involved
nodes with a 1.0-1.5 cm expansion in all
dimensions. PTV is institution-specific but may
incorporate physiological motion. For the lower
third esophagus and gastro-esophageal junction
(GEJ) tumors the European consensus guidelines
175

b.

can be followed.21 Several institutes have their


own guidelines for delineation of the CTV.
Nodal Levels contouring guidelines There is
controversy regarding the volume of lymph nodal
irradiation: elective versus involved. Only grossly
involved nodes are included in the target volume.
The CTV should include the celiac axis in tumours
of the GEJ and lower esophagus. In patients
treated with 3D-CRT(3-Dimensional Conformal
Radiotherapy) for esophageal squamous
carcinomas, the omission of elective nodal
irradiation was not associated with a significant
amount of failure in lymph node regions not
included in the planning target volume. Local
failure and distant metastases remained the
predominant problems.22

3. Dose Prescription.
a.

176

Radical and post-operative doses (standard


fractionation): For definitive concurrent
chemoradiation, 50 Gy in 25# over 5 weeks has
been described. There was no evidence for dose
escalation as evidenced in the INT 0123 trial3.
For definitive radiotherapy alone, higher doses
of external Radiotherapy (RT) alone, 60-64 Gy in
30-32 fractions with reducing fields or
combination of external RT and intraluminal
brachytherapy (External RT-50.4 Gy in 28# with
reducing fields and IntraLuminal brachytherapy
(High Dose Rate) 6 Gy per fraction X 2 fractions,
once weekly, or Low Dose Rate- 20 Gy single
fraction)maybe considered.

b.

c.

d.

Hypo-fractionation: Generally Stereotactic Body


Radiotherapy (SBRT) /Stereotactic Radio Surgery
(SRS) are contraindicated in esophageal cancer
due to higher chances of perforation. SBRT/SRS
has been tried only in locally recurrent cases who
have exhausted trimodality treatment options
with complete response at local site with
significant relief of symptoms and good quality
of life.23
Altered
fractionation:
Accelerated
hyperfractionation has been tried in esophageal
cancer with no benefit in control rates and higher
normal tissue toxicity.24
Dose Escalation: The pattern of failure in
esophageal cancer patients treated with definitive
chemoradiation continues to be local in-field
recurrence. This led to efforts to escalate dose
to the gross tumour. The INT0123 trial3 was one
such initial effort, which has set the standard of
care at 50.4Gy/28#. However INT0123 utilised
conventional planning techniques which are
much inferior to conformal techniques in sparing
of OARs so use of advanced radiotherapy
techniques like IMRT, VMAT, helical tomotherapy,
PET-CT based radiotherapy and adaptive RT may
help in dose escalation by providing more
conformal dose distributions to the target and
better sparing of organs at risk (OARs). Although
there are several dosimetric studies
demonstrating this, robust clinical data is still
being generated.25,26,27 A single phase I study
from China reports successful dose escalation to
177

70 Gy using PET-based delineation and


simultaneous integrated boost (SIB) with no dose
limiting acute toxicity. However late toxicity
outcomes are still awaited. 28

4. Treatment delivery Techniques:


a.

b.

178

3D-CRT: is the present standard in treatment of


esophageal cancer as per all recent
RTOG(Radiation Therapy Oncology Group)
studies. Conformal radiotherapy techniques
offer the potential for a 5-10 Gy escalation in
dose delivered to the oesophagus, without
increasing the mean lung dose. This is expected
to increase local tumour control by 15-25% using
TCP-NTCP (Tumour Control Probability-Normal
Tissue Complication Probability) calculations.29
Conformal radiotherapy reduces cardiac doses
received. 30
IMRT: 4-field IMRT offers comparable dose
homogeneity as 3D-CRT and is capable of
reducing the mean lung doses. 31, 32 IMRT has
the potential to allow further dose escalation and
thereby improvement in tumour control.33 When
the number of intensity beams increased to five,
IMRT plans were better than 3D-CRT plans in
terms of the dose conformity and homogeneity
in targets and the dose to OARs. The dose
distributions changed little when the beam
number increased from five to seven and nine.34
IMRT provides superior target volume coverage
and conformality, with decreased dose to normal
structures such as spinal cord, brainstem and
parotid glands.35

c.

d.

Several retrospective series reporting institutional


experience and outcomes with IMRT have been
reported, including the MD Anderson and
Memorial Sloan Kettering Cancer Centres.36-42.
These show comparable outcomes in terms of
local control and survival 38,40 as 3D-CRT but with
reduced toxicity. The MD Anderson Cancer Centre
however reported a decreased risk of dying in
patients treated with IMRT as compared with 3DCRT.43 However there is no randomized clinical
data to show superiority of IMRT over 3D-CRT in
terms of clinical outcome.
HELICAL TOMOTHERAPY: On dosimetric analysis
tomotherapy plans showed sharper dose
gradients, more conformal coverage, and
better Homogeneity Index for both gross and
elective PTVs compared with IMRT or 3D-CRT
plans. The mean V20 of lung was significantly
reduced in tomotherapy plans. However,
tomotherapy and IMRT plans resulted in larger
V10 of lung compared to 3DCRT plans. The heart
was significantly spared in tomotherapy and
IMRT plans compared to 3D-CRT plans in terms
of V30 and V45.44
Hybrid IMRT: in which 3D-CRT technique and
IMRT technique are used simultaneously in each
fraction of treatment, was found to be useful
for reducing low dose to lung while also reducing
the potential magnitude of dose deviations due
to intrafraction motion and small field calculation
inaccuracy. Largest reductions were for
contralateral lung V5, V13, and V20(-16%, -20%, 7%)45
179

e.

f.

VMAT : Compared with conformal-IMRT, VMAT,


especially using 2 arcs slightly improves the OAR
dose sparing, such as lungs and heart, and
reduces NTCP and monitor units with a better
PTV coverage.46 A greater proportion of the body
received low doses (V5 was 18% greater) with
VMAT compared to IMRT. 47VMAT combined with
Active Breath Control (ABC) to achieve moderate
Deep Inspiratory Breath Hold (mDIBHrepresenting 80% of peak DIBH value) is a feasible
approach for radiotherapy of thoracic esophagus
and has the potential to effectively reduce lung
dose in a shorter treatment time and with better
targeting accuracy. VMAT combined with DIBH
reduced mean lung doses as well as V20, V30, V40
significantly and also had shorter treatment
times.48
Respiratory
motion
management:
Conformal radiotherapy with respiratory gating
for esophageal cancer decreases the radiation
doses to OARs such as heart, ipsilateral lung and
spinal cord.49

5. Planning
a.

b.

180

Prescription: in 3D-CRT, target doses are


prescribed to the isocentre of PTV as per ICRU
50 and 62
Critical structures: are delineated as per RTOG
atlas both lungs, heart, spinal cord, liver,
brachial plexus (for upper esophageal tumours)
and kidneys (especially in lower esophageal
tumours)50

6. Plan Evaluation
1.

2.

3.

Target Coverage: > 95% of the PTV should receive


100% of the dose, with maximum dose 110% of
the prescribed dose.8
Critical Normal Tissues: Commonly followed
constraints include Lung (minus PTV)- Mean Lung
Dose 20 Gy, V20 25%, V5 50%
Heart- Max dose 52Gy, Mean dose 32 Gy, V40
50%
Esophagus- Max dose 74 Gy, Mean dose 34 Gy
Spinal Cord- Max dose 45 Gy
Adaptive planning: has been reported in only a few
studies, mostly adaptive replanning based on Conebeam CT (CBCT) images taken for verification.51, 52.
They demonstrated significantly reduced OAR doses
with adaptive replanning based on the first week of
treatment CBCT images.PET-CT based treatment
adaptation has also been tried. 53
Verification.
a. Image verification: may be done with
2-dimensional or 3-dimensional Kilovoltage or
Megavoltage imaging. As a minimum
requirement, verification images at the start of
treatment and each week thereafter should be
obtained. For 3D-CRT this imaging can include
individual portal views however the poor soft
tissue detail obtained in these images makes
verification difficult. Consequently, bony anatomy
is used as a surrogate to verify treatment position
and tumour location is confirmed by
181

4.

182

extrapolation . Twice weekly imaging can consist


of portal views for 3D-CRT and isocenter
verification images. For IMRT orthogonal images
verifying isocenter position are required. More
frequent (daily) imaging is preferred, particularly
for patients treated with motion management
techniques. CBCT verification offers adequate 3
dimensional volumetric image quality to improve
the accuracy of treatment delivery and is
recommended to be used for image guidance
where available.54
b. Best matching: In Portal views, the soft tissue
detail is very poor, hence bony anatomy is used
as a surrogate to verify treatment position.
Substantial residual setup errors would occur for
treatment fractions without image guidance even
if the most frequent less-than-daily image
guidance strategy was to be used, which could
lead to significant daily dose variations for the
target volume and adjacent normal tissues. Daily
image guidance is recommended throughout the
course of treatment in conformal radiotherapy
for esophageal cancer.55
Toxicity: A larger volume of lung receives lower doses
of radiation because of multiple beam arrangement
and a smaller volume of lung receives higher doses
because of better dose conformity in conformal plans.
Acute pneumonitis correlates more with V30 values,
whereas chronic pneumonitis was predominantly
seen in patients with higher V20 values.56Patients with
metastatic disease and adverse Dose-Volume
Histogram (DVH) doses were more likely to develop

5.

6.

7.

severe pneumonitis independent of other risk


factors.57
Quality of Life assessment: may be routinely carried
out using European Organisation for Reasearch and
Treatment of Cancer Quality of Life Questionnaire
(EORTC QOLQ-C30), EORTC QLQ-OES18
questionnaire or Functional Assessment of Cancer
Therapy-Esophageal Cancer (FACT-E) score.
The quality-of-life score deteriorates from before
treatment to end of treatment due to acute
complications of chemoradiotherapy, but recovers at
4 or 5 months and becomes better than before
treatment.58
Protons and Heavy Particles: Welsh et al59 compared
dosimetric parameters for photon IMRT with intensitymodulated proton therapy (IMPT) for unresectable,
locally advanced distal esophageal cancer. Relative to
IMRT the IMPT plan with antero-posterior/ left
posterior oblique/ right posterior oblique (AP/LPO/
RPO)beam arrangement led to considerable
reductions in dose to the lung (p0.005), heart
(p0.003), and liver (p0.04).
Follow up: Clinical evaluation, Endoscopy, CECT and/
or PET-CT. The intensity and frequency would be
determined by intent of primary treatment and the
scope for salvage therapy/ effective palliation in the
event of a recurrence.

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194

BREAST CANCER
External Radiation Techniques
INTRODUCTION:
Breast cancer is the most common female cancer in the
world, with an estimated 1.67 million new cases diagnosed
in 2012.Majority of breast cancer patients require RT either
in adjuvant or palliative settings with robust evidence for
its clinical benefit in different contexts. The indications for
RT to breast, chest wall or regional nodes, general
description of the commonly used techniques and specific
technical aspects or indications of advanced techniques
and the Indian context will be discussed in this chapter.

INDIAN CONTEXT
With an estimated annual incidence of 1,44,000(1) new
cases of breast cancers being detected in India annually, it
is now the most common female cancer in urban India.
As for other cancers in India, late stage presentation is
common in even breast cancer (2). Almost 80% of all breast
cancer patients would require RT in adjuvant or palliative
setting. In developing countries with low per capita
income, high out of pocket expenses on health care and
long waiting lists in publically funded institutes, threshold
195

for adopting a technique or fractionation in routine


practice requires careful consideration of the strength of
evidence for long term clinical benefit, resource utilization
and cost effectiveness. Safe and effective radiation
techniques should be developed, standardized and
propagated taking in account the feasibility of safely
executing them in majority of departments across the
country. India has witnessed a rapid increase in the number
of centers with advanced radiation technologies and
expertise to use it over the last decade. However, a
significant proportion of cancer patients either do not have
access to or cannot afford treatment with advanced Linacs.
Hence there is a need to define the scope and limitations
of using tele-cobalt or low energy Linacs without MLCs as
well as the clinical, anatomical and dosimetric contexts
where more advanced techniques are clearly indicated.

INDICATIONS FOR RT IN BREAST CANCER


RT has a role in all stages and types of breast cancer,
significantly improving local control and survival (3-5) and
producing prompt palliation of bone and brain metastasis.
Indications for RT to various sites are as follows.
1.

196

Whole Breast: Post op RT to whole breast after Breast


Conserving Surgery (BCS) is standard of care in all
women with non-metastatic invasive carcinomas,
irrespective of histological type(6); malignant
phylloides or borderline phylloides with adverse
features; sarcomas and most DCIS (7). Post BCS, RT
may be avoided in elderly women small T1N0, low
grade, ER/PR +ve breast cancers with clear resection
margins (8). Post BCS, RT is also indicated in select
women with oligometastatic disease. Definitive or

2.

3.

palliative breast RT is also considered for nonmetastatic breast cancer which remains unresectable
after Neo Adjuvant Chemo Therapy (NACT) or for
metastatic breast cancer with distressing breast
symptoms.
Partial Breast: After Breast Conserving Surgery (BCS),
post-op RT only to the partial breast (excision cavity
with 1-2 cm margins) may be considered in selected
women with up to 3cm node negative tumours with
clear resection margins and clinico-pathological
features indicative of low risk of multicentric
recurrence (9). Safety and efficacy of Accelerated
Partial Breast Irradiation (APBI) is being compared to
conventional whole breast irradiation (WBI) in several
ongoing RCTs and some have completed accrual or
reported early results. These RCTs have used various
inclusion criteria and techniques. Till the results of
these trials are available, APBI should be used outside
trial setting in carefully select group of women with
low risk of multicentric disease.
Chest wall: Post mastectomy RT (PMRT) to chest wall
is indicated in all patients with T3-4 tumours; positive
resection margins or presence of axillary node
metastasis. The Danish RCT (10) which demonstrated
survival benefit with PMRT also included women with
1-3 node, the axillary dissection was suboptimal with
a median of only 9 nodes removed. Hence most
centres in the world where axillary clearance often
yields >10 nodes, PMRT was recommended in
women with metastastis in >3 nodes or T3-4
tumours. The SUPREMO trial is examining the role of
PMRT in women with T1-2 tumours and 1-3 positive
197

4.

5.

6.

198

nodes. A recent metaanalysis of subgroups of patients


with 1-3 nodes in RCTs of RT vs no RT showed
improvement in DFS and overall survival with addition
of RT (11).
SCF: RT to SCF is indicated in all patients with >3
axillary node metastasis and when chest wall or breast
RT is being considered for patients with 1-3 axillary
node metastasis.
IMC RT: RT to IMC region fell into disuse after the
cardiac morbidity and mortality associated with its
use became evident in the last 20 years. However
recent evidence from the EORTC and MA-20 RCTs
(12, 13) show that in women with medial/central
quadrant tumours or axillary LN metastasis, addition
of RT to IMC plus SCF region significantly improved
DFS by 3-5% and overall survival by 1.6%. Of the small
net benefit with IMC plus SCF RT, the contribution of
IMC RT is likely to be <1%. Only one RCT (14) has
specifically examined the role of IMC RT versus no
IMC RT with SCF RT at the discretion of the oncologist.
This RCT could not find a significant survival benefit
with IMC RT. Considering these facts and technical
challenges with cardiac safe IMC RT, most centres
around the world have not yet changed practice and
still offer IMC RT only for cases with radiological or
pathological evidence of IMC node involvement.
Axilla: In the Danish study which demonstrated
survival benefit with PMRT, the SCF and axilla were
routinely irradiated along with the chest wall. However
axillary dissection was deemed suboptimal in this
study and resulted in an unacceptably high 28%
axillary recurrence rate in the no RT arm (15). Since

7.

RT to a dissected axilla significantly increases


morbidity, centres around the world, where adequate
axillary clearance is performed, do not routinely use
axillary RT in axillary LN+ cases. The clear indication
of post op axillary RT is for known or suspected
residual axillary disease. In cases with heavy nodal
burden (>10 metastatic nodes) or peri-nodal
extension, axillary RT remains a grey area with no clear
evidence for or against it. Only recently evidence has
emerged that in women with a positive sentinel node
biopsy, axillary RT can be used as an alternative to
completion axillary dissection with equivalent locoregional control but different morbidity pattern (16).
Metastatic sites: RT is the mainstay of palliative
treatment of symptomatic bone, brain or choroidal
metastasis. The technique and dose fractionation
depends on the site and extent of disease; type and
severity of symptoms and patients life expectancy.
Fractionation for bone metastasis is 6-8Gy single
traction to localized sites or Hemi Body. For patients
with risk of pathological fracture or cord compression
a protracted radiotherapy schedule of 20Gy/5# or
30Gy/10# is preferred. Brain and choroidal metastasis
are often treated with 20Gy/5# or 30Gy/10# followed
by a conventional or stereotactic boost in select cases
of solitary brain metastasis. In patients with poor
performance status and short life expectancy, palliative
whole brain RT can be given as two fractions of 6Gy
each, with few days interval between fractions.
Palliative RT for unresectable and symptomatic breast
or chest wall disease can be delivered by tangential
photon portals or as en face electron portal to a dose
of 20Gy/5# or 30Gy/10# or as 4 or 5 weekly fractions
199

of 5-6Gy each. The treatment has to be individualized


and the technical details of palliative RT for various
sites is beyond the scope of this chapter.

PATIENT POSITIONING AND


IMMOBILIZATION
Rigid immobilization is not feasible for the treating breast
or regional nodes. Breast being a soft tissue external organ
is quite mobile and deformable. Most RT techniques for
breast or chest wall with or without nodal RT have been
developed for supine position and a few techniques have
been developed for prone position. In both positions, the
ipsilateral or bilateral arms are moved away from the
beams. Careful positioning using specially designed breast
boards can achieve repositioning accuracy within 5-10 mm
in different directions (17). If breast or chest wall RT is
being given with regional nodal RT, it is imperative that
irrespective of the technique, the arm or body position
SHOULD NOT BE CHANGED between the treatment of
breast / chest wall and regional nodes. Changing the arm
position between tangential breast fields and the matched
anterior SCF field resulted in higher incidence of radiation
induced brachial plexopathy in a large cohort of women
treated in 1980s in the UK. There is no ideal solution for
matching the anterior SCF and the two tangential fields.
Most departments will keep a 5-10 mm gap between the
SCF and breast tangents or match at skin with nondivergent junctional border using asymmetric half beam
block or a few degree couch tilt for the tangential fields.
The best solution for matching the SCF and breast is monoisocentric technique but this requires strict QA and high
positioning accuracy with negligible intra-fraction
movement (18).
200

Different positioning methods, their variations and factors


which may obviate the need for complex planning or
prevent toxicity are described here.
Supine position: This position is conventionally used for
most patients due to certain inherent advantages like
patient comfort, ease of set up with skin marks or tattoos
and ability to see beam entry, exit and anterior flash. The
patient is positioned carefully on a specially designed breast
board with adjustable inclination of the torso and
adjustable arm, forearm and hand support. Some breast
boards have a T shaped rod at cranial end for hand grip.
The inclined breast board aims to make the sternum parallel
to the treatment couch. This minimizes the need for
collimating the tangential fields, thereby reducing overlap
with the matching anterior SCF field. Supine positioning
also achieves better regional nodal coverage compared to
prone positioning with conventional technique (19).
Certain specific issues for supine position treatment are as
follows:
1.

2.

Rotation of the body and rotational errors may be


minimized if both arms are abducted and resting on
arm support or holding the T shaped grip. However
planning CT scan in this position may not be possible
even in wide bore CT gantry. This may necessitate
keeping the opposite arm by the side in most patients.
Some patients may have marked restriction in
shoulder movement due to surgery or pre-existing
diseases, precluding the use of tangential beams for
breast or chest wall. If this does not improve with
intensive physiotherapy treatment may be possible
only in prone position.
201

3.

202

In women who are obese or with large or pendulous


breast, specific positions may either create or
accentuate the existing skin folds. The skin sparing
effect of megavoltage beams is lost in the skin folds
due to self bolus effect and may result in moist
desquamation (20). The common sites of skin folds
and the solutions are as follows:
a.

Lower neck : Increasing abduction and


extension of shoulder may create skin fold within
the SCF field. Reducing the shoulder extension
to the minimum required and by turning the face
to opposite side may minimize the lower neck
skin fold to variable extent.

b.

Inframammary fold: In women with large or


pendulous breast, inframammary fold may pose
special challenges. Moist desquamation in this
region is often painful and takes long time to
heal due to constant friction and sweating. This
is the most common acute complication of breast
RT and the key to prevent it is by careful
positioning and sometimes resorting to advanced
planning techniques. Inframammary fold may
exist naturally but can also be created or
accentuated if patient is lying on a sloping breast
board. It may be minimized or obviated by
reducing or eliminating the inclination and to
some extent by greater shoulder abduction.
When large inframammary fold persists, the
possible solutions include taping of the breast
superiorly, asymmetrically reducing the inferior

border to come off the fold in the last few


fractions, Field in Field (FiF) IMRT in which the
skin fold (delineated by a thin wire placed at the
base of the fold) is treated as an OAR or by using
the prone position.
c.

4.

5.

Axillary tail: Skin fold in axillary tail region is


invariably irradiated in the tangential portals. This
is seen commonly when patients are very obese,
the axillary tail scar is indrawn or has dog ears,
or due to the large seroma. Change in arm
position or seroma aspiration may reduce this
fold in some cases. However if a large and deep
fold exists, especially when axillary tail is to be
included in the boost area, refashioning of scar
may be required. This should be assessed during
the pre RT clinical evaluation.

The aperture size of CT scanner for acquiring planning


images (or of the Helical Tomotherapy) may not permit
use of standard breast boards with arms abducted.
Cone beam CT based treatment position verification
may also be not possible in supine breast board due
to limitation of jaw opening. In such instances either
a small thermocol wedge is used with hands above
head or for greater reproducibility, customized
vacuum bags or memory foam may be used.
Thermoplastic mould is used in few centres for women
with large pendulous breasts or for IMRT / IGRT. As
breast is a soft flabby structure, its repositioning and
movement within the mould remains unpredictable.
Moreover moulds invariably increase skin dose and
203

may lead to moist desquamation. Moulds may also


create or accentuate skin folds. Thermoplastic moulds
should NOT BE USED, irrespective of the technique
unless the treating centre has large experience with
custom designing breast mould and have a very low
rate of severe skin reaction in patients treated with
moulds. Even in such centres their utility will be
primarily for cases where the breast is hanging laterally
beyond the posterior axillary line.

Prone position:
Patient is positioned prone on a board which allows the
treated breast to hang freely through an aperture while
the opposite breast is compressed flat against the board.
This improves dose homgeneity within the breast, allows
greater sparing of heart and lung (19, 21), reduces
respiratory motion and improves repositioning accuracy
(22). The trade off is the challenge in ease of treating
regional nodes and their coverage of nodal areas (19).
Prone breast RT may also affect the PTV coverage towards
the chest wall in some deep seated or eccentrically located
tumours and for LABC where chest wall is part of the target
volume. Hence prone positon RT is best suited for women
with large pendulous breast requiring RT only to the breast,
especially left breast (23) where it can significantly reduce
the incidence of acute side effects (24).

DOSE FRACTIONATION
With the exception of north England and Manchester
where the hypo-fractionated 3 weeks schedule has been
the standard of care since 1940s, in rest of the world 45
50 Gy in 25 fractions over 5 weeks was the standard
fractionation for breast, chest wall and regional nodes. In
204

BCT, whole breast RT is followed by tumour bed electron


boost of 1016Gy in 5 8 fractions. Mature results of the
3 RCTs from the UK and Canada and their meta-analysis
confirm that hypofractionated regimen is equivalent to
the conventional regimen it terms of overall survival,
locoregional control and cosmesis(25-28). In fact, hypofractionation results in significantly lower incidence of
acute and late breast toxicity and without excess cardiac
morbidity at 15 years (27, 28). The 3 week hypofractionated regime has become the standard of care in
the UK, Canada and many other centres across the world.
At TMH, 40Gy/15# hypofractionated regime (with 12.5Gy
/ 5# boost for BCT) has become the standard practice for
all breast cancer patients since 2014. This includes post
mastectomy RT as well as BCT cases and irrespective of
the stage. The protracted 5 week fractionation is required
for <5% of cases in whom 3DCRT or FiF IMRT is unable to
achieve acceptable dose homogeneity or in select cases of
phylloides tumour or whole breast reconstruction. While
the 3 week hypofractionation has gained wide acceptance,
the quest for finding the ideal fraction size is not over.
Newer studies like FAST and FAST Forward are analysing
safety of extreme hypofractionation using 5 fractions of
6Gy each, given once weekly or daily. Till the results are
not published, decision of treating whole breast with a
fraction size of >3 Gy should be limited to trial setting.

CONTOURING GUIDELINES
The most widely used guideline for contouring breast,
chest wall and regional nodes is the RTOG. The Danish
guideline is relatively new and takes into consideration
vasuclar, muscular and bony anatomy whereas PROCAB
205

guideline to based on vascular anatomy for delineating


regional nodes (30). In the absence of bony landmarks,
contouring is based on clinical boundaries of breast
delineated by radio-opaque marker wires placed during
planning CT . The CTV to PTV margins depend on the
institutional estimates for systematic and random error
plus the ITV generated for respiratory motion. Almost all
long term tumour control data for breast cancer has been
obtained with conventional bi-tangential 2D or 3DCRT
technique in which the high dose volume tapers sharply
at medial and lateral edges. In contrast, an IMRT plan
generated for a breast PTV contoured conventionally will
invariably increase the treated volume at the medial and
lateral edges. This may be avoided by limiting the PTV for
IMRT to high dose volume obtained in bitangential fields.
The organs at risk typically contoured for all cases are the
heart, both lungs and contralateral breast. Left Anterior
Descending artery can be contoured using university of
Michigan guidelines (31).
Conventional bitangential breast RT, with or without
wedges, for tissue compensation in the transverse plane
has long term data for efficacy and is safety with respect
to the doses received by the lungs, heart and contra-lateral
breast. Until 3D planning and DVH were available,
measurement of the Maximum Heart Distance (MHD) and
the Central Lung Distance (CLD) in the tangent fields served
as a benchmark for plan evaluation. Restricting the CLD
to 2.5-3 cm and MHD <2cm was considered a safe
practice with regard to heart and lung toxicity (32). Simple
cardiac sparing with MLC reduces the heart dose to
minimum. Despite the increasing use of advanced RT
planning techniques, lack of robust cardiac dose volume
206

constraints specific to breast cancer makes it difficult to


make firm evidence based recommendation about specific
techniques. There are several issues with the current
contouring guidelines, especially for delineation of the
clinical target volume of the breast and chest wall. It is
noteworthy that with the conventional bitangential
arrangement which has long been the standard practice
and with proven efficacy, only 74% to 96% of the anatomybased RTOG consensus volumes is covered by the
prescription dose (33). An attempt to encompass the target
volumes leads to excess irradiation of the lung and heart.
Hence it seems that in addition to the dose constraints
greater attention should be paid to the target volume
delineation. Restricting the target volumes within the
confines of the high dose region of conventional tangential
technique seems reasonable. Concerns have also been
raised regarding the high variability in target and OAR
delineation for breast irradiation between institutions or
observers using the RTOG guidelines (34).
The recommended dose constraints from QUANTEC for
radiation pneumonitis have commonly been adopted from
the lung cancer studies and can be used for breast cancer
when using conventional fractionation (35). Clinical studies
in breast have reported dosimetric and clinical safety of
these recommendations and ability of a 3D plan to improve
the dose volume parameters further (36-38). Similarly, the
QUANTEC recommendations for dose volume parameters
for the heart are very general and lack robustness (39). In
patients with breast cancer, the authors recommended
that the irradiated heart volume be minimized to the
greatest possible degree without compromising the target
coverage.
207

The dose constraints for hypofractionated 40Gy/15 #


regimen suggested by the UK group is ipsilateral lung V12
<15% and heart V2Gy <30% and V10Gy <5%. (Yarnold
personal communication). With respect to partial breast
irradiation using 3DCRT, the dose constraints of the
ongoing NSABP B-39/RTOG4311 trial (40) can be used.

ADVANCED RADIOTEHRAPY TECHNIQUES


Majority of patients requiring breast or chest wall RT with
or without SCF RT can be safely treated with 2D or 3DCRT
using 6MV LINAC or on telecobalt if interfield separation
is not large. Need for advanced techniques, complex
shielding, mixed beam or intensity modulation arises
primarily for 2 reasons:
1.

2.

208

Cardiac mortality is associated with inadvertent


irradiation of the heart during adjuvant RT for breast
cancer (41-42). The dose received by the heart is
significantly more from tangential beams in left sided
breast cancers or when IMC is being treated with a
direct anterior photon beam. Recent systematic review
of Swedish breast cancer women suggests that major
coronary event rates increase linearly with the mean
dose to the heart by 7.4% per Gy, with no apparent
threshold (42). This prompted development of
advance techniques for delivering cardiac safe RT.
However clinical benefit with their use is expected
only in some cases of left sided breast cancer and in
women receiving RT for IMC nodes.
In women with large breasts, use of higher photon
energy or 3DCRT with wedges to compensate for
missing tissue in the transverse plane may fail to
eliminate large areas of high dose across the sagittal

plane. In such cases, prone breast RT may achieve


acceptable dose homogeneity with simple 3DCRT
methods. However due to certain limitations with
prone position, forward or inverse planned IMRT in
supine position may be required in some patients to
achieve acceptable dose homogeneity, coverage and
to reduce toxicity.

Selection of appropriate technique:


There are various planning and radiotherapy delivery
techniques and appropriate choice of technique is the key
to optimal clinical outcome. All possible teletherapy
techniques have been developed and reported for breast
cancer. These include 2DRT, 3DCRT, Field-in-Field (FiF),
forward planning IMRT, inverse planning IMRT, Helical
Tomotherapy, VMAT, 4DRT and Proton Therapy. Each
technique has its merits and demerits and is best suited
for specific indications. Hence the appropriate advanced
technique should be chosen for select patients in whom
conventional 3DCRT in supine or prone position is unable
to achieve acceptable homogeneity or coverage and this
is likely to adversely impact toxicity or tumour control.
A)

Conventional 2D-RT or 3DCRT: This is a simple,


safe, time tested and widely used technique with long
term results for all possible end points. Acceptable
doses to critical OARs can be achieved with
conventional techniques on Linacs without MLC or
on Telecobalt with the use of collimation, half beam
blocks or insertion of simple cardiac shielding blocks
(43-44). However in some patients it becomes difficult
to achieve acceptable dose homogeneity, target
coverage or OAR dose. In these patients one may
209

resort to complex planning. Comparisons are provided


here to aid evidence based decision regarding choice
of technique after reviewing each patient individually.
B) Multi-field Inverse planned IMRT Vs Forward
planned Field in Field (FiF) IMRT
Breast alone: In most anatomical sites across the body,
multi-field inverse planned IMRT is superior in almost all
dosimetric aspects except the low dose spillage. However
in breast cancer the anatomical location, size and shape
of the target volume and the OARs allow simpler FiF IMRT
to score over inverse planned IMRT in several important
respects. Alison et al (45) compared OAR sparing in left
sided breast cancer with FiF IMRT using standard
bitangents with dynamic wedges or subfields versus inverse
planning IMRT for a PTV which mirrored the treated volume
of bitangents, using 5-8 beams which entered only from
ipsilateral side. The study was stopped prematurely as
Inverse planning IMRT failed to achieve most objectives
consistently in all patients and resulted in significant doses
to the heart and contralateral breast.
Breast and IMN: This is a more complex composite target
volume and in closer proximity to critical OARs. Bekham
et al (46) reported that inverse planned IMRT was superior
to the standard plan in terms of homogeneity index (0.95
Vs 0.74), heart volume receiving >30Gy (1.7% Vs 12.5%)
and V20 Lung (17.1% Vs 26.6%) but at the cost of greater
low dose spillage with V5 of contralateral lung and breast
being 13.7% Vs 2% and 29.2% Vs 7.9% respectively. The
mean dose to Healthy Tissue Volume (HTV) defined as
Volume of body PTV received 6.9Gy compared to 6Gy
with standard plan. The major advantage with IMRT in

210

treatment of IMN region with WBI is better coverage with


elimination of hotspots, eliminating set-up uncertainties
of junctions, and their complex interactions. With increased
low dose plillage, risk of second malignancies especially in
young women with low risk of systemic relapse needs
consideration.
C)

D)

Challenges with inverse planning IMRT for


breast: These are secondary to the highly conformal
dose distribution with IMRT with high sensitivity to
Intrafraction breathing movements and set up errors.
Various strategies have been devised to overcome
these problems, such as the virtual bolus concept (47)
and the manual extension of the fluence matrix into
air (48). Hybrid IMRT employs a combination of 2DRT
with additional fields of IMRT through the same beam
angles to correct the inhomogeneities. Hybrid
approach optimally assigns minimal weight to the
IMRT beams, thus minimizing the impact of
positioning uncertainty. The wobbling effect is
minimized when IMRT fluence is low. The time
required for its planning is less as compared to 3DCRT
planning (49).
Methods of inverse planning IMRT modulation:
Donovan et al. compared different modulation
methods in breast IMRT with the simple physical
model and a corroborative comparative planning
study with a fixed set of analysis parameters (50).
Majority of IMRT methods improved over wedge-only
plans. BEV isodose-contouring and equalization of
the maximum dose achieved the best reduction of
high-dose volumes, but with a consequent increase
in the volume below 95% dose compared with the
211

other compensation methods with increased PTV


mean dose. Overall, no modulation method showed
a clear dosimetric advantage over the others, and their
use needs to be determined on a patient-specific basis.
For patients with a breast volume < 1000 cm3, IMRT
may be inappropriate. Although any type of input
could be given to an inverse planning algorithm, in
practice the constraints are often based around DVH
curves that possess no information on the spatial
distribution of the dose. This may result in higher dose
to the chest wall and other OARs compared to the
standard wedged plans. Table 1 summarizes various
methods of IMRT planning.

IMPACT OF IMRT ON CLINICAL AND


DOSIMTERIC PARAMETERS:
Few retrospective studies, RCTs and systematic reviews have
compared various techniques including conventional 2DRT
or 3DCRT and FiF IMRT.
1.

2.

212

Tumour control and survival: In a retrospective


study of 245 breast cancer cases treated with 2DRT
or IMRT, at a median follow up of 6.3 years, no
significant difference was seen between the two
groups in terms of loco-regional control, contralateral
breast cancer and overall survival (55). A recent
systematic review (56) also did not confirm any benefit
with IMRT for any oncological outcome.
Cosmetic outcome: In a RCT comparing IMRT with
conventional technique, Donovan et al. (57) reported
that significantly better cosmesis at 2 years with IMRT.
In a review, Staffurth and colleagues (58) reported
better long term cosmesis with IMRT. Recent update

213

Author

Aref (51)
Hurkman (52)
Wilks (53)

Vicini (54)

Donovan (50)

Method of Modulation

Inverse planning

(minimize PTV dose variation)

Plan Compensation equivalent


path length missing tissue
compensation

BEV Dose Contouring

Minimizationof dose variation


equalization of max dose

10.7%
reduction

V>105%

0 (0- 38.6)

V>110%

11(0- 67.6)

22

90.8

10

IMRT %

42.9

92.8

24

2DRT %

Outcome

V>105%

V>105%

V95 107%

V>105%

DVH Parameter

Table 1. Dosimetric comparison of various IMRT planning methods

3.

4.

5.

214

from Mukesh et al (59) also suggest that improved


dose homogeneity with simple IMRT translates into
superior cosmesis and reduces the risk of skin
telangiectasia.
Quality of Life (QOL): The two RCTs and a systematic
review (57,58,60) showed that despite superior
cosmetic outcome with IMRT, there was no impact
on patient reported QOL.
Acute Toxicity: Randomized controlled studies (6061) and systematic review (56) has shown significant
reduction in moist desquamation particularly in the
inframammary fold with IMRT compared to 2DRT.
However they couldnot demonstrate statistically
significant difference in other toxicity parameters like
breast pain and edema. Freedman et al. (62) reported
that as compared to 2D RT, IMRT of the breast
significantly decreases the time spent during
treatment with grade 2/3 dermatitis and also the
severity of dermatitis. The investigators have
subsequently reported on 5-year outcomes of breast
IMRT at the Fox Chase Cancer Center. Oedema and
erythema of the breast were consistently noted early
after IMRT and peaked at 3-6 months but infection
was rare, seen in <1.5% patients (63).
Late Toxicity: Donovan et al. (61) reported that all
women with breast volume 1000 cc developed
higher than average risk of late radiotherapy adverse
effects. Significantly fewer patients developed
palpable induration at the center of breast, pectoral
fold, inframammary fold and at the boost site when
treated with IMRT. However there were no significant
differences in patient reported breast discomfort and

6.

breast hardness with IMRT. Another RCT by Barnett


et al (64) reported significantly lower incidence of
telangiectasia with IMRT as compared to 2DRT at 2
years. Dayes et al in their systemic review (56) found
that there was insufficient data to show benefit of
IMRT on long term toxicities.
Dosimetric Impact:
Set up uncertainty and breathing effect: Besides
breathing effect, there are other concerns with breast
IMRT such as setup uncertainty, skin dose and total
monitor units used in the course. Without breathing
factor, setup uncertainty may affect the dose delivery
more in IMRT than 3DCRT as the modulated fluence
in IMRT is more sensitive to patient positioning than
the relatively uniform fluence in 3DCRT (65-66).
Because of the wobbling nature of the target, patient
positioning may thus pose a challenge when using
IMRT (67).
Homogeneity: IMRT significantly improved dose
distribution inside the PTV. Barnett and colleagues (64)
noted that inhomogeneity (V107% > 2cc) occurred
when inter-field separation was 21cm with 2DRT.
The study however failed to demonstrate any
difference in clinical outcomes with inhomogeneity
correction using IMRT. In the RCT reported by Donovan
et al (57) comparing 2DRT with IMRT for whole breast
(breast volume > 500cc), 92% patients treated with
2DRT Vs 19% with IMRT had volumes of hot spots
> 105%. A cohort study by Hardee et.al (68) showed
significant reduction of Dmax when comparing 3DCRT
(110%) with IMRT (107%).

215

Lung and Heart Doses: Selvaraj et al.(69) conducted a


dosimetric study on a small number of patients and
reported a reduction in ipsilateral lung mean dose by 9.9%
and significant reduction in percentage volume of
contralateral lung receiving > 5% of prescription dose by
35%. This resulted from improvement in homogeneity with
IMRT. IMRT can potentially reduce heart and left ventricle
dose in left-sided breast cancers and unfavourable cardiac
anatomy (70). Similarly, a study evaluating Aperture based
IMRT (71) for left-sided breast cancer found that the
average heart volume exposed to >30 Gy was reduced
from 45 cm3 to 5.84 cm3. The mean dose to the left
ventricle was reduced by average of 10.7% (10.86 vs. 9.7
Gy), and the mean heart dose increased by an average of
24% (from 6.85 to 8.52 Gy). The model-based reduction
of the probability for excess therapy-associated cardiac
death risk was 6.03% for the 3D plans and 0.25% for the
IMRT plans. They concluded that IMRT significantly reduces
the maximal dose to the left ventricle, which might
translate into reduced cardiac mortality. Biological
modelling might aid in future for decision making to treat
with IMRT but has to be validated prospectively.

SPECIAL TECHNIQUES FOR BREAST RT


Tomotherapy: Careful planning with geometrically limited
arc on tomotherapy can reduce both high and low dose
regions to OARS in left-breast-affected patients. Due to
limitation of the size of gantry bore, patients are usually
positioned using vacuum bags. Dosimetric comparison of
left-breast-affected patients with 3DCRT, Inverse planning
IMRT, FiF IMRT and helical tomotherapy shows that all the
techniques provide acceptable target coverage but
216

inhomogeneity correction was better with tomotherapy,


topotherapy and inversely planned IMRT (72). However,
helical tomotherapy corrected homogeneity at the cost of
low doses to normal tissues. In a study comparing
hypofractionation with Simultaneous Integrated Boost
(SIB) to the tumor bed using tomotherapy with
conventional fractionation and technique, the short course
RT on tomotherapy was feasible without excess toxicities
(73). There are special scenarios where helical tomotherapy
has been reported to be particularly beneficial. These
include synchronous bilateral breast cancer (SBBC) where
multiple field junctions may results in dose inhomogeneity
and higher irradiation volume of OAR. While there are
only a few case reports reports of Tomotherapy for SBBC
in the literature, at ACTREC we have developed
Tomotherapy technique for SBBC. Comparing conventional
RT with various advanced techniques like Tomotherapy
(Helical & fixed beam) and FiF for SBBC, we find that
radiation doses to heart and lung can be significantly
reduced with Helical Tomotherapy without compromising
PTV coverage (Wadasadawala T BJR, in press). Other
indications for which tomotherapy has been dosimetrically
evaluated include unfavourable anatomy, loco-regional
radiotherapy and hypofractionated protocols involving SIB.
Proton Therapy: Several dosimetric and a few prospective
clinical studies have evaluated role of proton beam therapy
in breast cancer. Protons seem promising in terms of NTCP
for lung and heart (74-75), especially in node-positive leftsided breast cancer. Bush et al. (74) recently reported
excellent 5 years local control rate of 97%; DFS of 94%;
and overall survival of 95% in 50 women treated with
partial breast irradiation with protons. There were no cases
217

of grade 3 or higher acute skin reactions, and late skin


reactions included 7 cases of grade I telangiectasia. Patientand physician-reported cosmesis was good to excellent in
90% of responses and was maintained throughout the 5year follow-up period. Respiratory motion, lack of skin
sparing and set up uncertainties pose challenges for Proton
Beam therapy for breast cancer. Various positions have
been tried to eliminate the shortcomings like lateral
decubitus, prone position etc. In absence of long term
data of its safety, it remains an investigational approach.
Breath Holding, Respiratory Gating and Tracking:
Target motion makes it difficult to minimize the OAR doses.
Breath hold, gating or tracking are methods to reduce the
target motion to as low as reasonably achievable, which
allows for reduction in ITV and subsequently PTV margin.
Smaller PTV may allow sparing of OARs even with simple
techniques. The result of breathing control techniques
largely depends on the patient status during dose delivery.
Breath-holding technique may not be suitable for each
patient, and gating practice requires 4D CT techniques
and longer treatment time. To be able to reliably implement
complex plans many investigators have studied the above
techniques for feasibility and reproducibility and to know
its impact on dosimetry, patient outcome and throughput.
A study from M.D. Anderson Cancer Care (76) reported
significantly lower dose to the contralateral breast and
heart with forward planned IMRT during deep-inspiration
breath-hold (DIBH). This reduction is largely due to
increasing distance of heart from the chest wall due to
inflation of intervening lung parenchyma. Another study
from University of Virginia (77) demonstrated OAR sparing
ability of DIBH with 3DRCT technique. A recent study by
218

Sarah et al.(78) showed that VMAT when delivered alone


had inferior OAR sparing for left sided breast cancers, but
when delivered with DIBH, it significantly reduced dose to
heart and ipsilateral lung. If breath holding technique has
to be used routinely then its reproducibility and accuracy
has to be evaluated carefully. Betgen et al. evaluated (79)
3D set-up variability in DIBH RT and showed that patients
are able to perform a very stable and reproducible DIBH
within a treatment fraction. However, relatively large interfraction variability requires online image guided set-up
corrections. Hence this technique when coupled with
image guidance can act as a reliable tool to reduce toxicity
while implementing complex plans. As compared to free
breathing, voluntary moderate deep inspiratory breath
hold did not increase set-up error (80).

RESOURCE IMPLICATIONS OF COMPLEX


TREATMENT PLANNING AND DELIVERY
Advanced RT techniques have resource implications for
contouring, planning, delivery and verification of RT. For
3D conventional planning, only some OARs need
contouring to evaluate doses to heart and lung. However
target delineation is necessary for inverse planning IMRT.
While it takes 15 -20 minutes to make a conventional 2DRT
or 3DCRT breast plan, inverse planning IMRT or Helical
tomotherapy planning usually takes more than 2 hrs. This
may heavily burden an already busy medical physics
department. Additional time and resources are required
for image guidance, patient-specific quality assurance and
treatment delivery. In a time measurement study, Evelyn
et al (81) found that the median time to treat a patient
with conventional technique is 12 minutes whereas for 9219

14 field IMRT it took a median time of 25.5 minutes. The


cost of advanced RT techniques is significantly higher than
the conventional 2D or 3DCRT. These factors are to be
carefully balanced against the clinical benefit that a patient
is likely to derive before choosing a resource intensive
technique for a patient and especially before making it a
standard of care.

ACCELERATED PARTIAL BREAST


IRRADIATION
Detailed discussion of various APBI techniques is beyond
the scope of this chapter and the current status is
summarized here. APBI refers to an accelerated course of
RT over 1-5 days to the tumour bed plus 1-2 cm margin
and is being currently investigated in several large RCTs
some of which have completed accrual or reported early
results (82). Careful selection of patients who are at least
risk of breast recurrence outside index quadrant and use
of quality assured APBI technique is the key to success of
this approach. Till the RCT results become available, APBI
should be considered investigational and offered cautiously
outside studies. ASTRO has made recommendation for
clinico-pathological criteria where APBI can be considered
a suitable method for treatment or should be used with
caution or an unsuitable method of treatment (9). At TMH
a prospective study investigating interstitial brachytherapy
APBI was initiated in the year 2000 long before the ASTRO
guidelines and majority of cases fall in cautionary or
unsuitable category without any excess local recurrence
at 98 months median follow up [unpublished data]. There
are a large number of external beam as well as
brachytherapy techniques and different applicators for
220

APBI, each with their distinct advantages and


disadvantages (83). While there is no high level evidence
showing superiority of one technique over other, external
beam techniques in general provide better target volume
coverage but at the cost of higher dose to the surrounding
breast and this may be the reason behind inferior cosmetic
outcome with 3DCRT based APBI. Interim cosmetic and
toxicity results of a multi-center randomized trial
comparing accelerated partial-breast irradiation (APBI)
using 3D-CRT with whole-breast irradiation (WBI) were
recently reported (84). Increased rates of adverse cosmesis
and late radiation toxicity were observed in the 3D-CRT
APBI arm compared with standard WBI. Hence the authors
cautioned clinicians and patients against the use of 3DCRT APBI outside the context of a controlled trial. Livi et
al. reported preliminary results of 259 patients randomized
to conventional fractionated whole breast RT versus APBI
with IMRT (9). RTOG Grade 1 and 2 skin toxicity was
observed in 22% and 19% with whole breast RT versus
5% and 0.8% with IMRT APBI respectively.

TUMOR BED BOOST


In women undergoing BCS, boost to the tumor bed is
routinely given after whole breast RT. The EORTC RCT
examined the benefit of tumour bed boost 16 Gy/8# after
50Gy/25# whole breast RT and the value of boost dose
escalation in women with early stage breast cancer after a
microscopically incomplete lumpectomy (85). Use of boost
had an adverse impact on cosmesis but led to significant
improvement in local control, with the effect being more
pronounced in younger women. The absolute risk
reduction at 10 years seemed to be larger in the younger
221

patients: reduced from 23.9% to 13.5% in those age 40


years, from12.5% to 8.7% in the 41- to 50-year age group,
from 7.8% to 4.9% inthe 51- to 60-year age group, and
from 7.3% to 3.8% in those older than 60 years.There
was no benefit of dose escalation in the 251 randomized
between 10Gy/5# versus 26Gy /13#. In Indian practice
where larger and higher grade tumours are more common,
vast majority of BCT cases require boost. The practice is
more variable in the west where up to one third of women
do not receive tumour bed boost when it is left to the
discretion of the physician, as seen in the START
trials (27,86). Women who are least likely to benefit from
boost are elderly women with T1N0 low grade, ER+ve
tumours and clear resection margins. Boost is usually given
with en face electron portal but can also be given using
brachytherapy, photons or even protons. While it is
generally given after completion of whole breast RT, it can
be given concomitantly as Simultaneous Integrated Boost
(SIB) during whole breast RT. The boost technique, dose
and fractionation need attention as it may affect cosmetic
outcome and local control.
1.

222

Tumor bed localization: The ideal methods for


localizing the tumour bed is using radio-opaque
surgical clips placed on the base of the excision cavity
at the center, superior, inferior, medial and lateral
edges. However if the clips are not secured firmly on
the muscle or tissue, they may migrate leading to
errors in localization. The seroma cavity is a good
guide in localization of the tumour bed but it may
have resolved by the time planning CT scan is taken
or oncoplasty techniques may change the extent and
location of the seroma cavity. Hence boosting the

2.

seroma cavity without extracting information from


surgical notes and visualizing the clips may lead to
errors in localization. Some surgical clips may not be
clearly seen on MV imaging hence gold seeds have
been recommended by Coles et al (87). Accurate
localization of the tumour bed allows shrinkage of
PTV margin to 5mm which is recommended for the
IMPORT HIGH study.
Boost Techniques
a)

Electrons: En face electron beam boost has


become standard practice in most institutions
due to inherent advantages like the ease of set
up, patient comfort and minimal dose to
underlying lung. However the target volume may
not be covered uniformly, especially in areas with
sudden change in depth like the inframammary
and axillary tail region. Electrons may produce
unacceptable coverage or result in excess OAR
dose in deep seated tumour bed in women with
large breast or tumour bed situated very close
to heart or lungs and in the folds (96).

b)

Interstitial Brachytherapy: Needles are placed


in the tumor bed either intra-operatively or under
fluoroscopic guidance and later replaced with
nylon tubes for HDR brachytherapy. The
technique requires considerable operator skill and
careful case selection. For more details readers
are requested to refer to the breast brachytherapy
chapter.

223

c)

Photons: If electrons are not able to cover the


depth of the cavity and interstitial implant is not
being considered, boost can be given with
photons using mini-tangents, 3DCRT or IMRT
depending on the location and size of the tumour
bed in relation to breast and OARs. While breast
IMRT has several issues as discussed earlier, it can
be used for simultaneous integrated boost (88)
which decreases the number of fractions and
avoids re-planning for boost. Some of the
fundamental issues pertaining to IMRT of the
breast in general and boost in particular include
patient positioning, accurate target volume
delineation, inter-fraction and intra-fraction
motion, dose constraints to critical structures
such as heart and lung, dose calculation at the
interfaces and change in the boost volume that
may require re-planning/ adaptive RT.

CHEST WALL IRRADIATION TECHNIQUES


Treatment planning and delivery for chest wall is different
from whole breast not only due to differences in target
shape but also due to routine inclusion of ribs and
intercostals muscles in the target. Conventional 2D RT or
3DCRT is the most commonly used method and employs
bitangential fields with or without wedges for tissue
compensation. Treatment on telecobalt can be done with
or without breast cone, wedges or cardiac shield. Most
breast cones produce half beam block, thereby reducing
beam divergence in lung. Use of breast cones on telecobalt
is being largely abandoned with increasing use of isocentric
224

3DCRT for chest wall RT on telecobalt and the need for


wedges in some patients.
The shape and thickness of the chest wall and inter-field
separation is quite variable and requires individualized
planning. A reasonable plan may be produced by shifting
the normalization point and using appropriate wedges or
bolus. When inter-field separation is more than 18-20 cm
or the anatomy is unusual, even a 3DCRT plan on telecobalt
may fail to achieve the planning objectives. In such cases
6MV Linac or FiF with telecobalt, as practiced at TMH,
may help achieve acceptable coverage and OAR doses in
many cases.
A tissue equivalent bolus over the chest wall is
recommended even for telecobalt in order to increase the
skin dose in cases with skin involvement. Maximum sparing
of heart and lungs is an important planning objective in
chest wall RT as it is for intact breast RT. Occasionally, bolus
can also be used for dose build up especially in thin chest
wall planning. The Central Lung Distance (CLD) seen in
the tangential portals should preferably be within 2 cm
and not exceed 3 cm which may result in higher lung
toxicity (32). However in some patients the convexity of
the chest wall or the need to cover more laterally or
medially across midline may increase the CLD and is either
accepted on a case to case basis or whenever possible use
IMRT to reduce high doses to the lung. Cardiac shielding
with MLC or blocks should be used for left chest wall RT,
especially if >1 cm of cardiac silhouette is seen in the
tangential portal. If required, standard adjustable shields
can be used for cardiac shielding even on telecobalt
machines.

225

Set up uncertainty and breathing motion for chest wall


IMRT remains same as for intact breast. Hence when
contours are made for inverse planning IMRT, movement
due to breathing cycle has to be accounted for. Volker
and colleagues (89) evaluated the dosimetric impact of
tangential inverse planning IMRT with 3DCRT. They
reported statistically significant reduction in ipsilateral
mean lung doses by 21%. Mean heart dose for all patients
reduced by about 20%. To account for respiratory motion
PTV margin was extended upto 1.5 cm anteriorly in air.
This ensured appropriate opening of MLCs to account for
chest wall motion with breathing cycle. For the 3DCRT
plans PTV was edited by 3mm from the skin inside to avoid
overdosage of the skin.
Few studies have examined the use of IMRT for chest wall.
Rudat et al compared IMRT with 3D-CRT for chest wall RT
in 20 patients (89). They reported significantly decreased
heart and lung high dose-volume and significantly
improved conformity index with IMRT but no significant
difference in the homogeneity index. In a study comparing
electron IMRT to helical photon IMRT and conventional
RT, the target coverage by the 95% isodose was best with
tomotherapy, mean ipsilateral lung doses were similar with
all techniques and electron IMRT achieved best sparing of
heart and contralateral breast (90). Compared with photon
IMRT, electron IMRT allowed better sparing of contralateral
lung and total healthy tissue. Electron IMRT may be
considered for select cases in whom conventional and
complex photon planning fail to achieve dose constraints.
At TMH we prefer electron arc for select cases requiring
RT to bilateral chest wall and have a relatively flat chest
wall where tangential incidence of electron beam is
minimized (91).
226

PATIENT SET UP AND ITS VERIFICATION


Breast is a soft, non-rigid, deformable structure which lacks
bony landmarks and moves with respiration. Positioning
and immobilization devices improve the set up
reproducibility to some extent but highly reproducible
breast set up remains challenging in many ways. A careful
set-up can reproduce the patients position with errors in
all directions to be < 10 mm. However with conformal
techniques like 3DCRT and IMRT a 10 mm error may lead
to inadequate coverage of target or excess dose to critical
structures. Increasing PTV margins may increase normal
breast irradiation during external beam APBI or in photon
based tumour bed boost. Advanced techniques such as
cardiac sparing 3DCRT, FiF, SIB and IMRT are being
increasingly used and also show greater dosimetric impact
due to set up errors and breathing motion. Hence
improving the set up reproducibility and its verification
assumes greater importance in modern breast RT.
Rotational movement of the patient or variation in arm or
body position on a sloping breast board can create
variation in the angle at which the tangents coincide with
the skin marking. Seroma formation or breast oedema
during RT can alter breast contour can cause errors in daily
set up beyond the acceptable limits of < 5 mm and
patients may have to be replanned in such cases.
The QA study of IGRT protocols by the IMPORT study group
reported population systemic error of 10 mm for set up
only on skin marks and concluded that to create an
acceptable partial breast RT plan without overdosing OARs,
tighter margins through error correction is required (92).

227

Electronic Portal Imaging Device (EPID): EPID in breast


poses difficulty in interpreting bony and soft tissue
landmarks in the tangential beams. AP and lateral images
are required for isocentre verification and oblique images
to ascertain if the entire breast is adequately covered. Interobserver error in matching EPIDs is < 2 mm in 92.5%
cases and < 5mm in most cases (93). A QA study (94) of
daily set up and treatment found highest percentage
(17.5%) of >3 mm mean deviations for breast cases as
compared to other anatomical sites. For SCF RT, 2.3 - 3.9
mm deviation has been reported in a recent study (95)
which also concluded that systematic errors are more in
the AP direction for the tangential fields and in the ML
direction. Displacements of 10 mm were found in 1.2%
of breast/chest wall tangential treatments and in 6.2% of
SCF treatments. The IMPORT HIGH study group reported
a population systematic error in locating tumor bed with
orthogonal KV imaging bony anatomy matching protocol
to be 8 mm (92). Hence weekly or more frequent EPID
can help reducing OAR dose and target coverage
(17,94,95).
Cone Beam CT (CBCT): Volumetric data provides better
perspective and more accurate set-up compared to 2D
imaging and various protocols ranging from 360 degree
scanning to limited sectoral scans have been adopted in
different centres. Compared to 360 degree scanning,
limited scans reduce radiation exposure to organs at risk.
A study comparing set-up using skin marks versus CBCT
based registration reported that, skin marks based set up
was reasonably accurate within 5mm tolerance both
systematic and random error included (96) which could
be reduced to <2mm with CBCT. This degree of accuracy
228

was beneficial for APBI more than whole breast


radiotherapy as the clinical relevance in the latter was
questionable considering wide margins are given for WBI.
Recently the IMPORT HIGH study group (92) evaluated
the quality of image guidance protocols across 5 centres
in UK for set-up accuracy of tumor bed and found that
least errors (< 5 mm) in localizing the tumor bed occurred
when soft tissue and surgical clip matching was done with
KVCT scans.
When using CBCTs for adaptive radiotherapy numerous
corrective measures for improving dose calculation
accuracy (inherent difference in HU between planning CT
and CBCT) have been used. These methods (97) are, direct
use of CBCT for dose calculation with established specific
CBCT Hounsfield Unit (HU) density calibration curve; the
planning CT-based method with correction of CBCT using
planning CT information; and the projection scatter
correction method which reduces the scatter before CBCT
image reconstruction. Among them, the HU-density
calibration method, which uses phantom or specific
population to get the HU density curve without complex
image process algorithm can be easily be implemented in
the clinic. However, in certain cases, severe image scatter
artefact will cause dose calculation error and better
methods are needed for correcting the artefact. A simpler
correction method was suggested by a study where the
after rigid registration of CBCT with planning CT the images
were separated into 4 different parts as air, bone, lung ,
and soft tissue and masks were generated for each part.
This was followed by calculation of local ratios for each
mask which then reduced the high spatial frequency
allowing enhanced CBCT image view for better target
localization and dose calculation.
229

3D Surface Registration: In a comparative study at


MDACC, it was found that Allign RT software for surface
based matching could reduce set up errors as compared
to reference surface topogram for matching patient
alignment from skin marks (98). Alignment with skin marks
was noticeably poor in the AP directions. Another study
(25) found verification based on the 3D localization of a
hybrid configuration of surface control points to be feasible
in clinical practice, providing valuable information for
improving set-up and minimal requirement of operatordependant procedure.
Ultrasound guided verification: This has been
evaluated to localize the lumpectomy cavity for APBI or
tumor bed boost. The lumpectomy cavity position may
vary by 1 1.5 cm and this can cause target under dosing
in 25- 35% of patients for both photon as well as electron
boost plans (99). If substantial time has elapsed between
planning of boost and its delivery, change in cavity volume
is seen in 49% of cases. Ultrasound guided verification is
feasible but for clinical use further studies are required for
refining the protocol.

QUALITY ASSURANCE
A strict QA protocol has to be adhered to before embarking
on treatment with advance technique. A full knowledge
of all steps in planning and treatment delivery are essential
for recognizing the source of error when encountered with
one. Daily machine specific QA and patient specific QA
before start of therapy has to be performed. There are
small but significant differences when IMRT or equivalent
complex technique is used compared to conventional
technique. To keep the balance tilted in favour of the
230

modern treatment systematic errors have to be corrected


and minimized before initiation of therapy. Evelyn and
colleagues (81) conducted a study where time
measurements were performed on daily treatment delivery
with the aim to quantify the impact of QA using EPID on
RT delivery time and to validate the time burden of IMRT.
Both increased QA and the delivery of IMRT were found
to be significant parameters determining daily treatment
time, which in turn translates in to lower throughput and
higher treatment costs. Hence advanced techniques should
be employed only when clinically indicated and without
compromising on the general QA and specific QA required
for the technique used.

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Brachytherapy in Breast Cancers


Introduction
Radiation therapy is an integral component of
management of breast cancer with impact on local control
as well as overall survival rates (1, 2). All women who have
undergone breast conserving therapy (BCT) and select
group of patients after mastectomy are considered for
radiation (1, 3). Traditionally radiation therapy involves
external beam therapy using bitangential portals, with or
without regional lymphatics irradiation, given over a period
of 4-6 weeks. Role of brachytherapy has evolved, from
1920s where the implant was done for unresectable
tumors, to now where brachytherapy is considered as the
sole modality of radiation after breast conserving surgery
(BCS).
Currently brachytherapy is practised in following situations
in breast cancer:


Boost to the tumor bed after BCS and whole breast


RT
As the sole modality of radiation: Accelerated Partial
Breast Irradiation
Surface mould brachytherapy for chest wall
recurrences

Brachytherapy as boost
Boost to the tumor bed after whole breast RT was highly
controversial in 1990s. While the advantages were of
improved local control with higher doses, the concerns
were essentially impaired cosmetic outcome after RT. Boost
251

to the tumor bed became standard of care after the


landmark publication of EORTC trial which initially showed
improved local control in women <40 years with additional
boost (4, 5). The updated 20 year follow up results
confirmed a continuing and statistically significant
improvement in the local control in women upto 50 years
of age. They suggested that boost may be considered
selectively in older women (6).
Tumor bed boost delivery can be achieved by electrons,
multicatheter interstitial brachytherapy (MIB) or 3CDRT
techniques (5, 7). Brachytherapy is the most conformal
form of treatment among these modalities. Deep seated
tumors, with a smaller volume of disease are best suited
for brachytherapy, which has superior dosimetry & better
cosmesis.

Accelerated Partial Breast Irradiation


It has been observed that approximately 40-90% of the
recurrences occur in close proximity to the tumour bed
and recurrences outside this area are more often second
primary tumours rather than true recurrences (8, 9). Thus,
it has been argued that targeting the whole breast may
not be necessary and treating the tumour bed with
adequate margins would be sufficient. Also, one third of
women who undergo BCS are not able to complete the
entire treatment schedule and do not take radiotherapy.
This is typically due to long duration of the treatment,
inability to stay away from the home, increased treatment
cost and financial constraints due to loss of wages (10).
Accelerated partial breast irradiation (APBI) is an attractive
alternative in such situations where in tumor bed with
252

adequate margin is irradiated in 1 day to 1-3 weeks. This


treatment has the potential to reduce late cardiac and
lung toxicities and at the same time reduce overall
treatment duration.
Various techniques of APBI include
Brachytherapy

Intraoperative electrons (IORT)

Targeted intraoperative therapy (TARGIT)

External Bream Radiation : 3DCRT, IMRT
Brachytherapy in this setting has garnered sufficient interest
worldwide with prospective trials being published
periodically to report outcomes. There are various
brachytherapy techniques employed amongst various
institutions depending on the availability of resources,
expertise & experience and are as follows:





Multi-catheter interstitial brachytherapy (MIB): Low


dose rate (LDR) or high dose rate (HDR)
Balloon based (Mammosite) brachytherapy
Hybrid multichannel devices such as SAVI, clearpath
etc.
Electronic Brachytherapy

Selection Criteria:
Currently multiple randomized trials are ongoing
evaluating the equivalence of APBI with whole breast RT
(11-14). Till that time APBI remains investigational
treatment. ASTRO and ESTRO have therefore given strict
criteria for considering patients for APBI outside the clinical
trial and they are shown in Table 1 (15,16).
253

254

IDC or other
favourable
subtypes

Any

Not allowed

Not allowed

Allowed

Unicentric
only

Grade

Pure DCIS

EIC

Associated LCIS

Multicentricity

Unicentric
only

Allowed

Not allowed

Not allowed

Any

IDC,
mucinous,
tubular,
medullary &
colloid ca

3 cm

2 cm

Tumor size

Histology

>50 years

>60 years

Low risk

Suitable

Age

GEC-ESTRO

ASTRO

Not allowed

3 cm
Unicentric
only

Unicentric
only

Allowed

Allowed

3 cm

Invasive
lobular
allowed

3 cm

Any

Allowed

Unsuitable

ASTRO

Multicentric

Allowed

>3 cm

>3 cm

Any

Any

>3 cm

>40-50 years <50 years

Intermediate
risk

GEC-ESTRO

Any

Invasive
lobular
allowed

2.1-3 cm

50-59 years

Cautionary

ASTRO

Multicentric

Allowed

Allowed

Any

Any

Any

>3 cm

40 years

High risk

GEC-ESTRO

255

p N0(i-,i+)

Not present

Not allowed

BRCA1/2
mutation

Neoadjuvant
therapy

2 mm

2 mm

Surgical margins

Lymph node
status

Any

Positive

Estrogenreceptor

Not allowed

Not defined

p N0

Not allowed

Not allowed

LVI

Unifocal

Clinically
munifocal
2 cm

GEC-ESTRO

Multifocality

ASTRO

Not allowed

Not present

p N0(i-,i+)

Close
(<2mm)

Negative

Limited/
focal

Clinically
unifocal

ASTRO

Not allowed

Not defined

pN1mi,
pN1a

Close
(<2mm)

Any

Not allowed

Multifocal
(limited
within 2 cm
of index
lesion)

GEC-ESTRO

If used

If used

Not defined

p N2a

p N1
Present

Positive

Any

Allowed

Multifocal
(>2 cm of
index lesion)

GEC-ESTRO

Positive

Any

Extensive

Clinically
multifocal

ASTRO

There have been multiple reports in the literature


suggesting equivalent tumor control in patients with
cautionatory/intermediate risk groups (17-19). In majority
of the studies following criteria has been used:
Age > 50 years
Pathological tumour size 3cm.

Negative surgical margins 2mm.

Histology: IDC, mucinous or colloid with no ILC

Unicentric & unifocal tumours

Any histological grade

Any hormone receptor status

No EIC, DCIS or LVI

No neoadjuvant chemotherapy.
Optimum selection of patients is very important as
unacceptable high recurrence rates have been reported in
poorly selected patients in the range of 8-37% (20-23).



Multicatheter Interstitial Brachytherapy


(MIB)
MIB is the oldest practised form of breast brachytherapy
with excellent local control rates and good to excellent
cosmetic outcome in majority of the patients (24-26). The
first randomized trial of APBI using MIB was published by
Polgar et al where they showed equivalent local control
rate with APBI when compared to WBRT (27). The GermanAustrian trial reported 2.9% local recurrence (LR) rate in
274 patients at a follow up of 5 years (28). Similarly, the
prospective studies by King et al & Arthur et al have
reported LR of 4% at a follow up of 6 & 7 years respectively
(29,26). The William Beaumont Hospital updated 10 year
256

results of the matched pair analysis of patients treated


with Whole breast radiotherapy (WBRT) versus APBI
reported LR of 5% in the patient group who underwent
MIB which was similar to the WBRT group (30).

Techniques of MIB
The technique essentially involves placement of catheters
within & around the tumour bed under anaesthesia which
can be done either as an open cavity procedure during
the time of lumpectomy itself or as a closed cavity
procedure if the patient has been referred after the surgery.
Placement of catheters requires sufficient expertise as the
dose distribution depends greatly on the geometry of the
implant.
When done as an open cavity technique, timely and close
co-ordination of the surgeon, radiation oncologist & the
pathologist is required to obtain the final histopathology
to rule out adverse features unsuitable for the continuation
of this form of treatment.
The technique per se has not undergone many changes
over the years with the basic principles to be followed
remain intact such as:
1.

2.
3.

Pre-evaluation of the implant to be done & reviewing


the patient & tumour parameters. The aid of previous
clinical diagrams, mammogram, or a pre-implant CT
scan should be taken for proper identification of the
tumor bed.
Choosing the number of planes in the implant
optimally.
Ensuring equidistant and parallel placement of
catheters.
257

4.
5.

Skin distance from the superficial plane of atleast


5mm.
Free hand or a template may be used.

Procedure
Open Cavity Technique

After tumor excision & axillary clearance, the surgical
clips are placed in the superior, inferior, medial, lateral
and the centre of the cavity.

Rigid steel tubes are used for implantation, which are
replaced by flexible nylon tubes. ABS recommends a
minimum of 2 planes with the additional planes
depending on the volume of the cavity (31).

The inter planar distance should be 1.5 cm and the
the catheter spacing should be around 1-1.5 cm.

The entry & exit sites of the catheters should be atleast
2 cm beyond the target volume (31).

Implant is performed to obtain a triangular geometry.

It is advisable to use radio-opaque buttons at the ends
of the tubes for identification of the entry and exit
sites which would give the distance of the target
volumes from the skin.

The tubes are secured at the exit to avoid day to day
variation. In the open cavity technique, the error is
minimised due to the direction visualisation of the
lumpectomy cavity.

Closed Cavity Technique


The procedure of closed cavity is similar to the open cavity.
However there is no direct visualization of the cavity and
hence placement is based on preimplant CT scan,
ultrasonography and/or fluoroscopy.
258

Cuttino et al reported the improvement in the implant


geometry & coverage of the target volume when the
procedure is done when guided with CT Scan under sterile
conditions (32). Ultrasound guided instillation of the dye
into the lumpectomy cavity and better visualisation during
the procedure has also been practised (33). Either of the
procedures can be done depending on the availability.
However, CT scan gives a three dimensional view which
can be used for planning purpose too.
When the above facility is not available, a pre-planning
CT Scan can be acquired to have a fair idea of the three
dimensional target volume based on the surgical clips.

Image based planning & dosimetry


Two dimensional orthogonal x ray based planning has
limitations in the form of disproportionate estimation of
the target volume & lesser scope of optimisation. Das et
al showed that CT based planning improved the quality
of implants by better visualisation of lumpectomy cavity,
organs at risk (OARS) such as normal breast tissue, heart
& lung (34). Similarly, Cuttino et al & Sharma et al have
emphasised the importance of 3D planning (32,35).CT
Scan is acquired with the patient in supine position with
arms overhead, images are taken from the thyroid cartilage
to 2 cm below the breast tissue with radio-opaque dummy
wires in situ.

Contouring & Planning




Cavity is defined as the GTV including the surgical


clips. In the intra-operative setting, where air is seen
in the seroma, the air is also contoured as part of the
GTV.
259




GTV is expanded by 1 2 cm isotropically to generate


a CTV/PTV. The PTV has to be edited from the skin to
a minimum of 5 mm and also along the edges of
pectoralis muscle.
Multiplanar reconstruction of the catheters is done
with 3 dimensional visualisation.
Loading of the source is done 0.5-0.75 cm beyond
the PTV.
Dose is normalised according to the basal dose points
that are assigned along the central axis based on Paris
system.
Geometric optimization is done based on the volumes.
Evaluation of the dosimetric indices with a clear
improvement has been another important advantage
of image based planning (32,34,35).

Plan evaluation
Dosimetric Indices

Coverage Index (CI)of the cavity & the planning target
volume & conformal index (COIN) are determining
factors for optimal results.

Target coverage is defined as more than 90% of the
CTV covered by 90% of the prescribed isodose line.

Coverage Index (CI): V100%/V.

Conformal index (COIN): C1*C2
o C1: PTV100/PTV
o


260

C2: PTV100/V100

Dose homogeneity index (DHI): V100%-V150%/


V100%

A DHI > 0.75 is considered as a good plan.



The high dose regions should be kept within the
acceptable limits such as the maximum skin dose
should always be less than 100% of the prescribed
dose, the V150% & V200% volume should be less
than 70cc& 20cc respectively (11).

Over dose volume Index (OI): PTV200% / VPTV

External volume Index (EI): (V100% - PTV100%) / VPTV

Less than 60% of the whole breast reference volumes
should receive > 50% of the prescribed dose.
With the above, the chances of geographical miss and/or
the overestimate of the tumour volume and the
unnecessary dose to OARS would be minimised (36).


Dose
Boost
The most common doses for boost brachytherapy are
15-20Gy with low dose rate brachytherapy technique.
Equivalent doses with high rate system such as 10Gy in 1
fraction, 12Gy in 3 fractions and 16 Gy in 4 fractions have
been considered (37).
APBI
The most common dose regimen followed in APBI is 34
Gy delivered in 10 fractions over 5 days with 2 fractions
delivered per day with minimum of 6 hours difference.
This dose was arrived at after calculation of BED of 45 Gy
delivered with WBRT or LDR equivalent (38).

261

Other Brachytherapy Techniques


Mammosite
Though MIB has good dosimetric coverage for the irregular
cavities, the main disadvantage is that it is highly operator
dependent & requires experience. This led to the
development of Mammosite. This device consists of a single
balloon with a dual lumen catheter for inflation & for
source entry. It was approved for clinical use by U.S food
& drug administration (FDA) in 2002.
The placement can be done in the intra-operative setting
after lumpectomy or in the postoperative setting. With
the help of a trocar, the uninflated balloon is inserted into
tumor bed cavity. In the post-operative setting, image
guidance is essential for appropriate placement of the
balloon. Ultrasound or CT scan can be used for the same.
Once the placement is done, the balloon is inflated with
diluted radiographic contrast so that the device conforms
to the shape of the cavity.
CT scan is taken after the procedure for planning purpose.
It is very important to avoid air between the device & the
cavity. An implant is considered to be optimum if the air
within the implant is less than 10%. Placement should be
optimized as the proximity to the skin will lead to higher
skin toxicities. Ideally, a 7 mm distance from the skin is
advocated.
The target volume is the cavity with a 1cm uniform margin
around the cavity. Dickler et al reported that the target
volume (cavity after the inflation) in mammosite is
approximately 1.6 cm margin around the empty
lumpectomy cavity (39). This has both merits & demerits
262

in the form of better conformity & higher skin, heart &


lung doses respectively.
The major advantage is the relative simplicity of the
procedure. There are a few dosimetric studies which have
equal coverage of the target volume in comparison to MIB
(40). The volumes of the target volumes were however
high in the mammosite group of patents. Though better
conformity has been shown in mammosite, it has to be
noted that the uniform margin has the disadvantage of
splaying higher doses to the normal tissues.
However, the main disadvantage is the poorer dose
distribution in irregular cavities which is the most common
clinical scenario. Another factor is the dose inhomogeneity
corrections for the contrast inserted into the balloon is
not accounted for in the present planning systems (41)
The largest evidence of mammosite is by Vicini et al where
1440 patients have been treated with mammosite with a
follow up of 63 months showed a local recurrence rate of
1.6% (42).Benitez et al in their report of longer follow up
of 5 years have shown 100% local control rates (43).
However, caution to be applied if this technique has be
practised in the clinical setting in view of lack of long term
data & also the application in properly selected patients.

Multi-channel Balloon Catheters


Strut Adjusted Volume Implant (SAVI) &Clearpath
These devices were developed mainly to incorporate the
advantages of MIB & mammosite. These devices consist
of multiple struts so as to attain inhomogeneous dose
distribution adapting the cavity for which various sizes are
263

available. SAVI consists of one centre channel & peripheral


source channels (6,8 or 10). The device is inserted into
the cavity under ultrasound guidance in a collapsed state
which is then modulated with the help of a knob & a tool
to expand which is removed after expansion to the
optimum size.The only large experience with SAVI is the
retrospective study by Yashar et al, who reported good
coverage of the cavity and local recurrence of 1% at a
follow up of 21 months (44).
Clearpath is also a similar hybrid device which has shown
target volume coverage comparable to mammosite.
The above techniques are still experimental & would require
a considerable amount of time before they can be safely
practised in clinical setting.

Electronic Brachytherapy
Modified forms of balloon based brachytherapy devices
have been introduced in attempt to improve the dose
distribution (45).
Axxent electronic brachytherapy system is similar to the
Mammosite device, however, with an extra channel for
drainage of seroma. The main advantage of this device is
the use of 50kv X Rays and hence reduces the radiation
protection requirement. This also, has the benefit of
steeper dose gradient as compared to Ir-192. However
this may have implications in the skin dose received as the
higher RBE of 50kv X Rays cannot be ignored (46). In
addition, there is no sufficient clinical evidence to back
this device.

264

Cosmesis
The practice of interstitial brachytherapy in the APBI setting
has yielded good to excellent long term cosmesis in
majority of the properly conducted trials in the range of
75% to 99% (47,48). Mammosite has also shown
comparable cosmesis (42,43).

Late sequelae
Since the patients of EBC are long term survivors, the late
toxicity documentation & reporting is very essential. The
reported series of APBI with MIB have reported acceptable
toxicities.
The William Beaumont hospital series reported late
infection of 4% & fat necrosis of 11%.
Fat necrosis has been reported in the range of 12-20% in
many of the published series (49).However, symptomatic
fat necrosis is observed in less than 3% of the women.
Fibrosis & telangiectasia are also less common in the range
of 1-4 % (24-26).
In the boost setting, the rates of fibrosis are three fold
higher (4.4% vs 1.1%) as compared to no boost (EORTC)
(50,51).
At present, none of the new techniques offer distinct
advantage with respect to toxicities.

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275

Gynaecological Cancer

External Radiation
INTRODUCTION :


276

Radiation therapy (RT) is an established method of


treatment for gyneacological (GYN) cancers where it
is frequently employed in the primary, adjuvant
therapy or palliative setting.
Definitive / Radical radiation therapy chemotherapy
in above malignancies significantly improves the local
control as well as survival.
With conventional radiation techniques, the acute and
late toxicities reported range from 9-22 % (1)
In past 2 decades, with the advent of newer radiation
technology, refinement of treatment techniques to
improve the therapeutic ratio have been attempted.
Historically, conventional RT planning was done by
fluoroscopic or X-ray based 2 dimensional imaging
with major limitations being poor soft tissue
delineation and non-visualisation of tumor.
To a large extent, 2 D imaging with radio-opaque
contrast for eg. Bladder, rectal filling etc. was tried
but had no major impact on the outcome.

The transition from 2D to 3D radiation planning


involved incorporation of newer imaging modalities,
better treatment algorithms, treatment delivery
systems and better quality assurance.
Modern radiation techniques both external radiation
and brachytherapy have been successfully
implemented in the treatment of GYN Cancers

Modern Radiation Oncology Practice in


GYN Cancers:
There are well-known pre-treatment prognostic factors for
cervical cancer which include clinical staging, tumor
diameter and tumor volume.
Compared with surgical staging, clinical staging as defined
by the International Federation of Gynecology and
Obstetrics (FIGO) has been shown to under stage up to
2030% of stage IB patients, and up to 64% of stage IIIB
patients [4]. Newer Imaging modalities like CT, MR, PET
etc.. have been utilized to improve staging accuracy, tailor
treatments and in the post treatment evaluation of
Gynaecological Cancers.

Incorporation of Newer Imaging


modalities:
CT Imaging: Diagnosis and Staging
Computed Tomography has been shown a sensitivity,
specificity, negative predictive value & positive predictive
value of 75%, 91%, 91% & 75% respectively in detecting
metastatic tumor in pelvic and/or para-aortic lymph
nodes [3].

277

However, CT has been shown slightly inferior to the MRI


in the evaluation of the tumor size, stromal invasion and
parametrial invasion in the pre-treatment imaging for
cervical cancer (2).For eg. the accuracy of staging is 90%
with MRI as compared to 65% with CT (2).
CT imaging is widely used in RT planning purposes, as
apart from providing good quality diagnostic images (for
evaluation of lymph node involvement) it also provides
3D information, which is used for target and OAR
delineation. Moreover, the electron density information
of the CT dataset is utilized for dose calculations by modern
dose calculation algorithms.

MR Imaging :
Improvements in tumor delineation by imaging modalities,
like magnetic resonance imaging (MRI), can improve
treatment decisions and increase the precision of
radiotherapy.
For cervical cancer, T2-weighted MRI is considered at
present as the gold standard for the evaluation, diagnosis
& staging of local tumor extension due to its high soft
tissue contrast (ACRIN, GOG).
Till now, there is a limited role of MRI in the treatment
planning for EBRT. The MR findings are used to assist or at
times co-registration with CT for contouring the GTV for
primary and nodal disease.

PET as a tool for diagnosis & staging:


Although, the involvement of para-aortic lymph node is
an important prognostic factor for cervical cancers, the
staging system used by FIGO-2009 is based on clinical
278

examinations only. FDG-PET has been shown to be a


reliable indicator of tumor involvement in the PALNs (5).
PET-CT Imaging has higher sensitivity, specificity and
accuracy as compared to MR and CT for pelvic and paraaortic lymph node detection (Paul Grant et al Semin Nucl
Med 44:461-478) for newly diagnosed cervical cancer FIGO
stage IB and has been recommended as a supplement to
the FIGO staging procedure.
PET Imaging based lymph nodal staging at diagnosis has
been shown to be an emerging prognostic factor for
disease progression and survival in a prospective cohort
study on 560 patients. (5)

PET-based RT planning & feasibility for dose


escalation:
The RTOG 7920 & RTOG 92-10 [6]studies have shown a
definitive improvement in survival in patients treated with
extended field RT encompassing the para-arotic lymph
nodes (PALN) electively but at the cost of significant bowel
toxicity.
PET Based pelvic and PALN Nodal mapping and contouring
with radiation dose escalation from 45 Gy/ 25# to 59.4
Gy/33# using IMRT technique is feasible with acceptable
toxicities. [7]
Clinical outcome comparison between conventional (2D/
3D) Vs PET Based IMRT has shown better outcome in terms
of both control rates and toxicities [6]
Pathological uptake detected on PET may modify treatment
strategy, either by extending radiation fields to the paraaortic area, or by modifying the total doses to the involved
nodes within the pelvis and/or the para-aortic area. [8]
279

PET-CT based RT planning in recurrent cervical


cancer :
Recurrent cervical carcinoma can also be salvaged with
radiotherapy PETCT helps in limiting the irradiated
volumes, especially to decrease the risk of complications
after surgery [9].
PET Based RT planning [extended field RT] in stage-IIIC
Ovarian & Endometrial cancers : No robust data / evidence
to define role of PET in advanced Epithelial or ovarian
Cancers for treatment or radiation therapy planning.
In a limited study of 40 patients with Stage IA to IIIC
endometrial cancers, overall node-based sensitivity,
specificity, and accuracy of PETCT were 53.3%, 99.6%,
and 97.8%, respectively [10]. Moreover, lymph nodal
dissection is the gold standard for treatment of endometrial
cancers.

Conformal Radiation Techniques:


Radical and Post-operative pelvic external
radiation:
Conventional 2 D Vs Conformal 3D Dosimetric
studies:
As compared to 3D technique, gross tumour volume (GTV)
was not entirely covered by the 95% isodose in 25%
patients in conventional 2D technique suggesting a
potential for geographical miss of primary tumor [11].
3D-CRT process allows for individualised shaping of all
the fields to the target thus allows greater shielding of
the organs at risk. The mean volume receiving at least
90% of the prescribed dose (V90) with conformal
280

radiotherapy relative to virtual simulation was reduced by


23%, 4%, 18% and 11% for the bladder, rectum, small
bowel and large bowel, respectively.[11].
Conventional, conformal & IMRT plans for cervical cancer
comparison showed that the average volume receiving
95% of the prescribed dose by the conventional,
conformal, and IMRT plans were 626 cc, 427 cc, and 232
cc for the bowel, for 101 cc, 90 cc, and 60 cc for rectum
and 89 cc, 70 cc, and 58 cc for bladder respectively. The
volumes of critical organs at this dose level were
significantly reduced using IMRT compared with
conventional and conformal planning (p < 0.02 in all
cases). [12]

Clinical outcomes (2D Conventional Vs 3D-CRT) :


There was reduction in bladder and bowel late
complications rates from 23% to 4% in patients receiving
post-operative adjuvant EBRT for endometrial cancer in
favour of 3D CRT as compared to conventional 2D planning
(A retrospective analysis in 301 patients).[13]
Reduction in bowel complications from 17.5% to 3% and
lymphedema from 28.6% to 3% was achieved in patients
treated withthree-dimensional planning using beams eye
view computed tomography simulation as compared to
patients treated with parallel opposing fields. [14]
However, there are no randomized studies reported so far
for a direct comparison between Conventional 2D Vs
Conformal 3D in radical setting for gynaecological cancers.

281

Conventional (2D / 3D) Vs IMRT


Dosimetric studies:
In the study mentioned earlier, volumes of critical organs
(bowel, rectum and bladder) receiving significant radiation
doses were significantly reduced by using IMRT compared
with conventional and conformal planning (p < 0.02 in
all cases). [12]
A meta-analysis of 13 dosimetric studies comparing 3Dconformal and IMRT treatment plans reported a 17.3%
reduction in volume of the small bowel receiving 45 Gy
and a 39.5% reduction in rectal volumes receiving 45 Gy.
No statistically significant decreases in bladder dose seen.
A significant mean volume reductions in small bowel,
bladder and rectum were detected (small bowel: -27%,
p=0.03; bladder: -41%, p=0.01; rectum: -26%, p=0.004)
but not for bone marrow volumes with IMRT. [15]
In post-operative pelvic radiation settings, IMRT has been
shown to offer higher than conventional conformal dose
distributions with better sparing of bladder, rectum, small
bowel & bone marrow for WPRT [RTOG 0418][18].

Clinical Outcome studies:


Toxicities:
A significant reduction in acute gastrointestinal (GI)
toxicities from 90% to 60% (grade 2) [16] and grade 1-2
from 80% to 36% [23] were reported with the use of
IMRT as compared to conventional 4 field box radiation
techniques.

282

A significant reduction in Grade 1-2 acute genitourinary


(GU) toxicities from 60% to 30% with IMRT has been
seen[16].
A statistically significant reduction in chronic
gastrointestinal toxicity, with a reduction in grade 2
toxicities from 16.7% to 2.8%, and grade 3 toxicity from
3.3% to 0% (p = 0.001) in patients with gynaecological
cancers treated with IMRT (40 patients) as compared to
conventional whole pelvis (35 patients) has been reported.
[16]
In a small randomized study of 44 patients, acute grade 2
acute gastrointestinal toxicities (31.8% Vs 63.6%, P=.034)
and grade 3 gastrointestinal toxicities (4.5% vs 27.3%,
P=.047) were significantly lower in favour of whole pelvic
IMRT arm. However, there was no statistical difference in
chronic gastrointestinal toxicity (13.6% vs 50%,
P=.011) [17].
Similarly, with respect to the improvements in acute
haematological toxicity profile, pooled outcomes show
rates of acute grade 3 or greater hematologic toxicity
ranging from 6% to 32% in bone marrow sparing IMRT
to 10 % to 65% in conventional RT techniques. [19]
In post-operative pelvic radiation settings, IMRT by virtue
of better sparing of bladder, rectum and small bowel may
reduce both acute and late toxicities in patients with
endometrial cancers [26,27].
In summary, use of IMRT in pelvic irradiation results in
better organ sparing which translates into significant
reduction in gastro-intestinal and hematologic toxicities.

283

Disease Outcome:
In the only prospective study of 135 patients treated with
IMRT, a disease free and overall survivals of 67% and 93%
at a mean follow-up of 22 months has been reported. In
this series, survival was improved and toxicity (acute and
chronic) was reduced with IMRT as compared to historical
patients treated with 3D CRT from the same institution.
Loco-regional failure was reported at 13%. [33].
Other series demonstrate 23 year DFS rates ranging from
51% to 68%, and loco-regional failure rates of 14% to
20% .These results compare very favourably to the results
of other small randomized trials where 3 year OS ranged
from 67% to 83%, 3 year PFS 59% to 78%, and 3 year
pelvic failures 11% to 25%. [20].
Similarly, in a prospective cohort study of 452 patients, a
significant benefit in favour of IMRT compared with nonIMRT regimens for overall survival (IMRT: 67.4% v. nonIMRT: 49.2%; p<0.0001) has been reported [16].
No phase III randomized studies comparing Conventional
Vs IMRT available. Mature results of Ongoing Phase II / III
randomized studies (NCT00193804 and NCT 01279135)
are awaited.

Volumetric Arc therapy (VMAT / Rapid Arc) IMRT


in Gynaecological Cancers:
Dosimetric studies: In a dosimetric study, Volumetric arcIMRT & fixed beam IMRT in Cervical Cancer resulted in
equivalent target coverage but VMAT had an improved
homogeneity (D5%D95% = 3.5 0.6 Gy for VMAT while
4.3 0.8 Gy for IMRT) and conformity index (CI90% =
1.30 0.06 for VMAT and 1.41 0.15 for IMRT). As
284

compared to IMRT, VMAT planning achieved a reduction


in doses to rectum (by 6 Gy) and bladder (by 2-3 Gy).
Similar trends but with smaller absolute differences were
observed for the small bowel. Also, there was a reduction
in integral dose by 12% with VMAT. The strong conclusion
of this dosimetric study was the treatment delivery time
(beam on time) was reduced by atleast half with VMAT.

Special Indications for Radiation in Gynecological


Cancers:
Extended Field Radiation Therapy (EFRT):
Dosimetric studies:
Better normal tissue sparing without changes in target
coverage was achieved with IMRT (Portelance et al)[21]
Radiation Dose escalation assisted by PET Imaging from
conventional 45 Gy/25 fractions to 60 Gy/25 fractions,
@2.4Gy/fraction) with PALN IMRT with significant normal
tissue sparing was achieved (Ahmed et al)[22]

Clinical outcome:
Small series with clinical outcome has been reported
(Beriwal et al, Grigsby et al)[23] .In this study, Thirty-six
patients with Stage IB2-IVA cervical cancer treated with
EF-IMRT were evaluated. The 2-year actuarial locoregional
control, disease-free survival, overall survival, and Grade
> or = 3 toxicity rates for the entire cohort were 80%,
51%, 65%, and 10%, respectively.
No high impact studies showing control rates and
toxicities have been reported so far.
Potential benefits of EFRT in high risk patients in prospective
studies are ongoing (EMBRACE II)
285

Whole Abdominal Radiation: Background:


Recurrence rate of 60-70% has been reported after
completion of planned standard treatment for epithelial
ovarian cancers and Stage III Endometrial Cancers. Whole
Abdomen Radiotherapy (WART) has been attempted as
adjuvant or as salvage approach with limited success.
In the era of Conventional Radiation techniques, WAR was
attempted but was limited by the following reasons:
-

286

WART is technically challenging because of


inadequate coverage of large target volume and poor
sparing of organs at risk (OAR) with risk of severe
toxicity.
RT doses higher than 30 Gy to whole abdomen and
pelvic doses are associated with higher incidence of
small bowel toxicities, requiring surgery.
However, a substantial benefit in progression free and
overall survivals have had a component of pelvic boost
in abdominal-pelvic radiation protocols has been
reported in a Norwegian randomized trial.
Other prescription of radiation doses between 20 and
30 Gy over 20 -25 fractions for WART and a boost
between 40.4 and 51 Gy has been reported.
Studies which have shown a substantial benefit in
progression free and overall survivals have had a
component of pelvic boost in abdominal-pelvic
radiation protocols. Pelvis is the also a major site of
relapse which is another rationale for including a
boost directed to this region.

Dosimetric studies
IMRT or IMAT has shown potential to achieve
sufficient uniformity to the target with improved
sparing of OARs. The prescribed doses reported range
from 30 Gy 33 Gy @ 1.5 Gy per fraction and pelvic
boost upto 44.4Gy. [24]
Dosimetric plans for IMRT and RapidArc /
Tomotherapy for prescribing 25 Gy to the whole
abdomen and 45 Gy to the pelvis and pelvic nodes
with Simultaneous Integrated Boost (SIB) technique
showed better liver, kidney and bone marrow sparing
with volumetric arc therapy. [24]
Clinical outcomes:
Epithelial Ovarian Carcimoma: In a retrospective review of
71 patients with Stage IIII ovarian carcinoma treated with
WART (median doses of 36 Gy to whole abdomen and 51
Gy to pelvis & 31 patients received chemotherapy after
completing WART) a 5-year overall survival rate of 93%,
48%, and 29% for Stage I, II, and III patients, respectively
with 21% of the patients developing RTOG Grade 3 or 4
chronic small or large bowel toxicity (11% requiring surgical
intervention) was reported. In subset analysis, a whole
abdominal dose >30 Gy and a pelvic dose >50 Gy were
associated with a significant increase in small bowel
obstruction (p < 0.01) independent of other factors. Two
patients had Grade 3 (RTOG) hepatic toxicity. Grade 3 or
4 renal toxicity (RTOG) was observed in 4%.[25].
Stage-III/IV Endometrial cancer: The WART in 174 patients
with Stage III and IV endometrial cancers with a prescribed
dose of 30Gy/20fx to the whole abdomen followed by
boost to the pelvis to a dose of 19.8Gy/11fx, reported
287

toxicities of 12.6% with bone marrow depression, 15%


GI, and 2.2% liver related toxicities with recurrence-free
survival rates of 29% and 27% (at 3 years) and overall
survival of 31% and 35% respectively. No patient with gross
residual disease survived.[26]

Image Guided Radiation Therapy (IGRT):



Pelvic organs are naturally prone to positional and
volumetric changes over time.

As a result, the pelvic anatomy at the time of
radiotherapy planning may differ from the pelvic
anatomy during treatment. These individual organ
changes may result in variations in the clinical target
volume (CTV) position and shape.

However, such patterns of internal organ motion is
of less important as the CTV is more likely to remain
within the irradiated volume in case of conventional
box radiotherapy techniques where the irradiated
volume encompasses the whole pelvis from the sacral
promontory to the obturator foramen.

But, in case of IMRT , in contrast to conventional RT,
the dose distributions are quite complex with
concavities and relatively steep dose gradients, which
implies that the potential impact of internal organ
motion needs to be revisited in order to avoid
geographical miss.

The successful implementation of IMRT relies on
accurate delineation of the CTV and selection of an
appropriate margin around the CTV to form the
planning target volume (PTV).

The CTV-PTV margin has two components: the
internal margin, which accounts for organ motion
288




A.

(uterus, cervix, organ filling etc.), and the set-up


margin for whole pelvis, which accounts for patient
set-up and delivery errors [28].
IGRT in GYN Cancers is mandatory with the use of
highly conformal techniques (IMRT, VMAT etc)
Various processes involved to define the IGRT
protocols are as follows :

Interfraction Organ Motion :

Movement of the Cervix :



Eleven studies (including a total of 160 patients of
cervical cancers) have examined the inter-fraction
cervix movement. Out of them, there were four studies
using computed tomography-based imaging
(computed tomography/megavoltage computed
tomography/four-dimensional
computed
tomography), two using magnetic resonance imaging
(MRI) and five using portal imaging with fiducial
markers.[27]

Motion was measured either at the cervix itself (centre
of mass, cervical os, cervical boundaries) or by using
fiducial markers as a surrogate.

Inter-fraction mean cervical movements ranged from
2.3 to 16 mm in the anterior-posterior, 2.7 to 8 mm
in the superior-inferior and 0.3 to 10 mm in the lateral
directions.

Most studies showed greater cervical motion in the
antero-posterior and superior-inferior directions.
However, heterogeneous nature of the data collection
makes direct comparisons difficult. Nevertheless,
studies using fiducial markers reported smaller
movements than other methods.
289

Uterine Movement :

Five studies reported inter-fraction uterine motion
[27]. The uterine fundus had more motion than the
uterine canal. Overall, the uterus moved more than
and independently of the cervix.

A further study reported uterine angle rotations of
300 or more in 18% of patients. The degree of rotation
was higher in patients under the age of 60 years.11%
of patients who had an anteverted uterus at planning
became retroverted during treatment [27].

An individual uterine rotation of 910 was reported,
with the fundus moving up to a maximum of 48 mm
in the anterior-posterior direction [27].
Lymph Node Motion

Inter-fraction nodal motion was assessed in two
abstracts [27]. Assessment of the elective nodal CTV
(obturator nodes and common, internal and external
iliac) showed median translations ranging between
7 and 30 mm [27].

Assessment of the motion of enlarged lymph nodes
using weekly MRI required inhomogeneous margins
of 5-9 mm to cover 95% of the volumes [27].
Overall Clinical Target Volume Motion
CTV motion (comprising pelvic nodes, cervix, uterus,
parametrium and upper vagina)was assessed in one study
using daily cone beam computed tomography (CBCT),
showing a predominance of anterior-posterior and
superior-inferior movement. [27]

290

B. Intra-fraction Organ motion :



Around seven studies examined intra-fraction organ
motion.The different techniques were used as follows
: cinematic-MRI, computed tomography and portal
imaging before and after each fraction. Intra-fraction
uterine & cervix motion had a mean range of 0.1-3.0
mm. Displacements greater than 5 mm occurred less
than 3% of the time, although the range of motion
increased with time. There was no predominant
direction of intra-fraction movement. The movements
of uterus and cervix are also dependent on rectal and
bladder filling. [27]
a.

Impact of Bladder Filling on Organ Motion :

The correlation of bladder filling with inter-fraction


cervix-uterine motion has been examined in 11 studies
including 217 patients.

Bladder volumes altered the position of the fundus


of the uterus in both anterior-posterior and superiorinferior directions and the effect was patient specific.
[27]

With variable bladder filling, ranges of fundus of


uterus motion of 5-40 mm in the superior-inferior
and 0-65 mm in the anterior-posterior direction has
been reported [27].

Those with a more consistent bladder volume


(variability <50 ml) on consecutive days had an
average superior fundus of uterus motion of 4.2 mm
compared with those with greater variability (>50
ml), who had superior motion of 11.2 mm. Bladder
filling had less impact on cervix motion than uterine
motion, with a 5.5 mm inferior and 3.9 mm anterior
291

shift in cervical position shown from empty to full


bladder [27]. So it is very important to establish a
reproducible bladder filling protocol for
implementation of newer radiation techniques in
cervical cancers with intact uterus and cervix.
One study examined the relationship of bladder filling
on small bowel position. The small bowel sparing
effect of IMRT correlated with bladder size (Pearsons
correlation coefficient 0.7).
Larger bladder volumes seemed to displace the small
bowel, reducing the volume receiving >50 Gy by 83
cm3 (range 0-292 cm3) [27].
Over the course of radiotherapy treatment, a
systematic reduction in mean bladder volume was
found in three studies. A decrease in mean bladder
volumes from 156 to 88 cm3 between the first and
last weeks of treatment was reported. For every 10 cc
decrease in bladder volume, the uterine fundus moved
18 mm inferiorly, the uterine canal moving 8 mm
inferiorly and the cervical os 3 mm anteriorly [27].
A retrospective analysis suggested that pre-treatment
bladder volumes may influence CTV-ITV margins
Larger (>115 ml) baseline. bladder volumes required
a greater (12 mm) inferior CTV-ITV margin than the 7
mm required for those with smaller volumes (<115
ml) [27].

b. Impact of Rectal Filling on Organ Motion



Five studies including 103 patients reported the
impact of rectal filling on cervix-uterine motion,
particularly in anterior-posterior and supero-inferior
movements [27].
292

A greater influence on cervical and upper vaginal


motion as compared with the uterus has been
reported. Significant correlations between rectal
volume and anterior-posterior shifts in the GTV, CTV
and upper vagina were noted, with correlation
coefficients of 0.71, 0.79 and 0.66, respectively. A 6
cc decrease in rectosigmoid filling corresponded to
inferior motion of the uterine canal (3.6 mm) and
cervical os (2.6 mm) [27].
A retrospective analysis showed those with pretreatment rectal volumes >70 cc required greater
posterior and inferior internal margins (20 and 12mm,
respectively), than those with a smaller baseline rectal
volume (<70 cc) (10 and 6mm). Although daily
variations in rectal volumes were reported (ranges
between 21 and 150 cm3), no systematic change
during the course of treatment was identified [27].
Tumor Regression during RT:
A 50% clinical response can be seen as early as
21 days during RT is noted. A 46% volume
reduction in the GTV after initial 30 Gy has been
reported. [12]
In another study, a mean cervical volumes
changed from 97 to 32 cc after treatment with
45 Gy of EBRT, resulting in a mean volume
reduction of 62%, with a median time to
regression of 20 days. [28]
However, it was noted that target volume
coverage by the 95% isodose line remained
adequate with tumor shrinkage, and when
repeat planning was performed after tumor
293

regression, no significant changes were noted


in doses to bladder and bowel, except for a small
subgroup of patients. [12] So, while shrinkage
of the primary tumor in intact cervix remains a
consideration, the clinical impacts seem to be
relatively minimal, although more studies are
needed to fully evaluate this effect.

Particle Beam Therapy / Hadron Beam Therapy :


Proton Beam Therapy:
In a small study of 25 patients with squamous cell
carcinoma of the uterine cervix (stages IIBIVA) who were
treated between 1983 and 1991with a curative intent by
external photon irradiation to the pelvis, followed by
proton irradiation (median proton tumor dose of 61 Gy
,range 37101 Gy, in three to four fractions weekly) to
the primary tumor, delivering a median total tumor dose
of 86 Gy (range 71 Gy/26 Fr101 Gy/46 Fr), and were
followed for a median period of 139 months (range 11
184 months, a 10 year overall survival rates for stages IIB
and IIIB/IVA patients were 89% and 40%, respectively has
been reported. The 5 year local control rates for stages IIB
and IIIB/IVA patients were 100% and 61%, respectively.
Severe (Grade 4 or more) late complications in the intestine
or urinary bladder were seen in 4% patients at 5 years.
[29]
Carbon Ion Therapy:
A single study evaluated the toxicity and efficacy of carbon
ion radiotherapy (CIRT) for locally advanced cervical cancer
by two phase I/II clinical trials. Between June 1995 and
January 2000, 44 patients were treated with CIRT. In the
294

first phase , the total dose range was 52.8 to 72.0 GyE
(2.23.0 GyE per fraction). In the second phase, the whole
pelvic dose was 44.8 GyE followed by boost to the cervical
tumor to a total dose 68.8 or 72.8 GyE .No patient
developed severe acute toxicity. In contrast, 8 patients
developed major late gastrointestinal complications. The
doses resulting in major complications were >60 GyE. The
5-year local control rate for patients in the first and second
phase was 45% and 79%, respectively. When treated with
>62.4 GyE, the local control was favorable even for the
patients with stage IVA disease (69%). Although the
number of patients in this study was small, the results
support continued investigation to confirm therapeutic
efficacy.[30].

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Salehpour MR, DSouza D, et al. A phase II multiinstitutional study of postoperative pelvic intensity
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cervical cancer while reducing dose to bone marrow
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ion radiotherapy for locally advanced carcinoma of
the uterine cervix. Int. J. Radiation Oncology Biol.
Phys., Vol. 65, No. 2, pp. 388397, 2006

299

Brachytherapy





Radical external radiotherapy +/- concurrent


chemotherapy and brachytherapy (BT) is the treatment
of choice for inoperable and locally advanced cervix
cancer.
BT is a vital component for improving outcomes (1).
Increasing the component of dose delivered using BT
results in improved outcomes (1).
Historical series evaluating replacement of BT by
conventional external radiation techniques have
resulted in poor outcomes.(2, 3)
With the advent of newer radiation techniques like
IMRT, Stereotactic radiotherapy etc., and dosimetric
studies to compare conventional BT dose distribution
have been reported.(4-6)These studies concluded
that:
High dose gradient of BT is not achieved (6).
IMRT /IMPT is inferior to MR based BT (5).
Comparison with advanced BT techniques is
lacking.

2D Orthogonal X-ray based Intracavitary BT and


clinical outcome

Addition of brachytherapy to chemo-radiation
improves local control by 5-10% depending on stage
of the disease

With EBRT +/- Concurrent chemotherapy followed
by brachytherapy, the following outcomes in terms
of local control rates and survival are reported (7)

300

Stage

Mean local control rate

5 year survival rate

IB

90%

85%

IIA

83%

78%

IIB

77%

65-70%

IIIB

44-66%

34-52%

IVA

18-48%

0-20%

Tod and Meredith(8) proposed the Manchester system


incorporating variable loading of an intracavitary
tandem and paired vaginal ovoids, which delivered a
constant dose rate to predefined points, irrespective
of the variation in size and shape of the uterus and
vagina. Salient features of Manchester system were
the following:
1. Defined BT treatment in terms of dose to points
A & B. These points defined were anatomically
comparable and in a region which was not
located in a very high dose gradient region.
2. They also designed a set of applicators and their
loading to give same dose rate irrespective of
the combination used.
3. Point A was described as a point 2 cm superior
to the mucosa of the lateral fornix of the vagina
and 2 cm lateral to the centre of the uterine canal
in the plane of the uterus., Point B was defined
as a point 5 cm from the midline and at the same
level as Point A.

301

Transition from 2D to 3D Image Based


Brachytherapy

ICRU-38 report published in 1985 gave
recommendations for reporting of dose and volumes
in intracavitary BT. The report suggested that the
concept of target volumes could be successfully
borrowed from external beam radiotherapy and gave
recommendations for the dose which should
encompass this volume.

ICRU 38 recommendations were as follows:
1. Description of technique used
2. Total Reference Air Kerma (TRAK)
3. Description of Reference Volume
4. Absorbed dose at reference points (Bladder &
Rectum points)
5. Time dose pattern

This mode of dose reporting, had the advantages of
easy reproducibility and wide applicability with
reasonable high accuracy even in resourceconstrained settings. However they had some notable
limitations which prevented wider adoption:
o Complex calculations involved in estimation of
the reference isodose volumes as well as nonuniform correlation with outcomes across all
stages(9).
o Poor correlation of doses at the bladder point
(10) and the rectal point (10, 11) with late
toxicity.

302

Introduction of 3D Image based brachytherapy:


The Groupe Europe en CurietherapyEuropean Society
of Therapeutic Radiation Oncology (GEC-ESTRO) has been
instrumental in formalizing the standards for 3D image
based brachytherapy since 2000. The major
recommendations that have been published by this group
deal with various aspects of images based brachytherapy
from applicator design to treatment. The evolution of 3D
Image Based Brachytherapy can be summarized as follows
1.
2.
3.
-

Imaging
Applicators
Treatment Planning
Volume definitions
Dose Volume Parameters reporting(Revised ICRU- 38
which is ICRU-GEC ESTRO recommendations)
Optimization
IMAGING: Various imaging modalities like CT, PET, MR,
US etc. have beed utilised to refine the 2D X-ray based
Intracavitary BT planning.


Multiplanar imaging capability, excellent soft tissue


contrast and the ability to characterize the primary
tumor through functional imaging make MRI as the
gold standard imaging modality for 3D Image Based
Brachytherapy. (12)
GEC-ESTRO IV Recommendations details out the MR
Imaging parameters, sequences and machine
technical parameters including strength with
applicators in situ etc (13). MRI (T2 sequence) offers
excellent soft tissue resolution. Tumor shows area of
high signal intensity which tends to stand out starkly
303

in contrast to the normal musculature, which is hypo


intense.

GEC-ESTRO Recommendations IV for MR Imaging


(13)
To exploit the full potential of MRI for the brachytherapy
application technique and to accurately define the target
volumes and the organs at risk, certain MR imaging criteria
have to be fulfilled:
o Pelvic MRI scanning prior to radiotherapy (Pre-RTMRI examination) and at the time of BT (BT MRI
examination) should be performed with one MR
imager.
o Multiplanar (transversal, sagittal, coronal and oblique
image orientation) T2-weighted images should be
obtained with pelvic surface coils.
o Use of complementary MRI sequences (e.g. contrastenhanced T1-weighted or 3D isotropic MRI
sequences) is optional.
Applicators
o Conventional stainless steel applicators do not allow
the OARs to be visualized clearly.
o New applicators made from polymer material and/or
titanium have been introduced which are CT/ MR
compatible and do not throw artefacts. However
these applicators are expensive and less durable as
compared to standard stainless steel applicators.
o GEC-ESTRO Recommendations III (14)mainly deals
with commissioning and applicator reconstruction for
image based brachytherapy to minimise geometrical
reconstruction errors which can lead to major dose
deviations in target and OAR.
304

Treatment Planning Process:


a. Standard Target Volume Definitions GEC ESTRO
Recommendation I (15)
Target volume assessment to be done by clinical
examination and Sectional MR imaging at
diagnosis and at BT
DVH analysis for a fixed dose and/or a fixed
volume
It deals mainly with MRI assessment of GTV and
CTV. The target volume concept was advanced
by means of the following nomenclature
1) Gross tumour volume at diagnosis (GTVD)includes macroscopic tumour extension at
diagnosis as detected by clinical examination
(visualisation and palpation) and as
visualised on MRI: high signal intensity
mass(es) at fast spin echo sequences (FSE)
T2 in cervix/corpus, parametria, vagina,
bladder and rectum.
2)

Gross tumour volume for brachytherapy


(GTV BT)- includes macroscopic tumour
extension at time of as detected by clinical
examination and as visualised on MRI: High
signal intensity mass(es) (FSE) T2 in cervix/corpus, parametria, vagina, bladder and
rectum. In patients treated with upfront
brachytherapy or with brachytherapy alone,
GTVBT is identical with GTVD.

305

3)

Two clinical target volumes were proposed:


a)

b.

306

High risk CTV (HR-CTV)-Tissue with a


major risk of local recurrence because
of residual macroscopic disease.
b) Intermediate Risk CTV (IR-CTV)-Tissue
with a major risk of local recurrence in
areas that correspond to initial
macroscopic extent of disease with at
most residual microscopic disease at
time of brachytherapy
Dose Volume Parameters Reporting: Based on GECESTRO Recommendations II (16).
Focuses on 3D Dose-Volume Parameters for BT
for cervical cancers.
Prefers reporting in terms of EQD2 which is
reproducible and can be compared with different
dose rate and dose fractionation schedules.
Also gives recommendations for recording and
reporting of 3D gynaecological brachytherapy.
Includes ICRU 38 recommendations, target
volume & applicator parameters:
o

Prescribed dose

Total Reference Air Kerma (TRAK)

Dose at point A (right, left and mean)

D100, D90 for GTV and HR CTV and IR CTV,


respectively

Dose to bladder and rectum for ICRU


reference points

D0.1cc,D1cc ,D 2cc for organs at risk (e.g. rectum,


sigmoid, bladder)

D5cc,D10cc for organs at risk if contouring of


organ walls is performed

Complete description of timedose pattern:


physical and biologically weighted doses
(BED / EQD2 calculation parameters:
/=10 Gy for GTV and CTV; /=3 Gy for
OAR; T1/2 = 1.5 h for GTV, CTV and OAR)

GEC ESTRO I & II recommendations are being adopted


and a revised ICRU 38 report as ICRU- GEC ESTRO Report
has been proposed

C. Optimisation
o First step in treatment planning in case of MR based
BT (IC+IS) is standard loading (Insitutional
Intracavitary BT practice) according to applicator size
and evaluation of dose distribution
o Manual optimization of dwell time / dwell positions
to improve therapeutic ration in case of intacavitary
alone (IC) is performed.
o In case of IC +IS application, the manual optimization
is expanded with appropriate loading of dwell
positions in needles and dwell times (usually not more
than 10-20% of Standard IC loading) to improve the
therapeutic ratio (target Vs Organ doses).

SUMMARY OF IGBT PROCESS

Brachytherapy - EUA, Appropriate CT/ MR compatible


Applicator with / without additional needles/ tubes
placement
307

MR Imaging Standardized Bladder filling protocol,


T2 axial, sagittal, coronal (3-5mm with 1 mm) (GECESTRO RECOMMENDATION-IV)
Contouring - Targets (GTV-B, HR-CTV, IR-CTV & Outer
walls of organs namely Rectum, Bladder, Sigmoid,
small bowel)(GEC-ESTRO RECOMMENDATION-I)
Planning
1) Catheter
reconstruction
(GEC-ESTRO
RECOMMENDATION-III)
2) Loading pattern (Standard with/ without Needles
loading ( < 15 - 20% only)
3) Optimization (Manual / Graphical)
Plan evaluation
1) EQD2 values (GEC-ESTRO RECOMMENDATIONII)
2) Doses to HR-CTV, GTV (D90, D100, V100 etc)
3) Doses to OARs ( rectum, bladder, sigmoid and
small bowel 0.1 cc, 1 cc, 2cc)

Clinical Evidence for 3D MR Image Based


Brachytherapy:
Many dosimetric as well as prospective studies have
established role of MRI guided brachytherapy in cervix
cancer.

DOSIMETRIC DATA:
o

308

The opportunities for selective dose escalation and


modification of the classical pear shaped isodose
curve, combined with selective sparing of OARs that
were enabled due to better visualisation on MRI were

exploited by means of a combined intracavitaryinterstitial applicator designed by the Vienna Group.


Using combined interstitial-intracavitary applicators
Investigators managed to achieve an additional 15mm
of coverage on the lateral side of either point A while
maintaining the same OARs doses and achieving
V 100(volume receiving 100% dose) of 93% in a
dosimetric study(17).
Subsequently the same group reported complete local
remission rate of 95% at a median follow up of 20
months in 22 patients with locally advanced
carcinoma cervix (18).
Recently published data from TMH in the form of a
validation study of 24 patients concluded that the
technique was feasible in an Indian setting. However
in view of the advanced nature of the cases, the target
volumes tended to be large and the D0.1cc and D2cc
doses to bladder and sigmoid were higher(19).
Investigators from Princess Margaret Hospital
compared 2D vs 3D (MRI based) planning for patients
with small cervix showed that with MRI-guided
brachytherapy optimization, it was possible to
maintain tumor coverage and reduce the dose to the
normal tissues, especially in patients with small cervix
where the target volume treated to 100% of the
intended dose approached 100% in all cases, and
the minimal D2cc of the rectum, sigmoid, and bladder
was 12%-32% less than with conventional 2D
brachytherapy planning (20).
Similar dosimetric results have been published by
Aarhus and Leuven for (after definitive chemoradiotherapy in advanced disease (21))
309

CLINICAL OUTCOMES
In a series of publications by the Vienna group, MR guided
BT has resulted in improved local control. For locally
advanced cervical cancer, local control rate achieved has
been as high as 85%, with complete remission rates in
range of 85 - 95%.
a.

b.

c.

MRI guided brachytherapy was added to 3D


conformal radiotherapy with cisplatin based
chemotherapy in 48 patients of advanced cervical
cancer, resulting in a 3 years overall survival of 61%,
progression free survival of 51% and pelvic control
rates of 85%.(22).
A subsequent report of 145 prospectively treated
patients from 1998 to 2003, showed that local control
rates in excess of 85% could be achieved with
improvement primarily noted in tumors > 5 cm.(23)
In a series of 156 consecutively treated with 3D CRT
with or without concurrent chemotherapy and MRI
guided brachytherapy, it was shown that 97 % local
complete remission rates were achieved. Overall local
control at 3years was 95%; 98% for tumours 2-5cm,
and 92% for tumours >5cm (p=0.04), 100% for IB,
96% for IIB, 86% for IIIB. Cancer specific survival at
3years was overall 74%, 83% for tumours 2-5cm, 70%
for tumours >5cm, 83% for IB, 84% for IIB, 52% for
IIIB.(24)

OVERALL SURVIVAL
Since locoregional failure is the primary mode of failure in
cervical cancers, improved loco-regional control may
translate into a significant improvement in overall survival,
especially in locally advanced disease
310

a.

b.

c.

In a series of 145 patients, Improvements in overall


survival from 53% to 64% (p=0.03) and cause specific
survival from 62% to 74% (p=0.13) were observed
after MRI based planning was incorporated into the
protocol in 2001. The improvement was only for
tumours >5cm.(23)
Finally, in a series of 156 patients, achieved overall
survival at 3 years was 68% (74% for IB, 78% for IIB,
45% for IIIB) , with survival being 65% for tumors
greater than 5cm , and 3 year cause specific survival
rates of 74%( 83% for IB, 84% for IIB, 52% for
IIIB).Compared to the historical series treated at the
same institution , there was a 65-70% reduction in
local recurrences ,coupled with a significant reduction
in late morbidity. (24).
In EMBRACE study, One year actuarial survival rate of
94 % was achieved. (25)

Toxicities
Robust data for toxicity in patient treated with IGBT is
lacking. Preliminary data from Vienna group reported no
grade III/IV GI toxicity (22).
In EMBRACE study, out of 305 patients, only 3 pts have
experienced G3 morbidity (oedema, pain, osteo and soft
tissue radionecrosis) and 2 pts G4 vaginal stenosis. No
G3-4 bladder and gastro-intestinal morbidity was seen.(25)
A recent publication from the same group has shown a
Grade 3 or more vaginal toxicity rate of 3.6% at 2 years
which is significantly lower than that reported in previous
series. (26)

311

Reasons for limited use of MR based Brachytherapy


in current practice:
o Conventional stainless steel applicator cannot be used
o MR not universally available in Oncology Centers or
Radiation Oncology Departments
o MRI compatible applicators are expensive
Attempts to replace MRI by various other Imaging
modalities like CT, PET, US etc. has been tried and is still
area of current research. Some of the early reports with
alternative imaging have been described

CT Imaging:

The wide spread availability of CT imaging coupled
with its cheaper cost makes it one of the most
attractive alternatives to MRI for image based
brachytherapy.

With the use of appropriate intravenous and bladder
filling protocols and details of tumor extension at
diagnosis and BT CT based contouring for various
organs and to some extent CTV at BT is feasible.
Limited studies have compared the efficacy of CT as
compared to MRI during BT.(27-29)
1) CT was found to overestimate the width of the
high & intermediate risk tumour volumes
(27).However total volume measurements, and
dose volume parameters to sub-volumes of OARs
were found to be similar (27-29).
2) The CT volumes tend to underestimate disease
in its cranio-caudal extent, and over-estimate
disease in its lateral extent. This is probably a
consequence of the inherent limitations of CT in
312

terms of soft tissue resolution as compared to


MRI.

PET Imaging:

Positron emission tomography has the capacity to
provide biological information about the tumour
which cannot be provided by anatomical imaging.

Due to poor spatial resolution it must be
supplemented by anatomical information which to a
large extent done by hybrid PET-CT scanners now.

PET based brachytherapy was deemed feasible in
planning studies (30) with reasonable accuracy of
applicator reconstruction in the axial direction of
2mm, however reconstruction uncertainity in the
craniocaudal direction was 4.3 mm, which may not
be satisfactory given the steep fall off of brachytherapy
doses.

When supplemented by CT information as is possible
with PET-CT scanners, FDG-PET base treatment plans
have been found to be superior to conventional
treatment planning in terms of target coverage,
without increasing dose to organs at risk, and also
resolving dilemmas where masses appeared
indeterminate on CT alone (31).

However no robust clinical data are available.
Ultrasonography:

Ultrasonography has certain distinct advantages in
its use as a tool to assist optimal brachytherapy
insertion (Real time Image guidance).

It is a widely available and inexpensive modality. Transabdominal Ultrasonography can be used to accurately
313

314

distinguish the limit & extent of the uterine wall and


therefore allows one to detect inadvertent perforation
of the uterus during applicator insertion. It can also
identify with reasonable accuracy the location of the
cervix and the extent of disease in the cervix,
particularly central disease.
Study have shown that there is no significant
difference between the target volume as defined by
ultrasound and MRI (32), therefore one can surmise
that USG offers comparable anatomical detail when
contrasted against MRI, allowing adequate doses to
be delivered to the target and reducing the chances
of a miss. In addition, the same study showed in
significant differences between doses delivered to the
ICRU bladder points and vaginal mucosal points
between plans generated on MR & USG images.(33)
A comprehensive study done to compare USG findings
relevant for brachytherapy with MRI findings was
carried out in an Indian setting, which found
reasonably strong correlation between USG & MRI
findings, on the basis of comparison of reference
distances calculated from nine reference points (D1D9) with respect to central tandem & flange. However
it particularly noticed that points placed in reference
to the anterior surface had a stronger correlation with
distances measured on MRI, than the points
representing the posterior surface. This was attributed
to the loss of echogenicity while traversing the uterine
wall. Therefore given the resource limitations in a
typically overburdened under-equipped developing
world sitting, ultrasound in trained hands remains
an excellent modality for ensuring propriety of

insertion, adequacy of coverage of tumor & sparing


of normal tissue and ultimate improvement of
outcomes in cervical cancer(34) Ultrasound has several
important limitations, chief among which are its
pronounced operator dependence, and the fact that
physiological variations like retroversion and flexion,
and pathological conditions like pyometra can
significantly alter image acquisition.

Endometrial Cancers

Endometrial cancer is the most common gynecologic
malignancy in developed world.

Early-stage endometrial cancer can usually be treated
with surgery with or without radiation therapy.
Adjuvant radiation therapy (external-beam pelvic
radiation and/or vaginal cuff brachytherapy) has been
shown to decrease local recurrence.(35)

Locoregionally advanced endometrial cancer is treated
with a combination of surgery, radiation therapy, and
chemotherapy.(35)
Early Endometrial Cancer:

Vaginal brachytherapy has been shown to be
equivalent to whole pelvic radiation therapy in
achieving local control and providing reasonable
disease-specific and overall survival in patients with
high-intermediate-risk endometrial cancers(36-38).

These findings apply to all patients regardless of
whether they have undergone a comprehensive
surgical staging procedure. Vaginal brachytherapy is
associated with significantly fewer gastrointestinal
toxic effects as well as a better quality of life (36-39)
315

Vault BT
Applicators

In current practice, there are variations in applicators
used in vaginal vault brachytherapy, such as vaginal
ovoids or colpostats, custom-made vaginal moulds,
but most commonly used is a single line source in a
rigid vaginal cylinder

The choice of applicator for treatment of the vagina
is both patient- and institution-dependent.

Some applicators, including vaginal ovoids and the
Houdek vaginal applicator, will treat only the vaginal
cuff; whereas,vaginal cylinders can treat the entire
vaginal canal, including the introitus, if desired. In
some patients, the vagina may have adog-ear
configuration that is better treated by vaginal ovoids.
Dose

For brachytherapy alone (36)
o LDR 30 Gy at 0.5 cm
o HDR 7 Gy x 3 at 0.5 cm

Boost dose: (after 50.4 Gy)
o LDR 20 Gy at surface (at dose rate 0.8-1.2 Gy/
hr)
o HDR 6 Gy x 2 at surface (=12 Gy)
Prescription

ABS recommends reporting doses at both the vaginal
surface and at 0.5-cm mucosal depth.(40)
Length of vagina to be treated

It is recommended that the proximal 35 cm of the
vagina be treated.
316

For serous and clear cell histologies, treatment of the


entirevaginal canal should be considered.(40)

Need for Individualized Image based


brachytherapy planning

In a study carried out of 25 patients receiving vaginal
vault brachytherapy. It was found that 8 out of 25
patients had air gaps >2 mm in the superior 2
cm of vagina (41)

Another study (42) found 90 air pockets in 150
procedures for a cohort of 25 patients, 80% having
one or more air pockets. Air gaps between the
applicator and the vaginal wall can potentially reduce
the dose to the clinical target volume (CTV), which in
this case is the mucosal lymphatics of the upper
vagina.

In a retrospective study it was shown that use of an
individualized prescription depth resulted in
significantly lower rates of late toxicity as compared
to a standard prescription based on 5 mm depth.
While local control rates were not different, further
prospective validation is recommended.(43)

Advantage of bladder filling during vaginal cylinder
brachytherapy was demonstrated in dosimetric study.
Treatment with a distended bladder preferentially
reduces high dose to the small bowel around the
vaginal cuff without a significant change in dose to
the bladder, rectum, or sigmoid (44).
Advantage of Image guidance
Use of image guidance helps to optimise doses to target
volume and avoid inhomogeneity due to air pockets.(45)
317

For OAR Sparing Since no separate data are available


for OAR dose tolerance in endometrial cancer in the setting
of brachytherapy standard practice is to constraint doses
as per the recommendations for cervical cancer
brachytherapy
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328

Urology Cancers
Prostate Cancer
1. ELEMENTS OF RADIATION THERAPY
PRACTICE


Cancer of the Prostate is a major health concern


among males worldwide with incidence of 8.9 lakhs
per year per 1000(1). In India, it is the 8th most
common cancer among men.
As approximately 90% of men have disease confined
to the prostate, treatment goals are to prevent death
and disability from prostate cancer while minimizing
intervention-related complications. Treatment options
include watchful waiting (expectant management or
active surveillance), radical prostatectomy, externalbeam radiation therapy (EBRT), brachytherapy, and
androgen deprivation(2).
After the appropriate assessment of tumour extension,
the choice of treatment is made based on a
multidisciplinary approach, taking into account the
TNM classification, Gleason score, baseline PSA, age
of the patient, comorbidity, life expectancy and quality
of life.
329

Approximately 50% of men with localized prostate


cancer undergo radical prostatectomy and 25%
receive external beam radiation and brachytherapy,
in the western world(3). There are no randomized
studies that compare radical prostatectomy with either
external beam therapy or brachytherapy for localized
Ca Prostate. However, non-randomized data have
shown that external irradiation provides a quality of
life at least as good as that provided by surgery.

2. EVOLUTION OF RADIATION THERAPY


IN CARCINOMA PROSTATE:


330

In the last two decades, technological improvements


in the delivery of EBRT have improved the ability of
radiation oncologists to target radiation to the
prostate with better sparing the surrounding normal
tissue.
With improvements in conformal radiation delivery,
there arose a need to adapt the delivery to the prostate
motion. Movement occurs primarily in the anteriorposterior direction, although it also occurs in the
superior-inferior and lateral directions. To address
these concerns, a number of daily prostate localization
techniques have been developed. A common
technique utilizes a trans-abdominal ultrasound to
daily localize the prostate during the delivery of a
fractionated course of radiotherapy. Other approaches
involve, imaging implanted radio-opaque fiducial
markers, electromagnetic implantable transponders
(Calypso) and using daily KV/MV computed
tomography (CT). The ability to image the position of
the prostate on a daily basis has allowed the

development of image-guided radiotherapy (IGRT),


where imaging has helped to reduce set-up errors
caused by organ motion and thus has improved the
overall accuracy of treatment.

3. SUMMARY OF INDICATIONS FOR


RADIATION THERAPY
1.

2.

3.

4.

T1c-T2c N0 M0: 3D-CRT with or without IMRT,


is recommended. Dose escalation is
recommended for intermediate risk patients.
Interstitial brachytherapy may be performed on
patients cT1-T2a, Gleason score < 7 (or 3+4),
PSA < 10 ng/mL, prostate volume < 50 mL,
without a previous TURP and with a good IPSS
(International Prostate Symptom Score).
In locally advanced prostate cancer, OS (Overall
Survival) is improved by external irradiation along
with total androgen blockade (for a total
duration of 2-3 years).
Immediate postoperative external irradiation
after radical prostatectomy for patients with
pathological tumour stage T3 N0 M0 prolongs
biochemical and clinical disease-free survival.
Alternatively, RT can be reserved and used at the
time of biochemical failure but before PSA
reaches above 1-1.5 ng/mL.

4. Volume and Field Delineation:




In primary RT, the CTV, is the prostate SV volume


plus consideration of additional margin in areas where
the GTV is perceived to contribute to a risk of extension
beyond the gland.
331

The CTV for low- and intermediate-risk (T1T2)


patients includes the prostate proximal SV
(10 mm). In high-risk patients, the CTV1 includes at
least 50% of the SV, in addition to the prostate and
any extra-prostatic extension.
In the high risk patients, the nodal CTV comprises of
the external iliac, obturator, and internal iliac lymph
nodes.
The planning target volume (PTV) is defined as the
CTV with a margin to account for physical
uncertainties including setup reproducibility and interand intra-fraction organ motion.

5. IMAGING, LOCALIZATION &


REGISTRATION
1.

332

Inconsistencies in contouring are the result of


poor definition of the prostate relative to adjacent
structures and wide variation in anatomic
position relative to the pelvic bones. Magnetic
resonance imaging considerably resolves these
boundaries and makes accurate contouring of
the prostate more consistent. In addition, MR is
less sensitive to imaging artifacts and allows
better delineation of treatment volumes. MR
based prostate volumes correlate with ultrasound
volumes; CT prostate volumes are about 30% to
40% larger than MR volumes. However, current
planning algorithms are based on CT, making CT
MR fusion the best approach to define the
prostate, seminal vesicles, and pelvic lymph node
regions(5).

2.

3.

Fusion of CT and MR is fraught with potential


problems that could lead to significant errors if
not performed appropriately. The CT should be
used primarily and the MR only used as a
reference because of the inherent problems with
the accuracy of the fusion. The position of the
prostate on MR may be substantially different
from that on the CT because of bladder and rectal
filling. The random error for CTMR registration
along the three spatial directions is estimated to
be on the order of 0.5 mm and around 0.4 in
rotation (standard deviation) for each axis.
Because MR is better than CT in determining
extracapsular extension and seminal vesicle
involvement, the clinical target volume (CTV) may
be modified more accurately by using MR to
include additional margin for subclinical spread
in these areas(6).
Seminal vesicles can vary in size and differences
in dimension between the right and left SV have
been reported. Contouring of seminal vesicles
and prostatic apex, similar to that of prostate, is
better done on MR because of enhanced
anatomic detail. The bulb of the penis is attached
superiorly to the inferior surface of the urogenital
diaphragm and is best visualized on T2-weighted
(T2w) MR images as an oval-shaped,
hyperintense midline structure. Although the
penile bulb can also be identified on CT imaging
and transverse trans-rectal ultrasound, MR is best
for the superior and inferior aspects. Contouring
should stop inferiorly when the bulb loses the
333

4.

5.

6.

334

lateral bulging aspects of the corpus


spongiosum(7).
The sparing of the penile bulb, corporal bodies,
and neurovascular structures has sometimes
been associated with increased preservation of
erectile function, but results have been mixed.
Intensity-modulated RT reduces the dose received
by the penile bulb, as shown by some authors.
Regarding the relationship between the penile
bulb dose and the development of erectile
dysfunction, some studies have not shown any
significant association between the dose received
and the development of erectile dysfunction,
whereas other studies have found a significant
relationship between the doses received by the
proximal penis and the incidence of erectile
dysfunction and Roach et al. advocates keeping
the penile bulb dose to less than 52.5 Gy.
Magnetic resonance proton spectroscopy, DWI
(Diffusion weighted imaging), and DCE-MR
(Dyanamic contract enhanced MRI) have been
used to image the prostate to determine tumor
location and extent. Localization accuracies of
greater than 80% may be achieved by combining
these methods. Each has shown promise when
combined with T2w MR. Several alternatives of
gray-scale ultrasound for visualization of prostate
cancer have been considered(8). The principal
modalities competing with MR have been
contrast- enhanced ultrasound (CEUS), and
positron emission tomography (PET) performed
with 18F-fluorocholine and 11C-choline.

6. MODALITIES FOR IMAGE GUIDANCE :




Due to many physiological reasons, the expected


position and shapes of prostate, seminal vesicles and
pelvic lymph nodes can change from day to day (interfraction changes) or during an individual delivery
(intra-fraction changes). These changes can result in
motion or deformation of the targeted areas. Since
external radiation therapy, unlike surgery or
brachytherapy, is delivered in multiple fractions,
variability in the internal anatomy of patients from
day to day can affect the precise targeting. Fractions
can vary in number anywhere from 5 (defined as
Stereotactic Body Radiotherapy) to 45, with the course
of treatment ranging from 2 weeks to 9 weeks.
A multitude of techniques are currently utilized for
daily prostate localization such as trans-abdominal
ultrasound, intra-prostatic metallic fiducials detected
with in-room X-rays or CT scans, and electromagnetic
tracking(911).They are described below:
1. Trans-abdominal ultrasound: This is available for
daily prostate localization and does not require
implanted metallic fiducials. However, it suffers
from notable inter-user variability, with large
variations in the rates of usable images and the
accuracy of alignments. Compared to positioning
with implanted markers, the accuracy of transabdominal ultrasound has also been suboptimal.
2. On-board MV imagers: Electronic portal imaging
can be done using either the treatment beam to
get a 2D X-ray images, or an X-ray imager
mounted on the gantry of the treatment
335

3.

4.

336

machine. Typically, metallic fiducial markers are


implanted in the prostate and used as surrogates
for the position of the prostate. All standard
linear accelerators are capable of obtaining EPIs
(Electronic portal images), and most have onboard imagers. However, the process to obtain
these images is somewhat slow. The quality of
images is sub-optimal when the treatment beam
is used, requiring relatively large size fiducials.
With the latest generation machines, on-board
imagers are better integrated and provide better
quality images. However, they still are relatively
inefficient in obtaining frequent images during
treatment delivery.
Stereoscopic X-rays:This consists of 3D X-ray imaging
systems that are not dependent on the treatment
beam from imaging and are mounted in the room to
obtain good resolution X-ray images that can be
utilized for efficient and accurate target localization.
Cone-beam CT: Megavoltage cone beam CT scans are
useful to assess the anatomy in greater detail,
specifically assessing the normal tissues such as the
rectum or the bladder. Metallic fiducials can be used
since they decrease the inter-user variability of
interpreting the position of the prostate on the CT
images. These are obtained immediately prior to
therapy. Due to the inefficiency and increased
radiation dose of repeat imaging, CT images are not
used for tracking target areas while the radiation is
delivered, but only immediately before the delivery.
Recording of transit dose for dose reconstruction is
an active area of investigation.

5.

6.

Electromagnetic Tracking: This system requires the


implantation of implanted beacon transponders. The
beacons are then electromagnetically detected. This
provides continuous, real-time localization and
monitoring information. This is a non-ionizing IGRT
treatment option where real-time data on prostate
motion provides feedback to the treatment machine.
Little interpretation is needed of the localization
information, unlike the necessity of analyzing images
in other techniques. The main advantage of the system
is its ability to track positions continuously.
Gold Fiducials: To visualize the postoperative prostate
bed and to facilitate target alignment in the delivery
of EBRT, gold seed fiducials are implanted into the
tissues of the prostate bed trans-rectally under
ultrasound guidance before treatment planning. As
in the treatment of the intact prostate gland, daily
EPID images are acquired before each fraction. Online
compensatory patient shifts are then made to align
the gold marker seed positions on the daily portal
image with their position on the DRR.

7. DOSE ESCALATION IN CARCINOMA


PROSTATE:


Conformal radiotherapy techniques, including


IMRT,have been used to deliver higher than standard
radiation doses (exceeding 80 Gy) without dramatic
increases in toxicity rates(12,13). There is a clear
radiation dose response with respect to biochemical
failures. Clinically relevant outcomes such as local
failure and/or distant failure have been impacted by
radiation dose in all risk groups; radiation dose was
337

338

demonstrated to be associated with less local or


distant failure independently from risk groups defined
by T stage, pretreatment PSA and biopsy Gleason
score.
Two randomised trials focused on clinical stages T13 N0 M0 paved the way for dose escalation. The MD
Anderson study(14) comparing 78 Gy with 70 Gy
conventional radiotherapy included 305 stage T1-3
patients with a pre-treatment PSA level of more than
10 ng/mL and, with a median follow-up of 8.7 years.
It showed a significant increase in freedom from
biochemical and/or clinical failure for low-risk patients
(p = 0.04). The PROG 95-09 study evaluated 393
T1b-T2b patients, of whom 75% had a Gleason score
< 6 and a PSA < 15 ng/mL. Patients were randomised
to receive an initial boost to the prostate alone, using
conformal protons of either 19.8 Gy or 28.8 Gy, and
then 50.4 Gy to a larger volume. With a median
follow-up of 5.5 years, there was a significant increase
in 5-year freedom from biochemical failure (p <
0.001) in favour of low-risk patients given a higher
dose (79.2 Gy) versus those given a conventional dose
(70.2 Gy)(15).
Many non-randomised studies have shown that dose
escalation (range, 76-81 Gy) has a significant impact
on 5-year biochemical relapse free survival for patients
with cT1c-T3 cancers. A Dutch randomised phase III
trial(16) comparing 68 Gy with 78 Gy showed a
significant increase in 5-year freedom from clinical or
biochemical failure for patients in an intermediaterisk group. The phase III trial of the French Federation
of Cancer Centres comparing 70 Gy with 80 Gy(17)

in 306 patients with a pelvic lymph node involvement


risk of < 10% (Partin) or pN0, showed that with a
median follow-up of 59 months, a high dose should
provide a better 5-year biological outcome in
intermediate-risk patients, especially if the initial PSA
> 15 ng/mL.
In high risk patients, a Dutch study(16) comparing
68 Gy with 78 Gy showed a 10% increase in the 5year freedom from clinical or biochemical failure (p
= 0.02). The MRC RT01 study(18), comparing a dose
of 64 Gy with 74 Gy, both with neoadjuvant hormonal
therapy, showed an 11% difference in 5-year
biochemical disease-free survival.
With respect to toxicity, dose escalation to the 78-80
Gy range has been associated with relatively minimal
increases in toxicity rates. A recent report of a large
trial comparing different dose groups from 68.4 to
78.0 Gy observed that a mild increase in rectal and
urinary morbidity was observed with the higher
radiation doses. The urinary and gastrointestinal grade
3 and higher toxicity events were observed in 6% and
7% of the patients who were in the highest dose
groups. These are overall relatively low toxicity
rates(12). Although complications, in general, have
remained relatively minimal, increasing doses to
increasing rectal volumes does result in increased
rectal bleeding. The typical limits used to minimize
rectal toxicity are: 1) limit volume receiving >70 Gy
to <25% of the rectal volume (more stringently
<15%), or 2) limit volume receiving 78 Gy to <10 cc
of the entire rectum. However, changing daily
anatomy can result in unexpected low or high
339

cumulative doses within normal structures, particularly


the rectum.
Urinary toxicity is more difficult to correlate with
bladder dose/volume parameters. However, a limit of
<25% of the bladder to receive >65 Gy has been
typically used. Finally, with respect to potency after
radiation therapy, the results are highly variable for a
multitude of reasons. A recent review of the literature
showed that 44-100% of patients are potent prior to
radiotherapy. Post radiotherapy, the potency rates
reported are 27-65% evaluated at different time
intervals ranging from 12-78 months. However, if
patients were potent prior to radiotherapy, 46-65%
of patients retain potency after radiotherapy(13).
These ranges indicate the heterogeneity of patient
cohorts and the heterogeneity of methods of
evaluating and reporting on potency after treatment
in localized prostate cancer patients. With respect to
treatment planning, there is data emerging that the
doses to the penile bulb / crurae are important in
predicting radiation induced impotence. Typically, a
limit of <50% of the penile bulb to receive >50 Gy is
a reasonable guideline with respect to the evaluation
of treatment plans. However, there is still controversy
about the correlation between penile bulb doses and
post-treatment potency status.

8. INTENSITY MODULATED
RADIOTHERAPY (IMRT):


340

With 3DCRT, multiple shaped radiation beams were


used to limit dose to structures other than the
prostate, however with escalation of the radiation

dose, there were limitations in its ability to constrain


high doses of radiation to the immediately adjacent
bladder and rectum. In light of the experience with
higher toxicity rates in in the dose-escalation
randomized trials using 3DCRT, there was significant
interest in new treatment delivery approaches. The
dosimetric improvements in the conformality to the
target are likely major contributors to the widespread
adoption of IMRT for prostate cancer, with a rise from
<5% to >95% of external beam cases between 2000
and 2008 in men older than 65 years(19,20).
Although there is paucity of randomized controlled
trial comparisons of IMRT and 3DCRT, several studies
have investigated directly whether IMRT results in
fewer toxicities than 3DCRT. The RTOG Protocol
0126(21) was a randomized trial comparing standarddose (70.2 Gy) versus dose-escalated (79.2 Gy)
radiation therapy for intermediate-risk prostate cancer.
The study further stratified between IMRT and 3DCRT
in the high-dose arm, and a 38.5% risk reduction
was observed in the composite of grade 2 or higher
GI or genitourinary acute toxicities with the use of
IMRT. In another larger, single-institution,
nonrandomized series of 1571 men, the 10-year
likelihood of developing grade 2 or higher GI toxicities
was reduced from 13% to 5% with the use of IMRT
compared with 3DCRT despite treating to higher
doses with IMRT(22).
The Memorial Sloan-Kettering Cancer Centre reported
on 772 patients treated between 1996 and 2001 with
doses ranging from 81 to 86.4 Gy using an inverse
planning approach. With a median follow-up time
341

of 24 months (6-60 months), the 3-year actuarial


likelihood of > late grade 2 rectal toxicity was 4%;
the 3-year actuarial likelihood of > grade 2 urinary
toxicity was 15%; and the 3-year actuarial PSA relapsefree survival rates for favourable-, intermediate- and
unfavourable-risk group patients were 92%, 86% and
81%, respectively(23).
Most of the studies compared treatments between
3DCRT and IMRT for prostate radiotherapy alone. The
role of pelvic radiotherapy in the management of
prostate cancer remains controversial; however, if
used, whole pelvic radiotherapy may exacerbate acute
and late GU and GI side effects due to increased
volumes of normal tissues irradiated versus prostate
only radiotherapy. The role of IMRT for normal tissue
sparing in the setting of whole pelvic radiotherapy
remains an area for continued investigation.
Likewise, the use of IMRT for the treatment of patients
in the postoperative setting (either adjuvant or
salvage) remains an area of investigation. The nature
of regional (versus localized) postoperative treatment,
the lower radiation doses required, and the lack of
consensus around target volumes (prostate bed
definition, requirement to treat pelvic nodes) and
image guidance strategies (in the absence of a welldefined target following prostate removal) creates less
certainty as to the degree of benefit of IMRT
techniques in this setting.

9. HYPOFRACTIONATION


342

The rationale behind shortening radiation therapy


courses in prostate cancers has been the greater

sensitivity to dose fractionation, with an assumed


improvement in the therapeutic ratio with the use of
large fraction sizes. Large fraction size delivery can
only be achieved over small volumes, thereby requiring
adequate shaping and targeting. In addition, large
fraction size would indicate a shorter treatment
course, increasing convenience for patients(24).
Modern high-dose hypofractionated radiotherapy has
been performed with a variety of schedules ranging
from 2.1 to 10 Gy per fraction, and total radiation
doses ranging from around 33 Gy to 75 Gy. The
shortest treatment schedules have consisted of only
5 fractions and the treatment has been termed
Stereotactic Body Radiotherapy which is defined as
5 fractions or less.
A growing literature derived from retrospectively
reviewing outcomes in treated men suggests that the
/ for prostate cancer may in fact be quite low. These
data have supported the investigation of 2 general
types of hypofractionation: moderate, in which 2.4Gy to 4-Gy fractions are used, and extreme, in which
fraction sizes range from 6.5 to 10 Gy.
Moderate hypofractionation: Many randomized trials
have compared moderate hypofractionation with
standard fractionation in localized prostate cancer. A
936-patient trial(25) comparing 66 Gy in 2-Gy
fractions versus 52.5 Gy in 2.625-Gy fractions found
a 5-year biochemical failure rate of 53% in the
standard arm and 60% in the hypofractionated arm,
resulting in a failure to establish the noninferiority of
the shorter course treatment. A smaller study(26) that
randomized men to 64 Gy in 2-Gy fractions or 55 Gy
343

344

in 2.75-Gy fractions showed an improvement in


disease control at 7.5 years in the hypofractionation
arm without associated greater late toxicities.
However, in both studies, the acute toxicities were
worse in the hypofractionated arms. Three modern,
moderate hypofractionation studies(25,27,28) have
used 75.6 to 80 Gy in 1.8-Gy to 2-Gy fractions in the
standard arms and compared them with 62 to 72 Gy
in 2.4-Gy to 3.1-Gy fractions, thereby reducing
treatment times from nearly 8 weeks to 4 to 6 weeks.
With approximately 5 years of follow-up, none of
these 3 studies identified significant differences in
either disease control or GU or GI toxicities between
the 2 arms. The Fox Chase Cancer Center, randomized
307 men with intermediate-risk and high-risk prostate
cancer to receive 76 Gy in 2-Gy fractions or 70.2 Gy
in 2.7-Gy fractions. The 5-year biochemical diseasefree rate was 21.4% in the conventional arm versus
23.3% in the hypofractionated arm. The overall
incidence of grade 2 or higher late GI toxicity was
22.5% versus 18.1% in the standard and
hypofractionated arms, respectively; and, for late GU
toxicity, the overall incidence was 13.4% and 21.5%,
respectively. Available data have demonstrated that
moderately hypofractionated radiation can be
delivered with acceptable acute side effects and that
disease control and late toxicities appear comparable
to those of standard fractionation. However, longterm efficacy results from noninferiority trials are
needed before hypofractionation can confidently be
widely adopted.
Extreme hypofractionation: Men with low-risk,
intermediate-risk, and high-risk prostate cancer have

been treated on the published extreme


hypofractionation studies with fraction sizes ranging
from 6.7 to 10 Gy. In a phase I/II study(29), 40 men
with low-risk disease received five 6.7-Gy fractions to
a total dose of 33.5 Gy. With 41 months of followup, 10% of patients had evidence of disease
recurrence, and 20% and 7.5% had grade 2 or higher
late GU and GI toxicities, respectively. In the RTOG
protocol(30), dose escalation from 45 Gy in 9-Gy
fractions to 50 Gy in 10-Gy fractions was tested; and,
with less than 3 years of follow-up, 1 late grade 4 GI
toxicity was identified. Pooled outcome data on 1100
men with low-risk (58%), intermediate-risk (30%), and
high-risk (11%) prostate cancer who received extreme
hypofractionation to 35 to 40 Gy in 5 fractions and
were followed for a median of 36 months indicated
relapse-free survival rates of 95%, 84%, and 81%,
respectively. A randomized phase 2 study is currently
underway through the RTOG comparing five 7.25Gy fractions with twelve 4.3-Gy fractions.
The widespread adoption of moderate
hypofractionation for prostate cancer has not yet
begun as we await results from large noninferiority
trials. The convenience and reduced cost of these
approaches should help drive adoption if randomized
data show noninferiority or superiority compared with
standard fractionation.

10. PROTON THERAPY :




Proton beams are an attractive alternative to photon


beam radiotherapy for prostate cancer because they
deposit almost all their radiation dose at the end of
the particles path in tissue (the Bragg peak), in
345

contrast to photons, which deposit radiation along


their path. Additionally, there is a very sharp fall-off
for proton beams beyond their deposition depth,
meaning that critical normal tissues beyond this depth
could be effectively spared.
In a randomized trial(31) of conventional radiation
to 67.2 Gy versus 50.4 Gy of conventional radiation
to the prostate followed by an additional 25.2 Gy of
proton radiation (75.6 Gy in total), there was no
overall improvement in local control identified with
the proton boost, but there were significantly higher
rates of rectal bleeding in the high-dose arm using
protons. A subsequent randomized trial(15) of dose
escalation compared 70.2 Gy versus 79.2 Gy using
proton beam radiation for the boost in both arms
and reported a 1% rate of grade 3 GI toxicity in the
high-dose arm. Prospective series from centers with
proton facilities generally report excellent cancercontrol rates and low late toxicity rates for men with
localized prostate cancer. For example, 5-year data
on 211 patients from the University of Florida indicate
rates of 5% for grade 3 GU toxicities and 1% for grade
3 GI toxicity(32). Very low rates (1% or less) of late GI
and GU grade 3 toxicities were observed among 1255
men who were treated at Loma Linda University
Medical Center and were followed for a medium of 5
years(33).

11. CARBON IONS:




346

Carbon ions offer similar theoretical advantages as


protons, as an alternative to photon beam therapy.
In a phase II study, 175 patients with T1-3, N0-1 were

treated with carbon ions in a dose equivalent to 66


Gy in 20 fractions over 5 weeks. Treatment appeared
to be well tolerated, with no RTOG grade 3 or 4 bowel
or genitourinary toxicity, and an overall four-year BDFR
(Biochemical disease free rate) of 88%(34). As with
protons, a randomized trial comparing carbon ions
with IMRT and using equivalent doses is required.

12. PROSTATE BRACHYTHERAPY:




Brachytherapy remains the most conformal radiation


technique and appears to be the most cost-effective
initial treatment for localized prostate cancer.
Iodline-125 or Palladium-103 are used as isotopes,
and the sources are placed transperineally with
ultrasound guidance. Approximately 100 of these 4mm to 5-mm sources are used to treat the entire
prostate.
Low dose-rate brachytherapy has excellent results,
with single institution series reporting 10-year diseasespecific survival rates greater than 95%. Use of
brachytherapy varies by location and disease risk, and
approximately 15% to 20% of men in the west with
lower risk disease select this modality compared with
less than 5% of those with high risk prostate cancer.
High-dose-rate brachytherapy uses iridium-192 as a
source, and, radiobiologically, this approach more
closely corresponds to hypofractionated treatment.
The latter approach allows for the treatment of higher
risk features, such as extracapsular extension. Typically
delivered over fewer than 10 fractions, several singleinstitutional series have demonstrated both excellent
disease control and modest acute GU and GI side
347

348

effects(35). In this technique, catheters are placed


transperineally into the prostate. High dose- rate
brachytherapy has also been used as a boost approach
combined with external beam for men with
intermediate-risk and high-risk disease, including in
a phase 2 study from RTOG(36). Among 129 men
who were treated with 45 Gy of external beam
radiation followed by 19 Gy in 2 fractions, 3 developed
acute grade 3 side effects, and 4 had late grade 3
toxicities.
In permanent implants, iodine-125 in granule form
is the radio-element of reference, while palladium103 may be used for less differentiated tumours with
a high doubling time. The dose delivered to the
planning target volume is 160 Gy for iodine-125 and
120 Gy for palladium-103. Results of permanent
implants have been reported from different
institutions with a median follow-up ranging between
36 and 120 months. Recurrence-free survival after 5
and 10 years was reported to range from 71% to
93% and from 65% to 85%, respectively. A significant
correlation has been shown between the implanted
dose and recurrence rates. Patients receiving a D90
of > 140 Gy demonstrated a significantly higher
biochemical control rate (PSA < 1.0 ng/mL) at 4 years
than patients receiving less than 140 Gy (92% vs
68%)(37).
In a study(38) including 2,991 patients diagnosed
with T1-2 consecutive localized prostate cancer
treated at the Cleveland Clinic Foundation and
Memorial Sloan-Kettering Cancer Centre with a
minimum 1-year follow-up, the 5-year biochemical

failure rates are similar for permanent seed


implantation, high-dose (> 72 Gy) external radiation,
combination seed/external irradiation, and radical
prostatectomy.

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355

Bladder Cancer
Role of radiotherapy as a modality for
organ preservation:
Combined Modality treatment (CMT) involving maximal
TURBT (TransUretheral Resection of Bladder Tumour),
radiotherapy and chemotherapy is an established modality
for organ preservation in Transitional Cell Cancers of the
Urinary Bladder. The current 5-year overall survival rates
range from 50 to 67% with CMT, and approximately 7580% of the surviving patients preserve their bladder1. After
bladder preservation therapy, complete response is
obtained in more than 70% of patients with muscleinvasive bladder cancer.
It is fundamental to carefully select patients for bladder
preservation CMT protocols. Best results have been
obtained with patients harbouring small sized (<5cm)
early tumours, a visibly and microscopically complete
TURBT, absence of ureteral obstruction and
hydroureteronephrosis, no evidence of pelvic lymph node
metastases, and absence of carcinoma in situ (Tis). To
achieve optimal results in bladder preservation it is essential
to have well-coordinated teamwork with urologists and
medical oncologists.

Challenges in planning Radiotherapy to


bladder:
The difficulty in planning bladder radiotherapy arises due
to inter and intra fraction variation in target volume. The
bladder is a mobile, distensible hollow organ which
356

changes its shape, size, and position during a course of


irradiation2-9. Margins of 2.5 cm in the superior and
anterior direction may be required to account for 95% of
the intra-fraction and inter-fraction changes in bladder
position and filling.
The current guidelines for target volume delineation
include the tumour and the entire bladder in the clinical
target volume (CTV). With the uncertainty in the target
location in the absence of image guidance, CTV to planning
target volume (PTV) margins of 2-3 cm are required to
account for organ motion4-9. Such generous Internal Target
Volume (ITV) margins limit the possibilities for dose
escalation, with late bowel toxicity being an area of
concern. This inability to deliver an adequate tumoricidal
dose to an accurately defined target volume has been the
Achilles heel of radiotherapy in bladder TCC.

Bladder RT planning:
The decision to treat on a full bladder or an empty bladder
is based on the need for boosting the tumour bed. Patients
with a solitary tumour or two tumours in close proximity
can be considered for boost in the form of simultaneous
integrated boost (SIB) and treated with a full bladder10. A
full bladder would facilitate better identification of the
tumour bed and minimise the volume of normal bladder
receiving a higher dose. For whole bladder RT without
boost, an empty bladder is ideal. It allows better treatment
reproducibility and significantly better sparing doses to
rectum and intestines11. Suburothelial lipiodol (radiopaque
fiducial marker) injections around the tumour inserted
through a flexible cystoscope may be used to demarcate
the tumour bed and identify the area of boost. It also
357

helps to decrease inter observer variability in tumour bed


delineation12,and may also help in daily setup corrections.

Evolution of radiation technique:


Progress in radiation technology has enabled accurate
target localisation and treatment delivery, possible dose
escalation and improvement in local control and limit
normal tissue toxicity leading to long term bladder
preservation, better overall survival and quality of life.
2D v/s 3DCRT planning: In a comparative dosimetric study
of 3D conformal radical radiotherapy for bladder cancer
patients versus conventional 2D radical radiotherapy by
Mahmoud et al13 it was recommended to use 3D planning
for radical radiotherapy for cases of cancer bladder
especially in elderly patients as it improves the therapeutic
ratio as compared to the conventional 2D plan.
Intensity modulated radiotherapy and use of image
guidance: The use IMRT along with image guidance has
further improved the precision of dose delivery in bladder
carcinoma as compared to conventional techniques14.
Intensity-modulated RT (IMRT), uses beams with varying
intensity across the fields and can shape the high dose
isodose surfaces very close to the bladder target with
considerable sparing of nearby normal tissues. However it
has to be integrated with image guidance to account for
organ motion.

The advantages with use of Newer


technology in bladder cancer:
1.

358

The dose for whole bladder radiotherapy is


traditionally limited to 60-66Gy. However there is

2.

3.

some evidence for a dose response relationship in


bladder cancers15,16 and a possible benefit with dose
escalation. One of the major limiting factor in such
dose escalation is small bowel and bone marrow
toxicity. Implementation of bowel sparing strategies,
such as intensity-modulated RT (IMRT) along with
image-guided and/or adaptive strategies may not only
reduce the overall toxicity for bladder cancer patients
while employing escalated radiation doses but also
allow use of more intensive chemotherapy in the
concurrent / adjuvant setting.
Bladder Radiotherapy is delivered to treat the whole
pelvis, encompassing the pelvic lymph nodes and the
bladder followed by a boost to the tumour bed, or to
treat only the bladder only to the full dose in a single
phase. At present, there is no randomized controlled
trial evidence favouring any one approach over the
other. The concern with whole pelvic radiation is acute
and late gastrointestinal toxicity resulting from the
irradiation of large volumes of bowel. This can be
limited with IMRT. It is known that IMRT helps to
decrease the amount of bowel irradiated during
treatment14. In addition, IMRT can be used in selected
cases to concomitantly boost the dose to the defined
gross disease or to the tumour bed.
IMRT allows simultaneous integrated boost(SIB) in
which all treatment volumes are treated
simultaneously using different fraction sizes. The SIB
IMRT strategy not only produces superior dose
distributions but is also an easier and efficient way of
planning and delivering IMRT because it involves the
use of the same plan for the entire course of
treatment.
359

4.

5.

6.

360

IMRT has been shown to decrease the acute toxicities


during treatment which may reflect in increased
compliance and less treatment gaps. A comparison
of morbidity following conformal versus intensitymodulated radiotherapy for urinary bladder cancer
by Sondergaard et al17 showed that acute diarrhoea
grade> or = 2 (due to bowel irradiation) was more
frequent in patients treated by conformal (56%)
compared to IMRT (30%)(p 0.008). Severe late
toxicities showed no statistical difference between the
IMRT and conformal RT groups.
IGRT and Adaptive Radiotherapy: Image Guided
Radiotherapy (IGRT), has the potential to improve the
therapeutic ratio in carcinoma bladder by reducing
margins and the treatment volumes. Kilo voltage Cone
beam CT which helps in soft tissue imaging is ideal
for bladder cancer imaging and treatment. IGRT based
adaptive radiotherapy helps to further optimise and
reduce the treatment volume. With IGRT the PTV
margin can isotropically be reduced to 12 mm, which
can be further reduced using anisotropic
margins10,18,19. A study from the Christie Hospital in
Manchester, United Kingdom, showed that with conebeam CT (CBCT) image-guided online adaptive
radiotherapy anisotropic margins in the range 10-15
mm can be applied 20. Plan of the day adaptive
radiotherapy involves generation of multiple plans
with different margins to account for organ motion.
Each day pre-treatment CBCT is taken and the most
appropriate plan encompassing the target is chosen10.
Online adaptive RT was first proposed by Burridge et
al 20 in which CBCT images were acquired before

7.

treatment to correct patient setup errors determined


from automatic registration of the CBCT with the
planning CT and select the most appropriate PTV (CTV
bladder with margin) from several PTVs created with
a variable cranial margin that covers the shape of the
bladder on that day. They concluded that online CBCTassisted plan selection based on quantized margins
can significantly reduce the volume of small bowel
receiving high doses. CBCT allows the 15-mm margins
used in some directions to be safely reduced to 10
mm. However the anterior and superior margins show
significant variations. Future enhancements in
planning software may allow true adaptive
radiotherapy with plan of the day being generated
on the couch, allowing further improvement in the
therapeutic ratio.
Radiotherapy in the adjuvant setting: High risk
pathologic features post operatively include lymph
node positivity, positive margins and extravesical
disease. It has been shown in surgical series that local
failures with or without distant metastasis occur in
about 13-30% of these patients with high risk
features. Post op RT may be beneficial in such
settings21. Despite having a greater proportion of
patients with node positive disease and extravesical
tumor extension, use of adjuvant radiotherapy was
associated with a 3 times improvement in disease
specific survival in the study reported from the Bladder
Cancer Consortium 22.The extent of lymph node
dissection also has a direct impact on the outcome
of the patient. Given the variation in extent of LN
dissection in clinical practice, radiotherapy might help
in sterilizing the microscopic disease post operatively.
361

8.

362

With the use of IMRT, the amount of bowel irradiated


and hence the toxicity, can be reduced. Significant
reduction in bowel volumes irradiated to high doses
and, subsequently, potential reduction in toxicity has
been reported with pelvic IMRT after hysterectomy, a
condition where excessive small bowel in the pelvis is
often present23.The newer technologies such as IMRT
and IGRT have made it possible to deliver RT that is
well tolerated in the adjuvant setting. With
appropriate patient selection and careful planning and
delivery of treatment, adjuvant radiotherapy may
emerge as a useful tool in reducing potentially morbid
local recurrences and improve outcome in patients
undergoing cystectomy21.
Partial bladder RT: Conventionally, the CTV in bladder
RT consists of the whole bladder. A possible strategy
to reduce treatment volumes in radiotherapy for
bladder cancer could be to irradiate only the bladder
tumour, leaving the healthy part of the bladder out
of the high dose area, that is, partial bladder
irradiation19. In a randomised control trial comparing
conventional whole bladder radiotherapy with dose
escalated partial bladder radiotherapy ( to tumour
with a 1.5 cm margin), it was found that the reduction
in treatment volume allowed delivery of an increased
radiation dose without a reduction in local tumor
control or the development of excess toxicity. However,
this dose-escalated partial bladder approach did not
result in significantly improved overall survival24.

Role for hypoxic modification: In a
randomised trial by Hoskins et al25,the addition
of carbogen and nicotinamide to radical radiotherapy versus RT alone, showed that differences

in OS and local relapse were significantly in favour


of RT +CON. Late morbidity was similar in both
trial arms. The results indicated a benefit of
adding CON to radical RT. Trials comparing this
regimen with other forms of chemoradiotherapy
are now warranted.
Future directions: Proton beam irradiation can
produce excellent dose localization to the target,
compared to conventional photon irradiation,
further increasing the therapeutic ratio. In a
prospective study by Hata M et al26, radiotherapy
was combined with intraarterial chemotherapy
for bladder preservation therapy and proton
beam was used as local irradiation boost,
resulting in encouraging outcomes.
The incremental advances in modern
radiotherapy technology are path breaking and
hold a promise to position organ preservation
protocols as the standard of care in muscle
invasive bladder cancer. Clinicians are now
equipped to deliver more effective radiotherapy,
enabling future studies looking at dose
escalation, novel altered fractionation regimens
and combination therapies.

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367

Gastro-Intenstinal Cancers

Stomach
Role of adjuvant radiation in gastric
cancers
Adjuvant chemoradiotherapy after gastrectomy is
associated with improved overall survival (OAS) benefit (1),
a benefit that is maintained even on extended follow up
of 10 years (2). While the impact of adjuvant chemoradiation may be greater in patients undergoing D1/D1+
nodal dissection, a recent meta-analysis suggested benefit
in disease free survival (DFS) even in patients undergoing
D2 nodal dissection(3). The 7 year update of ARTIST trial
evaluating the role of adjuvant chemo-radiation in patients
undergoing D2 dissection suggests benefit in DFS in
patients with positive nodes, intestinal type histology and
high lymph node ratio (4). While the confirmatory benefit
of adjuvant chemo-radiation in node positive patients is
being investigated in ARTIST II study, adjuvant chemoradiation should be offered to all patients undergoing
upfront gastrectomy (without neo-adjuvant chemoradiation) without D2 dissection and in those with either
one of the adverse features namely positive nodes,
368

intestinal histology and high lymph node ratio after a D2


dissection. Patients undergoing D2 dissection with low
nodal yield (less than 15) should be considered for adjuvant
chemo-radiation. In patients undergoing adequate upfront
D2 dissection (i.e 15-40 dissected nodes) with negative
nodes the option of adjuvant chemo-radiation and
chemotherapy vs adjuvant chemotherapy alone should be
given to the patient due to conflicting results of
randomized trials and subsequent meta-analyses.(3,
4)Patients with R1 resection may also be considered for
adjuvant chemo-radiation and chemotherapy.
Level of Evidence for use of Adjuvant Chemoradiation: Level 1a / Grade A

Rationale for investigating 3DCRT/IMRT


Though SWOG/INT0116 demonstrated improvement in
OAS, the use of large antero-posterior portalsfor radiation
led to acute grade III, IV and V toxicity in 41%, 32% and
1% of the patients, a large proportion of which were
gastrointestinal (GI) in origin (1). This high incidence of
grade III-V toxicity led to reduced compliance, with only
64% of the patients completing the planned treatment.
Overall 17% patients stopped treatment due to treatment
associated side effects. The high toxicity observed with
conventional radiation provided the rationale for
investigating 3DCRT and IMRT.

Results of 3DCRT and IMRT for adjuvant


gastric radiation
Earlier series using 3DCRT continued to report high
incidence of grade III GI(34-57%) and hemato-lymphoid
(HL) toxicity (10%-33%), as in one study investigators did
369

not reduce the 5 Fluorouracil dose during the concurrent


phase (as in INT 0116) and used increasing doses of
cisplatin which could have increased the incidence of grade
III toxicity(5). The other 3DCRT study used combination of
capacetabine and oxaliplatin rather than 5FU alone which
could have increased the acute toxicity.However the use
of intensive doublet chemotherapy regimen with IMRT was
associated with statistically significant improvement in
overall survival (67% vs 37%, p=0.04)(6).

Comparative Results: 3DCRT vs IMRT


Four studies have compared 3DCRT and IMRT for toxicity
and overall outcomes. A German study(6)reported on
outcomes of 27 and 33 patients treated with 3DCRTand
IMRT respectively. Authors reported grade III GI toxicity
rate of 57% and grade III HL toxicity of 10%. The high
rate of GI toxicity was attributed to capacetabine/oxaliplatin
combination used concurrently with IMRT. While
comparative acute toxicity data were not reported for two
cohorts, there was no difference in late toxicity between
3DCRTor IMRT.
A North American study (7) compared 3DCRT and IMRT
for adjuvant gastric chemo-radiation in 61 patients. With
a compliance rate of 93.5%, grade III GI toxicity was
observed in 15% and 16% patients in 3DCRT and IMRT
cohort respectively. There was no difference in local control
(83% and 81%, p=0.9), 2 year relapse free survival (60%
vs 54%, p=0.80) or 2 year OAS (51% and 65% p=0.50)
between the two cohorts. The loco-regional failure
rateswere 15% and 13% respectively.
Another small study of 24 patients from North America
recorded grade III GI toxicity of 8.3% each in 3DCRT and
370

IMRT arm(8). No late grade III toxicity was observed in


either cohort. The 3 year DFS and OS were 41% and 40%
respectively with no difference in the study cohorts.
A recent matched pair analysis of patients receiving 3DCRT
or IMRT(n=26 and 25 respectively) at Tata Memorial Centre
reported a compliance rate of 92.2%. Overall 3.9% and
5.9% of the patients had grade III GI and HL toxicity. No
difference was observed in acute grade II-V GI or HL toxicity
or late GI, HL or renal toxicity between 3DCRT and IMRT.
No difference was observed in local relapse rates(11.5%
vs 12%, p=0.14) or overall survival (39% and 38%
(p=0.97)) between 3DCRT and IMRT(12).
Given equivalent toxicity and local control outcomes with
3DCRT, IMRT cannot be routinely recommended for
adjuvant gastric irradiation.

Rotational vs Non Rotational IMRT


No comparative data exists between rotational and nonrotational IMRT for adjuvant gastric irradiation.

Proton or Heavy Ion Irradiation


No data exists for use of proton or heavy ion irradiation
for adjuvant gastric radiation.
Level of evidence
Reduction in toxicities with use of 3DCRT/IMRT:
Level III/ Grade C
Lack of superiority of IMRT over 3DCRT: Level III /
Grade C

371

Rotational vs Non-Rotational IMRT: No Clinical


Data

Rationale for use of image guidance for


gastric radiation
Volumetric changes in shape of gastric remnant leads to
medio-lateral (ML), supero-inferior(SI) and antero-posterior
(AP) displacement of 3-25 mm, 3-16mm, and 1-10mm
respectively (9). Based on these observations on daily
Megavoltage CT images (Tomotherapy) we proposed ITV
margins of 19.2 mm, 13.5 mm and 7.8 mm in ML, SI and
AP direction(9). Another study reported mean intra-fraction
(respiratory origin) shifts of 9.9 mm, 22.7 mm, 13.7 mm
and inter-fraction (gastric deformation origin)displacement
of 5 mm, 9.1 mm, 1.3 mm and proposed margins of
41mm, 30 mm and 50.8mm in ML,SI and AP direction
(10). Due to large displacements observed in a portion of
the gastric remnant, daily image guidance is mandatory.
However, the use of proposed ITV margins may increase
PTV and adjacent organs at risk. Therefore an adaptive
strategy with multiple executable plans as in stomach
lymphomas need to be further investigated(11).
Category of evidence of Image Guidance Level III
/ Grade C
Category of Evidence for Adaptive Re-planning:
Level IV/ Grade D

372

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375

Hepato Pancreatic Biliary Tumours


Introduction:
Management of hepato-biliary pancreatic tumours is
challenging. These tumours have a poor prognosis with
propensity for distant metastases. Traditionally surgery has
been the main modality of management with limited role
of radiotherapy due to associated acute and late toxicity.
Due the recent advances in technology, it is becoming
increasingly evident that radiotherapy (RT) can be delivered
safely in these tumours.

Pancreatic Cancer:
Pancreatic tumours generally have a very poor prognosis
with a 5 year survival rate of 5% for all stages with
multidisciplinary approach. As per NCCN guidelines
localised pancreatic cancer has been divided into 3 groups
for the purpose of local management a) potentially
resectable pancreatic cancer (stage I and II), b) borderline
pancreatic cancer, c) Unresectable or locally advanced
pancreatic cancer. (NCCN Guidelines V 1.2015)

Potentially Resectable Pancreatic Cancer:


Surgery is considered to be the main stay of treatment in
this group of patients. Autopsy series have shown that
they have a very high risk of local recurrence of up to
about 50-80% and the pattern of failure has not been
changed despite improvement in the preoperative imaging
(1). There have been several randomised and nonrandomised trials of adjuvant therapies in terms of

376

radiotherapy/chemotherapy (CT) or chemo-radiotherapy (CRT). Three most important 5-FU based


randomised trials were conducted by the Gastrointestinal
Study Group (GITSG), the European Organisation for
Research and Treatment of Cancer (EORTC), and the
European Study Group for Pancreatic Cancer (ESPAC-1)
(2,3,4). Although GITSG had shown a survival advantage
with adjuvant 5-FU based chemo-radiation compared to
observation only (21 months vs 10.9 months, p=0.035),
this could not be reproduced by subsequent EORTC trial.
Also results of ESPAC-1 trial concluded that chemoradiotherapy failed to benefit patients and reduced survival
when given before chemotherapy. The overall survival in
this group of patients ranges from 20 months to 23.6
months whatever treatment strategy may be applied and
has not changed over the years. The failure of adjuvant
therapies to improve outcomes may be attributed to the
higher incidence of R+ resection accounting for 50% of
the operated cases even in university based hospitals.
Studies have shown that patients with a positive surgical
margin have a median survival ofless than 12 months,
irrespective of adjuvant therapies (5, 6). Suboptimal
radiation doses and techniques used in these trials, as well
as lack of appropriate imaging for metastatic disease may
be other reasons for such dismal outcomes. It is known
that 15-20% patients enrolled in adjuvant trials with no
distant metastasis become metastatic after several weeks
when no imaging done prior to starting adjuvant
treatment.
Data from several retrospective studies have shown that
adjuvant radiotherapy, particularly in the setting of positive
lymph nodes or involved margins leads to improved survival
377

(7, 8). The on-going RTOG-0848 trial which is evaluating


a combined approach with adjuvant radiotherapy
administered only for those patients in whom disease has
not progressed following the administration of
gemcitabine, is awaited to provide an answer for the role
of adjuvant radiation in this disease.
Within the limitations of the currently available data,
adjuvant radiotherapy (RT) should be strongly considered
for patients with node-positive or margin-positive tumours
(7, 8). Patients should be encouraged to participate in
clinical trials whenever feasible.
Recently pre-operative chemo-radiation with higher
radiation dose (50.4Gy) is being investigated with the aim
of achieving margin negative resection. The results are
encouraging (9, 10).

Borderline Resectable Pancreatic Cancer:


Limited retrospective data suggest that both systemic
chemotherapy and chemo-radiation when used in neoadjuvant setting improve R0 resection rates and outcome
in these groups of patients (11). A recent meta-analysis of
retrospective and prospective studies of neo-adjuvant
therapy reported that 35% of patients with unresectable
disease had a response to preoperative therapy, and 33%
underwent resection. However, majority of these studies
(53%) had not defined the objective staging criteria, only
40% reported response criteria, and the indications for
surgery following treatment were not known (12). A study
from MDACC shows that response assessment by
radiologic criteria is not ideal and the patient should
undergo surgery in the absence of distant metastasis (13).
Neo-adjuvant strategies are not widely used in this setting
378

and the role of radiotherapy is being redefined in locally


advanced pancreatic tumours, so it is critical that the
distinction between borderline resectable and locally
advanced unresectable tumours be made before the
initiation of therapy.

Unresectable or Locally advanced Pancreatic


Cancer:
Traditionally, these tumours have been treated with
concurrent chemo-radiotherapy with modest improvement
in survival (14). Induction chemotherapy helps to identify
the patients who progress rapidly and are less likely to
benefit from local therapy (15,16). The nature of local
therapy has to be properly defined. ECOG 4201
demonstrated improved outcome with the addition of RT
to gemcitabine compared with gemcitabine alone for
unresectable tumours (17). The results of a recent phaseIII randomised study, European LAP-07 shows
improvement in progression free survival with chemoradiotherapy compared to chemotherapy alone
(p<0.0001) (18).

Advances in Radiation Therapy:


Technical Advances: IMRT and Implications
Chemo-radiotherapy in pancreatic cancer often causes
grade III GI (gastrointestinal) toxicities with attendant
reduction in quality of life. Conventionally. 3DCRT had been
routinely used to treat these tumours. Recently IMRT has
been proposed as an alternative for conventional 3DCRT
with the aim of reducing treatment related toxicity by
improving normal tissue sparing. A recent systematic
review had compared the toxicity profiles of the two
379

treatment modalities. Acute grade III GI toxicities were


significantly less in the patients treated with IMRT
compared to 3DCRT (nausea and vomiting 7.8% vs 13.8%,
p<0.001:Diarrhoea 2% vs 11.6%,p <0.001). IMRT also
significantly reducedthe grade-III late toxicities like GI
bleeding and duodenal ulcer from 10.6% to 5% (p=0.017)
when compared to 3DCRT (19). However, no differences
in overall survival or progression free survival were observed
between the two treatment techniques (19).
Modulated arc therapy has been shown promising results
in pancreatic cancer. Compared to fixed beam IMRT,
tomotherapy, Vero 4DRT and Rapid Arc has been shown
to reduce the doses to normal tissues with faster treatment
times (20,21,22).

IGRT: Rationale, Methods and Outcome:


Inter-fractional and intra-fractional variations in position
in target and organs at risk are important considerations
while deciding for margin in radiotherapy planning. These
variations are may be due to set up errors, respiration
induced motion or motion of the GI tract. Based on
consensus guidelines current expansions from GTV (Gross
tumour volume) to PTV (Planing target volume) are 2-3
cm CC, 1.5-2 cm AP and 1.5-2 cm LR directions (23). Use
of individualised margin based on respiratory motion has
been shown to reduce the mean PTV volume by one third
compared to standard margins (24). 4DCT is the most
widespread method to measure motion for treatment
planning. But due to difficulty in target delineation in all
phases of respiration, surrogates have been used. Although
stent has been used as a surrogate for interfraction tumour
motion (25), it cannot be relied on fully due to the stent
migration and spontaneous loss of stent in about 5.8% of
380

cases (26). Fiducials have been widely used for image


guidance, placement is safe, has reduced the set up error
by 54% and result in additional craniocaudal shift of
4.1mm after matching with bony anatomy (27,28).
Different methods to decrease respiratory motion include
respiratory gating, respiratory breath hold and abdominal
compression. Respiratory gating has been shown to reduce
displacement by factor of 4-5, even up to 10 times and
reduces the ITV (Internet target volume) volume by
20% (29).

Dose escalation: IMRT, Proton, particle beam


therapy and Intraoperative radiotherapy:
Dose escalation using IGRT and IMRT has been shown to
be dosimetrically feasible. A recent phase I/II prospective
trial using IMRT with dose escalation with concurrent
gemcitabine has shown that intensification of local therapy
may improve outcomes and perhaps even facilitate
resection (30). The recommended dose was 55Gy/25#.
Based on the results of the study, RTOG 1201 is assigning
patients with locally advanced unresectable pancreatic
cancers to receive gemcitabine plus nab-paclitaxel followed
either by 63 Gy of IMRT with capecitabine, 50.4 Gy of
IMRT/three dimensional RT with capecitabine, or further
gemcitabine plus nab-paclitaxel. This trial addresses the
need for radiation in this population as well as the role of
dose escalation (31). Also the biophysical model of tumour
response evaluation shows the potential benefit of dose
escalation (32). However, this comes at the expense of
moderate increase in GI toxicity.
Proton therapy with the aim of achieving this goal has
not been successful in unresectable pancreatic head
carcinoma when compared to photon beam therapy (33).
381

However, it has been shown to decrease the normal tissue


toxicity in resected pancreatic head carcinoma in postoperative settings. Particle beam therapy using carbon ion
with 4DCT has been tried for dose escalation with better
sparing of normal tissue (34).
IORT (Intra operative radiotherapy) is another effective
method of delivering high dose radiotherapy while
excluding part or all of normal tissue out of the treatment
field. But no phase III data clearly supports the use of IORT
in management of pancreatic cancer.

Role of SBRT and Adaptive RT:


Stereotactic body radiation therapy (SBRT) is being
increasingly evaluated in locally advanced pancreatic cancer
due to the advantages of shorter treatment times, higher
biologically effective doses, and less delay in the
administration of systemic therapy. Several studies on SBRT
have demonstrated the safety and efficacy of this treatment
strategy (35-39). Various dose fractionation schedules are
used: 15Gy-60Gy/1-5# and it leads to improvement in
local control without increase in acute GI toxicities.
However late toxicities, especially duodenal toxicities, are
more when higher doses are used and correlate with
maximum dose and volume receiving >25Gy (37-38).
These studies have shown that D max of 35 Gy and 38 Gy
correlated with a 5% and 10% rate of grade 3+ gastro
duodenal toxicity, respectively. They also found that V
25>20cc correlated with a 50% rate of intestinal toxicity
compared with 4% for V 25 < 20cc. They also reported
that treatment on consecutive days leads to increased
toxicity compared to treatment period of 4-8 days (0% vs
18%, p<0.037) suggesting that inter-fraction interval of
382

>24hrs leads to decrease in toxicity (37-38). Adaptive


radiotherapy (ART) involves daily imaging that allows
treatment plan modification depending upon anatomical
changes or tumour shrinkage. ART shows also promise in
reducing normal tissue irradiation. For example, the V 50
of the duodenum was reduced from 43.4% to 15.6% with
ART (40). Research is on-going for efficient implementation
of ART in clinic and may allow efficient treatment delivery
in patients with rapid weight loss or rapid change in target
volume.

Cost-effectiveness and Modern radiation


Oncology:
Murphy et al in a study of locally advanced pancreatic
tumours have analysed and compared the cost
effectiveness of using modern technologies compared to
conventional radiation techniques. The probabilistic
sensitivity analysis demonstrated that SBRT is more cost
effective than conventional and IMRT techniques in terms
of QALY (Quality adjusted life year) (41).

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389

Hepatocellular Cancers (HCC):


While surgery (partial hepatectomy) is the treatment of
choice for hepatocellular cancers (HCC) without vascular
invasion, 5year survival rates of 50% and recurrence rates
exceeding 70% have been reported. Advances in
technology have resulted in a resurgance of interest in
radiotherapy in HCC in the past decade. It has been used
as definitive therapy in early stage tumours, in combination
with trans-arterial chemoembolization (TACE) for
intermediate stage tumours and along with systemic
therapy in locally advanced tumours. However, due to the
lack of high level of evidence it has not been incorporated
into standard management guidelines of HCC.

Role of Radiotherapy (RT):


Key Concepts:
As liver behaves as a parallel organ, overt complications
occur only when a critical volume of liver is irradiated. If
the irradiated liver volume is limited, tumouricidal radiation
dose can be delivered safely. Liver also has the unique
potential of regeneration after partial ablation. Limitations
in achieving these dose volume constraints have restricted
the application of radiotherapy in these tumours in past.
Modern radiotherapy can be used in the following
situations in the management of HCC.
As Bridge therapy:
Bridge therapy is used to decrease tumour progression
and reduce dropout rate for the patients waiting for liver
transplantation. Trans arterial radioembolisation (TARE)
with Y90 radionucleotide (1) and 3D conformal RT are
used for the bridge therapy (2).
390

As Down staging Therapy:


Down staging therapy is used for reduce tumour burden
in more advanced HCC (without metastasis) which dose
not meet the accepted transplant criteria. Down staging
therapy improves disease free survival (DFS) in transplant
patients. Brachytherapy using Y90 microspheres in the
form TARE have resulted in higher rates of
tumordownstaging as compared to chemo-embolization
when used for down staging therapy (3).
As Loco-regional Therapies:
Brachytherapy (TARE) using Y-90 nuclide, a beta emitter
might be a treatment option in intermediate or advanced
HCC. TARE when compared with TACE has similar survival
time, but longer time to progression and lesser toxicity.
131I lipoidol also has been used for radioembolisation.
EBRT has been effectively used in HCC and its role is
expanded with the development of conformal techniques
(3DCRT/IMRT), stereotactic radiotherapy and proton beam
therapies. Both 3DCRT and IMRT show good tumour
control, palliation and progression free survival in patients
with good liver function (4-7).

Advances in Radiotherapy:
3DCRT/IMRT:
3DCRT has been shown to irradiate the target volume
accurately to a median dose of 54Gy with minimal dose
to normal liver and may offer a longer survival in small
HCCs ( size <5cm) in patients without alternative treatment
options (8). A dosimetric study comparing 3DCRT versus
IMRT in 68 patients of HCC treated with 3DCRT, (of whom
391

12 had RILD) IMRT could achieve similiar levels of target


volume coverage while reducing the spinal cord
significantly. However the impact on liver sparing was
unclear as while there was a reduction in the NTCP, an
increase in the mean dose was observed with IMRT (9). A
comparative study of 3DCRT and IMRT using helical
tomotherapy showed that IMRT delivered higher median
dose (62.5 Gyvs 53.1 Gy) with better 3 year OS (33.4% vs
13.5 %, P < 0.001), PFS (11.1% vs 6.0 %, P = 0.004)
with no significant difference in the incidence of RILD (10).
Studies comparing volumetric modulated arc therapy
(VMAT), IMRT and 3DCRT show that VMAT leads to better
target coverage and better sparing of liver particularly in
right lobe tumours compared to 3DCRT and IMRT (11,12).
However, the mean dose to liver is less for 3DCRT plans in
tumours of size >8cm compared to IMRT and VMAT which
indicate that 3DCRT may be more suitable for larger
tumours (12).

SBRT:
There has been growing evidence of use of SBRT in locally
advanced, inoperable and recurrent HCC from several nonrandomised trials (13-17). SBRT induces complete and
partial response after incomplete TACE (16) and can be
used as bridge therapy before liver transplantation (15). A
study from Princess Margaret Hospital reports a 1 year
local control of 87% and median survival of 17 months in
patients of locally advanced HCC treated with SBRT in
sequential phase I and phase II trials (17). The problem of
disease progression outside the HCC provides rationale
for combining SBRT with regional and systemic therapies.
The typical dose of SBRT ranges from 24 Gy to 60 Gy in 36 fractions. SBRT can be used in 1-3 tumours with minimal
392

or no extra hepatic disease. There is sufficient data on


safety and efficacy of SBRT in Child-Pugh class A liver
function and limited data in class B liver function. However,
its use in class C is not established.

IGRT and Motion Management:


Considering the precise radiotherapy planning , accurate
deliver of beams should be ensured. Since the average
livermotion is 3-50mm (18) monitoring of uncertainty is
very important in treatment of HCC. The uncertainties can
be intra-fractional or inter-fractional, but the inter-fraction
component leads to a greater geometric uncertainty. The
American Association of Physicist in Medicine Task Group
(AAPMTG) on the management of respiratory motion in
radiation oncology (TG-76) recommends that motion
management strategies be considered in patients whose
breathing motion exceeds 5 mm (19). Clinically different
strategies include simple addition margin to the target
volume craniocaudally (by fluoroscopic assessment of
target motion/Use of cine MRI), reducing the target motion
(by abdominal compression), eliminating target motion
(by breath hold method) or incorporating the target
motion (gating using 4DCT and real time tumour tracking
using cyber knife). Abdominal compression leads to a
median 7mm reduction in liver motion (20). Breath hold
technique is more reproducible in exhale position
compared to inhale position with intra fraction and
interfraction reproducibility of 1.5-2.5 mm and 3.4 -4.4mm
in superior-inferior direction respectively (21,22). In gated
radiotherapy, external surrogates are used as reference for
monitoring tumour position and RT is delivered at a
predefined location of tumour. Real time tumour tracking
is the most accurate method, in which radiopaque fiducials
393

are implanted near the tumour and radiation beam is


delivered corresponding to the tumour motion. Both gated
treatment and tracking reduces PTV margin, however setup
uncertaintity and uncertainty in the relationship between
surrogate and the tumour must be accounted for (23,24).

Particle Beam Therapy:


In a large series from Japan 162 patients of HCC were
treated with proton beam therapy (PBT) to dose of 72Gy
with or without TAE, with an estimated 5 year local control
of 87% and survival of 23.5% (25). However higher than
expected levels of GI toxicity and hepatic dysfunctions were
reported.
In the first reported series of carbon ion treatment by Kato,
et al, 24 patients were treated with 49.5-79.5 cobalt gy
equivalents in 15 fractions with 5 year local control of
81% and 5 year survival of 25% (26). Particle beam
treatment is expected to improve the treatment out-come
in the future.
Dawson has suggested that photon beams (3DCRT, IMRT,
SBRT) might be best employed in patients with Child-Pugh
A with tumours in the right lobe near the dome and of
smaller than 6 cm. Protons may be best used in ChildPugh B, tumours larger than 8 cm, and in those that are
located centrally/medically in the liver. (27,28) It is not
known whether SBRT or PBT is superior or equivalent in
outcomes of patients with HCC.
Only level 2a evidence supports any form of radiation in
HCC; however, combined with the retrospective reports
of hundreds of patients, there is a significant amount of
evidence supporting RT in all stages of HCC.
394

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399

Biliary Tract Cancers:


Biliary tract cancers include both gall bladder cancer (GBC)
and cancers of biliary tree. Gall bladder cancer is the most
common, most aggressive of biliary tract cancers and is a
distinct clinical entity.
Surgery is the only curative treatment modality for gall
bladder cancers. However, given the dismal prognosis of
T2 and/or N+ GBC even after surgery with clear margins,
adjuvant strategies have been adopted by some institutes.
However, no standard regimen is defined. NCCN guidelines
for GBC suggest adjuvant fluoropyrimidine chemoradiation or fluoropyrimidine, or gemcitabine
chemotherapy. A recent systematic review and metaanalysis showed a non-significant improvement in survival
when comparing any adjuvant therapy with surgery alone.
Those receiving CT or CRT derived statistically greater
benefit than RT alone (OR, 0.39, 0.61, and 0.98,
respectively; p= .02) Node-positive and margin-positive
(R1) patients derived the clearest survival benefit from the
use of adjuvant therapies (1). Analysis of SEER database
predicts that certain subsets of patients with at least T2 or
N1 disease will gain a survival benefit from adjuvant
chemoradiotherapy (2). Although primary option for
unresectable GBC is chemotherapy/ best supportive care,
chemoradiation is an alternative treatment option in
selected patients (3).
Cholangiocarcinomas encompass all the tumours arising
from the epithelium of bile duct and are classified as
intrahepatic (IHCC) and extrahepatic (EHCC) depending
on the location of the tumor. Complete resection with
negative margins, which is the potentially curative
400

treatment for resectable tumours, is not achievable in


majority of patients due to advanced stage of disease.
Italian Intrahepatic Cholangiocarcinoma study group have
reported that margin negative resection is associated with
higher survival rate (5year survival 39.8% versus 4.7%) and
lower recurrence rates (53.9% versus 73.6%) (4). Optimal
adjuvant treatment for these tumours is not known as
there is limited data to support standard adjuvant
treatment. A systematic review by Horgan et al shows the
benefit of adjuvant chemo and chemo-radiotherapy (1).
This includes both GBC and cholangiocarcinomas.
Adjuvant treatment options include fluoropyridine or
gemcitabine based chemotherapy for R0 resection and
fluoropyridine based chemo-radiotherapy for R1 resection
and N+ disease. Similarly definitive chemo-radiation is a
treatment option for R2 and unresectable IHCC.
Retrospective studies of adjuvant chemo-radiotherapy in
resected EHCC show improvement in local control and
survival. Chemo-radiation has significant survival benefit
in T3/T4 tumours and those with high risk for LR (R+
resection and node positivity) (5,6,7). Chemo-radiation in
locally advanced cancer may improve local tumour control
and survival, but there is no level 1 evidence.

Advances in Radiotherapy:
Limited studies are available on advancement of radiation
techniques. A dosimetric study comparing 3DCRT vs IMRT
to dose of 46Gy-56Gy in post-operative setting in GBC
showed that of IMRT could reduce the mean liver dose
and achieved better sparing of right kidney (8). IMRT also
led to better target coverage compared to 3DCRT
(p<0.05). Other studies also show the advantage of
401

IG-IMRT in terms of better sparing of normal tissue


including clinical studies (9-11). A Study by Patera et al
showed that use of IMRT allowed safe dose escalation to
60Gy/25# with SIB with effective sparing of OARs (9).
In a study by Ben Joseph et al, patients of hepatobilliary
tumours and metastatic colorectal tumours were treated
with 3DCRT to median dose of 60.75 Gy/1.5Gy bid with
hepatic arterial fluxuridine infusion. Compared to their
historic cohort, high dose focal irradiation lead to
improvement in survival with acceptable toxicity (12). They
observed an in field failure of 36% and intrahepatic failure
of 40%. Baisden et al reported the results of a study where
IMRT to dose of 50 Gy/20# was combined with concurrent
capecitabine and photodynamic therapy in patients of
unresectable cholangiocarcinoma. Local disease
progression was the predominant pattern of failure with
an estimated median survival of 13 months (13). From
the above studies, it may be concluded that reduction in
local failure may translate into improved survival. The
reduced acute toxicity may be due to incorporation of IMRT
(13). There is increasing use of SBRT in GBC and
cholangiocarcinomas (14, 15). SBRT to dose of 40Gy/5#
is considered safe in terms of biliary toxicity (15). There is
an ongoing study on IMRT using helical tomotherapy with
dose escalation in gall bladder cancers at tata memorial
hospital (16).

Conclusion:
The failure patterns in hepato-pancreatic-biliary
malignancies indicate that high doses of radiation may be
useful to achieve tumour control in an area which is
surrounded by radiosensitive normal structures. Image
402

guided radiotherapy assists in achieving the goal in these


cases. Prospective studies of IMRT/IGRT/SBRT evaluating
the effectiveness in terms of disease control and
preservation of quality of life (QOL) are urgently mandated.

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ClinicalTrials.gov.in. NCT01118897.

405

Rectal Cancers
Introduction
Preoperative radiotherapy has emerged as the standard
of care in bulky T2/T3 N+ rectal cancers as it allows higher
rates of sphincter preservation and reduces local failures
even in the setting of total mesorectal excision(1, 2).Neoadjuvant chemo-radiation may be administered as a 5 week
protracted schedule with concurrent 5-Fluorouracil or
Capacetabine to a dose of 45 50.4Gy at 1.8 -2 Gy per
fraction, or may be alternatively be administered as a short
course hypo-fractionated regimen(25 Gy/5# over 5 days
without concurrent chemotherapy in patients with
resectable rectal cancer(3). For locally advanced
unresectable disease long course neo-adjuvant chemoradiation remains as the standard of care(4). In the present
era postoperative radiation should be restricted to patients
who underwent inadvertent surgery for a presumed early
rectal cancer.

Acute and Late Toxicity with Preoperative


3D conformal Radiation+/-chemo
The incidence of acute and late toxicities with conformal
radiation is best reported from studies investigating either
long course of short course preoperative radiation with or
without chemotherapy.
Long course preoperative chemo-radiation has been
associated with acute grade III-IV GI toxicity (diarrhea) rates
of 12-13% during the concurrent part of treatment(1).
While short course RT (5x5 Gy) was associated with no
406

grade III/IV acute toxicities, there was an increased risk of


late bowel toxicity when compared against long course
chemo-radiation (10.1% vs 7.1%) (5). Long term follow
up of patients treated within Dutch Colorectal group study
demonstrated increase in fecal incontinence (62% vs 38%;
p<0.001), pad usage (56% vs 33%; p<0.001), anal blood
loss (11% vs 3%p=0.004) and mucus loss (27% vs 15%,
p=0.005) in patients receiving preoperative radiation as
compared to patients undergoing surgery only. Irradiated
patients also reported more dissatisfaction with bowel
function(6) as compared to those undergoing surgery
alone. Similar results have been reported in other
series(7).An increased relative risk of admission for
gastrointestinal complaints was observed in irradiated
patients on long term follow up of the Swedish Rectal
Cancer Trial, which delivered short course radiotherapy(8).

Acute and Late Toxicity with 3D


conformal radiation for postoperative
adjuvant radiation
A prospective randomized study comparing adjuvant
radiation against chemo-radiation reported incidence of
acute grade II, III, IV diarrhea as 23%, 20% and 2%
respectively with an increase in incidence of diarrhea in
patients receiving chemotherapy as opposed to those
receiving only radiation (22% vs 4%; p=0.0001)(9). An
increase in the incidence of grade III-IV diarrhea was
observed in those undergoing low anterior resection rather
than abdomino-perineal resection (30% vs 13%;p
=0.006)(10). Similarly Gastrointestinal Study Group Trial
71-75 reported a 19.6% incidence of grade III-V diarrhea
in patients receiving adjuvant chemo-radiation(11).
407

Though improved survival has been observed with


protracted infusion of 5 FU alongside radiation higher rates
of grade III or more diarrhea have been observed in patients
receiving protracted infusion of 5-Flurouracil rather than
bolus injection (24% vs 14%; p<0.001)(12)
In a postoperative short course RT study (25 Gy/ 5fractions)
sandwiched between 3 cycles of 5 FU chemotherapy before
and after radiation the incidence of grade III acute toxicity
was 17.5%. Grade III or higher late bowel toxicity of 9.3%
has been reported in patients undergoing postoperative
short course radiotherapy(13)which is higher than 3% rate
of late toxicity during a protracted course of adjuvant
chemo-radiation(14). In another series using postoperative
adjuvant radiation,small bowel obstruction rate of 11%
was reported. However the study used higher doses of
radiation (60 Gy).

Rationale for IMRT


The acute and late toxicity observed in the above studies
rationalize the need for investigating Intensity Modulated
Radiation Therapy (IMRT). Prospective and retrospective
dosimetric and clinical studies using pelvic conformal
radiation or IMRT have demonstrated strong correlation
between V15 small bowel (SB) doses and incidence of
acute grade III toxicity(15). Apart from toxicity reduction
IMRT may be used in specific situation like dose escalation
in locally advanced unresectable rectal cancers and in
clinical situations where intensive systemic chemotherapy
is planned.
Following is the summary of existing evidence for use of
IMRT in specific clinical contexts.
408

A) IMRT for reducing acute and late toxicity


Multiple dosimetric studies have demonstrated 26-42%
reduction in volume of SB, 20% reduction in bladder and
6-10% reduction in femoral head and pelvic bone (marrow)
doses as compared to 3DCRT(16-18). Small single
institutional studies have also demonstrated statistically
significant reduction in incidence of acute grade II diarrhea
with the use of IMRT (42-60% to 10-30%; p=0.01 and
p=0.03 respectively)(19, 20). Garofalo et al. published the
preliminary results of RTOG 0822 where sequentially
delivered IMRT (45Gy/25 # to PTV followed by a boost of
5.4Gy/3# to gross disease) was associated with statistically
non-significant reduction in grade II or higher GI toxicity
when compared to RTOG 0247(where both 2D & 3D RT
were allowed).None of the studies have demonstrated the
impact of IMRT in late toxicity reduction. Indirect
extrapolation of results from our institutional series of
gynecological cancers(21)suggest towards potential of late
bowel toxicity reduction with IMRT however conclusive
evidence is missing in patients with rectal cancers.
Level and Grade of recommendation: Level IIb
Grade C

B) IMRT for RT dose escalation in locally


advanced unresectable rectal cancers
A Phase II randomized study from our institution evaluating
radiation dose escalation (45 Gy+ 20 Gy 3- dimensional
conformal boost without chemotherapy) did not
demonstrate increased resectability against standard dose
chemo-radiotherapy.It was however was associated with
delayed postoperative wound healing (22).
409

Initial experience with simultaneous integrated boost (SIB)


to gross tumor (55Gy/25 #) resulted in unacceptable rates
of toxicity (23). However, Li et al demonstrated the
feasibility of delivering 50.6Gy/22# with concurrent
capacetabine @ 825mg/m2BD with Grade III diarrhea of
9.5% and a higher pathological complete response rate
(24). In another recently published Phase II study, Zhu et
al. treated 78 patients to a boost dose of 55Gy/25# with
concurrent and adjuvant doublet chemotherapy
(capacetabine-oxaliplatin). The incidence of grade III
hematologic toxicity, diarrhea, and radiation dermatitis
were 3.8%, 10.3%, and 17.9%, respectively(25). The
results from these prospective studies demonstrate that
IMRT can allow safe dose escalation for locally advanced
rectal cancers while using intensive systemic chemotherapy
schedules. However as the benefit of dose escalated
radiotherapy and intensive systemic adjuvant
chemotherapy remains to be proven, IMRT for dose
escalation is recommended within the context of clinical
trials only.
Level of evidence: Level III Grade C

IMRT Technique: Rotational vs. Non-rotational


IMRT
Volumetric Arc Therapy/ Intensity Modulated Arc
Therapy (VMAT/IMAT)/ Tomotherapy
The use of VMAT/IMAT is associated with improved
conformity and reduced treatment time as compared to
3DCRT (2 minutes vs 3.4 minutes) (26, 27). A dosimetric
study comparing 3DCRT, SIB static field IMRT (57.5Gy/25
# to gross disease and 45Gy/25# to elective nodal
410

volumes) and SIBVMAT demonstrated highest degree of


conformity with SIB-VMAT with 40%, 53% and 58%
reduction in the percentage of volume of SB irradiated to
30, 40 and 50 Gy while reducing treatment time by 20%
with respect to static field IMRT (50 mins versus 14
mins)(28).Thus VMAT offers an attractive option where
one is able to achieve the high conformity of IMRT with
the short treatment times of 3DCRT (28, 29).
A study on 28 patients treated on Helical Tomotherapy
(SIB dose of 55Gy/25 fractions to patients with threatened
circumferential resection margin and 45 Gy/25# to elective
volumes) was associated with grade III toxicity in only 1/
28 patients (30). Engels et al have demonstrated that use
of Helical Tomotherapy was associated with grade III
intestinal and urinary late toxicity rates of 6% and 4% at
32 months. (31)
Level of evidence for use of Rotational IMRT in
terms of increased throughputLevel III /Grade C

Adaptive Re-planning for Rectal Cancers


Motion is found to maximal in the upper mesorectum
maximally in the anterior direction, and is attributed to
rectal and bladder filling. In addition, rectal gas(32) and
rectal motion(33) can lead to mesorectal displacement.
.Adaptive re-planning has been investigated during long
course chemo-radiation and has demonstrated ability to
reduce PTV margins from 2.4 cm to 1.7 cm with a
consequent reduction in PTV volume and volume of bowel
receiving 15, 45 and 50 Gy (34). Interval imaging using
MRI and FDG PET is able to quantify tumor shrinkage

411

during RT course however as CTV encompasses structures


with relatively fixed spatial extent (like mesorectum and
lymph node regions), adaptive re-planning may have little
to offer within the context of executing neo-adjuvant
radiation for rectal cancer(35) when following currently
accepted target volume delineation guidelines.
Level of Evidence/ Grade of Recommendation:
Level IV Grade D

Proton and Heavy Ion Therapy


A comparative study investigating 3DCRT,IMRT, VMAT and
proton plans demonstrated higher conformity and better
sparing of organs at risk with use of proton beams(36).
Another comparative planning study of 3D CRT, IMRT and
conformal proton therapy demonstrated significantly
reduced median OAR doses as compared to the 3DCRT
and IMRT plans with respect to pelvic bone marrow (V5,
V10, V15, and V20), the small bowel (V10&V20Gy) and
bladder (V40)(37).Carbon Ion Radiotherapy (CIRT) 3DCRT
plans were superior over combination of 3DCRT,
chemotherapy and hyperthermia while treating
postoperative recurrences. CIRT was found to be more cost
effective, allowing shorter hospital stays (37 vs 66 days),
with higher survival and reduced risk of mortality(38).A
phase I study to determine the optimal dosage, toxicity
and progression free survival in recurrent rectal cancer is
currently under way (39).
Level of evidence : Level III /Grade C

412

Stereotactic Body Radiotherapy (SBRT) for rectal


cancers
SBRT may be used for rectal cancers for specific scenarios
A) Reirradiation for unresectable recurrent rectal
cancers
SBRT has been used while treating isolated unresectable
presacral and pelvic wall recurrences. Using
hypofractionated RT doses of 30-51 Gy/ 3#, 2 year year
local control and overall survival rates of 68%-74% and
78% have been demonstrated with no early or late grade
III-IV toxicities (40, 41).
Recommendation: Level IV/ Grade D

B) SBRT for Oligometastatic Rectal cancer


Early experiences with SBRT in metastases to various sites
in colorectal cancer yielded 2 year local control rates as
high as 86%, with acceptable rates of toxicity in the
majority of patient. A summary of outcomes of various
studies of Liver SBRT for oligometastasis is summarized
below.
On the basis of above results, SBRT may be used for patients
with colorectal metastasis not amenable to surgical
resection or radiofrequency ablation
Level of Recommendation: Level III/ Grade C

413

414

III

III

III

III

III

III

III

Wulf(43)

Herfarth(44)

Mendez R(45)

Kavanagh(46)

Katz(47)

Rusthoven(48)

Lee(49)

TMH Series
(unpublished)

III

III

Bloomgren(42)

Level

Author

60-70%

100%

100%

80%

80-90%

65%

80%

65%

65%

30-37.5Gy/3#

27.7-60 Gy/6 #

36-60 Gy/3#

50 Gy/5#

60 Gy/3#

37.5Gy/3#

14-26/1#

30-37.5 Gy/3#

20-45 Gy/2-4#

Prescription Dose
Isodose (%)

7/ 9

70/ 10.8

47/ 16

20/ 14.5

09/19

14/ 12.9

33/ 5.7

23/ 15

17/ 9.6

No: of pts/
follow up
(mths)

1yr: 50%

1 yr: 71%

1 yr :95 %
2 yr :92 %

57% at 20
months

93% at 18
months

1 yr: 100%
2 yr: 86%

81% at
18 months

2yr 56-58%

1 yr:95%

Local
Control

None

Grade III:10%

None

None

SoftTissue:
10%

Grade III:21%

None

None

11%

Grade III/IV
Toxicity

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424

Anal Canal
Radical radiation with concurrent 5 Fluorouracil and
Mitomycin C is the current standard of care for patients
with anal canal cancer of squamous histology.
Combination regimen leads to 4 year survival of 60-72%,
local control of 61-84% and colostomy free survival of
approximately 70%(1-3). Radiotherapy has traditionally
been delivered with parallel opposed shaped portals
encompassing the primary tumor and draining lymph
nodes to a dose of 45- 50 Gy, followed by a boost to a
dose of 54-56 Gy for T1-T2 tumors and 60 -66Gy for
T3-T4 tumorswhich may either be delivered by means of
external radiation or a combination of external radiation
or brachytherapy(4).

Rationale for IMRT


A) To reduce toxicity and minimize treatment
breaks
In the aforementioned trials the incidence of acute grade
III or higher skin, hematological and GI toxicity was 1741%, 5-34% and 5-31% respectively which resulted in
treatment breaks and admissions for management of skin
reactions.
Late grade III or higher skin and GI toxicities were observed
in 5-10% of patients. The hazard of developing a hip
fracture was increased after large field radiation (HR 3.16
(95% CI 1.4-6.7) and as much as 14% of elderly women
had avascular necrosis of femoral head.(5-7)
Therefore using treatment techniques that can reduce
acute and late treatment toxicity are desirable.
425

B) To improve local control and outcomes.


Traditionally an intended gap of 4-6 weeks was
recommended between phase I and boost to allow healing
of normal tissues however unplanned post-hoc analysis
of Radiation Therapy Oncology Group (RTOG 92-08)
demonstrated superior local control , colostomy free
survival and overall survival in the absence of gap (8)
C) To facilitate dose escalation
While the current recommendations do not demonstrate
a dose response relationship our institutional data suggests
superior loco-regional control, disease free survival and
overall survival in patients with T1-2 tumors receiving 5560Gy and T3 -4 tumors receiving more than 60Gy.(4).
Therefore techniques like IMRT may be helpful in avoiding
severe toxicity when dose escalation is being attempted.
Results of IMRT for Anal Cancers
A) Toxicity Reduction
RTOG 0529 study (which uses IMRT with concurrent
chemotherapy) was associated with statistically significant
reduction in Grade III Skin (49% vs 23%, p<0.0001), GI
(36% vs 21%, p=0.008) and grade II hematological toxicity
(85% vs 73%,p=0.03)(10). Other prospective studies have
reported Grade III or higher Skin, GI and hematological
toxicity of 29-37%, 10-27%,12-34% respectively(9-12)
B) Improved outcomes
Limited prospective non randomized comparisons
performed by Bazan et al. in 46 patients show significantly
improved OS,DFS and LRC at 3 yrs in patients treated with
IMRT as compared to conventional radiotherapy, with
426

lesser treatment interruptions and clinically significant


toxicities(13). Other prospective studies have reported 2
year local control of 84% (9, 11, 12).Limited experience
with SIB IMRT in prospective series has also shown
encouraging OS and DFS at 2 yrs (92& 88%
Respectively)(14). However further follow up is required
for comparison with conventional techniques
Level of Evidence/ Grade of Recommendation:Level IIA
Grade B

Rotational IMRT (VMAT/Tomotherapy)


Two studies have compared performance of rotational
IMRT over fixed beam IMRT. VMAT plans had superior
planning target volume coverage and dose homogeneity,
with improved conformality in treatment of the elective
nodal volume, in comparison to IMRT. Mean dose to the
small bowel, genitalia, and femoral heads were significantly
lower with VMAT, and similar with respect to bladder, pelvic
bones, and normal tissues. Integral dose was comparable
between the 2 techniques. VMAT plans required 36.8%
fewer monitor units, and beam delivery time was shorter
by 9 minutes.
Another study did not show any superiority to standard
IMRT in terms of target and organ at risk dose however
was superior to IMRT in terms of reduced treatment time
(570 vs 290 sec)(15)
Level of Evidence/ Grade of Recommendation: Level III/
Grade C

427

Adaptive Radiation for Anal Cancer:


No Clinical Data
Level of Evidence/ Grade of Recommendation: Not
Applicable

Proton Beam/ Heavy Ion Therapy for Anal


Cancer:
No clinical Data
Level of Evidence/ Grade of Recommendation: Not
Applicable

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431

HEMATOLYMPHOID TUMORS

Introduction
Lymphoma is the most common hematologic malignancy
in the developed world, accounting for 5.3% of all cancers
in the United States and 55.6% of all blood cancers. In
India it accounts for 3.1% of all cancers. Hodgkin
lymphoma (HL) is commonly seen in young adults and
with standard treatment has a 10-year overall survival (OS)
rates of 90%. Non-Hodgkin lymphoma (NHL) generally
affects older patients and with standard-of-care treatment
the 10-year OS rates ranges between 15% and 50% for
aggressive histologies and 60% to 70% for indolent
histologies. Both types of lymphomas, despite different
epidemiology and disease process, have a very favourable
outcome compared to other solid tumours with patients
surviving for decades after treatment.

Standard management
The treatment of early stage favorable HL includes 2 cycles
of multiagent chemotherapy (CTh) followed by involved
field radiation therapy (IFRT). Partial responders (PR) receive
2 more cycles of CTh followed by IFRT. For early stage
unfavorable, 4 cycles of multiagent CTh followed by IFRT
432

is the standard of care. Radiation therapy (RT) is used as


single treatment modality for early stage nodular
lymphocyte predominant HL. For advanced stage HL 6-8
cycles of CTh with or without adjuvant RT remains the
standard treatment. Consolidative IFRT is advocated for
those with PR and to sites of initial bulky disease in case of
complete responders (CR). The radiation dose varies from
20-36 Gy.
For nodal high grade NHL, the standard treatment consists
of CHOP or CHOP like chemotherapy with Rituximab
followed by consolidative IFRT to sites of bulky disease
and partial response. For primary extranodal NHL,
treatment comprises of combined modality therapy with
R-CHOP followed by IFRT (40-45Gy). NK/T cell lymphomas
are aggressive and show good response to radiation
requiring higher dose 45-50Gy for local control.

Role of Radiation
Over the last 2 decades the radiation target volume has
evolved from total nodal irradiation to subtotal nodal
irradiation, involved field radiation & involved nodal/ site
radiation therapy with equivalent overall survival (OS) and
disease free survival (DFS) rates.
The Cochrane metanalysis compared combined-modality
therapy (CMT) in early-stage HL with chemotherapy alone.
Both tumor control and OS were significantly better in
patients receiving CMT. (1)The Tata Memorial Hospital
(TMH) study evaluating the role of consolidation RT after
CR to ABVDx6 cycles showed a statistically significant
improvement of both 8-year event free survival (EFS) and
8-year OS, especially for patients with bulky disease at
presentation. (2)
433

Similarly in NHL, two large cooperative trials from


Southwest Oncology Group (SWOG) and Eastern Oncology
Group (ECOG) have reported improvement in both
progression free survival (PFS) and OS in patients with early
stage disease with CMT compared to CTh alone. (3)(4)

Toxicity patterns
Long-term survivors of lymphoma have been shown to
have an increased risk of developing secondary
malignancies, cardiovascular disease, hypothyroidism, and
cerebrovascular accidents as a result of unintentional
irradiation of normal tissues. Oeffinger et al. reported a
cumulative incidence of 40% grade 3 to 5 toxicities
attributed to chemotherapy and radiotherapy among
lymphoma survivors 25 years following treatment.(5) The
evidence of long term morbidity is based on the era of
large treatment fields, higher radiation doses and
chemotherapy.

Second malignancy
For survivors of HL, there is an increased risk of second
malignancy compared to the general population in the
form of solid tumors, NHL and leukemia with a relative
risk (RR) of 2.3-2.9. Leukemia occurs with a latency of 3-5
years and has a RR of 9.9-14.6. Solid tumours account for
75-80% of SM with a long latency of 7-10 years. These
include breast, lung,colorectal, thyroid, sarcoma, and
stomach cancers. The highest risk is for lung and breast
cancer. For women treated for HL before the age of 30
the risk of developing breast cancer is 6 times greater than
in the general population.

434

Similarly, NHL patients who were treated with radiation


have an increased risk for second malignancy with RR of
1.88. There was an elevated risk of leukemia, lung and
colorectal cancers.

Cardiovascular disease:
The cardiac complications include pericarditis, valvular
dysfunction, conduction abnormalities, coronary artery
disease, and ventricular dysfunction. The risk is higher for
patients receiving anthracyclines and radiotherapy. The
cumulative risk of cardiovascular events at 5 and 12 years
are 5.5% and 14% respectively.(6) The relative risk of death
from cardiac disease is 3.1.

Hypothyroidism
Thyroid abnormalities following RT are observed in
approximately 20%30% of survivors. Most of the times
it is subclinical with elevated TSH and normal T4 levels.

Other toxicity
The combination of mediastinal RT with chemotherapy
including bleomycin is associated with increased risk of
pulmonary toxicity with reduction in median forced vital
capacity (FVC) and diffusing capacity of carbon monoxide
(DLCO). The reported frequency of pulmonary toxicity
ranges between 10 to 25%.

Efforts to Reduce Toxicities


Radiotherapy related toxicities can be reduced by the
following methods:

435

1)
2)
3)

Reduction of dose.
Reduction of radiation fields.
Modern radiation delivery techniques.

Reduction of dose
Engert et al have tried to reduce the intensity of treatment
in early stage favourable HL comparing 2 different dose
intensities of chemotherapy with two different IFRT doses
(30Gy vs 20Gy). There was no significant difference in
freedom from treatment failure or overall survival between
the 2 doses of radiation. Treatment with two cycles of
ABVD followed by 20 Gy IFRT is as effective as, and less
toxic than, four cycles of ABVD followed by 30 Gy IFRT.
Long-term effects of these treatments remain to be
assessed.(7)

Reduction of Radiation Field Size.


IFRT is the most appropriate field for treatment of
lymphomas as the most common site of relapse after
chemotherapy alone is the site of initial disease. It is
essentially part of the classic extended fields and includes
the entire lymph node region. The European HL study
groups recently introduced an additional reduction in the
size of the involved radiation. The reduced size field is
tailored to the involved lymph nodes, is thus termed
involved node radiotherapy (INRT). INRT requires pre-CTh
diagnostic Computed Tomography (CT) and Positron
emission tomography (PET-CT) imaging with the patient
in the treatment position, post-CTh contrast-enhanced CT
simulation, and fusion of the pre-CTh and post-CTh
images. The fields are designed to treat only the initially
involved nodes with modification to avoid organs at risk
436

(OARs). INRT has proven to be as effective as IFRT in terms


of local control as per various retrospective analysis.
However this has not yet been proven in a randomized
trial.
Mulvihill et al compared IFRT and INRT treatment
approaches with respect to the doses delivered to OAR.
All OAR compared in this investigation (kidneys, heart,
thyroid, parotids, and lungs) had significantly lower doses
of radiation with INRT when compared to IFRT (p < 0.05).
Furthermore, the volume of the breast receiving at least
50% of the initial prescription dose was statistically lower
in the INRT.(8)
With evolution of INRT/ISRT, accurate delineation of the
involved node is essential to achieve good control rates
and avoid geographic miss. PET CT based planning has
become essential for implementing INRT. It role is still not
established as a routine. The PET data can be used in 2
ways: 1) Performing a planning PET CT 2) Co registration
of diagnostic PET CT with CT planning. The target volume
is defined using PET CT data by manual delineation or
automatic delineation which is based on quantitative
techniques derived from standardized uptake value (SUV).
(See Table 1)

Advanced techniques
Advanced imaging techniques like PET CT and
sophisticated planning and delivery systems further allow
reduction in the normal structure exposure to radiation.
In an effort of lowering the treatment-related toxicity even
further many advanced conformal radiation techniques
have been introduced.
437

438

135 Stage I/II


supradiaphragmatic
HL

Girinsky et al
2014 (9)

Single center

Multicenter

Type of study

* Radiation Oncologist $ Nuclear Medicine Physician

Terezakis et al 118 patients 2014 (10)


70 NHL, 10 HL,
12 plasma-cell
neoplasm and
3 others.

Number and type

Study

Table 1

INRT
SUV (Max 40)

INRT and visual


assessment
method (VAM)

Technique of
RT and PET CT
interpretation

Target volume was changed


in 87 defined by RO* and in
79 patients defined by
NMP$. PET-GTV (Gross
target volume) defined
by ROs were larger than
those defined by NMPs.

1 additional avid lymph


node in 95 patients and
1 additional lymph node
area in 55. The Clinical
target volume (CTV) was
increased in 60% of
patients.

Findings

Such techniques include 3 dimensional conformal radiation


therapy (3DCRT), Intensity modulated RT (IMRT) and Proton
therapy.
In most situations conventional AP/PA techniques may be
preferred as smallest volume of tissue will be irradiated. A
standard 3D conformal treatment is most appropriate to
reduce normal tissue toxicity. IMRT has been thought to
be less useful in lymphomas as they are highly sensitive to
radiation requiring low doses. Although we have moved
to smaller nodal volumes, larger treatment volumes may
still be necessary to treat bulky disease even after
chemotherapy. Mediastinal Lymphomas present a
challenge for treatment owing to the large treatment
volume and the close proximity of the critical structures.
This is of specific concern in relapsed or refractory cases
where re-irradiation may be required.
There is limited clinical experience in the use of advanced
conformal methods of RT with majority of studies being
dose planning studies. Very few studies report on clinical
outcomes and there is no long term toxicity data derived
from patients treated with modern techniques. There is
also wide variation among the studies with respect to dose
delivered and fields used. The patient numbers in the
studies are also small. Hence the studies should be
interpreted with caution.

Mediastinal Lymphomas
Goodman et al showed that planning target volume (PTV)
coverage was also improved using IMRT compared with
APPA but was not different from the planning target
volume coverage obtained with 3D-CRT. The risk of
439

pulmonary toxicity as measured by the fractional damage


was reduced on average with IMRT by 28% compared
with APPA and 22% compared with 3D-CRT. The mean
lung doses were reduced with IMRT on average, by 12%
compared with APPA and 14% compared with 3DCRT.(11)
Lu et al evaluate the dosimetric and clinical outcomes of
involved-field intensity-modulated radiotherapy (IF-IMRT).
The PTV coverage was excellent. The median mean lung
dose and V20 was reduced with 3-year OS, local control
(LC), and PFS of 100%, 97.9%, and 96%, respectively. (12)
Xu et al studied the use of IMRT in primary mediastinal
large B-cell lymphoma (PMBCL). IMRT gives excellent target
coverage with reduction in mean lung dose and V20. Large
lung volumes received small radiation doses. Owing to
the large target volume, patients had low median doses
to the heart, left ventricle, and female breast. The 5-year
OS and LC were 95.1%and 89.8%.(13)
Koeck et al compared involved-node (IN) and IMRT with
involved-field (IF) and 3DCRT. For IF-PTV/IN-PTV, conformity
was better with IMRT and homogeneity was better with
3D-RT. Mean doses to the heart and spinal cord were
reduced by IMRT, whereas mean doses to lung and breasts
were increased. Pronounced benefits of IMRT were
observed for patients with lymph nodes anterior to the
heart. IN-RT achieved substantially better values than IFRT for almost all OAR parameters,i.e., dose reduction of
20% to 50%, regardless of radiation technique.(14)
Chen et al evaluated noncoplanar IMRT techniques in 19
female patients with mediastinal lymphoma. Compared
to Coplanar IMRT, the mean dose delivered and regions
440

receiving a low radiation dose were significantly reduced


for bilateral breasts and lungs in noncoplanar IMRT (p <
0.05). Breast V5 and lung V5 were relatively reduced by
21% and 12%, respectively. (15)
Filippi et al compared involved-site IG-IMRT with involvedsite 3D conformal RT (3D-CRT) in 90 patients of early stage
mediastinal HL. Three-year RFS was 98.7% for 3D-CRT and
100% for IG-IMRT. IG-IMRT was significantly associated
with a lower incidence of grade 2 acute toxicity (p=0.043).
(16)
Fiandra et al compared five different treatment techniques
3D-CRT, Volumetric Arc therapy(VMAT) (single arc), BVMAT (butterfly, multiple arcs), Helical Tomotherapy (HT)
and Tomodirect (TD) in 10 female patients of early stage
HL receiving INRT. PTV coverage was excellent for all plans
with highest conformality with HT and VMAT. For thyroid
gland and heart/coronary ostia, HT, VMAT and B-VMAT
techniques allowed a better sparing in terms of both
Dmean and volumes receiving intermediate-high doses
compared to 3D-CRT and TD. (17)
Active breathing control (ABC) is an emerging tool to
reduce heart and lung dose in patients of mediastinal
lymphoma. The greatest benefit is for patients with
tumours in upper part of the mediastinum.
Paumier et al assessed the clinical outcomes of INRT
concept in Hodgkins Lymphoma using IMRT and deep
inspiration breath hold technique (DIBH) with 3DCRT. The
lung doses were moderate with both modern radiation
techniques. The median heart dose and V30 was low and
further reduced with DIBH. (18)

441

Charpentier et al evaluated the role of moderate DIBH in


47 patients of lymphoma receiving Mediastinal IFRT. The
use of mDIBH significantly improved average mean lung
dose compared to free breathing lung V20 (28% vs 22%),
and mean heart dose (14.3Gy vs. 11.8 Gy), but increased
the mean breast dose. (19)

Gastric Lymphoma
Biancia et al evaluated IMRT, 3DCRT and AP/PA
conventional fields in 15 patients of lymphoma of stomach.
Patients were categorized into 3 types based on degree of
overlap between the PTV and kidneys. For type I patients
(no overlap between PTV and kidneys), there was essentially
no benefit from using 3DCRT over AP/PA. For patients with
PTVs in close proximity to the kidneys (type II) or with high
degree of overlap (type III), the 4-field 3DCRT plans were
superior, reducing the kidney V15 Gy by approximately90%
for type II and 50% for type III patients. For type III, the
use of a 3DCRT plan rather than an AP/PA plan decreased
the V15 Gy by approximately 65% for the right kidney
and 45% for the left kidney. In the selected cases, IMRT
led to a further decrease in left kidney dose as well as in
mean liver dose. (20)

Orbital Lymphoma
Goyal et al evaluated IMRT in 4 patients of orbital
lymphoma and compared with standard RT plans using
wedged pair fields. IMRT showed good target coverage
with all 4 patients showing complete clinical response.
The average dose to the contralateral orbit, lacrimal gland,
and lens were all significantly reduced in IMRT patients as
compared to the RT patients. IMRT reduced the V5 and
442

V10 for the contralateral lens, orbit, lacrimal gland and


the optic chiasm. (21)

Total scalp irradiation


Gupta et al evaluated the role of HT in brain sparing total
scalp irradiation in 3 patients with extensive scalp
involvement. HT achieved highly conformal and
homogeneous dose distributions with substantial OAR
sparing in all three patients. The volume of PTV receiving
>95% of prescribed dose (V95%) was >98% in all three
patients. The mean dose to the brain parenchyma outside
the PTV was reduced. (22)
Ostheimer et al evaluated coplanar and non-coplanar IMRT
in four patients (2 angiosarcoma, 1 cutaneous B-cell NHL
and 1 mycosis fungoides) receiving scalp irradiation. Noncoplanar plans showed a more homogeneous dose
distribution and superior PTV coverage. Mean and
maximum brain doses were comparable. The optic chiasm
and brain stem was spared most with non-coplanar plans
and mean doses to the lenses ranged between 4 and 8
Gy.(23)

NK T cell Nasal Lymphoma


Shen et al compare radiotherapy treatment planning and
treatment outcomes following 3DCRT and IMRT in 94
patients with stage I-II NK/T-cell lymphoma, nasal type.
IMRT demonstrated significantly better dose coverage and
homogeneity than 3DCRT. 4 year OS and LC rates were
comparable with 3DCRT and IMRT. Of the18 patients who
received cervical lymph node irradiation, those in the IMRT
group received a lower mean parotid dose.(24)
443

Proton therapy (PT)


Proton can help in further reducing doses to the gut, bone
marrow and other organs particularly while treating
mediastinum. It allows for maximal sparing of heart,
esophagus and lungs and at the same time avoids low
dose radiation to lung and heart. The experience is very
limited.
Hoppe et al compared proton therapy (PT) with threedimensional conformal radiotherapy (3D-CRT) and
intensity-modulated radiotherapy (IMRT). The median
relative reduction with PT in body V4 was 51% compared
with 3D-CRT and 59% compared with IMRT. PT provided
the lowest mean dose to the heart, lungs,and breasts for
all 10 patients compared with either 3D-CRT or IMRT.(25)
Hoppe et al reported the early clinical outcomes of
consolidative involved-node proton therapy (INPT) in HL
and showed 3-year Relapse free survival (RFS) rate of 93%,
and the 3-year EFS of 87%. No acute or late grade 3 non
hematologic toxicities were seen.(26)
Sachman et al treated patients with classical HL involving
diaphragmatic or subdiaphragmatic regions with protons
and compared it with 3DCRT and IMRT plans. Median dose
reductions with PT compared with 3DCRT and IMRT were
13 Gy and 8 Gy for the stomach. There was also significant
dose reduction for the liver, pancreas, bowel, left kidney
and right kidney.(27)
The advanced modern techniques increase the volume of
normal tissues receiving low dose (low dose bath)
predisposing to late effects and secondary malignancies.
The risk of late effects have been estimated through normal
tissue complication probability (NTCP) Models.
444

Cella et al compared five treatment radiation techniques


and showed that IMRT, Tomotherapy (TOMO) and Proton
(PRO) plans generally reduced the OARs dose and the
related radio-induced toxicities. For the IMRT and TOMO
plans an increased risk of development of breast, and lung
SM compared with AP-PA and IMRT techniques was
estimated. Only PRO plans seemed to reduce the risk of
predicted SM compared with AP-PA technique. (28)
Various authors have reported on the individualized risk
estimates for the development of second cancers and
cardiovascular disease.
Weber et al compared 3 DCRT with IMRT and VMAT
(radiation-induced lung, breast, and thyroid cancer)(29),
Filippi et al (breastcancer)(30), Maraldo et al (radiationinduced lung and breast cancer)(31), and Jorgensen et al
(esophageal cancer) compared 3DCRT with VMAT and
PT(32). While Weber et al, Filippi et al, and Jorgensen et al
found no significant differences; Maraldo et al estimated
an increased risk from VMAT due to the low-dose bath.
Maraldo et al compared 3DCRT with VMAT and PT and
found that risk for cardiovascular disease were not
significantly reduced with VMAT compared with 3DCRT,
whereas risk was lower with PT.(31)

SUMMARY:
Advanced Radiation techniques have shown an
improvement over conventional techniques in terms of
reduction in dose to lung and heart particularly in
mediastinal lymphomas. (Level Evidence IV) There is
equivalent clinical outcome, however long term toxicity
data is sparse.
445

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452

PAEDIATRIC SOLID TUMORS

The incidence of childhood cancer in most populations in


the world ranges between 75 to 150 per million children
per year. The reported age standardized incidence rate for
India ranges between 38 to 124 per million children per
year. Radiotherapy has been an integral part of the
treatment protocol in most of the paediatric solid tumours.
In children, because the timing coincides with the time of
life where maximum growth and development occurs, it
is particularly important to minimise potential long-term
effects. Late sequelae of radiation in children include
impaired cognitive development and growth, altered
physical appearance and organ dysfunction, leading to
impaired quality of life and the risk of second malignant
neoplasms (SMN). The major advance in paediatric
radiotherapy in recent years has been to restrict maximally
the radiation to the target and to enhance the definition
of the target volume using improved and new methods
of imaging. Newer techniques including intensity
modulated radiotherapy (IMRT), image guided
radiotherapy (IGRT) and particle therapy has been major
steps in respect to these.

453

NASOPHARYNGEAL CARCINOMA (NPC)


Introduction
It accounts for less than 1% of the paediatric cancers. Most
often it presents as an advanced loco regional disease.
More than 90% of patients have EpsteinBarr Virus (EBV)
associated tumors with the predominant histology of
WHO Type II (non-keratinizing) and WHO Type III
(undifferentiated) in endemic countries. The current
standard of care is chemo-radiation including neoadjuvant
chemotherapy followed by radiotherapy. The Rare Cancer
Network study on Pediatric NPC (1) reports a 5-year overall
survival (OS) of 77.4% and the actuarial 5-year diseasefree survival (DFS) rate as 68.8%.The ten year follow-up
study (2) from Tata Memorial Center with a median followup of 50 months, showed disease-free survival (DFS) and
overall survival (OS) rate of 45% and 54% respectively,
using conventional radiotherapy techniques.
Toxicities
The TREP project (3) reported that around 65 % of patients
post radiotherapy treatment had late side effects. Most
commonly observed were hypothyroidism (54 %),
Xerostomia (50%), Neck fibrosis (38%), Trismus (35%),
Hearing loss (27%), GH deficiency (23%), Dental Caries
(23%), Chronic/recurrent sinusitis and otitis (19%) and
pulmonary fibrosis (15%). Severe late (Grade 34) effects
included clinical hypothyroidism, neck fibrosis, blindness,
myelitis and secondary cancer.

454

Conventional and advanced techniques


Conventional techniques
In conventional techniques, external beam radiotherapy
is delivered to the nasopharynx and lymphatic drainage
areas using 60Co rays or 6-MV photons with bilateral
parallel opposed fields or with three field techniques. In
paediatric and adolescent NPC treated with twodimensional radiotherapy, the loco regional relapsefree
survival rate was approximately 80%, with an incidence
of late sequelae of 65%85%. Total dose usually delivered
is around 70.2Gy/1.8Gy per fraction/5 days a week. Rare
Cancer Network study group (1) also reports that a
radiation dose of >66 Gy resulted in a significantly better
outcome (LRC rate of 90% vs. 73%, p = 0.01).
Advanced Techniques
Conformal techniques including IMRT have been shown
to have good LRC, DFS and OS in adult nasopharyngeal
carcinoma. But there is no clear cut evidence in paediatric
patients. The Tata Memorial Centre study (4) reported on
the feasibility and outcome with the use of IMRT for
children with nasopharyngeal cancer. The study reported
a significant reduction in acute Grade 3 toxicities of the
skin (p =0.006), mucous membrane (p = 0.033), and
pharynx (p = 0.035) with the use of IMRT. The median
time for the development of Grade 2 toxicity was delayed
with IMRT (skin, 35 vs. 25 days, p = 0.016; mucous
membrane, 39 vs. 27 days, p = 0.002; and larynx, 50 vs.
28 days, p = 0.009). The average mean dose to the first
and second planning target volume was 71.8 Gy and 62.5
Gy with IMRT as compared to 66.3 Gy (p = 0.001) and
64.4 Gy (p = 0.046) with Conventional RT. The dose to
455

the parotid glands, spinal cord, optic chiasm, inner ears,


and brain stem was significantly greater with conventional
RT .The mean dose to the parotid glands was 37.17 Gy
(right) and 39.44 Gy (left) using IMRT vs. 57.31 Gy and
56.82 Gy with conventional RT respectively.

RHABDOMYOSARCOMA
Introduction
Rhabdomyosarcoma (RMS) is the most common soft tissue
sarcoma in children and adolescents. The treatment
algorithm for RMS is based on risk stratification, which
incorporates group, stage, histology and age of initial
diagnosis. Three histological types of RMS have been
described: embryonal, alveolar and pleiomorphic.
Management includes surgery, radiation therapy and
chemotherapy. The 3 year FFS and OS rates for group I/II
orbital and eyelid tumours on IRS IV (5) were 89 and 100%,
respectively. The reported 5 year local control rate in
primary head and neck RMS is of the range of 70%. In
parameningeal RMS, 5 year local failure rate reported is
around 17% and the 5 year OS and FFS rates are 73 and
69%, respectively. Gynaecological RMSs are highly curable
tumours with a 5 year overall survival rate of 82% in IRS IIV (5, 6). In case of extremities the 3 year survival for
patients with lymph node-positive disease was 46%
compared with 80% for patients with lymph node-negative
disease.
Toxicities
Head and neck
The IRS II and III data of 469 patients showed that 48% of
children failed to maintain their initial height velocity.
456

Hypoplasia or asymmetry of tissues in the primary tumour


site was reported in 15% of patients. Poor dentition or
malformed teeth were noted in 13% of patients. Impaired
vision developed in 7.8% of patients, owing primarily to
cataracts, corneal changes, and optic atrophy. About
eight percent of patients had decreased hearing acuity.
Other toxicities noted include learning problems, and
second malignancies.

Pelvis
The study by Spunt et al (7) noted the late effects in pelvic
RMS, of which endocrine effects were the most frequent
(77%). Endocrine effects include short stature, obesity,
hypothyroidism, GH deficiency and precocious puberty.
GI toxicities (69%) notably intestinal complications
(strictures, obstruction, perforation, and chronic enteritis)
were the most common grade 3/4 late effects.
Gynaecological late effects in the form of vaginal stenosis
requiring dilation, fistula, chronic pelvic pain, pelvic floor
disorder and vaginal dryness were noted in and around
58 % of patients. Other noted side effects include
musculoskeletal, renal and second cancers. The cumulative
incidence was 13.5% at 20 years.
Conventional and advanced technologies
Conventional therapies
The dose, duration and timing of external beam
radiotherapy (EBRT) are dependent on the clinical group
and the site of disease. After surgery, most patients with
microscopic residual and uninvolved nodes received 36
Gy, patients with involved nodes received 41.4-50.4 Gy
and patients with orbital primary tumours received 45 Gy
as definitive treatment.
457

Advanced Technologies
IMRT is particularly useful in the region of the head and
neck (H&N) where gross residual disease is frequently
present and therefore, a higher dose of 50.4 Gy is required
for disease control. Wolden et al (8) showed that excellent
local control can be maintained with the use of decreased
margins using IMRT for H&N. Three year local freedom
from relapse was 95%. Acute toxicity was comparable with
reported rates from the IRS and late toxicity was mild. The
study by Curtis et al (9) showed excellent results with 4year overall survival and local control rates being 76% and
92.9% respectively. From these studies, late toxicity was
seen in 32% to 47% of patients and reported as endocrine
abnormalities (4% to 11%), facial hypoplasia (4% to 10%),
dry eye (0% to 16%), cataracts (0% to 11%), and secondary
malignancies (0% to 5%).
Lin et al (10) compared dosimetric parameters of IMRT
and 3D-CRT in the 375 intermediate-risk patients enrolled
in the COG protocol D9803 study. They found no
differences in the 5 year local failure (18% versus 15%) or
FFS (72% versus 76%) rates between the two groups. The
coverage of the IMRT planning target volume by the
prescription dose was improved compared with
3D-CRT.Surprsingly this study failed to show a statistically
significant reduction in dose to the critical organs with
IMRT .The study also showed that patients receiving IMRT
were more likely to receive >50 Gy, photon energy of
</=6 MV, and >5 radiation fields than those who received
3D-CRT.. Studies on dose painting IMRT (11) also has
shown similar local control rates to that of sequential IMRT.

458

Proton therapy
There have been several dosimetric studies comparing and
showing superiority with proton therapy. In the study by
Yock et al (12) on orbital RMS found that with protons
there was significant dosimetric sparing of orbit, lens and
the brain. In comparison with 3-DCRT, a significant
percentage saving of the contralateral orbital structures
was noted.
A recently published study by Labra et al (13) did show
similar local control, EFS (Event free survival) and OS with
proton therapy as well as better toxicity profile. 5-year EFS
was 69%, local control 81% and OS was 78% in the entire
cohort. Acute side effects with Grade 3 reactions in the
form of radiation dermatitis occurred in 9% of the patients
(16 % with conventional treatment -IRS-IV data) and
mucositis in 16% (46% with conventional treatment). Late
toxicity of any grade was seen in 35% of the patients. In
patients with orbital and head and neck sites, observed
late side effects were endocrine abnormalities in 9% (0%
orbital and 14% head and neck and parameningeal sites),
facial Hypoplasia in 9% (8% orbital and 10% head and
neck and PM sites), dry eye in 9% (17% orbital and 5%
head and neck and PM sites), cataracts in 3% (8% orbital
and 0% head and neck and PM sites), and no secondary
malignancies.
IMRT or proton radiotherapy has particular utility in the
parameningeal region where the close proximity of the
critical structures, such as the optic apparatus, can limit
the target volume (14). A dosimetric comparison of proton
therapy and IMRT for 10 patients with parameningeal
tumours showed increased sparing of contralateral optic
structures, cochlea and mastoids (15).
459

In bladder and rectal rhabdomyosarcoma the use of


conformal therapy with IMRT or protons may improve the
preservation of bladder and rectal function and reduce
the dose to the pelvic bones. The study by Cotter et al (16)
showed that proton radiotherapy led to a significant
decrease in mean organ dose to the bladder (25.1 CGE
vs. 33.2 Gy; p = 0.03), testes (0.0 CGE vs. 0.6 Gy; p =
0.016), femoral heads (1.6 CGE vs. 10.6 Gy; p = 0.016),
growth plates (21.7 CGE vs. 32.4 Gy; p = 0.016), and
pelvic bones (8.8 CGE vs. 13.5 Gy; p = 0.016) compared
to IMRT.

RETINOBLASTOMA
Introduction
It is the most common intraocular malignant tumour in
early childhood and the second most common tumour in
all age groups. Retinoblastoma has excellent cure rates
with 10-yr ocular preservation and patient survivals being
75.4% and 92.3%, respectively (17). External beam
radiotherapy is an established and extremely effective
treatment for retinoblastoma.
Toxicity
The proximity between the retina and the other structures
of the visual system, which are sensitive to radiation, pose
a challenge for RT planning. During treatment radiation
dermatitis, conjunctival and corneal congestion are of
major concern. Effect on lens leading to cataract occurs
in almost all cases in view of its low tolerance
(approximately 12 Gy) and because of its close proximity
to ora serrata (18-19). Radiation to orbit leads to late
effects in the form of hypotelorism, enophthalmos,
460

depressed temporal bones, atrophy of the temporalis


muscle, and narrow and deep orbits. Study by Peylan Ramu
et al (20) found the mean volume of radiated
Retinoblastoma orbits (14.4 cc) was significantly smaller
than control orbits (17.8 cc). Also the mean orbital
asymmetry index in control children (2.6%) was
significantly lesser than RB survivors (14%). Doses applied
to the lacrimal gland could lead to dry eye syndrome and
keratoconjunctivitis sicca, impairing the patients quality
of life .The study by Rodjan et al (21) looking at the second
primary tumour found those associated with retinoblastoma were predominantly osteosarcomas and
rhabdomyosarcomas. Predilection sites seen were:
temporal fossa, ethmoid sinus, orbit, maxillary sinus and
intracranial duramater (4%).

Conventional and advanced technologies


Conventional treatment
An ideal treatment in retinoblastoma should be able to
generate a homogeneous coverage of the entire retina
and of the entire vitreous in patients with advanced stages
of retinoblastoma (Stage Va and Vb in Reese Ellisworth
classification). Most commonly a dose of 45 Gy/25# is
used. There are about 13 techniques being described
including both conventional and conformal in treating
retinoblastoma. In conventional techniques lateral
collimated D-shaped field by Schipper et al (22) and
another lateral field technique by McCormick/ Blach (23,
24) generated the best dosimetric results. Newer
radiotherapy delivery techniques including IMRT and
fractionated stereotactic RT and new technologies such
as VMAT and helical tomotherapy and new modalities such
461

as protons provide better sparing of normal structures than


previously possible.

Intensity Modulated radiotherapy


In a dosimetric study by Reisner et al (Level IV
recommendation) (25) comparing IMRT with other
conventional and conformal techniques found out that
the therapeutic dose to the ora serrata retinae was achieved
better with IMRT compared to most of the other
techniques. The IMRT technique achieved the lowest
volume that received a dose of >34 Gy (14%) in the
lacrimal gland. The study by Krasin et al (26) showed IMRT
techniques reduced the dose to the surrounding bony orbit
by more than one-third compared with anterior-lateral
photon and electron techniques, and by 23 % compared
with conformal techniques. The mean volumes of ipsilateral
bony orbit treated above 20 Gy (a suggested threshold
for bone growth) are 60%, 78%, 91% and 89% for
intensity-modulated, conformal photon, anterior-lateral
photon and en face electron techniques, respectively, with
a prescribed dose of 45 Gy. IMRT technique has shown
similar integral dose as compared to other techniques. In
the study Eldebawy et al (27) comparing conventional
treatment with 3-DCRT, IMRT, VMAT (Volumetric
modulated arc therapy) and helical tomotherapy(HT) found
that the volume receiving at least 20 Gy (V20Gy) for the
ipsilateral bony orbit was lowest for the VMAT and HT
techniques (56%) and highest for the CRT techniques
(90%). Similarly VMAT and helical tomotherapy showed
the highest conformity index.

462

Plaque therapy
Episcleral brachytherapy is considered an attractive option
in retinoblastoma which can avoid or delay external beam
radiotherapy. 25 I, 103 Pd, 106 Ru, and 90 Sr plaques are
commonly used. American Brachytherapy Society Ophthalmic Oncology Task Force (ABS-OOTF) recommends
(Level 2 Consensus) that ideal tumours for primary
brachytherapy are located anterior to the equator and in
unilaterally affected children (28). Residual or recurrent
tumours are treated irrespective of location. The study by
Merchant et al (29) noted the eye preservation rate was
about 60% (15/25) with a median follow-up of 47 months
with plaque brachytherapy.
Proton therapy
There are published studies showing superiority of protons
in local control with minimal toxicity .The study by Mouw
et al (30) with a median followup of 8 years showed post
proton radiotherapy enucleation rate was low (18%),
especially in patients with early-stage disease (Level IV
recommendation). Twenty percent of the post proton
radiotherapy patients required an intervention, in which
cataract was the most common. There was no incidence
of second cancers.

WILMS TUMOUR
Introduction
Wilms tumour (WT) or nephroblastoma is the most
common renal neoplasm of childhood. Treatment is
multimodality including radiation therapy, chemotherapy
and surgery. At this moment, with an overall survival rate
463

of 85%, WT is one of the most successfully treated


childhood cancers.

Toxicities
Common treatment-related adverse events in WT survivors
are tissue hypoplasia, orthopaedic events, cardiovascular
events, pulmonary events (in case of chest radiotherapy)
and second malignancies. Orthopaedic events noted in
the study by Paulino et al (31) were in the form of scoliosis
(42.9%), muscular hypoplasia (16.7%), limb length
inequality (11.9%), kyphosis (7.1%), and iliac wing
hypoplasia (7.1%). Bowel obstruction noted at 5, 10, and
15 years was 9.5 %, 13 % and 17%. About 9.5% developed
benign neoplasms (osteochondroma, lipoma) and 7.1%
developed a second malignant neoplasm. Only one
patients developed ovarian failure. Toxicities were mostly
reported in the NWTS (National Wilms tumour studies)
protocols where patients had received a higher dose of
radiotherapy and also orthovoltage therapy. Currently with
the lower dose of mega voltage equipment the late toxicity
of radiotherapy may be less than previously reported. The
cumulative frequency of congestive heart failure (CHF) is
4.4% at 20 years with the relative risk of CHF increasing
with doxorubicin dosage (3.3/100 mg/m2), lung irradiation
(1.6/10 Gy), and left abdominal irradiation (1.8/10 Gy)(32).
Pulmonary complications are seen in approximately 4%
of patients at 15 years from diagnosis, with substantially
higher risk in patients who received whole-lung irradiation
(WLI) due to pulmonary metastases (33).

464

Conventional Techniques
Before the introduction of chemotherapy, radiation used
to be used to be a substantial part in the treatment this
tumour. Conventional treatment is usually given to flank
or whole abdomen with parallel opposed portals. In Stage
III Wilms, 10.8 Gy to flank or whole abdomen is given. In
patients with pulmonary metastases, a dose of 12 Gy to
whole lung is given. The study by Van Dijk et al (34) showed
that radiotherapy itself was the highest risk factor for
adverse events. Study by Paulino et al showed that children
treated with lower doses (<2400 cGy) had a lower
incidence of scoliosis compared with those who received
more than 2400 cGy.
Advanced Technologies
Though there are no controlled trials, studies have shown
that 3-D conformal radiotherapy (35) helps in reducing
toxicities and escalating doses for better tumour control.
A study by Hill brand et al (36) compared conventional
techniques with IMRT and proton therapy. Using IMRT,
V15Gy for the kidneys was reduced by a factor of 23 and
V12Gy of liver was reduced by 40% compared to
conventional techniques. With respect to the conventional
2 field technique, proton therapy and intensity modulated
proton therapy (IMPT) enabled to reduce mean liver and
kidney dose by 4060%.
In the study by Kalapurakal et al(37), in patients of Wilms
tumour with liver metastasis undergoing whole liver
radiotherapy, the IMRT and 4D treatment planning resulted
in the delivery of a higher RT dose to the liver compared
with the standard AP-PA technique.
465

NEUROBLASTOMA
Introduction
It is the most common extra cranial tumour of childhood.
Historically, the survival rates were dismal, <20%. The
modalities employed in the management include surgery,
chemotherapy, and radiation therapy with radiation
therapy being employed mainly in the high risk group.
With improvements in aggressive multimodality treatment,
the 5- and 7-year survival rates are about 60% and 53%,
respectively. The addition of RT to the group of patients
with more residual loco regional disease does improve the
local failure rate to approximately that of patients with
less residual disease (38). Although the radiation doses
used for neuroblastoma are low, the volume of tissue
receiving radiation is often large, and the patients are very
young. Although there have been no randomized trials of
radiation therapy in patients with high-risk disease, there
is evidence of a dose response in the Childrens Cancer
Group (CCG-3891) trial (39).
Toxicities
For typical retroperitoneal locations, the main organs at
risk are the kidneys and liver. Acute toxicities observed
during radiation include vomiting and skin erythema
.Vertebral bodies, liver and kidney are the major organs at
risk. Heterogeneous dose distribution in the vertebrae can
lead to long term skeletal side effects.The study by Paulino
et al (40) showed the 10 and 15-year musculoskeletal
toxicity rates were 38.5% and 47.3% for those receiving
RT and 3.3% without RT (p=0.02). Musculoskeletal
abnormalities noted in the study were bony hypoplasia,
scoliosis, soft tissue hypoplasia, slipped capital femoral
466

epiphysis, kyphosis and osteochondroma. Evaluation of


liver and kidney toxicities as a function of time is a complex
endpoint, since these organs may sustain subclinical
damage and the potential toxicity of high dose
chemotherapy (of more concern in patients undergoing
transplantation).

Conventional and advanced technologies


Conventional techniques
Commonly conventional techniques include that of
AP-PA portals. In the setting of minimal residual disease, a
dose of 21-24 Gy is considered while in the presence of
gross disease the dose is increased up to 36 Gy.
Advanced Technologies
Intensity modulated Radiotherapy
A St Judes study (41) showed that IMRT delivered is
feasible, safe in the short term, and yields excellent local
control. They also recommended that dose escalation to
control gross residual disease may not be necessary with
improvement in target volume coverage when using IMRT.
IMRT plan reduced the mean PTV and the mean body dose.
The dose to ipsilateral kidney was reduced from 70.1% to
66.0%, that to the contralateral kidney was reduced from
56.3% to 40.7%, and that to the liver was reduced from
57.8% to 22.1%.
In a dosimetric study by Piergenelli et al (42) the conformity
index and the healthy tissues conformity index were nearer
the ideal value 1 for IMRT than for the 3D conformal, and
the percent difference between the mean values was 25%
and 31%, respectively.
467

In the study by Paulino et al (43) comparing IMRT with


conventional RT found that Technique C (a type of IMRT
in which vertebral body adjacent to GTV included in the
target) was the best method of RT delivery in midline
tumours with respect to kidney doses, but this was at a
cost of a higher mean dose to the liver, stomach, and
spleen. It also showed that IMRT was not found to be
better than the conventional AP/PA field for lateralized
tumours.

Image guidance
In the study by Nazmy et al (44) found the use of EPID or
CBCT to help in reducing the PTV margins especially when
daily image guidance is employed. The range of target
movement in the craniocaudal direction (CC) was 5 mm.
Proton therapy
In study by Hattangadi et al(45) in a dosimetric study
showed substantial improvement in normal tissue sparing
of heart, lungs, and kidneys with the use of IMPT(Intensity
modulated proton therapy) in comparison to IMRT and
also 3- D conformal proton therapy (Level 4 evidence). At
a median follow-up of 38 months with proton therapy
(range 11-70 months), there were no local failures. In
another study by Fuji et al (46) comparing conventional
RT with proton therapy and IMRT found in the evaluated
OARs, the mean dose in Proton therapy was 2080% of
that in Conventional RT. Assessments of second cancer
risk showed that Proton beam therapy reduces the risk of
secondary cancer in most organs, whereas IMRT is
associated with a higher risk than Conventional RT. The
risk of secondary cancer in proton therapy based on risk
estimation calculations found that it was 2483% of that
468

in Conventional treatment for five organs, but 121% of


that in CRT for pancreas. The risk of secondary cancer in
IMRT was equal to or higher than CRT for four organs
(range 100124%).

Summary
Though outcome data is limited there is evidence to
suggest a better toxicity profile with the use of advanced
technologies in paediatric patients. In view of the rarity of
these tumours controlled trials may not be always feasible
and thus clinical judgment plays an important role. There
still exists a tremendous scope for further research in this
field which needs to be encouraged.

References
1)

2)

3)

Ozyar E, Selek U, Laskar S, Uzel O, Anacak Y, BenArush M, Atahan IL. Treatment results of 165
paediatric patients with non-metastatic
nasopharyngeal carcinoma: a Rare Cancer Network
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476

BONE AND SOFT TISSUE


SARCOMAS

SOFT TISSUE SARCOMAS


Introduction
Soft Tissue Sarcomas (STS) comprise 1% of all adult
cancers. A wide spectrum of histological varieties namely
Fibrous tumours, Fibro-histiocytic tumours, Lipomatous
tumours, Leiomyosarcoma, Rhabdomyosarcoma,
Malignant neural tumours, Synovial sarcoma etc are
described. Most occur in the extremities (60%), followed
by retroperitoneum (20%), abdominal/thoracic wall (15%)
and head and neck (5%). Median age of onset is 50-55
years. Reported 5-year survival for all stages is 5060%.
Radiobiologically, they are considered to be relatively less
radiosensitive (documented alpha/beta ratio is 0.4).
Standard Management
Limb-sparing surgery followed by adjuvant radiotherapy
is considered the standard of care for most patients with
soft-tissue sarcoma of the extremities. Preoperative
radiotherapy is advocated in unresectable tumours and in
some institutions as a standard of care. In selected group
of patients, adjuvant brachytherapy is feasible. In pelvic
477

and head and neck regions, treatment is tailored to


individual patient depending on tumour location and
characteristics with respect to the adjacent normal tissue
to ensure less morbidity without jeopardizing the outcome.
Dose delivered in definitive setting is 66-68 Gy, in post
operative setting is 60 Gy and in preoperative setting 4550 Gy (with postoperative boost if indicated).

Role of Radiation Therapy


It has been shown that overall survival is not compromised
by Wide loeal excision (WLE)+ Radiotherapy (RT)vs.
Amputation; hence Radiotherapy is an integral component
of Limb salvage treatment. In high grade STS and residual
disease, adjuvant radiotherapy is indicated.
Outcomes of treatment with conventional
techniques of radiation therapy
1) Local controlThe 3 and 5-year local relapse rate for extremity STS treated
by conventional techniques of EBRT are approximately 22%
(1335%) and 25% (1539%) respectively (1) .Local
recurrence for pelvic STS is seen in 23% patients (2).
2) ToxicityReported toxicities are fibrosis (57%), moderate to severe
decrease in the range of joint motion (32%), moderate to
severe decrease in muscle strength (20%), contracture
(20%), >grade I muscle edema (19%), pain requiring
medications (7%), bone fracture (6%)(3). In retroperitoneal
sarcomas, there is 18% severe (Grades 35) toxicities such
as elevated creatinine levels, ureteral injury requiring
stenting, and neuropathy (4). Wound complication is a
significant complication with preoperative RT (34%).
478

3) Determinants of toxicityRadiation treatment volume and radiation dose are


independent factors predicting grade 2 or higher fibrosis,
edema and joint stiffness. The risk of radiation-induced
fracture is reduced with V40 <64%. The incidence of
fracture is lower with mean bone doses of <37Gy or
maximum dose anywhere along the length of bone of
<59Gy. Grade 3 or greater wound complications can be
decreased using meticulous treatment planning to
decrease the tissue volume encompassed by the 150%
isodose line, especially in lower limb locations.
4) Patterns of failureMajority of patients relapse within the primary site of
disease or within the original tumour bed or within 2cm
from the tumour margin.
Implications of advanced radiation technologies
a)
b)

Dose escalation and better disease control.


Reduction of late toxicities improving quality of life.

Advances in target definition


MRI-CT fusion helps in proper target delineation as shown
by Vancouver cancer centre. Mean target volume was
reported be 1.2 times smaller with fusion rather than with
CT alone. Intra and inter-observer variation is reduced
significantly with the help of MRI fusion(5). Poor correlation
between the PET/CT defined and MRI defined volumes
leads us to conclude that it is unlikely that PET/CT will
make a significant contribution in GTV redefinition for STS
patients. If used, a threshold SUV value of 2 or 2.5 is
recommended (6).
479

Advances in Radiotherapy planning


1) Extremity STSFor patients with a small, superficial PTV, 3 dimensional
conformal radiation therapy (3D-CRT) may provide
adequate treatment without the added cost and
complexity of an IMRT approach. A greater decrease in
dose was seen using Intensity Modulated Radiotherapy
(IMRT) in patients with large PTVs (volume of the central
PTV slice greater than 50% of the central thigh slice) and/
or where PTV covered greater than 50% of the transverse
diameter of the femur (7) . Better conformity and
significantly reduced high dose to surrounding structures
with IMRT compared to 3DCRT has been proven in multiple
studies (8,9). IMRT can be used to spare the planned skin
flap site in preoperative RT to reduce incidence of wound
complications (10).
Improved dosimetry has been documented to translate
into better local control. The reported 5 year actuarial local
control, distant control and overall survival rates with
adjuvant IMRT are 94%, 61% and 64% respectively.
Toxicities documented commonly are Grade 1 RT dermatitis
(61%), grade 2 dermatitis (36%), wound infection (13%),
non-infectious wound complications (10%), fractures
(6.5%), grade 1 sensory deficit (29%), grade 2 sensory
deficit (9.5%), grade 1 and 2 joint stiffness (each 19%),
grade 1 edema (19%) and grade 2. (13%) IMRT was not
associated with an increased risk of marginal miss(11).
In an analysis of 319 non metastatic extremity STS patients,
Folkert et al (12) showed that in spite of a preponderance
of patients with poorer prognostic factors, IMRT resulted

480

in superior local control rates compared to conventional


RT (HR 0.46). In a retrospective comparison of adjuvant
IMRT Vs Brachytherapy (BRT)(13) , the 5-year Local control
(LC) rate was 92% for patients treated with IMRT compared
to 80% for BRT(p= 0.03). On multivariate analysis, IMRT
was the only predictor of improved LC (p = 0.029).

2) Retroperitoneal SarcomasIMRT significantly improves target coverage with reduction


of dose to small bowel and ipsilateral kidney compared to
3DCRT though dose to contralateral kidney is marginally
increased. In a study of 10 patients treated with
preoperative RT, Mean dose to small bowel decreased from
36Gy with 3D-CRT to 27 Gy using IMRT. Importantly,
maximum and minimum doses delivered to the PTV were
significantly increased by 6 and 22%, respectively. Volume
of small bowel receiving > 30Gy was significantly
decreased from 63.5 to 43.1% with IMRT compared with
conventional treatment. There was 100% resectability and
no patient had local recurrence at median follow up of 58
months. It was concluded that there is possibility of dose
escalation leading to enhanced resectability in preoperative
setting thereby resulting in superior outcomes. Late
morbidities are consequently reduced to a great extent (14).
3) Other sitesIMRT helps to reduce cardiac dose, lung dose
heterogeneity, mean liver dose in whole lung irradiation
of patients treated for oligolung metastases (15).

481

4) SBRT for Lung MetastasesReported 5-year overall survival rates following


metastasectomy is 20 to 40%. With SBRT to lung
metastases to a median dose of 54 Gy, local control was
94%. Overall survival at 4 years was 72%. No patient
experienced G2-4 radiation pneumonitis, and no patient
experienced radiation esophagitis (16).
Particle therapy in STSThe five-year overall and recurrence-free survival rates with
proton beam therapy to a dose of 76.6 Cobalt grey
equivalent (CGE) were 87% and 63% respectively, and the
five-year local control rate was 78% (17). Compared with
IMRT, target coverage is significantly improved while
integral dose is almost halved when using proton beam
therapy (18). In intra abdominal sarcoma, proton therapy
significantly reduces dose to bowel, ipsilateral as well as
contralateral kidney allowing scope for dose escalation (19).
In unresectable sarcomas of retroperitoneum, radical RT
with carbon beam therapy has shown promising results
(LC at 2 and 5 years of 77% and 69% without any grade 2
or more toxicity) (20).
Advances in treatment delivery verification
Image guided radiotherapy (IGRT) plays a very crucial role
especially in case of paraspinal sarcomas. Without
corrected positioning, the dose to 0.1 cc of the spinal
cord increased by 9.4 Gy, and the doses to 95% of clinical
target volumes 1 and 2 were reduced by 4 Gy and 4.8 Gy
respectively in a study by Hansen et al (21). Optimal doses
can thus be delivered due to tighter PTV margins.

482

Immobilization techniques in extremity STS


Proper immobilization is a critical component for safe
execution of advanced radiotherapy techniques.
Immobilization of the extremity is usually achieved using
alpha-cradle, ankle casts, customized immobilization
devices, or negative pressure vacuum air cushions. However
customized immobilization devices namely modified
thermoplastic mould helps in accurate reproducibility as
seen in reports (22). For thigh lesions, a frog leg position
enabling the limb to go away from the pelvis and opposite
limb is ideal. For upper limb lesions, the swimmers
position is described. For treatment with IMRT a neutral
supine position is recommended to maximize
reproducibility.
Contouring guideline
CTV for high-grade large STS typically includes the GTV
plus 3-cm margins in the longitudinal directions. If this
causes the field to extend beyond the compartment, the
volume can be trimmed at appropriate fascial / bony /
cutaneous boundaries. The radial margin from the lesion
should be 1.5 cm, including any portion of the tumor not
confined by an intact fascial barrier, bone, or skin
surface (23).
Brachytherapy
The American Brachytherapy Society (ABS) recommends
the use of BRT as adjuvant monotherapy for patients with
completely resected intermediate or high-grade sarcomas
of the extremity or superficial trunk with negative margins
(R0 resection). In recurrent STS, Salvage Surgery with
Brachytherapy is a feasible option.
483

EWINGS SARCOMA/PNET
(Primitive Neuroectodemal Tumour)
Introduction
Ewing sarcoma is the second most common primary bone
tumor in children and adolescents with an incidence of
2.8 per million children population. 30% occur in first
decade of life and 10% occur in the third decade. The
most common primary sites are pelvis followed by the
femur, tibia and flat bones of the axial skeleton. The 5year OS ranges from 40% to 60% in multiple studies. They
are characterized by unique chromosomal translocations
and are relatively radiosensitive tumours. Chest wall is a
unique location for Ewings sarcomas (6% to 11% of total
ES) characterized by more local relapses.
Standard management
Poly-chemotherapy (vincristine, etoposide and
actinomycin-D/doxorubicin based) with tailored local
treatment (surgery and/or radiotherapy) is the standard
management for non metastatic Ewings sarcoma. Surgery
is preferred as local treatment whenever feasible. In critical
locations with anticipated surgical morbidity, radiotherapy
is often chosen as the local modality. Adjuvant EBRT is
indicated in the setting of residual disease and in poor
responders to chemotherapy. Hyperfractionated
radiotherapy is found to be beneficial in some studies but
it is not the standard of care. The dose of radiotherapy in
definitive setting is around 55.4 Gy @ 1.8 Gy/fraction
whereas in adjuvant setting it is administered to a dose of
50.8 Gy @ 1.8 Gy/fraction.

484

Role of radiation therapy


The 5-year local and combined relapse rate after radiation
alone or combined surgery and irradiation was 13% in
CESS 86 and EICESS 92 (24). The 5-year outcome following
multidisciplinary therapy reveals local control rates of 74
93%. With a local failure of only 18-23% among all
patients treated with RT, RT is an effective modality for ES
in most patients.
Outcomes of treatment with conventional
techniques of radiation therapy
1) Local controlThe total local recurrence rate documented is 33% for
central lesions, 25% for proximal, and 7% for distal, with
an overall recurrence rate of 23% with chemotherapy and
radical radiotherapy (25). Suboptimal doses and portals lead
to unacceptably high incidence of relapse as seen in CESS
81 concluding that proper radiotherapy is in integral factor
for local control. For pelvic Ewings sarcoma, documented
results are a 5-year survival rate of 31% and a local failure
of 34% after radical radiotherapy (26).
2) ToxicityReported toxicities are atrophy (80%), fibrosis (80%), bone
growth retardation (67%), impairment in extremity
mobility and function (40%), edema (20%), peripheral
nerve injury (13%) and incidence of fractures(44%)(27).
Donaldson et al. reported the results of the Pediatric
Oncology Group #8346 and found that at 5 year, only 61%
were free from any serious orthopedic complications and
majority of them needed secondary surgeries like prosthesis
repair, fracture reduction, secondary amputation (28). This
485

has important clinical implications. Other toxicities are


scoliosis or leg shortening, breast hypoplasia, peroneus
paresis, artificial menopause, second malignant neoplasm
and femoral head necrosis. In spinal ES, toxicities are spinal
curvature deformation (35%), growth retardation (28%),
spinal reduction mobility (40%), spinal pain (25%) and
neurological sequelae (32%) (29). In pelvic RT, there is risk
of hemorrhagic cystitis and proctitis also.

3) Second malignant neoplasm in ES survivorsIt was seen that there is 6.5% incidence of secondary
sarcoma at 20 years in the irradiated field of Ewings
sarcoma patients. The incidence of secondary sarcomas
was radiation dose dependent, with no secondary
sarcomas occurring at <48 Gy(30).
Advances in radiotherapy techniques
In extremity and pelvic Ewings sarcomas, the benefit of
conformal techniques has been documented along with
other histological varieties also. When 3DCRT was
compared to IMRT in a study (31), it was seen that IMRT
plans had a higher conformity index compared to the 3DCRT plans but lower Homogeneity Index (statistically
significant). For the bowel, Dmean and D1%, as well as
V2 to V60 were reduced in IMRT plans. For the bladder
and the rectum, though Dmean in both the plans was not
statistically different, but the V30 to V50 were lower for
the rectum in IMRT plans. The V2 was significantly higher
in IMRT plans compared with 3D-CRT, whereas at high
dose levels (V30) it was significantly lower.
Irradiation in chest wall tumours is challenging due to
natural curvature of chest, surface non homogeneity and

486

proximity to critical structures like heart, lungs and spinal


cord. After conventional radiotherapy, 26% are
documented to have severe (CTCAE Grade 3 or higher)
complications namely gastrointestinal, lymphatic,
musculoskeletal, and cardiac toxicity. Late morbidities
include second malignancy, constrictive pericarditis, chest
wall muscle atrophy, scoliosis, pneumonitis, decreased lung
volume, compliance, and diffusing capacity. Parallel
opposed fields and tangential wedged fields for these
tumours irradiate a large portion of lung. Electron beam
therapy is associated with frequent inhomogeneity as well.
In a dosimetric comparison of electron arc with IMRT, it
was concluded that for the tumors located close to the
heart and spinal cord, IMRT resulted in superior dose
coverage of the PTV compared to EA with reduced normal
tissue doses; while in PTVs located away from the OAR,
Electron arc produced lower doses to the SC and heart
compared to IMRT. IMRT plans were superior with respect
to conformity and homogeneity indices (32).
With IMRT, documented LC rate is 79% in non metastatic
patient (33). Conformal RT enhances the possibility of
intensification of chemotherapy schedule and even
concurrent administration of chemotherapy (though to
be tested in larger number of patients) (34). In case of Reirradiation, IMRT helps in optimal dose delivery without
significant normal tissue effects (35).
However, in non chest wall sites, RT dose (<55.8 or >55.8
Gy), technique (IMRT versus 2-dimensional/3-dimensional),
fractionation schedule, and time to RT did not significantly
predict Local failure (LF) in a series (36).

487

Particle Therapy in Ewings Sarcoma / PNET


Depending on the chest wall sub-region, 3 dimensional
conformal proton therapy (3DCPT) has the potential to
minimize cardiac, pulmonary, hepatic, and renal toxicity.
With pelvic sarcoma, protons were superior in eliminating
any dose to the ovaries (0% of mean ovarian volume was
irradiated at >2 Gy with protons) and to some extent, the
pelvic bones and vertebrae. Intensity-modulated
radiotherapy did show more bladder dose reduction than
the other techniques. For rectum and femoral heads, both
the techniques showed similar dose distribution (37). The
3-year LC for all 30 patients (non extremity sites, treated
radically to a median total dose of 54 CGE of proton) was
86%. 5/30 patients had grade III acute toxicity (dermatitis)
(38). In long term survivors, there may be lower risks of
radiation-induced second malignancies, particularly breast
cancer (39).
Contouring guideline:
CTV comprises the initial tumor extent with an additional
longitudinal margin of at least 23 cm and lateral margins
of 2 cm in long bone. In patients with an axial tumor site,
a minimum of a 2 cm safety margin around the initial
tumor extent must be employed. In tumors protruding
into preformed cavities without infiltration, the residual
intra-cavitary tumor volume following chemotherapy is
used. Surgically contaminated areas, scars, and drainage
sites must be included in the radiation fields (28). In post
operative setting of chest wall ES clinical target volume
(CTV) includes the volume voided by the excised rib with a
longitudinal margin of 2 3 cm beyond the margin of
excision along the length of the rib(32). The superficial
margin includes the subcutaneous tissue around the tumor
488

while the deep margin included the adjacent pleura and


0.51.0 cm of underlying lung. Superiorly and inferiorly
the CTV includes a normal uninvolved rib and the
associated inter-costal spaces and muscles beyond the
involved chest wall. PTV margin should be generated
depending on the site of the tumour and the institutional
protocol.

OSTEOSARCOMA
Introduction
Osteosarcoma, an osteoid-producing malignant
mesenchymal tumour, accounts for about 20-45% of all
skeletal malignancies. It has a bimodal age distribution.
The peak incidence is seen at 10-19 years of age and again
over 60 years (secondary to conditions like prior
Radiotherapy exposure, Pagets disease). Male:Female ratio
is 1.6:1. Most common sites of origin of osteosarcoma
are femur (in 50%), followed by tibia, humerus, pelvis,
jaw, fibula and ribs. Relatively radioresistant.
Standard management
Present standard of care for non-metastatic high grade
osteosarcoma is Neoadjuvant Chemotherapy (for 2-3 cycles
including high-dose methotrexate, cisplatin, doxorubicin
and ifosfamide) followed by local therapy (surgery alone
and/or radiotherapy) and maintenance chemotherapy.
Role of Radiation therapy
Adjuvant radiotherapy has been shown to compensate
for the cut margin positivity of osteosarcoma. After
effective induction chemotherapy for non-metastatic
osteosarcoma of the extremities Limb sparing surgery
489

followed by adjuvant radiotherapy can be used as a reliable


modality to control local disease and preserve limb function
with comparable results. Approximately 10% of patients
with osteosarcoma of head and neck and 25% of those in
pelvis present with non-resectable primary disease and
about 30% of patients undergoing surgery have positive
surgical margin. Cumulatively around 40-50% of patients
merit Radiotherapy either in Radical or in Adjuvant setting.

Outcome with conventional techniques of


Radiotherapy
1) Disease control-The COSS analysis of craniofacial
osteosarcoma(40) reported an actuarial 5-year survival
rate of 73.6% with multidisciplinary therapy(RT
planning details not available).
2) Toxicity- Documented results with AP-PA portals(41) are:
delayed wound healing (20.9%), local infection
(16.2%), moderate to severe disability in the extremity
functions (53.4%), subcutaneous fibrosis (16%),
disability related to joints and extremity motion (20%),
osteoradionecrosis and pathologic fracture (4%).
Advances in Radiotherapy techniques
In head and neck as well as Pelvic osteosarcoma, dose to
critical structures is significantly reduced with conformal
techniques as shown in studies comprising of varieties of
sarcomas (elaborated in the section on STS).
Paraspinal Osteosarcomas are a unique entity with
challenging management. Due to anticipated surgical
morbidity, radiotherapy is often chosen as the definitive
local treatment. To respect the adjacent spinal cord,
optimal dose delivery is often compromised when using
490

conventional techniques (wider PTV margin). With image


guided intensity-modulated radiotherapy, greater doses
of radiation delivered in multiple fractions can be
prescribed with excellent target coverage, effective
palliation, and acceptable toxicity and local control. A
median prescribed dose of 6,600 cGy has been tried in a
series with resultant local control of 74% and no late
toxicities (42).
Mature studies are pending to establish role of SBRT in
unresectable osteosarcomas.

Particle Therapy in Osteosarcoma


Ciernik et al analysed clinical outcome and the role of
proton therapy for local control of osteosarcoma
(unresectable) of all sites (43). The mean dose delivered
was 68.4 CGE. Of the total dose, 58.2% was delivered
with protons. At 3 and 5 years, the local control rate was
82% (95% confidence interval 68%-90%) and 72% (95%
CI, 52%-84%), respectively. In paraspinal sarcomas, 5 year
local control of 78% has been reported with proton beam
therapy.

CHORDOMA AND CHONDROSARCOMA


Introduction
Chordomas constitute 1-5% of primary malignant bone
tumours. Sites of involvement in order include sacrum
(50%), skull base (25-35%), cervical vertebrae, thoracolumbar vertebrae. SEER database (2001) showed a median
survival of 629 years with 5 year, 10 year, and 20 year
survival of 676%, 399%, and 131%, respectively.

491

Chondrosarcoma is the 2 nd most common primary


malignant bone tumour. They are a spectrum of tumours
with production of cartilaginous matrix. The peak incidence
is seen within the age range of 30-60 years. SEER data:
Median overall survival was 22 years, and 10 year survival
was 68.2%.

Standard management
Surgery is considered whenever feasible as the preferred
modality for non-metastatic Chondrosarcoma and
Chordoma. Adjuvant RT is considered especially in high
grade varieties with close or positive margin. In
unresectable tumours, radical radiation therapy is
considered. Chemotherapy has little role to play. Targeted
therapy is an evolving strategy in Chordomas (with Imatinib
Mesylate).
Role of Radiation Therapy
About 66% of sacral and 43-72% of skull base chordomas
are resectable at presentation. In view of proximity to
critical structures, radical surgery with wide margins is
challenging. For sacral lesions, surgical resections above
the level of S2 has significant perioperative morbidity and
long-term sequelae (incontinence). Only with the
preservation of both S3 nerve roots bladder and bowel
function is found to remain normal. High rates of positive
surgical margins also have been reported. So, radiotherapy
has significant role either in radical or adjuvant setting.
Attempt of near total resection is possible in only 68% of
treatment nave and 56% recurrent skull base chordoma
and chondrosarcomas necessitating radiotherapy in the
management protocol. In gross or microscopic residual,
492

Surgery and postoperative radiotherapy confers longer


Progression free survival (PFS) than surgery alone.

Treatment outcome with conventional


radiotherapy techniques
1) Disease control- Dose that could be delivered by
conventional technique was suboptimal due to
adjacent normal tissues. At doses up to 4060 Gy,
local control at 5 years with conventional photon
beam radiation therapy was found to be in the range
of 1040% (44). The overall survival rate at five years
was 62%, and at 10 years was 28% after total doses
of only 4000 to 5500 cGy(45).
2) Toxicities- There is paucity of data regarding toxicity
in conventional technique. In a study of 58 patients
(46)
treated with AP-PA portals in pelvic chordomas,
2% needed colostomy and 4% had joint movement
restriction.
Advances in radiotherapy techniques
In challenging sites like clival chordoma with subtotal
resection followed by adjuvant radiotherapy to around 65
Gy by 3DCRT, results were found comparable (5 year PFS
was 23% and OS was 35% with minimal treatment
morbidity)(47).Conformal radiotherapy helped in escalation
of the dose delivered and thus results also started
improving. The 3- and 5-year cause-specific survival
increased to 88% and 75% respectively (48). In recurrent
Chordoma and Chondrosarcoma of clivus, spine and
sacrum, doses as high as 65 Gy could be delivered using
Intensity Modulated Radiotherapy producing actuarial 3year LC of 68% for those receiving upto 65 Gy and 78%
493

for those who received more than 65 Gy. There were no


RTOG Grade 2 or higher acute or late toxicity observed
(49).

Role of RadiosurgeryWhere proton beam therapy is unavailable, linear


accelerator-based Stereotactic radiotherapy (SRT) or
radiosurgery remains a safe option for adjuvant therapy
of chordomas and chondrosarcomas of the skull base. With
a dose of 18-36 Gy, 53% showed clinical improvement,
20% had stable disease and 27% died without treatment
related morbidity in a case series (50).The exposure of the
optic apparatus, pituitary stalk, and brainstem must be
considered during planning to minimize complications. If
the optic apparatus is included in the 80% isodose line, it
might be best to fractionate therapy. Exposure of the
pituitary stalk should be kept to <30 Gy to minimize
endocrine dysfunction. Brainstem exposure should be
limited to <60 Gy in fractions(51). SRS is also a feasible
modality in Reirradiation with good local control without
significant morbidity (52).
Role of Particle therapy
There is data in favour of proton beam therapy especially
in skull base chordoma and chondrosarcoma. In a series
by Eugen Hug et al (53) Local control was maintained in
60% patients with chordoma, 100% with
chondrosarcoma. The actuarial 5-year local control and
overall survival rate were 72% and 56% respectively with
severe late effects in 7% of patients. Multiple other series
demonstrate encouraging local control rates of 86% to
100% (54,55) . Combined photon and proton beam
irradiation is another promising approach with excellent
494

dosimetry (56). Proton beam therapy to a median dose of


of 75.6 RBE has resulted in 2-year estimate for local control
of 85% when used for re-irradiation. Late toxicity
documented are bitemporal lobe radionecrosis,
cerebrospinal fluid leak with meningitis (57).
Carbon ion therapy due to the high RBE, has shown
excellent results in skull base as well as sacral chordoma
and chondosarcoma. In a study where Sacral chordomas
were treated with carbon ion therapy to a median dose of
70.4 Gy equivalent, the local recurrence-free survival rate
at 5 years was 62.5% for the surgery and 100% for the
carbon ion RT group, and the disease-specific survival rate
at 5 years was 85.7% and 53.3%, respectively. Urinaryanorectal function worsened in 60% in the surgery group,
but it was unchanged in all the patients who had
undergone carbon ion RT. Postoperative wound
complications requiring reoperation occurred in 30% after
surgery and in 14% after carbon ion RT. The functional
outcome evaluated using the Musculoskeletal Tumor
Society scoring system revealed 55% in the surgery group
and 75% in the carbon ion RT group (58). Similar control
rates with favourable toxicity patterns have been
reproduced in other studies as well (59).

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