ASTRO Rectal Guideline

Radiation Therapy for Rectal Cancer: An
ASTRO Clinical Practice Guideline
Jennifer Y. Wo, MD,a Christopher J. Anker, MD,b Jonathan B. Ashman,

MD, PhD,c Nishin A. Bhadkamkar, MD,d Lisa Bradfield, BAe Daniel T.
Chang, MD,f Jennifer Dorth, MD,g Julio Garcia-Aguilar, MD,h David
Goff,i Dustin Jacqmin, PhD,j Patrick Kelly, MD,k Neil B. Newman, MD,
MSl Jeffrey Olsen, MD,m Ann C. Raldow, MD, MPH,n Erika Ruiz-Garcia,
MD,o Karyn B. Stitzenberg, MD,p Charles R. Thomas, Jr, MD,q Q.
Jackie Wu, PhD,r and Prajnan Das, MD, MS, MPHs
a. Massachusetts General Hospital, Boston, Massachusetts, Department of Radiation Oncology

b. University of Vermont Cancer Center, Burlington, Vermont, Division of Radiation Oncology
c. Mayo Clinic, Phoenix, Arizona, Department of Radiation Oncology
d. MD Anderson Cancer Center, Houston, Texas, Department of General Oncology
e. American Society for Radiation Oncology, Arlington, Virginia
f. Stanford University, Stanford, California, Department of Radiation Oncology
g. University Hospitals, Seidman Cancer Center, Cleveland, Ohio, Department of Radiation Oncology
h. Memorial Sloan Kettering Cancer Center, New York, New York, Department of Colorectal Surgery
i. Patient Representative, Las Cruces, New Mexico
j. University of Wisconsin, Madison, Wisconsin, Department of Human Oncology
k. Orlando Health, Orlando, Florida, Department of Radiation Oncology
l. Vanderbilt University Medical Center, Nashville, Tennessee, Department of Radiation Oncology
m. University of Colorado, Aurora, Colorado, Department of Radiation Oncology
n. University of California, Los Angeles, California, Department of Radiation Oncology
o. Instituto Nacional de Cancerologia, Mexico City, Mexico, Department of Medical Oncology
p. University of North Carolina, Chapel Hill, North Carolina, Department of Surgery
q. Oregon Health & Science University, Portland, Oregon, Department of Radiation Oncology
r. Duke University, Durham, North Carolina, Department of Radiation Oncology
s. MD Anderson Cancer Center, Houston, Texas, Department of Radiation Oncology
Source of support: This work was funded by the American Society for Radiation Oncology.
* Corresponding author: Prajnan Das, MD, MS, MPH; Email: PrajDas@mdanderson.org
Online supplements are not copyedited, and the authors are responsibility for the accuracy of the data.
J.Y. Wo et al ASTRO Rectal Cancer Guideline Practical Radiation Oncology 2020
Task Force Members’ Disclosure Statements
All task force members’ disclosure statements were reviewed before being invited and were shared with other
task force members throughout the guideline’s development. Those disclosures are published within this report.
Where potential conflicts were detected, remedial measures to address them were taken.
Christopher Anker: International Journal of Radiation Oncology, Biology, and Physics (associate senior editor),
Lake Champlain Cancer Research Organization and J. Walter Juckett Cancer Research Foundation (research
grant), National Cancer Institute (NCI) Rectal-Anal Task Force (member); Northern New England Clinical
Oncology Society (research grants, honoraria, travel expenses), Susan G. Komen Foundation (research grant),
Syntactx (honoraria - data safety monitoring board for pancreatic cancer trial); Daniel Chang: Varian (research
grants honoraria, travel expenses), ViewRay (stock); Prajnan Das (chair): ASTRO, MD Anderson Cancer Center
Madrid, NCI/Leidos (honoraria), NCI Rectal-Anal Task Force vice chair; Dustin Jacqmin: Asto CT, WePassed LLC
(consultant, honoraria – Initiated June 2020, during final approval); Patrick Kelly: Viewray (research grant);
Jeffrey Olsen: International Journal of Radiation Oncology, Biology, and Physics (associate editor); Syntactx
Clinical Events Committee chair (Initiated April 2020, after draft development); Ann Raldow: Clarity PSO/RO-ILS
Radiation Oncology Healthcare Advisory Board (consultant, honoraria), Intelligent Automation (consultant),
ViewRay (research grant); Karyn Stitzenberg (Society of Surgical Oncology representative): Johnson and
Johnson, Merck, Pfizer, Myriad Genetics, United Healthcare, Vertex Pharmaceuticals, Mygen (all stocks); Q.
Jackie Wu: NIH/NCI, Varian (research grants). Jonathan Ashman, Nishin Bhadkamkar (American Society for
Clinical Oncology representative), Lisa Bradfield, Jennifer Dorth, Julio Garcia-Aguilar (Society of Surgical
Oncology representative), David Goff (patient representative), Neil Newman, Erika Ruiz-Garcia (American
Society for Clinical Oncology representative), Charles Thomas, and Jennifer Wo (vice chair) 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 developments that are not
reflected in this guideline and that may, over time, be a basis for ASTRO to revisit and update the guideline.
2
Table of Contents
Preamble .......................................................................................................................................... 4
1. Introduction .................................................................................................................................. 6
2. Methods ........................................................................................................................................ 6
2.1. Task Force Composition............................................................................................................... 6
2.2. Document Review and Approval ................................................................................................. 6
2.3. Evidence Review .......................................................................................................................... 6
2.4. Scope of the Guideline ................................................................................................................ 7
3. Key Questions and Recommendations .......................................................................................... 9
3.1. Key Question 1: Indications for neoadjuvant RT (Table 3) ........................................................... 9
3.2. Key Question 2: Neoadjuvant regimens (Table 4) ..................................................................... 11
3.3. Key Question 3: Nonoperative and local excision approaches (Table 5) ................................... 15
3.4. Key Question 4: Treatment volumes, dose-constraints, and techniques (Table 6) .................... 19
4. Conclusions ................................................................................................................................. 21
5. Acknowledgements ..................................................................................................................... 21
Figure 1. PRISMA Diagram............................................................................................................... 22
References ...................................................................................................................................... 23
Appendix 1. Peer Reviewers and Disclosures (Comprehensive) ....................................................... 29
Appendix 2. Abbreviations .............................................................................................................. 31
Appendix 3. Literature Search Strategy ........................................................................................... 32
3
Preamble
As the leading organization in radiation oncology, the American Society for Radiation Oncology (ASTRO) is
dedicated to improving quality of care and patient outcomes. A cornerstone of this goal is the development and
dissemination of clinical practice guidelines based on systematic methods to evaluate and classify evidence,
combined with a focus on patient-centric care and shared decision-making. ASTRO develops and publishes
guidelines without commercial support, and members volunteer their time.
Disclosure Policy — ASTRO has detailed policies and procedures related to disclosure and management of
industry relationships to avoid actual, potential, or perceived conflicts of interest. All task force members are
required to disclose industry relationships and personal interests from 12 months before initiation of the writing
effort. Disclosures go through a review process with final approval by ASTRO’s Conflict of Interest Review
Committee. For the purposes of full transparency, task force members’ comprehensive disclosure information is
included in this publication. The complete disclosure policy for formal papers is online.
Selection of Task Force Members — ASTRO’s Guideline Subcommittee strives to avoid bias by selecting a
multidisciplinary group of experts with variation in geographic region, gender, ethnicity, race, practice setting,
and areas of expertise. Representatives from organizations and professional societies with related interests and
expertise are also invited to serve on the task force.
Methodology — The task force uses evidence-based methodologies to develop guideline recommendations in
accordance with the National Academy of Medicine standards. The evidence identified from key questions (KQs)
is assessed using the Population, Intervention, Comparator, Outcome, Timing, Setting (PICOTS) framework. A
systematic review of the KQs is completed, which includes creation of evidence tables that summarize the
evidence base task force members use to formulate recommendations. Table 1 describes ASTRO’s
recommendation grading system.
Consensus Development — Consensus is evaluated using a modified Delphi approach. Task force members
confidentially indicate their level of agreement on each recommendation based on a 5-point Likert scale, from
“strongly agree” to “strongly disagree”. A prespecified threshold of ≥75% (≥90% for expert opinion
recommendations) of raters that select “strongly agree” or “agree” indicates consensus is achieved.
Recommendation(s) that do not meet this threshold are removed or revised. Recommendations edited in
response to task force or reviewer comments are resurveyed before submission of the document for approval.
Annual Evaluation and Updates — Guidelines are evaluated annually beginning 2 years after publication for
new potentially practice-changing studies that could result in a guideline update. In addition, the Guideline
Subcommittee will commission a replacement or reaffirmation within 5 years of publication.
4
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, or expert Should”
recommended choice. opinion)
• Benefits are finely balanced with risks and burden or
appreciable uncertainty exists about the magnitude
of benefits and risks. Any
• Most informed people would choose the (usually moderate, “Conditionally
Conditional
recommended course of action, but a substantial low, or expert Recommend”
number would not. opinion)
• A shared decision-making approach regarding patient
values and preferences is particularly important.
Overall QoE Grade Type/Quality of Study Evidence Interpretation

The true effect is very likely to lie close to the
• 2 or more well-conducted and highly generalizable
High estimate of the effect based on the body of
RCTs or meta-analyses of such trials.
evidence.
• 1 well-conducted and highly generalizable RCT or a
meta-analysis of such trials OR The true effect is likely to be close to the
• 2 or more RCTs with some weaknesses of procedure estimate of the effect based on the body of
Moderate
or generalizability OR evidence, but it is possible that it is
• 2 or more strong observational studies with substantially different.
consistent findings.
• 1 RCT with some weaknesses of procedure or
generalizability OR
The true effect may be substantially different
• 1 or more RCTs with serious deficiencies of
from the estimate of the effect. There is a risk
procedure or generalizability or extremely small
Low that future research may significantly alter
sample sizes OR
the estimate of the effect size or the
• 2 or more observational studies with inconsistent
interpretation of the results.
findings, small sample sizes, or other problems that
potentially confound interpretation of data.
Strong consensus (≥90%) of the panel guides
• Consensus of the panel based on clinical judgment the recommendation despite insufficient
Expert Opinion* and experience, due to absence of evidence or evidence to discern the true magnitude and
limitations in evidence. direction of the net effect. Further research
may better inform the topic.
Abbreviations: ASTRO = American Society for Radiation Oncology QoE = quality of evidence; RCT = randomized controlled
trial.
*
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.
5
1. Introduction
Colorectal cancer has consistently been one of the top 3 causes of cancer incidence and mortality in the
United States. Rectal adenocarcinomas represent about one-third of all colorectal cancers, with an estimated
incidence of 43,340 cases in the United States in 2020.1 The incidence of rectal cancer has been increasing
among young adults, leading to heightened interest in this disease.2 For many years, preoperative radiation
therapy (RT) has widely been accepted as standard of care for locally advanced rectal cancer, with either
standard fractionated chemoradiation (5000-5400 cGy in 180-200 cGy per fraction) or short-course RT (2500 cGy
in 500 cGy per fraction). However, many questions remain about the optimal role of RT for rectal cancer,
including indications, appropriate radiation regimens, role in nonoperative/local excision (LE) approaches, and
treatment techniques. ASTRO previously developed a clinical document addressing some of these issues.3
Subsequently, the treatment approach to rectal cancer has continued to evolve, with increasing interest in total
neoadjuvant therapy (TNT), nonoperative management (NOM), and selective use of RT. Therefore, ASTRO
commissioned a task force to formulate evidence-based recommendations for 4 clinical key questions (KQs)
regarding the use of RT for rectal cancer.
2. Methods
2.1. Task Force Composition

The task force consisted of a multidisciplinary team of radiation, medical, and surgical oncologists,
medical physicists; a radiation oncology resident; and a patient representative. This guideline was developed in
collaboration with the American Society of Clinical Oncology and the Society of Surgical Oncology, who provided
representatives and peer reviewers.
2.2. Document Review and Approval

The guideline was reviewed by 19 official peer reviewers and revised accordingly. The modified
guideline was posted on the ASTRO website for public comment in April 2020. The final guideline was approved
by the ASTRO Board of Directors and endorsed by the American College of Radiology, Canadian Association of
Radiation Oncology, European Society for Radiotherapy and Oncology, the Royal Australian and New Zealand
College of Radiologists and the Society of Surgical Oncology.
2.3. Evidence Review

A systematic search of human subject studies retrieved from the database MEDLINE (through PubMed)
was conducted. The inclusion criteria required studies to be published in English, from January 1999 through
April 2019. It built upon a previous search of rectal cancer that included articles through July 2013 that were
identified in PubMed, Embase, and the Cochrane Library. For the current guideline, the included studies
evaluated adults with a diagnosis of operable primary rectal cancer treated with or without neoadjuvant therapy
6
and either surgery or a nonoperative approach. For KQ1 and KQ2, the evidence base was restricted mostly to
randomized controlled trials (RCTs) and meta-analyses. A small number of nonrandomized prospective studies
with ≥50 patients were also included to address areas not covered by RCTs. For KQ3, RCTs, meta-analyses,
prospective trials with ≥50 patients, and retrospective studies with ≥200 patients were included. For topics not
well-addressed by prospective data, retrospective studies with ≥50 patients were considered. For KQ4, the
evidence base consisted of RCTs, meta-analyses, prospective trials with ≥100 patients, retrospective studies with
≥150 patients, and dosimetric studies with ≥50 patients (≥10 patients for those looking at patient setup). The
following concepts common to all KQs were searched using Medical Subject Heading (MeSH) terms and key
search terms were used: rectal cancer, rectal neoplasms[MeSH], radiation; radiotherapy[MeSH],
chemoradiation, chemoradiotherapy and chemoradiotherapy[MeSH]. Additional terms specific to the KQs and
hand searches supplemented the electronic searches.
The data used by the task force to formulate recommendations are summarized in evidence tables
available in the supplementary materials (https://doi.org/10.1016/j.prro.2020.08.004). References selected and
published in this document are representative and not all-inclusive. The outcomes of interest are listed in
Table 2.
See Figure 1 for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
diagram showing the number of articles screened, excluded, and included in the evidence review; Appendix 1
(peer reviewer’s disclosure information); Appendix 2 (list of abbreviations); and Appendix 3 (literature search
strategy).
2.4. Scope of the Guideline

This guideline covers only the subjects specified in the KQs (Table 2). Outside the scope of this guideline
are many other important questions that may be subjects of other guidelines, including indications, dose and
technique for adjuvant therapy, RT in the setting of oligometastatic disease, locally recurrent disease, palliative
RT, contact RT, proton RT, intraoperative RT, re-irradiation, and detailed discussions of surgical approaches and
chemotherapy regimens. While outside the scope of this guideline, efforts to proactively address potential
survivorship issues including fertility and sexual dysfunction should be made, especially given the increasing
incidence of rectal cancer among young adults.
Table 2. KQs in Population, Intervention, Comparator, Outcome (PICO) format
KQ Population Intervention Comparator Outcomes

1 What are the indications for neoadjuvant RT for operable rectal cancer?
Patients with • Long-course preop RT • Surgery alone • Overall survival
pathologically • Long-course preop • Postop RT • Local control
confirmed rectal chemoradiation • Disease-free survival
cancer • Short-course preop RT • Sphincter preservation
• Acute and late grade ≥3
toxicity
2 What neoadjuvant regimens are appropriate for patients with operable rectal cancer?
7
Patients with • Preop short-course RT followed • Preop long-course • Overall survival

pathologically by surgery and postop chemo chemoradiation • Local control
confirmed operable • Preop short-course RT followed followed by surgery • Disease-free survival
rectal cancer by chemo followed by surgery and postop chemo • Pathologic complete
• Preop long-course • Neoadjuvant strategy response
chemoradiation followed by with long interval to • Sphincter preservation
chemo followed by surgery surgery • Acute and late grade ≥3
• Preop chemo followed by long- toxicity
course chemoradiation followed
by surgery
• Preop chemo followed by surgery
• Neoadjuvant strategy with short
interval to surgery
What are the appropriate indications for consideration of a nonoperative management (active surveillance) or local
3 excision approach after definitive/preop chemoradiation?
Patients with • Definitive chemoradiation Total mesorectal • Overall survival
operable rectal cancer • Active surveillance excision • Local control/regrowth
• Local excision • Disease-free survival
• Pathologic and clinical
complete response
• Sphincter preservation
• Salvage rate
toxicity
4 What are the appropriate treatment volumes, dose-constraints, and techniques for patients treated with RT?
Patients with • IMRT/VMAT Standard 3-D CRT with • Acute grade ≥3 GI
pathologically • 3-D CRT classic pelvic fields toxicity
confirmed operable • Elective lymph node coverage • Local control
rectal cancer • Dose escalated RT • Disease-free survival
toxicity
• HR-QoL
Abbreviations: 3-D CRT= 3-dimensional conformal radiation therapy; chemo = chemotherapy; GI = gastrointestinal; HR-QoL
= health-related quality of life; IMRT = intensity modulated radiation therapy; KQs = key questions; preop = preoperative;
postop = postoperative; RT = radiation therapy; VMAT = volumetric modulated arc therapy.
8
3. Key Questions and Recommendations
3.1. Key Question 1: Indications for neoadjuvant RT (Table 3)

See evidence tables in supplementary materials for the data supporting recommendations for KQ1.
What are the indications for neoadjuvant RT for operable rectal cancer?
Table 3. Recommendations for neoadjuvant RT indications

Strength of Quality of
KQ1 Recommendations
Recommendation Evidence (Refs)
1. For patients with rectal cancer, pelvic MRI with a rectal cancer Moderate
Strong
protocol is recommended for preoperative clinical T and N staging. 4-7
2. For patients with stage II-III rectal cancer, neoadjuvant RT is High

Strong
recommended. 8-15
3. For patients with stage II rectal cancer at lower risk of locoregional

recurrence, omission of neoadjuvant RT is conditionally
recommended after discussion with a multidisciplinary team.
Moderate
Conditional 6,7,12,16
Implementation remark: Lower risk is defined as a cT3a/b N0
tumor that is >10 cm from the anal verge* and with mrCRM ≥2
mm and no mrEMVI.
4. For patients with cT1-2N0 rectal cancer who may need an APR,
Expert Opinion
neoadjuvant chemoradiation is conditionally recommended to Conditional 17-19
improve the chance of sphincter preservation.
5. For patients with rectal cancer where radiation is indicated, RT High
Strong
should be performed preoperatively rather than postoperatively. 9-11,17-19
Abbreviations: APR = abdominoperineal resection; KQ = key question; mrCRM = MRI-determined circumferential resection
margin; mrEMVI = MRI-determined extramural vascular invasion; MRI = magnetic resonance imaging; RT = radiation
therapy.
* cT3a/b = 1 to 5 mm extramural tumor spread; tumor height should be surgeon defined.
Clinical staging, including physical examination with digital rectal examination (DRE) by an experienced
examiner and radiographic imaging, is critical to selecting the appropriate treatment pathway for patients with
rectal cancer. Pelvic magnetic resonance imaging (MRI) with a rectal cancer protocol is the primary imaging test
recommended to determine the clinical T and N stage.20 Endorectal ultrasound can be considered if MRI pelvis is
unavailable, contraindicated, or equivocal. The major phase 3 trials establishing the role of neoadjuvant RT did
not require MRI for study enrollment. However, in the years since those trials were designed, multiple
prospective studies have established the value of MRI to risk-stratify patients into subgroups who may not
require radiation or who may benefit from intensification of neoadjuvant treatment.4-7 The oncologic outcomes
of the prospective observational Mercury II study are pending and may provide additional evidence supporting
9
the value of MRI in treatment decision making for low rectal cancer.4 An important component of developing a
high-quality, MRI-based rectal cancer staging protocol is the implementation of a synoptic form to ensure
completeness of staging reports.21
For patients with clinical stage II-III rectal cancer, there is strong evidence to recommend neoadjuvant
RT. Multiple prospective trials have demonstrated that neoadjuvant RT decreases the risk of local recurrence,
even in the era of total mesorectal excision (TME).8-12 These results were confirmed by several meta-analyses,
which consistently found that the hazard ratio for local recurrence with RT was approximately 0.5 compared
with surgery alone.13-15 The long-term follow-up of the Dutch TME study identified an overall survival (OS)
benefit with preoperative RT in the subgroup of patients with stage III disease and negative circumferential
resection margins (CRMs), but this OS benefit was not observed in the entire study population.12
Despite the strong evidence supporting the use of neoadjuvant RT for patients with stage II-III rectal
cancer, a subset of patients may be at low risk for locoregional recurrence based on proximal tumor location and
MRI-determined “safe” CRM.6,7,12,16 Omission of neoadjuvant RT in favor of surgery alone may be considered in
these patients to avoid the acute and chronic toxicities associated with pelvic RT. Based on this moderate
evidence, a conditional recommendation may be made to omit neoadjuvant RT in favor of upfront surgery in
clinical stage IIA (cT3a/b N0) patients when the cancer is located >10 cm from the anal verge and there is a
predicted CRM ≥2 mm and the absence of extramural vascular invasion as determined by MRI with rectal cancer
protocol. Tumor height (low = 0 to <5 cm from the anal verge; mid = 5 to <10 cm; proximal ≥10 cm) should be
defined by the surgeon at initial diagnosis. This measurement is most accurately assessed by rigid proctoscopy,
but flexible endoscopy is more commonly performed in the modern office setting. A critical component of this
recommendation is the shared decision-making process within a multidisciplinary care team, high-quality
surgical resection (ie, TME with negative margins) and follow-up of final pathologic staging to determine
whether adjuvant therapy should be recommended in the setting of pathologic upstaging. Moving forward,
improved stratification of risk within stage II-III rectal cancer is required to further individualize the use of
neoadjuvant RT. Advancements in MRI will be central to this progress, including field strength, coil technology,
identification of novel MRI contrast agents, and multiparametric imaging.
Sphincter preservation is a major quality of life (QoL) objective for many patients. Two phase 3 trials and
a meta-analysis including those trials demonstrated that preoperative chemoradiation led to conversion of a
group of patients initially deemed to require an abdominoperineal resection to low anterior resection.17-19
However, this endpoint is subjective because it is based on the surgeon’s preoperative assessment of the need
for abdominoperineal resection, and the rate of sphincter preservation was ultimately equivalent in the
preoperative and postoperative arms. These trials included only stage II-III patients, for whom neoadjuvant RT is
already the standard of care. Based on an extrapolation of this evidence, neoadjuvant RT (with concurrent
chemotherapy) is conditionally recommended when sphincter preservation is being considered for a patient
with a clinical stage I (cT1-T2 N0) tumor in a distal location. However, patients with early-stage tumors have not
been shown to benefit from RT in terms of local control and preoperative RT may not result in sphincter
preservation. Thus, some patients with early-stage tumors may experience the acute and late toxicities of pelvic
radiation without a commensurate benefit.12
Three prospective trials randomizing patients between preoperative and postoperative chemoradiation
demonstrated improvements in disease-free survival and/or local recurrence-free survival with the preoperative
approach.9-11,17,18 One of these trials, the German rectal trial, also reported fewer acute and long-term toxicities
in the patients treated with preoperative chemoradiation.10,19 However, a fourth trial from Korea did not show
10
significant differences in either oncologic outcomes or toxicities.18 A meta-analysis, which included this Korean
trial, confirmed a significant reduction in local recurrence and acute toxicity in the patients treated
preoperatively.17 Therefore, when RT is indicated for rectal cancer, the evidence strongly supports a
recommendation favoring preoperative over postoperative treatment.
3.2. Key Question 2: Neoadjuvant regimens (Table 4)

See evidence tables in supplementary materials for the data supporting the recommendations for KQ2.
What are appropriate neoadjuvant regimens for operable rectal cancer when neoadjuvant therapy is
indicated?
Table 4. Recommendations for neoadjuvant regimens

KQ2 Recommendations
1. For patients with rectal cancer receiving neoadjuvant
chemoradiation, conventional fractionation from 5000-5040 cGy High
Strong
in 25-28 fractions with concurrent chemotherapy is 10,22,23
recommended.
2. For patients with rectal cancer receiving neoadjuvant short-course
High
RT, 2500 cGy in 5 fractions without concurrent chemotherapy is Strong 8,12
recommended.
3. For patients with rectal cancer undergoing neoadjuvant
High
chemoradiation, only concurrent 5-fluorouracil or capecitabine is Strong 22-29
recommended with RT for radiosensitization.
4. For patients with rectal cancer undergoing neoadjuvant therapy,
chemotherapy alone (FOLFOX or CAPOX) is conditionally Low
Conditional
recommended only in the context of a clinical trial or multi- 30
institutional registry.
5. For patients with rectal cancer undergoing neoadjuvant therapy
without tumor factors that portend increased recurrence risk, (1)
chemoradiation or (2) short-course RT are recommended.
High
Strong 8,12,31-36
Implementation remark: Risk factors for increased recurrence
include cT3 tumors ≤5 cm from the anal verge or mrCRM <2 mm;
cT4 tumor or cN2 disease, presence of mrEMVI.
without tumor factors that portend increased recurrence risk, Low
addition of multiagent (FOLFOX or CAPOX) chemotherapy (1) Conditional 5,37-41
before or after chemoradiation or (2) after short-course RT is
conditionally recommended.
11

cT4 or cN2 disease, presence of mrEMVI.
with tumor factors that portend increased recurrence risk,
addition of multiagent (FOLFOX or CAPOX) chemotherapy (1)
before or after chemoradiation or (2) after short-course RT is
conditionally recommended. Moderate
Conditional 5,25,37-41

cT4 or cN2 disease, presence of mrEMVI.
8. For patients with rectal cancer receiving neoadjuvant
chemotherapy as a component of a total neoadjuvant therapy
Moderate
strategy, 3-4 months of either FOLFOX or CAPOX (without Strong 38,41
additional agents, targeted therapy or immunotherapy) is
recommended.
9. For patients with rectal cancer undergoing neoadjuvant High
chemoradiation with no further neoadjuvant chemotherapy (≥6 weeks)
planned, an interval of 6-11 weeks from the end of 42-46
Strong
chemoradiation to surgery is recommended. Moderate
(6-11 weeks)
42-44,46
10. For patients with rectal cancer undergoing neoadjuvant short-

course RT with no further neoadjuvant chemotherapy planned, an
interval of either ≤3 days or 4-8 weeks from the end of RT to
surgery is recommended. Moderate
Strong 31,47
Implementation remark: An interval of 4-8 weeks is preferred for

patients who may benefit from tumor downstaging before
resection.
Abbreviations: CAPOX = capecitabine and oxaliplatin; FOLFOX = folinic acid, 5-Fluorouracil, and oxaliplatin; KQ = key
question; mrCRM = MRI-determined circumferential resection margin; mrEMVI = MRI-determined extramural vascular
invasion; RT = radiation therapy.
The German rectal trial10 established reduced risk of relapse and increased rates of sphincter-sparing
surgery with neoadjuvant conventionally fractionated chemoradiation to 5040 cGy in 28 fractions. Doses of 5000
cGy in 200 cGy fractions have also become a standard approach based on favorable outcomes in several
RCTs.18,22,23,46 A meta-analysis based on 5 RCTs revealed that while there is no improvement in survival, the
addition of concurrent chemotherapy to conventionally fractionated RT increases the 5-year local control and
pathologic complete response (pCR) rates compared with preoperative RT alone.22 This was confirmed by
another meta-analysis evaluating 7 RCTs which demonstrated that preoperative chemoradiation significantly
12
reduced the recurrence rate compared with preoperative RT alone,23 although there was no difference in distant
metastasis rate or OS. Based on these data, 5000 to 5040 cGy in 25 to 28 fractions with concurrent
chemotherapy is recommended for patients undergoing neoadjuvant conventionally fractionated RT. For
patients receiving conventionally fractionated treatment, after an initial 4500 cGy in 25 fractions delivered to
the pelvis, a boost of 540 cGy in 3 fractions to the tumor plus margin may be delivered to achieve 5040 cGy
composite dose to the tumor, involved mesorectum, and involved nodal regions.10
The Swedish rectal trial,8 which predated implementation of TME, randomized patients to
hypofractionated “short-course” RT before surgery compared with surgery alone. Both a local control and OS
benefit was observed for neoadjuvant radiation at a median follow-up of 13 years. This was confirmed by the
Dutch rectal study12 which utilized similar arms to the Swedish trial and confirmed a local control benefit for
short-course RT in the era of TME. These studies, as well as additional trials comparing neoadjuvant short-course
RT to long-course chemoradiation,33,48 establish 2500 cGy in 5 fractions without concurrent chemotherapy as a
standard of care for patients undergoing neoadjuvant short-course RT.
Among patients requiring neoadjuvant therapy, conventionally fractionated chemoradiation or short-
course RT are recommended equally, given high-quality evidence that either approach improves local control,8-12
and randomized studies suggesting similar efficacy and patient reported QoL outcomes for either
treatment.32,33,35,48 In a subset analysis of distal tumors (<5 cm from the anal verge) in the TROG randomized
trial, there appeared to be more local recurrences in the short-course RT arm compared with the conventionally
fractionated chemoradiation arm, but this difference was not statistically significant.33
Several RCTs have found no additional clinical benefit in terms of OS, disease-free survival, local control,
pCR rate, tumor downstaging, or rates of sphincter-sparing surgery with the addition of oxaliplatin to
neoadjuvant chemoradiation compared with standard 5-fluorouracil (5-FU) or capecitabine with RT.27,28,49
Addition of oxaliplatin in these RCTs, however, was noted to markedly increase the rates of diarrhea such as in
the NSABP R-04 study28 or grade 3 or 4 adverse events, such as in the STAR-01 study.49 These results were not
uniformly noted across all studies, however, as the German CAO/ARO/AIO-04 study demonstrated an increased
disease-free survival with the addition of oxaliplatin, with suggestion of a survival benefit in younger
patients.50,51 A single arm phase 2 study found the addition of bevacizumab to S-1 chemotherapy increased
postoperative toxicity without clinical benefit.29 Weighing results of the CAO/ARO/AIO-04 study against other
trials, there is not sufficient evidence that the addition of other agents to 5-FU or capecitabine provides clinical
benefit in the neoadjuvant setting. Although only concurrent 5-FU or capecitabine are considered current
standard of care radiosensitizers during chemoradiation, trials such as the ongoing NRG-GI002 study
(NCT02921256) will evaluate addition of concurrent targeted therapies or immunotherapy to current standard
of care.
For patients requiring neoadjuvant therapy, use of neoadjuvant chemotherapy alone with selective use
of neoadjuvant RT is an ongoing area of research to avoid the potential toxicities of pelvic RT. Emerging data on
neoadjuvant chemotherapy alone in selected populations appears promising.30,52,53 The FOWARC study was
designed to compare the efficacy of 5-FU and leucovorin with RT versus mFOLFOX6 (folinic acid, 5-fluorouracil,
and oxaliplatin) with or without RT for the neoadjuvant treatment of locally advanced rectal cancer.30,54 The final
results have shown improved pCR with the inclusion of RT, with no significant differences in disease-free survival
or local recurrence rate, although the trial design did not allow for a noninferiority comparison.54 Given these
results, additional investigation of chemotherapy without RT is needed before a recommendation can be made
13
for this approach outside of a clinical trial or multi-institutional registry setting. Ongoing trials will provide
additional insight about this approach including the PROSPECT trial (NCT01515787).53
Several studies have evaluated potential benefits of a TNT approach, where multiagent (FOLFOX or
CAPOX (capecitabine and oxaliplatin)) chemotherapy is added before or after chemoradiation or after short-
course RT. Current prospective data suggest that addition of multiagent chemotherapy after chemoradiation in
the neoadjuvant setting improves downstaging38 and tolerability39,41 of chemotherapy compared with adjuvant
treatment, while observational data suggest a possible disease-free survival benefit for TNT.40 Possible risks of
TNT include delaying local treatment and potential over-treatment, in particular, for patients with stage II
disease without other risk factors for increased recurrence.
In this guideline, a TNT approach is conditionally recommended, but with differing qualities of evidence
based on risk factors for disease recurrence including clinical T4 or N2 stage, low (<5 cm) tumors, threatening of
the CRM, or presence of extramural vascular invasion as determined by MRI.4,33 For patients with lower risk
disease, preoperative chemoradiation or short-course RT is recommended, while a TNT approach is conditionally
recommended to improve tolerability of therapy, acknowledging a lower level of evidence in this setting and
possible risk of overtreatment. For patients with clinical factors that portend increased recurrence risk, TNT is
conditionally recommended with moderate-quality evidence. In this setting, there is a potential benefit from
earlier treatment of micrometastatic disease, and a downstaging benefit which may facilitate margin negative
resection, as well as improved tolerability of TNT compared with adjuvant chemotherapy. Patients with
persistent close circumferential margin after upfront chemoradiation or short-course RT may derive particular
downstaging benefit from addition of chemotherapy after radiation, although the long-term impact on clinical
outcome remains unclear. If a TNT approach is considered, addition of 3 to 4 months of FOLFOX or CAPOX
chemotherapy is consistent with evidence that suggest TNT has the potential to optimize compliance compared
with adjuvant chemotherapy, without compromising a patient’s risk of surgical complications.38,41,55 This
guideline allows for addition of FOLFOX or CAPOX chemotherapy to be given either before or after
chemoradiation or after short-course RT, acknowledging absence of outcome data to support a specific
sequence. For patients with threatened CRM or other high-risk features, delivery of RT or chemoradiation
before FOLFOX or CAPOX chemotherapy may improve the extent of downstaging, although absence of high-
quality data precludes recommendation of a specific sequence. Future studies will help to further establish risk
stratification groups, clarify the ideal regimen for rectal cancer in the neoadjuvant setting, and clarify the
optimal sequencing of chemotherapy and radiation in the setting of TNT.
The task force notes that recently published and presented studies provide additional information
regarding TNT. In the 2019 publication of the German CAO/ARO/AIO-12 trial, patients treated with
chemotherapy followed by chemoradiation had better compliance with chemotherapy, while patients treated
with chemoradiation followed by chemotherapy had better compliance with chemoradiation and higher pCR.55
The Rectal Cancer Followed by Pre-Operative Induction Therapy and Dedicated Operation (RAPIDO) trial
compared preoperative chemoradiation versus preoperative, short-course radiation therapy followed by CAPOX
or FOLFOX chemotherapy (NCT01558921). The PRODIGE 23 trial compared preoperative chemoradiation versus
FOLFIRINOX chemotherapy followed by preoperative chemoradiation (NCT0804790). Results from the RAPIDO
and PRODIGE 23 trials have been presented but not yet published. Since all 3 of these trials were outside the
inclusion criteria for this guideline, findings from these studies could not be incorporated into this guideline.
Further data from the RAPIDO, PRODIGE 23, and CAO/ARO/AIO-18 trials will provide additional information on
TNT-based approaches to better characterize potential advantages of this strategy.
14
The German rectal trial19 established a standard interval of 6 to 7 weeks between the completion of
neoadjuvant chemoradiation and surgical resection for patients with rectal cancer. Subsequently, retrospective
studies and at least 2 RCTs44,46 have examined the benefits of increasing this interval beyond 6 to 7 weeks. These
studies have suggested somewhat inconsistent findings. While some studies have suggested an increase in the
rate of pCR with an increased interval, the largest RCT, the GRECCAR-6 trial,46 did not demonstrate an
improvement in tumor downstaging. Moreover, increasing the interval between completion of chemoradiation
and surgery from 7 to 11 weeks resulted in increased perioperative complications and worse surgical quality,
based on fewer patients resected with a completely intact mesorectum. As a result of these conflicting findings,
the optimal interval between completion of neoadjuvant chemoradiation and surgical resection remains
uncertain. As such, this guideline recommends an interval of 6 to 11 weeks between completion of
chemoradiation and surgery for patients in whom no further neoadjuvant chemotherapy is planned,
acknowledging that there is strong evidence for waiting ≥6 weeks and moderate evidence to support an optimal
time frame within the 6 to 11 weeks window. Within this window, clinical judgment should be used to weigh the
potential benefits of a longer interval to improve tumor downstaging versus the potential increase in operative
complications that comes with this approach.
Traditionally, surgery was performed immediately (≤7 days) after the completion of neoadjuvant short-
course RT for rectal cancer.8,12 However, delaying surgery after short-course RT may allow for clinical
downstaging before resection. In the Stockholm III study,31 short-course RT with immediate surgery (≤7 days)
was compared with short-course RT with delayed surgery (4-8 weeks), and long-course RT (5000 cGy in 25
fractions) with delayed surgery (4 to 8 weeks). In a pooled secondary analysis of the short-course cohorts, no
differences were seen in the incidence of local failure, OS, or late complications between the immediate surgery
and delayed surgery cohorts. Subset analyses including data from the Dutch TME trial suggest reduced morbidity
for patients undergoing resection within 3 days of completion of short-course RT.47 Balancing outcomes from
Stockholm III against the volume of data in which short-course RT is followed by immediate surgery, a time
interval of ≤3 days, or 4 to 8 weeks, between completion of short-course RT and surgical resection is
recommended to allow for different clinical scenarios including the relative need for clinical downstaging.
3.3. Key Question 3: Nonoperative and local excision approaches (Table 5)

What are the appropriate indications for consideration of a nonoperative management (NOM) or LE approach
after definitive/preoperative chemoradiation?
Table 5. Recommendations for nonoperative or LE approaches

KQ3 Recommendations
1. NOM is conditionally recommended after multidisciplinary
Moderate
discussion if a cCR is achieved after neoadjuvant treatment in Conditional 56-59
patients with rectal cancer who:
15
a. would have a permanent colostomy or inadequate bowel

continence after TME AND
b. decline TME AND
c. agree to close follow-up by a multidisciplinary team.
2. Organ preservation through neoadjuvant chemoradiation followed
by LE is conditionally recommended after multidisciplinary
discussion for patients with cT2 N0 rectal cancer who:
a. would have a permanent colostomy or inadequate bowel
Conditional Moderate
continence after TME AND 60-62
b. decline TME AND
c. are found to have ≤ypT1 disease and R0 margins upon LE AND
d. agree to close follow-up by a multidisciplinary team.
3. For patients with rectal cancer considering NOM or LE after RT,
conventional fractionation from 5000-5400 cGy in 25-30 fractions Strong Moderate
56,60-62
with concurrent chemotherapy is recommended.
4. For patients with rectal cancer considering NOM, concurrent
chemoradiation with or without induction or consolidation Conditional Moderate
chemotherapy is conditionally recommended. 56-58,63
5. For patients with rectal cancer considering NOM, assessment for

response is recommended with rectal protocol MRI, CT
Strong Moderate
abdomen/pelvis, and proctoscopy/sigmoidoscopy with DRE 2-3 57,60,61,64
months after completion of treatment.
6. For patients with rectal cancer undergoing NOM or LE, surveillance
is recommended with:
• proctoscopy/sigmoidoscopy with DRE every 3 months for
the first 2 years, then every 6-12 months thereafter,
• rectal protocol MRI every 3-6 months for the first 2 years,
then every 6-12 months thereafter, and Moderate
Strong 57,60,61,64
• cross-sectional imaging of the chest, abdomen and pelvis
every 6-12 months for the first 2 years, then every 12
months thereafter.
Implementation remark: Follow-up should continue for a minimum

of 5 years.
Abbreviations: cCR = complete clinical response; CT = computed tomography; DRE = digital rectal examination; LE = local
excision; KQ = key question; MRI = magnetic resonance imaging; NOM = nonoperative management; RT = radiation
therapy; TME = total mesorectal excision.
There are increasing data indicating the safety and feasibility of NOM after a complete clinical response
(cCR) to neoadjuvant therapy.56-58,65-67 However, given the rigor and nuance of the required follow-up, NOM
should preferably be pursued at centers with experienced multidisciplinary teams. In a meta-analysis of NOM
after a cCR, the majority of patients avoided regrowth; the only factor associated with regrowth was increasing
16
T-stage.56 Several series have reported a distant metastasis rate between 5% to 9%63,68-70 among patients with an
initial cCR who underwent NOM. While a recent retrospective study showed that most distant metastases were
found in patients who also had local tumor regrowth,63 the overall rate of distant metastases and the OS rate in
patients undergoing NOM after cCR were no different from patients undergoing TME that had a pCR.58 Given the
potential QoL benefits noted with NOM compared with standard treatment59 and patient interest in these QoL
benefits,71 NOM offers a potentially appealing option to discuss with patients during the shared decision-making
process, especially for those who would have a permanent colostomy or inadequate bowel continence after
TME, and decline TME. Although data on NOM are encouraging, it is only moderate quality given the lack of
RCTs comparing NOM to standard surgery, leading to the conditional recommendation for NOM.
Selected patients with cT2N0 rectal cancer may be treated with preoperative chemoradiation followed
by restaging and transanal LE, instead of TME, thus allowing functional organ preservation. Ideal candidates are
those with distally (<8-10 cm from the anal verge) located invasive tumors, favorable histology, and size <4
cm.60-62 In such cases, it is critical that LE is performed by surgeons experienced with transanal LE techniques,
preferably at centers with experienced multidisciplinary teams. Multi-institutional phase 2 and 3 trials support
this approach, with 1 trial not requiring TME if ypT2 disease was found (ACOSOG Z604161), and 2 trials requiring
TME if ypT2-3 disease was found in the surgical specimen (GRECCAR 2,60 CARTS62). Therefore, organ preservation
through neoadjuvant chemoradiation followed by LE is conditionally recommended for patients with cT2 N0
rectal cancer who are subsequently found to have ≤ypT1 disease and R0 margins (defined as ≤1 mm) upon LE
who also agree to close follow-up by a multidisciplinary team. It is important to note, however, TME conversion
after LE for ypT2-3 may lead to major complications and poor functional outcomes.60,62 Although there are data
on LE that include patients with cT3 and/or cN+ disease, such data are limited.60,62,72-74 If organ preservation is
desired for patients with cT3 and/or cN+ disease, QoL might be best served by instead pursuing NOM for those
who achieve cCR.75 Functional outcomes and QoL are variably impacted by chemoradiation and LE depending on
the neoadjuvant regimen, patient gender and tumor distance from the anal verge.62,76
The majority of series of NOM utilized RT doses between 4500 to 5400 cGy.56,60,68,77 While some studies
report high rates of cCR with radiation dose escalation, they have been limited in size, demonstrate early signs
of increased toxicity such as rectal bleeding, and do not report long-term patient-reported QoL outcomes.78,79
Although dose has not been shown to affect local regrowth,56 as most NOM series involved at least 5000 cGy, a
dose of 5000 to 5400 cGy is recommended. In the setting of LE, although a higher rate of toxicity was noted with
5400 cGy compared with 5040 cGy in the ACOSOG trial, this may have been instead due to the concurrent
oxaliplatin.28,49,61,80 Other prospective series have not reported an increased toxicity with 5400 cGy; therefore,
doses between 5000 to 5400 cGy are recommended for both NOM and LE.60,62,74,75 Short-course RT without
chemotherapy is not routinely recommended as part of NOM because of limited data81 and some data
suggesting that it may result in lower cCR rates; however, it could be considered in the setting of a clinical trial.82
However, there are data noting similar oncologic and QoL outcomes with neoadjuvant short-course RT followed
by chemotherapy as compared with long-course chemoradiation when TME is part of the treatment plan.25,40 At
this time, NOM via sequential short-course RT and chemotherapy is recommended only in the setting of a
cancer registry or clinical trial.
NOM has typically involved long-course RT with concurrent chemotherapy, either alone56-58,64,66,70,77,83 or
with induction or consolidation chemotherapy.56-58,63,66,70 For cT1-2N0 patients, there are insufficient data to
support the practice of additional chemotherapy before or after CRT. Although there is evidence of an increased
pCR rate with a TNT approach for cT3 or node-positive patients,61,84 given that no superiority of any
17
chemoradiation regimen has been determined for NOM for oncologic control or QoL outcomes, all of these
options are conditionally recommended. The Organ Preservation in Rectal Adenocarcinoma (OPRA,
NCT02008656) trial has compared chemoradiation followed by chemotherapy versus chemotherapy followed by
chemoradiation in the setting of NOM. The results from the OPRA trial have been presented but not yet
published, so the findings could not be incorporated into this guideline. Longer-term, prospective, and ideally
randomized data are needed to both confirm the initial oncologic and QoL results with NOM and to help
determine the optimal neoadjuvant regimen.
The success of the NOM strategy is strongly dependent on proper patient assessment after neoadjuvant
therapy and strict follow-up surveillance. Tumor response to neoadjuvant chemoradiation may take longer than
originally thought, and patients with a near cCR may eventually convert to a full cCR.85 Therefore, response is
now typically assessed 2 to 3 months after completion of neoadjuvant therapy. The definition of cCR is based on
DRE, endoscopic features, and imaging studies, specifically rectal protocol MRI.56,57,64,83 On MRI, complete
response is characterized by a uniform dark scar on T2-weighted sequences, while restricted diffusion on
diffusion-weighted imaging and intermediate T2 signal are considered indications of persistent tumor. The
combination of the 3 diagnostic modalities (ie, DRE, flexible sigmoidoscopy and MRI) is able to identify
responders with a high degree of accuracy and should be included in the selection of patients for NOM.64 The
Magnetic Resonance Tumour Regression Grade as Biomarker for Stratified Management of Rectal Cancer
Patients (TRIGGER, NCT02704520) study is evaluating MRI tumor regression grading as a predictive biomarker
for NOM.
Organ preservation strategies are associated with increased risk of tumor regrowth in patients treated
with NOM, or local recurrence in patients treated with LE. If identified promptly, many of these patients could
be salvaged with curative intent surgery. Most regrowths and local recurrences occur in the bowel wall and can
be identified by DRE and/or flexible sigmoidoscopy.61,63 A few occur in the mesorectal nodes (<5% failure rate for
those undergoing NOM) and are only identified by imaging.70,85 As most tumor regrowths occur during the first 2
years, current NOM and LE protocols recommend DRE and flexible sigmoidoscopy every 3 months for the first 2
years and every 6 to 12 months for the following 3 years.60-62,64 Rectal protocol MRI is recommended every 3 to 6
months for the first 2 years and every 6 to 12 months for at least the following 3 years. In selected cases,
endorectal ultrasound may provide better visualization than MRI. As patients treated with organ preservation
are at risk of distant metastases, they should also have surveillance with cross sectional imaging of the chest,
abdomen and pelvis every 6 to 12 months for the first 2 years and then annually.86 The risk of local recurrence
for LE patients diminishes 5 years after treatment and therefore, routine imaging is not necessary beyond that
time.60,61 The long-term outcome of patients treated with NOM is currently unknown, and therefore registering
in a long-term survivorship and surveillance program is strongly encouraged.
18
3.4. Key Question 4: Treatment volumes, dose-constraints, and techniques

(Table 6)
What are the appropriate treatment volumes, dose-constraints, and techniques for patients treated with RT?
Table 6. Recommendations for appropriate treatment volumes and techniques

KQ4 Recommendations
1. For patients with cT3-4 and/or cN + rectal cancers, inclusion of the
High
rectum, mesorectal nodes, presacral nodes, internal iliac nodes, Strong 87,88
and obturator nodes in the CTV is recommended.
2. For patients with rectal tumors invading an anterior organ or
structure (eg, prostate, seminal vesicles, cervix, vagina, and/or
Low
bladder), inclusion of the external iliac nodes in the CTV is Conditional 88
conditionally recommended in addition to the rectum, mesorectal
nodes, presacral nodes, internal iliac nodes, and obturator nodes.
3. For patients with rectal cancer involving the anal canal, inclusion of
inguinal and external iliac nodes in the CTV is conditionally
Conditional Expert Opinion
recommended in addition to the rectum, mesorectal nodes,
presacral nodes, internal iliac nodes, and obturator nodes.
4. For patients with rectal cancer treated with RT, an IMRT/VMAT
technique is conditionally recommended.
Low
Implementation remark: IMRT/VMAT may be beneficial when the Conditional 89-94
external iliac nodes and/or the inguinal nodes require treatment or
when 3-D conformal techniques may confer a higher risk for
toxicity.
5. For patients with rectal cancer receiving IMRT/VMAT, daily image
Conditional Expert Opinion
guidance to verify localization is conditionally recommended.
6. For patients with rectal cancer in whom the CTV does not include
Low
the inguinal nodes, simulation prone with a belly board is Conditional 95-97
Abbreviations: 3-D = 3-dimensional; CTV = clinical target volume; IMRT = intensity modulated radiation therapy; KQ = key
question; RT = radiation therapy; VMAT = volumetric modulated arc therapy.
For patients with cT3-4 and/or cN + rectal cancers, the task force recommends including the rectum,
mesorectal nodes, presacral nodes, internal iliac nodes, and obturator nodes in the clinical target volume (CTV).
Pooled analyses have demonstrated that these sites are at increased risk of local recurrence for patients with
locally advanced rectal cancer.87,88 For further clarification in specific clinical scenarios, international guidelines
for optimal target delineation for rectal cancer are available.98 Generally, similar considerations should be given
19
to treatment volumes and treatment techniques for both conventionally fractionated chemoradiation and short-
course RT.
Similar analyses have shown that if the primary tumor invades anterior structures or organs, nodal
drainage may extend via the lymphatics of the involved organ.88 Therefore, for patients with rectal tumors
invading the prostate, seminal vesicles, cervix, vagina, and/or bladder, inclusion of the external iliac nodes in
addition to the rectum, mesorectal nodes, presacral nodes, internal iliac nodes, and obturator nodes is
Although lesions that extend to the anal canal can spread to the inguinal and external iliac nodes,
limited data supports the inclusion of these lymph node regions in the CTV for patients with rectal cancer
involving the anal canal.88,99 While some data may suggest low rates of inguinal recurrence, for patients with
rectal tumors that extend into the anal canal, inclusion of the inguinal and external iliac nodes in addition to the
rectum, mesorectal nodes, presacral nodes, internal iliac nodes, and obturator nodes is conditionally
recommended.
Modulated RT techniques like intensity modulated radiation therapy (IMRT) and volumetric modulated
arc therapy (VMAT) have the potential to reduce treatment-associated side effects to bladder, large bowel and
small bowel by reducing the dose to these organs. In the RTOG 0822 phase 2 trial100 of preoperative
chemoradiation, using IMRT in combination with capecitabine and oxaliplatin did not reduce the rate of
gastrointestinal toxicity compared with conventional radiation in a prior trial, RTOG 0247.101 Of note, the RTOG
0822 trial used concurrent capecitabine and oxaliplatin, which is not the current standard. A meta-analysis
found that IMRT lowered the incidence of grade ≥2 acute toxicity for overall gastrointestinal toxicity, as well for
diarrhea and proctitis.89 Additional studies report that IMRT and VMAT result in reduced toxicity versus 3-
dimensional conformal radiation therapy (3-D CRT).90-94 The effect seems to be more consistent for diarrhea and
genitourinary toxicities compared with other endpoints. The use of modulated RT techniques does not appear to
affect tumor control. Therefore, the task force felt the evidence of improved toxicity is sufficient to make a
conditional recommendation for the use of IMRT or VMAT over 3-D CRT, particularly when the external iliac
nodes with or without the inguinal nodes require treatment or when 3-D CRT techniques may confer a higher
risk for toxicity.
Modern planning techniques like 3-D CRT and IMRT/VMAT produce plans that are more conformal but
less robust to daily variations in setup. This is particularly true of IMRT/VMAT because of the creation of concave
dose distributions designed precisely to follow the contour of the target and spare critical structures.
Recognizing the lack of published data, the task force conditionally recommends daily image guidance for
patients with rectal cancer receiving IMRT/VMAT. Image guidance with volumetric imaging (eg, cone-beam and
megavoltage computed tomography) can help account for differences in bladder filling, rectal filling, and
movement of the small bowel. Daily alignment to bony anatomy using planar orthogonal imaging is acceptable if
planning margins are sufficient to mitigate daily variations in soft tissue anatomy.
The choice of patient positioning is an important consideration in the treatment of rectal cancer.95-97
Patient positioning can affect the relative positions of the target and normal tissues. Furthermore, patient
positioning decisions can also affect setup reproducibility during treatment. Options for patient positioning
include supine and prone. The decision to treat supine or prone impacts the positioning of the peritoneal cavity
and small bowel more than other organs at risk. The belly board can position abdominal organs more superiorly,
displacing some of the small bowel out of the treatment field. A study of rectal cancer patients comparing prone
and supine positioning showed that prone positioning with a belly board reduces overlap between the small
20
bowel and the planning target volume, relative to supine positioning.97 A separate study investigating 5
treatment planning techniques in both supine and prone positioning found that all treatment techniques
provide superior sparing of organs at risk in the prone position.96 In the prone position, the use of a belly board
reduces dose to the small bowel over a wide range of dose levels compared with not using a belly board.95 The
superiority of prone treatment with a belly board has been established in terms of dosimetric indices and
differences in overlap between the target and organs at risk, but not in terms of patient outcomes. The
limitations of these studies notwithstanding, the evidence is sufficient to make a conditional recommendation of
simulation in the prone position with a belly board. However, in patients treated with IMRT/VMAT or with a
colostomy, a supine position may also be suitable, particularly for patients whose CTV includes the inguinal
lymph nodes. Regardless of whether a patient is treated in the supine or prone position, treating with a full
bladder may further decrease dose to the small bowel.
Based on the available evidence, the task force was not able to provide specific recommendations
regarding dose constraints. Additional treatment-planning studies are needed to identify optimal dose
constraints to minimize treatment toxicity.
4. Conclusions
Since the publication of the German Rectal Cancer Trial10,19 which established the role of neoadjuvant
chemoradiation, TME and adjuvant chemotherapy for locally advanced rectal cancer, the necessity and the
optimal sequencing of all 3 of these treatment modalities have been challenged. In the era of personalized
medicine, clinical decision making will look to move beyond traditional American Joint Committee on Cancer
(AJCC) staging102 to incorporate additional radiographic, pathologic, and molecular features which may influence
treatment decisions to optimize treatment outcomes and QoL while mitigating risks of treatment related
toxicities. Whenever possible, patient outcomes should be collected as part of clinical trials and prospective
registries to strengthen the overall quality of evidence on this topic.
5. Acknowledgements
We are grateful to Elisha Fredman, MD, Cristina Decesaris, MD, Neil Newman, MD, MS, Michael Stolten,
MD, Sherry Yan, MD, Rebecca Levin-Epstein, MD, Todd Pezzi, MD, MBA, Olsi Gjyshi, MD, PhD, Sara Zakem, MD,
and Jie Deng, MD, PhD, for literature review assistance; and to Caroline Patton for guidance regarding guideline
methodology and literature search support.
The task force thanks the peer reviewers for their comments and time spent reviewing the guideline.
See Appendix 1 for their names and disclosures.
21
Figure 1. PRISMA Diagram, based on Moher et al, 2009103
* Includes both original and updated searches

Abbreviation: PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
22
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28
Appendix 1. Peer Reviewers and Disclosures (Comprehensive)

Disclosure Company/
Name Employment Disclosure Category
Organization
Pramila Rani Anne, MD Thomas Jefferson University • American Board of • RO GI exam
Hospital – Associate Professor; Radiology committee co-chair
Bodine Center for Cancer • Seanstrong Charity • Board member
Therapy – Medical Director of
Clinical Operations
Shauna Campbell, DO Cleveland Clinic Taussig Cancer None N/A
(Guideline Subcommittee Institute – Chief Resident,
Lead Reviewer) Radiation Oncology
Christopher Crane, MD Memorial Sloan Kettering • NRG Oncology-GI • Co-chair
Cancer Center – Vice Chair Committee
Brian Czito, MD Duke University – Professor • ASTRO • Committee chair
• NCCN • Guideline panel
• Oakstone Institute • Honoraria
• Springer • Royalty
• UptoDate
• Varian • Travel expense &
honoraria
(educational)
Corinne Doll, MD University of Calgary – Professor • Canadian Association • President-Elect
(CARO Reviewer) & Deputy Clinical Department of Radiation Oncology
Head; Alberta Health Services – • NCI Gynecologic • Special Expert
Radiation Oncologist Cancer Steering
Committee
• Deputy Medical
• Tom Baker Cancer
Director
Centre, Calgary
Cathy Eng, MD Vanderbilt-Ingram Cancer • Karyopharm • Advisor
(ASCO Reviewer) Center – Professor of Medicine,
Hematology and Oncology
Michael Haddock, MD Mayo Clinic Alix School of • International Society • Board member
Medicine – Professor of of Intraoperative
Radiation Oncologist Radiation Therapy
Mark Lee, MD Cancer Services, Liverpool • Oncosil Medical • Safety review
(RANZCR Reviewer) Hospital, NSW, Australia – committee member
Radiation Oncologist
Christopher Lieu, MD University of Colorado – None N/A
(ASCO Reviewer) Associate Professor; Director, GI
Medical Oncology; Associate
Director for Clinical Research
Bruce Minsky, MD MD Anderson – Professor of None N/A
Radiation Oncology, Frank T.
McGraw Endowed Chair
Harvey Mamon, MD, Brigham and Women’s Hospital, • UptoDate • Honoraria
PhD Dana Farber Cancer Institute –
Director, GI Radiation Oncology
Nima Nabavizadeh, MD Oregon Health & Science • RadOnc Questions, • Consultant
University – Assistant Professor LLC
29
of Radiation Oncology,
Residency Program Director
Samuel Ngan, MD Peter MacCallum Cancer Centre None N/A
(RANZCR Reviewer) – Head, GL Radiation Oncology
Steven Nurkin, MD Roswell Park Comprehensive • CMSS MACRA Clinical • Colon Resection
(SSO Reviewer) Cancer Center – Associate Committee Workgroup
Professor of Oncology, Surgery • NCCN • Colon Cancer Panel
Claus Roedel, MD University of Frankfurt – • German Cancer Aid • Research funding
(ESTRO Reviewer) Department of Radiotherapy (humanitarian funding
organization)
Terence Sio, MD Mayo Clinic Scottsdale – • Novocure • Advisory board &
(Guideline Subcommittee Assistant Professor of Radiation speakers bureau
Lead Reviewer) Oncology
Tarita Thomas, MD, PhD Loyola University – Associate None N/A
(ACR Reviewer) Professor of Radiation Oncology
Y. Nancy You, MD University of Texas MD None N/A
(SSO Reviewer) Anderson Cancer Center –
Associate Professor
Vincenzo Valentini, MD Fondazione Policlinico • Elekta • Research funding
(ESTRO Reviewer) Universitario A.Gemelli IRCCS - • Merck
Università Cattolica S.Cuore, • Varian
Rome • ViewRay
Abbreviations: ASCO = American Society for Clinical Oncology; CMSS = Council for Medical Specialty Societies; ESTRO
= European Society for Radiotherapy & Oncology; N/A = not applicable; NCCN = National Comprehensive Cancer
Network; NCI = National Cancer Institute; RANCR = Royal Australian and New Zealand College of Radiologists; and
SSO = Society of Surgical Oncology.
This table represents the reviewers reported disclosures at the time this document was under review
(January/February 2020); not necessarily their disclosures at the time of publication.
30
Appendix 2. Abbreviations
3-D CRT = 3-dimensional conformal radiation therapy
CAPOX = capecitabine and oxaliplatin
cGy = centigray
cCR = complete clinical response
CRM = circumferential resection margin
CTV = clinical target volume
DRE = digital rectal examination
FOLFOX = folinic acid, 5-fluorouracil, and oxaliplatin
IMRT = intensity modulated radiation therapy
KQ = key question
LE = local excision
MRI = magnetic resonance imaging
NOM = nonoperative management
mrCRM = MRI-determined circumferential resection margin
mrEMVI = MRI-determined extramural vascular invasion
OS = overall survival
pCR - pathologic complete response
PICOTS = Population, Intervention, Comparator, Outcome, Timing, Setting framework
QoL = quality of life
RCT = randomized controlled trial
RT = radiation therapy
TME = total mesorectal excision
TNT = total neoadjuvant therapy
VMAT = volumetric modulated arc therapy
31
Appendix 3. Literature Search Strategy
Search Date(s): 04/26/2019
Search Limits:
Age Range Adult (>18 years old)
Language English only
Species Humans
Publication Types RCTs
Meta-analyses
Prospective trials (see restrictions by KQ)
Retrospective studies (see restrictions by KQ)
Timeframe 1999 to 2019
Filters Language, publication date
Universal Exclusion Criteria:

1. Pre-clinical/non-human studies
2. Health economics/cost analysis studies
3. Studies available in abstract only
4. Comment or editorial
5. Otherwise not relevant or out of scope
Item No. Item Details

Literature Search Strategy
Key Question and PICO(TSS) Framework
1. Key clinical Key Question 1 Search terms:
question(s) 1. “Rectal cancer”
What are the indications for neoadjuvant radiation therapy for 2. "Rectal Neoplasms"[Mesh]
operable rectal cancer? 3. “Surgery”
4. “Resection”
 To be addressed: 5. “Operable”
32
o Patient selection based on MR and other staging studies 6. “Resectable”

(e.g., how to synthesize NCCN/European/US-based risk 7. “Neoadjuvant”
groups) 8. "Neoadjuvant Therapy"[Mesh]
o Role of pelvic radiation in patients with operable rectal 9. “Preoperative”
cancer and metastatic disease 10. “Radiation”
2. Definitions • Indications: Tumor Location (upper rectum/rectosigmoid vs. 11. “Radiotherapy”
middle rectal vs. lower rectal); Tumor Staging (T1-2N1 vs. T3N0 12. "Radiotherapy"[Mesh]
vs. T3-4N+), Depth of Extramural Invasion (<5 mm vs. ≥ 5 mm), 13. “External beam”
threatened CRM, EMVI 14. “EBRT”
• Metastatic disease: Treatment Intent (Potentially resectable 15. “Chemoradiation”
disease to NED vs. synchronous unresectable disease); Primary 16. “Chemoradiotherapy”
Tumor Staging (T1-2N1 vs. T3N0 vs. T3-4N+) 17. "Chemoradiotherapy"[Mesh]
3. Condition or domain AJCC 8th edition Stage II-IV adenocarcinoma of the rectum 18. “magnetic resonance imaging”
being studied 19. “MRI”
4. Participants/ Patients with pathologically confirmed rectal cancer Search strategy:

1. “Rectal cancer” OR “Rectal
population
Neoplasms"[Mesh]
5. Intervention(s)/ • Long course preoperative radiation therapy 2. “Operable” OR “Resectable”
exposure(s) • Long course preoperative chemoradiation
3. “Surgery” OR “Resection”
• Short course preoperative radiation therapy 4. “Neoadjuvant” OR "Neoadjuvant
6. Comparator(s)/ • Surgery alone Therapy"[Mesh] OR “Preoperative”
control • Postoperative radiation therapy 5. “Radiation” OR “Radiotherapy” OR
7. Outcomes: Overall survival, local control, disease-free survival "Radiotherapy"[Mesh] OR “External beam”
primary/critical OR “EBRT”
8. Outcomes: • Disease-specific survival 6. “Chemoradiation” OR
secondary/ • Sphincter preservation “Chemoradiotherapy” OR
important but not • Acute and late grade ≥ 3 toxicity "Chemoradiotherapy"[Mesh] OR "Magnetic
critical outcomes resonance imaging" OR "MRI"
• HR-QOL
7. #2 AND #3
9. Timing Any
8. #5 OR #6
10. Setting/context Any 9. #4 AND #8
11. Study design • Studies comparing preoperative long course chemoradiation to 10. #1 AND #7 AND #9
postoperative chemoradiation or radiation
33
• Studies comparing preoperative short course radiation to

surgery alone 333 with date and language filters
• Studies comparing preoperative short course radiation to
postoperative chemoradiation
• Prospective studies evaluating outcomes for patients with cT3-
4 or N+ rectal cancer treated without neoadjuvant therapy.
Studies published from 1999 to 2019

• RCTs
• Meta-analyses
• Selected prospective studies with at least 50 patients identified
by the chairs and writing group to address areas not covered in
RCTs
12. Summary of the key Inclusion criteria:
selection criteria Adults ≥ 18 years with operable rectal cancer treated with or
without neoadjuvant chemoradiation
Exclusion criteria:
• Patients with operable rectal cancer receiving wide local
excision alone
• Recurrent disease

1. Key clinical Key Question 2 Search terms and strategy:
question(s) 1. See KQ1
What neoadjuvant regimens are appropriate for patients with
operable rectal cancer?
 To be addressed:
34
o Short-course RT versus chemoradiation, and situations where

one may be preferred
o Optimal integration and sequencing of chemotherapy and
radiation in neoadjuvant treatment
o Patients for whom chemotherapy alone is appropriate
neoadjuvant therapy
o Appropriate duration between completion of
(chemo)radiation and surgery
2. Definitions • Dose fractionation schema: numbers of radiation fractions,
dose per day, and total dose
• Optimal RT treatment schema: Short Course vs. Standard
Chemoradiation- Potential Impact of Tumor Location (upper
rectum/rectosigmoid vs. middle rectal vs. lower rectal); Tumor
Staging (T3 vs. T4); Threatened Mesorectal Fascia (yes vs no);
Presence of M1 disease
• Timing of radiation: Upfront chemoradiation vs. neoadjuvant
chemotherapy followed by neoadjuvant RT vs neoadjuvant RT
followed by neoadjuvant chemotherapy
• Omission of RT: neoadjuvant chemotherapy alone vs.
neoadjuvant RT
• Optimal duration between RT and surgical resection: 6-8 weeks
vs. 11-12 weeks
3. Condition or domain AJCC 8th edition Stage II-IV adenocarcinoma of the rectum
being studied
4. Participants/ Patients with pathologically confirmed operable rectal cancer

population
5. Intervention(s)/ • Preoperative short course RT followed by surgery and
exposure(s) postoperative chemotherapy
• Preoperative short course RT followed by chemotherapy
followed by surgery
• Preoperative chemotherapy followed by short course RT
followed by surgery
35
• Neoadjuvant strategy with short interval to surgery

6. Comparator(s)/ • Preoperative long course chemoradiation followed by surgery
control and postoperative chemotherapy (German rectal study arm)
• Preoperative long course chemoradiation followed by
chemotherapy followed by surgery
• Preoperative chemotherapy followed by chemoradiation
followed by surgery
• Preoperative chemotherapy followed by surgery
• Neoadjuvant strategy with long interval to surgery

7. Outcomes: Overall survival, local control, disease-free survival
primary/critical
8. Outcomes: • pCR
secondary/ • Local control
important but not • Disease-free survival
critical outcomes • Sphincter preservation
• Acute and late grade ≥ 3 toxicity
• HR-QOL
9. Timing Any
10. Setting/context Any
11. Study design • Studies comparing preoperative long course CRT to short
course RT
• Studies comparing preoperative chemotherapy followed by
long course CRT followed by surgery vs. preoperative long
course CRT followed by surgery followed by postoperative
chemotherapy
• Studies comparing preoperative long course CRT followed by
chemotherapy followed by surgery vs. preoperative long
course CRT followed by surgery followed by postoperative
chemotherapy
• Studies comparing short course RT followed by chemotherapy
followed by surgery vs. preoperative long course CRT followed
by surgery followed by postoperative chemotherapy
36
• Studies comparing preoperative chemotherapy alone to

preoperative CRT
• Studies comparing short interval to surgery vs. long interval to
surgery
Studies published from 1999 to 2019

• RCTs
• Meta-analyses
• Selected prospective studies with at least 50 patients identified
by the chairs and writing group to address areas not covered in
RCTs
12. Summary of the key Inclusion criteria:
selection criteria Adults ≥ 18 years with locally advanced operable rectal cancer
undergoing total mesorectal excision
Exclusion criteria:
• Patients with operable rectal cancer receiving wide local
excision alone
• Recurrent disease

What are the appropriate indications for consideration of a non- 2. "Rectal Neoplasms"[Mesh]
operative (active surveillance) or local excision approach after 3. “Inoperable”
definitive/preoperative chemoradiation? 4. “Refuse”
5. “Refusal”
 To be addressed: 6. “Decline”
o When a non-operative (active surveillance) or local excision 7. “Alternative”
approach can be considered 8. “Complete response”
37
o Optimal integration and sequencing of therapy in a non- 9. “Complete clinical response”

operative approach 10. “Good responder”
o Optimal methods of evaluating response and surveillance 11. “Non surgical”
12. “Non operative”
2. Definitions • Surgical approach after neoadjuvant treatment: TME vs. 13. “NOM”
Wide Local excision vs active surveillance 14. “Watchful waiting”
• Neoadjuvant treatment: Long course CRT vs. Chemotherapy 15. “Watch and wait”
followed by long course CRT vs. Long course CRT followed by 16. “Active surveillance”
chemotherapy vs. short course RT vs. short course RT 17. “Total neoadjuvant therapy”
followed by chemotherapy, chemotherapy followed by short 18. “Organ preservation”
course RT 19. “Organ sparing”
• Optimal method/frequency of surveillance: MRI, flexible 20. “Sphincter sparing”
sigmoidoscopy and biopsy, restaging CT 21. “Transanal endoscopic”
3. Condition or domain AJCC 8th edition Stage I-III adenocarcinoma of the rectum 22. “TEM”
being studied 23. “TAMIS”
24. “Non radical”
4. Participants/ Patients with operable rectal cancer 25. “Local excision”
26. “Radiation”
population
27. “Radiotherapy”
5. Intervention(s)/ • Definitive chemoradiation or radiation
28. "Radiotherapy"[Mesh]
exposure(s) • Active surveillance 29. “External beam”
• Local excision 30. “EBRT”
6. Comparator(s)/ Total mesorectal excision 31. “Endocavitary”
control 32. “Brachytherapy”
7. Outcomes: Overall survival, local control, disease-free survival 33. "Brachytherapy"[Mesh]
primary/critical 34. “Chemoradiation”
8. Outcomes: secondary/ • pCR 35. “Chemoradiotherapy”
important but not • cCR 36. "Chemoradiotherapy"[Mesh]
critical outcomes • Local control/local regrowth
Search strategy:
• Disease-free survival
1. “Rectal cancer” OR “Rectal
• Disease-specific survival
Neoplasms"[Mesh]
• Sphincter preservation
2. “Inoperable” OR “Refuse” OR “Refusal”
• Salvage rate OR “Decline” OR “Alternative” OR
• Acute and late grade ≥ 3 toxicity
38
• HR-QOL “complete response” OR “complete

9. Timing Any clinical response” OR “good responder”
10. Setting/context Any 3. “Non surgical” OR “Non operative” OR
“NOM” OR “Watchful waiting” OR “Watch
11. Study design • Studies published from 1999 to 2019
and wait” OR “Active surveillance” OR
• RCTs
“total neoadjuvant therapy”
• Meta-analyses
4. “Organ preservation” OR “Organ sparing”
• Prospective trials with at least 50 patients OR “Sphincter sparing” OR “Transanal
• Retrospective studies with at least 200 patients, except endoscopic” OR “TEM” OR “TAMIS” OR
selected studies not well addressed in prospective data, “Non radical” OR “Local excision”
which had a threshold of 50 patients 5. “Radiation” OR “Radiotherapy” OR
12. Summary of the key Inclusion criteria: "Radiotherapy"[Mesh] OR “External
selection criteria Adults ≥ 18 years with operable rectal cancer beam” OR “EBRT” OR “Endocavitary” OR
“Brachytherapy” OR
Exclusion criteria: "Brachytherapy"[Mesh]
• Patients with metastatic disease 6. “Chemoradiation” OR
• Recurrent disease “Chemoradiotherapy” OR
"Chemoradiotherapy"[Mesh]
7. #3 OR #4
8. #2 AND #7
9. #5 OR #6
10. #1 AND #8 AND #9
351 with date and language filters

What are the appropriate treatment volumes, dose-constraints, 2. "Rectal Neoplasms"[Mesh]
and techniques for patients treated with radiation therapy? 3. “Radiotherapy”
39
4. "Radiotherapy"[Mesh]
 To be addressed: 1. “Neoadjuvant”
o Role of IMRT versus 3D conformal and when each might be 2. "Neoadjuvant Therapy"[Mesh]
preferred 3. “Preoperative”
o Appropriate treatment volumes and dose-constraints in 4. “Adjuvant”
different clinical situations based on extent of disease and 5. “Postoperative”
surgery 6. “EBRT”
o Role of and indications for dose-escalation and IORT 7. “Chemoradiation”
o Role of image-guidance 8. “Chemoradiotherapy”
o Appropriate simulation techniques 9. "Chemoradiotherapy"[Mesh]
10. “3D conformal”
2. Definitions • RT technique: IMRT vs. 3D 11. “3D CRT”
• Nodal volumes: Standard field, External Iliac, Inguinal, Lateral 12. “Intensity modulated”
LN coverage 13. “IMRT”
• Optimal Bowel DVH constraints based on fractionation 14. “volumetric modulated”
• IORT: Intraoperative Radiation Therapy 15. “VMAT”
3. Condition or domain AJCC 8th edition Stage II-IV adenocarcinoma of the rectum 16. “intraoperative”
being studied 17. “IORT”
18. “IGRT”
4. Participants/ Patients with pathologically confirmed operable rectal cancer 19. “image guidance”
20. “image guided”
population 21. “prone position”
5. Intervention(s)/ • IMRT 22. “supine position”
exposure(s) • 3D-Conformal RT 23. “bladder filling”
• Elective LN Coverage 24. “dose volume”
• Dose escalated RT 25. “target volume”
• Intraoperative RT 26. “treatment volume”
6. Comparator(s)/ Standard 3D-CRT with Classic Pelvic Fields 27. “dose constraint”
control
7. Outcomes: Acute grade ≥ 3 GI toxicity , local control, disease-free survival Search strategy:
primary/critical 1. “Rectal cancer” OR “Rectal
Neoplasms"[Mesh]
8. Outcomes: secondary/ • Local control
important but not • Disease-free survival
critical outcomes • Disease-specific survival
40
• Acute and late grade ≥ 3 toxicity 2. “Neoadjuvant” OR "Neoadjuvant

• HR-QOL Therapy"[Mesh] OR “Preoperative” OR
9. Timing Any “adjuvant” OR “postoperative”
3. “Radiation” OR “Radiotherapy” OR
10. Setting/context Any
"Radiotherapy"[Mesh] OR “External
11. Study design • Studies published from 1999 to 2019
beam” OR “EBRT”
• RCTs
4. “Chemoradiation” OR
• Meta-analyses “Chemoradiotherapy” OR
• Prospective trials with at least 100 patients "Chemoradiotherapy"[Mesh]
• Retrospective studies with at least 150 patients 5. “3D conformal” OR “3D CRT”
• Dosimetric studies with at least 50 patients, except selected 6. “Intensity modulated” OR “IMRT” OR
studies addressing setup for which threshold is 10 patients “volumetric modulated” OR “VMAT”
7. “intraoperative” OR “IORT” OR “IGRT” OR
12. Summary of the key Inclusion criteria: “image guidance” OR “image guided”
selection criteria Adults ≥ 18 years with operable rectal cancer receiving 8. “prone position” OR “supine position” OR
neoadjuvant or adjuvant RT “bladder filling” OR “dose volume” OR
“target volume” OR “treatment volume”
Exclusion criteria: OR “dose constraint”
• Patient receiving palliative RT 9. #3 OR #4
• Recurrent disease 10. #5 AND #6 AND #9
11. #7 OR #8
12. #9 AND #11
13. #10 OR #12
14. #1 AND #2 AND #13
403 with date and language filters
Total for all searches: 1048 articles
41
Online supplements are not copyedited, and the authors are responsibility for the accuracy of the data.

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Radiation Therapy for Rectal Cancer: An

ASTRO Clinical Practice Guideline

Jennifer Y. Wo, MD,a Christopher J. Anker, MD,b Jonathan B. Ashman,

a. Massachusetts General Hospital, Boston, Massachusetts, Department of Radiation Oncology

* Corresponding author: Prajnan Das, MD, MS, MPH; Email: PrajDas@mdanderson.org

Task Force Members’ Disclosure Statements

Table 1. ASTRO recommendation grading classification system

Overall QoE Grade Type/Quality of Study Evidence Interpretation

2.1. Task Force Composition

2.2. Document Review and Approval

2.3. Evidence Review

2.4. Scope of the Guideline

Table 2. KQs in Population, Intervention, Comparator, Outcome (PICO) format

KQ Population Intervention Comparator Outcomes

Patients with • Preop short-course RT followed • Preop long-course • Overall survival

3. Key Questions and Recommendations

3.1. Key Question 1: Indications for neoadjuvant RT (Table 3)

Table 3. Recommendations for neoadjuvant RT indications

2. For patients with stage II-III rectal cancer, neoadjuvant RT is High

3. For patients with stage II rectal cancer at lower risk of locoregional

3.2. Key Question 2: Neoadjuvant regimens (Table 4)

Table 4. Recommendations for neoadjuvant regimens

Implementation remark: Risk factors for increased recurrence

Implementation remark: Risk factors for increased recurrence

10. For patients with rectal cancer undergoing neoadjuvant short-

Implementation remark: An interval of 4-8 weeks is preferred for

3.3. Key Question 3: Nonoperative and local excision approaches (Table 5)

Table 5. Recommendations for nonoperative or LE approaches

a. would have a permanent colostomy or inadequate bowel

5. For patients with rectal cancer considering NOM, assessment for

Implementation remark: Follow-up should continue for a minimum

3.4. Key Question 4: Treatment volumes, dose-constraints, and techniques

Table 6. Recommendations for appropriate treatment volumes and techniques

Figure 1. PRISMA Diagram, based on Moher et al, 2009103

* Includes both original and updated searches

Appendix 1. Peer Reviewers and Disclosures (Comprehensive)

Appendix 3. Literature Search Strategy

Search Date(s): 04/26/2019

Universal Exclusion Criteria:

Item No. Item Details

o Patient selection based on MR and other staging studies 6. “Resectable”

4. Participants/ Patients with pathologically confirmed rectal cancer Search strategy:

• Studies comparing preoperative short course radiation to

Studies published from 1999 to 2019

Item No. Item Details

o Short-course RT versus chemoradiation, and situations where

4. Participants/ Patients with pathologically confirmed operable rectal cancer

• Neoadjuvant strategy with short interval to surgery

• Neoadjuvant strategy with long interval to surgery

• Studies comparing preoperative chemotherapy alone to

Studies published from 1999 to 2019

Item No. Item Details

o Optimal integration and sequencing of therapy in a non- 9. “Complete clinical response”

• HR-QOL “complete response” OR “complete

351 with date and language filters

Item No. Item Details

• Acute and late grade ≥ 3 toxicity 2. “Neoadjuvant” OR "Neoadjuvant

403 with date and language filters

Total for all searches: 1048 articles