Guidelines by the AAPM and GEC-ESTRO on the use of innovative

brachytherapy devices and applications: Report of Task Group 167

Ravinder Nath
Department of Therapeutic Radiology, School of Medicine, Yale University, New Haven, Connecticut 06510

Mark J. Rivarda)
Department of Radiation Oncology, School of Medicine, Tufts University, Boston, Massachusetts 02111

Larry A. DeWerd
Accredited Dosimetry and Calibration Laboratory, University of Wisconsin, Madison, Wisconsin 53706

William A. Dezarn
Department of Radiation Oncology, School of Medicine, Wake Forest University, Winston-Salem,
North Carolina 27157

H. Thompson Heaton II
Hagerstown, Maryland 21740

Geoffrey S. Ibbott
Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030

Ali S. Meigooni
Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada 89169

Zoubir Ouhib
Radiation Oncology, Lynn Regional Cancer Center, Delray Beach, Florida 33484

Thomas W. Rusch
Xoft, Inc., A Subsidiary of iCAD, Inc., San Jose, California 95134

Frank-André Siebert
Clinic of Radiotherapy, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany

Jack L. M. Venselaar
Department of Medical Physics and Engineering, Instituut Verbeeten, Tilburg LA 5000, The Netherlands

(Received 15 January 2016; revised 26 April 2016; accepted for publication 10 May 2016;
published 1 June 2016)
Although a multicenter, Phase III, prospective, randomized trial is the gold standard for evidence-
based medicine, it is rarely used in the evaluation of innovative devices because of many practical and
ethical reasons. It is usually sufficient to compare the dose distributions and dose rates for determining
the equivalence of the innovative treatment modality to an existing one. Thus, quantitative evaluation
of the dosimetric characteristics of innovative radiotherapy devices or applications is a critical part in
which physicists should be actively involved. The physicist’s role, along with physician colleagues,
in this process is highlighted for innovative brachytherapy devices and applications and includes
evaluation of (1) dosimetric considerations for clinical implementation (including calibrations, dose
calculations, and radiobiological aspects) to comply with existing societal dosimetric prerequisites
for sources in routine clinical use, (2) risks and benefits from a regulatory and safety perspective, and
(3) resource assessment and preparedness. Further, it is suggested that any developed calibration
methods be traceable to a primary standards dosimetry laboratory (PSDL) such as the National
Institute of Standards and Technology in the U.S. or to other PSDLs located elsewhere such
as in Europe. Clinical users should follow standards as approved by their country’s regulatory
agencies that approved such a brachytherapy device. Integration of this system into the medical
source calibration infrastructure of secondary standard dosimetry laboratories such as the Accredited
Dosimetry Calibration Laboratories in the U.S. is encouraged before a source is introduced into
widespread routine clinical use. The American Association of Physicists in Medicine and the Groupe
Européen de Curiethérapie-European Society for Radiotherapy and Oncology (GEC-ESTRO) have
developed guidelines for the safe and consistent application of brachytherapy using innovative devices
and applications. The current report covers regulatory approvals, calibration, dose calculations,
radiobiological issues, and overall safety concerns that should be addressed during the commissioning
stage preceding clinical use. These guidelines are based on review of requirements of the U.S.
Nuclear Regulatory Commission, U.S. Department of Transportation, International Electrotechni-
cal Commission Medical Electrical Equipment Standard 60601, U.S. Food and Drug Administra-

3178 Med. Phys. 43 (6), June 2016 0094-2405/2016/43(6)/3178/28/$30.00 © 2016 Am. Assoc. Phys. Med. 3178

3179 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
tion, European Commission for CE Marking (Conformité Européenne), and institutional review
boards and radiation safety committees. C 2016 American Association of Physicists in Medicine.
[http://dx.doi.org/10.1118/1.4951734]
Key words: brachytherapy, medical devices, NRC, FDA, IRB, CE marking, dosimetry, calibration
TABLE OF CONTENTS
1 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.A U.S. FDA regulations . . . . . . . . . . . . . . . . . . . . .
2.B Source calibrations . . . . . . . . . . . . . . . . . . . . . . .
2.C Brachytherapy dose calculations . . . . . . . . . . .
3 GUIDELINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.A Regulatory requirements . . . . . . . . . . . . . . . . . .
3.B Calibration requirements . . . . . . . . . . . . . . . . . .
3.C Dosimetric requirements . . . . . . . . . . . . . . . . . .
3.D Radiobiological requirements . . . . . . . . . . . . .
3.E Team organization and training . . . . . . . . . . . .
4 BRACHYTHERAPY INNOVATIONS . . . . . . . . . . .
4.A High-dose-rate (HDR) 192Ir sources and
afterloaders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.B HDR 60Co sources . . . . . . . . . . . . . . . . . . . . . . .
4.C LDR 125I and 103Pd sources . . . . . . . . . . . . . . .
4.D LDR 131Cs sources . . . . . . . . . . . . . . . . . . . . . . .
4.E Elongated sources . . . . . . . . . . . . . . . . . . . . . . . .
4.F Intermediate energy photon emitters . . . . . . .
4.G Electronic brachytherapy sources . . . . . . . . . .
4.H Intravascular brachytherapy sources . . . . . . . .
4.I Neutron emitting 252Cf sources . . . . . . . . . . . .
4.J 90Y microspheres . . . . . . . . . . . . . . . . . . . . . . . .
4.K Collimated applicators and sources . . . . . . . .
4.L Intracavitary breast balloon brachytherapy . .
4.M Intracavitary brain balloon brachytherapy . . .
4.N NonCOMS eye plaques . . . . . . . . . . . . . . . . . . .
5 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDIX A: CURRENT REGULATORY
ENVIRONMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 U.S. Nuclear Regulatory Commission . . . . . .
2 U.S. Food and Drug Administration . . . . . . . .
3 Health Canada brachytherapy regulations . . .
4 European Union regulatory structure . . . . . . .
APPENDIX B: RADIOBIOLOGICAL AND
CLINICAL CONSIDERATIONS . . . . . . . . . . . . . . . .
1. INTRODUCTION
For over a century, radioactive materials have been used
extensively to treat human diseases that exhibit unwanted
hyperproliferation of underlying cells, the primary example
being cancer. Almost immediately after the discovery of
radioactivity in 1896, sealed tubes containing 226Ra, purified
by Maria Sklodowska Curie were implanted in patients to
treat gynecological cancers. In conventional external-beam
radiotherapy (EBRT), radiation beams emanate from a linear
accelerator with the source located about 1 m from the tumor.
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3179
However in brachytherapy, radioactive or miniature x-ray
emitting sources are implanted directly into the tumor or
3179
placed at a short distance from the tumor. Brachytherapy
3180
has several advantages over EBRT, e.g., the higher degree
3180
of dose localization in the target volume, better normal tissue
3181
sparing, and lower costs. However, brachytherapy is generally
3182
an invasive modality that requires special procedures for the
3182
proper handling of radioactive materials to mitigate risks and
3182 hazards to medical personnel, family members, the general
3183 public, and of course to the patient. The American Association
3184 of Physicists in Medicine (AAPM) and the Groupe Européen
3185 de Curiethérapie-European Society for Radiotherapy and
3185 Oncology (GEC-ESTRO) have developed guidelines for the
3185 dosimetry and calibration of brachytherapy sources in several
protocols such as the AAPM Task Group 43 report (TG-43),1,2
3185 quality control and quality assurance (QA) for brachytherapy
3187 procedures such as the Task Group 56 report (TG-56)3
3187 and ESTRO-issued Booklet 8,4 and clinical standards for
3188 source calibrations.5,6 There are limited guidelines for the
3188 dosimetric requirements of innovative brachytherapy devices
3189 or for implementation of new clinical applications.
3189 Through the process of reviewing advances in the field and
3190 identifying instances where brachytherapy innovations were
3191 not optimally implemented, common weaknesses and oppor-
3192 tunities were identified for improved evaluation methods.
3192 Formed in 2008, the charge of TG-167 entailed the following
3193 items:
3193
3194 (1) To review the current practice in the U.S. marketplace,
3195 current U.S. Food and Drug Administration (FDA)
requirements for new brachytherapy sources, and the
3196 difficulties encountered regarding the dosimetry of
3196 novel brachytherapy sources for permanent implanta-
3196 tion using examples such as the historical introduction
3198 of the model 200 103Pd TheraSeed® source (Theragen-
3198 ics, Corp., Buford, GA) and the model CS-1 Rev2 131Cs
Proxcelan® source (IsoRay Medical, Inc., Richland,
3198 WA).
(2) To review critical physical, dosimetric, and radiobio-
logical issues that arise when a novel source is intro-
duced for permanent interstitial brachytherapy such as
calibration traceability, accuracy of dosimetry param-
eters, and choice of prescribed dose for equivalent
results. Also, the need to receive pertinent information
about the source design from the manufacturer will be
outlined so that a proper evaluation of a novel source
can be accomplished.
(3) To develop consensus guidelines on the methodology
for these dosimetry issues that can minimize the
potential risk to the human subjects and maximize
the efficiency with which these novel sources can be

3180 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
widely adopted for the benefit of patients. The overall
objective is to highlight the critical issues and missing
information that may affect the clinical response so that
investigators address them as a deliberate part of their
study design.
Brachytherapy has been and continues to be an area of
intense research interest.7–9 Examples include beta-emitting
90
Sr sources for intravascular brachytherapy (IVBT), 131Cs for
interstitial permanent implants, miniaturized x-ray emitting
electronic sources, and neutron emitting sources for temporary
brachytherapy. Also, many innovative brachytherapy applica-
tors have been introduced such as intracavitary balloons for
the breast and brain, slotted and notched eye plaques, and
applicators with high-Z shielding to considerably alter dose
distributions.
In the U.S., manufacturers need to obtain approval from
the FDA to introduce new products into the marketplace.
In Europe, a similar approval is performed using the CE
(Conformité Européenne) Marking to indicate compliance
with European regulations. CE Marking has been a legally
binding statement by the manufacturer since 1998. The goal
usually is to demonstrate equivalence of innovative products to
existing medical devices in promotion of patient safety. The
AAPM and GEC-ESTRO present guidelines in the current
report that address the critical regulatory and dosimetry
issues that must be considered by the medical physicist
when innovative brachytherapy devices or applications are
introduced. In this report, devices are defined to include
brachytherapy sources; associated devices like seed spacers,
needles, and catheters; and brachytherapy applicators.
Although it is always risky to predict the special challenges
and opportunities that are going to be presented by any
innovative medical device in the future, one can learn some
general principles from past experiences with similar systems.
This report presents a history of the development of several
brachytherapy devices, which can be used as an educational
resource by the investigators. From this prior experience with
brachytherapy devices, it is apparent that there is a strong need
for developing robust calibration procedures and maintaining
a chain of dosimetric consistency across institutions whenever
new sources are introduced. However, these requirements
should be treated as a starting point for the evaluation of patient
safety and efficacy for innovative devices in the brachytherapy
community. The original intent was to develop consensus
guidelines; however, it became clear that development of
specific guidelines was not possible. Therefore, based on
the focused review of the issues that have arisen in the past
during the introduction of innovative brachytherapy devices
or applications, guidelines are made in a generalized fashion.
New devices and applications are considered in the
following context:
(a) During early stages of development being used by a
single institution in a research or clinical setting.
(b) Commercially available sources that are being used
in routine clinical practice, but lack consensus data
and posting on the Brachytherapy Source Registry10
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3180
managed jointly by the AAPM and the MD Anderson
IROC Houston Quality Assurance Center.
These guidelines reflect clinical practice suggestions of
the AAPM and GEC-ESTRO for its members. Beyond this
target audience, the vendors, regulatory agencies, and other
professional societies should also consider these guidelines to
develop good practices for brachytherapy. As these guidelines
are made jointly by the AAPM and GEC-ESTRO (as
approved by the Advisory Committee on Radiation Oncology
Practice), some of the specifically mentioned U.S. agencies,
organizations, and standards laboratories should be interpreted
in the context of similar arrangements in other countries where
applicable. Since it is not practical to list all laboratories and
the calibrations they provide, the reader is referred to the
Calibration and Measurement Capabilities report of national
metrology institutes (NMIs) as maintained by the Bureau
International des Poids et Mesures (BIPM, Sèvres, France)
as a starting point.11 Also, specific companies and devices
are identified in this work in order to specify adequately the
guidelines, but identification of these companies and devices
does not imply endorsement by either the AAPM or GEC-
ESTRO.
2. BACKGROUND
Medical use of radiation sources and their marketing are
regulated by the FDA in the U.S. as described in Appendix A.
Similarly, the Health Products and Food Branch of Health
Canada reviews manufacturer applications and issues medical
device licenses for brachytherapy sources and related devices
that are marketed in Canada. European legislation states that
only medical devices that have been certified with a CE
Marking according to the Council Directive 93/42/EEC may
be sold or exported as commercial products on/to the European
market.12 As examples, an afterloading machine and each
individual applicator, transfer tube, connector, and all other
devices must be CE certified.
2.A. U.S. FDA regulations
In the U.S., the FDA approval for medical devices started
on May 28, 1976. Therefore, any device that was designed
and fabricated prior to this date has been grandfathered FDA
approval for its intended use at that time. Generally, if a
medical device is being introduced, it can be categorized
as being similar or not to an existing medical device. It
is the experience of the writing team that the requirements
for receiving FDA clearance have been variable across
manufacturers and over time.
For the first class, if the new device is substantially
equivalent (SE) to a legally marketed device, the regulatory
route is a premarket notification, more commonly called a
510(k), as this is the section of the Federal Food, Drug, and
Cosmetic Act (FFDCA) that deals with this class of device.
SE does not mean identical, rather the indication for use is
the same as the predicate device, the material and technology

3181 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
are the same as the predicate, or if they are different there
are sufficient data in the submission to show that there are
no new safety or effectiveness issues. Usually only technical
information is needed to make the evaluation, but in some
cases animal or clinical data are required. Typical examples of
this class are new 125I or 103Pd interstitial brachytherapy seeds,
where the new sources differ from existing ones in minor ways
such as changes in source configuration or encapsulation.
If one wants to use these sources in a clinical trial or
investigational study, the sponsor simply needs to obtain
approval from the local institutional review board (IRB).
The second class is the one found to be not substantially
equivalent (NSE) to a predicate device or a predicate device
does not exist. In this case, the regulatory route to market
is the premarket approval (PMA) application. This type of
application requires both clinical and nonclinical data. Clinical
trials must first be approved by an IRB. If the IRB determines
that the medical device as it is to be used in the clinical trial is
of not significant risk (NSR) to the patient, the trial can begin
upon receiving IRB approval. While uncommon, the FDA
may disagree with the IRB’s NSR designation and require an
FDA-approved investigational device exemption (IDE) before
the trial begins. An IDE allows an unapproved device to be
used in a clinical trial under the set of very specific conditions
identified in the trial protocol. As a specific example, the initial
use of IVBT sources to treat in-stent restenosis was deemed to
be NSR by an IRB. However, the FDA determined that this was
a new indicated use of radiation (treating nonmalignant disease
in the vascular system), that these devices involved new safety
and effectiveness issues, and that these devices presented
a significant risk (SR). Thus, clinical trials involving these
devices needed an FDA-approved IDE as well as institution-
specific IRB approval.
2.B. Source calibrations
A key component for the accurate delivery of dose by
brachytherapy sources is the ability to determine the absolute
radiation output from the source at a reference point. For
photon sources, this is usually performed by correlating
the radiation output to air-kerma strength SK in the U.S.
and to reference air-kerma rate in Europe. Since primary
measurements of brachytherapy source strength are beyond
the capabilities and resources of most clinics, a system
of traceability to a primary standards dosimetry laboratory
(PSDL) has been established using secondary standards
dosimetry laboratories (SSDLs), i.e., Accredited Dosimetry
Calibration Laboratories (ADCLs) in the U.S., for most of
the sources discussed in this report. In the U.S., the National
Institute of Standards and Technology (NIST) is the PSDL
that establishes a national primary calibration standard for
SK . The national standard is then transferred to the ADCLs.
The clinical physicist thus receives a traceable calibrated
instrument through the ADCLs. Some SSDLs and ADCLs
develop interim standards for source calibrations that are
not yet available at PSDLs. Like NIST, the same role is
performed by other PSDLs such as the National Physical
Laboratory (NPL) in the U.K., the Laboratoire National
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3181
Henri Becquerel (LNHB) in France, and the Physikalisch-
Technische Bundesanstalt (PTB) in Germany. Equivalence
of measurements is demonstrated through the International
Committee on Weights and Measures Mutual Recognition
Arrangement among the countries of these labs as monitored
by the BIPM.13
According to the AAPM, brachytherapy source manu-
facturers are required to annually compare their in-house
standard to the NIST standard for low-energy sources,14 and
every two years to a PSDL-traceable standard for high-energy
sources,15 where an energy cutoff of 50 keV is used to separate
low- and high-energy sources. It is expected that the transfer
standard will be used to characterize the manufacturing source
calibration system and that there is a routine quality control
program in place to ensure that the manufacturer’s source
calibration system is operating within statistically expected
limits. This chain of traceability to a PSDL is essential to
the efficacious and consistent application of brachytherapy
sources in widespread use at clinics having varying degrees of
expertise for the measurement of source strength. In addition,
when errors are discovered or improvements in measurement
technology occur and the standard is revised, the chain of
traceability allows physicians to revise their prescriptions in a
careful and consistent manner.16 To our knowledge there are
no FDA requirements for calibrations, but of course there are
NRC regulations for users in the U.S. requiring them to have
HDR 192Ir source calibrations be performed with traceability
to the ADCLs.
To illustrate issues that may arise when dosimetry cali-
bration standards are revised or new sources are introduced,
consider the brief history of the calibration of 125I and 103Pd
sources. A primary calibration standard for low-energy, low-
dose-rate (LDR) 125I brachytherapy sources was developed
at the National Bureau of Standards (the former name for
NIST) in 1984 by Loftus using the Ritz free air ionization
chamber.17 Because of its low sensitivity, four to six sources
were mounted in an array to produce an adequate measurement
signal. The source calibration was then transferred to the
ADCLs. From 1985 through 1988, measurements and Monte
Carlo (MC) simulations identified the contribution of titanium
x-rays at 4.5 keV, which added 10% to the source output
in air with no influence on tissue dose at clinically relevant
depths.18,19 In 1993, Loevinger revised the calibration standard
by introducing the design of the NIST Wide-Angle Free-Air
Chamber (WAFAC) for the measurement of these sources. It
included an aluminum filter to remove the titanium x-rays,
radiation that contributed to measurements by Loftus.20 The
NIST WAFAC allowed measurement of a single source at
30 cm because of its higher sensitivity. The measured air-
kerma rate at 30 cm distance, corrected for air attenuation
between the NIST WAFAC and the source, was presented
at 1 m using the inverse square law, yielding SK . During
this time, 103Pd sources were introduced by manufacturers
without traceability to a primary calibration standard. Testing
and establishment of the NIST WAFAC standard continued
through 1998 and a plan for the implementation of the new
standard was established to begin on January 1, 1999. A
provisional standard was transferred to the ADCLs in 1998.

3182 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
Late in 1999, it was discovered that the NIST WAFAC was
producing a systematic error in measurement throughout 1999.
The 1999 value for a given 125I source disagreed with the 1998
standard by 3%. All source models were measured again in
2000, finding that in 1999 there were discrepancies of 2%–7%.
2.C. Brachytherapy dose calculations
For all radiotherapy modalities (including brachytherapy),
the accuracy of dose delivery can greatly influence both the
benefits and risks to the patient. The radiation treatment has to
be delivered within a therapeutic window around the prescrip-
tion dose as too low a dose could compromise tumor control
and too high a dose may cause unnecessary normal tissue
toxicity. Although the therapeutic window may be generally
considered as narrow in some clinical situations and as wide
in other situations, quantitative patient-specific information on
the therapeutic window is generally not well known. Thus, the
accuracy of dose delivery to the correct target is considered
to be a critical factor by the radiation oncology team for all
radiotherapy modalities, including brachytherapy. According
to Williamson and Rivard, while no major breakthroughs have
occurred in the last decade, the uncertainty of brachytherapy
dose estimation using MC methods and thermoluminescent
dosimeters (TLD) had become better established: 3%–5%
(k = 1) for MC and 7%–10% (k = 1) for TLD,21 where k indi-
cates the coverage factor on the expected distribution. Confi-
dence increased in these quantitative dosimetry techniques
after they were applied to more source models. As a result,
broader intercomparisons of theoretical and measured dose
distributions became possible. In 2005, Williamson and Rivard
anticipated the following for the next decade: (a) Improved
dose measurement techniques with k = 1 uncertainties near
4%; and (b) development of more accurate dose-calculation
engines based upon MC simulation and other transport
equation methods for patient-specific treatment planning for
brachytherapy.21 Williamson and Rivard published revised
uncertainty budgets for determination of the dose-rate constant
Λ, indicating that lower k = 1 uncertainties (1.5%–2% for
MC and 6%–7% for TLD) are feasible.22 The 2011 TG-138
report has confirmed this general trend of improvement in the
field of brachytherapy dosimetry.23 The 2014 report by GEC-
ESTRO and AAPM on clinical brachytherapy identified much
larger uncertainties when considering the clinical treatment
procedure.24
In 2003, an intersociety group consisting of the American
Brachytherapy Society (ABS), the American College of
Medical Physics (ACMP), and the American College of
Radiation Oncology (ACRO) recommended standards for
brachytherapy performance and identified three types of accu-
racy requirements.25 These were numerical accuracy, physical
dose delivery accuracy, and clinical dose delivery accuracy.
Numerical accuracy of a computer-assisted dose calculation
should be assessed by comparing its output to independent
dose calculations based upon the same algorithm and the same
input data. A tolerance of 2% was recommended for numerical
accuracy checks, compared to a value of 3% as recommended
by TG-40.26 The intersociety group defined physical dose
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3182
delivery accuracy as the agreement between calculated dose
and dose actually delivered under idealized conditions. This
intersociety group recommended that physical dose delivery
accuracy have a tolerance of 6%, essentially specifying the
accuracy of single-source dose distributions in homogeneous
water. However, physical dose delivery accuracy is influenced
by source calibration accuracy, the accuracy of the dose
calculation algorithm, and the appropriateness of any user-
selected dosimetric parameters. Furthermore, the intersociety
group defined clinical dose delivery accuracy as the agreement
between calculated dose and dose actually administered
to anatomically defined reference points or surfaces. They
recommended that, if assessment of applicator placement
shows that the prescribed dose cannot be delivered to the target
volume with less than 20% deviation from the prescribed
dose, then a reassessment of the procedure is required and
the following options should be considered prior to initiating
therapy: (i) repositioning the applicator or sources to fulfill
the written directive requirements, (ii) adjusting the written
directive, or (iii) aborting the procedure.
3. GUIDELINES
It is difficult to predict future products, their potential new
applications, and new problems that may arise. Therefore,
the services of a medical physicist are even more critical
in the clinical implementation and evaluation of innovative
brachytherapy devices and applications. It is suggested that
a thorough review of any innovative brachytherapy device
or application should be performed by a qualified medical
physicist before clinical research or approval for routine
clinical use. The medical physicist must play an active role
in the evaluation of risks and benefits of new products
or new applications,27 evaluation of preparedness (resource
assessment), and evaluation of the regulatory consequences of
clinical implementation when the delivered dose substantially
differs from the prescription. For the safe implementation of
new technologies, the medical physicist should include the
suggestions of this report in his/her department policy manual.
Further, it is especially important that adopters of new tech-
nology diagram their workflow and perform a failure modes
and effects analysis to streamline future clinical use.28–32
3.A. Regulatory requirements
If a new medical device (i.e., research device) fabricated by
an individual is to be used on human subjects at the individual’s
institution, the institution is obligated to document a safety and
efficacy analysis. If the device is a new brachytherapy source,
ideally it should be listed on the National Sealed Source
and Device Registry (NSSDR) of the Nuclear Regulatory
Commission (NRC). However, for sources not listed on
the NSSDR, the Radiation Safety Committee (RSC) at the
individual’s institution is obligated to perform a safety analysis
similar to that done by an NSSDR reviewer. The RSC at
the individual’s institution is also obligated to perform a
safety analysis if the radiation source is not a radionuclide,
i.e., electronic brachytherapy. Similar procedures are to be

3183 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
followed in European countries. This report is silent on
necessary approvals for licensing radioactive materials as the
topic is outside the approved charge and due to the broad
diversity on specific regulatory requirements.
For compliance with Standard 2919 of the International
Organization for Standardization (ISO, Geneva, Switzerland)
radiation protection requirements for sealed radioactive
sources,33 special form certification by the U.S. Department
of Transportation may be necessary for some brachytherapy
sources. This is to demonstrate the structural integrity of
the sealed source under unusual conditions that could occur
during transportation to the individual’s institution. Effects
of temperature, capsule composition, and capsule dimensions
may need to be examined.34
If the source is a radionuclide, a broadscope licensee in
the U.S. has authority to use any of the listed radionuclides
allowed by its license. For research purposes, this must be
performed under a clinical trial that is approved by the IRB
overseeing the individual’s institution, regardless of the FDA-
approval status of the research device. A suitably trained
medical physicist or physician may serve as the principal
investigator of the trial.
If an FDA-approved device is to be used for an unapproved
clinical indication (i.e., off-label use as described in detail
in Appendix A 2) outside of human-use research,27 then
IRB approval is necessary. For designing a clinical trial, the
following items are examples of what should be considered:35
• device description,
• specific indication for use,
• safety and effectiveness information,
• risk analysis,
• protocol for conducting the trial,
• hypothesis to be tested,
• statistical analysis including sample size needed to test
the hypothesis,
• type of trial, e.g., randomized, double blinded, placebo
trial,
• specific primary safety and effectiveness endpoints for
trial,
• secondary endpoints for trial,
• patient inclusion and exclusion criteria,
• informed consent form, and
• case report forms.
The medical physicist should become familiar with the above
items if participation is required in a clinical trial using a
brachytherapy source or application for research purposes.
The following items are examples of additional brachy-
therapy-specific information that should be evaluated for all
types of usage:
• source decay scheme (plus any daughter or grand-
daughter products),
• source integrity to prevent radioactivity leakage,
• procedures for receiving, handling, transporting, and
disposing of sources,
• confirmation of source sterility when appropriate,
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3183
• biocompatibility of the source or device should be
ensured, and
• any specific source usage issues for clinical use (e.g.,
source pullback and source delivery), any unusual
precautions for shielding staff, or any issues from
prescription dose to nearby organs in the patient. The
use of robotics in brachytherapy for source delivery is
covered in detail within the TG-192 report.36
Individuals with expertise and background in the appropriate
discipline should be consulted.
Another issue of concern for brachytherapy sources con-
taining new radionuclides is radionuclide purity. Long half-life
radio-impurities may prohibit cremation of the patient after
death. In brachytherapy, the desired radionuclide is created
from nuclear activation of an enriched or natural target. A
nuclear reactor or an accelerator is used with the energy fluence
and irradiation time chosen to maximize the isotopic yield of
the desired radionuclide. Radiochemical separation is then
employed to remove unwanted elements from the irradiated
target. Further target refinement is made by waiting for short-
lived isotopes to decay to increase the proportion of the desired
radionuclide. Unlike for nuclear medicine, to our knowledge
there are no radionuclide purity standards for brachytherapy
sources. As detailed standards would need to account for
photon and beta emissions as a function of radionuclide, it is
not possible to set a simple percentage limit in terms of activity,
i.e., Bq. However, radionuclide impurities should be limited
by manufacturers such that their total dosimetric contributions
would be less than 5% of the dosimetric contributions of the
primary radionuclide. This value is based on observations
of 103Pd sources37 and the experience of the writing team
for other brachytherapy radionuclides. This suggested limit
would be constrained to clinically relevant distances in the
vicinity of the implant, and would be subject to the useful
source life. If upon decay the radionuclide impurities result
in total dose contributions greater than 5% of that due
to the primary radionuclide, the medical physicist should
account for this change or else remove the source from the
clinical inventory. This issue may be assessed by the medical
physicist by requesting documentation of the radionuclide
purity from the manufacturer and subsequently evaluating the
dosimetric influence of any contaminating radionuclides based
on their halflives and emission energies. The approach taken
by Nuttens and Lucas for brachytherapy sources purposefully
containing two different radionuclides may be helpful for
performing this assessment.38,39
3.B. Calibration requirements
Suitable instrumentation should exist to determine the
source strength of the device. ESTRO Booklet 8 has an exten-
sive description on required features for such instruments.4 It
is suggested that a measure of the source strength (independent
from the manufacturer-provided value) be performed by the
medical physicist preceding clinical use of the device. This
measurement should be traceable to a PSDL, and for photon
sources typically will be in units of SK or reference air kerma

3184 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
rate (RAKR) for a sealed source as measured in a re-entrant
well-type air ionization chamber having an insert specific to
the source design.6,14 In the U.S., this calibration will require
NIST-traceability with transfer to the ADCLs for availability
to U.S. medical physicists. In Europe, the medical physicist
should send their instrumentation to an NMI for calibration.
The AAPM and GEC-ESTRO suggest that primary cali-
bration standards be developed for all clinical brachytherapy
sources that have received FDA clearance in the U.S. or the
CE Mark in Europe. Also, the AAPM and GEC-ESTRO
should maintain a formal mechanism for encouraging and
supporting the SSDLs to develop interim calibration standards
when a primary calibration standard is not available for
sources having FDA approval or CE Marking. Because the
development of a primary calibration standard is a time-
consuming and expensive process, an interim solution for
the safe and efficacious introduction of new brachytherapy
sources in the market place is needed. Such situations are
likely to be more frequent in the future as several new national
and international clinical trials using innovative brachytherapy
sources and devices are anticipated.
If NIST or another PSDL has not developed a primary
calibration standard for a new source, the SSDLs may establish
an interim calibration standard. This interim standard needs to
be based upon good metrological procedures by being trace-
able in some manner to another PSDL calibration standard.
Generally, this also involves a publication in a peer reviewed
journal. Comparison with a PSDL primary calibration stan-
dard when available should be done to determine if there is
any discrepancy between the interim standard and the new
primary standard. In this case, the focus is to provide a means
where all clinics will be delivering a consistent prescription
dose whose absolute value may need to be adjusted once a
primary calibration standard for that source is developed.
If a research device is at an early stage such that there
are no suitable PSDL-traceable calibrations available, the
medical physicist should contact a PSDL or SSDL for
guidance in developing an in-house calibration standard at the
physicist’s institution. Development of a rigorous primary or
secondary calibration standard (especially for beta-emitters
and low-energy photon-emitting sources) can be a major
undertaking beyond the capabilities of most academic centers
or commercial source developers.
The AAPM is the only organization in the U.S. that
has the expertise and committee infrastructure, without a
conflict of interest, to maintain close supervision over an
interim brachytherapy standard as established at an ADCL.
As the PSDL in the U.S., NIST also has close supervision
over the ADCLs such as through proficiency tests. These
brachytherapy standards are transferred to the clinic via ADCL
calibrations. The Sistema Interamericano de Metrologia is
a regional metrology organization that includes the NMIs
of the 34-member nations of the Organization of American
States. In Europe, the European Association of National
Metrology Institutes (EURAMET) is the regional metrology
organization of Europe. It coordinates the cooperation of
European NMIs in fields like research in metrology, national
measurement standards, and the calibration and measurement
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3184
capabilities of its members. ESTRO, as the international
professional organization for radiation oncology in Europe,
has the infrastructure to interact with EURAMET on the needs
and requirements for the field of radiation oncology.
3.C. Dosimetric requirements
It is of course possible for brachytherapy sources to have
all regulatory approvals in place and a robust calibration
infrastructure available, yet the source would still be deemed
deficient by the AAPM and GEC-ESTRO from a dosimetric
perspective.40 The source dose distribution should be well
characterized and be evaluated thoroughly before its use.
This is often performed by dosimetry investigators using MC
methods for radiation transport simulations and/or experi-
mental measurements. The AAPM has issued methodological
recommendations to dosimetry investigators for obtaining
reference dosimetry parameters for low- and high-energy
photon emitters.2,15 These dosimetry parameters or some other
quantitative characterization of the dose distribution (such as
an along/away dose rate table) should be available.
It is suggested that medical physicists utilize societal-issued
consensus data on brachytherapy dosimetry parameters when
available. In the U.S., these consensus data are posted on the
Brachytherapy Source Registry.10 Using different evaluation
criteria, data are also posted on the ESTRO website.41 If
such consensus data are not available, the medical physicist
should review the literature and evaluate candidate datasets
in the manner described in the 2004 AAPM TG-43U1 report
to obtain interim dosimetry parameters.2 If none exist, the
medical physicist should serve as the dosimetry investigator
and perform the necessary studies using MC methods and
radiation dose measurements for use in clinical brachytherapy
treatment planning.
With a well-characterized source dose distribution, the
medical physicist should then carefully consider the broad
goal of determining the dose to target volumes and critical
tissues in the study subjects. This involves the following tasks,
which are similarly concerned for when commissioning a new
brachytherapy modality:
Basic procedure flow: protocol for source placement and
treatment planning.
• Example: preplanning/volume study; image-guided
insertion; image-based dose evaluation,
Inputs
• images: patient anatomy and target volume, guidance
during applicator insertion, source and applicator locali-
zation, and postimplant/intraoperative dose evaluation,
all of which may not be applicable to intraoperative
radiotherapy (IORT) procedures,
• availability of software for brachytherapy treatment
planning that is compatible with dose calculation for
the source,
• source strength and other brachytherapy dosimetry
parameters,

3185 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
• verification and validation of brachytherapy treatment
planning system (TPS) for the new device,3
• planning constraints and goals,
Dose calculations
• single-source dose kernels,
• applicator dose modulation function,
Outputs
• isodose curves, line profiles, and dose-volume histo-
grams (DVHs),
• dose specification quantities and criteria, and
• maps of dose differences and dose ratios.
3.D. Radiobiological requirements
There are several biological and clinical issues that are
primarily evaluated by a radiation oncologist. These issues
include consideration of any new long-term effects of radiation
linear energy transfer (LET) and relative biological effective-
ness (RBE) of source radiation if there is reason to believe
that these effects may be substantial or different from those
of conventional sources. Equivalent doses for treating specific
diseases should be evaluated by a radiation oncologist with the
assistance of a medical physicist if there is a reason to believe
that the LET or dose rate or other radiobiological factors
may alter the effectiveness of radiation. Although the primary
responsibility for these biological and clinical issues lies with
the radiation oncologist, a medical physicist should assist in
this process. Additional information is given in Appendix B.
3.E. Team organization and training
Another important component of introducing newly
approved brachytherapy devices or applications is the orga-
nization and training of the clinical team. This can be
challenging for small clinics where the staffing and resources
are minimal.29 The physicist should evaluate whether or
not his/her clinic is ready to introduce new brachytherapy
modalities. Each of the members of the clinical team should
have to present their qualifications in their given field. Once the
team is created, vendor-specific training should follow. Here
the details of the treatment device should be explained and the
team taught how to safely administer the treatment. Offsite
training is most likely used in the early stages, but institution-
specific training should be requested to fit the local team. The
onsite training will help illuminate potential problem areas
that are unique to the local team configuration and practices.
During this training period the local team should minimize
distractions in order to acceptably benefit from the training.
Training requirements supplied by the manufacturer are
set as part of obtaining approval by the FDA or other
regulatory body. Manufacturers of new brachytherapy medical
devices may require a certain number of proctored cases.
For example, both of the current brachytherapy microsphere
vendors (see Sec. 4.G) require three proctored cases to be
completed before a site has completed their training. These
proctored cases cover all aspects of the case, including
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3185
ordering the microspheres, determining if the patient meets the
treatment indications, performing eligibility exams, assisting
with radioactive materials licensing, delivering the patient’s
treatment and continued patient follow-up.
After the team is created, trained, and has performed solo
patient cases at the training center, the team should develop
pathways for continuing education and local QA standards.
One approach to meet this need is through the RSC. These
standards can be placed into the radioactive material license
application for both documentation and enforcement. Periodic
meetings with disciplines outside the reach of the radioactive
materials license, such as medical oncology, are beneficial
to the team as methods evolve and indications change. The
overall goal for any multidisciplinary treatment modality
should be clear communications.
Liver microsphere brachytherapy provides an example of
a multidisciplinary team in which a medical physicist must
participate. The required specialties in liver microsphere
brachytherapy include: individuals to provide the overall
management of the cancer patient, serve as the authorized
user (radiation oncologist or nuclear medicine physician),
perform the vascular catheterization, order and interpret the
correct radiology exams, take responsibility for handling the
radioactive materials, perform dosimetric calculations, and
oversee the radiation safety aspects of the procedure. From
one institution to another, the division of these responsibilities
will be different as the availability of disciplines varies. In the
broadest case, personnel from interventional radiology, radi-
ation oncology, nuclear medicine, medical physics, medical
oncology, and radiation safety could all participate in liver
microsphere brachytherapy.
4. BRACHYTHERAPY INNOVATIONS
In order to illustrate the application of the guidelines
stated in Sec. 3 to current uses of brachytherapy, this
section presents several case studies. These descriptions are
organized based on regulatory issues, source calibrations,
dose calculation methods, and radiobiological concerns.
Highlighted are historical scenarios that caused problems upon
clinical implementation, strategies that are now addressed by
TG-167 report guidelines, and issues currently unresolved
where additional development and guidelines are required.
Additional aspects are given in Table I.
4.A. High-dose-rate (HDR) 192Ir sources and
afterloaders
HDR 192Ir sources have presented several challenges in
the U.S. for primary calibration standards. The need for an
interim standard was so evident that a calibration standard
was developed by the University of Wisconsin in 1993.43 Since
then, calibration of the VariSource® (including both old and
new designs) by Varian Medical Systems, Inc. (Palo Alto,
CA), GammaMedplus® (Varian Medical Systems, Inc., Palo
Alto, CA), and the Nucletron microSelectron® and Nucletron
Flexitron-HDR (both from Elekta Brachytherapy, Veenendaal,
The Netherlands) sources has been shown to fall within 1%
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3186 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications 3186

T I. Use of various brachytherapy sources, applicators, or applications.

ADCL Ability to calculate

Primary calibration Primary calibration calibration patient dose Clinical
Section Name Year introduced standard in the U.S. standard in Europe availability distributionsa experienceb

4.A HDR 192Ir sources/afterloaders 1964 No Yes Yes Yes Extensive

4.B HDR 60Co sources 1960s No Yes No Yes Moderate
4.C LDR 125I and 103Pd sources 1990s Yes Yes Yes Yes Extensive
4.D LDR 131Cs sources 2004 Yes No Yes Yes Extensive
4.E Elongated sources 1960s Yesc Yes Yes No 103Pd minimal
192Ir extensive

4.F Intermediate energy sources 1987 No Yes No Yes Minimal

4.G Electronic brachytherapy 1992 Yes No Yes Yes Extensive
4.H Intravascular brachytherapy 1990s Yesd No Yes Yes Extensive
4.I Neutron-emitting 252Cf sources 1965 Yes No No Noe LDR moderate
HDR minimal
4.J 90Y microspheres 1980s Nof Yes No No Moderate
4.K Collimated applicators and sources 1990s N/A N/A N/A Yesg Moderate
4.L Breast balloon applicators 1990s N/A N/A N/A Yes Extensive
4.M Brain balloon applicators 2001 N/A N/A N/A No Moderate
4.N Non-COMS eye plaques 1990s N/A N/A N/A Yes Moderate

Note: N/A indicates not applicable.

a
Using patient-specific source localization in a homogeneous medium without tissue heterogeneity and default scatter corrections.
b
Minimal is defined as the number of new patients treated worldwide being less than 103 moderate is defined as between 103 and 104 patients, and extensive as over 104
patients. Data were provided by the manufacturers.
c
A 1 cm RadioMed® coil source was calibrated by NIST and the standard was transferred to the ADCLs in 2003, but no formal calibration standard has been established.
See Paxton et al. for more details (Ref. 42). More recently, a 1 cm CivaString® 103Pd source was calibrated by NIST in 2014 and then transferred to the ADCLs.
d
There was a primary calibration standard in the U.S. during the period in which treatment was most prevalent. However, NIST no longer performs measurements on
intravascular brachytherapy sources, and clinical users in the U.S. may obtain calibrations from the ADCLs.
e
The ability to calculate dose equivalent, including RBE, is limited.
f
The TheraSphere manufacturer participates in the NIST Radioactivity Measurement Assurance Program. Dial settings have been determined by NIST for the measurement
of TheraSphere in commercially available dose calibrators. However, it is not a primary national standard that has been transferred to ADCLs.
g
It is possible to generate 3D dose distributions for shielded skin applicators and single-axis treatments using the AccuBoost® system. However, it is not yet possible to
generate 3D dose distributions for multi-axis AccuBoost treatments due to the need to model tissue deformation for performing dose summation.

of each other in terms of source strength calibrations.44,45
Another HDR remote afterloader is the MultiSource® HDR
(Eckert and Ziegler BEBIG GmbH, Berlin, Germany), which
delivers brachytherapy with either 192Ir or 60Co sources. There
currently is no ADCL-approved calibration standard for any
of the Eckert and Ziegler HDR sources.
The ADCL ionization chamber calibration technique for
192
Ir source is to average air-kerma calibration factors,
interpolating between primary Kair standards for 137Cs gamma
rays and medium-filtered M250 kVp x rays. This way, the
detector sensitivity to 192Ir photons may be approximated.
The paper by Rasmussen et al.45 has shown that the various
ways of obtaining a calibration coefficient for an ionization
chamber for HDR 192Ir sources also yield the same result
as does the methodology mentioned above. After the cali-
bration coefficient for the ionization chamber is obtained, a
measurement is taken at seven distances.43,46 In this manner,
the HDR 192Ir source can be calibrated and that calibration can
be transferred to a re-entrant well-type air ionization chamber
with subsequent transfer to the end-user’s clinic well chamber.
These well chambers should then be used to calibrate clinical
HDR 192Ir sources since the seven-distance technique is too
cumbersome for proper use in a typical clinical setting and
should be performed at PSDLs or SSDLs. However, those
clinics without access to calibration of their well chamber by
PSDLs or SSDLs will follow the methods described in the
ESTRO-issued Booklet 8.4 With the increased accessibility to
PSDLs and SSDLs, this practice is diminishing. Calibration
standards for HDR 192Ir using similar techniques have been
developed at a number of European PSDLs such as LNHB,
NPL, and PTB, and at the National Research Council of
Canada,47 but not yet at NIST in the U.S. Intercomparisons of
these standards have shown good agreement.48–52
The preferred method for traceability in clinical source
calibrations is to have the well-type chamber calibrated
against the traceable standard (e.g., at an ADCL). This
calibration should be carried out for each source, including the
appropriate source holder made by the well chamber or source
manufacturer for that source. Calibration of well ionization
chambers is performed using the appropriate source holder,
which is a critical part of the calibration system.45
The dose calculation methods for HDR 192Ir brachytherapy
are well established, and the joint TG-229 report by AAPM
and GEC-ESTRO provides detailed information on current
HDR 192Ir source models and their dosimetry parameters.15
HDR 192Ir source calibrations are available with PSDL
traceability in Europe and with ADCL traceability in the U.S.
This case study shows that development of a robust calibration
infrastructure can greatly reduce the variability in clinical
source calibrations, in this case from over 11% based on user-
developed standards lacking PSDL or ADCL traceability to
less than 2%.23

Medical Physics, Vol. 43, No. 6, June 2016


3187 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
4.B. HDR 60Co sources
While the short halflife of 192Ir (74 days) is beneficial
for production of high-specific activity sources with small
geometrical dimensions that may be used both for interstitial
and intracavitary implants, 192Ir sources require replacement
about every two to four months. In developed countries like the
U.S. and most of Europe, this source exchange frequency is
not a serious concern as the entire process of source exchange
and commissioning can be accomplished within a few days.
However, for many developing countries, HDR 192Ir sources
are not easily accessible and occasionally, by the time the cus-
toms paperwork and source shipment clearance are completed,
a large proportion of useful activity can decay away.53
Therefore, HDR 60Co brachytherapy sources (5.27 yr halflife)
have been introduced to overcome some of these difficulties.
While HDR 60Co remote afterloaders were first used in
the 1960s,54 presently four HDR 60Co remote afterloading
systems are commercially available outside the U.S. These
are the Ralston remote afterloader (Shimadzu Corporation,
Japan), the MultiSource® remote afterloader by Eckert and
Ziegler BEBIG GmbH (Berlin, Germany), the Flexisource®
60
Co source as used in the Flexitron remote afterloader (Elekta
Brachytherapy, Veenendaal, The Netherlands), and the model
GZP6 60Co source by the Nuclear Power Institute of China
(Chengdu, People’s Republic of China). While HDR 60Co
sources have CE Marking, the FDA has not reviewed HDR
60
Co sources or remote afterloaders at this time and users in
the U.S. cannot yet purchase such equipment.
The PSDL in Germany (i.e., PTB) provides source strength
calibrations for HDR 60Co sources, but there are currently no
U.S. PSDLs or ADCLs that offer calibrations. The current
U.S. HDR 192Ir interim calibration standard could be modified
to develop a secondary standard for HDR 60Co brachytherapy
sources with direct traceability to the NIST 60Co teletherapy
standard if these brachytherapy sources are ever reviewed by
the FDA.
Dosimetric characteristics of Ralston HDR 60Co sources
have been determined using MC-based dosimetry.55 Dosi-
metric characteristics of MultiSource® HDR 60Co sources
have been evaluated by Ballester et al., Granero et al., and
Richter et al.56–58 The joint TG-229 report by AAPM and
GEC-ESTRO included consensus datasets for these sources.15
HDR 60Co remote afterloaders have been used in clinical
trials outside the U.S. where regulatory approvals were in
place,59,60 and there are no substantial radiobiological differ-
ences with HDR 192Ir sources due to both being temporary
implants of high-energy photon-emitting sources.
This case study presents the need to go through the
regulatory channels for a new source. Following commercial
availability, clinical users in the U.S. may consider utilizing
the source under IRB approval if FDA approval and cali-
brations through the ADCLs are unavailable. While there
are European-based PSDL-traceable calibration standards for
source strength, clinical users in the U.S. require a NIST-
traceable calibration standard for general clinical use outside
of an IRB-approved protocol. This could be established
through creation of an in-house calibration technique.
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3187
4.C. LDR 125I and 103Pd sources
Because of the growing popularity of prostate implants
in the mid-1990s, a variety of new designs of 125I and
103
Pd sources were developed. Since FDA clearance for
these medical devices is predicated on the original interstitial
brachytherapy sources and grandfathered for approval, the
regulatory approval process for new 125I and 103Pd sources was
already established. New 125I and 103Pd source models were
considered SE to legally marketed sources already in clinical
use by the FDA and qualified for premarket notification 510(k).
125
I sources were the first to receive a standard for source
strength.17 103Pd sources became available in 1988 and were
later included in the 1995 TG-43 report.1 However, a 103Pd
primary calibration standard was not available until NIST
developed the WAFAC in 1999. This lack of a primary
calibration standard and a PSDL-traceable calibration resulted
in a complex history of changes in prescription doses and,
consequently, delivered dose. This history is well described
by Williamson et al. and is briefly summarized here.61
Calibrations preceding those made with the NIST WAFAC
involved a 109Cd NIST Standard Reference Material activity
standard comparison by the manufacturer, which resulted in
−1.7% to +8.7% variations of prescribed dose to delivered
dose from 1988 to 1999. After moving away from the
109
Cd activity standard and implementing the NIST WAFAC
calibration standard, the prescribed dose still differed from
the delivered dose by −4.3% until the WAFAC calibration
standard was established via a number of measurements and a
Λ value was established in the AAPM 2004 TG-43U1 report.2
Although the outside dimensions of these 103Pd sources
were nearly identical, their internal geometric structure, such
as the shape and materials of the x-ray marker, thickness
and materials of the end caps, and radionuclide distribution
varied amongst source models. Other sources were designed
to improve ultrasound appearance, radiographic visualization,
minimize imaging artifacts from computerized tomography
(CT), or reduce seed migration. Although the design changes
for new 125I and 103Pd sources are likely to be minor, these
changes can substantially alter the dosimetric characteristics
due to the steep dependence of low-energy photon interactions
as a function of energy and atomic number. This was
demonstrated by variations in Λ of up to 10% for the same
radionuclide in different configurations.62 To a lesser extent,
the radial dose functions were also different for different
designs of the same radionuclide sources. The 2D anisotropy
functions that represent the angular dose dependence around
the source can be profoundly different for different source
models containing the same radionuclide. Differences in
source geometry can also have other dosimetric consequences.
For example, Afsharpour et al. demonstrated that variations
in seed designs lead to up to 4% variations in interseed
attenuation (not taken into account by the AAPM TG-43
protocol), which leads to measurable differences in treatment
planning parameters such as prostate D90.63,64 Consequently,
it is imperative that calibration methods and brachytherapy
dosimetry parameters be specified for individual source
models of 125I and 103Pd. Further, the practice of experimental

3188 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
dosimetry for these brachytherapy sources containing low-
energy photon-emitting radionuclides is highly sensitive to
the phantom composition.65,66
This history of 103Pd source calibrations presented in this
case study underscores the concern for introducing a source
into clinical practice with an unstable vendor-maintained
relative calibration standard and not having a suitable primary
calibration standard. In the absence of regulatory bodies
failing to require dosimetric criteria in their approval pro-
cess, professional societies and voluntary standards can be
developed and promulgated to fill the void. The AAPM,
U.S. PSDL (i.e., NIST), and SSDLs (i.e., ADCLs) developed
the necessary calibration infrastructure needed by clinical
users at the time when new 125I and 103Pd source models
were considered innovative.14 Without a suitable primary
calibration standard, early adopters of new sources should take
responsibility for developing an in-house calibration standard
with PSDL traceability as appropriate for that source.
4.D. LDR 131Cs sources
131
Cs sources have an average photon energy of approxi-
mately 30 keV, which is slightly higher than 125I and 103Pd.
The model CS-1 Rev2 source was introduced by IsoRay
Medical, Inc. (Richland, WA), considered as SE by the FDA,
and qualified for premarket notification 510(k) by the FDA
for the treatment of cancer. This source model also has CE
Marking.
Before first clinical use, NIST and the ADCLs developed a
calibration standard for 131Cs, having learned from the expe-
rience when 103Pd sources were introduced as described in
Sec. 4.C. Soon after clinical use, the initial reported Λ value67
was determined to be 13% lower than currently accepted
values,68–71 as demonstrated in several publications by dosim-
etry investigators soon after this source was made generally
available. Subsequently, the brachytherapy dosimetry param-
eters have been evaluated using several experimental and
computational tools and an AAPM consensus dataset has
been prepared. The key radiobiological issue presented by this
source is that it has a radionuclide having a shorter halflife than
any other LDR brachytherapy seed. Because of this shorter
halflife, the initial dose rate in permanent 131Cs seed implants is
higher than that for 103Pd and 125I permanent implants in order to
deliver the same biological effect. Consequently, the prescrip-
tion for a permanent implant with 131Cs will differ from 125I or
103
Pd, and it was necessary to determine the prescribed dose for
131
Cs that would result in the same biological effect as produced
by 125I or 103Pd implants. For prostate monotherapy, prescrip-
tion doses of 110 Gy for 131Cs, 125 Gy for 103Pd, and 145 Gy
for 125I are common. Before utilizing 131Cs to treat new disease
sites, a careful calculation should be performed using radiobio-
logical models (e.g., linear quadratic model) to deliver similar
biologically equivalent dose to predicate sources if available.
As similar to the development of 125I and 103Pd sources,
this case study highlights the need for established brachy-
therapy dosimetry parameters preceding general clinical im-
plementation and a careful radiobiological evaluation before
widespread clinical use.
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3188
4.E. Elongated sources
Elongated brachytherapy sources with active lengths
L ≥ 1 cm are readily visualized radiographically and do not
migrate as much as single sources. With such sources, it is
theoretically possible to obtain better implant quality, with
a more homogeneous dose in the proximal tissue region,
than using conventional brachytherapy seeds. Encapsulated
LDR 192Ir wires were used primarily in Europe for interstitial
brachytherapy since the 1960s and were cut to the desired
lengths in clinical practice, but since 2014 are no longer
available. Since the wires were designed and first fabricated
prior to 1976, these sources were grandfathered approval by
the FDA. 103Pd wires were introduced in the U.S. market as
RadioCoil® by RadioMed, Corp. (Tyngsboro, MA), granted
510(k) approval in 2000 (K001070). About 30 patients were
treated between 2004 and 2006, after which the sources were
no longer available.72 103Pd strings were introduced in the U.S.
market as CivaString® by CivaTech Oncology, Inc. (Research
Triangle Park, NC), and granted a 510(k) clearance in 2008
(K082159).
Due to their longer active lengths than conventional brachy-
therapy sources, direct calibration of elongated brachytherapy
sources is not straightforward. Calibrations of LDR 192Ir
wires were performed in a re-entrant well-type air ionization
chamber with either a short sample (<1 cm) snipped from
the inventory using the assumption of uniform source strength
over the inventory length73 or with collimated chamber insert
to measure sections of an uncut wire.74 Due to their low-
energy photon emissions, primary calibrations of 103Pd wires
and 103Pd strings with L ≤ 1 cm have been performed with the
NIST WAFAC air-kerma strength standard. Longer sources
cannot be calibrated with the NIST WAFAC due to its
primary collimator aperture. Consequently, the NIST WAFAC
calibration standard is transferred to the ADCLs with 1 cm
length sources in a re-entrant well-type air ionization chamber
having a length such that the chamber response is uniform over
the elongated source length.42,75,76 If a chamber is used without
an appropriately long collecting volume, the measurement of
source strength can be substantially underestimated.42,75
Calculation of dose distributions in the vicinity of elongated
brachytherapy sources can be challenging, especially in the
close vicinity of a sharp curve. For wire-type sources, there
is a general assumption of constant radiation emissions
throughout the source length. This assumption should be
validated, especially for low-energy photon-emitting sources
where its influence would be more pronounced. The point-
source approximation (i.e., 1D source dosimetry formalism)
is currently the most commonly used dosimetry methodology
for interstitial brachytherapy. Some TPSs accept the 2D source
dosimetry formalism, but CT-based imaging may not be able to
always identify the source orientation, and no TPS can account
for source flexibility. Dose calculations may be accurately
performed using conventional treatment planning systems
by dividing an elongated source into discrete segments.77–79
However, the accuracy of dose calculation methods in the
vicinity of elongated brachytherapy sources is sensitive to the
spatial resolution of the brachytherapy dosimetry parameters,

3189 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
interpolation and extrapolation techniques, and the dose
calculation coordinate system (polar or cylindrical).80 For
the reasons listed above, a new protocol based on source
strength per unit length and new guidelines are needed to
evaluate the dosimetric aspects of elongated linear sources
and their clinical implementation. In 2006, the AAPM and
GEC-ESTRO formed Task Group 143 with charges to review
the shortcomings of the formalisms in the TG-43 (Refs. 1
and 2) and TG-149 (Ref. 81) reports for the dosimetric
evaluation of elongated sources, and to develop a new
dose calculation formalism and associated guidelines for
the clinical implementation of elongated sources containing
photon-emitting radionuclides.
There are no substantial radiobiological issues between
elongated brachytherapy sources and their conventional source
counterparts containing the same radionuclide and similar
overall source strength.
This case study highlights that implementation of a PSDL-
traceable calibration method for elongated brachytherapy
sources requires calibration transference to an instrument
capable of uniformly measuring the elongated sources.
Clinical users should commission a system for assuring
linear density constancy, especially for newer low-energy
sources. Another issue for elongated brachytherapy sources
is identifying a method for dose calculations. Clinical users
should commission a method that can accommodate the
curvatures intrinsic to the elongated brachytherapy sources
being considered, yet produce accurate dose distributions
throughout the volume of interest.
4.F. Intermediate energy photon emitters
Interest and research on photon-emitting brachytherapy
sources with energies between 131Cs (0.03 MeV) and 192Ir
(0.37 MeV), termed as intermediate-energy photon emitters
within this report, began three decades ago. In 1987, Nath
et al. noted the key advantage of encapsulated sources of
241
Am (0.06 MeV photons) compared to the conventional 192Ir
or 137Cs brachytherapy sources for intracavitary brachyther-
apy.82–84 They had shown that the energies of these sources
are high enough to provide adequate penetration depth for
intracavitary brachytherapy, yet are low enough to allow
customized shielding within the patient with light-weight,
high-Z shields. This can be especially useful in treating
recurrent gynecological cancers.85,86 Using similar arguments,
Loft et al. identified the potential for 169Yb (93 keV mean
gamma emission) as a brachytherapy radionuclide.87 169Yb is
promising because the photon energies are high enough to
minimize the photoelectric interactions in soft tissue, yet are
low enough to require less radiation shielding than needed for
192 88
Ir. Other radionuclides such as 170Tm (129 day halflife),
153
Gd (240 day halflife), and 57Co (272 day halflife), all
with mean photon energy of about 0.1 MeV, have also been
considered as new HDR sources.89–92 None of these sources
are currently available.
The FDA has ruled that several applications for HDR 169Yb
sources were substantially equivalent to predicate devices such
as HDR 192Ir sources. Implant Sciences, Corp. (Wakefield,
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3189
MA) received 501(k) clearances in 2005 for their model HDR-
4140 source (K042864) and in 2007 for their model HDR-
4254 source (K070468). Oncology Systems, Inc. (Champaign,
IL), obtained an FDA 510(k) clearance (K051753) in 2006 for
an HDR 169Yb remote afterloader.
Presently, there are no PSDL-traceable source calibrations
for any of these intermediate-energy sources and the ADCLs
do not offer any accredited calibration services.
The most developed aspect of intermediate-energy sources
is characterization of their dose distributions. Like low-
energy photon-emitting sources, the dose distributions from
intermediate-energy sources are highly sensitive to their
design. Often, the dose distributions include a high-energy
beta component that extends several millimeters into tissue.
Care must be taken to ensure that the design used by dosimetry
investigators to measure or estimate (using MC methods) the
brachytherapy dosimetry parameters is the same as those that
would be used for patient treatments.
Given the lower energy photons in comparison to other con-
ventional HDR sources such as HDR 192Ir and more recently
HDR 60Co, intermediate-energy brachytherapy sources may
have a higher RBE. Zellmer et al. computed an RBE of 1.60
for 169Yb using a microdosimetry approach.93 However, Plume
et al. observed an RBE of 1.2 ± 0.3 for measurements of
in vitro cell kill, which was similar to the RBE for a 93 keV
x-ray beam.94
This case study highlights that several HDR 169Yb sources
have FDA approval and have been dosimetrically charac-
terized. However, PSDL-traceable calibrations are not yet
available and clinical users should require the vendor to offer
these and to develop an in-house calibration standard that
is PSDL-traceable. Also, just like for all new sources, the
potential RBE enhancements of HDR 169Yb sources over HDR
192
Ir sources need to be addressed.
4.G. Electronic brachytherapy sources
As defined by AAPM Task Group 152, Electronic Brachy-
therapy is “a method of radiation therapy using electrically
generated x-rays to deliver a radiation dose at a distance
of up to a few centimeters by intracavitary, intraluminal, or
interstitial application, or by applications with the source
in contact with the body surface or very close to the
body surface.”95 In most of the 20th century, brachytherapy
treatments were almost exclusively based on radionuclides.
However, in the past two decades, two different types of
electronic brachytherapy (eBT) sources have been utilized
for brachytherapy as alternatives to radioactive sources.
These sources, INTRABEAM® (Carl Zeiss Surgical GmbH,
Oberkochen, Germany) and Axxent® (Xoft, Inc., a subsidiary
of iCAD, Inc., San Jose, CA), offer the possibility for high-
dose-rate treatments in a wider variety of treatment settings
than HDR 192Ir such as operating rooms and examination
rooms with minimal (if any) additional shielding other than a
portable shield.
eBT sources present unique electrical and thermal safety
issues because high voltage may be present inside the body
and the x-ray device may generate a considerable amount of

3190 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
heat. All electrical equipment should follow medical electrical
equipment standards such as International Electrotechnical
Commission (IEC) 60601 and collateral standards.96,97 Most
of these recommendations are applicable and offer useful
design guidance.
Unlike radionuclide disintegration, the output of the
eBT sources does not decay with time and is monitored
electronically. Therefore, control of eBT source output is
paramount for safe delivery and an accurate understanding
of the delivered radiation dose. Another feature unique to
eBT sources is that for the same design, the output from
the x-ray tube can vary from one tube to another because of
possible variations in the fabricated product. Thus, the source
strength is measured prior to each fraction with treatment
times adjusted proportionately. The INTRABEAM source is
calibrated in air using an ionization chamber. This chamber
reading is, in turn, related to the dose rate in water at 1 cm
from the source on the transverse plane. The INTRABEAM
calibration protocol uses a parallel plate chamber and filtered
superficial x-ray sources, and is traceable to a kVp x-ray
beam standard at a PSDL. Calibration of the Axxent source
in terms of air kerma at 50 cm has been established by NIST
using the Lamperti free air chamber and transferred to the
ADCLs.98 Thus, the ADCLs can calibrate a well chamber for
this measure of source strength.
Treatment planning for the INTRABEAM system is
performed using manufacturer-provided parameters.99 While
these are based on published studies,100–102 the source is not
characterized using either the AAPM TG-43 or AAPM TG-61
protocols. TG-43 brachytherapy dosimetry parameters have
been determined for the model S700 Axxent source.103 Due
to their low energy photons from a broad continuous energy
spectrum and a more distant prescription point than for LDR
low-energy sources, eBT dose calculations using the AAPM
TG-43 formalism were in error by >20% for most organs
examined due to differing radiological properties between
tissue and water.104 For prostate and breast tissues, this was
also demonstrated by Landry et al.105 Thus, TPS-depicted
dose for both eBT sources may substantially differ from
administered dose due to tissue composition heterogeneities.
If the reference data are based on dose to water, the proposed
disease site should have a mass density ∼1 and Zeff ∼ 7.4.
Alternatively, the reference data can be determined for an
alternate medium like muscle or other soft tissue. In this case,
the physicist would identify the material associated with the
reference data and determine suitable disease site(s) where the
treatment planning system would accurately depict absorbed
dose to the patient. Admittedly this is not general practice,
and the prescription doses for low-energy photon-emitting
sources are generally based upon the erroneous dose to water
and not tissue. These issues should be carefully evaluated
by the medical physicist before clinical implementation.
The TG-186 report identifies methods to evaluate these
effects.106
While both eBT sources are used only for temporary HDR
implants, dose delivery over a large radial range may cause
variations in the biological effectiveness of the absorbed dose
as a function of distance from the source.107
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3190
This case study highlights the potential safety problems
of eBT sources through their electrical means of generating
radiation and heat. There should be compliance with current
IEC electrical standards, not commonly concerned for with
brachytherapy sources. Medical physicists should strive to
provide PSDL-traceable source calibrations, and work with
manufacturers to achieve this for their applicable PSDL. NIST
and the ADCLs responded to provide an air-kerma standard
for one source type with subsequent traceable calibrations to
clinical well chambers made available through the ADCLs.
Also, the method for calculating clinical dose distributions
should be validated by the physicist following commissioning
of the eBT system.105,106 The physicist should validate that the
disease site to be treated is radiologically well-represented
by the reference data in the dose calculation formalism.
Treatments over large radial ranges may warrant analysis of
varying biological effectiveness (see Appendix B).
4.H. Intravascular brachytherapy sources
At the start of the new millennium, IVBT held the
spotlight in brachytherapy as a high visibility procedure with
few similarities to other brachytherapy procedures. IVBT
was the first medical modality in a clinical trial to show
substantial reduction of in-stent restenosis following balloon
angioplasty.108 Its use was championed by interventional
cardiologists, and the field of radiation oncology leapt at the
opportunity to participate in this multidisciplinary procedure
to broaden radiotherapy beyond cancer. Most of the devices
were beta-emitters, which were not addressed by existent
societal guidance documents that focused on photon emitting
sources.
Compared to brachytherapy for cancer treatments, a
different regulatory paradigm was used when evaluating
brachytherapy sources for the treatment of nonmalignant
disease in the vascular system. The FDA first determined
that the use of radiation to treat disease in the vascular
system was a new intended use of radiation. Second, the
FDA determined that the use of radiation to treat disease
in the vascular system was SR, i.e., a FDA-approved IDE
was needed to gather clinical data. Thus for IVBT sources, a
PMA application was needed before the product was legally
marketed. To date, the only brachytherapy sources requiring
a PMA application rather than the more common premarket
notification application are IVBT sources and radiolabeled
microspheres. The FDA approved the following devices
for in-stent restenosis: the 192Ir Checkmate® system by
Cordis, Corp. (Miami, FL), the 90Sr/90Y Beta − Cath® system
by Novoste, Corp., now Best Medical, Corp. (Springfield,
VA), and the 32PGalileo® system by Guidant, Corp. (Hous-
ton, TX).109 Currently only the Novoste Beta-Cath system
(sold by Best Medical International, Inc.,) is commercially
available.
NIST developed a primary calibration standard for these
sources before the IDE clinical trials began. This included both
photon-emitting and beta-emitting brachytherapy sources.
These sources were directly calibrated at NIST for contained
activity and/or absorbed dose rate to water at the prescription

3191 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
depth. Also, NIST directly calibrated either a reference or
transfer instrument with a radiation source of the same manu-
facturer and model, which was used as an in-house standard.
NIST transferred these calibrations to the ADCLs, which offer
calibration services for these sources. If there had not been a
PSDL-traceable calibration standard, the clinical user would
have needed to establish an interim calibration standard (e.g.,
extrapolation chamber), which would be more challenging for
beta-emitting sources than photon-emitting sources.
The dose rate was calculated using TG-43 (Ref. 1)
or TG-60 (Ref. 110) formalisms. Consensus data for the
TG-43 brachytherapy dosimetry parameters for the three
aforementioned systems were given in TG-149.81 That report
extended the TG-43 formalism in polar coordinates to cylin-
drical coordinates, which was more appropriate for handling
elongated sources. The key IVBT dosimetry problem was that
the prescription distance was much smaller than the source
length compared to conventional brachytherapy. The AAPM
has issued recommendations on dose calculation methods
for consistent derivation of absorbed dose.81,110 GEC-ESTRO
has issued recommendations on standardized terminology,
dose prescription, recording and reporting criteria, quality
assurance practices, and radiation safety aspects.111
This case study highlights the need for a clear understand-
ing of the regulatory approval process as rapid acceptance and
general clinical utilization of IVBT stressed the brachytherapy
community through widespread off-label use with medical
physics and radiation oncologist practitioners generally lack-
ing the necessary expertise to evaluate the regulatory impli-
cations of the medical decisions. For example, prescription
deviations from the simple activity-based approach outlined
in the package inserts are considered off-label uses. The source
calibration infrastructure rapidly responded to users’ needs to
provide the necessary facilities for medical physicists. Also,
dosimetry investigators had to quickly establish the TG-43
brachytherapy dosimetry parameters necessary for clinical
dose calculations.
4.I. Neutron emitting 252Cf sources
In 1965, Schlea and Stoddard first introduced the concept of
using 252Cf, a neutron emitting radionuclide (halflife 2.65 yr),
for intracavitary and interstitial brachytherapy.112 Neutron-
emitting 252Cf sources are unique in brachytherapy as these
sources emit radiation with high-LET.113 Since 1976, several
clinical trials have been conducted by Maruyama et al. to
test the feasibility and potential of 252Cf sources and to
develop methods for using the neutron-emitting radionuclide
in the treatment of cancer.114–118 The trials initially treated
advanced (Stages III and IV) cervical cancer patients using
different doses and schedules; they were extended to include
unfavorable presentations of stages I and II because of favor-
able results in the initial trials where different schedules and
sequencing of neutrons and photons greatly altered outcome.
The above-mentioned clinical studies at the University
of Kentucky and Wayne State University used Applicator
Tube type LDR 252Cf medical sources based on a 30-year-
old design containing ≤30 µg of 252Cf. Subsequently, Oak
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3191
Ridge National Laboratory (ORNL) pursued development of
high-specific activity 252Cf sources for use with an HDR
remote afterloading unit in order to reduce treatment times,
diminish personnel exposure, and expedite treatment of other
diseases such as brain tumors.119,120 These LDR 252Cf sources
were used before the U.S. FDA established a mechanism for
approving medical devices, and has been grandfathered for
FDA IDE approval as an established medical device. However,
252
Cf source models (such as HDR 252Cf) would require either
IRB approval or FDA review to determine whether there is
similarity to existing medical devices. In particular, HDR
252
Cf sources may require manufacturers to submit via the
PMA route since they may qualify as SR and NSE as there
are no adequate radiobiological data available to warrant a
510(k). These concerns are based in part on neutron RBE
varying as a function of dose rate and tissue type. Moreover,
HDR 252Cf sources differed substantially from conventional
LDR and HDR photon-emitting sources due to differences
in their oxygen enhancement ratios, cell cycle dependence,
and radiation scattering properties. Thus, clinical experience
learned from LDR 252Cf or from LDR and HDR photon-
emitting sources cannot transfer to HDR 252Cf sources.
NIST offers several methods for calibrating 252Cf source
strength such as neutrons per second, 252Cf mass, or in terms of
dose equivalent rate.121 While the latter measurement may be
corrected to obtain air-kerma strength in terms of Gy h−1 m2,
it is not identical to SK as measured by the NIST WAFAC for
photon-emitting brachytherapy sources. The ADCLs do not
offer 252Cf source calibration services, and medical physicists
had derived source strength as decayed from the calibration
certificate provided by ORNL.
252
Cf sources present challenging problems to radiation
dose measurements and calculations because of the emission
of both neutrons and high-energy gamma rays. Accurate
dosimetry in mixed neutron-gamma fields remains a chal-
lenging area of research, and there are no clinical TPSs
with FDA approval or CE Marking that can accommodate
mixed-field dose. Since their introduction in 1969, dosimetric
characteristics of 252Cf sources have been the subject of
clinical and dosimetric research activities.122–128
The neutrons deposit energy in tissue by generating
secondary charged particles (protons and other heavy charged
particles) which have the higher LET. The high-LET radiation
confers unique radiobiological advantages because it over-
whelms the oxygen effect that renders the hypoxic cells pres-
ent in most solid tumors resistant to radiation damage.129–132
However, high-LET radiation minimizes the influence of
sublethal damage that is advantageous for dose fractionation
with low-LET radiation. A radiobiological model for the
biological effectiveness of HDR 252Cf brachytherapy has also
been developed.133
This case study indicates that the regulatory status for 252Cf
sources depends on the source model, be it LDR or HDR style,
just like for non-neutron-emitting sources. Clinical users in
the U.S. should consider using the source under IRB approval
before FDA approval and calibrations by the ADCLs are made
available. Dose distributions for source models other than the
LDR sources lack TG-43 dosimetry parameters, and it is a

3192 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
great challenge to measure these independently due to the
mixed-field dose environment. Clinical application of 252Cf is
based upon radiobiology, where a firm understanding of the
radiation dosimetry is first required.
90Y
4.J. microspheres
Microspheres labeled with radioactivity have been used for
treatment of cancer in the liver since 1947 (see the review by
Kennedy et al.).134 Microspheres are injected intra-arterially
into the hepatic artery and flow with the blood until they lodge
in capillaries. This therapy selectively delivers dose to the
tumors because they receive almost all of their blood supply
from the hepatic artery, while the liver properly receives 80%
of its blood supply from the portal vein.135,136 Microspheres
require a higher level of concern for radioactivity contami-
nation than conventional brachytherapy sources, and nuclear
medicine staff generally assist with the procedure.
Currently there are two manufacturers of radioactive
microspheres with FDA approval for human use in the U.S.
One of the manufacturers, BTG International, Ltd. (Lon-
don, UK) markets glass microspheres called TheraSphere®.
TheraSpheres were approved with HDE H980006 on 10
December 1999.137 The instructions for use (IFU) states
“TheraSphere is indicated for radiation treatment or as a
neoadjuvant to surgery or transplantation in patients with
unresectable hepatocelluar carcinoma who can have place-
ment of appropriately positioned hepatic arterial catheters.”138
The other manufacturer, Sirtex Medical, Inc. (Lane Cove,
NSW, Australia), markets resin spheres called SIR-Spheres®.
SIR-Spheres were approved with PMA P99065 on 5 March
2002 along with supplements S001 and S004 since then. The
IFU states, “SIR-Spheres is indicated for the treatment of
unresectable metastatic liver tumors from primary colorectal
cancer with adjuvant intra-hepatic artery chemotherapy of
Floxuridine.” As with any other medical device, off-label
use of 90Y microspheres should be conducted under the
supervision of an IRB.
While microspheres are radioactive solutions, they are
not radiopharmaceuticals and were classified by the NRC as
manual brachytherapy sources used for permanent implan-
tation therapy.139 In addition to the information in the
manufacturer’s packaging and the FDA website, the NRC has
provided a radioactive material licensing guidance document
on microsphere brachytherapy sources and devices.140
The current prescription paradigm is based on delivery of
radioactivity (i.e., Bq) rather than absorbed dose. Activity veri-
fication for TheraSphere (NIST-traceable) can be performed
with a dose calibrator, such as by Capintec (Ramsey, NJ),
having the appropriate setting while SIR-Spheres do not have
a NIST-traceable activity calibration (an interim calibration
process is available). In general, it is more difficult to establish
interim calibration standards and dosimetric parameters for
beta-emitting brachytherapy sources than for photon-emitting
sources.
For all liver microsphere brachytherapy, a pretreatment
liver angiogram study determines the blood supply to the
liver.141–143 The liver vasculature is meticulously mapped with
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3192
contrast injection into the hepatic arteries by an interventional
radiologist. Special attention is paid to any vessels that could
carry microspheres away from the liver and into the stomach,
duodenum, or gall bladder. Once the liver blood flow has been
mapped, a 99mTc-labeled macroaggregated albumin procedure
is carried out to predict the 90Y-microspheres distribution
within the liver and to calculate the quantity of microspheres
required to alter the pulmonary ventilation/perfusion ratio.
While standardized anatomical or biokinetic models have
been historically used, this is not adequate and patient-specific
approaches should be used.144–146 The average dose to an
organ does not characterize the dose variability within the
organ. Dose information should be represented using 3D dose
distributions and DVHs. Imaging of patients using CT or
magnetic resonance imaging has typical voxel resolutions on
the order of 1 mm. Single photon emission computerized
tomography (SPECT) and positron emission tomography
(PET) imaging systems can provide 3D patient activity voxels
with resolutions of around 3–7 mm. Utilization of PET/CT
or SPECT/CT imaging systems permits concurrent imaging
of patient anatomy and activity distribution without having to
move the patient. New to the field are 3D dose calculations,
which may be performed with MC-calculated dose kernels146
or other deterministic dose calculation methods,147 and quan-
titative evaluation of radioactivity spatial distributions from
PET and SPECT data with activity quantification uncertainty
from SPECT/CT and PET/CT.
This case study highlights the need for an understanding
of the regulatory approval process, such as use of an IRB
when performing off-label use. The calibration infrastructure
is not fully in place to provide medical physicists the ability to
perform independent, PSDL-traceable activity calibrations for
all microsphere types. Furthermore, conventional methods for
brachytherapy dose calculation, such as the TG-43 formalism,
are not applicable. Sophisticated image-based approaches for
dose calculation are under development. Guidance for these
issues is included in the AAPM TG-144 report.136
4.K. Collimated applicators and sources
There are two types of collimated applicators that apply
brachytherapy with the source positioned more than a
centimeter from the patient surface in a noninvasive manner
in contrast to most other brachytherapy applications. These
include applicators used to treat superficial disease, such as the
skin or for IORT,148–152 and applicators used to treat at depths
exceeding several centimeters, such as for noninvasive image-
guided breast brachytherapy (NIBB).153,154 The rationale
for using shielded applicators for treating the skin or for
IORT is to provide collimation of the radiation, yet not to
penetrate beyond the target. The applicator face is usually
flat, and this helps to provide a uniform dose distribution
for elastic anatomy. Both HDR 192Ir and eBT sources have
been used over a variety of treatment sites, and prescription
depths generally do not exceed 1 cm. These applicators are
manufactured by Varian Medical Systems, Inc. (Palo Alta,
CA), Elekta Brachytherapy (Veenendaal, The Netherlands),
and Xoft, Inc. Currently there is one manufacturer of NIBB

3193 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
applicators, referred to as AccuBoost by Advanced Radiation
Therapy, LLC (Tyngsboro, MA). The rationale for NIBB
is to immobilize the breast and standardize the geometry
compared to en face irradiation with electrons, to direct the
radiation away from the chestwall, and use mammographic
image-guidance to guide irradiation of the target.155,156 Both
applicator types are approved by the FDA and have CE
Marking for their respective disease sites. Another type of
applicator used in brachytherapy is the shielded applicator as
used for treating the vagina or rectum.157,158 This shielding
may be brought even closer to the source and incorporated
into its design.159,160
Unshielded source strengths for the HDR 192Ir or HDR
eBT sources used with these applicators are evaluated through
conventional means, using a re-entrant well-type air ionization
chamber with PSDL-traceable calibration and a parallel-plate
air ionization chamber. However, use of the AAPM TG-
61 protocol for the Axxent source or a modified external
calibration technique has been proposed to calibrate these
applicators.149,150
For both applicator types, dose is calculated using lookup
tables based on MC simulations. This approach may be
confirmed using the TG-43 dose calculation formalism where
reasonable results may be expected in the region not shielded
by the applicator. A dose calculation approach using the TG-
43 hybrid method has been developed where the collimated
dose distribution is used to derive dosimetry parameters for
a virtual source.154,161 However, inability to sum dose from
orthogonal NIBB brachytherapy beams is a current limitation
for understanding the cumulative dose from this treatment
modality.
Given the high-dose-rate treatment delivery, there are no
substantial radiobiological issues for either type of applicator.
This case study identifies the need to establish dose
calculation methods such as by Fulkerson et al.149,150 for
innovative brachytherapy applicator designs that do not have
established TG-43 dosimetry parameters.
4.L. Intracavitary breast balloon brachytherapy
For early stage cancers such as ductal carcinoma in situ, an
alternative to whole-breast external-beam radiotherapy (WB-
XRT) is partial breast irradiation. By applying the radiation
over 4–5 days instead of over 5–6 weeks as is commonly done
for EBRT, this procedure is referred to as accelerated partial
breast irradiation (APBI). Clinical studies were conducted in
the early 1990s using LDR 192Ir APBI to treat women with
interstitial brachytherapy, effectively covering the area around
the surgical cavity and only treating women who had a true
lumpectomy.162,163 In conjunction with HDR 192Ir sources, the
MammoSite® balloon (Hologic, Corp., Bedford, MA) was
first used in 2001 as an out-patient alternative to LDR 192Ir
brachytherapy, which required hospitalization for 4–5 days.
The dose distributions of the balloon-based technique were
compared to the interstitial method,164 and revealed better
coverage of the planning target volume.
Due to the success of the MammoSite applicator, the
Axxent balloon applicator was introduced in 2007 by
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3193
Xoft, Inc. Following this, other multicatheter balloon-type
applicators were introduced. These included the MammoSite
Multi-Lumen® by Hologic, Corp. (Bedford, MA), Contura®
by C. R. Bard, Inc. (Murray, NJ), and SAVI® by CIANNA
Medical, Inc. (Aliso Viejo, CA) to provide the radiation
oncology community more tools and options to tailor the
dose distribution. All three devices use multiple catheters,
multiple dwell positions, and variable dwell times. When
compared to the original single-channel single-dwell position
MammoSite and Axxent balloons, these devices provide better
dose coverage to the intended target while delivering dose to
the organs-at-risk at an acceptable level.
The MammoSite balloon was approved by the FDA for use
as a radiation boost. However, clinicians primarily used them
for APBI. As a condition for clearance, the FDA required
the manufacturer to include a warning in the product labeling
stating that the safety and effectiveness of MammoSite as a
replacement for WB-XRT to treat breast cancer had not yet
been established. In addition, the device was only approved
as a boost therapy in conjunction with WB-XRT following
lumpectomy. Given widespread off-label use of these breast
balloon applicators and the consequent need for each center to
pursue clinical use under an IRB approved study, the Radiation
Therapy Oncology Group (RTOG) and National Surgical
Adjuvant Breast and Bowel Project (NSABP) conducted a
phase III clinical trial (RTOG 0413/NASBP B-39) to evaluate
APBI as monotherapy for stage I and II breast cancers. This
trial is closed to enrollment after enrolling approximately 2050
subjects, patient follow-up is ongoing. A body of clinical
data has grown to support use for both the FDA approved
indication (boost for WB-XRT) and for the off-label intent
(APBI-only monotherapy).165–172 There are no brachytherapy
source calibration issues with breast balloon applicators as the
HDR source is a separate entity.
While calculations of dose distributions in patients im-
planted with breast balloon applicators is a straightforward
clinical task, it has been shown that dose at the air:skin inter-
face is underestimated by up to 20% due to differences in radi-
ation scatter conditions between the implant and the compu-
tational TPS environment.106 Further, the presence of air can
also alter the dose distribution in a substantial manner.173
Though these effects on dose have existed since the use of LDR
192
Ir sources, the TG-186 report makes recommendations on
how to utilize TPS that correct for radiation scatter conditions.
There are no radiobiological issues as there are societal-
recommended dose fractionation schedules using state-of-the-
art radiobiological models.174
This case study highlights the need for a clear understand-
ing of the scope of regulatory approval for a medical device
as there was widespread off-label use of APBI-based balloon
brachytherapy without having IRB approval. Prospective users
should consult their local IRB and review FDA or CE Marking
materials in addition to NSSDR literature to prevent any
inappropriate off-label use.
4.M. Intracavitary brain balloon brachytherapy
The dosimetric rationale for intracavitary breast balloon
brachytherapy may be similarly applied to the brain, where

3194 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
conventional brachytherapy implants using seeds may cause
unacceptably nonuniform dose distributions.175,176 The
GliaSite® applicator is available from IsoRay Medical, Inc.
(Richland, WA), for brachytherapy of primary, metastatic, or
recurrent brain tumors. The double-walled balloon approved
by the FDA (K132996) for these uses is filled with a liquid
solution of either 125I or 131Cs after surgical placement. The
radioactive solution is drained from the balloon following
the prescribed treatment time (2–4 days) after delivering the
desired dose.
Source strength provided by the manufacturer is based on
a NIST-traceable calibration standard that was developed by
the manufacturer. Source strength is independently checked
by the end-user using a nuclear medicine dose calibrator with a
NIST-traceable activity calibration for a specific vial type and
for each radionuclide. These dose calibrators differ from the
re-entrant well-type air ionization chambers used for assaying
source strength for brachytherapy sealed sources.6,14 Further,
the ADCLs do not offer services for transferring calibration
standards to clinical users for liquid sources.
The prescribed treatment time is calculated from the
inflated balloon diameter, injected solution volume, and
desired dose.177,178 Treatment planning data for 125I and 131Cs
are based on tabulated values provided by the manufacturer.
These data were obtained using MC simulations by IsoRay
Medical, Inc., and an independent dosimetry investigator,
with results being in good agreement. For 131Cs, results
were parameterized such that a clinical physicist could
calculate the dose parameters for nontabulated volumes,
margin depths, and treatment duration. This approach is
analogous to entering brachytherapy dosimetry parameters
into a TPS for conventional brachytherapy seeds.
There are no substantial radiobiological issues for this
type of applicator because of the temporary implant duration,
similar dose rates, and similarity in photon energies of 125I
and 131Cs.
This case study highlights the need for including qualified
dosimetry investigators and establishing calibration standards
as PSDL calibration standards (and ADCL calibration ser-
vices). Additionally, image-based treatment planning tech-
niques are needed for calculating 3D image-based dose
distributions.
4.N. NonCOMS eye plaques
Eye plaques are manually -loaded radionuclide applicator
systems. Most of the clinical evidence for eye plaque brachy-
therapy of uveal melanoma was obtained under the Collabora-
tive Ocular Melanoma Study (COMS).179,180 The COMS was
formed in 1986 as a multi-institutional cooperative clinical
trial group with the goal of conducting a prospective random-
ized clinical trial to compare enucleation vs radiation therapy
for medium sized lesions (apical height of tumor 2.5–10 mm
and basal diameter ≤16 mm). While COMS-style plaques
initially used only 125I seeds, 103Pd and 131Cs seeds have been
employed. Dosimetry for COMS-style plaques is examined
in detail within the TG-129 report,181 while the forthcoming
TG-221 report examines nonCOMS style plaques.
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3194
In addition to COMS-style plaques, eye plaques using
106
Ru/106Rh have been used with success primarily in Europe,
but also for the past 15 years in the U.S. COMS plaques were
designed and fabricated prior to 1976, and were grandfathered
for FDA IDE approval. Newer plaque designs have been
developed with notches or slots.181–186 Plaques introduced
after 1976 having newer designs that operate using a different
fundamental scientific technology; e.g., seed collimation, than
a legally marketed device, i.e., COMS plaques, may require
manufacturers desiring to market the device to submit for
premarket notification and review by the FDA or for CE
Marking to determine if they are SE in comparison to existing
medical devices.
For plaques using LDR seeds such as 125I, 103Pd, or 131Cs,187
the source calibration procedure is straightforward, and the
seeds are measured preceding plaque assembly. Beta-emitting
plaques containing the longer-lived 106Ru/106Rh radionuclides
require the clinical medical physicist to calibrate the plaque
in terms of dose preceding clinical use.
COMS included a strict physics protocol to provide consis-
tency of dose delivery, and mandated that all participants
use the same point-wise dosimetry parameters in a dose
calculation formalism similar to the TG-43 approach. No
corrections for silastic or gold plaque were allowed, nor
was the line-source formalism used. The calculations did not
allow the use of finite, realistic geometry for the patient.
Using these assumptions, the dose was calculated and the
prescribed dose to the tumor apex for selected patients was
85 Gy.188 Later, more accurate dose calculation algorithms
such as MC simulations indicated that the actual dose
delivered in COMS patients was about 76 Gy for 125I and
67 Gy for 103Pd. Thus, if a physician wants to reproduce
the COMS clinical experience and adopt the more accurate
new dosimetry methods (correction for silastic and gold
plaque, finite and realistic geometry for the patient), then the
prescribed dose should be decreased by about 10% and 20%
for 125I and 103Pd, respectively.189 This highlights some of the
dosimetric considerations that can arise when an innovative
brachytherapy applicator is introduced.
While COMS provided benefit to the brachytherapy
community through standardization to compare this modality
to enucleation, the brachytherapy community has lost this
consistency. Eye plaque brachytherapy is now delivered with
innovative plaques and a wide variety of prescription doses,
prescription points, and implant durations.181 For example,
changing implant duration for COMS plaques from 7 to 3
days increases the biologically effective dose by 14%.190
This case study highlights a type of medical device where
there are several plaque models in clinical use, but without
FDA approval or CE Marking. Institutions using these devices
must either obtain IRB approval or request the manufacturer
to obtain FDA approval or CE Marking. There are no
recommended methods in place for the end-user to perform
an independent measurement of the assembled plaque.191
The dosimetric influence of customized plaques remains to
be evaluated and illustrates the need for national guidelines
for clinical implementation of new sources and applicators.
Simulations using MC methods for radiation transport should
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3195 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications 3195

be used to quantitatively compare newer plaques to the more BIPM Bureau International des Poids et Mesures, located
established COMS-style plaque for providing similar dose in Sèvres, France
deliveries through prescription scaling.182,189 These issues are CDRH Center for Devices and Radiological Health, a
being examined jointly by the AAPM and GEC-ESTRO under branch of the U.S. FDA
Task Group 221. CE Marking Conformité Européenne Marking
COMS Collaborative Ocular Melanoma Study for eye
plaque brachytherapy
5. SUMMARY
CT Computerized tomography imaging using x rays
The current report presents methods for evaluating innova- DOE U.S. Department of Energy
tive brachytherapy devices and applications for the safe and DVH Dose-volume histogram
consistent implementation of this radiotherapy modality. An EBRT External-beam radiotherapy
introduction to the regulatory processes is given, including eBT electronic brachytherapy using x rays, not radio-
listing on the U.S. NRC NSSDR, U.S. DOT requirements nuclides
of sealed sources and devices, the IEC 60601 Medical ERDA Energy Research and Development Administra-
Electrical Equipment Standard, U.S. FDA approval process tion, predecessor to the U.S. DOE
for review devices substantially equivalent to legally marketed EURAMET European Association of National Metrology
devices, the CE marking standard, and IRB oversight and Institutes
institutional requirements for research and clinical use. The FFDCA Federal Food, Drug, and Cosmetic Act
current report also issues guidelines for the calibration of FDA U.S. Food and Drug Administration
brachytherapy sources, ability to obtain 3D dose distributions GEC-ESTRO Groupe Européen de Curiethérapie-European
for clinical implementation, evaluation of radiobiological SocieTy for Radiotherapy & Oncology
issues, and commissioning issues such as team formulation. HDR High-dose-rate brachytherapy, >12 Gy/h
While medical physicists are the target audience for this IEC International Electrotechnical Commission
report, vendors, regulatory agencies, and other professional IDE Investigational device exemption
societies should give consideration to these AAPM and GEC- IFU Instructions for use
ESTRO guidelines. IORT Intraoperative radiotherapy
IRB Institutional review board
ISO International Organization for Standardization,
CONFLICT OF INTEREST DISCLOSURE located in Geneva, Switzerland
Toward disclosing real or apparent conflicts of interest: IVBT Intravascular brachytherapy
R.N. serves as a research consultant to Theragenics, Corp. Kair Air-kerma for radiation source strength
(Buford, GA); M.J.R. serves as a research consultant to CivaT- L Active length for a brachytherapy source
ech Oncology, Inc. (Durham, NC) and is a minor shareholder Λ Dose-rate constant, with units cGy h−1 U−1
of Advanced Radiation Therapy, LLC (Tewksbury, MA); LDR Low-dose-rate, <2 Gy/h
L.A.D. is principally employed by the University of Wisconsin LET Radiation linear energy transfer
Medical Radiation Research Center (Madison, WI), an Ac- LNHB Laboratoire National Henri Becquerel, located in
credited Dosimetry Calibration Laboratory; G.S.I. is director Saclay (Paris), France
of the University of Texas MD Anderson Cancer Center MC Monte Carlo simulations for radiation transport
Accredited Dosimetry Calibration Laboratory (Houston, TX); calculations
Z.O. is on the speaker bureau for Elekta, Inc. (Atlanta, GA) MDD Medical Devices Directive for CE Marking
and Varian Medical Systems, Inc. (Palo Alto, CA) and also NIST National Institute of Standards and Technology,
serves as a consultant to Theragenics, Corp. (Buford, GA); located in Gaithersburg, Maryland
and T.W.R. is a consultant and shareholder for Xoft, Inc. NMI National metrology institute
(San Jose, CA) a subsidiary of iCAD, Inc. (Nashua, NH), NPL National Physical Laboratory, located in Tedding-
which develops and manufactures the Axxent® electronic ton (London), UK
brachytherapy system. The other authors (W.A.D., H.T.H. NRC U.S. Nuclear Regulatory Commission, located in
II, A.S.M., F.A.S., and J.L.M.V.) have no real or apparent Rockville, Maryland
conflicts of interest. NSABP National Surgical Adjuvant Breast and Bowel
Project
NSE Not substantially equivalent
NOMENCLATURE NSR Not significant risk device
AAPM American Association of Physicists in Medicine NSSDR National Sealed Source and Device Registry,
ABS American Brachytherapy Society maintained by the NRC
ACMP American College of Medical Physics ORNL Oak Ridge National Laboratory, located in Oak
ACRO American College of Radiation Oncology Ridge, Tennessee
ADCLs Accredited Dosimetry Calibration Laboratories PET Positron emission tomography
AEC Atomic Energy Commission PMA Premarket approval
APBI Accelerated partial breast irradiation PSDL Primary standards dosimetry laboratory

Medical Physics, Vol. 43, No. 6, June 2016


3196 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
PTB Physikalisch-Technische Bundesanstalt, located in
Braunschweig, Germany
QA Quality assurance
RBE Relative biological effectiveness
RSC Radiation safety committee
RTOG Radiation Therapy Oncology Group
SE Substantially equivalent
SK Air-kerma strength, with units 1 U = 1 cGy cm2
h−1
SPECT Single-photon emission computerized tomog-
raphy
SR Significant risk device
SSDL Secondary standards dosimetry laboratory
TLD Thermoluminescent dosimeter
TPS Treatment planning system
WAFAC Wide-Angle Free-Air Chamber
WB-XRT Whole-breast external-beam radiotherapy
Z Atomic number
APPENDIX A: CURRENT REGULATORY
ENVIRONMENT
1. U.S. Nuclear Regulatory Commission
The NRC is a U.S. government agency that was es-
tablished by the Energy Reorganization Act in 1974, and
began operations on 19 January 1975. The NRC took
over the role of oversight of nuclear energy matters and
nuclear safety from the Atomic Energy Commission (AEC).
Oversight of nuclear weapons, as well as the promotion
of nuclear power, was transferred to the Energy Research
and Development Administration (ERDA) by the same act,
thereby eliminating the AEC. In 1977, ERDA became the
U.S. Department of Energy (DOE). Like its AEC predecessor,
the NRC oversees reactor safety, reactor licensing and
renewal, radioactive material safety and licensing, and waste
management (storage and disposal). The NRC’s mission is
to regulate the U.S. civilian use of byproduct, source, and
special nuclear materials to ensure adequate protection of
public health and safety, to promote national defense and
security, and to protect the environment. This mission was
amended in 2005 to include naturally occurring radioactive
materials.
Regulatory authority over the medical use of ioniz-
ing radiation is shared among several federal, state, and
local government agencies. The NRC (or the responsible
Agreement State) has regulatory authority over the posses-
sion and use of byproduct, source, or special nuclear
material in medicine. Byproduct material is used in some
calibration sources, radioactive drugs, bone mineral ana-
lyzers, portable fluoroscopic imaging devices, brachyther-
apy sources, gamma stereotactic radiosurgery devices, and
teletherapy units used in medicine. A few cardiac pace-
makers are still powered by special nuclear material batte-
ries.
With the exception of the use of radioactive drug capsules
containing ≤37 kBq (1 µCi) of 14C urea for in vivo diagnostic
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3196
use in humans, all internal or external administrations of by-
product material, accelerator-produced radioactive material,
or naturally occurring radioactive material to human patients
or human research subjects must be performed in accordance
with a medical use license or authorization issued pursuant to
NRC’s regulations in 10 CFR Part 35, ”Medical Use.” NRC
licenses the medical use of byproduct materials in diagnostic
devices in the practices of dentistry and podiatry. The medical
use of plutonium in nuclear powered pacemakers is licensed
pursuant to 10 CFR Part 70.
The NRC oversees medical uses of nuclear material
through licensing, inspection, and enforcement programs. The
NRC issues medical use licenses to medical facilities and
authorized physician users, develops guidance and regulations
for use by licensees, and maintains a committee of medical
experts to obtain advice about the use of byproduct materials
in medicine. The Advisory Committee on the Medical Uses
of Isotopes, comprised of medical physicists, physicians,
medical scientists, and other healthcare professionals, meets
twice a year to be briefed by, and provide advice to, the
NRC staff on current initiatives in the medical uses of
radioactive materials. The NRC (or the responsible Agreement
State) also regulates the manufacture and distribution of these
products with information available for the NRC Medical
Uses Licensee Toolkit192 and specific information on medical
products.193
In the U.S., the NRC and the Agreement States evaluate
the design of sealed sources and devices to safely contain
radioactivity under the conditions of their possession and
use. These evaluations are summarized in registrations on
the NSSDR as maintained by the NRC. These registration
certificates contain detailed information on the sources and
devices such as how they are permitted to be distributed and
possessed (i.e., specific license, general license, or exempt),
on their design and function, radiation safety characteristics,
and on limitations of their use. Registration is often a first step
for new sources or devices. Sources or devices listed on the
NSSDR meet a minimum level of design and radiological
safety, but this is not an indicator of meeting AAPM or
GEC-ESTRO guidelines on source calibrations and dosimetry.
For sources not having dedicated regulatory sections, Part
35.1000 allows the NRC to provide regulation through license
conditions and posted guidance.
2. U.S. Food and Drug Administration
The FDA oversees good practices in the manufacturing
of radiopharmaceuticals, medical devices, and radiation-
producing products (e.g., x-ray machines and accelerators).
The states regulate the practices of medicine and pharmacy
and administer programs associated with radiation-producing
x-ray machines and accelerators.
The FDA is an agency of the United States Department of
Health and Human Services and is responsible for assuring the
safety of most types of foods, dietary supplements, drugs, vac-
cines, biological medical products, blood products, medical
devices, radiation-emitting products, veterinary products, and
cosmetics. The Center for Devices and Radiological Health

3197 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
(CDRH) is the branch of the FDA responsible for the approval
of all medical devices before they can be legally marketed in
the United States, as well as overseeing the manufacturing,
performance, and safety of these devices. The definition of a
medical device is given in the FFDCA, and it includes products
ranging from a simple toothbrush to complex devices such as
implantable brain pacemakers. CDRH also oversees the safety
and performance of medical and nonmedical devices which
emit certain types of electromagnetic radiation. Examples
of CDRH-regulated devices include brachytherapy sources,
airport baggage screening equipment, television receivers,
microwave ovens, tanning booths, and laser products. CDRH
regulatory powers include the authority to require technical
reports from the manufacturers or importers of regulated
products, to require that radiation-emitting products meet
mandatory safety performance standards, to declare regulated
products defective, and to order the recall of defective or
noncompliant products. The CDRH also conducts limited
amounts of direct product testing.
FDA approval for medical devices started in 1976. There-
fore, any device that was designed and fabricated prior to 1976
has been grandfathered FDA approval for its use at that time.
Further, if a device is made by an investigator for one case
with special situations and is not marketed, FDA needs only
to be informed but no approval is required.
The FDA’s role is to assure the public that medical
devices are safe and effective when used as described by the
“label,” i.e., the label on the product, the package insert, or
other documents that accompany the device. The FDA issues
approval or clearance for the device when it is determined that
the device is safe and effective if used as described in the IFU.
The FDA clearance allows the manufacturer to promote and
sell the device for the indications described in the labeling. If
used as described in the label, payors following the guidelines
of the Centers for Medicare and Medicaid Services usually
reimburse medical providers for that specific use in patients.
However, licensed practitioners of medicine have the right to
use approved devices for an individual patient in any way
they deem appropriate, either according to the label or “off-
label” unless such use has been deemed SR. Many novel
drugs and devices have resulted from creative off-label use by
experienced medical practitioners.
Any new device including a new brachytherapy source is
generally evaluated for its approval as a medical device by
the FDA based on relation to a legally marketed predicate
device and includes its risk factor. If a medical device is being
introduced, it can be categorized into two groups: (1) similar
to an existing device and (2) one for which no comparable
device exists. For devices in the first group, the vendor has
to provide the FDA enough evaluation data from either the
vendor or some independent investigators in order to receive
approval and to market the device. Specifically, the vendor has
to demonstrate for approval that new material or technology
in the device did not raise new safety and/or effectiveness
issues. In order for the FDA to determine if the new device
may be categorized as an SE device with equivalence to
an existing device, the vendor must submit device specifics
prior to the approval. If the device does not qualify for SE
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3197
categorization and therefore falls into the second group, then
sufficient information including clinical and nonclinical data
must be provided showing that it is safe and effective for its
intended use.
An SR device is defined as an investigational device if
it is one of the following: (1) intended as an implant and
presents a potential for serious risk to the health, safety, or
welfare of a subject; (2) purported or represented to be for
a use in supporting or sustaining human life and presents a
potential for serious risk to the health, safety, or welfare of a
subject; (3) for a use of substantial importance in diagnosing,
curing, mitigating, or treating disease, or otherwise preventing
impairment of human health and presents a potential for
serious risk to the health, safety, or welfare of a subject; or
(4) otherwise presents a potential for serious risk to the health,
safety, or welfare of a subject. New brachytherapy sources or
applicators that are NSE will typically meet one or more of
the SR definitions.
The FDA-approved IDE will contain an explicit protocol to
be followed during the trial; conditions for use in the protocol
are very specific. In general the IDE involving ionizing
radiation products will include the following: nonclinical
data including animal data, bench testing, dosimetry, specific
indication for use, trial protocol, test hypothesis, statistical
analysis including sample size needed to test the hypothesis,
specific primary safety and effectiveness endpoints for trial,
secondary endpoints for trial, patient inclusion criteria, patient
exclusion criteria, informed consent form, and case report
forms.
Part of the information submitted by the manufacturer
for a PMA is intended to provide the FDA with sufficient
clinical and nonclinical data to show that the device provides
reasonable assurance of safety and effectiveness for its
intended use. This information will form the bulk of the
material in the device’s label. This includes the indicated use
of the device, IFU, advertising literature, and oral information
from company representatives. The FDA can only evaluate
safety and effectiveness of the device for its intended use
based on the information submitted in the PMA so this is
the only information in the labeling. Hence, if the device is
used in a manner not included in the PMA, it is being used
off-label. Here off-label refers to any use of the device that is
not specified in its approved labeling.
When an approved medical product is used for an unlabeled
indication it is considered to be used in an ”off-label” manner.
This is allowed under the practice of medicine when used
by a qualified licensed healing arts practitioner. The FDA
Modernization Act of 1997 explicitly includes a section on
the practice of medicine which allows the clinician to make
a medical decision (practice of medicine) to use a medical
device approved for one indication in an off-label manner
for another. However, it is then the clinician’s (or clinical
team’s) responsibility to evaluate the safety and effectiveness
for this off-label use of the device for the individual patient
being treated. If the majority of patients are treated in the
same off-label manner with a SR device at an institution,
there is a gray area that this should be conducted under a
clinical trial. If human use research is being conducted, then

3198 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
prior IRB approval and an FDA-approved IDE are required. If
the results of a study involving off-label use are published, it
could be interpreted as conducting an unapproved clinical trial
involving a SR medical device. Thus the sponsor of the clinical
trial using a SR device is the one responsible for obtaining both
approval from the IRB and for an FDA-approved IDE. The
sponsor can be either the manufacturer of the device or an
individual investigator.
Any time an investigator decides to treat a number of
patients with a SR device in the same off-label manner,
the investigator should realize that a clinical trial is being
conducted and as part of the clinical trial the investigator
should have obtained approval from the local IRB as well as
an FDA-approved IDE.
3. Health Canada brachytherapy regulations
Health Canada is a department of the Canadian federal
government that is responsible for regulations on medical
devices. Following the establishment of the Canadian Depart-
ment of Health in 1919, the Food and Drugs Act was voted
upon in 1920 by the Parliament of Canada. Medical devices
such as brachytherapy sources and devices are regulated by the
Therapeutic Products Directorate, which is within the Health
Products and Food Branch of Health Canada. This govern-
mental Branch has many similarities to the U.S. FDA where
regulations are primarily designed for premarket licensing and
licensing is needed for the selling and marketing of medical
devices. It is the manufacturer’s responsibility to apply for
market authorization, where evidence is demonstrated for the
quality, safety, and efficacy of a medical device as required
by the Food and Drugs Act and Regulations of Canada.
The regulations set by Health Canada have set classification
levels for medical devices based on the level of risk to
the patient. These classification levels range from 1 to 4,
with 4 representing the highest risk. Brachytherapy sources
containing radionuclides are class 3. The approval method
outlined in Sec. 2.A for investigational devices is similar
between Canada and the U.S.
4. European Union regulatory structure
The CE Marking is an important step before a medical
device can be sold in Europe. Since June 1998 the CE Marking
is a legally binding statement by the manufacturer. It is not a
mark of quality, rather a sign that the product has reached the
requirements of special European device directives, Medical
Devices Directive (MDD 93/42/EEC), In Vitro Diagnostic
Device Directive (IVDD 98/79/EC), or the Active Implantable
Medical Device Directive (AIMDD 90/385/EEC). Most med-
ical devices, like brachytherapy devices, are in the scope of
the MDD 93/42/EEC. All manufacturers that can demonstrate
compliance with the MDD are allowed to apply the CE
Marking on their products. A requirement for this is to have a
full quality management system according to ISO 13485 for
products up to a risk classification class IIb (see below). The
local notified bodies will in such cases check the development
documents of the product in the frame of an audit procedure.
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3198
At the time of writing, CE Marking is required in 28
countries within the European Union. Additionally, Nor-
way, Iceland, Switzerland, Turkey, and Liechtenstein are
signatories of the European Economic Area and require CE
Marking. Switzerland has transposed the Medical Devices
Directives into their national law, and thus the CE Marking
requirements.
European medical devices are classified into different
groups: Class I devices are low risk devices. Medium risk
devices are subdivided into two groups: Class IIa and Class
IIb devices. Class IIa devices are for example diagnostic
ultrasound devices or hearing aids. Class IIb devices have a
greater risk than Class IIa devices. To this group belong, e.g.,
surgical lasers, heart defibrillators, and radiation treatment
devices (including brachytherapy devices) where product
failure can result in serious health risk for the patient or
other personnel. The highest risk devices are in Class III.
In this category are for instance stents, intracardiac catheters,
and breast implants. Classification rules are specified in the
Annex IX of the MDD. Furthermore, for devices of Classes I
(sterile or measuring devices) II, IIa, IIb, and III, a quality
management system must be implemented that complies
with Annex II or V of the MDD. Many manufacturers
use ISO 13485 to meet those requirements. In this ISO
standard a comprehensive management system for medical
devices is described. After the quality management system is
implemented, a technical file must be prepared for medical
devices of all classes. It includes among other components a
device description, product specification, technical drawings,
performance testing, risk analysis, and a clinical validation.
If the company has no place of business in Europe, the
appointment of an authorized qualified representative in
Europe is necessary. This representative acts as liaison
between the company and the competent authorities in Europe.
The CE Marking certificate is issued after the successful
review of the technical file and the quality management
system by a notified body. To maintain the certification, the
auditing must be repeated every year. Finally, a declaration
of conformity must be prepared. In this short document,
the companies state that they are in full compliance with
the MDD. Moreover, it is required to translate the relevant
documentation such as the information for use and the labeling
of the medical device for those European countries where the
device will be sold. Even if this point is not addressed in the
MDD, it is necessary to be in concordance with national laws.
In summary, it is of course possible for a brachytherapy
source or device to have both FDA approval and CE Marking
and to also be listed on the NSSDR, yet lack key clinical
aspects such as having a PSDL-traceable calibration or
satisfying societal dosimetric prerequisites.2,40
APPENDIX B: RADIOBIOLOGICAL AND CLINICAL
CONSIDERATIONS
The effectiveness of brachytherapy implants is influenced
by several radiobiological factors. In LDR permanent implant
brachytherapy, the tumor cells are subjected to continuous
irradiation of low-energy photons with instantaneous dose

3199 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
rate varying in both space and time and in some HDR
brachytherapy regimens they are subjected to 1–5 fractions
separated by 1–5 days. The prescribed initial dose rates vary
from approximately 5 cGy/h to 30 cGy/h for permanent
implants using 125I, 103Pd, or 131Cs sources to about 12
cGy/s for HDR 192Ir temporary brachytherapy. The duration
needed to deliver, for example, 80% of the total dose
varies from minutes for temporary HDR 192Ir implants to
approximately 22 days for permanent LDR 131Cs implants
or 140 days for 125I implants. With such diverse spatial and
temporal variations, the physical absorbed dose distribution
alone becomes insufficient to fully characterize the biological
responses of different tumors and normal tissues at risk.
Yet accurate representations of delivered physical dose are
a necessary first step for introducing any new brachytherapy
source.106
The cell repopulation, cell loss, migration, and sublethal
damage repair all compound with each other producing
substantial effects on cell killing during the course of dose
delivery. In assessing the effectiveness of brachytherapy
with an innovative device, there is a need to consider the
interplay between the spatial and temporal patterns of dose
delivery and the underlying cell kinetics. In addition, with
LDR brachytherapy, the dose delivery occurs over many
weeks with the “delivery position” varying greatly such as
walking, running, and sleeping. With EBRT and HDR, the
“delivery position” is, relatively speaking, more consistent.
Distance to surrounding critical structures is therefore more
variable during the LDR dose delivery, a factor that should
be considered when discussing dosimetric uncertainties in
different modalities.
Over the last several decades, various models have been
developed to characterize the interplay of spatial–temporal
patterns of dose delivery with the underlying cell kinetics in
brachytherapy and EBRT. For permanent implants, an analytic
expression of biologically effective dose has been derived
by Dale based on the linear-quadratic (LQ) cell inactivation
model.194 This model has been used by many investigators
to examine various issues related to prostate implants.
In reviewing clinical trials using innovative brachytherapy
devices, one must keep in mind that radiobiological modeling
is intrinsically organ specific. For a given organ, factors that
are important to the calculation of radiobiological indices
include not only the physical dose or dose-rate distribution
but also the properties of intrinsic dose response, tissue
architecture of the irradiated organs, fractionation factors
(e.g., the α/ β ratio in the LQ cell inactivation model), cell
repopulation, and sublethal damage repair. The 2006 GEC-
ESTRO Guidelines on brachytherapy for cervical cancer
and the 2009 AAPM TG-137 report on permanent prostate
brachytherapy provide recommendations on radiobiological
models and biophysical parameters.195,196 The key intent of
these reports is to promulgate consistent biological effective
dose through prescriptions and protocols having equivalent
dose-time fractionation.
In addition, the radiobiological effects for a given dose may
be different than those for conventional sources if the energy
spectrum of the emitted radiation, the radiation type, or the
Medical Physics, Vol. 43, No. 6, June 2016
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3199
dose rate is different. If the new brachytherapy source has
such unique features, then it may be necessary to conduct
radiobiological studies to investigate the microdosimetric
aspects of the emitted radiations such as the LET and its
influence on the RBE and the oxygen enhancement ratio
(OER). In these cases, a clinical trial may be necessary to
show that the device is safe and effective for the proposed
indication for use.
Before device manufacturers start clinical trials on an inno-
vative brachytherapy device, they should conduct extensive
nonclinical studies. Nonclinical studies involve bench studies,
in vitro (test tube), and in vivo (animal) experiments using
wide-ranging doses of the study device to obtain preliminary
efficacy, toxicity, and pharmacokinetic information. Such
tests assist manufacturers in deciding whether a drug/device
candidate has scientific merit for further development as an
investigational new drug (IND) or an IDE.
Typically, clinical trials for new drugs involve four
phases. Phase 0 studies are first-in-human trials conducted
in accordance with the 2006 FDA Guidance on exploratory
investigational new drug/device studies. Phase 0 trials are also
known as human microdosing studies. Phase 0 trials include
the administration of single subtherapeutic doses of the study
drug/device to a small number of subjects (10–15) to gather
preliminary data on the agent’s pharmacokinetics.
In phase I trials, a small group of patients (20–80) who
have end-stage disease and lack other treatment options are
selected to assess the safety, tolerability, pharmacokinetics,
and pharmacodynamics of a drug/device. Healthy volunteers
may be recruited to gather data on certain aspects of the trial.
Phase I trials normally include dose-ranging, also called dose
escalation, studies so that the appropriate dose for therapeutic
use can be found.
Phase II trials are performed on larger groups (20–300) and
are designed to assess how well the drug/device works, as well
as to continue phase I safety assessments in a larger group of
volunteers and patients. Phase II studies are sometimes divided
into phase IIA (designed to assess dosing requirements) and
phase IIB (designed to study efficacy).
Phase III trials are randomized controlled multicenter
studies on large patient groups (300–3000 or more) and are
aimed at being the definitive assessment of how effective
the drug/device is, in comparison with the currently accepted
standard treatment. Because of their size and comparatively
long duration, these are the most expensive, time-consuming,
and difficult trials to design and run, especially for chronic
diseases like cancer.
Phase IV trials are also known as postmarketing surveil-
lance trials. Phase IV trials involve the safety surveillance
(e.g., pharmacovigilance) and ongoing technical support of a
drug or device after it receives approval to be sold.
There are three types of clinical trials: (1) those that require
only IRB approval and are normally at a single institution for
a marketed device, home-made device, or off-label use of an
approved device, (2) those that require both IRB approval
and an FDA-approved IDE, and are normally multicenter to
gather information for marketing a new medical device, and
(3) co-operative group trials, which may be sponsored by the

3200 Nath et al.: Task Group 167: Innovative brachytherapy devices and applications
National Cancer Institute (NCI) to study various treatment
protocols with marketed devices.
If a clinical trial uses a medical device which meets the
FDA definition of SR, a FDA-approved IDE must be obtained
in addition to IRB approval. This would also apply to drugs
used in radiation therapy, such as requiring IRB approval and
an FDA-approved IND to utilize an unapproved PET tracer
(e.g., [18F]-fluoro-3′-deoxy-3′-:-fluorothymidine) to guide
radiotherapy dose escalation. Clinical trials for devices typi-
cally involve only two phases. The sample size is much smaller
than for drug clinical trials as the sample size is determined
to be that which will have statistical significance (usually
at the 95% confidence level) to support the trial hypothesis.
Additionally, the sample size for device clinical trials is just for
the participants meeting the inclusion/exclusion criteria and
not for a larger population typical of drug clinical trials. Part
of the IDE approval process involves the applicant submitting
nonclinical data as well as a protocol for conducting a clinical
trial, which must be designed to show that the device is safe
and effective for the proposed indication for use. However,
clinical trials have been used rarely in the introduction of
innovative brachytherapy devices because of the difficulties
in patient accrual and the need for long-term follow-up in
cancer trials. An exception has been in the evaluation of
IVBT sources for prevention of restenosis after angioplasty.
A number of phase III studies were carried out for IVBT with
different devices as thousands of patients were accrued in a
few years. Only a well-designed clinical trial can evaluate
the clinical efficacy of brachytherapy compared to that for
existing therapeutic approaches. This is especially pertinent
for treatment of disease other than cancer where the clinical
safety and efficacy of radiation are not well established and
a new class of human disease is to be treated by a radiation
emitting device.
Most cooperative group trials involving brachytherapy
have been designed with a goal of achieving a dose deliv-
ery accuracy of ±15%. It is commonly accepted that the
radiation output of therapeutic devices should be known
with accuracy better than a few percent in the entire target
volume. Unlike EBRT, brachytherapy presents an even more
challenging problem because the dose gradient in the vicinity
of the brachytherapy sources is very steep and position and
orientation of each source in the patient must also be known
to a high precision. In addition, brachytherapy sources need to
be calibrated, and therefore a practical mechanism is needed
to ensure that source strength provided by the vendor in a
package delivered to a clinic has the correct value. All of these
factors are essential to accurately determine the dose distri-
butions in individual patients and must be addressed when an
innovative brachytherapy device or application is introduced.
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