ACR Appropriateness Criteria® Resectable Rectal Cancer
ACR Appropriateness Criteria
William E Jones III 8
Charles R Thomas Jr 0
Joseph M Herman 7
May Abdel-Wahab 13
Nilofer Azad 12
William Blackstock 11
Prajnan Das 10
Karyn A Goodman 15
Theodore S Hong 14
Salma K Jabbour 9
Andre A Konski 5
Albert C Koong 6
Miguel Rodriguez-Bigas 3
William Small Jr 4
Jennifer Zook 1
W Warren Suh 2
0 Knight Cancer Institute at Oregon Health and Science University , Portland, Oregon , US
1 Indiana University School of Medicine , Indianapolis, Indiana , USA
2 Cancer Center of Santa Barbara , Santa Barbara, California , USA
3 MD Anderson Cancer Center, American College of Surgeons , Houston, Texas , USA
4 The Robert H. Lurie Comprehensive Cancer Center of Northwestern University , Chicago, Illinois , USA
5 Wayne State University School of Medicine , Detroit, Michigan , USA
6 Stanford University Medical Center , Stanford, California , USA
7 Sidney Kimmel Cancer Center at Johns Hopkins , Baltimore, Maryland , USA
8 UT Health Science Center San Antonio , San Antonio, Texas , USA
9 Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey , New Brunswick, New Jersey , USA
10 MD Anderson Cancer Center , Houston, Texas , USA
11 Wake Forest University , Winston Salem, North Carolina , USA
12 Sidney Kimmel Cancer Center at Johns Hopkins, American Society of Clinical Oncology , Baltimore, Maryland , USA
13 University of Miami , Miami, Florida , USA
14 Massachusetts General Hospital , Boston, Massachusetts , USA
15 Memorial Sloan- Kettering Cancer Center , New York, New York , USA
The management of resectable rectal cancer continues to be guided by clinical trials and advances in technique. Although surgical advances including total mesorectal excision continue to decrease rates of local recurrence, the management of locally advanced disease (T3-T4 or N+) benefits from a multimodality approach including neoadjuvant concomitant chemotherapy and radiation. Circumferential resection margin, which can be determined preoperatively via MRI, is prognostic. Toxicity associated with radiation therapy is decreased by placing the patient in the prone position on a belly board, however for patients who cannot tolerate prone positioning, IMRT decreases the volume of normal tissue irradiated. The use of IMRT requires knowledge of the patterns of spreads and anatomy. Clinical trials demonstrate high variability in target delineation without specific guidance demonstrating the need for peer review and the use of a consensus atlas. Concomitant with radiation, fluorouracil based chemotherapy remains the standard, and although toxicity is decreased with continuous infusion fluorouracil, oral capecitabine is non-inferior to the continuous infusion regimen. Additional chemotherapeutic agents, including oxaliplatin, continue to be investigated, however currently should only be utilized on clinical trials as increased toxicity and no definitive benefit has been demonstrated in clinical trials. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.
Appropriateness criteria; Rectal cancer; Chemoradiotherapy; Radiotherapy; Chemotherapy
Summary of literature review
The American Cancer Society estimates there will be
103,170 new cases of colorectal cancer in 2012 with
40,290 of those being located in the rectum [
Anatomically, the rectum begins above the dentate line, which
marks the cephalad extent of the anal canal, and extends
above the peritoneal reflection to the sigmoid colon. The
location of the rectum deep in the pelvis with its tight
confines complicates surgical resection, leading to an
increased risk of local recurrence with surgical resection
alone. Local and distant recurrence rates after non-total
mesorectal excision (TME) surgery alone are as high as
], thus warranting adjuvant therapy to
improve local/regional control. Clinical trials have
investigated the use of multimodality therapy to decrease the
incidence of both local and distant recurrence.
Historically, after surgical resection adjuvant therapy would be
delivered if high-risk features were discovered upon
pathologic examination of the surgical specimen.
Subsequent investigation examined the role of neoadjuvant
therapy, and most recently comparisons of these
techniques have been published. This document summarizes
the major clinical trials and the role for multimodality
In 2004, a randomized trial from Germany was
published establishing a regimen of preoperative
chemoradiotherapy and surgery followed by additional cycles of
chemotherapy alone as the standard of care for clinical
stages T3 or T4, or for node-positive rectal cancer [
Other clinical studies from the United States, Europe,
and Asia have also influenced the treatment strategies
for operable rectal cancer, as various approaches using
preoperative or postoperative radiotherapy, with or
without chemotherapy, have been examined. A summary of
the major randomized clinical trials spanning the past
several decades is provided below.
Overall survival (OS) is most affected by the extent of
disease, with increasing depth of rectal wall penetration
and lymph node involvement being harbingers of worse
outcome. Tumor location appears to be important in
rectal cancer, with low-lying tumors having a greater
propensity for local recurrence. Histological tumor grade
is prognostic, with poorly differentiated tumors having a
worse prognosis. The signet ring cell and mucinous
varieties also portend a less favorable outcome. The
mucinous variety can be visualized via magnetic resonance
imaging (MRI) defined by greater than 50% mucin in the
tumor, and this variety has recently been shown to
respond less favorably to neoadjuvant chemoradiation.
The pathologic circumferential resection margin (CRM)
has been demonstrated to be prognostic, and at least
one retrospective series confirms decreased
cancerspecific survival with a CRM ≤2 mm [
the ypCRM status (after neoadjuvant
chemoradiotherapy) is a significant risk factor for local recurrence .
High-quality surgery with pathological evaluation of
TME specimens is associated with a decreased risk of
local recurrence. A pathological review of specimens
from the Medical Research Council/United Kingdom
(MRC CR07) trial, which required TME, clearly
demonstrates that excellent surgical technique is directly
related to local recurrence [
]. Only 52% of the
specimens demonstrated a “good” resection truly in the
mesorectal plane, 34% were found to be “intermediate”
in the intramesorectal plane, and 13% were “poor”
involving the plane of the muscularis propria. The 3-year risk
of local recurrence was directly related to quality of
surgery, with high-quality surgery resulting in a lower
recurrence. Importantly, all surgical groups, regardless
of quality of resection, benefitted from neoadjuvant
Preoperatively large radiotherapy portals covering the
tumor, entire mesorectum, and lymph node regions at
risk are typically treated to 45 Gy with a boost
delivered to the tumor and presacral lymph nodes. The
boost dose typically ranges in clinical trials from 5.4
to 9 Gy. The Radiation Therapy Oncology GroupW
(RTOGW) conducted a phase II study (R-0012)
investigating combined-modality therapy with higher doses
and hyperfractionation [
]. Higher doses were associated
with a similar pathologic complete response (pCR) rate
at the cost of increased grade 3-4 acute toxicity; thus,
the standard remains 50.4 to 54 Gy.
Postoperative radiotherapy with or without
Several classic trials have examined the use of
postoperative irradiation alone or in combination with
chemotherapy; conducted by the Gastrointestinal Tumor Study
Group (GITSG), the North Central Cancer Treatment
Group (NCCTG), and the Norwegian Adjuvant Rectal
Cancer Project Group, radiotherapy delivered with
concurrent chemotherapy improved both local control and
]. Subsequently, studies R-01 and R-02 by
the National Surgical Adjuvant Breast and Bowel Project
(NSABP) demonstrated that the role of radiotherapy is
primarily local control in the postoperative setting
The method of administrating chemotherapy appears
to be important in obtaining optimal results. Protracted
venous infusion of 5-fluorouracil (5-FU) was found to be
superior to bolus 5-FU, with a 45%-50% decrease in
hematologic toxicity [
] and is considered to be a
standard adjuvant therapy; more recent studies have
investigated alternate means of optimizing chemotherapy
. The choice of early versus late radiotherapy with
respect to chemotherapy may also be important
according to the preliminary results of a recent randomized
] and warrants further investigation. Because
neoadjuvant chemoradiotherapy is superior to
postoperative delivery, in cases where chemoradiation is
clearly indicated, cT3-4 or N + neoadjuvant delivery is
preferred. (See Table 1 and Table 2.)
Preoperative radiotherapy with or without chemotherapy
Exploring the role of preoperative radiotherapy alone
(25 Gy in 5 fractions), a Swedish trial showed
improvements in both local control and survival that persisted at
13 years of follow-up [
]. Late toxicity with this
hypofractionated regimen is substantial and includes an
increased risk of small-bowel obstruction, abdominal
pain, diarrhea, bleeding, and fistula formation [
Both the MRC CR07 trial and the Dutch Colorectal
Cancer Group (CKVO 95-04) investigated the role of
radiation therapy with high-quality TME surgery. The
Dutch study randomized 1,805 eligible patients to either
surgery alone or short course radiation therapy (5 x 5
Gy) followed by surgery, and concluded that the addition
of radiation significantly decreases the rate of local
recurrence at 2 years even with high-quality surgery
(P < 0.001) [
]. The MRC CR07 study attempted to
select high risk patients to selectively treat with radiation
therapy; 1,350 patients were randomized to either
neoadjuvant short-course radiation therapy (5 x 5 Gy)
or selective postoperative concurrent chemoradiation
therapy (45 Gy in 25 fractions with 5-FU) to those
patients with CRM involvement (defined as ≤1 mm)
]. Patients with resectable rectal cancer who received
preoperative radiation had a decreased rate of local
recurrence at 3 years compared to patients who received
adjuvant long-term radiation therapy. Together, the
CKVO 95-04 and MRC CR07 studies confirm that
radiation improves local control even with TME surgical
technique. Because of the toxicity of long-term radiation
treatment and the inability to safely combine the
hypofractionated radiotherapy regimen with systemic
chemotherapy, this approach is rarely used in the United
States or Southern Europe, but it is more common in
Northern Europe [
Importantly, two trials from Europe have examined
the role of incorporating concurrent chemotherapy with
preoperative irradiation using standard radiotherapy
fractionation, in keeping with the postoperative
combined chemoradiotherapy model. Two studies — one by
the European Organisation for Research and Treatment
of Cancer (EORTC 22921), the other by the Fondation
Francaise de Cancerologie Digestive (FFCD 9203) —
demonstrated a significant improvement in local control,
in the absence of a survival or sphincter-preservation
benefit, with the addition of chemotherapy [
expected, acute toxicity was increased with the addition
of chemotherapy, as had been noted in the FFCD 9203
trial . (See Table 3.)
Preoperative versus postoperative chemoradiotherapy
The important question of comparing preoperative
versus postoperative chemoradiotherapy, as noted above,
was addressed by a randomized trial from Germany. The
preoperative regimen, as published by Sauer et al [
was associated with significantly improved local control
and increased sphincter-preservation rates with no
differences in disease-free or OS. As surgical technique
continues to improve, it becomes increasingly difficult to
demonstrate a benefit in disease-free or OS.
Neoadjuvant delivery also resulted in decreased rates of acute
and chronic treatment toxicity, when compared to the
postoperative approach. Another randomized trial
(NSABP R03) exploring the same question in the United
States was terminated early due to poor accrual. This
study did not require TME, but it did show a trend
towards improved survival, with a significant
improvement in recurrence-free survival and disease-free
]. Clinical response to the preoperative therapy
was associated with significantly improved disease-free
and OS [
]. The current standard of care in the United
States is, therefore, to provide preoperative
chemoradiotherapy, using standard radiotherapy fractionation
and concurrent fluorouracil for clinical stage T3 or T4
or for node-positive rectal cancer.
Physical positioning to displace the small bowel is a
simple way of maximizing the therapeutic ratio. A
comparative study shows that when a patient is placed prone, the
use of a belly board combined with a full bladder
reduces the volume of small bowel irradiated by 70%
(about 100 cc) [
]. Use of intensity-modulated radiation
therapy (IMRT) with supine positioning potentially
obviates the geometric benefit of placing the patient in the
prone position on a belly board, which is uncomfortable
and presumably more difficult for the patient to tolerate.
A retrospective study comparing prone or supine setup
with daily image guidance versus a no-action-level
protocol confirmed that prone positioning leads to a greater
systematic error. However, the study noted increased
random error with the supine position. Error was
decreased with either setup using increased frequency of
image guidance [
]. One study from the UK evaluated
prone versus supine positioning in 19 consecutive
patients and found the prone position did decrease dose
to the small bowel, but primarily only in the low dose
region of the dose-volume histogram [
]. At doses
above 20 Gy, there was no appreciable difference
between supine and prone positioning, lending support
to the notion of using the supine position in patients
who may not tolerate lying prone with a full bladder.
Timing of surgery
One of the major differences in the adjuvant trials from
Europe versus those from the United States has been
regarding the timing of surgery after chemoradiotherapy.
The short-course regimens from Europe with surgery 1
week after completing radiotherapy have not allowed
adequate time for downstaging, yet it appears that with a
longer interval from neoadjuvant therapy to surgery
downstaging may occur. In a retrospective review of
patients treated with neoadjuvant chemoradiation
followed by surgery with a time interval ≤7 weeks versus
>7 weeks, the longer interval before surgery
demonstrated an improved pCR and near-pCR rates as well as
increased disease-free survival interval [
]. A primary
concern with an extended interval from
chemoradiotherapy to surgery is that tumor clonogens are afforded time
for repopulation and potential spread. A delay to surgery
beyond 12 weeks has been investigated in selected
patients and appears to be safe without an increase in
metastatic spread [
Infusional versus oral 5-FU
Since the advent of oral 5-FU, capecitabine, its
equivalence has been called into question. A multitude of
retrospective data exists with conflicting results. Several
randomized phase III studies have recently been
reported that add support to the use of capecitabine.
NSABP R-04 is a randomized trial of radiotherapy with
concurrent chemotherapy investigating four different
chemotherapy regimens (5-FU or oral capecitabine with
or without oxaliplatin). Preliminary results have recently
been reported and show no significant difference
between the arms with respect to pCR, sphincter
preservation, or downstaging. However, the addition of
oxalaplatin was associated with a notable increase in grade
3 and 4 gastrointestinal (GI) toxicity [
randomized trial of 401 patients from Germany comparing
infusional 5-FU versus oral capecitabine concurrent with
neoadjuvant radiation therapy suggests different toxicity
profiles between the two chemotherapy regimens with
less leucopenia and increased hand-foot skin reactions
associated with capecitabine. This noninferiority
German study suggests that oral capecitabine is not inferior
to infusional 5-FU, and is associated with an increased
rate of ypN0 tumors demonstrating increased
downstaging with the oral drug [
The role of neoadjuvant chemoradiotherapy in
resectable rectal cancer has been established, but the
possibility of increasing the therapeutic gain via newer
chemotherapeutic agents exists. Two large trials, the
French ACCORD and the Italian STAR trial, both
evaluate the role of oxaliplatin, which increases the efficacy of
fluorouracil-based chemotherapy in treating colon
]. These trials clearly show an increase in
toxicity with the addition of oxaliplatin with no apparent
improvement in local response. This use of oxalaplatin is
supported by the recent preliminary results from NSABP
R-04, which showed no apparent benefit with the
addition of oxalaplatin to neoadjuvant concurrent
chemoradiotherapy. The use of IMRT with capecitabine and
oxaliplatin is being examined in a phase II study
(RTOGW 08-22), but the results are not yet available.
The role of biologic agents in treating rectal cancer has
not yet been established.
The role of additional adjuvant chemotherapy after
chemoradiotherapy in either the neoadjuvant or adjuvant
setting is also in question. Although it is clearly
indicated with colon cancer, several large trials from Europe
and a meta-analysis have failed to show any benefit.
Adjuvant chemotherapy after either neoadjuvant or
adjuvant chemoradiotherapy has remained the standard
of care based on extrapolated data from colon cancer. A
randomized trial was initiated to determine whether
additional chemotherapy is necessary in rectal cancer,
but unfortunately due to lack of clinical equipoise, the
study failed to accrue and closed early. Analysis of the
Surveillance, Epidemiology, and End Results (SEER)
database comparing patients who received adjuvant
chemotherapy with those who did not suggests that patients
who are node positive may benefit from additional
IMRT has a demonstrated benefit in the treatment of
anal malignancies, with fewer treatment breaks
presumed to be due to the decreased toxicity associated
with more conformal dose delivery. The RTOGW
launched a phase II study investigating the use of IMRT
for T3-4N0-2 patients with capecitabine and oxaliplatin.
The preliminary results, presented in abstract form only,
revealed a trend towards decreased preoperative GI
grade ≥2 toxicity when compared to RTOGW 0247 [
A recent single-institution retrospective review
comparing IMRT to classic 3-field conventional radiotherapy
demonstrated a significant decrease in GI toxicity grade
≥2 for patients receiving IMRT [
]. It is the consensus
of the expert panel authoring this document that IMRT
clearly decreases toxicity in the treatment of rectal
cancer. Certain situations requiring larger treatment
volumes such as postoperative therapy after an
abdominoperineal resection (APR) or radiation of the
inguinal nodes warrants a stronger recommendation for
IMRT; however, there are concerns regarding delivery
of IMRT outside the confines of a clinical trial. IMRT
requires a greater knowledge of anatomic spread and
understanding of the surrounding normal tissues and
tolerances than the conventional 3-field pelvis
treatment based on bony anatomy. This difficulty in
contouring was clearly demonstrated in RTOGW 0529
where there were a significant number of inadequately
contoured cases; however, due to a rapid review
process, corrections were made prior to patient treatment.
Multiple studies document the interobserver variability
in target delineation with highly conformal therapy,
and the need for guidance or aids in target delineation
to avoid missing critical targets [
]. The need for
education regarding IMRT volumes in the pelvis was
addressed by consensus panel of experts convened by
RTOGW to create an anorectal contouring atlas that
helps delineate targets . The preferred delivery for
IMRT is via clinical trials; however, when being
performed outside of a clinical trial, the atlas and peer
review through colleagues or an established review
process is strongly recommended.
Patients with low-lying rectal tumors extending below
the dentate line and with extensive involvement of the
anal canal receive treatment resembling that used for
anal cancer, including treatment of the external iliac and
inguinal nodes based on patterns of lymph node
drainage. Retrospective data from MD Anderson Cancer
Center suggests that the inguinal spread of rectal cancer,
even with involvement of the anal canal, may be a rare
event and that prophylactic radiotherapy to the groin
may be unnecessary [
]. This study defines patients
having disease within 4 cm of the anal verge as having
involvement of the anal canal, but it does not comment
on extensive involvement with extension to the anal
verge or margin. Further validation is necessary before
omitting inguinal radiation therapy in patients with
extensive involvement of the anal canal. (See Table 4.)
Need for future trial
Despite the published data from randomized trials that
support the shift to preoperative chemoradiotherapy, a
subset of patients will require surgical resection upfront
for a variety of clinical reasons. A pooled analysis of five
randomized clinical trials in the United States suggests
that not all patients with resected tumors may require a
trimodality (surgery, chemotherapy, radiotherapy)
treatment approach. Patients with favorable or
“intermediaterisk” (T3N0 or T1-2N1) tumors were found to have
benefited equally from either postoperative
chemoradiotherapy or chemotherapy alone [
]. Other data
from the Memorial Sloan-Kettering Cancer Center
(MSKCC) suggests that understaging may be a
significant problem, as 22% of the patients in the trial who
were cT3N0 were found to be pN + at the time of
A risk-adapted approach, selecting patients for
minimal surgery based on their response to preoperative
chemoradiotherapy has been investigated. Preliminary
results from a recently reported small phase II trial by
the American College of Surgeons Oncology Group
(ACOSOG Z6041) suggests select patients who have a
small cT2N0 tumor may be candidates for preoperative
chemoradiotherapy followed by local excision rather
than proctectomy [
]. The possibility of deferring or
eliminating surgery for patients with a complete
response to neoadjuvant chemoradiotherapy has also
been suggested [
]. A future clinical study is warranted
to validate the appropriateness of such risk-adapted
For additional information on ACR Appropriateness
CriteriaW, refer to www.acr.org/ac.
As of August 19, 2011, Joseph Herman, MD reported “Nucletron, Genentech”
As of June 27, 2011, Prajnan Das, MD reported “Research Support –
For the remaining authors none were declared.
WJ, CT, JM, MW, NA, WB, PD, KG, TH, SK, AAK, ACK, MB, WS, JZ, WS. All
authors read and approved the final manuscript.
The American College of Radiology seeks and encourages collaboration with
other organizations on the development of the ACR Appropriateness Criteria
through society representation on expert panels. Participation by
representatives from collaborating societies on the expert panel does not
necessarily imply individual or society endorsement of the final document.
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