Practical Radiation Oncology® (2020) xx, 1-15

www.practicalradonc.org

Clinical Practice Guidelines

Radiation Therapy for Cervical Cancer: Executive

Summary of an ASTRO Clinical Practice Guideline
Junzo Chino, MD,a,* Christina M. Annunziata, MD, PhD,b
Sushil Beriwal, MD, MBA,c Lisa Bradfield, BA,d Beth A. Erickson, MD,e
Emma C. Fields, MD,f KathrynJane Fitch, PhD,g
Matthew M. Harkenrider, MD,h,i Christine H. Holschneider, MD,j
Mitchell Kamrava, MD,k Eric Leung, MD,l Lilie L. Lin, MD,m
Jyoti S. Mayadev, MD,n Marc Morcos, MS,o
Chika Nwachukwu, MD, PhD,p Daniel Petereit, MD,q and
Akila N. Viswanathan, MD, MPHr
a
Department of Radiation Oncology and Guideline Vice-Chair, Duke University Cancer Center, Durham, North Carolina;
b
Women’s Malignancies Branch, National Cancer Institute, Bethesda, Maryland; cDepartment of Radiation Oncology,

Sources of support: This work was funded by the American Society for Radiation Oncology.
Task Force Members’ Disclosure Statements
All task force members’ disclosure statements were rigorously reviewed before being invited and were shared with other task force members
throughout the guideline’s development. Those disclosure are published within this report. Where potential conflicts were detected, remedial measures to
address them were taken.
Christina Annunziata (American Society of Clinical Oncology representative): MaxCyte, Medivir, and Precision Biologics (research), Horizon
Pharma and Merck (provided drugs for clinical trial), BMC Cancer and Frontiers in Oncology (editor); Sushil Beriwal: American Board of Radiology
(board examiner), Brachy Journal and iJROBP (editorial board); Eisai, Institute of Education, and Via Oncology (honoraria), International Journal of
Radiation Oncology, Biology, Physics (senior editor); Varian (consultant), XOFT (DSMB); Junzo Chino (vice chair): American Board of Radiology
(board examiner); NanoScint (stock); International Journal of Radiation Oncology, Biology, Physics (editorial board); Matthew Harkenrider: ACR
(program director and trustee), AstraZeneca (advisory board [ended]), International Journal of Radiation Oncology, Biology, Physics (editorial board);
Varian (advisory board [ended]); Christine Holschneider (Society of Gynecologic Oncology representative): NRG-GOG and GOG Foundation
(research), National Institutes of Health grants (researchdfamily member), UpToDate (honoraria); Mitchell Kamrava: American Board of Radiology
(board examiner), Augmenix (speaker’s bureau), Brachytherapy and International Journal of Radiation Oncology, Biology, Physics (editorial board);
Lilie Lin: American Board of Radiology (board examiner); AstraZeneca (research); Jyoti Mayadev: AstraZeneca (consultant), NRG GOG Foundation
(member), NRG Oncology Cervical Board (cochair), Varian (advisory board); Marc Morcos: Elekta (travel); Daniel Petereit (American Brachy-
therapy Society representative and President): American Board of Radiology (board examiner), BMS Foundation (research and salary support), Irving
A Hansen Memorial Foundation (patient funding), Ralph Lauren Pink Pony Foundation (board member); Akila Viswanathan (chair): NCI Uterine Task
force (cochair), American Board of Radiology (board examiner), Brachytherapy and Gynecologic Oncology Journal (editorial board), Springer textbook
(chapter editor); Beth Erickson: American Brachytherapy Society (CME cochair); ASTRO (MOC-CME cochair); Brachytherapy and International
Journal of Radiation Oncology, Biology, Physics (editorial board), Elekta (research and travel), Springer textbook (chapter editor). Emma Fields,
KathrynJane Fitch (patient representative), Eric Leung, and Chika Nwachukwu reported no disclosures.
Disclaimer and Adherence: American Society for Radiation Oncology (ASTRO) guidelines present scientific, health, and safety information and
may reflect scientific or medical opinion. They are available to ASTRO members and the public for educational and informational purposes only.
Commercial use of any content in this guideline without the prior written consent of ASTRO is strictly prohibited.
Adherence to this guideline does not ensure successful treatment in every situation. This guideline should not be deemed inclusive of all proper
methods of care or exclusive of other methods reasonably directed to obtaining the same results. The physician must make the ultimate judgment
regarding therapy considering all circumstances presented by the patient. ASTRO assumes no liability for the information, conclusions, and findings
contained in its guidelines. This guideline cannot be assumed to apply to the use of these interventions performed in the context of clinical trials. This
guideline is based on information available at the time the task force conducted its research and discussions on this topic. There may be new de-
velopments that are not reflected in this guideline and that may, over time, be a basis for ASTRO to revisit and update the guideline.
* Corresponding author: Junzo Chino, MD; E-mail: junzo.chino@duke.edu

https://doi.org/10.1016/j.prro.2020.04.002
1879-8500/Ó 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
2 J. Chino et al Practical Radiation Oncology: --- 2020

UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania; dAmerican Society for Radiation Oncology, Arlington, Virginia;
e
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin; fDepartment of Radiation
Oncology, Virginia Commonwealth University, Richmond, Virgina; gPatient Representative, Charlotte, North Carolina;
h
Department of Radiation Oncology, Loyola University Chicago, Chicago, Illinois; iDepartment of Radiation Oncology,
Edward Hines Jr. VA Hospital, Hines, Illinois; jDepartment of Obstetrics and Gynecology, Olive View/UCLA Medical
Center, Sylmar, California; kDepartment of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California;
l
Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, University of Toronto,
Toronto, Ontario, Canada; mDepartment of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas;
n
Department of Radiation Medicine and Applied Sciences, University of California, San Diego, California; oDepartment of
Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland; pDepartment of
Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas; qDepartment of Radiation Oncology, Rapid City
Regional Health, Rapid City, South Dakota; and rDepartment of Radiation Oncology and Molecular Radiation Sciences and
Guideline Chair, Johns Hopkins University, Baltimore, Maryland

Received 1 April 2020; accepted 2 April 2020

Abstract
Purpose: This guideline reviews the evidence and provides recommendations for the indications and appropriate techniques of radiation
therapy (RT) in the treatment of nonmetastatic cervical cancer.
Methods: The American Society for Radiation Oncology convened a task force to address 5 key questions focused on the use of RT in
definitive and postoperative management of cervical cancer. These questions included the indications for postoperative and definitive
RT, the use of chemotherapy in sequence or concurrent with RT, the use of intensity modulated radiation therapy (IMRT), and the
indications and techniques of brachytherapy. Recommendations were based on a systematic literature review and created using a
predefined consensus-building methodology and system for grading evidence quality and recommendation strength.
Results: The guideline recommends postoperative RT for those with intermediate risk factors, and chemoradiation for those with high-
risk factors. In the definitive setting, chemoradiation is recommended for stages IB3-IVA, and RT or chemoradiation is conditionally
recommended for stages IA1-IB2 if medically inoperable. IMRT is recommended for postoperative RT and conditionally recommended
for definitive RT, for the purposes of reducing acute and late toxicity. Brachytherapy is strongly recommended for all women receiving
definitive RT, and several recommendations are made for target dose and fractionation, the use of intraoperative imaging, volume-based
planning, and recommendations for doses limits for organs at risk.
Conclusions: There is strong evidence supporting the use of RT with or without chemotherapy in both definitive and postoperative
settings. Brachytherapy is an essential part of definitive management and volumetric planning is recommended. IMRT may be used for
the reduction of acute and late toxicity. The use of radiation remains an essential component for women with cervical cancer to achieve
cure.
Ó 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Preamble interests from 12 months before initiation of the writing

effort. Disclosures go through a rigorous review process
with final approval by ASTRO’s Conflict of Interest Re-
As the leading organization in radiation oncology, the view Committee. For the purposes of full transparency,
American Society for Radiation Oncology (ASTRO) is task force members’ comprehensive disclosure informa-
dedicated to improving quality of care and patient out- tion is included in this publication. The complete disclo-
comes. A cornerstone of this goal is the development and sure policy for formal papers is online.
dissemination of clinical practice guidelines based on Selection of Task Force Members d The Guideline
systematic methods to evaluate and classify evidence, Subcommittee strives to avoid bias by selecting a multi-
combined with a focus on patient-centric care and shared disciplinary group of experts with variation in geographic
decision making. ASTRO develops and publishes guide- region, gender, ethnicity, race, practice setting, and areas
lines without commercial support, and members volunteer of expertise. Representatives from organizations and
their time. professional societies with related interests and expertise
Disclosure Policy d ASTRO has detailed policies and are also invited to serve on the task force.
procedures related to disclosure and management of in- Methodology d The task force uses evidence-based
dustry relationships to avoid actual, potential, or methodologies to develop guideline recommendations in
perceived conflicts of interest. All task force members are accordance with the National Academy of Medicine
required to disclose industry relationships and personal standards. The evidence identified from key questions
Practical Radiation Oncology: --- 2020 ASTRO cervical cancer guideline 3

(KQs) is assessed using the Population, Intervention, Document Review and Approval
Comparator, Outcome, Timing, Setting (PICOTS)
framework. A systematic review of the KQs is completed, The guideline was reviewed by 20 official peer re-
which includes creation of evidence tables that summarize viewers and revised accordingly. The modified guideline
the evidence base task force members use to formulate was posted on the ASTRO website for public comment in
recommendations. Table 1 describes ASTRO’s recom- November 2019. The final guideline was approved by the
mendation grading system. ASTRO Board of Directors and endorsed by the Amer-
Consensus Development d Consensus is evaluated ican Brachytherapy Society, Canadian Association of
using a modified Delphi approach. Task force members Radiation Oncology, European Society for Radiotherapy
(except for the patient representative) confidentially and Oncology, Royal Australian and New Zealand Col-
indicate their level of agreement on each recommendation lege of Radiologists, and the Society of Gynecologic
based on a 5-point Likert scale, from “strongly agree” to Oncology.
“strongly disagree.” A prespecified threshold of
75%
(
90% for expert opinion recommendations) of raters
Evidence Review
who select “strongly agree” or “agree” indicates
consensus is achieved. Recommendation(s) that do not
meet this threshold are removed or revised. Recommen- A systematic search of human subject studies retrieved
dations edited in response to task force or reviewer from the database Ovid MEDLINE was conducted. The
comments are resurveyed before submission of the inclusion criteria required research to involve adult
document for approval. women (age
18 years), who had received a diagnosis of
Annual Evaluation and Updates d Guidelines are cervical cancer, published in English, from January 1993
evaluated annually beginning 2 years after publication for through October 2018, and RT delivered with curative
new potentially practice-changing studies that could result intent. The literature review excluded studies with 50
in a guideline update. In addition, the Guideline Sub- participants; those focused on diagnostic methods; pre-
committee will commission a replacement or reaffirma- clinical studies, health economics and cost analyses,
tion within 5 years of publication. comments and editorials; those focused on metastatic
Full-Text Guideline d The reader is encouraged to disease or recurrent disease, or otherwise not relevant to
consult the full-text guideline supplement for the sup- the scope of the guideline. Because different qualities of
portive text, abbreviations list, and additional information evidence were available for each KQ, inclusion criteria
on radiation therapy for cervical cancer because the ex- were further refined as follows: KQ1 was limited to meta-
ecutive summary contains limited information. analyses and randomized controlled trials (RCTs); KQ2 to
meta-analyses, RCTs, and prospective nonrandomized
trials; and KQs 3, 4, and 5 to meta-analyses, RCTs,
prospective nonrandomized trials, and retrospective
Introduction studies (N
100). For subquestions with limited data,
retrospective study results and expert opinion were relied
Despite improvements in screening and prevention, on to support recommendations as reflected in the low-to-
cervical cancer remains a significant cause of morbidity and moderate quality of evidence cited in these cases.
mortality. In the last 2 decades there have been notable All supplementary materials, including the full-text
advances in surgical procedures, external radiation therapy guideline and evidence tables (which summarize the
(RT), brachytherapy techniques, and chemotherapy. data used to formulate recommendations), are available at
https://doi.org/10.1016/j.prro.2020.04.002. The full-text
guideline also includes Figure 1 which is the Preferred
Reporting Items for Systematic Reviews and Meta-
Methods Analyses (PRISMA) diagram showing the number of
articles screened, excluded and included in the evidence
Task Force Composition review; and Appendix 1 (peer reviewer’s disclosure in-
formation); Appendix 2 (list of abbreviations) and
The task force consisted of a multidisciplinary team of Appendix 3 (literature search strategy).
radiation oncologists; a gynecologic oncologist, medical
oncologist, radiation oncology resident, and medical Scope of the Guideline
physicist; and a patient representative. This guideline was
developed in collaboration with the American Brachy- This guideline covers only the subjects specified in the
therapy Society, American Society of Clinical Oncology 5 KQs (see Table 2 in the full-text guideline for KQs and
and the Society of Gynecologic Oncology, who provided outcomes of interest). The scope is limited to curative
representatives and peer reviewers. management of invasive carcinomas of the uterine cervix,
4 J. Chino et al Practical Radiation Oncology: --- 2020

Table 1 ASTRO recommendation grading classification system

ASTRO’s recommendations are based on evaluation of multiple factors including the QoE, individual study quality, and panel
consensus, all of which inform the strength of recommendation. QoE is based on the body of evidence available for a particular key
question and includes consideration of number of studies, study design, adequacy of sample sizes, consistency of findings across
studies, and generalizability of samples, settings, and treatments.
Strength of Overall QoE Recommendation
Definition
Recommendation Grade Wording
 Benefits clearly outweigh risks and burden, or risks Any
and burden clearly outweigh benefits. (usually high, “Recommend/
Strong  All or almost all informed people would make the moderate, Should”
recommended choice. or expert opinion)

 Benefits are finely balanced with risks and burden

or appreciable uncertainty exists about the magni- Any
tude of benefits and risks. (usually moderate, “Conditionally
Conditional  Most informed people would choose the recom- low, or expert Recommend”
mended course of action, but a substantial number opinion)
would not.
 A shared decision-making approach regarding patient
values and preferences is particularly important.
Overall QoE Grade Type/Quality of Study Evidence Interpretation
 2 or more well-conducted and highly generalizable The true effect is very likely to lie close to the
High RCTs or meta-analyses of such trials. estimate of the effect based on the body of
evidence.

 1 well-conducted and highly generalizable RCT or The true effect is likely to be close to the
a meta-analysis of such trials OR estimate of the effect based on the body of
Moderate  2 or more RCTs with some weaknesses of evidence, but it is possible that it is
procedure or generalizability OR substantially different.
 2 or more strong observational studies with consistent
findings.

 1 RCT with some weaknesses of procedure or The true effect may be substantially different
generalizability OR from the estimate of the effect. There is a
 1 or more RCTs with serious deficiencies of risk that future research may significantly
procedure or generalizability or extremely small alter the estimate of the effect size or the
Low sample sizes OR interpretation of the results.
 2 or more observational studies with inconsistent
findings, small sample sizes, or other problems that
potentially confound interpretation of data.

 Consensus of the panel based on clinical judgment Strong consensus (
90%) of the panel guides
Expert Opinion* and experience, due to absence of evidence or the recommendation despite insufficient
limitations in evidence. evidence to discern the true magnitude and
direction of the net effect. Further research
may better inform the topic.
Abbreviations: ASTRO Z American Society for Radiation Oncology; QoE Z quality of evidence; RCTs Z randomized controlled trials.
* A lower quality of evidence, including expert opinion, does not imply that the recommendation is conditional. Many important clinical
questions addressed in guidelines do not lend themselves to clinical trials, but there still may be consensus that the benefits of a treatment or diagnostic
test clearly outweigh its risks and burden.

which include squamous cell carcinomas and adeno- indications, techniques, and outcomes. It additionally
carcinomas, and does not include rare histologies, covers other therapies that modify the efficacy of RT
noninvasive disease or palliative treatment. It focuses on when used concurrently or in sequence (eg, chemotherapy
management of cervical cancer with RT and its or surgery).
Practical Radiation Oncology: --- 2020 ASTRO cervical cancer guideline 5

Key Questions and Recommendations treatment versus adjuvant pelvic RT.9 Adjuvant radia-
tion was associated with a 47% reduction in recurrence
Key Question 1: Postoperative RT with and (a 12.6% absolute reduction) with acceptable morbidity
without systemic therapy (Table 2) and a 6% versus 2% grade 3 or 4 adverse event rate.5 A
2012 meta-analysis, which included data from GOG 92,
See evidence tables in supplementary materials for the further supports the benefit of adjuvant RT for those
data supporting the recommendations for KQ1. with intermediate-risk factors, with a significantly lower
Following primary surgery for cervical cancer, risk of disease progression at 5 years.6 For cases
when is it appropriate to deliver postoperative RT meeting these intermediate-risk criteria, whole pelvic
with or without systemic therapy? RT can be delivered to a total dose of 4500 to 5040 cGy,
in 180 cGy per fraction or 4000 to 4400 cGy in 200 cGy
per fraction.5
High-risk surgicopathologic findings
The evidence is strong that adjuvant concurrent
Occult cervical cancer after total hysterectomy
cisplatin-based chemoradiation improves overall sur-
For women who are found to have an occult invasive
vival and progression-free survival for patients with
cervical cancer after total hysterectomy (either for
cervical cancer who have high-risk pathologic features
benign disease or uterine cancer), further treatment is
after radical hysterectomy (eg, positive margins or
needed for stages greater than or equal to IA2 because a
positive lymph nodes or extension into the parametrial
radical hysterectomy with lymph node dissection is
tissue)1; the benefit of chemoradiation compared with
required for curative surgery in these cases.10 Options
RT alone is similar to the benefit observed for locally
would be additional surgery (a parametrectomy, upper
advanced patients with cervical cancer who undergo
vaginectomy, and lymph node dissection) or RT. In
definitive chemoradiation compared with RT alone.8
practice, if additional surgery is expected to be techni-
For cases meeting these high-risk criteria, whole pel-
cally difficult and/or potentially morbid, RT or chemo-
vic RT can be delivered to a total dose of 4500 to 5040
radiation may be offered as an alternative, particularly if
cGy, in 180 cGy fractions, with concurrent weekly
RT is already indicated from surgicopathologic findings.
cisplatin (40 mg/m2).
Although prospective evidence is lacking, pelvic RT to
4500 to 5040 cGy, followed by a boost to the sites at
Intermediate-risk surgicopathologic findings high risk of additional occult disease (either with vaginal
The Gynecologic Oncology Group (GOG) conducted brachytherapy or external beam radiation therapy
an RCT (GOG 92) of 277 patients with cervical cancer (EBRT) depending on location) is a reasonable
(including both squamous cell and adenocarcinomas) approach. Concurrent chemotherapy may also be
treated by radical hysterectomy and intermediate-risk considered depending on factors described earlier in this
Sedlis criteria who were randomized to no further section.

Table 2 Recommendations for postoperative RT with or without systemic therapy

Strength of Quality of
KQ1 Recommendations
Recommendation Evidence (Refs)
1. For women undergoing surgery for cervical cancer who have high surgicopathologic risk
factors, adjuvant EBRT and concurrent platinum-based chemotherapy is recommended.
Implementation remark: Strong High
1-4
High-risk factors include positive margin(s) or positive lymph node(s) or extension into the
parametrial tissue.

2. For women with cervical cancer and intermediate-risk factors, adjuvant EBRT is
recommended to decrease locoregional recurrence.
Implementation remark: Intermediate-risk factors include*: Strong High
 LVSI plus deep one-third cervical stromal invasion with any tumor size 5-7

 LVSI plus middle one-third stromal invasion and tumor size
2 cm

 LVSI plus superficial one-third stromal invasion and tumor size
5 cm
 No LVSI but deep or middle one-third stromal invasion plus tumor size
4 cm
Abbreviations: EBRT Z external beam radiation therapy; LVSI Z lymphovascular space involvement; RT Z radiation therapy.
* The original Gynecologic Oncology Group (GOG) 92 protocol estimated tumor size based on palpation; however, estimation based on
pathologic or magnetic resonance imaging findings are an acceptable substitute.
6 J. Chino et al Practical Radiation Oncology: --- 2020

Figure 1 Cervical cancer algorithm. Abbreviations: BT Z brachytherapy; EBRT Z external beam radiation therapy; IMRT Z
intensity modulated radiation therapy; LND Z lymph node dissection; RT Z radiation therapy.

Key Question 2: Definitive RT with and without platinum-based chemotherapy compared with RT alone
systemic therapy; hysterectomy after RT (Table 3) for women with stage IB3-IVA cervical cancer.8 If
treatment of the extended field is indicated, concurrent
See evidence tables in supplementary materials for the chemotherapy with cisplatin is administered with appro-
data supporting the recommendations for KQ2 and priate symptom management, consideration of intensity
Figure 1 for a visual representation of the cervical cancer modulated radiation therapy (IMRT; refer to KQ3) to
recommendations. spare bowel; close monitoring of laboratory tests with
When is it appropriate to deliver definitive RT with special attention to assess neutropenia, anemia, and
and without systemic therapy? When is it appropriate thrombocytopenia; and a potential need to stop chemo-
to perform a hysterectomy after RT for cervical therapy before the completion of 5 cycles.22,23
cancer? For definitive RT, whole pelvic RT or extended field
RT can be delivered to a total dose of 4500 to 5040 cGy,
Integration of chemotherapy with radiation in 180 cGy fractions, with concurrent weekly cisplatin (40
Multiple RCTs demonstrate an approximately 10% mg/m2). Additional nodal boosts may be included
survival benefit at 5 years for radiation with concurrent (described in KQ3). This is followed by brachytherapy
Practical Radiation Oncology: --- 2020 ASTRO cervical cancer guideline 7

Table 3 Recommendations for definitive RT with and without systemic therapy and hysterectomy after RT
Strength of Quality of
KQ2 Recommendations
Recommendation Evidence (Refs)
1. For women with FIGO stage IB3-IVA* squamous cell or adenocarcinoma of the cervix, RT
with concurrent platinum-based chemotherapy is recommended for definitive treatment. Strong High
8,11-18
Implementation remark:
Recommended dose for cisplatin is 40 mg/m2 weekly for 5-6 cycles.

2. For women with FIGO stage IB3-IVA cervical cancer, a planned adjuvant hysterectomy
Strong High
after RT or chemoradiation is not recommended.y 13,19-21

3. In women with FIGO stage IA1-IB2 that are deemed medically inoperable, RT with or
Conditional Expert Opinion
without chemotherapy is conditionally recommended.
Abbreviation: FIGO Z International Federation of Gynecology and Obstetrics; RT Z radiation therapy.
* Stage IIA1 cancers may be managed with radical hysterectomy in well-selected (eg, nonbulky, with limited vaginal involvement) cases.
y
In the setting of biopsy-proven gross residual disease after point-Aebased dose specification for brachytherapy, surgery may be an option.

(described in KQ4 and KQ5), with a goal to limit the total salvage hysterectomy or exenteration, if feasible, to
treatment time to 7 to 8 weeks. improve local control and survival, at the risk of sig-
nificant morbidity.25
Hysterectomy after radiation
In the era of combined chemoradiation and image Key Question 3: Intensity modulated radiation
guided brachytherapy (IGBT), pelvic control is very high therapy (Table 4)
even for women with bulky stage IB3-IIB cervical cancer.
Therefore adjuvant hysterectomy after radiation is not See evidence tables in supplementary materials for the
routinely recommended, particularly when IGBT is data supporting the recommendations for KQ3.
available. When a lower dose of brachytherapy is given For patients receiving definitive or postoperative RT
and IGBT is not available, hysterectomy may be consid- for cervical cancer, when is it appropriate to deliver
ered, especially in the presence of cervix-confined resid- IMRT?
ual disease.
Despite high rates of local control, a small per- In the treatment of postoperative and definitive cervical
centage of cancers do not respond well to chemo- cancer, dosimetric studies of IMRT have demonstrated
radiation and have evidence of residual disease after decreased volumes of the bladder, rectum, bowel, and
treatment. Time should be allowed for delayed bone marrow receiving clinically significant doses of
response, with consideration of positron emission to- RT.26,29,31,33 Single and multi-institution series of post-
mography imaging approximately 3 months after operative RT have demonstrated a favorable toxicity profile
treatment completion.24 However, if recurrence and/or with the use of IMRT.32,39 RTOG 1203 (TIME-C) is the
persistence of disease is confirmed by biopsy as early only published phase III RCT of 3-dimensional (3-D) RT
as 8 to 12 weeks after therapy, there may be a role for versus IMRT in the postoperative treatment of patients with

Table 4 Recommendations for IMRT

Strength of Quality of
KQ3 Recommendations
Recommendation Evidence (Refs)
1. In women with cervical cancer treated with postoperative RT with or without
Strong Moderate (acute)
chemotherapy, IMRT is recommended to decrease acute and chronic toxicity. 26,27

Low (chronic)
26,28
2. In women with cervical cancer treated with definitive RT with or without chemo-
Conditional Moderate (acute)
therapy, IMRT is conditionally recommended to decrease acute and chronic toxicity. 29-34

Moderate (chronic)
29,31,35-38

Abbreviations: IMRT Z intensity modulated radiation therapy; RT Z radiation therapy.

8 J. Chino et al Practical Radiation Oncology: --- 2020

early-stage endometrial or cervical cancer.27 This study In this example case of stage IIB cervical cancer, a
demonstrated significantly improved acute patient-reported final PTV for 45 Gy can be seen in the blue shaded
gastrointestinal (primary endpoint) and urinary outcomes, contour. The PTV includes the primary CTV of the
thus supporting the use of IMRT, when available, in these cervix and uterus, proximal vagina, paracervical tis-
populations.27 sue, parametrial tissue including uterosacral liga-
Similarly, retrospective comparisons of 2-dimensional ments, and pelvic nodal basins with additional
(2-D) and 3-D RT to IMRT found decreased acute and margins for daily setup variation and internal target
chronic toxicities with use of IMRT during the pelvic/ motion. The PA nodes are not included in this case
para-aortic phase of definitive RT.29,30,36,38 Three pro- because of the absence of any concerning nodes in the
spective randomized trials and one meta-analysis collec- pelvis or PA chain on PET imaging; thus the superior
tively demonstrate decreased acute and late border is set at the level of the aortic bifurcation
gastrointestinal and urinary toxicities with IMRT (approximately L4-5) and inferiorly into the vagina, to
compared with 3-D RT.31,33,34,38 IMRT for irradiation of 4 cm distal to extent of disease. At the level of the
the para-aortic nodal chain is also likely to decrease risk acetabulum (A), note the anterior extension of the
of toxicities compared with 2-D/3-D RT while allowing PTV well into the bladder as a result of significant
dose escalation to intact positive nodes, especially for variation in uterine position. Also note posterior
patients receiving concurrent chemotherapy.22,23,40-45 extension of the PTV in the rectum to allow for
There are, however, no data that IMRT improves coverage of the uterosacral ligaments and motion of
disease-specific survival or overall survival over 2-D/3-D the cervix and the presacral lymph nodes; coverage of
techniques. Utmost care must be taken to account for the mesorectum may be required in some cases with
target motion both at time of simulation and throughout rectal invasion or posterior uterosacral ligament
treatment with the use of image guidance (Figure 2). involvement. At the level of S3 (B), note the exten-
Refer to the full-text guideline for a more in-depth dis- sion of the PTV posteriorly to allow for coverage of
cussion of these issues. the uterosacral ligaments. Midsagittal CT (C) and

A B

C D

Figure 2 Example of IMRT PTV definition for intact cervical cancer. A and B axial CT images; C sagittal CT images; and D sagtital MRI
images, showing uterine motion; refer to the full-text guideline for a detailed description of PTV definitions. Abbreviations: CT Z computed
tomography; IMRT Z intensity modulated radiation therapy; MRI Z magnetic resonance imaging; PTV Z planning target volume.
Practical Radiation Oncology: --- 2020 ASTRO cervical cancer guideline 9

Table 5 Recommendations for brachytherapy

Strength of Quality of
KQ4 Recommendations
Recommendation Evidence (Refs)
1. For women receiving definitive RT for intact cervical cancer, brachytherapy is recommended. Strong Moderate
47-51

2. For women with cervical cancer receiving postoperative whole pelvis radiation, a
brachytherapy boost is conditionally recommended in the presence of positive margin(s).
Implementation remark: Conditional Low
52
The brachytherapy technique selected is based on the location and volume of the positive
margin(s).
Abbreviation: RT Z radiation therapy.

MRI (D) obtained on the same day show significant chemotherapy.48 Other smaller retrospective studies show
motion of the uterus with partial bladder emptying. similar results with improved survival in patients treated
The PTV encompasses this entire excursion of the with brachytherapy compared with nonbrachytherapy
uterine body (may be several centimeters), with cohorts.49-51 Therefore neither SBRT nor IMRT are a
additional margin for daily setup. The use of regular suitable substitute for brachytherapy and should only be
image guidance at the time of treatment is necessary considered for those ineligible because of complex
to ensure all targets remain within the PTV, and medical factors. Referral to tertiary centers for brachy-
replanning may be necessary if the PTV margin is therapy is necessary if the originating facility has a
found to be too small. This is provided as an example limited capacity to support a patient with complex
of a large PTV rather than a recommended volume for comorbidities. Previous 2-D prospective cohort studies
all cases; reference to the appropriate contouring found high control rates and acceptable toxicities, though
atlases is indicated for each individual considered for these have improved further with 3-D IGBT tech-
IMRT. niques.8,11-14,17,18,53-65 Prospective and retrospective
IMRT may also be used to boost selective sites of cohort data of 3-Debased planning for brachytherapy
nodal involvement. The dose required is dependent on the indicates high rates of cervical control and decreased
size of the grossly involved node. Generally, between toxicity, so it is emerging as standard practice in many
5500 to 6500 cGy is delivered to involved nodes based on centers.56,58,60,62,63,66
size, location, contribution from brachytherapy, and dose Brachytherapy may be considered in the postoperative
per fraction.46 setting in the presence of a positive vaginal mucosal
margin. For positive margins beyond the vaginal mucosa
Key Question 4: Brachytherapy (Table 5) surface (ie, parametrial, paravaginal) or positive macro-
scopic margins, an advanced brachytherapy technique
(eg, an intracavitary multichannel cylinder) or interstitial
See evidence tables in supplementary materials for the
needles may be required to adequately deliver conformal
data supporting the recommendations for KQ4.
doses to the areas at risk. For regions at risk not amenable
For patients receiving definitive or postoperative
to brachytherapy, a targeted external beam boost may be
RT for cervical cancer, when is brachytherapy
considered.
indicated?

Brachytherapy is an integral component of definitive

treatment for patients with locally advanced cervical Key Question 5: Brachytherapy technique
cancer. Results from national databases have consistently (Table 6)
found improved outcomes using brachytherapy.47,48 In
multiple large national retrospective data sets, the use of See evidence tables in supplementary materials for the
brachytherapy in women with cervical cancer declined data supporting the recommendations for KQ5, and see
between 2003 to 2011, whereas use of IMRT or SBRT Figure 3 for a visual representation of the recommenda-
instead increased during this period.47,48 The use of tions for locally advanced cervical cancer.
brachytherapy has been consistently associated with For patients receiving definitive RT for cervical
improved survival compared with IMRT or SBRT as a cancer, what is the optimal dose/fractionation
boost. The omission of brachytherapy has a stronger schedule, imaging, and technique for the delivery of
negative effect on survival than the exclusion of brachytherapy?
10 J. Chino et al Practical Radiation Oncology: --- 2020

Table 6 Recommendations for brachytherapy technique

Strength of Quality of
KQ5 Recommendations
Recommendation Evidence (Refs)
Optimal imaging and technique for the delivery of brachytherapy
1. For women receiving brachytherapy for cervical cancer, intra-procedure imaging is Strong Low
67
recommended if available.
2. For women receiving brachytherapy for cervical cancer, MRI or CT-based planning to a Strong Moderate
56,62,63,68-72
volume-based prescription is recommended.
3. For women receiving brachytherapy for cervical cancer, if volume-based planning cannot Strong Moderate
8,11-13,73
be performed, then 2-D/point-based planning is recommended.
Optimal dose/fractionation schedule for the delivery of brachytherapy
4. For women treated with definitive RT for cervical cancer, the total EQD210 of EBRT and Strong Moderate
56,74
brachytherapy should be
8000 cGy. (Table 9 in the full-text guideline)
5. For women with cervical cancer receiving volume-based brachytherapy, HR-CTV D90
greater than or equal to prescription dose (
8000 cGy) is conditionally recommended,
with careful consideration of normal tissue constraints. (Table 7)
Implementation remark:
 For patients with poor response or large-volume (>4 cm) disease, D90
8500 cGy is Conditional Moderate
57,75-77
reasonable.
 Utilization of a hybrid intracavitary/interstitial technique can help improve the dose
distribution when not achieving appropriate target and/or OAR dose constraints with an
intracavitary alone approach.
Optimal OAR constraints of brachytherapy
6. In women treated with brachytherapy for intact cervical cancer, volumetric contouring of Strong Moderate
60,63,72,77-79
the OARs and use of appropriate dose constraints are recommended.
7. If volumetric planning is not available for women treated with brachytherapy for intact Strong Moderate
8,11-13
cervical cancer, 2-D/point-based dose constraints should be applied.
Abbreviations: 2-D Z 2-dimensional; CT Z computed tomography; EBRT Z external beam radiation therapy; EQD210 Z dose calculation to an
equivalent dose of 2 Gy with an a-to-b ratio of 10; HR-CTV Z high-risk clinical target volume; MRI Z magnetic resonance imaging; OARs Z
organs at risk; RT Z radiation therapy.

Definitions for volume-based targets were estab- after EBRT or allow for optimal sparing of the sur-
lished by the GEC-ESTRO (Groupe Européen de rounding organs at risk (OARs). Supplemental interstitial
CuriethérapieeEuropean Society for Radiotherapy & needles in addition to standard tandem and ovoid or
Oncology),85 including the gross tumor volume, high- tandem and ring applicators may help optimize dose
risk clinical target volume, and intermediate-risk clin- distributions by allowing higher doses to targets, while
ical target volume (Table 8). Validation of these target still meeting normal OAR constraints.87
concepts comes from multiple retrospective and pro- Intraoperative imaging to evaluate the applicator
spective series. One of the largest of these studies, placement should be performed. Real-time guidance
retroEMBRACE, found that women treated with IGBT with either transabdominal or transrectal ultrasound is
had improved local control, reduced toxicity, and an easy to obtain and can reduce the risk of uterine
altered pattern of relapse relative to 2-D perforation.67
brachytherapy.56,62,64,66,72,86 Aside from improved Magnetic resonance imaging (MRI) and computed
local control rates, there is also prospective, though tomography (CT) are standard for brachytherapy treat-
nonrandomized, data indicating significantly reduced ment planning. MRI, however, provides superior soft
grade 3 to 4 toxicities in 3-D versus 2-D planned tissue definition, making it easier to visualize the cervix
patients treated with chemoradiation for locally and residual disease compared with CT imaging. Com-
advanced disease (2.6% versus 22.7%, P < .002).63 parisons of MRI versus CT-based planning reveal
Taken together these studies support improved out- similar OAR doses, but CT may overestimate the tumor
comes and reduced toxicities when using an image- width compared with MRI, particularly in advanced
based brachytherapy approach. disease.69,88
Standard tandem and ovoid/ring/mold applicators may The combined prescription dose calculation to an
not always adequately cover the residual extent of disease equivalent dose of 2 Gy with an a-to-b ratio of 10
Practical Radiation Oncology: --- 2020 ASTRO cervical cancer guideline 11

Figure 3 Locally advanced cervical cancer algorithm. Abbreviations: 2-D Z 2-dimensional; BT Z brachytherapy; EBRT Z external
beam radiation therapy; EQD2 Z equivalent dose at 2 Gy per fraction; HR-CTV Z high-risk clinical target volume; OAR Z organ at risk.

(EQD210) of EBRT and brachytherapy should be
8000 For cervical cancer brachytherapy, OARs include the
to 8500 cGy, with doses
8500 cGy for tumors with bladder, rectum, sigmoid/bowel, and vagina. The dose
poor response to EBRT or adenocarcinoma histology or volumeeeffect relationships for predicting late rectal
for stage III disease at presentation. Suggested brachy- morbidity indicate a threshold rectal D2cc be kept to
therapy doses in combination with EBRT are listed in 6500 cGy.58 In regard to high-grade toxicity, the fistula
Table 9 in the full-text guideline. risk was 12.5% at 3 years for patients who received a
12 J. Chino et al Practical Radiation Oncology: --- 2020

Table 7 Dose constraints

Organ at risk Ideal dose Maximum* dose ICRU point (cGy) References
constraint (cGy) constraint (cGy) (EQD23)
(EQD23) (EQD23)
Rectum <6500 D2cc <7500 D2cc <7500 point dose 58,65,78,80,81

Bladder <8000 D2cc <9000 D2cc <9000 point dose 78,80-82

Vagina (recto-vaginal point)y <6500 point dose <7500 point dose d 59,60

Sigmoidz <7000 D2cc <7500 D2cc d 83

Bowelz <7000 D2cc <7500 D2ccy d 83,84

Abbreviations: ICRU Z International Commission of Radiation Units and Measurements; EQD23 Z dose calculation to an equivalent dose of 2 Gy
with an a-to-b ratio of 3. D2cc is the minimal dose to the 2 cm3 (2 mL) of the organ at risk receiving the maximal dose.
* There will be occasions when exceeding these maximum constraints is necessary to adequately treat the targets of therapy, according to the
clinical judgment of the treating physician.
y
The rectovaginal point is defined 5 mm posterior to the vaginal mucosa from the center of the vaginal sources.
z
Dose constraints for sigmoid and bowel are based largely on expert opinion because there is minimal evidence of a dose response.

D2cc dose
7500 cGy compared with 0 to 2.7% for IMRT and IGBT are effective at reducing normal tissue
patients receiving lower doses. Single-institution data toxicity and allow for dose escalation to residual disease
suggest limiting the bladder D2cc to 8000 cGy.82 The in the central pelvis (in the case of brachytherapy) or
EMBRACE study also shows that vaginal stenosis is positive nodes (in the case of IMRT). All these factors
correlated with the dose to the rectovaginal point (20% at have resulted in safer and more effective treatment for
6500 cGy, 27% at 7500 cGy, and 34% at 8500 cGy) and women with this disease.
proposes that this point be kept to 6500 cGy.59,60
Although OAR sparing is expected to improve quality Acknowledgements
of life for many women, control of the cervical tumor
continues to be of primary importance. In situations in
which OAR constraints cannot be met despite best efforts, We are grateful to Yimin Geng, MSLIS, MS, the
tumor coverage may be prioritized after careful discussion University of Texas MD Anderson research medical
with the patient. librarian, for her assistance with creating the search
strategy for this guideline. The task force also thanks
Elisha Fredman, MD, Sarah Hazell, MD, Blair Mur-
Conclusions phy, MD, Steven Seyedin, MD, Sarah Stephens, MD,
and Michael Stolten, MD, for literature review
Radiation is an integral part of the management of assistance.
locally advanced disease, either as an adjuvant treatment The task force thanks the peer reviewers for their
after surgery in the presence of risk factors or as a primary comments and time spent reviewing the guideline. See
curative treatment, used in combination with chemo- Appendix 1 in the full-text guideline for their names and
therapy and a brachytherapy boost to the primary site. disclosures.

Table 8 Target volume definitions for image guided brachytherapy81

Volume Components Dose goals
GTV Gross tumor at the time of brachytherapy, determined At a minimum, dose should be
8000 cGy
by imaging or examination
HR-CTV GTV, the entire cervix, and regions of indeterminate D90
8000 cGy, with consideration of escalation for
T2-weighted MRI signal (ie, gray zones) advanced disease or poor response to initial therapy
IR-CTV HR-CTV with an asymmetrical expansion,* not Optional: D90
6000 cGy, with consideration of
extending into OARs, and including sites of initial escalation for advanced disease
disease involvement
Abbreviations: GTV Z gross tumor volume; HR-CTV Z high-risk target volume; IR-CTV Z intermediate-risk target volume; MRI Z magnetic
resonance imaging; OARs Z organs at risk.
* The IR-CTV expansion is 0.5-1.0 cm globally with an additional 0.5 cm superiorly into the uterus, inferiorly into the vagina, and laterally in
bilateral paracervical tissues.
Practical Radiation Oncology: --- 2020 ASTRO cervical cancer guideline 13

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