Académique Documents
Professionnel Documents
Culture Documents
Karyn A. Goodman, M.D., M.S.1*, Caroline E. Patton, M.A.2, George A. Fisher, M.D., Ph.D.3, Sarah E.
Hoffe, M.D.4, Michael G. Haddock, M.D.5, Parag J. Parikh, M.D.,6 John Kim, M.D.7, Nancy Baxter,
M.D., Ph.D.8, Brian G. Czito, M.D.9, Theodore S. Hong, M.D.10, Joseph M. Herman, M.D., M.S.11,
*
Corresponding author: Caroline Patton, MA, American Society of Radiation Oncology, 8280 Willow
Oaks Corporate Drive, Suite 500, Fairfax, VA 22031, 703-286-1560 (phone), 703-286-1561 (fax),
carolinep@astro.org
Working Group
Before initiation of this Clinical Practice Statement, all members of the working group were required to
complete disclosure statements. These statements are maintained at the ASTRO headquarters in Fairfax,
VA and pertinent disclosures are published with the report. The ASTRO Conflict of Interest Disclosure
Statement seeks to provide a broad disclosure of outside interests. Where a potential conflict is detected,
remedial measures to address any potential conflict are taken and will be noted in the disclosure
statement. Nancy Baxter, MD, PhD receives research funding from Pfizer. Brian Czito, MD receives
1
research funding from Abbvie and serves on an advisory board for Pfizer. George Fisher, MD, PhD
receives research funding from Bristol Myers Squibb, Genentech, Tercica, New Link Genetics, Polaris
Group, and Advanced Accelerator Applications. He serves on an advisory board for Genentech.
Theodore Hong, MD, serves on advisory boards for Novartis and Eisai. John Kim, MD receives research
funding from Philips. Parag Parikh, MD receives research funding, honoraria, and travel expenses from
Varian and research funding from Philips. He owns stock in Innovative Pulmonary Solutions and
consults for Ethicon. The Best Practices Subcommittee chairs reviewed these disclosures and
determined they do not present a conflict with respect to these members’ work on this Clinical Practice
Statement.
Expert Panel
Harvey Mamon, MD, PhD received honoraria from UptoDate. Jeffrey Tokar, MD consulted for Boston
Scientific. He served on an advisory board for and received honoraria and travel expenses from
Augmenix. Dr. Tokar was also a board member for the Center for GI Innovation and Technology
(CGIT) and received patent fees. Richard Goldberg, MD received research funding and honoraria from
Sanofi and served on a data and safety monitoring board for Lilly. Salma Jabbour, MD provided a talk
Acknowledgements:
The authors thank the expert panel: George J. Chang, MD, MS, David Dietz, MD, Patrick Francke, MD,
Julio Garcia-Aguilar, MD, PhD, Richard Goldberg, MD, Salma Jabbour, MD, Bruce Lin, MD, Harvey
Mamon, MD, PhD, Marilyn M. Schapira, MD, MPH, and Jeffrey Tokar, MD. They also acknowledge
2
Eunice Chang, PhD for conducting the expert panel rating statistics and Margaret Amankwa-Sakyi for
3
Introduction
Treatment of rectal cancer has made great strides over the last five decades with improvements
in surgical techniques and the use of combined modality therapy. Prior to the use of the total mesorectal
excision (TME) technique, surgery alone resulted in local recurrence rates of 30-60% for locally
advanced disease.1 The use of adjuvant 5-fluorouracil (5-FU)-based chemoradiation reduced local
failure rates to 10-12% and improved overall survival compared to surgery alone,2-4 leading to the 1990
National Cancer Institute (NCI) consensus statement recommending adjuvant chemotherapy and
radiotherapy for all patients with stage II or III (T3-4 or node positive) rectal cancer.5 The phase III
randomized German Rectal Study subsequently demonstrated an improvement in the 10-year cumulative
incidence of local relapse and reduced acute and overall toxicity rates with the use of pre-operative
versus post-operative chemoradiation.6,7 This study has established the standard of care for stage II or
III rectal cancer as neoadjuvant 5-FU-based chemotherapy with conventionally fractionated radiotherapy
to 50.4 Gy.8-10
However, a number of important questions remain regarding how to define subgroups of stage II
and III and individualize use of multimodality therapy. With 5-year survival rates upwards of 75% for
these patients,6 weighing potential long-term effects of surgery, radiotherapy and chemotherapy must be
considered in determining appropriate management strategies. Given the potential morbidity associated
with a multimodality approach, there are emerging efforts to identify subgroups of patients who can
There have been attempts to further stratify Stage II and III rectal cancer patients by risk to
identify subgroups that could potentially be over-treated using tri-modality therapy. In a pooled analysis
of prospective and randomized datasets of patients treated with or without chemotherapy and/or
radiation after radical rectal resection, Gunderson et al. identified three risk groups among Stage II and
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III rectal cancer based on relapse rates: 1) intermediate risk, characterized by tumor, node, metastasis
classification system (TNM) T1–2N1 and T3N0 lesions; (2) moderately high risk, with T1-2N2, T3N1,
T4N0 lesions; and (3) high risk in patients with T3N2, T4N1, T4N2 tumors.12,13 Patients in the
intermediate group, with a single high-risk factor, were shown to have better overall survival and disease
control than patients with moderately high or high risk tumors. In terms of local control, patients with
intermediate risk tumors had a local relapse rate of 5-15% compared to 10-20% and 15-30% for patients
in the moderately high risk and high risk categories. These data suggest that different adjuvant treatment
strategies may be indicated for each risk group. However, the challenge remains in determining which
patients can be spared adjuvant chemoradiation. This question is further complicated by the fact that
imaging may not correctly identify all patients with involved lymph nodes, making it difficult to omit
With significant reductions in local recurrence rates in more modern surgical series with the use
of TME,15,16 pre-operative chemoradiation may not be as essential to eradicate disease often left behind
with older surgical techniques. Neoadjuvant folinic acid, fluorouracil, and oxaliplatin (FOLFOX)
chemotherapy alone has also been evaluated in a small, single institution pilot study17 and is being
Radical rectal surgery is also associated with significant morbidity.19-25 Patients with distal
rectal tumors may require either permanent colostomy, often associated with poor body image and
quality of life,22-25 or a low anterior resection with a coloanal anastomosis, which is often associated
with impaired bowel function.24,25 Moreover, 20% of patients who receive neoadjuvant chemoradiation
experience a pathologic complete response (pCR), in which no residual tumor is appreciable in the
5
surgical specimen.26,27 These patients have particularly favorable outcomes, compared to those with
residual cancer at the time of TME,27,28 and may not derive additional benefit from radical surgery.
Recent studies have demonstrated the feasibility of non-operative management for highly selected
patients achieving clinical complete response (cCR) to chemoradiotherapy, suggesting that surgery can
potentially be omitted, which could significantly improve long-term quality of life, particularly in the
While the establishment of tri-modality therapy for rectal cancer, including surgery,
radiotherapy, and chemotherapy, is the result of decades of randomized trials designed to address key
questions, ambiguity remains due to patient and disease heterogeneity and the emerging attempt to better
customize treatment strategies. Moreover, a growing body of evidence indicates that subgroups of stage
II and III patients have differing risk profiles and warrant a more tailored therapeutic approach that
spares unnecessary morbidity while achieving good outcomes. The current standard approach using the
same therapeutic regimen for all Stage II or II rectal cancer patients suggests additional study is required
to further refine specific approaches. Ultimately, the goal will be to intensify treatment for tumors
demonstrating aggressive biologic behavior and limit treatment for more indolent tumors. Without better
validated biomarkers, clinicians are faced with making decisions about therapy based on stage, tumor
location, and other clinical factors. Currently, there are limited data and clinical guidance available to
help clinicians navigate the emerging options and, therefore, the American Society for Radiation
Oncology (ASTRO) proposed the development of a Clinical Practice Statement to address two clinical
situations that provide opportunities for a more individualized approach. Specific questions addressed
included:
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How to appropriately individualize the use of (neo)adjuvant radiation therapy for patients with
How to appropriately customize non-surgical therapy for rectal cancer patients who are
medically inoperable or who have low-lying tumors and are attempting to avoid an
abdominoperineal resection.
Appropriateness Method to define best practice with respect to neoadjuvant or adjuvant radiation
therapy and non-operative management among stage II or III rectal cancer patients. Specific clinical
scenarios incorporating known risk factors for recurrence were developed to help stratify these patients
into more discrete subgroups and were presented to a multi-specialty expert panel to determine
appropriate management for these cases. The Clinical Practice Statement also addresses radiation
techniques, such as intensity modulated radiotherapy (IMRT), and other clinical considerations. We
believe that a Clinical Practice Statement on this subject will be useful for oncology and for day to day
Process
The ASTRO Board of Directors approved the creation of a Clinical Practice Statement on how to
appropriately customize radiation therapy for stage II and III rectal cancer in May 2013. A working
group of physicians from radiation oncology, medical oncology, and surgery who specialize in
gastrointestinal cancers oversaw a comprehensive literature review conducted by ASTRO staff and
developed the scenarios and definitions during a series of discussions by conference call and electronic
mail. A multidisciplinary expert panel was selected to review the literature and rate the scenarios. The
7
working group reconvened to interpret the ratings from the expert panel and draft the Clinical Practice
Statement. The document was reviewed by the expert panel, the Best Practices Subcommittee, and the
Clinical Affairs and Quality Committee. It also underwent four weeks of public comment during March
and April 2015. The final draft was approved by the Board of Directors in June 2015.
This Clinical Practice Statement uses the RAND/UCLA Appropriateness Method, which was
created during the 1980s with the goal of offering a rigorous way to “combine the best available
scientific evidence with the collective judgment of experts to yield a statement regarding the
appropriateness of performing a procedure at the level of patient-specific symptoms, medical history and
test results.”33 This method has been applied to a wide range of medical disciplines, including a number
of other oncology topics,34-38 and incorporates a multidisciplinary expert panel to rate the scenarios in
order to mitigate the fact that physicians often rate treatments they deliver as more appropriate than
For this Clinical Practice Statement, each scenario was rated Appropriate, May Be Appropriate,
or Rarely Appropriate. An Appropriate rating indicates that the expected benefit for the patient is
sufficiently greater than the risks under most circumstances to make it worthwhile and reasonable to use
the treatment. However, because a therapy is Appropriate does not mean it is required in all patients like
those described in the scenario. Similarly, a Rarely Appropriate rating shows that the anticipated risks
are considered higher than the benefits in most patients with the characteristics in that scenario, but
should not be taken to mean that it is never reasonable to apply the intervention under those
circumstances. Treatments rated May Be Appropriate have evidence that is limited, mixed, or subject to
disagreement or the balance of the risks and benefits is currently unclear. However, the therapy may be
appropriate and reasonable for some patients similar to those in the scenario.
8
Literature review
A systematic literature review was carried out using MEDLINE PubMed, Embase, and the
Cochrane Library to identify studies published between January 1990 and July 2013 that evaluated
patients 18 years or older with stage II or III rectal cancer receiving radiotherapy and/or chemotherapy.
Both resectable and medically inoperable patients were included. The electronic searches were
supplemented by hand searches and a total of 1571 articles were initially retrieved. These were screened
based on the exclusion criteria to remove articles that were: case reports, stage I or IV only, non-English
language, recurrent disease, abstract only, phase I studies, focused on tolerability or dosage without
survival or relapse outcomes, or otherwise not relevant. For trials of neoadjuvant or adjuvant radiation
therapy, studies that were retrospective or had ten patients or fewer were also excluded. Where the same
study was reported at multiple time points, only the latest one was retained. Ultimately, 228 full-text
articles were selected for inclusion and the data were abstracted to create detailed literature tables.
The scenarios were split into four sections: neoadjuvant therapy, adjuvant therapy, medically
inoperable patients, and patients seeking to avoid abdominoperineal resection (APR). First, the working
group compiled a list of factors that might influence physicians’ choice of therapy. Second, factors
relevant to each section were combined to create a set of scenarios representing patients a radiation
oncologist might see in practice, along with potentially appropriate therapies. Both the factors included
and the treatments assessed varied by section and are described in the Results. The Clinical Practice
Statement also included two questions addressing the relative appropriateness of delivering neoadjuvant
and adjuvant radiation with three-dimensional conformal radiation therapy (3D-CRT) versus IMRT.
9
There were 237 total initial scenarios. A definition list was also created to give a common understanding
Expert Panel
The expert panel was charged with rating the scenarios based on the literature review and
definitions developed by the working group. The panel was composed of physicians in radiation
oncology (including both specialists and a non-specialist in gastrointestinal tumors), medical oncology,
colorectal surgery, gastroenterology, and general internal medicine. Prospective participants were
identified through nominations from ASTRO committees and external outreach to other medical
specialty societies. Invited panelists were selected by the Best Practices Subcommittee based on
specialty, geographic region, practice setting, and availability for the in-person meeting and
subsequently screened for potential conflicts and bias. The final ten-member panel (Table 1) was made
up of eight physicians who worked in academic settings and two who were in private or community-
based practice.
For each scenario, the panel rated the appropriateness of the treatment from 1 to 9. A “1”
indicated much greater anticipated harm than benefit and a “9” much higher expected benefit than harm.
A “5” signified balanced harm and benefit or that the rater felt unable to reach a conclusion.
physician” in an “average facility” and not to consider cost or cost-effectiveness. Prior to rating, an
orientation to the rating procedure and materials was held. The expert panel rated the scenarios in two
rounds. The initial rating was performed independently via an online survey during February and March,
2014.
A face-to-face meeting of the expert panel was held on April 5th, 2014 in Alexandria, Virginia
and was overseen and moderated by a moderator experienced in the RAND process. Each panelist
received an individualized form showing their own rating per indication and the median and mean
distance from the median for the entire panel. During the meeting, the panelists discussed the scenarios
and then re-rated them using the same survey and process. Panelists were not forced to reach agreement.
The expert panel was asked in July 2014 to rate three scenarios a third time due to inconsistencies in the
second round results and the resulting ratings replaced those from the second round.
Statistical analyses
Ratings for the first and second rounds were analyzed by a statistician using SAS statistical
software. For the third round, due to the small number of ratings, Excel was used. For all rounds, the
median and the mean distance from the median were calculated for each scenario. The median was used
to measure central tendency because the responses were ordinal and the distance between points on the
11
scale was not fixed. Average distance from the median was used to measure dispersion. Treatments were
rated Rarely Appropriate when the median was 1 to 3 without disagreement, May Be Appropriate when
it was 4 to 6 or there was disagreement, and Appropriate when it was 7 to 9 without disagreement.
Disagreement was defined as ≥3 ratings from 1 to 3 and ≥3 from 7 to 9 on the same item.
Results
The expert panel evaluated 237 scenarios during the initial round of rating and 209 during the
second. The scenarios were organized in four sections and an additional question on IMRT. Throughout
the scenarios, only patients with stage II or III rectal cancer were included. In the first round, 28.3% (67
scenarios) were rated Appropriate, 38.4% (91 scenarios) were rated May Be Appropriate, and 33.3% (79
scenarios) were rated Rarely Appropriate. There was disagreement on 7.2% (17 scenarios). After face-
to-face discussion, 27.3% (57 scenarios) were rated Appropriate, 44.0% (92 scenarios) were rated May
Be Appropriate, and 28.7% (60 scenarios) were rated Rarely Appropriate. There was only one second
round scenario with disagreement. Three scenarios were rated a third time due to an inconsistency in the
ratings during the second round. As a result, one scenario moved from a rating of May Be Appropriate
to Rarely Appropriate and one scenario changed from a rating of Rarely Appropriate to May Be
Neoadjuvant therapy
The first section included 105 scenarios. It considered the role of the distance of the distal edge
of the tumor from the anal verge, distance from the radial tumor edge to edge of mesorectal fascia
(based on magnetic resonance imaging [MRI]), and risk classification on the appropriateness of
radiation and/or chemotherapy. Intermediate risk was defined as T1-2N1 or T3N0. Moderately high risk
12
included T1-2N2, T3N1, or T4N0 tumors. High risk encompassed T3N2 or T4N1-2. These
classifications were adapted from Gunderson et al.13 The use of distance to the edge of the mesorectal
fascia on MRI (see Figure 1 for example) reflects the trend in the United States for MRI to replace
endoscopic ultrasonography (ERUS) as the standard for staging, although ERUS may still be more
reliable at distinguishing between T2 and T3 disease. It also aligns with the National Comprehensive
Cancer Network (NCCN) guideline on rectal cancer, which likewise considers MRI part of the staging
workup.8 For patients in the high risk category, the distance from the tumor to the mesorectal fascia was
fractions based on the Dutch TME study41,42 and endorectal brachytherapy was based on a Canadian
13
applicator and Iridium-192 afterloading technique.43 Standard chemoradiation was considered to be 45
Gy to the whole pelvis with a conedown to exclude small bowel to 50.4 Gy with concurrent infusional
For the initial round, 26.7% (28 scenarios) were rated Appropriate, 16.2% (17 scenarios) were
rated May Be Appropriate, and 57.1% (60 scenarios) were rated Rarely Appropriate. Disagreement was
present on 8.6% (9 scenarios). At the meeting, 27.6% (29 scenarios) were rated Appropriate, 24.8% (26
scenarios) were rated May Be Appropriate, and 47.6% (50 scenarios) were rated Rarely Appropriate.
There were no scenarios with disagreement. In the third round, one scenario was changed to Rarely
Appropriate from May Be Appropriate and another became May Be Appropriate from Rarely
Appropriate.
The expert panel always rated conventionally fractionated chemoradiation Appropriate for
patients with stage II and III rectal cancer with a median rating of 9 (Figure 5). While the ratings were
not as high (medians 5 to 7) as for long-course chemoradiation, the panel also rated neoadjuvant short-
course radiation May Be Appropriate to Appropriate depending on risk and tumor location (Figure 2).
There were no situations where short-course radiation was rated Rarely Appropriate. The panel rated
neoadjuvant chemotherapy alone May Be Appropriate for certain patients, particularly those with large
margins from the mesorectal fascia in intermediate and moderately high risk disease. Panelists mostly
rated this approach Rarely Appropriate in patients with closer mesorectal fascia margins as well as high
risk disease (Figure 3). The expert panel rated endorectal brachytherapy alone as Rarely Appropriate for
all patients (Figure 4) although it was noted that this could be considered in the setting of a clinical trial.
Finally, regarding panelists’ views on omitting neoadjuvant therapy in stage II and III rectal cancer, they
rated it May Be Appropriate in patients with intermediate risk disease ≥5 cm from the anal verge with
non-threatened mesorectal fascia, and moderately high risk disease that was >10 cm from the anal verge
14
and had no threatened mesorectal fascia (Figure 6). In other situations, the expert panel rated it Rarely
15
Figure 2. Appropriateness of neoadjuvant short-course RT
M A M A M A M
* Intermediate risk = T1-2N1, T3N0, Moderately high risk = T1-2N2, T3N1, High risk = T3N2, T4N1-2
^ Based on MRI
A = Appropriate (median 7-9 without disagreement), M = May Be Appropriate (median 4-6 or disagreement)
16
Figure 3. Appropriateness of neoadjuvant chemotherapy alone
R M R M M R R M R M R
* Intermediate risk = T1-2N1, T3N0, Moderately high risk = T1-2N2, T3N1, High risk = T3N2, T4N1-2
^ Based on MRI
M = May Be Appropriate (median 4-6 or disagreement), R = Rarely Appropriate (median 1-3 without disagreement) 17
Figure 4. Appropriateness neoadjuvant Figure 5. Appropriateness of neoadjuvant
endorectal brachytherapy alone chemoradiation
R A
A = Appropriate (median 7-9 without disagreement), R = Rarely Appropriate (median 1-3 without disagreement)
18
Figure 6. Appropriateness of no neoadjuvant therapy
R R M R M R R M R
* Intermediate risk = T1-2N1, T3N0, Moderately high risk = T1-2N2, T3N1, High risk = T3N2, T4N1-2
^ Based on MRI
M = May Be Appropriate (median 4-6 or disagreement), R = Rarely Appropriate (median 1-3 without disagreement) 19
1 Adjuvant therapy
2 There were 38 scenarios in the second section addressing the options for adjuvant therapy in
3 stage II and III rectal cancer. Only patients with no gross residual disease after curative surgery were
4 included and patients had not received neoadjuvant therapy. The scenarios looked at the impact of
5 circumferential resection margin (CRM), risk classification, distance from the anal verge, and total nodal
6 count. A positive margin was defined as tumor within 1 mm from the inked margin. The first round
7 resulted in 52.6% (20 scenarios) rated May Be Appropriate, and 47.4% (18 scenarios) rated Appropriate.
8 There was disagreement on 5.3% (2 scenarios). For the second round, 50.0% (19 scenarios) were rated
9 Appropriate and 50.0% (19 scenarios) were rated May Be Appropriate. Disagreement was seen on 2.6%
11 The expert panel was asked to consider the benefit of chemoradiation in addition to ≥4 months of
12 chemotherapy and of chemotherapy alone in the adjuvant setting in the setting of a patient resected with
13 a positive CRM. Chemoradiation was assumed to be standard, long-course pelvic radiotherapy with
14 concurrent infusional 5-FU or capecitabine and chemotherapy could be adjuvant 5-FU and leucovorin,
15 FOLFOX, capecitabine, or CapeOx. Panel members identified the occurrence of a positive margin in a
16 patient who did not undergo pre-operative chemoradiation as “inadvertent” and potentially suggestive of
17 poor quality surgery in the era of TME, more accurate pre-operative staging and imaging, and the
18 established role of pre-operative pelvic radiotherapy. The panel rating of 9 (the maximum in the
20 chemotherapy (Figure 7). The panel rating of 4 for chemotherapy alone just met criteria for May Be
21 Appropriate, reflecting some uncertainty to this approach in the setting of positive margins, although it
20
23 The reporting of pathologic assessment of the quality of TME surgery was identified as not being
24 routinely and consistently available. Given that the quality of surgery is a well-established determinant
25 of locoregional recurrence risk, the number of lymph nodes examined was used as a surrogate of optimal
26 surgery. Panel experts were provided a cut off of <12 or ≥12 nodes examined as a surrogate of the
27 quality of TME surgery and pathologic evaluation. In the setting of negative margins and intermediate
28 risk, the expert panel did not alter the recommendation for post-operative chemoradiation plus adjuvant
29 chemotherapy based on the number of nodes examined. The primary cancer location as measured by
30 distance from the anal verge was a determinant of score for post-operative chemoradiation plus adjuvant
31 chemotherapy. The expert panel rating changed from Appropriate to May Be Appropriate for tumors
32 >10 cm from the anal verge indicating less certainty about pelvic chemoradiation for more proximal
33 rectal tumors. Chemotherapy alone was rated May Be Appropriate for all scenarios.
34 In the setting of negative margins and moderately high risk, the number of nodes examined also
35 did not alter the expert panel’s recommendation for post-operative chemoradiation plus adjuvant
36 chemotherapy. The panel provided a slightly lower rating within the Appropriate category for post-
37 operative chemoradiation plus adjuvant chemotherapy as the distance from the anal verge increased.
38 Chemotherapy alone was also rated Appropriate for tumors >10 cm above the anal verge and May Be
39 Appropriate for more distal tumors. In the setting of negative margins and high risk, the expert panel felt
40 that post-operative chemoradiation plus adjuvant chemotherapy was Appropriate, regardless of the
41 number of nodes examined or distance from the anal verge. Chemotherapy alone was rated May Be
42 Appropriate in the negative margin, high risk group, also regardless of number of nodes examined or
21
Figure 7. Appropriateness of adjuvant chemoradiation (plus ≥4 months of chemo)
Circumferential
Positive margin Negative margin
margin
A A M A A
* Intermediate risk = T1-2N1, T3N0, Moderately high risk = T1-2N2, T3N1, High risk = T3N2, T4N1-2
A = Appropriate (median 7-9 without disagreement), M = May Be Appropriate (median 4-6 or disagreement)
22
Figure 8. Appropriateness of adjuvant chemotherapy alone
1
Stage II and III
rectal cancer
M M M A M
* Intermediate risk = T1-2N1, T3N0, Moderately high risk = T1-2N2, T3N1, High risk = T3N2, T4N1-2
A = Appropriate (median 7-9 without disagreement), M = May Be Appropriate (median 4-6 or disagreement)
23
2 Medically inoperable patients
3 The third section contained 60 scenarios. The factors considered in this section were
4 performance status, presence of local symptoms, and distance from the anal verge. Good performance
5 status was defined as Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 and poor
6 performance status as ECOG performance status 2 or greater. The appropriateness of five treatments
7 was rated: external beam radiation alone, endorectal brachytherapy, chemoradiation alone,
8 chemoradiation plus endorectal brachytherapy, and chemotherapy alone. In the first round, 18.3% (11
9 scenarios) were rated Rarely Appropriate, 71.7% (43 scenarios) were rated May Be Appropriate, and
10 10% (6 scenarios) were rated Appropriate. Only 1.7% (1 scenario) had disagreement. In the second
11 round, 10.0% (6 scenarios) were rated Appropriate, 73.3% (44 scenarios) rated May Be Appropriate,
12 and 16.7% (10 scenarios) rated Rarely Appropriate. There were no scenarios with disagreement.
13 Although data regarding best treatment for medically inoperable rectal cancer are limited, there
14 was general agreement from the expert panel across all scenarios. Chemoradiation alone was
15 consistently rated Appropriate for good performance status patients and May Be Appropriate for poor
16 performance status patients (Figure 12). External beam radiation alone was rated May Be Appropriate
17 for all medically inoperable scenarios (Figure 11). Chemotherapy alone was also rated May Be
18 Appropriate, although supporting data are limited (Figure 13). Endorectal brachytherapy alone was not
19 rated Appropriate for any scenario, but rather was largely rated May Be Appropriate for tumors less than
20 10 cm from the anal verge (Figure 9). The combination of chemoradiation and endorectal brachytherapy
21 was rated May Be Appropriate for scenarios with tumor <10 cm from the anal verge with the exception
22 of poor performance status patients with tumors 5-10 cm from the anal verge, which was rated Rarely
24
24 Location from the anal verge was only a factor for endorectal brachytherapy and the presence or
25 absence of symptoms had minimal impact on ratings. It is important to note that, if definitive doses of
26 endorectal brachytherapy are delivered (6.5 Gy x 4), patients may have increased rectal symptoms if
27 they do not undergo resection. The only effect of performance status was on the use of chemotherapy in
28 combination with radiation, which was rated Appropriate in good performance status patients. These
29 were the only scenarios rated Appropriate by the panel. Patients with medically inoperable rectal cancer
30 were rated May Be Appropriate for external beam radiation alone or chemotherapy alone, for most
31 scenarios for endorectal brachytherapy alone and chemoradiation plus endorectal brachytherapy if < 10
25
Figure 9. Appropriateness of definitive endorectal brachytherapy
Medically inoperable
stage II and III rectal
cancer
M R M R M R
M = May Be Appropriate (median 4-6 or disagreement), R = Rarely Appropriate (median 1-3 without disagreement)
26
Figure 10. Appropriateness of definitive chemoradiation plus endorectal brachytherapy
Medically inoperable
stage II and III rectal
cancer
Good Poor
Performance status performance performance
status status
M R M R M R
M = May Be Appropriate (median 4-6 or disagreement), R = Rarely Appropriate (median 1-3 without disagreement)
27
Figure 11. Appropriateness of definitive Figure 12. Appropriateness of definitive Figure 13. Appropriateness of definitive
1
EBRT chemoradiation chemotherapy alone
2
Medically inoperable Medically inoperable Medically inoperable
stage II and III rectal stage II and III rectal stage II and III rectal
cancer cancer cancer
M A M M
A = Appropriate (median 7-9 without disagreement), M = May Be Appropriate (median 4-6 or disagreement)
28
3 Patients seeking to avoid/refusing APR
4 The fourth section was comprised of 32 scenarios in the initial round. All patients covered had
5 low-lying tumors (<5 cm from the anal verge) and were otherwise operative candidates but were
6 attempting to achieve response to chemoradiation and avoid permanent colostomy. It was specified that
7 patients who progressed or did not respond to chemoradiation (based on physician assessment) should
8 receive an APR. The scenarios incorporated three factors: nodal status, T-category, and whether a full
9 thickness transanal excision had been performed. Patients who had T1 or T2 tumors and were node
10 negative were excluded since they have stage I disease and are outside the scope of this Clinical Practice
11 Statement. The treatments rated in the first round were endorectal brachytherapy, chemoradiation,
13 After extensive discussion during the in-person meeting, the expert panel, which was composed
14 of a multidisciplinary group including several colorectal surgeons, decided not to rate the individual
15 scenarios since the overall question was whether there is any alternative to an APR in patients who
16 refuse surgery. The surgeons also made the argument that, although the original scenarios made a
17 distinction between whether a patient had a full thickness transanal excision or not, if a full-thickness
18 transanal excision were possible then a low anterior resection with a coloanal anastomosis could be
19 performed and an APR is not needed. The panel was also concerned that by rating the radiation options,
20 they would be recommending use of a non-standard therapy rather than having another surgeon
21 potentially perform a radical resection without an APR. Therefore, the panel opted to replace the section
22 with a single new question regarding patients with stage II or III very low lying tumors refusing the
23 standard treatment, APR, and emphasized the fact that this was in the setting of patient refusal and
24 therefore outside of the standard approach. Panelists were asked to then rate chemoradiation (standard
29
25 dose), chemoradiation (standard dose) plus endorectal brachytherapy boost, and chemoradiation with
27 In the first round, using the original questions, 25% (8 scenarios) were rated Rarely Appropriate,
28 28.1% (9 scenarios) were rated May Be Appropriate, and 46.9% (15 scenarios) were rated Appropriate.
29 Disagreement was found for 12.5% (4 scenarios). In the second round, with the new question, all three
30 scenarios were rated Appropriate with no disagreement. The panel felt that in the scenario of patient
31 refusal of an APR, any of the radiation approaches could be justified (Figures 14 to 16).
30
32 Figure 14. Appropriateness of definitive Figure 15. Appropriateness of definitive Figure 16. Appropriateness of definitive
chemoradiation (standard dose) chemoradiation (standard dose) plus endorectal chemoradiation (standard dose) with EBRT
33 brachytherapy boost
Stage II and III rectal Stage II and III rectal Stage II and III rectal
cancer cancer cancer
Patient with very low Patient with very low Patient with very low
lying tumor refusing lying tumor refusing lying tumor refusing
abdominoperineal abdominoperineal abdominoperineal
resection resection resection
A A A
35 In addition to the four sections, two supplemental questions were also included, which asked the
36 Expert Panel to rate the appropriateness of using IMRT to deliver neoadjuvant and adjuvant treatment.
37 IMRT was rated May Be Appropriate in both settings during the first round, with disagreement seen for
38 neoadjuvant therapy. For the second round of rating, neoadjuvant therapy was separated into short-
39 course RT and chemoradiation at the request of the expert panel. All three options were subsequently
41 While the question addressed the use of IMRT in three different scenarios, neoadjuvant short-
42 course pelvic radiotherapy, neoadjuvant long-course chemoradiation, and adjuvant chemoradiation, the
43 ratings were all May Be Appropriate (Figures 17 to 19). Further distinction between the situations was
44 not possible due to the lack of familiarity with the technical aspects of IMRT versus 3D-CRT among the
45 non-radiation oncologists on the panel. Thus, the multidisciplinary expert panelists deferred for this
46 question to the radiation oncologists who generally felt that the use of IMRT would be a case-by-case
47 decision and there might be extenuating circumstances when it would add substantial benefit.
32
48
Figure 17. Appropriateness of neoadjuvant short- Figure 18. Appropriateness of neoadjuvant Figure 19. Appropriateness of adjuvant therapy
course RT delivered with IMRT chemoradiation delivered with IMRT delivered with IMRT
Stage II and III rectal Stage II and III rectal Stage II and III rectal
cancer cancer cancer
M M M
50 The analysis of the ratings of the many clinical scenarios that were evaluated by the expert panel
51 demonstrate that, while a standard treatment approach exists in stage II and III rectal cancer, further
52 studies are necessary to refine the treatment recommendations. The expert panelists had very good
53 agreement (only one final scenario had disagreement) for the appropriateness of the various treatment
54 options presented, which reflects the excellent multidisciplinary approach that has been applied to the
56 chemotherapy alone, and non-operative management in the setting of patient refusal of an APR were
57 included in this Clinical Practice Statement, despite the lack of widespread use or limited high level
58 evidence regarding these options in the United States, to provide practicing radiation oncologists with
59 the current assessment of the appropriateness of these options. Given the strong relationship between the
60 quality of TME surgery and local recurrence, a relationship that is not mitigated by the use of adjuvant
61 radiation,44 we assumed high quality TME surgery was performed when rating scenarios that included
62 surgery.
63
64 Neoadjuvant therapy
65 Patients presenting for neoadjuvant therapy before definitive surgery make the bulk of referrals
66 for rectal cancer to the radiation oncologist. Following the seminal German rectal cancer trial,7 it was
67 established that neoadjuvant chemoradiation improves local control with decreased toxicity as compared
68 with adjuvant chemoradiation. The approach offered in this trial, conventionally fractionated radiation
69 therapy with concurrent 5-FU based chemotherapy, was considered appropriate by all of the expert
70 panel members for stage II and stage III rectal cancer. This is also reflected in other clinical guidelines,
34
72 More interestingly, panelists rated neoadjuvant short-course radiation therapy Appropriate in
73 many patients with non-threatened mesorectal fascia margins and May Be Appropriate in other patients.
74 This is consistent with the fact that short-course is not intended for downstaging as usually surgery is
75 performed within one to two weeks of finishing radiation therapy. The ratings have also been supported
77 therapy,48 and no therapy.42 There are also ongoing randomized studies looking to incorporate short-
78 course radiation with neoadjuvant chemotherapy.49,50 Although the use of short-course radiation has
79 been relatively uncommon in North America and has only recently been included in the current NCCN
80 guidelines, the Appropriate rating from the expert panel in this Clinical Practice Statement, based on
82 option.51,52
83 Another emerging area is the use of neoadjuvant chemotherapy alone for selected patients with
84 stage II or III rectal cancer. While the accrual of a large, phase III randomized trial is ongoing,18 the
85 expert panel rated this approach May Be Appropriate for selected patients in intermediate and
86 moderately high risk disease with non-threatened mesorectal fascia. There was no patient group that
87 neoadjuvant chemotherapy alone was rated Appropriate for and this regimen is not offered in the NCCN
88 guidelines currently. However, NCCN does now include induction chemotherapy followed by
89 chemoradiation, which was not part of the scenarios for this clinical practice statement.
90 Neoadjuvant brachytherapy alone was rated Rarely Appropriate across the scenarios. This has
91 been performed by select centers.53 This remains an area of active investigation and may be more
92 relevant in patients who are not surgical candidates, as described in the medically inoperable section, or
93 as a boost in well-selected patients.54 Finally, the expert panel rated forgoing neoadjuvant therapy
94 altogether for certain patients with stage II or III rectal cancer May Be Appropriate. These included
35
95 patients with mid to high rectal cancers with a non-threatened mesorectal fascia, undergoing TME. This
96 acknowledges that potential patient benefit from neoadjuvant therapy may be diminished by treatment-
97 related toxicity, and that these patients may be evaluated for adjuvant therapy based on pathologic
98 findings.
99
101 Since modern practice has established the role of neoadjuvant radiation regimens as the standard
102 treatment for locally advanced rectal tumors,6 a positive CRM should be an uncommon clinical scenario
103 and may reflect inadequate pre-operative imaging, suboptimal TME technique, or very poor or
104 aggressive tumor biology. Understaging or lack of identification of a threatened mesorectal margin pre-
105 operatively may also increase the risk of a post-operative positive CRM. When a positive margin does
106 occur, especially in the setting of high-quality surgery, it is associated with poor outcomes and the
107 question of how to address the potentially residual disease in the post-operative setting is always a
108 difficult one. There is no level 1 evidence to guide the management of a positive CRM but data from
109 clinical trials highlight the increased risk of local recurrence.42,44 High rates of long term local failure,
110 48.6% R1 vs. 7.7% R0, were observed on the adjuvant chemoradiation arm of the pre-operative vs. post-
111 operative randomized German rectal cancer trial.7 A randomized trial (MRC CR07 + NCIC CTG C016)
112 of selective chemoradiation for patients with a positive CRM demonstrated inferior local control
113 compared to pre-operative short-course pelvic radiation therapy.55 However, there is no clinical trial
114 comparing adjuvant pelvic chemoradiotherapy to chemotherapy or observation alone on the setting of
115 positive margins. In the absence of clinical trials, post-operative chemoradiotherapy plus adjuvant
116 chemotherapy remains the standard treatment regimen in the setting of a positive CRM.
36
117 However, the alternative strategy of adjuvant chemotherapy alone in the setting of positive CRM
118 was also rated May Be Appropriate to Appropriate. This may be an option for patients who are not
119 eligible for post-operative therapy due to comorbid conditions, known contraindications to radiation
120 therapy, or patient refusal. Adjuvant chemotherapy alone might also be appropriate for patients with a
121 very high risk of systemic relapse, with the caution that chemotherapy alone may be associated with a
122 higher rate of locoregional recurrence, which is associated with significant morbidity both from the
124 For adjuvant radiation and chemotherapy in the setting of negative CRM , the data are largely
125 derived from studies performed in the pre-TME era, when transmural or node positive cancers had a
126 local recurrence risk as high as 50%,56 which led to the NCI consensus statement in 19905 that adjuvant
127 chemoradiation was the new standard regimen. The expert panel was asked to consider the role of
128 adjuvant chemoradiation in the TME era, considering the individualized local control benefit and the
129 potential for normal tissue toxicity when pelvic radiotherapy is delivered in the post-operative setting.7
130 For most scenarios, adjuvant chemoradiation plus chemotherapy was rated Appropriate (Figure 7).
131 Adjuvant chemotherapy alone was rated May Be Appropriate or Appropriate (Figure 8), indicating that
132 the expert panel supported the approach that, with pathologic information demonstrating that for
133 intermediate risk disease (T3N0, T1-2N1), adjuvant chemotherapy results in similar outcomes as
134 adjuvant chemoradiation, based on pooled analyses of prospective data comparing adjuvant therapy
136 The panel was also provided the number of lymph nodes reported in the pathology report as a
137 surrogate to estimate the adequacy of the surgical resection since this may often be the only quality
138 indicator available. However, node count may be a marker of the quality of pathology as well as surgery
139 and may also reflect disease biology. While the optimal lymph node yield for rectal cancer without
37
140 neoadjuvant therapy is still controversial, the <12 vs. ≥12 nodes examined was used in each risk based
141 scenario.57 Interestingly, the lymph node count did not alter the expert panel’s ratings for most scenarios,
142 thus reflecting the relative lack of utility of nodal count as a measure of quality of rectal cancer surgery.
143 The relationship between the location of the primary rectal cancer as measured by distance from
144 the anal verge and the benefit of pelvic radiotherapy also remains the subject of differing opinions. In
145 the pre-operative setting with TME surgery, secondary subset analyses have evaluated the benefit of
146 pelvic radiotherapy based on primary tumor location. The long term report of the Dutch TME trial
147 demonstrated that the benefit of short-course pre-operative pelvic radiotherapy was greater for greater
148 distance from the anal verge (p=0.03).42 If patients with a positive CRM were excluded from the
149 analysis, the relationship between the distance from the anal verge and radiotherapy disappeared and
150 irradiated patients had higher cancer-specific survival independent of distance from the anal verge.42
151 The Trans-Tasman Radiation Oncology Group (TROG) compared pre-operative short-course pelvic
153 (p=0.21) trend toward decreased local recurrence for long-course treatment and tumors <5 cm from the
154 anal verge.47 In the adjuvant setting, 11 year data from the pre-operative vs. post-operative German
155 Rectal Cancer Trial, showed that at 10 years, post-operative chemoradiation was associated with a LR
156 risk of 9.3% vs. 18.7% if no post-operative treatment was delivered if the tumor was at 5 to <10 cm and
157 2.7% vs. 10.4% if the tumor was at 10-16 cm. On multivariate analysis, not receiving chemoradiation
158 was significantly associated with a higher local recurrence risk.7 Overall, there was general agreement
159 among the expert panel that increasing distance from the anal verge was associated with lower risk of
161 For low lying rectal cancers <5cm from the anal verge, there was strong agreement in rating
162 adjuvant chemoradiation Appropriate for all patients regardless of risk category or number of nodes
38
163 examined. Long-term data from the Swedish Rectal Cancer Trial in the pre-TME era shows that the
164 local recurrence rate was 27% for tumors ≤5cm from anal verge, 26% for tumors 6-10 cm, and 12% for
165 tumors ≥11 cm.58 Moreover, the type of surgery performed may be considered as well, since data from
166 the Dutch CKVO trial have shown that, even with a good TME and a negative CRM, APR was
167 associated with presacral local recurrences.59 Post-operative chemoradiation was also associated with a
168 higher risk of local recurrence on multivariate analysis from updated data from the German Rectal
169 Cancer Trial in patients who had surgery that included intersphincteric resection or APR compared with
171 The panelists rated adjuvant chemotherapy alone May Be Appropriate for patients with low-
172 lying rectal cancers, including those where there is concern about an increased risk of toxicity to the
173 anastomosis depending on the type of surgery that has been performed (i.e. a hand-sewn coloanal
174 anastomosis). With post-operative chemoradiation, grade 3-4 anastomotic toxicity was seen in 12% of
176 For R0 resected tumors at 5-10 cm from the anal verge, there was again strong consensus that
177 adjuvant regimens containing pelvic radiotherapy are appropriate. The surgeons on the panel noted that
178 more proximal anastomoses would be anticipated to better tolerate pelvic radiation. Strategies to
180 As the distance of the tumor from the anal verge increased to >10 cm, the strength of the
181 recommendation for adjuvant regimens containing radiation decreased. Intermediate risk tumors in this
182 category were rated as May Be Appropriate. Within the intermediate risk category, data from
183 Gunderson et al. have noted a 7% local failure for T1-2/N1 tumors vs. a 9% local failure for T3N0
184 tumors.13 Thus by risk category as well as distance from the anal verge, this category of patients would
185 be expected to have a relatively low rate of local failure, particularly in the more modern era with the
39
186 use of TME. For high risk tumors >10 cm from the anal verge, panelists rated the adjuvant radiation
187 regimens Appropriate but at the lowest end of this category (median of 7). However, it should be noted
188 that the location of the peritoneal reflection can vary in relation to the distance from the anal verge.
189 Therefore tumors at >10 cm from the anal verge may or may not be intraperitoneal. Adjuvant
190 chemotherapy only regimens were rated May Be Appropriate for intermediate and high risk tumors
191 regardless of nodes examined and Appropriate for tumors of moderate risk.
192
194 Medically inoperable patients are rare and there are limited data to guide choice of therapy. In
195 addition, this group of patients is heterogeneous with regard to reasons for inoperability. Factors other
196 than performance status and presence of symptoms likely impact choice of therapy. Uncontrolled pelvic
197 malignancy is known to be associated with significant symptoms in most patients. Thus, there was clear
198 consensus by the expert panel that local therapy, including some form of chemoradiation, is appropriate
200 With the emerging data from the operable patients showing non-operative management may be
201 curative for selected patients with a clinical complete response after pre-operative chemoradiation,31,32,60
202 there was general consensus that chemoradiation was rated Appropriate. External beam radiation
203 combined with endorectal brachytherapy without surgery has been associated with excellent outcomes in
204 patients with favorable rectal cancers (<12 cm from anal verge, <3cm diameter, mobile without
205 ulceration, T1-2, grade 1-2) and may be used for unfavorable patients who are medically inoperable.61,62
206 Local control in more advanced T2-3 distal rectal cancers has been reported in >70% of patients treated
207 with a combination of endorectal brachytherapy, external radiation and interstitial brachytherapy with 5-
208 year survival in excess of 60%.63 Given the excellent local control rates reported in selected patients and
40
209 potential for long-term survival, all medically inoperable patients should be evaluated for potentially
211 Endorectal brachytherapy alone has been demonstrated to be effective curative treatment for
212 grade 1-2, T1N0, < 3 cm diameter rectal cancers located < 10 cm from the anal verge.64 Extrapolating
213 from these data, the expert panel rated endorectal brachytherapy alone May Be Appropriate for
214 medically inoperable patients with distal tumors. In general, definitive endorectal high dose rate
215 brachytherapy is limited to tumors that are within 15 cm from the anal verge and less than 5 cm in
216 diameter given the dose of radiation to the surface.43,65 Also, endorectal brachytherapy is generally
217 contraindicated in patients with invasion of the anal sphincters given potential effects on sphincter
218 function. It should be noted that there are several approaches to rectal brachytherapy. The endorectal
219 approach based on the use of an endoluminal applicator and delivery of high-dose rate Iridium-192
220 using a remote afterloading technique was the technique evaluated in these clinical scenarios. However,
221 in Europe, early stage rectal tumors may be treated with Contact X-ray (50KV) brachytherapy (Papillon
222 technique) and more advanced tumors are addressed with interstitial transperineal Iridium-192 implants.
223 These approaches were not addressed in this Clinical Practice Statement since they are not commonly
225 The panel also felt that some patients in this section, particularly those with poor performance
226 status and an absence of local symptoms, should receive palliative treatment. However, this option was
228
230 There is also growing interest in non-operative management for operable patients with low-lying
231 rectal cancers who have achieved a cCR to pre-operative chemoradiation to improve quality of life
41
232 following treatment for rectal cancer. While sphincter preservation can be achieved in some patients by
233 performing a low anterior resection with a coloanal anastomosis, these procedures may be associated
234 with impaired long-term bowel function.22 In addition, patients face the morbidity and mortality
235 attendant with major abdominal surgery and the need for temporary diversion if restoration of intestinal
236 continuity is possible. Finally, rectal cancer surgery also impacts sexual functioning. Several prospective
237 studies have evaluated patient-reported quality of life after treatment for rectal cancer and have
238 demonstrated low scores, particularly in patients with stomas or low rectal anastomoses.23-25
239 However, since non-operative management for stage II or III disease is still considered a non-
240 standard approach, the panel did not want to rate its use for various clinical scenarios. The decision was
241 to address the situation in which a patient refuses standard therapy and consensus of the panel was that
242 local therapy with chemoradiation with or without endorectal brachytherapy was an inferior but
243 acceptable alternative to radical surgery. As more studies evaluate the non-operative approach with
244 intensive follow-up for patients with complete response to chemoradiation there may be future Clinical
245 Practice Statements that will have sufficient supporting literature to rate more specific clinical scenarios
246 and address additional considerations such as how to assess treatment response after chemoradiation.
247
248 IMRT
249 Further improvements in outcomes for rectal cancer patients may also come with incorporating
250 newer radiotherapy techniques to deliver more focal dose to the tumor and lymph node regions while
251 sparing the radiosensitive structures of the pelvis. By minimizing the toxicity to the normal tissues,
252 acute and long-term toxicities of pelvic radiotherapy may be reduced, thus improving the therapeutic
253 ratio of this approach. IMRT allows for more conformal delivery of radiotherapy by using computed-
254 tomography (CT) based planning and sophisticated computational software to generate treatment plans.
42
255 However, the increased cost and lack of reimbursement for IMRT in many gastrointestinal cancers has
256 also impacted on its use. For this reason, the question was framed to identify specific situations where
257 IMRT might be more useful, for instance with higher dose-per-fraction, such as with neoadjuvant short-
258 course RT where late effects have been shown to be significantly elevated versus surgery alone,19 as
259 well as in the post-operative setting, which is associated with more toxicity compared to neo-adjuvant
260 therapy.6
261 The use of IMRT for long-course neoadjuvant chemoradiation has been controversial in rectal
262 cancer given the lack of data addressing the benefit of a more conformal approach over standard 3-
263 dimensional conformal radiotherapy. The only prospective study evaluating the use of IMRT in rectal
264 cancer was a yet-to-be published, single-arm Phase II trial, RTOG 0822. This study evaluated the use of
265 concurrent capecitabine and oxaliplatin with pelvic radiotherapy using IMRT planning. The primary
266 endpoint was an improvement in Grade 2 or higher gastrointestinal toxicity in this study as compared to
267 the RTOG 0247 trial, which used the same chemotherapy regimen with non-IMRT pelvic
268 radiotherapy.66 RTOG 0822 failed to demonstrate a significant benefit to the use of IMRT. However,
269 interpretation of this study is limited by the use of concurrent oxaliplatin with 5-FU based
270 chemoradiation given there have been four large, phase III randomized trials demonstrating increased GI
271 toxicity when oxaliplatin is added to pre-operative chemoradiation.67-70 IMRT planning may not have
272 been able to overcome the effect of the oxaliplatin on GI toxicity. Several retrospective studies have
273 demonstrated a reduction in GI toxicity using IMRT over 3D-CRT for rectal cancer.71,72
274 IMRT is most likely to be of benefit when inclusion of external iliac lymph nodes is indicated on
275 the basis of a T4 tumor with adherence to or invasion of an anterior organ that has lymphatic drainage to
276 external iliac nodes, when there is a large volume of non-displaceable small bowel in the pelvis, or when
277 treatment of the inguinal nodal regions or perineal scar is indicated. IMRT may also be indicated in
43
278 patients with medical comorbidities such as inflammatory bowel disease, or a pelvic kidney, which may
280
282 Radiotherapy remains a standard component of management of rectal cancer; however, there is
283 still the need to further refine its role as part of neoadjuvant, adjuvant and definitive therapy in order to
284 better tailor therapy for patients with rectal cancer. This Clinical Practice Statement provides a
285 comprehensive overview of the therapeutic options for patients with locally advanced (Stage II/III)
286 rectal cancer and further classifies this larger group into subgroups based on known risk factors that
287 were described in the clinical scenarios. By utilizing a multi-disciplinary panel of experts, and including
288 both GI-specialized and non-GI-specialized radiation oncologists, the process effectively removes biases
289 which could result from a tendency to recommend treatments that are delivered by the panelists. Thus,
290 the appropriateness ratings were not only individualized and risk-stratified, but also representative of the
291 overall community of practitioners treating rectal cancer. Nonetheless, the ratings should not be taken
292 as absolutes, as there may be unique circumstances that require clinicians and patients to use best
293 clinical judgment in optimal decision making. The use of novel techniques such as IMRT was
294 considered in this Clinical Practice Statement and was felt to be potentially appropriate because it may
295 lead to less toxicity. However, further study to assess the impact of this approach on treatment outcomes
296 is warranted to ensure the appropriate technology utilization and this questions may be better answered
298 In the future, results of ongoing trials may help clarify areas of uncertainty, particularly with
299 regard to the use of neoadjuvant FOLFOX as an alternative to chemoradiation for selected risk-groups
300 of patients and the possibility of pursuing non-operative management in patients who have a complete
44
301 clinical response after chemoradiation. On-going studies of both molecular and imaging biomarkers may
302 also improve risk stratification and allow for more tailored therapies for rectal cancer patients.
303 Meanwhile, this Clinical Practice Statement will serve as an overview of options to help guide
304 physicians as we move toward more individualized approaches for our patients.
305
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500
502
503 Section 1: Neoadjuvant therapy
504
505 Neoadjuvant therapy, intermediate risk, <5 cm from anal verge
Short-course Endorectal Chemoradiation Chemotherapy No neoadjuvant
RT brachytherapy alone therapy
Tumor edge < 2 mm
from edge of 6 1
mesorectal fascia
3
Tumor edge 2-5 mm
from edge of 2 9
mesorectal fascia
7 3
Tumor edge >5 mm
from edge of 5
mesorectal fascia
506 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
507 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
508
509
510 Neoadjuvant therapy, intermediate risk, 5-10 cm from anal verge
49
Short-course Endorectal Chemoradiation Chemotherapy No neoadjuvant
RT brachytherapy alone therapy
Tumor edge < 2 mm
from edge of 5 3 1
mesorectal fascia
Tumor edge 2-5 mm
from edge of 2 9 3
mesorectal fascia 7
4
Tumor edge >5 mm
from edge of 4
mesorectal fascia
511 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
512 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
513
514
515 Neoadjuvant therapy, intermediate risk, >10 cm from anal verge
Short-course Endorectal Chemoradiation Chemotherapy No neoadjuvant
RT brachytherapy alone therapy
Tumor edge < 2 mm
from edge of 9 3
mesorectal fascia
4
Tumor edge 2-5 mm
from edge of 6 1 5
mesorectal fascia
8
Tumor edge >5 mm
from edge of 5 6
mesorectal fascia
516 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
517 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
518
519
520 Neoadjuvant therapy, moderately high risk, <5 cm from anal verge
Short-course Endorectal Chemoradiation Chemotherapy No neoadjuvant
RT brachytherapy alone therapy
Tumor edge < 2 mm
from edge of 5
mesorectal fascia
1
Tumor edge 2-5 mm
from edge of 2 9 3
mesorectal fascia
6
Tumor edge >5 mm
from edge of 2
mesorectal fascia
521 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
522 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
523
524
525 Neoadjuvant therapy, moderately high risk, 5-10 cm from anal verge
Short-course Endorectal Chemoradiation Chemotherapy No neoadjuvant
RT brachytherapy alone therapy
50
Tumor edge < 2 mm
from edge of 5 1
mesorectal fascia
3
Tumor edge 2-5 mm
from edge of 2 9
mesorectal fascia
7 2
Tumor edge >5 mm
from edge of 5
mesorectal fascia
526 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
527 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
528
529
530 Neoadjuvant therapy, moderately high risk, >10 cm from anal verge
Short-course Endorectal Chemoradiation Chemotherapy No neoadjuvant
RT brachytherapy alone therapy
Tumor edge <2 mm
from edge of 5 9 3 2
mesorectal fascia
Tumor edge 2-5 mm
from edge of 1 3
mesorectal fascia
7 8 4
Tumor edge >5 mm 4
from edge of
mesorectal fascia
531 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
532 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
533
534
535 Neoadjuvant therapy, high risk
Short-course Endorectal Chemoradiation Chemotherapy No neoadjuvant
RT brachytherapy alone therapy
<5 cm from anal verge 6
5-10 cm from anal 2 1
verge 1 9
5
>10 cm from anal 3 2
verge
536 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
537 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
538
51
545
546 Adjuvant therapy, negative circumferential margin, intermediate risk, <5 cm from anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes 9
examined 5
≥12 nodes 7
examined
547 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
548 disagreement)
549
550
551 Adjuvant therapy, negative circumferential margin, intermediate risk, 5-10 cm from anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes 5
examined 8
≥12 nodes 6
examined
552 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
553 disagreement)
554
555
556 Adjuvant therapy, negative circumferential margin, intermediate risk, ˃10 cm from the anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes 6
examined 6
≥12 nodes 5
examined
557 Yellow = May Be Appropriate (median 4-6 without disagreement)
558
559
560 Adjuvant therapy, negative circumferential margin, moderately high risk, <5 cm from the anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes
examined 9 5
≥12 nodes
examined
561 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
562 disagreement)
563
564
565 Adjuvant therapy, negative circumferential margin, moderately high risk, 5 -10 cm from the anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes
examined 9 6
52
≥12 nodes
examined
566 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
567 disagreement)
568
569
570 Adjuvant therapy, negative circumferential margin, moderately high risk, ˃10 cm from the anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes 8
examined 7
≥12 nodes 7
examined
571 Green = Appropriate (median 7-9 without disagreement)
572
573
574 Adjuvant therapy, negative circumferential margin, high risk, <5 cm from the anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes 6
examined 9
≥12 nodes 5
examined
575 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
576 disagreement)
577
578
579 Adjuvant therapy, negative circumferential margin, high risk, 5 -10 cm from the anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes 5
examined 9
≥12 nodes 5
examined
580 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
581 disagreement), grey = May Be Appropriate due to disagreement
582
583 Adjuvant therapy, negative circumferential margin, high risk, ˃10 cm from the anal verge
Chemoradiation (plus ≥4 Chemotherapy alone
months of chemo)
<12 nodes
examined 7 6
≥12 nodes
examined
584 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
585 disagreement)
586
587
588 Section 3: Medically inoperable patients
589
53
590 Medically inoperable, good performance status (ECOG 0-1), local symptoms present
External beam Endorectal Chemoradiation Chemoradiation Chemotherapy
RT alone brachytherapy plus endorectal alone
brachytherapy
<5 cm from anal verge 6
4 4
5-10 cm from anal 5 9 5
verge
>10 cm from anal 1 1 5
verge
591 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
592 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
593
594 Medically inoperable, good performance status (ECOG 0-1), local symptoms absent
External beam Endorectal Chemoradiation Chemoradiation Chemotherapy
RT alone brachytherapy plus endorectal alone
brachytherapy
<5 cm from anal verge 4 6
5
5-10 cm from anal 5 3 9 5
verge
>10 cm from anal 2 1 6
verge
595 Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without
596 disagreement), red = Rarely Appropriate (median 1-3 without disagreement)
597
598 Medically inoperable, poor performance status (ECOG ≥2), local symptoms present
External beam Endorectal Chemoradiation Chemoradiation Chemotherapy
RT alone brachytherapy plus endorectal alone
brachytherapy
<5 cm from anal verge 5 5
5
5-10 cm from anal 6 6 4 4
verge
>10 cm from anal 1 5 1
verge
599 Yellow = May Be Appropriate (median 4-6 without disagreement), red = Rarely Appropriate (median 1-3 without
600 disagreement)
601
602 Medically inoperable, poor performance status (ECOG ≥2), local symptoms absent
External beam Endorectal Chemoradiation Chemoradiation Chemotherapy
RT alone brachytherapy plus endorectal alone
brachytherapy
<5 cm from anal verge 5 4
6 5 4
5-10 cm from anal 4 3
verge
54
>10 cm from anal 1 1
verge
603 Yellow = May Be Appropriate (median 4-6 without disagreement), red = Rarely Appropriate (median 1-3 without
604 disagreement)
605
606 Section 4: Patients with very low lying tumor refusing APR
607 Patient with very low lying tumor refusing abdominoperineal resection
Chemoradiation (standard dose) Chemoradiation (standard dose) Chemoradiation with EBRT boost
plus endorectal brachytherapy
7 7 7
608 Green = Appropriate (median 7–9 without disagreement)
609
55
614 Appendix 2: Expert Panel members who were leads of rectal cancer clinical trials – January to June 2014
57