CLINICAL PRACTICE GUIDELINE GI-005

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EARLY STAGE RECTAL CANCER

Effective Date: October, 2013

The recommendations contained in this guideline are a consensus of the Alberta Provincial Gastrointestinal Tumour Team synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical

judgment in the context of individual clinical circumstances to direct care.

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BACKGROUND According to statistics provided by the Canadian Cancer Society in 2013, one in thirteen Canadian males and one in fifteen Canadian females will be diagnosed with colorectal cancer in their lifetime. A patient may be predisposed to develop colorectal cancer by a hereditary condition (e.g.: hereditary non-polyposis colon cancer, familial adenomatous polyposis) or a personal history of either inflammatory bowel disease (e.g.: Crohn’s disease, ulcerative colitis) or adenomatous polyps. Over 60 percent of colorectal cancers arise without a clearly identifiable predisposing factor, however. After a diagnosis of colorectal cancer, prognosis depends upon the stage at diagnosis; that is, prognosis is better with less penetration of the tumor into the bowel wall, fewer involved regional lymph nodes, and no evidence of metastatic disease. Because the prognosis is better when colorectal cancer is identified at an earlier stage, because of the relatively high incidence of colorectal cancer, and because of the simplicity and accuracy of screening tests, screening for colorectal cancer represent an important component of routine care for all adults aged fifty years or older. This is especially important in patients with first-degree relatives with colorectal cancer. This guideline was developed to outline the management recommendations for patients with rectal cancer (adenocarcinoma) amenable to resection with curative intent. GUIDELINE QUESTIONS • What are the recommendations for the diagnostic workup of adult patients with rectal cancer

amenable to resection with curative intent? • What are the treatment recommendations for adult patients with rectal cancer amenable to resection

with curative intent? DEVELOPMENT AND REVISION HISTORY This guideline was reviewed and endorsed by the Alberta Provincial Gastrointestinal Tumour Team. Members of the Alberta Provincial Gastrointestinal Tumour Team include medical oncologists, radiation oncologists, surgical oncologists, hepatologists, gastroenterologists, interventional radiologists, nurses, nurse practitioners, pathologists, and pharmacists. This guideline was originally developed in August, 2009. This guideline was revised in March, 2010, June, 2011 and October, 2013. SEARCH STRATEGY This guideline was developed to promote evidence-based practice in Alberta. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team’s interpretation of the data.

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TARGET POPULATION The recommendations outlined in this guideline apply to adults over the age of 18 years with early stage rectal cancer. Different principles may apply to pediatric patients. RECOMMENDATIONS AND DISCUSSION Suggested Diagnostic Work-up

• Prior to an attempt at resection of an intraluminal mass, it is recommended that, in the absence of a complete bowel obstruction, a complete colonoscopy be completed to exclude synchronous polyps or colorectal cancer. A digital rectal examination, endoscopic ultrasound, and/or MR provide additional information about the extent of the disease (e.g.: depth of penetration, lymph node involvement, fixation to adjacent structures).

• MR has been shown to help to establish whether the radial margin is adequate;1 it must be considered if short-course pre-operative radiotherapy is planned.

• A CT scan of the thorax, abdomen, and pelvis is also recommended to exclude the possibility of metastatic disease and to provide a baseline for the future surveillance CT scans. To evaluate an abnormality identified on CT scan, a correlative MR or an ultrasound of the liver may be necessary.

• A pre-operative CEA is recommended for future comparison. A post-operative CEA should be requested to ensure that it has normalized if it was elevated before surgery.

Stage Information Table 1. AJCC Cancer Staging System for Early Stage Rectal Cancer, Seventh Edition.

Stage Depth of Tumour Penetration Regional Lymph Node Involvement Metastases Stage 0 Tis Carcinoma in situ N0 None M0 Absent Stage I T1 Invasion into submucosa N0 None M0 Absent

T2 Invasion into muscularis propria N0 None M0 Absent Stage IIA T3 Invasion through muscularis propria

into peri-rectal tissues N0 None M0 Absent

Stage IIB T4a Penetration to surface of visceral peritoneum

N0 None M0 Absent

Stage IIC T4b Direct invasion into, or adherence§ to, other structures

N0 None M0 Absent

Stage IIIA T1-2 As described above N1 One to three lymph nodes M0 Absent N1c Tumour deposits in subserosa,

mesentery, or peri-rectal tissues T1 Invasion into submucosa N2a Four to six lymph nodes M0 Absent

Stage IIIB T3-4a As described above N1 One to three lymph nodes M0 Absent N1c Tumour deposits in subserosa,

mesentery, or peri-rectal tissues T2-3 As described above N2a Four to six lymph nodes M0 Absent T1-2 As described above N2b Seven or more lymph nodes M0 Absent

Stage IIIC T4a Penetration to surface of visceral peritoneum

N2a Four to six lymph nodes M0 Absent

T3-4a As described above N2b Seven or more lymph nodes M0 Absent T4b Direct invasion into, or adherence§ to,

other structures N1-2 As described above M0 Absent

Stage IVA Tany As described above Nany As described above M1a One site* Stage IVB Tany As described above Nany As described above M1b Multiple sites*

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* M1a refers to metastasis confined to one site (e.g.: liver, lung, ovary, non-regional lymph node) whereas M1b refers to metastasis in more than one site or within the peritoneum. § If the microscopic assessment of the adhesion identifies no tumour, classify based on anatomic depth of wall invasion. Note: A peri-tumoural nodule in the peri-rectal adipose tissue without histologic evidence of lymph node architecture may represent discontinuous spread, venous invasion with extravascular spread, or a totally replaced lymph node.

Goals of Therapy The goals of therapy are to render the patient free of disease, to delay or prevent recurrence, and to preserve anal sphincter, urinary, and sexual function. Recommendations

1. A multidisciplinary team is required to define and provide the optimal care for a patient with rectal cancer. It should be composed of gastroenterologists, general surgeons, hepatobiliary surgeons, and both radiation and medical oncologists.

2. Consider treatment on a clinical trial, if available.

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Table 2. Recommendations for Treatment of Patients with Rectal Cancer Amenable to Resection. Stage Recommendations Stage 0 • Perform local or transanal excision.2

• No adjuvant systemic therapy is indicated.Stage I • If sufficient rectum distal to the cancer permits a colorectal or coloanal anastomosis, perform a radical en

bloc excision of the rectum by low anterior resection. Otherwise, perform an abdominoperineal resection.• To precisely dissect the rectum and para-rectal lymph nodes within the mesorectal envelope and to

obtain an optimal circumferential radial margin, surgery should only be performed by a surgeonexperienced with the total mesorectal excision technique.3,4

• In a carefully selected patient with low-risk T1 disease who accepts an increased risk of tumor recurrence, a prolonged period of post-operative surveillance, and a decreased success after salvage surgery, consider transanal excision.5-7 A T1 rectal cancer is considered “low-risk” if it is T1sm1 or T1sm2 (invasion into the superficial or middle third of the submucosa).

• No adjuvant systemic therapy is indicated.Stage II and Stage III

• Patients with rectal cancer not immediately amenable to surgical resection as well as patients withclinical stage II and III disease8,9 should be offered long-course pre-operative radiotherapy (4,500 to5,400 cGy in twenty-five to thirty fractions) with either protracted venous infusion 5-Fluorouracil (225mg/m2 per day by ambulatory infusion pump during the entire period of radiation therapy)10 orCapecitabine (825 mg/m2 po BID).11 If sufficient rectum distal to the cancer permits a colorectal orcoloanal anastomosis, perform a radical en bloc excision of the rectum by low anterior resection.Otherwise, perform an abdominoperineal resection. Either surgery should be performed six to eightweeks after having completed the course of radiation.12

• Patients with rectal cancer amenable to surgical resection can be offered short-course pre-operativeradiotherapy (2,500 cGy in five fractions).12-14 If sufficient rectum distal to the cancer permits a colorectalor coloanal anastomosis, perform a radical en bloc excision of the rectum by low anterior resection.Otherwise, perform an abdominoperineal resection. Either surgery should be performed within one weekof having completed the course of radiation.

• Pre-operative chemoradiotherapy is associated with a lower rate of grade 3/4 acute toxicities, long-termtoxicities, and local recurrence, but no difference in five-year overall survival when compared to post-operative chemoradiotherapy.8

• To precisely dissect the rectum and para-rectal lymph nodes within the mesorectal envelope and toobtain an optimal circumferential radial margin, surgery should only be performed by a surgeonexperienced with the total mesorectal excision technique.3,4

• A total of six months of chemotherapy is recommended (for adjuvant chemotherapy options extrapolatedfrom colon cancer, see the Clinical Practice Guideline for Early-Stage Colon Cancer).

• If a patient with rectal cancer undergoes a low anterior resection or an abdominoperineal resectionwithout pre-operative radiotherapy, offer two months of adjuvant chemotherapy (as for colon cancer),then radiotherapy (4,500 to 5,400 cGy in twenty-five to thirty fractions) with either concurrent protractedvenous infusion 5-Fluorouracil (225 mg/m2 per day by ambulatory infusion pump)8 or Capecitabine (825mg/m2 po BID)11 and then two additional months of adjuvant chemotherapy (as for colon cancer).15-17

• As long as resection of a metachronous polyp, second colorectal cancer, or metastasis to liver or lung isappropriate, surveillance is recommended (see Clinical Practice Guideline for Colorectal CancerSurveillance).

Locally Recurrent Cancer

• Care should be directed by the Multidisciplinary Gastrointestinal Tumor Team.• If the recurrence is not amenable to surgical resection, see Clinical Practice Guideline for Metastatic

Colorectal Cancer.Stage IV • Consider palliative radiotherapy for local symptoms.

• See Clinical Practice Guideline for Metastatic Colorectal Cancer.

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GLOSSARY OF ABBREVIATIONS Acronym Description AJCC American Joint Committee CEA carcinoembryonic antigen CT computed tomography MR magnetic resonance SEER Surveillance, Epidemiology, and End Results database TNM tumour-node-metastasis

DISSEMINATION • Present the guideline at the local and provincial tumour team meetings and weekly rounds. • Post the guideline on the Alberta Health Services website. • Send an electronic notification of the new guideline to all members of CancerControl Alberta. MAINTENANCE A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2015. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. CONFLICT OF INTEREST Participation of members of the Alberta Provincial Gastrointestinal Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial Gastrointestinal Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner. REFERENCES 1. MERCURY Study G. Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results

of the MERCURY study. Radiology 2007 Apr;243(1):132-139. Level of Evidence: 2c

2. Bailey HR, Huval WV, Max E, Smith KW, Butts DR, Zamora LF. Local excision of carcinoma of the rectum for cure. Surgery 1992 May;111(5):555-561. Level of Evidence: 2b

3. Kapiteijn E, van de Velde CJ. The role of total mesorectal excision in the management of rectal cancer. Surg Clin North Am 2002 Oct;82(5):995-1007. Level of Evidence: 1a

4. Phang PT. Total mesorectal excision: technical aspects. Can J Surg 2004 Apr;47(2):130-137. Level of Evidence: 2a

5. Bentrem DJ, Okabe S, Wong WD, Guillem JG, Weiser MR, Temple LK, et al. T1 adenocarcinoma of the rectum: transanal excision or radical surgery?. Ann Surg 2005 discussion 477-9; Oct;242(4):472-477.

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Level of Evidence: 4 6. Kikuchi R, Takano M, Takagi K, Fujimoto N, Nozaki R, Fujiyoshi T, et al. Management of early invasive

colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum 1995 Dec;38(12):1286-1295. Level of Evidence: 2b

7. Nascimbeni R, Burgart LJ, Nivatvongs S, Larson DR. Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 2002 Feb;45(2):200-206. Level of Evidence: 2a

8. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004 Oct 21;351(17):1731-1740. Level of Evidence: 1b

9. Wong R, Berry S, Spithoff K, Simunovic M, Chan K, Agboola O, et al. Preoperative or postoperative therapy for the management of patients with stage II or III rectal cancer. Cancer Care Ontario 2008. Level of Evidence: 1a

10. O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994 Aug 25;331(8):502-507. Level of Evidence: 1b

11. Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012 Jun;13(6):579-588. Level of Evidence: 1b

12. Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean JP, Partensky C, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol 1999 Aug;17(8):2396. Level of Evidence: 1b

13. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997 Apr 3;336(14):980-987. Level of Evidence: 1b

14. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001 Aug 30;345(9):638-646. Level of Evidence: 1b

15. Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991 Mar 14;324(11):709-715. Level of Evidence: 1b

16. Sargent DJ, Wieand HS, Haller DG, Gray R, Benedetti JK, Buyse M, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2005 Dec 1;23(34):8664-8670. Level of Evidence: 1b

17. Sargent DJ, Patiyil S, Yothers G, Haller DG, Gray R, Benedetti J, et al. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 2007 Oct 10;25(29):4569-4574. Level of Evidence: 1a

Level Description of Evidence 1a Systematic reviews of randomized controlled trials 1b Individual randomized controlled trials 1c All or none randomized controlled trials 2a Systematic reviews of cohort studies 2b Individual cohort study or low quality randomized controlled trial 2c Outcomes research 3a Systematic review of case-control studies 3b Individual case-control study 4 Case series 5 Expert opinion without explicit critical appraisal or based on physiology, bench research, or “first principles”

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APPENDIX A Figure 1. Observed survival rates for 9,860 cases with adenocarcinoma of rectum. Data from SEER 1973-2005.

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