CLINICAL PRACTICE GUIDELINE GI-001

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ANAL CANAL 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 The anal canal is delimited superiorly by the proximal extent of the levator-external anal sphincter complex and inferiorly by the anal verge (the junction between the anal mucosa and the hair-bearing skin). Lesions that involve the hair-bearing skin (peri-anal skin within 5 cm of the anal verge) are considered cancers of the anal margin and should also be treated as anal cancers.

This guideline was developed to outline the management recommendations for patients with squamous cell carcinomas that arise within the anal canal. Adenocarcinomas of the anal canal should be treated like rectal cancers (see the Early-Stage Rectal Cancer Clinical Practice Guideline).

http://www.albertahealthservices.ca/hp/if-hp-cancer-guide-gi005-early-stage-rectal.pdf

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GUIDELINE QUESTIONS What are the goals of therapy and recommendations for the treatment of adult patients with potentially

curable cancer of the anal canal? What are the recommendations for management of adult patients who have undergone curative

therapy for cancer of the anal canal? What are the recommendations for management of adult patients with locally recurrent cancer of the

anal canal? What are the recommendations for management of adult patients with metastatic cancer of the anal

canal? 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 January, 2008. This guideline was revised in March, 2011, 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 Teams interpretation of the data. TARGET POPULATION The recommendations outlined in this guideline apply to adults over the age of 18 years with squamous cell carcinomas that arise within the anal canal. Different principles may apply to pediatric patients. RECOMMENDATIONS AND DISCUSSION Suggested Diagnostic Work-Up The incidence of squamous cell carcinomas that arise within the anal canal has increased with the prevalence of Human Papilloma Virus (HPV) infection, Human Immunodeficiency Virus (HIV) infection, and immunosuppression required for organ transplantation. If the use of chemotherapy or radiotherapy is considered and HIV infection is suspected, HIV serology and an evaluation of the CD4 count are suggested in addition to the complete blood count and both liver and renal function tests. Because prognosis depends upon the stage of disease, an anatomic assessment with digital rectal examination, anoscopy or sigmoidoscopy (with biopsy), and a CT scan of the abdomen and pelvis (and/or MR or transrectal ultrasound) plus chest x-ray are recommended. Suspicious lymph nodes should be

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evaluated with a biopsy by fine-needle aspirate. Female patients should have a gynecological assessment (including a Pap smear) to exclude a synchronous cervical cancer. A colonoscopy should be performed to detect synchronous lesions. Stage Information Table 1. American Joint Committee on Cancer Staging Information, Seventh Edition. Stage Tumour Stage Regional Lymph Node Involvement Metastases Stage 0 Tis Carcinoma in situ N0 None M0 Absent Stage I T1 Tumour 2 cm in size N0 None M0 Absent Stage II T2 Tumour between 2 cm and 5 cm N0 None M0 Absent

T3 Tumour > 5 cm in size N0 None M0 Absent Stage IIIA

T1 Tumour 2 cm in size N1 Perirectal lymph nodes M0 Absent T2 Tumour between 2 cm and 5 cm N1 Perirectal lymph nodes M0 Absent T3 Tumour > 5 cm in size N1 Perirectal lymph nodes M0 Absent T4 Invasion into adjacent organs

(e.g.: vagina, urethra, bladder) N0 None M0 Absent

Stage IIIB

T4 Invasion into adjacent organs (e.g.: vagina, urethra, bladder)

N1 Perirectal lymph nodes M0 Absent

Tany As described above N2 Unilateral internal iliac and/or inguinal lymph nodes

M0 Absent

Tany As described above N3 Perirectal and inguinal lymph nodes Bilateral internal iliac lymph nodes Bilateral inguinal lymph nodes

M0 Absent

Stage IV Tany As described above Nany As described above M1 Present Goals of Therapy and Recommendations for Potentially Curable Cancer of the Anal Canal 1. To render the patient free of disease and to delay or prevent recurrence. 2. To improve the patients quality of life (to eliminate tumour-related symptoms) and to preserve

continence. Consider treatment on a clinical trial, if available. Table 2. Recommendations for Potentially Curable Cancer of the Anal Canal. Stage Recommendations Stage 0 Consider a wide local excision provided that surgical resection can be completed to achieve

negative margins and to preserve continence (no involvement of the anal sphincter). Stage I Consider a wide local excision provided that surgical resection can be completed to achieve

negative margins and to preserve continence (no involvement of the anal sphincter). Consider primary chemoradiotherapy (as described for stage II and IIIA disease) if sphincter

preservation (maintenance of continence) is not possible with a wide local excision. Consider an abdominoperineal resection for residual or recurrent disease.

Stage II Stage IIIA

Primary chemoradiotherapy1-6 involves the sequential administration of Mitomycin C (10 to 12 mg/m2 IV) followed by a continuous intravenous infusion of 5-Fluorouracil (4,000 mg/m2 over ninety-six hours) during week one (and, possibly, week five) of a course of radiation (4,500 to 5,400 cGy to the perineum and regional lymph nodes). This regimen requires placement of a central venous catheter (CVC) or a peripherally inserted central catheter (PICC line).

Consider an abdominoperineal resection for residual or recurrent disease. Stage IIIB Primary chemoradiotherapy (as described for stage II and IIIA disease). Consider a boost, if

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Stage Recommendations indicated.

Consultation with the multidisciplinary and surgical team should be sought to determine the role of further surgery.

Post-Curative Therapy Guidelines

Perform a digital rectal examination and consider anoscopy at six to eight weeks after completion

of the therapy. Consider biopsy of any suspicious lesions at three months after completion of therapy, but recognize that tumors may continue to respond up to six months after the radiation.7

Perform salvage surgery for biopsy-proven persistent, progressive, or recurrent disease. After achieving a complete response, repeat digital rectal examination, anoscopy, and

examination of the inguinal lymph nodes every four months for two years then every six months for the balance of five years.

Female patients should have a gynecological assessment (including a Pap smear) due to the increased risk of cervical cancer. A colonoscopy should be obtained as outlined in the colorectal cancer screening guidelines.

Recommendations for Locally Recurrent Cancer of the Anal Canal 1. For patients whose disease recurs despite prior radical chemoradiotherapy, consider surgical

resection, if possible. Consider palliative therapy (see below) if surgical resection is not possible. 2. For patients whose disease recurs after not having received prior chemoradiotherapy, consider radical

chemoradiotherapy (see above) with or without surgery. Goals of Therapy and Recommendations for Metastatic Cancer of the Anal Canal 1. To maintain or to improve the patients quality of life (to control or to delay the onset of tumor-related

symptoms). 2. To prolong life, if possible. Metastatic anal canal cancer describes the situation where a cancer that originated within the anal canal has spread beyond the regional lymph nodes to other organs. This represents an incurable situation for which palliative options (e.g.: best supportive care, palliative chemotherapy) may be considered. Palliative chemotherapy regimens are generally continued as long as tumor shrinkage or stability is confirmed, as long as the side effects remain manageable, as long as the patient wishes to continue, and as long as the treatment remains medically reasonable. Palliative chemotherapy may involve the sequential administration of anti-emetics, adequate prehydration, and Cisplatin (75 mg/m2 in 250 mL of normal saline IV over one hour) followed by a continuous intravenous infusion of 5-Fluorouracil (4,000 mg/m2 over ninety-six hours) every twenty-eight days. This regimen requires placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port.

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GLOSSARY OF ABBREVIATIONS Acronym Description AJCC American Joint Committee on Cancer CT computed tomography CVC central venous catheter HIV human immunodeficiency virus HPV human papilloma virus IV intravenous PICC peripherally inserted central catheter 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. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy,

5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 1996 Oct 19;348(9034):1049-1054. Level of Evidence: 1b

2. Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB,3rd, Thomas CR,Jr, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA 2008 Apr 23;299(16):1914-1921. [Updated as J Clin Oncol 2012; 30(35): 4344-4351] Level of Evidence: 1b

3. Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a

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phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 1997 May;15(5):2040-2049. Level of Evidence: 1b

4. Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 1996 Sep;14(9):2527-2539. Level of Evidence: 1b

5. James RD, Glynne-Jones R, Meadows HM, Cunningham D, Myint AS, Saunders MP, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 x 2 factorial trial. Lancet Oncol 2013 May;14(6):516-524. Level of Evidence: 1b

6. Peiffert D, Tournier-Rangeard L, Gerard JP, Lemanski C, Francois E, Giovannini M, et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol 2012 Jun 1;30(16):1941-1948. Level of Evidence: 1b

7. Glynne-Jones R, James R, Meadows H, Begum R, Cunningham D, Northover J, et al. Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU in squamous cell carcinoma of the anus: results of ACT II. J Clin Oncol 2012 ASCO Annual Meeting Proceedings 2012;30(suppl; abstr 4004). Level of Evidence: 1b

Useful Review Articles: 8. Glynne-Jones R, Renehan A. Current treatment of anal squamous cell carcinoma. Hematol Oncol Clin North Am

2012 Dec;26(6):1315-1350. 9. Wietfeldt ED, Thiele J. Malignancies of the anal margin and perianal skin. Clin Colon Rectal Surg 2009

May;22(2):127-135.

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