Clinical Oncology 33 (2021) 567e578

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Clinical Oncology
journal homepage: www.clinicaloncologyonline.net

Advances in External Beam Radiation Therapy and Brachytherapy for

Cervical Cancer
C.W. Williamson *, H.C. Liu y, J. Mayadev *, L.K. Mell *y
* Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California, USA
y
La Jolla Center for Precision Radiation Medicine, La Jolla, California, USA

Abstract
The standard of care for the definitive treatment of locoregionally advanced cervical cancer is external beam radiation therapy (EBRT) with concurrent
chemotherapy followed by a brachytherapy boost. Historically, EBRT was delivered via a two-dimensional technique based primarily on bony landmarks. This
gave way to three-dimensional conformal radiation therapy, which allows for dose calculation and adjustment based on individual tumour and patient anatomy.
Further technological advances have established intensity-modulated radiation therapy (IMRT) as a standard treatment modality, given the ability to maintain
tumoricidal doses to target volumes while reducing unwanted radiation dose to nearby critical structures, thereby reducing toxicity. Routine image guidance
allows for increased confidence in patient alignment prior to treatment, and the ability to visualise the daily position of the targets and organs at risk has been
instrumental in allowing safe reductions in treated volumes. Additional EBRT technologies, including proton therapy and stereotactic body radiation therapy,
may further improve the therapeutic index. In the realm of brachytherapy, a shift from point-based dose planning to image-guided brachytherapy has been
associated with improved local control and reduced toxicity, with additional refinement ongoing. Here we will discuss these advances, the supporting data and
future directions.
Ó 2021 The Author(s). Published by Elsevier Ltd on behalf of The Royal College of Radiologists. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).

Key words: Cervix cancer; image-guided brachytherapy; IMRT; proton therapy; SBRT

Introduction recent years, technological advances have led to substantial

Cervical cancer is the second most common malignancy
by incidence and the third deadliest form of cancer for
women worldwide, with developing nations bearing a
disproportionate burden [1]. The most important risk factor
for the development of cervical cancer is infection with
high-risk subtypes of the human papillomavirus [2,3].
Despite the development of a vaccine, which has been
shown to substantially reduce the risk of developing cer-
vical cancer in young women [4], there were still about
570 000 cases and 311 000 deaths from cervical cancer in
2018 [1]. Standard treatment for the definitive management
of locoregionally advanced cervical cancers includes
external beam radiation therapy (EBRT) with concurrent
chemotherapy followed by a brachytherapy boost [5]. In
Author for correspondence: L.K. Mell, Department of Radiation Medicine
and Applied Sciences, University of California San Diego, La Jolla, California,
USA.
E-mail address: lmell@ucsd.edu (L.K. Mell).
changes in the delivery of both EBRT and brachytherapy.
Here we will discuss the shift from three-dimensional
conformal EBRT (3D-CRT) to intensity-modulated radia-
tion therapy (IMRT) and image-guided IMRT (IG-IMRT)
together with recommendations for planning objectives
and image guidance. We will also briefly review proton
therapy and stereotactic body radiation therapy (SBRT) in
the setting of cervical cancer, as well as the implementation
of image-guided brachytherapy (IGBT).
History
Radiation therapy has long been used for the treatment
of cervical cancer and can be traced back to the late 19th
century, with the discovery of the radioactive element
radium in 1898. Shortly thereafter, American surgeon Rob-
ert Abbe began treating cervical cancer patients with small,
internally placed pieces of radium d a rudimentary form of
brachytherapy [6]. Radiation therapy techniques continued
to advance throughout the 20th century, including the

https://doi.org/10.1016/j.clon.2021.06.012
0936-6555/Ó 2021 The Author(s). Published by Elsevier Ltd on behalf of The Royal College of Radiologists. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
568 C.W. Williamson et al. / Clinical Oncology 33 (2021) 567e578
development of 2D radiation therapy based on bony
landmarks.
Conventional Radiation Therapy
3D-CRT takes advantage of anatomic information from
3D imaging (i.e. simulation computed tomography (CT)
scan, which can be augmented by image registration with
magnetic resonance imaging [MRI] and/or positron emis-
sion tomography/computed tomography [PET/CT]) to
delineate target volumes and organs at risk (OARs) and to
design treatment plans incorporating dose requirements
and limitations, respectively. 3D-CRT was shown to improve
the probability of encompassing target volumes while
limiting dose to the nearby bowel and bladder compared
with 2D radiation therapy [7,8] and became standard by the
late 1990s.
Intensity-modulated Radiation Therapy
The use of IMRT has increased rapidly in recent years [9]
and at many institutions is now standard for both definitive
and postoperative therapy. Compared with conventional
EBRT, IMRT uses small beamlets that vary in intensity and
better conform to 3D target volumes while minimising the
dose to critical adjacent structures. Treatment can be
delivered via multiple beam angles or arcs and treatment
planning software uses advanced algorithms to optimise
dose delivery based on prespecified objectives. Initial
implementation of IMRT for women with gynaecological
cancers reported in 2002 showed excellent coverage of
planning target volumes while sparing normal tissues
compared with conventional radiation therapy [10].
Since then, multiple dosimetric modelling studies have
shown that IMRT can reduce toxicity [11e14] and early
outcome reports showed promising tumour control with
limited adverse events, especially in terms of gastrointestinal
and haematological toxicity [15e18]. IMRT has also recently
been associated with a decreased risk of pelvic fracture
compared with 3D-CRT [19]. A meta-analysis found that
although there was no difference in overall survival between
cervical cancer patients treated with IMRT and those treated
with 3D-CRT, there was significant improvement in gastro-
intestinal and genitourinary toxicity favouring IMRT [20].
However, questions related to increased cost, complexity and
uncertain magnitude of benefit have led to some controversy
about the widespread IMRT implementation.
More recently, emerging evidence has shifted the bal-
ance increasingly in favour of routine use of IMRT. Recent
and ongoing prospective trials involving advanced radiation
therapy are summarised in Table 1. The TIME-C trial
enrolled 289 postoperative patients with cervical and
endometrial cancer and randomised women to adjuvant
standard radiation therapy versus IMRT, with a primary end
point of change in patient-reported acute gastrointestinal
toxicity from baseline to the end of radiation therapy using
standardised quality of life instruments [21]. This trial found
statistically significant improvements in Expanded Prostate
Cancer Index Composite bowel and urinary scores together
with patient-reported diarrhoea metrics.
The PARCER trial randomised women to adjuvant IG-
IMRT versus 3D-CRT followed by two fractions of high
dose rate brachytherapy of 6 Gy with a primary end point of
grade 2 late bowel toxicity [23]. The final results (pub-
lished in abstract form) showed a 4-year incidence of grade
2 late bowel toxicity in 19.2% of patients treated with IG-
IMRT compared with 36.2% of patients treated with con-
ventional 3D-CRT (P ¼ 0.005), together with significant
differences in grade 3 bowel toxicity and grade 2 diar-
rhoea, also favouring IMRT.
The international multicentre randomised phase II
INTERTECC study treated 83 patients with stage IBeIVA cer-
vical cancer with IMRT and concurrent weekly cisplatin [24].
The primary end point was the occurrence of either acute
grade 3 neutropenia or clinically significant gastrointestinal
toxicity. The incidence of any primary event was 26.5%, which
was significantly lower than the prespecified 40% incidence
expected from historical data. This trial also examined the
value of PET-based IG-IMRT and found that patients treated
with IG-IMRT had a significantly lower incidence of acute
grade 3 neutropenia. Doses to the primary tumour and
grossly involved lymph nodes can be boosted relative to
elective nodal regions via the use of a simultaneous inte-
grated boost technique, which has been shown to be well
tolerated with encouraging control rates [35].
IMRT can be delivered via multiple static fields or in arcs
in the form of volumetric intensity-modulated arc radiation
therapy (VMAT). VMAT offers several advantages, including
faster treatment time and fewer monitor units, with a
recent meta-analysis of dosimetric studies favouring VMAT
with respect to the rectum V40 (the irradiated volume of
rectum receiving 40 Gy) [36]. Figure 1 shows a sample case
from a patient treated with extended-field VMAT.
Planning Considerations for Intensity-modulated Radiation
Therapy
Given the technical capacity to reduce treatment vol-
umes in an effort to spare normal tissue, a reproducible
treatment planning set-up, as well as the careful use of
relevant diagnostic imaging and thorough physical exami-
nation are critical for optimal treatment planning. With the
most recent update in 2018 to the International Federation
of Gynecology and Obstetrics (FIGO) staging system,
advanced imaging studies can be used for staging [37].
Indeed, dynamic contrast-enhanced MRI is highly accurate
for detecting cervical invasion and has been shown to be
superior to both CT and physical examination for quanti-
fying tumour size and the extent of invasion [38]. Pelvic MRI
can also be useful for detecting lymph node metastases [39],
although PET/CT has become the advanced imaging mo-
dality of choice for patients with at least stage IB disease
given superior sensitivity compared with CT [40] and the
ability to detect disease not just in the pelvis but also in
para-aortic nodes and distant metastases. MRI and PET/CT
Table 1
Summary of major recent published and active prospective trials involving advanced radiation therapy techniques in cervical cancer

Trial Design Study arms Population n Systemic therapy Key findings

TIME-C [21] Phase III RCT IMRT versus 4-field Postoperative 278 Cisplatin 40 mg/m2  5 IMRT associated with significantly
radiation therapy endometrial and cervix cycles (physician smaller decline in patient-reported
discretion based on bowel and urinary symptom score,
pathologic risk factors) less frequent or constant diarrhoea,
and fewer IMRT patients required
anti-diarrhoeal medications 4 or more
times daily
Uterus-11 [22] Phase III RCT Surgical versus Intact cervix 240 Cisplatin 40 mg/m2  5 IMRT associated with significantly less
clinical staging with cycles grade 2 anaemia, grade 3
subgroup analysis of gastrointestinal, and grade 2 bladder
radiation techniques toxicity compared with 3D-CRT

C.W. Williamson et al. / Clinical Oncology 33 (2021) 567e578

(60% IMRT versus 30%
3D-CRT)
PARCER [23] Phase III RCT IG-IMRT versus 3D- Postoperative cervix 300 Cisplatin 40 mg/m2  5 IG-IMRT associated with significantly
CRT cycles lower incidence of late grade 2
bowel toxicity; no difference in DFS
INTERTECC-2 [24] Phase II single-arm IG-IMRT versus IMRT Intact cervix (n ¼ 72) and 83 Cisplatin 40 mg/m2  5 IMRT associated with significantly
(non-randomised) postoperative cervix (n ¼ cycles reduced incidence of primary event
11) (acute grade 3 neutropenia or
clinically significant gastrointestinal
toxicity within 30 days of therapy
completion); bone marrow sparing
IG-IMRT associated with significant
reduction in grade 3 neutropenia
Huang et al. [25] RCT single centre Bone marrow sparing Intact cervix 164 Cisplatin 40 mg/m2 Bone marrow sparing IMRT associated
IMRT versus IMRT weekly, maximal dose with statistically lower incidence of
70 mg grade 2 haematological toxicity; no
difference in grade 2 gastrointestinal
toxicity
Gandhi et al. [26,27] RCT IMRT versus 4-field Intact cervix 44 Cisplatin weekly 40 mg/ IMRT group had significantly fewer
radiation therapy m2 acute grade 2 and acute 3
gastrointestinal toxicity, as well as less
late gastrointestinal toxicity; no
difference in overall survival or DFS
STIC [28] Multicentre IGBT versus 2D Cervix (some patients 705 Some patients radiation IGBT associated with improved local
prospective non- brachytherapy had surgery after therapy alone, some with control with half the toxicity of 2D
randomised trial dosimetry radiation therapy) weekly cisplatin brachytherapy
EMBRACE I [29] Multicentre EBRT þ 3D-IGBT Intact cervix 1416 Cisplatin 40 mg/m2  5 3D-IGBT was associated with
prospective cycles improved target dose coverage and
observational study decreased isodose surface volumes
compared to standard (Point A-based)
plans
(continued on next page)

569
 570
Table 1 (continued )

Trial Design Study arms Population n Systemic therapy Key findings

2
EMBRACE II [30] Interventional EBRT (IMRT) þ 3D Intact cervix Target 1000 Cisplatin 40 mg/m  5 Pending; primary goals are to
prospective study MRI-guided cycles prospectively test the efficacy of
brachytherapy with advanced techniques (e.g. IC/IS
increased use of brachytherapy), IMRT and IG-IMRT,
combined IC/IS and various dose prescription targets
brachytherapy in improving local, nodal, distant
control and survival rates, morbidity,
and quality of life outcomes
INTERTECC-3 [31] Phase III RCT Bone marrow sparing Intact cervix Target 415 Cisplatin 40 mg/m2  5 Pending; primary end point is PFS
IG-IMRT versus IMRT but study cycles with secondary end points of acute
closed early and late haematological and
after gastrointestinal toxicity

C.W. Williamson et al. / Clinical Oncology 33 (2021) 567e578

randomising
29 patients
NRG-GY006 [32] Phase III RCT Radiation therapy Intact cervix Target 450 Cisplatin 40 mg/m2  5 Pending; primary end point is overall
with concurrent cycles or cisplatin 40 mg/ survival
cisplatin  triapine m2  5 cycles  triapine
(radiation therapy
delivered via IMRT or
3D-CRT)
NRG-GY017 [33] Phase II RCT Atezolizumab before Intact cervix Target 40 Cisplatin 40 mg/m2  5 Pending: primary outcome is immune
and/or with IMRT cycles þ atezolizumab activation (clonal expansion of T cell
with concurrent receptor beta repertoires in peripheral
cisplatin blood)
Tata IIB Trial [34] Phase II RCT IMRT versus 3D-CRT Intact cervix (stage IIB Target 200 Cisplatin 40 mg/m2 Pending: primary outcome is normal
only) weekly tissue toxicity
3D-CRT, three-dimensional conformal radiation therapy; DFS, disease-free survival; EBRT, external beam radiation therapy; IC/IS, intracavitary/interstitial; IG-IMRT, image-guided
radiation therapy; IGBT, image-guided brachytherapy; IMRT, intensity-modulated radiation therapy; MRI, magnetic resonance imaging; PFS, progression-free survival; RCT,
randomised clinical trial.
 C.W. Williamson et al. / Clinical Oncology 33 (2021) 567e578 571

Fig 1. Volumetric intensity-modulated arc radiation therapy plan for a 32-year-old patient with FIGO 2009 stage IB2 cervical cancer and
involved para-aortic nodes (FIGO 2018 stage IIIC2). She was treated on the NRG-GY017 protocol with atezolizumab before and/or with con-
current cisplatin. The pelvis was treated to 45 Gy in 25 fractions to an extended field with simultaneous integrated boost to 54e58 Gy to gross
pelvic nodes and 58 Gy to gross para-aortic nodes. She received image guidance with daily cone beam computed tomography. This was followed
by intracavitary brachytherapy, 28 Gy in four fractions, for a total 2 Gy equivalent dose (EQD2) of 83.9 Gy (a/b ¼ 10). Dose is represented in
colourwash according to the legend in the bottom right.

can both be fused to the diagnostic CT scan and used to
enhance target delineation.
CT simulation is typically acquired with the patient su-
pine, and a customised cradle can be used for immobilisa-
tion. Scans with slice thickness 3 mm are preferable. Given
the possibility for large target and OAR movement due to
rectum and bladder filling status, the goal at CT simulation
is to replicate the positioning that will probably be
encountered during daily treatment. For example, patients
may be instructed to present for CT simulation with an
empty rectum and a (comfortably) full bladder. Scans can be
taken with a full and an empty bladder and later fused to
generate an integrated target volume. Treatment can be
delivered with a full or an empty bladder each day; for the
sake of consistency, it is recommended to choose one a
priori. Treatment with an empty bladder may be more
reproducible, reduces the absolute variation of bladder
volume and is generally easier for patients to achieve,
although treatment with a full bladder can displace bowel
out of the treatment field and thereby improve bowel
dosimetry [41]. Unless contraindicated, simulation with
intravenous contrast can be helpful for determining target
volumes, as the lymph node basins at risk are closely related
to the pelvic vasculature. Radio-opaque markers placed at
vaginal introitus and vaginal apex at the time of CT simu-
lation can also assist with volume delineation. For patients
with disease involving the distal half of the vagina, bilateral
inguinal nodes are generally treated. In order to minimise
skin fold toxicity in this situation, CT simulation can be
formed in the ‘frog-leg’ position.
Once CT simulation is complete and diagnostic imaging is
fused or otherwise carefully examined, the accurate delin-
eation of both target volumes and OARs is crucial to optimise
the probability of tumour control and minimise undue
toxicity. There are consensus contouring guidelines available
for both intact and postoperative scenarios to assist with
target volume segmentation [42,43], together with online
contouring resources [44]. Several ongoing prospective
clinical trials have also detailed protocols describing modern
techniques. For example, the NRG-GY006 protocol defines
the gross target volume (GTV) as all visible disease based on
all available clinical, radiographic and pathological infor-
mation [45]. The clinical target volume (CTV) encompasses
areas at risk for harbouring microscopic disease and is
subdivided into three subvolumes (Table 2). If there is para-
aortic or high common iliac (i.e. near the aortic bifurcation)
nodal involvement, an extended field should be used to
cover superiorly to the L1/L2 interspace or 3 cm caudal to
gross disease. The CTV3 subvolumes should be obtained by
placing a 7 mm margin around the vessels while including
any visible lymph nodes, lymphoceles and/or surgical clips.
If inguinal nodal basin coverage is indicated, these should be
delineated from the external iliac nodes to 2 cm caudal to
the saphenous/femoral junction. An anisotropic planning
target volume expansion strategy of 15 mm around CTV1, 10
mm around CTV2 and 5 mm around CTV is based on
advanced modelling [46] and was validated using prospec-
tive clinical trial data [47]. An integrated target volume
approach is also an option, which entails the delineation and
fusion of CTV1 on both full and empty bladder scans.
Table 2
Components of the overall clinical target volume (CTV) for defini-
tive external beam radiation therapy
Primary CTV Subvolume components
subvolume
CTV1 Primary GTV þ entire cervix þ entire uterus
CTV2 Parametria þ upper third of the vagina (or
upper half if there is clinical vaginal
involvement)
CTV3 Common, external iliac, internal iliac and
presacral lymph node basins, with a superior
border for a standard field at the aortic
bifurcation (which approximately
corresponds to the L4-L5 interspace). CTV3
should be modified anatomically to exclude
tissue not at risk for disease, including bone,
muscle, and bowel
GTV, gross tumour volume.
572 C.W. Williamson et al. / Clinical Oncology 33 (2021) 567e578
Interested readers can refer to the trial protocol for further
details. Typical dose prescriptions to the pelvis are 45 or 50
Gy in 25 fractions or 50.4 Gy in 28 fractions; involved lymph
nodes are generally treated with a simultaneous integrated
boost to 57e60 Gy over 28 total fractions. Importantly, the
nodal boost dose and/or dose per fraction may require
adjustment to respect bowel tolerance and there are mul-
tiple acceptable variations in dosing schemes [48].
IMRT allows the physician to specify dose requirements
to both the target and to OARs, which can then be given
varying relative priorities during the dose optimisation
process. Critical OARs include the bowel, rectum, bone
marrow, bladder and femoral heads. Recommended dose
constraints are also described in modern trial protocols,
with an example from the NRG-GY006 protocol [32] for
standard pelvic fields and the NRG-GY017 protocol [33] for
extended fields when para-aortic coverage is required. The
EMBRACE II protocol also provides detailed target delinea-
tion guidance and dose constraints [30].
Pelvic organs are naturally susceptible to displacement
and volumetric changes over time, both between and dur-
ing ‘beam-on’ treatment time. Consequently, the pelvic
anatomy of a patient can shift from the positions seen at
simulation, which can lead to error in dose delivery and
higher rates of side-effects and organ toxicity despite
appropriate target volume expansions [49,50]. Image
guidance has emerged as a valuable tool for assessing the
daily position of targets and OARs prior to daily treatment.
Daily orthogonal kV images can be used to improve align-
ment based on bony anatomy. Weekly or daily cone beam
CT prior to treatment delivery can identify changes in
rectum or bladder filling status as well as an overlay of the
treatment volumes on the scan of the day. Use of IG-IMRT
has been associated with reduced haematological and
gastrointestinal toxicity compared with using IMRT alone
[51] and can enable additional systemic therapy [52].
Other Advanced External Beam Radiation
Therapy Modalities
Proton Therapy
Proton therapy has become increasingly available for the
treatment of multiple malignancies, including cervical
cancer. Proton therapy carries dosimetric advantages
compared with photon-based EBRT due to the characteristic
Bragg peak, which illustrates a rapid dose fall-off distal to
the target depth. Several dosimetric studies have suggested
potential reductions in doses to normal organs, especially in
the lower dose regions [53e56]. A small study including 11
patients with post-hysterectomy gynaecological cancers
reported the clinical implementation of pencil beam scan-
ning proton therapy [57] and a comparison was made to
IMRT plans. The proton plans showed reduced volumes of
pelvic bone marrow, bladder and bowel receiving 10e30 Gy.
Nine of the patients were treated with concomitant
chemotherapy, and the rates of grade 2 and 3 haemato-
logical toxicities were 33% and 11%. One patient developed
grade 3 acute gastrointestinal toxicity and no patients
experienced grade 3 genitourinary toxicity, demon-
strating feasibility and dosimetric advantages. Another po-
tential benefit of proton therapy could be improved ovarian
sparing to preserve endocrine function in women requiring
whole pelvis EBRT, with early dosimetric data indicating
feasibility of sparing one ovary to a mean dose of <15 Gy
while maintaining dose to target volumes with intensity-
modulated proton therapy [58]. However, prospective
comparative clinical trials involving protons are lacking, and
the degree to which dosimetric improvements translate to
clinical benefit to patients remains uncertain at present.
Stereotactic Body Radiation Therapy
SBRT allows for the precise delivery of high-dose radia-
tion therapy with substantial sparing of nearby normal
tissues. Dosimetric analysis has shown reasonable con-
formality and dose distributions in comparison with
brachytherapy plans [59], and early clinical data showed
feasibility in the setting of cervical cancer patients unable to
undergo brachytherapy, albeit with a small number of pa-
tients [60]. However, a single-arm, single-institutional
phase II trial investigating the use of SBRT as an alternative
boost technique closed prematurely due to concern for
toxicity and lower than anticipated 2-year local control,
progression-free survival and overall survival, with a cu-
mulative boost 2-year grade 3 toxicity of 26.7% [61].
Notably, these patients had predominantly advanced dis-
ease with large tumours and multiple medical comorbid-
ities, including a median Charlson comorbidity score of 4,
which underscores the importance of considering patient
selection when evaluating such outcomes. Figure 2 shows
sample images from a patient who refused brachytherapy
but was amenable to an SBRT boost.
Advances in Brachytherapy
Brachytherapy towards the end of EBRT allows for dose
escalation to the primary site of disease by taking advantage
of a rapid dose fall-off. Brachytherapy has been used for the
treatment of cervical cancer since 1903 [62] and has been
associated with improved pelvic control and overall sur-
vival, thereby establishing the technique as an essential
component of definitive treatment for cervical cancer
[63,64]. In the initial era of brachytherapy it was impossible
to calculate specific doses to individual tissues. The Man-
chester system, first introduced in 1938, and modified in
1953, formalised the brachytherapy dose prescription to a
specific point [65,66]. Since the originating site of radiation
necrosis seemed to be where the uterine vessels cross the
ureter, point A was defined as a point that was 2 cm lateral
to the centre of the uterine canal and 2 cm superior to the
mucosa of the lateral fornix. This original definition of point
A was later modified to be relative to the brachytherapy
applicator itself to allow for visualisation on radiography,
which was defined as 2 cm superior to the external os and 2
 C.W. Williamson et al. / Clinical Oncology 33 (2021) 567e578 573

Fig 2. Stereotactic body radiation therapy (SBRT) boost for a 43-year-old woman with intact FIGO 2009 stage IB2 cervical cancer with hyper-
metabolic pelvic and inguinal lymph nodes. She received 47.6 Gy in 28 fractions to the pelvis with a simultaneous integrated boost of 56 Gy to
gross disease on a clinical trial with concurrent cisplatin and gemcitabine. The patient had a history of sexual assault and trauma. She declined
intracavitary brachytherapy. Her external beam treatment was therefore followed by an SBRT boost of 27.5 Gy in five fractions. This resulted in a
total 2 Gy equivalent dose (EQD2) of 81.9 Gy (a/b ¼ 10). Dose is represented in colourwash according to the legend in the bottom right, ranging
from 110% to 30%.

cm lateral to the tandem portion of the applicator [66].
Given heterogeneity in tumour size and location, as well as
patient anatomy, efforts have been made towards greater
personalisation of treatment planning and of target-based
dose prescription.
There are several modern options for intracavitary
brachytherapy applicators, including tandem and ovoid
(T&O) or tandem and ring (T&R) devices, and consideration
should be given to the possible utility of supplementation
with interstitial needles. This decision depends on tumour
size, location and degree of vaginal extent. In general,
intracavitary devices are best suited for smaller tumours
(i.e. <3 cm) with minimal vaginal extension and non-bulky
parametrial disease. A hybrid intracavitary/interstitial
technique can allow for improved dosimetry for larger tu-
mours, irregular tumour shape, parametrial extension,
vaginal extension and parametrial involvement. Interstitial
therapy alone may be appropriate for very large tumours
with extensive vaginal and/or parametrial disease. Recent
evidence suggests improvements in target dose with T&R
compared with T&O and that a combined intracavitary/
interstitial approach can improve both target dosing and
OAR sparing compared with IC alone, particularly for large
tumours [67].
Both CT and MRI can be used for IGBT treatment plan-
ning, which offers several advantages over conventional
point-based planning. IGBT incorporates tumour and OAR
anatomy and positioning into the treatment planning and
enables a paradigm shift from prescribing the dose to an
arbitrary point to the actual primary target while also
monitoring and appropriately sparing adjacent normal or-
gans [68,69]. Consensus guidelines for IGBT target delin-
eation have been published [70]. In brief, MRI near the time
of brachytherapy can be used to assist with identification of
the GTV. The dose is prescribed to the contoured high-risk
CTV, which should include the GTV, the entire cervix and
macroscopic extension or parametrial involvement. After
45 Gy in 25 fractions to the pelvis, for example, common
dose and fractionation schemes to achieve a total 2 Gy
equivalent dose (EQD2) of 80 Gy include 7 Gy  4 fractions
or 5.5e6 Gy  5 fractions.
Several institutional series have shown excellent local
control with limited toxicity [71e79]. The EMBRACE study
was initiated in 2008 as a prospective observational study
designed to assess outcomes from application of MRI-based
IGBT in a multicentre, international population according to
standards developed by the Gynaecological Groupe Euro-
peen de Curiethe rapie and the European Society for
Radiotherapy & Oncology (Gyn GEC-ESTRO) [68,80]. The
RetroEMBRACE cohort was a large international observa-
tional cohort of 852 patients treated with IGBT prior to
participation in EMBRACE [81]. At institutions that used
MRI-based IGBT, contouring was carried out based on Gyn
GEC-ESTRO recommendations [68]. Institutions using CT-
based IGRT contoured only the high-risk CTV [82]. The
crude local control rate was 90.6%, with overall local control
at 3 and 5 years of 91% and 89%, respectively. Even patients
with stage IVA disease had local control of 76% at 5 years.
Patients treated with MRI-based IGBT had a 95% local con-
trol rate at 3 years for tumours <5 cm versus 85% for tu-
mours 5 cm. The 3- and 5-year overall survival rates were
74% and 65%; 70% of the overall deaths were due to recur-
rent disease. The actuarial rates of 3- and 5-year grade 3e5
toxicity were 4% and 5% for bladder, 6% and 7% for gastro-
intestinal and 3% and 5% for vagina. There were two deaths
attributed to morbidity: one from bowel fistula and one
from vaginal bleeding.
More recently, the prospective EMBRACE I study reported
excellent outcomes. With a median follow-up of 51 months,
actuarial 5-year local control was 92% (95% confidence in-
terval 90e93%), with similar local control across all FIGO
stages [83]. A prior initial report showed that local failures
were synchronous with nodal or distant failures about 50%
of the time, and that the vast majority of local failures
occurred within the high-risk CTV or intermediate-risk CTV
with a dose-dependent relationship [84]. The primary target
dosimetric goal was an EQD2 of 85 Gy, assuming an a/b ratio
of 10. Early results from EMBRACE I support the use of
574 C.W. Williamson et al. / Clinical Oncology 33 (2021) 567e578

Fig 3. Image-guided high dose rate brachytherapy plan for a 32-year-old woman with FIGO 2009 IB2 cervical cancer with pelvic lymph node
involvement (FIGO 2018 IIIC1). Following external beam therapy with concurrent cisplatin, she underwent a brachytherapy boost of 28 Gy in
four fractions. She was treated with a hybrid approach, consisting of a tandem and ovoid apparatus supplemented by the placement of two
freehand interstitial needles. On the left panel, the orange arrow points to the tandem and the white arrows point to the freehand needles. The
bottom right legend identifies isodose curves (coloured lines) with dose expressed as percentages.

combined intracavity/interstitial brachytherapy, particularly
to larger tumours, in order to achieve the target dose with an
acceptable toxicity profile [85]. Similarly, the prospective
French STIC trial [28] randomised patients between 2D and
3D brachytherapy planning and showed that 3D IGBT is
feasible and safe, with improvement in local control and half
the incidence of grade 3e4 toxicity favouring IGBT. The
EMBRACE II study incorporates dosimetric and planning
advances for patients with stage IBeIVA disease who
received EBRT with IG-IMRT to 45 Gy in 25 fractions, MRI-
based IGBT and concurrent cisplatin [30]. Figure 3 shows
sample images from a patient treated with a combined
intracavitary/interstitial technique with CT-based image
guidance.
Conclusions
Technical advances have led to major paradigm shifts in
the delivery of radiation therapy for cervical cancer.
Although the efficacy of IMRT compared with 3D-CRT has
not been conclusively shown in the intact setting, radiation
oncologists have ‘voted with their feet’ when they have the
opportunity to utilise IMRT (e.g. on the ongoing NRG-GY006
where IMRT is optional, over two-thirds of the enrolled
patients have been treated with IMRT to date) [45]. How-
ever, a phase II randomised trial for stage IIB cervix cancer at
Tata Memorial Hospital was completed in 2019, with results
pending [34]. IGRT implementation has allowed for
increased confidence in treatment accuracy and VMAT of-
fers logistical advantages. Proton therapy may offer addi-
tional improvement in the therapeutic ratio of EBRT,
although additional prospective comparative clinical trials
should be conducted prior to routine use. SBRT can be
cautiously considered in situations where brachytherapy
boost is impossible, or for ablative intent treatment of
limited areas of metastasis or recurrence.
In the realm of brachytherapy, IGBT has been shown to
be superior to conventional point-based prescription plan-
ning [28,81]. Ongoing prospective trials will further refine
dose targets and limitations and clarify whether advanced
IMRT increases the ability to intensify systemic therapy [32]
and can synergise with immunotherapy [33,86]. Additional
investigation of other advanced techniques, including pro-
ton therapy, SBRT and further refinement in IGBT will
probably yield additional improvements in the care of pa-
tients with cervical cancer.
Conflicts of interest
J. Mayadev reports a relationship with AstraZeneca that
includes consulting or advisory; a relationship with Varian
Medical Systems Inc that includes consulting or advisory; a
relationship with The GOG Foundation Inc that includes
non-financial support; a relationship with NRG that in-
cludes funding grants.
Funding
This research did not receive any specific grant from
funding agencies in the public, commercial or not-for-profit
sectors.
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