Appropriate Customization of Radiation Therapy for Stage II … · · 2016-04-26Clinical Practice...

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Appropriate Customization of Radiation Therapy for Stage II and III Rectal Cancer: An ASTRO

Clinical Practice Statement Using the RAND/UCLA Appropriateness Method

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,

Christopher H. Crane, M.D.12, Karen E. Hoffman, M.D.12

1. Department of Radiation Oncology, University of Colorado, Aurora, CO

2. American Society of Radiation Oncology, Fairfax, VA

3. Department of Medical Oncology, Stanford University, Stanford, CA

4. Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL

5. Department of Radiation Oncology, Mayo Clinic, Rochester, MN

6. Department of Radiation Oncology, Washington University, St. Louis, MO

7. Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto,

Toronto, ON, Canada

8. Division of General Surgery, St. Michael’s Hospital, University of Toronto, Toronto, ON,

Canada

9. Department of Radiation Oncology, Duke University, Durham, NC

10. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA

11. Department of Radiation Oncology, Johns Hopkins University, Baltimore, MD

12. Department of Radiation Oncology, M.D. Anderson Cancer Center, Houston, TX

* 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),

[email protected]

Conflict of Interest Disclosure Statement:

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

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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

for Abbott Laboratories.

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

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Eunice Chang, PhD for conducting the expert panel rating statistics and Margaret Amankwa-Sakyi for

literature review assistance.

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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

safely forgo a component of standard management without sacrificing disease control.11

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

chemoradiation is administered pre-operatively when pathologic staging is not available. Pre-operative

imaging may not correctly identify all patients with involved lymph nodes, making it difficult to omit

radiotherapy within the setting of uncertainty regarding clinical staging.14

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

evaluated in a large, randomized Phase II/III trial as a potential alterative to pre-operative

chemoradiation, although results will not be available for many years.18

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

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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

group of patients for whom an operation would result in a permanent colostomy.29-32

Scope and purpose

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

T3-4 or node positive rectal cancer.

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.

We thus sought to employ the RAND/ University of California-Los Angeles (UCLA)

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

management of rectal cancer patients.

Methods and Materials

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

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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

those they do not.39,40

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.

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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.

Literature summaries were also developed.

Clinical scenarios and definitions of terms

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.

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There were 237 total initial scenarios. A definition list was also created to give a common understanding

of the terms across all participants in the project.

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.

Table 1. Expert Panel Members

Specialty Name Institution

Radiation Oncology Patrick Francke, MD 21st Century Oncology, Myrtle Beach, SC

Salma Jabbour, MD Rutgers University, New Brunswick, NJ

Harvey Mamon, MD, PhD Brigham and Women’s Hospital and Dana Farber

Cancer Institute, Boston, MA

Medical Oncology Richard Goldberg, MD Ohio State University, Columbus, OH

Bruce Lin, MD Virginia Mason Medical Center, Seattle, WA

Colorectal Surgery George Chang, MD M.D. Anderson Cancer Center, Houston, TX

Julio Garcia-Aguilar, MD, PhD Memorial Sloan-Kettering Cancer Center, New York,

NY

David Dietz, MD Cleveland Clinic, Cleveland, OH

Gastroenterology Jeffrey Tokar, MD Fox Chase Cancer Center, Philadelphia, PA

General Internal

Medicine

Marilyn Schapira, MD, PhD University of Pennsylvania, Philadelphia, PA

Moderator Michael Broder, MD Partnership for Health Analytic Research, LLC,

Beverly Hills, CA

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Rating process and panel meeting

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.

Additionally, panelists were instructed to envision an “average patient” treated by an “average

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

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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

Appropriate. The third scenario remained the same.

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

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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

not included in the scenarios.

Figure 1. Rectal MRI axial T2 image

Five treatments were rated: short-course radiation, endorectal brachytherapy, chemoradiation,

chemotherapy alone, and no neoadjuvant therapy. Short-course radiation was assumed to be 25 Gy in 5

fractions based on the Dutch TME study41,42 and endorectal brachytherapy was based on a Canadian

regimen of high-dose rate intraluminal delivery of a dose of 26 Gy in 4 fractions using an endoluminal

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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

5-FU or capecitabine. Neoadjuvant chemotherapy alone was assumed to be FOLFOX.17

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

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and had no threatened mesorectal fascia (Figure 6). In other situations, the expert panel rated it Rarely

Appropriate to not offer neoadjuvant therapy.

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Risk classification*

Distance from anal

verge

Distance from tumor

edge to edge of

mesorectal fascia^

Stage II and III

rectal cancer

Moderately high

risk disease High risk disease

Intermediate risk

disease

>10 cm ≤10 cm

≥2 mm

M A M M

<5 cm ≥5 cm

A

≥2 mm <2 mm

A M

<2 mm

* 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)

Figure 2. Appropriateness of neoadjuvant short-course RT

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^ Based on MRI

M = May Be Appropriate (median 4-6 or disagreement), R = Rarely Appropriate (median 1-3 without disagreement)


Distance from anal

verge

Distance from tumor

edge to edge of

mesorectal fascia^

Stage II and III rectal

cancer

High risk

disease

R

Moderately high

risk disease

>10 cm <5 cm 5-10 cm

R

>5

mm

≤5

mm

R M

≥2

mm

<2

mm

R M

Intermediate

risk disease

<5 cm 5-10 cm

>5

mm

≤5

mm

R M

≥2

mm

<2

mm

R M

>10 cm

M

Figure 3. Appropriateness of neoadjuvant chemotherapy alone

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cancer

R

All patient groups


cancer

A

All patient groups

A = Appropriate (median 7-9 without disagreement), R = Rarely Appropriate (median 1-3 without disagreement)

Figure 4. Appropriateness neoadjuvant

endorectal brachytherapy alone

Figure 5. Appropriateness of neoadjuvant

chemoradiation

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cancer

High risk

disease

R

Intermediate

risk disease

<5 cm

R

5-10 cm

R M

>5

mm

≤5

mm

>10 cm

≥2

mm

<2

mm

R M

Moderately high

risk disease

≤10 cm

R

>10 cm

>5

mm

≤5

mm

M R


Distance from anal

verge

Distance from tumor

edge to edge of

mesorectal fascia^


^ Based on MRI


Figure 6. Appropriateness of no neoadjuvant therapy

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Adjuvant therapy 1

There were 38 scenarios in the second section addressing the options for adjuvant therapy in 2

stage II and III rectal cancer. Only patients with no gross residual disease after curative surgery were 3

included and patients had not received neoadjuvant therapy. The scenarios looked at the impact of 4

circumferential resection margin (CRM), risk classification, distance from the anal verge, and total nodal 5

count. A positive margin was defined as tumor within 1 mm from the inked margin. The first round 6

resulted in 52.6% (20 scenarios) rated May Be Appropriate, and 47.4% (18 scenarios) rated Appropriate. 7

There was disagreement on 5.3% (2 scenarios). For the second round, 50.0% (19 scenarios) were rated 8

Appropriate and 50.0% (19 scenarios) were rated May Be Appropriate. Disagreement was seen on 2.6% 9

(1 scenario). No scenarios were rated Rarely Appropriate in either round. 10

The expert panel was asked to consider the benefit of chemoradiation in addition to ≥4 months of 11

chemotherapy and of chemotherapy alone in the adjuvant setting in the setting of a patient resected with 12

a positive CRM. Chemoradiation was assumed to be standard, long-course pelvic radiotherapy with 13

concurrent infusional 5-FU or capecitabine and chemotherapy could be adjuvant 5-FU and leucovorin, 14

FOLFOX, capecitabine, or CapeOx. Panel members identified the occurrence of a positive margin in a 15

patient who did not undergo pre-operative chemoradiation as “inadvertent” and potentially suggestive of 16

poor quality surgery in the era of TME, more accurate pre-operative staging and imaging, and the 17

established role of pre-operative pelvic radiotherapy. The panel rating of 9 (the maximum in the 18

Appropriate category) indicated a strong agreement for chemoradiation in addition to ≥4 months of 19

chemotherapy (Figure 7). The panel rating of 4 for chemotherapy alone just met criteria for May Be 20

Appropriate, reflecting some uncertainty to this approach in the setting of positive margins, although it 21

may be suitable in some scenarios (Figure 8). 22

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The reporting of pathologic assessment of the quality of TME surgery was identified as not being 23

routinely and consistently available. Given that the quality of surgery is a well-established determinant 24

of locoregional recurrence risk, the number of lymph nodes examined was used as a surrogate of optimal 25

surgery. Panel experts were provided a cut off of <12 or ≥12 nodes examined as a surrogate of the 26

quality of TME surgery and pathologic evaluation. In the setting of negative margins and intermediate 27

risk, the expert panel did not alter the recommendation for post-operative chemoradiation plus adjuvant 28

chemotherapy based on the number of nodes examined. The primary cancer location as measured by 29

distance from the anal verge was a determinant of score for post-operative chemoradiation plus adjuvant 30

chemotherapy. The expert panel rating changed from Appropriate to May Be Appropriate for tumors 31

>10 cm from the anal verge indicating less certainty about pelvic chemoradiation for more proximal 32

rectal tumors. Chemotherapy alone was rated May Be Appropriate for all scenarios. 33

In the setting of negative margins and moderately high risk, the number of nodes examined also 34

did not alter the expert panel’s recommendation for post-operative chemoradiation plus adjuvant 35

chemotherapy. The panel provided a slightly lower rating within the Appropriate category for post-36

operative chemoradiation plus adjuvant chemotherapy as the distance from the anal verge increased. 37

Chemotherapy alone was also rated Appropriate for tumors >10 cm above the anal verge and May Be 38

Appropriate for more distal tumors. In the setting of negative margins and high risk, the expert panel felt 39

that post-operative chemoradiation plus adjuvant chemotherapy was Appropriate, regardless of the 40

number of nodes examined or distance from the anal verge. Chemotherapy alone was rated May Be 41

Appropriate in the negative margin, high risk group, also regardless of number of nodes examined or 42

distance from the anal verge. 43

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Distance from anal

verge

Circumferential

margin

≤10 cm

Stage II and III

rectal cancer

Negative margin Positive margin

A A A M

High risk

disease

Intermediate

risk disease

>10 cm

Moderately high

risk disease

A

Figure 7. Appropriateness of adjuvant chemoradiation (plus ≥4 months of chemo)

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1




Distance from anal

verge

Circumferential

margin

≤10 cm

Stage II and III

rectal cancer

Negative margin Positive margin

A M

High risk

disease

Intermediate

risk disease

>10 cm

Moderately high

risk disease

M M M

Figure 8. Appropriateness of adjuvant chemotherapy alone

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Medically inoperable patients 2

The third section contained 60 scenarios. The factors considered in this section were 3

performance status, presence of local symptoms, and distance from the anal verge. Good performance 4

status was defined as Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 and poor 5

performance status as ECOG performance status 2 or greater. The appropriateness of five treatments 6

was rated: external beam radiation alone, endorectal brachytherapy, chemoradiation alone, 7

chemoradiation plus endorectal brachytherapy, and chemotherapy alone. In the first round, 18.3% (11 8

scenarios) were rated Rarely Appropriate, 71.7% (43 scenarios) were rated May Be Appropriate, and 9

10% (6 scenarios) were rated Appropriate. Only 1.7% (1 scenario) had disagreement. In the second 10

round, 10.0% (6 scenarios) were rated Appropriate, 73.3% (44 scenarios) rated May Be Appropriate, 11

and 16.7% (10 scenarios) rated Rarely Appropriate. There were no scenarios with disagreement. 12

Although data regarding best treatment for medically inoperable rectal cancer are limited, there 13

was general agreement from the expert panel across all scenarios. Chemoradiation alone was 14

consistently rated Appropriate for good performance status patients and May Be Appropriate for poor 15

performance status patients (Figure 12). External beam radiation alone was rated May Be Appropriate 16

for all medically inoperable scenarios (Figure 11). Chemotherapy alone was also rated May Be 17

Appropriate, although supporting data are limited (Figure 13). Endorectal brachytherapy alone was not 18

rated Appropriate for any scenario, but rather was largely rated May Be Appropriate for tumors less than 19

10 cm from the anal verge (Figure 9). The combination of chemoradiation and endorectal brachytherapy 20

was rated May Be Appropriate for scenarios with tumor <10 cm from the anal verge with the exception 21

of poor performance status patients with tumors 5-10 cm from the anal verge, which was rated Rarely 22

Appropriate (Figure 10). 23

25

Location from the anal verge was only a factor for endorectal brachytherapy and the presence or 24

absence of symptoms had minimal impact on ratings. It is important to note that, if definitive doses of 25

endorectal brachytherapy are delivered (6.5 Gy x 4), patients may have increased rectal symptoms if 26

they do not undergo resection. The only effect of performance status was on the use of chemotherapy in 27

combination with radiation, which was rated Appropriate in good performance status patients. These 28

were the only scenarios rated Appropriate by the panel. Patients with medically inoperable rectal cancer 29

were rated May Be Appropriate for external beam radiation alone or chemotherapy alone, for most 30

scenarios for endorectal brachytherapy alone and chemoradiation plus endorectal brachytherapy if < 10 31

cm from verge, and for chemoradiation with poor performance status. 32

26

Medically inoperable

stage II and III rectal

cancer

Present Absent

>10 cm ≤10 cm

M R

Performance status

Local Symptoms

Distance from anal

verge

Poor performance

status (ECOG ≥2)

Good performance

status (ECOG 0-1)

≥5 cm <5 cm >10 cm ≤10 cm

M R M R


Figure 9. Appropriateness of definitive endorectal brachytherapy

27


Performance status

Local Symptoms

Distance from anal

verge



cancer

Poor

performance

status

Good

performance

status

Present Absent

>10 cm ≤10 cm

M R

≥5 cm <5 cm

M R

>10 cm ≤10 cm

M R

Figure 10. Appropriateness of definitive chemoradiation plus endorectal brachytherapy

28

1

2




cancer

M

All patient groups

Figure 11. Appropriateness of definitive

EBRT



cancer

M

Poor

performance

status

Good

performance

status

A


chemoradiation



cancer

M

All patient groups


chemotherapy alone

29

Patients seeking to avoid/refusing APR 3

The fourth section was comprised of 32 scenarios in the initial round. All patients covered had 4

low-lying tumors (<5 cm from the anal verge) and were otherwise operative candidates but were 5

attempting to achieve response to chemoradiation and avoid permanent colostomy. It was specified that 6

patients who progressed or did not respond to chemoradiation (based on physician assessment) should 7

receive an APR. The scenarios incorporated three factors: nodal status, T-category, and whether a full 8

thickness transanal excision had been performed. Patients who had T1 or T2 tumors and were node 9

negative were excluded since they have stage I disease and are outside the scope of this Clinical Practice 10

Statement. The treatments rated in the first round were endorectal brachytherapy, chemoradiation, 11

chemoradiation together with endorectal brachytherapy, and APR. 12

After extensive discussion during the in-person meeting, the expert panel, which was composed 13

of a multidisciplinary group including several colorectal surgeons, decided not to rate the individual 14

scenarios since the overall question was whether there is any alternative to an APR in patients who 15

refuse surgery. The surgeons also made the argument that, although the original scenarios made a 16

distinction between whether a patient had a full thickness transanal excision or not, if a full-thickness 17

transanal excision were possible then a low anterior resection with a coloanal anastomosis could be 18

performed and an APR is not needed. The panel was also concerned that by rating the radiation options, 19

they would be recommending use of a non-standard therapy rather than having another surgeon 20

potentially perform a radical resection without an APR. Therefore, the panel opted to replace the section 21

with a single new question regarding patients with stage II or III very low lying tumors refusing the 22

standard treatment, APR, and emphasized the fact that this was in the setting of patient refusal and 23

therefore outside of the standard approach. Panelists were asked to then rate chemoradiation (standard 24

30

dose), chemoradiation (standard dose) plus endorectal brachytherapy boost, and chemoradiation with 25

external beam radiation boost. 26

In the first round, using the original questions, 25% (8 scenarios) were rated Rarely Appropriate, 27

28.1% (9 scenarios) were rated May Be Appropriate, and 46.9% (15 scenarios) were rated Appropriate. 28

Disagreement was found for 12.5% (4 scenarios). In the second round, with the new question, all three 29

scenarios were rated Appropriate with no disagreement. The panel felt that in the scenario of patient 30

refusal of an APR, any of the radiation approaches could be justified (Figures 14 to 16). 31

31

32

33


chemoradiation (standard dose)


cancer

A

Patient with very low

lying tumor refusing

abdominoperineal

resection


chemoradiation (standard dose) plus endorectal

brachytherapy


cancer

A



abdominoperineal

resection


chemoradiation (standard dose) with EBRT

boost


cancer

A



abdominoperineal

resection

A = Appropriate (median 7-9 without disagreement)

32

IMRT 34

In addition to the four sections, two supplemental questions were also included, which asked the 35

Expert Panel to rate the appropriateness of using IMRT to deliver neoadjuvant and adjuvant treatment. 36

IMRT was rated May Be Appropriate in both settings during the first round, with disagreement seen for 37

neoadjuvant therapy. For the second round of rating, neoadjuvant therapy was separated into short-38

course RT and chemoradiation at the request of the expert panel. All three options were subsequently 39

rated May Be Appropriate, with no disagreement. 40

While the question addressed the use of IMRT in three different scenarios, neoadjuvant short-41

course pelvic radiotherapy, neoadjuvant long-course chemoradiation, and adjuvant chemoradiation, the 42

ratings were all May Be Appropriate (Figures 17 to 19). Further distinction between the situations was 43

not possible due to the lack of familiarity with the technical aspects of IMRT versus 3D-CRT among the 44

non-radiation oncologists on the panel. Thus, the multidisciplinary expert panelists deferred for this 45

question to the radiation oncologists who generally felt that the use of IMRT would be a case-by-case 46

decision and there might be extenuating circumstances when it would add substantial benefit. 47

33

48

Figure 17. Appropriateness of neoadjuvant short-

course RT delivered with IMRT


cancer

M

Figure 18. Appropriateness of neoadjuvant

chemoradiation delivered with IMRT


cancer

M

Figure 19. Appropriateness of adjuvant therapy

delivered with IMRT


cancer

M

M = May Be Appropriate (median 4-6 or disagreement)

34

Discussion 49

The analysis of the ratings of the many clinical scenarios that were evaluated by the expert panel 50

demonstrate that, while a standard treatment approach exists in stage II and III rectal cancer, further 51

studies are necessary to refine the treatment recommendations. The expert panelists had very good 52

agreement (only one final scenario had disagreement) for the appropriateness of the various treatment 53

options presented, which reflects the excellent multidisciplinary approach that has been applied to the 54

management of rectal cancer. Emerging options such as short-course radiotherapy, neoadjuvant 55

chemotherapy alone, and non-operative management in the setting of patient refusal of an APR were 56

included in this Clinical Practice Statement, despite the lack of widespread use or limited high level 57

evidence regarding these options in the United States, to provide practicing radiation oncologists with 58

the current assessment of the appropriateness of these options. Given the strong relationship between the 59

quality of TME surgery and local recurrence, a relationship that is not mitigated by the use of adjuvant 60

radiation,44 we assumed high quality TME surgery was performed when rating scenarios that included 61

surgery. 62

63

Neoadjuvant therapy 64

Patients presenting for neoadjuvant therapy before definitive surgery make the bulk of referrals 65

for rectal cancer to the radiation oncologist. Following the seminal German rectal cancer trial,7 it was 66

established that neoadjuvant chemoradiation improves local control with decreased toxicity as compared 67

with adjuvant chemoradiation. The approach offered in this trial, conventionally fractionated radiation 68

therapy with concurrent 5-FU based chemotherapy, was considered appropriate by all of the expert 69

panel members for stage II and stage III rectal cancer. This is also reflected in other clinical guidelines, 70

such as the NCCN8 and Cancer Care Ontario.45 71

35

More interestingly, panelists rated neoadjuvant short-course radiation therapy Appropriate in 72

many patients with non-threatened mesorectal fascia margins and May Be Appropriate in other patients. 73

This is consistent with the fact that short-course is not intended for downstaging as usually surgery is 74

performed within one to two weeks of finishing radiation therapy. The ratings have also been supported 75

by randomized studies comparing short-course with conventional chemoradiation,46,47 selective adjuvant 76

therapy,48 and no therapy.42 There are also ongoing randomized studies looking to incorporate short-77

course radiation with neoadjuvant chemotherapy.49,50 Although the use of short-course radiation has 78

been relatively uncommon in North America and has only recently been included in the current NCCN 79

guidelines, the Appropriate rating from the expert panel in this Clinical Practice Statement, based on 80

level I evidence supporting short-course radiation as an option, supports this as an acceptable 81

option.51,52 82

Another emerging area is the use of neoadjuvant chemotherapy alone for selected patients with 83

stage II or III rectal cancer. While the accrual of a large, phase III randomized trial is ongoing,18 the 84

expert panel rated this approach May Be Appropriate for selected patients in intermediate and 85

moderately high risk disease with non-threatened mesorectal fascia. There was no patient group that 86

neoadjuvant chemotherapy alone was rated Appropriate for and this regimen is not offered in the NCCN 87

guidelines currently. However, NCCN does now include induction chemotherapy followed by 88

chemoradiation, which was not part of the scenarios for this clinical practice statement. 89

Neoadjuvant brachytherapy alone was rated Rarely Appropriate across the scenarios. This has 90

been performed by select centers.53 This remains an area of active investigation and may be more 91

relevant in patients who are not surgical candidates, as described in the medically inoperable section, or 92

as a boost in well-selected patients.54 Finally, the expert panel rated forgoing neoadjuvant therapy 93

altogether for certain patients with stage II or III rectal cancer May Be Appropriate. These included 94

36

patients with mid to high rectal cancers with a non-threatened mesorectal fascia, undergoing TME. This 95

acknowledges that potential patient benefit from neoadjuvant therapy may be diminished by treatment-96

related toxicity, and that these patients may be evaluated for adjuvant therapy based on pathologic 97

findings. 98

99

Adjuvant therapy 100

Since modern practice has established the role of neoadjuvant radiation regimens as the standard 101

treatment for locally advanced rectal tumors,6 a positive CRM should be an uncommon clinical scenario 102

and may reflect inadequate pre-operative imaging, suboptimal TME technique, or very poor or 103

aggressive tumor biology. Understaging or lack of identification of a threatened mesorectal margin pre-104

operatively may also increase the risk of a post-operative positive CRM. When a positive margin does 105

occur, especially in the setting of high-quality surgery, it is associated with poor outcomes and the 106

question of how to address the potentially residual disease in the post-operative setting is always a 107

difficult one. There is no level 1 evidence to guide the management of a positive CRM but data from 108

clinical trials highlight the increased risk of local recurrence.42,44 High rates of long term local failure, 109

48.6% R1 vs. 7.7% R0, were observed on the adjuvant chemoradiation arm of the pre-operative vs. post-110

operative randomized German rectal cancer trial.7 A randomized trial (MRC CR07 + NCIC CTG C016) 111

of selective chemoradiation for patients with a positive CRM demonstrated inferior local control 112

compared to pre-operative short-course pelvic radiation therapy.55 However, there is no clinical trial 113

comparing adjuvant pelvic chemoradiotherapy to chemotherapy or observation alone on the setting of 114

positive margins. In the absence of clinical trials, post-operative chemoradiotherapy plus adjuvant 115

chemotherapy remains the standard treatment regimen in the setting of a positive CRM. 116

37

However, the alternative strategy of adjuvant chemotherapy alone in the setting of positive CRM 117

was also rated May Be Appropriate to Appropriate. This may be an option for patients who are not 118

eligible for post-operative therapy due to comorbid conditions, known contraindications to radiation 119

therapy, or patient refusal. Adjuvant chemotherapy alone might also be appropriate for patients with a 120

very high risk of systemic relapse, with the caution that chemotherapy alone may be associated with a 121

higher rate of locoregional recurrence, which is associated with significant morbidity both from the 122

pelvic recurrence and from any surgical salvage approach. 123

For adjuvant radiation and chemotherapy in the setting of negative CRM , the data are largely 124

derived from studies performed in the pre-TME era, when transmural or node positive cancers had a 125

local recurrence risk as high as 50%,56 which led to the NCI consensus statement in 19905 that adjuvant 126

chemoradiation was the new standard regimen. The expert panel was asked to consider the role of 127

adjuvant chemoradiation in the TME era, considering the individualized local control benefit and the 128

potential for normal tissue toxicity when pelvic radiotherapy is delivered in the post-operative setting.7 129

For most scenarios, adjuvant chemoradiation plus chemotherapy was rated Appropriate (Figure 7). 130

Adjuvant chemotherapy alone was rated May Be Appropriate or Appropriate (Figure 8), indicating that 131

the expert panel supported the approach that, with pathologic information demonstrating that for 132

intermediate risk disease (T3N0, T1-2N1), adjuvant chemotherapy results in similar outcomes as 133

adjuvant chemoradiation, based on pooled analyses of prospective data comparing adjuvant therapy 134

options after surgery. 135

The panel was also provided the number of lymph nodes reported in the pathology report as a 136

surrogate to estimate the adequacy of the surgical resection since this may often be the only quality 137

indicator available. However, node count may be a marker of the quality of pathology as well as surgery 138

and may also reflect disease biology. While the optimal lymph node yield for rectal cancer without 139

38

neoadjuvant therapy is still controversial, the <12 vs. ≥12 nodes examined was used in each risk based 140

scenario.57 Interestingly, the lymph node count did not alter the expert panel’s ratings for most scenarios, 141

thus reflecting the relative lack of utility of nodal count as a measure of quality of rectal cancer surgery. 142

The relationship between the location of the primary rectal cancer as measured by distance from 143

the anal verge and the benefit of pelvic radiotherapy also remains the subject of differing opinions. In 144

the pre-operative setting with TME surgery, secondary subset analyses have evaluated the benefit of 145

pelvic radiotherapy based on primary tumor location. The long term report of the Dutch TME trial 146

demonstrated that the benefit of short-course pre-operative pelvic radiotherapy was greater for greater 147

distance from the anal verge (p=0.03).42 If patients with a positive CRM were excluded from the 148

analysis, the relationship between the distance from the anal verge and radiotherapy disappeared and 149

irradiated patients had higher cancer-specific survival independent of distance from the anal verge.42 150

The Trans-Tasman Radiation Oncology Group (TROG) compared pre-operative short-course pelvic 151

radiotherapy to long-course chemo-radiotherapy in T3 rectal cancers. There was a non-significant 152

(p=0.21) trend toward decreased local recurrence for long-course treatment and tumors <5 cm from the 153

anal verge.47 In the adjuvant setting, 11 year data from the pre-operative vs. post-operative German 154

Rectal Cancer Trial, showed that at 10 years, post-operative chemoradiation was associated with a LR 155

risk of 9.3% vs. 18.7% if no post-operative treatment was delivered if the tumor was at 5 to <10 cm and 156

2.7% vs. 10.4% if the tumor was at 10-16 cm. On multivariate analysis, not receiving chemoradiation 157

was significantly associated with a higher local recurrence risk.7 Overall, there was general agreement 158

among the expert panel that increasing distance from the anal verge was associated with lower risk of 159

local recurrence. 160

For low lying rectal cancers <5cm from the anal verge, there was strong agreement in rating 161

adjuvant chemoradiation Appropriate for all patients regardless of risk category or number of nodes 162

39

examined. Long-term data from the Swedish Rectal Cancer Trial in the pre-TME era shows that the 163

local recurrence rate was 27% for tumors ≤5cm from anal verge, 26% for tumors 6-10 cm, and 12% for 164

tumors ≥11 cm.58 Moreover, the type of surgery performed may be considered as well, since data from 165

the Dutch CKVO trial have shown that, even with a good TME and a negative CRM, APR was 166

associated with presacral local recurrences.59 Post-operative chemoradiation was also associated with a 167

higher risk of local recurrence on multivariate analysis from updated data from the German Rectal 168

Cancer Trial in patients who had surgery that included intersphincteric resection or APR compared with 169

pre-operative radiation (P=0.03).59 170

The panelists rated adjuvant chemotherapy alone May Be Appropriate for patients with low-171

lying rectal cancers, including those where there is concern about an increased risk of toxicity to the 172

anastomosis depending on the type of surgery that has been performed (i.e. a hand-sewn coloanal 173

anastomosis). With post-operative chemoradiation, grade 3-4 anastomotic toxicity was seen in 12% of 174

patients in the German study.6 175

For R0 resected tumors at 5-10 cm from the anal verge, there was again strong consensus that 176

adjuvant regimens containing pelvic radiotherapy are appropriate. The surgeons on the panel noted that 177

more proximal anastomoses would be anticipated to better tolerate pelvic radiation. Strategies to 178

consider chemotherapy alone were also felt to be reasonable. 179

As the distance of the tumor from the anal verge increased to >10 cm, the strength of the 180

recommendation for adjuvant regimens containing radiation decreased. Intermediate risk tumors in this 181

category were rated as May Be Appropriate. Within the intermediate risk category, data from 182

Gunderson et al. have noted a 7% local failure for T1-2/N1 tumors vs. a 9% local failure for T3N0 183

tumors.13 Thus by risk category as well as distance from the anal verge, this category of patients would 184

be expected to have a relatively low rate of local failure, particularly in the more modern era with the 185

40

use of TME. For high risk tumors >10 cm from the anal verge, panelists rated the adjuvant radiation 186

regimens Appropriate but at the lowest end of this category (median of 7). However, it should be noted 187

that the location of the peritoneal reflection can vary in relation to the distance from the anal verge. 188

Therefore tumors at >10 cm from the anal verge may or may not be intraperitoneal. Adjuvant 189

chemotherapy only regimens were rated May Be Appropriate for intermediate and high risk tumors 190

regardless of nodes examined and Appropriate for tumors of moderate risk. 191

192

Medically inoperable 193

Medically inoperable patients are rare and there are limited data to guide choice of therapy. In 194

addition, this group of patients is heterogeneous with regard to reasons for inoperability. Factors other 195

than performance status and presence of symptoms likely impact choice of therapy. Uncontrolled pelvic 196

malignancy is known to be associated with significant symptoms in most patients. Thus, there was clear 197

consensus by the expert panel that local therapy, including some form of chemoradiation, is appropriate 198

in good performance status patients. 199

With the emerging data from the operable patients showing non-operative management may be 200

curative for selected patients with a clinical complete response after pre-operative chemoradiation,31,32,60 201

there was general consensus that chemoradiation was rated Appropriate. External beam radiation 202

combined with endorectal brachytherapy without surgery has been associated with excellent outcomes in 203

patients with favorable rectal cancers (<12 cm from anal verge, <3cm diameter, mobile without 204

ulceration, T1-2, grade 1-2) and may be used for unfavorable patients who are medically inoperable.61,62 205

Local control in more advanced T2-3 distal rectal cancers has been reported in >70% of patients treated 206

with a combination of endorectal brachytherapy, external radiation and interstitial brachytherapy with 5-207

year survival in excess of 60%.63 Given the excellent local control rates reported in selected patients and 208

41

potential for long-term survival, all medically inoperable patients should be evaluated for potentially 209

curative intent radiation therapy. 210

Endorectal brachytherapy alone has been demonstrated to be effective curative treatment for 211

grade 1-2, T1N0, < 3 cm diameter rectal cancers located < 10 cm from the anal verge.64 Extrapolating 212

from these data, the expert panel rated endorectal brachytherapy alone May Be Appropriate for 213

medically inoperable patients with distal tumors. In general, definitive endorectal high dose rate 214

brachytherapy is limited to tumors that are within 15 cm from the anal verge and less than 5 cm in 215

diameter given the dose of radiation to the surface.43,65 Also, endorectal brachytherapy is generally 216

contraindicated in patients with invasion of the anal sphincters given potential effects on sphincter 217

function. It should be noted that there are several approaches to rectal brachytherapy. The endorectal 218

approach based on the use of an endoluminal applicator and delivery of high-dose rate Iridium-192 219

using a remote afterloading technique was the technique evaluated in these clinical scenarios. However, 220

in Europe, early stage rectal tumors may be treated with Contact X-ray (50KV) brachytherapy (Papillon 221

technique) and more advanced tumors are addressed with interstitial transperineal Iridium-192 implants. 222

These approaches were not addressed in this Clinical Practice Statement since they are not commonly 223

employed in the United States. 224

The panel also felt that some patients in this section, particularly those with poor performance 225

status and an absence of local symptoms, should receive palliative treatment. However, this option was 226

not included in the rating. 227

228

Patient refusal of an APR 229

There is also growing interest in non-operative management for operable patients with low-lying 230

rectal cancers who have achieved a cCR to pre-operative chemoradiation to improve quality of life 231

42

following treatment for rectal cancer. While sphincter preservation can be achieved in some patients by 232

performing a low anterior resection with a coloanal anastomosis, these procedures may be associated 233

with impaired long-term bowel function.22 In addition, patients face the morbidity and mortality 234

attendant with major abdominal surgery and the need for temporary diversion if restoration of intestinal 235

continuity is possible. Finally, rectal cancer surgery also impacts sexual functioning. Several prospective 236

studies have evaluated patient-reported quality of life after treatment for rectal cancer and have 237

demonstrated low scores, particularly in patients with stomas or low rectal anastomoses.23-25 238

However, since non-operative management for stage II or III disease is still considered a non-239

standard approach, the panel did not want to rate its use for various clinical scenarios. The decision was 240

to address the situation in which a patient refuses standard therapy and consensus of the panel was that 241

local therapy with chemoradiation with or without endorectal brachytherapy was an inferior but 242

acceptable alternative to radical surgery. As more studies evaluate the non-operative approach with 243

intensive follow-up for patients with complete response to chemoradiation there may be future Clinical 244

Practice Statements that will have sufficient supporting literature to rate more specific clinical scenarios 245

and address additional considerations such as how to assess treatment response after chemoradiation. 246

247

IMRT 248

Further improvements in outcomes for rectal cancer patients may also come with incorporating 249

newer radiotherapy techniques to deliver more focal dose to the tumor and lymph node regions while 250

sparing the radiosensitive structures of the pelvis. By minimizing the toxicity to the normal tissues, 251

acute and long-term toxicities of pelvic radiotherapy may be reduced, thus improving the therapeutic 252

ratio of this approach. IMRT allows for more conformal delivery of radiotherapy by using computed-253

tomography (CT) based planning and sophisticated computational software to generate treatment plans. 254

43

However, the increased cost and lack of reimbursement for IMRT in many gastrointestinal cancers has 255

also impacted on its use. For this reason, the question was framed to identify specific situations where 256

IMRT might be more useful, for instance with higher dose-per-fraction, such as with neoadjuvant short-257

course RT where late effects have been shown to be significantly elevated versus surgery alone,19 as 258

well as in the post-operative setting, which is associated with more toxicity compared to neo-adjuvant 259

therapy.6 260

The use of IMRT for long-course neoadjuvant chemoradiation has been controversial in rectal 261

cancer given the lack of data addressing the benefit of a more conformal approach over standard 3-262

dimensional conformal radiotherapy. The only prospective study evaluating the use of IMRT in rectal 263

cancer was a yet-to-be published, single-arm Phase II trial, RTOG 0822. This study evaluated the use of 264

concurrent capecitabine and oxaliplatin with pelvic radiotherapy using IMRT planning. The primary 265

endpoint was an improvement in Grade 2 or higher gastrointestinal toxicity in this study as compared to 266

the RTOG 0247 trial, which used the same chemotherapy regimen with non-IMRT pelvic 267

radiotherapy.66 RTOG 0822 failed to demonstrate a significant benefit to the use of IMRT. However, 268

interpretation of this study is limited by the use of concurrent oxaliplatin with 5-FU based 269

chemoradiation given there have been four large, phase III randomized trials demonstrating increased GI 270

toxicity when oxaliplatin is added to pre-operative chemoradiation.67-70 IMRT planning may not have 271

been able to overcome the effect of the oxaliplatin on GI toxicity. Several retrospective studies have 272

demonstrated a reduction in GI toxicity using IMRT over 3D-CRT for rectal cancer.71,72 273

IMRT is most likely to be of benefit when inclusion of external iliac lymph nodes is indicated on 274

the basis of a T4 tumor with adherence to or invasion of an anterior organ that has lymphatic drainage to 275

external iliac nodes, when there is a large volume of non-displaceable small bowel in the pelvis, or when 276

treatment of the inguinal nodal regions or perineal scar is indicated. IMRT may also be indicated in 277

44

patients with medical comorbidities such as inflammatory bowel disease, or a pelvic kidney, which may 278

be associated with higher toxicity from pelvic radiotherapy. 279

280

Conclusion/Future Directions 281

Radiotherapy remains a standard component of management of rectal cancer; however, there is 282

still the need to further refine its role as part of neoadjuvant, adjuvant and definitive therapy in order to 283

better tailor therapy for patients with rectal cancer. This Clinical Practice Statement provides a 284

comprehensive overview of the therapeutic options for patients with locally advanced (Stage II/III) 285

rectal cancer and further classifies this larger group into subgroups based on known risk factors that 286

were described in the clinical scenarios. By utilizing a multi-disciplinary panel of experts, and including 287

both GI-specialized and non-GI-specialized radiation oncologists, the process effectively removes biases 288

which could result from a tendency to recommend treatments that are delivered by the panelists. Thus, 289

the appropriateness ratings were not only individualized and risk-stratified, but also representative of the 290

overall community of practitioners treating rectal cancer. Nonetheless, the ratings should not be taken 291

as absolutes, as there may be unique circumstances that require clinicians and patients to use best 292

clinical judgment in optimal decision making. The use of novel techniques such as IMRT was 293

considered in this Clinical Practice Statement and was felt to be potentially appropriate because it may 294

lead to less toxicity. However, further study to assess the impact of this approach on treatment outcomes 295

is warranted to ensure the appropriate technology utilization and this questions may be better answered 296

in future Clinical Practice Statements. 297

In the future, results of ongoing trials may help clarify areas of uncertainty, particularly with 298

regard to the use of neoadjuvant FOLFOX as an alternative to chemoradiation for selected risk-groups 299

of patients and the possibility of pursuing non-operative management in patients who have a complete 300

45

clinical response after chemoradiation. On-going studies of both molecular and imaging biomarkers may 301

also improve risk stratification and allow for more tailored therapies for rectal cancer patients. 302

Meanwhile, this Clinical Practice Statement will serve as an overview of options to help guide 303

physicians as we move toward more individualized approaches for our patients. 304

305

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500

Appendix 1: Complete rating tables 501

502 Section 1: Neoadjuvant therapy 503 504 Neoadjuvant therapy, intermediate risk, <5 cm from anal verge 505

Short-course

RT

Endorectal

brachytherapy

Chemoradiation Chemotherapy

alone

No neoadjuvant

therapy

Tumor edge < 2 mm

from edge of

mesorectal fascia 6

2

9

3

1

Tumor edge 2-5 mm

from edge of

mesorectal fascia 7 3

Tumor edge >5 mm

from edge of

mesorectal fascia

5

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 506 disagreement), red = Rarely Appropriate (median 1-3 without disagreement) 507 508 509 Neoadjuvant therapy, intermediate risk, 5-10 cm from anal verge 510

50

Short-course

RT

Endorectal

brachytherapy


alone

No neoadjuvant

therapy

Tumor edge < 2 mm

from edge of

mesorectal fascia 5

2 9

3 1

Tumor edge 2-5 mm

from edge of

mesorectal fascia 7

4

3

Tumor edge >5 mm

from edge of

mesorectal fascia 4

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 511 disagreement), red = Rarely Appropriate (median 1-3 without disagreement) 512 513 514 Neoadjuvant therapy, intermediate risk, >10 cm from anal verge 515

Short-course

RT

Endorectal

brachytherapy


alone

No neoadjuvant

therapy

Tumor edge < 2 mm

from edge of

mesorectal fascia

6 1

9

4

3

Tumor edge 2-5 mm

from edge of

mesorectal fascia 8

5

Tumor edge >5 mm

from edge of


Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 516 disagreement), red = Rarely Appropriate (median 1-3 without disagreement) 517 518 519 Neoadjuvant therapy, moderately high risk, <5 cm from anal verge 520

Short-course

RT

Endorectal

brachytherapy


alone

No neoadjuvant

therapy

Tumor edge < 2 mm

from edge of

mesorectal fascia 5

2 9 3

1 Tumor edge 2-5 mm

from edge of

mesorectal fascia 6

Tumor edge >5 mm

from edge of

mesorectal fascia

2

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 521 disagreement), red = Rarely Appropriate (median 1-3 without disagreement) 522 523 524 Neoadjuvant therapy, moderately high risk, 5-10 cm from anal verge 525

Short-course

RT

Endorectal

brachytherapy


alone

No neoadjuvant

therapy

51

Tumor edge < 2 mm

from edge of

mesorectal fascia 5

2 9

3

1

Tumor edge 2-5 mm

from edge of


Tumor edge >5 mm

from edge of

mesorectal fascia

5

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 526 disagreement), red = Rarely Appropriate (median 1-3 without disagreement) 527 528 529 Neoadjuvant therapy, moderately high risk, >10 cm from anal verge 530

Short-course

RT

Endorectal

brachytherapy


alone

No neoadjuvant

therapy

Tumor edge <2 mm

from edge of

mesorectal fascia 5

1

9 3 2

Tumor edge 2-5 mm

from edge of

mesorectal fascia 7 8 4

3

Tumor edge >5 mm

from edge of

mesorectal fascia

4

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 531 disagreement), red = Rarely Appropriate (median 1-3 without disagreement) 532 533 534 Neoadjuvant therapy, high risk 535

Short-course

RT

Endorectal

brachytherapy


alone

No neoadjuvant

therapy

<5 cm from anal verge 6

1 9

2 1 5-10 cm from anal

verge 5

>10 cm from anal

verge 3 2

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 536 disagreement), red = Rarely Appropriate (median 1-3 without disagreement) 537 538

Section 2: Adjuvant therapy 539 540 Adjuvant therapy, positive circumferential margin 541

Chemoradiation (plus ≥4 months

of chemo)

Chemotherapy alone

9 4

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 542 disagreement) 543 544

52

545 Adjuvant therapy, negative circumferential margin, intermediate risk, <5 cm from anal verge 546

Chemoradiation (plus ≥4

months of chemo)

Chemotherapy alone

<12 nodes

examined 9

5

≥12 nodes

examined 7

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 547 disagreement) 548 549 550 Adjuvant therapy, negative circumferential margin, intermediate risk, 5-10 cm from anal verge 551


months of chemo)

Chemotherapy alone

<12 nodes

examined

8

5

≥12 nodes

examined 6

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 552 disagreement) 553 554 555 Adjuvant therapy, negative circumferential margin, intermediate risk, ˃10 cm from the anal verge 556


months of chemo)

Chemotherapy alone

<12 nodes

examined 6

6

≥12 nodes

examined 5

Yellow = May Be Appropriate (median 4-6 without disagreement) 557 558 559 Adjuvant therapy, negative circumferential margin, moderately high risk, <5 cm from the anal verge 560


months of chemo)

Chemotherapy alone

<12 nodes

examined

9

5

≥12 nodes

examined

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 561 disagreement) 562 563 564 Adjuvant therapy, negative circumferential margin, moderately high risk, 5 -10 cm from the anal verge 565


months of chemo)

Chemotherapy alone

<12 nodes

examined

9

6

53

≥12 nodes

examined

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 566 disagreement) 567 568 569 Adjuvant therapy, negative circumferential margin, moderately high risk, ˃10 cm from the anal verge 570


months of chemo)

Chemotherapy alone

<12 nodes

examined 8

7

≥12 nodes

examined 7

Green = Appropriate (median 7-9 without disagreement) 571 572 573 Adjuvant therapy, negative circumferential margin, high risk, <5 cm from the anal verge 574


months of chemo)

Chemotherapy alone

<12 nodes

examined

9

6

≥12 nodes

examined 5

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 575 disagreement) 576 577 578 Adjuvant therapy, negative circumferential margin, high risk, 5 -10 cm from the anal verge 579


months of chemo)

Chemotherapy alone

<12 nodes

examined

9

5

≥12 nodes

examined 5

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 580 disagreement), grey = May Be Appropriate due to disagreement 581 582 Adjuvant therapy, negative circumferential margin, high risk, ˃10 cm from the anal verge 583


months of chemo)

Chemotherapy alone

<12 nodes

examined

7

6

≥12 nodes

examined

Green = Appropriate (median 7-9 without disagreement), yellow = May Be Appropriate (median 4-6 without 584 disagreement) 585 586 587 Section 3: Medically inoperable patients 588 589

54

Medically inoperable, good performance status (ECOG 0-1), local symptoms present 590 External beam

RT alone

Endorectal

brachytherapy

Chemoradiation Chemoradiation

plus endorectal

brachytherapy

Chemotherapy

alone

<5 cm from anal verge

5

4

9

6

4 5-10 cm from anal

verge 5

>10 cm from anal

verge 1 1 5


Medically inoperable, good performance status (ECOG 0-1), local symptoms absent 594 External beam

RT alone

Endorectal

brachytherapy


plus endorectal

brachytherapy

Chemotherapy

alone


5

4

9

6

5 5-10 cm from anal

verge 3 5

>10 cm from anal

verge 2 1 6


Medically inoperable, poor performance status (ECOG ≥2), local symptoms present 598 External beam

RT alone

Endorectal

brachytherapy


plus endorectal

brachytherapy

Chemotherapy

alone


6

5

5 5

4 5-10 cm from anal

verge 6 4

>10 cm from anal

verge 1 5 1

Yellow = May Be Appropriate (median 4-6 without disagreement), red = Rarely Appropriate (median 1-3 without 599 disagreement) 600 601

Medically inoperable, poor performance status (ECOG ≥2), local symptoms absent 602 External beam

RT alone

Endorectal

brachytherapy


plus endorectal

brachytherapy

Chemotherapy

alone


6

5

5

4

4 5-10 cm from anal

verge 4 3

55

>10 cm from anal

verge 1 1

Yellow = May Be Appropriate (median 4-6 without disagreement), red = Rarely Appropriate (median 1-3 without 603 disagreement) 604 605

Section 4: Patients with very low lying tumor refusing APR 606

Patient with very low lying tumor refusing abdominoperineal resection 607 Chemoradiation (standard dose) Chemoradiation (standard dose)

plus endorectal brachytherapy

Chemoradiation with EBRT boost

7 7 7

Green = Appropriate (median 7–9 without disagreement) 608 609

Intensity-modulated radiation therapy 610

Please rate the appropriateness of using IMRT to deliver: 611 Neoadjuvant short-course RT Neoadjuvant chemoradiation Adjuvant therapy

5 5 5

Yellow = May Be Appropriate (median 4-6 without disagreement) 612 613

56

Appendix 2: Expert Panel members who were leads of rectal cancer clinical trials – January to June 2014 614

Panelist (specialty) Trial Name Role in Trial Phase of trial at time of

Expert Panel Participation

Salma Jabbour

(radiation oncology)

None Not applicable Not applicable

Harvey Mamon



Patrick Francke



Richard Goldberg

(medical oncology)


Bruce Lin

(medical oncology)

Bayer 15983 (NCT01939223) - A Randomized, Double-blind,

Placebo-controlled Phase-III Study of Adjuvant Regorafenib Versus

Placebo for Patients With Stage IV Colorectal Cancer After Curative

Treatment of Liver Metastases (COAST)

Site principal investigator Patient accrual

PledPharma PP095 (NCT01619423) - A Double Blinded

Randomised Three Armed Phase II Trial of PledOx in Two Different

Doses in Combination With FOLFOX6 Compared to Placebo +

FOLFOX6 in Patients With Advanced Metastatic Colorectal (Stage

IV) Cancer (PLIANT)


Pfizer B2151005 (NCT01925274) - A Randomized Phase 2 Study Of

PF-05212384 Plus Irinotecan Versus Cetuximab Plus Irinotecan In

Patients With KRAS Wild Type Metastatic Colorectal Cancer


Pfizer B2151007 (NCT01937715) - An Open-Label, Multi-Center,

Randomized Phase 1b/2 Study Of PF-05212384 Plus 5-Fluorouracil-

Leucovorin-Irinotecan (FOLFIRI) Versus Bevacizumab Plus

FOLFIRI In Metastatic Colorectal Cancer


Julio Garcia-Aguilar

(surgery)

Trial Evaluating 3-year Disease Free Survival in Patients With

Locally Advanced Rectal Cancer Treated With Chemoradiation Plus

Induction or Consolidation Chemotherapy and Total Mesorectal

Excision or Non-operative Management

Principal investigator Preparation for

accrual/patient accrual

George Chang

(surgery)

ACOSOG Z6051: A Phase III Prospective Randomized Trial

Comparing Laparoscopic-assisted Resection Versus Open Resection

for Rectal Cancer

Principal investigator Patient accrual

57

NCCTG N1048: A Phase II/III Trial of Neoadjuvant FOLFOX, with

Selective Use Of Combined Modality Chemoradiation versus

Preoperative Combined Modality Chemoradiation for Locally

Advanced Rectal Cancer Patients Undergoing Low Anterior

Resection with Total Mesorectal Excision


A single blind, randomized, controlled study to evaluate the safety

and effectiveness of EVICEL as an adjunct to GI anastomosis

techniques, 2012-0235


David Dietz

(surgery)

Timing of rectal cancer response to chemoradiation Site principal investigator Data analysis

Jeffrey Tokar

(gastroenterology)

CGI-066: Assessing Intratumoral Heterogeneity and Chemoradiation

Response In Locally Advanced Rectal Cancer Utilizing Sequencing

and PET/CT

Sub-investigator Patient accrual

(CIRB) N1048: A Phase II/III trial of Neoadjuvant FOLFOX, with

Selective Use of Combined Modality Chemoradiation versus

Preoperative Combined Modality Chemoradiation for Locally

Advanced Rectal Cancer Patients Undergoing Low Anterior

Resection with Total Mesorectal Excision

Sub-investigator Patient accrual

Marilyn Schapira

(internal med)


615

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