ANAL CANCER Updated May 2016 by Dr. Daniel Yokom (PGY-5 Medical Oncology Resident, University of Toronto)

Transcription

1 ANAL CANCER Updated May 2016 by Dr. Daniel Yokom (PGY-5 Medical Oncology Resident, University of Toronto) Reviewed by Dr. Lee-Ying (Staff Medical Oncologist, University of Calgary), Dr. Kzyzanowska (Staff Medical Oncologist, University of Toronto) and Dr. Cummings (Staff Radiation Oncologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology resident and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: Rare, cases in Canada per year(1) - Mortality: Less than 100 deaths in Canada per year RISK FACTORS - Environmental/Chemical/Infections: o HPV (Serotypes 16 and 18) o History of anal warts o History of cervical, vulvar or vaginal cancer o History of multiple sexual partners, anal-receptive intercourse and sexually transmitted infections o Immunosuppression (HIV, organ transplant) o Cigarette smoking - Genetic: o None known PREVENTION & SCREENING - Prevention: o Interventions to reduce HPV risk Vaccination against HPV (2) Safe sex interventions Male circumcision (3) o Smoking Cessation - Screening: o No specific Canadian guidelines o Medford and Salit (4) strongest recommendation for screening for men with HIV who have sex with men. Also recommend for all men and women with HIV, women with genital dysplasia or cancers, anyone with perianal high-grade lesions, and recipients of solid organ transplants. o Options for screening include: Anal Papanicolaou test for cytology and/or HPV testing Digital anal exam High resolution anoscopy with staining with vinegar or Lugol s iodine B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS

2 - Common Symptoms: o anal itching, discharge, bleeding o pain or pressure in the anal area that is not relieved by a bowel movement o change in bowel habits: changes to the caliber, constipation, diarrhea or alternating between constipation and diarrhea - Common Signs: o lump or swelling in the anal area o enlarged lymph nodes in the groin or anal area INVESTIGATIONS - Physical Exam o Include digital rectal exam and palpation of inguinal lymph nodes o Pelvic exam for all women with cervical Pap smear - Laboratory o Routine bloodwork, HIV, hepatitis screen - Diagnostic Imaging: o Pelvic MRI o CT chest, abdomen and pelvis - Diagnostic Procedures: o Biopsy PATHOLOGY & MOLECULAR BIOLOGY - Most commonly squamous cell carcinoma and variants (cloacogenic, basaloid, transitional) - Adenocarcinoma is managed like rectal cancer - Lymphatic drainage to peri-rectal, inguinal, and internal iliac nodes STAGING AJCC 7 th Edition

3 C) TREATMENT LOCALIZED AND LOCALLY ADVANCED(5) - Consider surgery alone for stage I (T1N0) - Stage II-III should be treated with concurrent chemoradiation: o Allows for sphincter preservation, but no overall survival benefit,as per the trials below o 45-65Gy/25-35# plus o 5-FU 1000mg/m2/d d1-4 and d29-32 plus o mitomycin 10mg/m2 d1 and 29 or cisplatin 75mg/m2 d1 and 29 if mitomycin contraindicated - Surgery for salvage treatment - Special considerations o HIV-infected and immunosuppressed (i.e. organ transplant) patients should be managed the same as non-immunosuppressed patients - Follow-up o Exam at 8-12 weeks post-treatment then q3-6 months for 5 years - Prognosis: o 5-year OS Localized = 80% Regional = 50% o Poor prognostic features: T4 N2-3 - Important Phase III Clinical Trials: ACT 1 Trial (UK-CCCR) Epidermoid anal cancer: Results from the UK-CCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and mitomycin. UK CCCR Anal Cancer Working Party. Lancet, Regimen Radiation (40-45Gy +/- boost) with or without concurrent 5-FU (1000mg/m2/d d1-4 or 750mg/m2/d d1-5) and mitomycin C (12mg/m2 d1) Primary Endpoint Local failure rate Inclusion/Exclusion Included everyone except T1N0 Patients with metastatic disease were included as the primary endpoint was local control Size (N) 585 Results Local control: Significantly improved with CRT (39%) compared to RT alone (61%) RR 0.54 (CI ) Survival: No difference in all-cause mortality but improved diseasespecific mortality with CRT (28%) compared to RT alone (39%) Toxicity Increased early toxicity with CRT (neutropenia, rash, diarrhea) Similar late toxicity profile Similar morbidity with salvage surgery when necessary Conclusion 5-FU and mitomycin should be added concurrently with radiation to improve colostomy-free survival Other Comments Surgery for incomplete response at 6 weeks EORTC Trial Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advance anal cancer: results of a phase III randomized trial of the

4 European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. H. Bartelink et al. JCO Regimen Radiation (45Gy +/- boost) with or without concurrent 5-FU and mitomycin C Primary Endpoint Local failure rate (colostomy-free survival) Inclusion/Exclusion Included T3-4N0-3 or T1-2N1-3 Size (N) 110 Results 5-yr colostomy-free survival: CRT reduced absolute rate of colostomy by 32% (p = 0.002) Survival: No difference in survival Toxicity Similar severe side-effects Increased rate of anal ulcers in CRT group Conclusion 5-FU and mitomycin should be added concurrently with radiation to improve colostomy-free survival Other Comments Surgery for incomplete response at 6 weeks RTOG 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. M. Flam et al. JCO Regimen Radiation ( Gy) and 5-FU (1000mg/m2/d) with or without mitomycin C (10mg/m2) For residual tumor: additional radiation (9Gy) and 5-FU and cisplatin (100mg/m2) Primary Endpoint Local failure rate (colostomy-free survival) Inclusion/Exclusion Any T or N No metastatic disease Size (N) 310 Results 4-y colostomy rate: Mitomycin reduced absolute rate of colostomy by 13% (p = 0.002) 4-y disease-free survival: Mitomycin improved DFS by 22% (73% vs 51%, p = ) Survival: No difference in survival Salvage therapy: 50% complete response to salvage therapy if required Toxicity Increased grade 4 and 5 toxicity in mitomycin group Conclusion Mitomycin should be added concurrently with radiation and 5-FU to reduce the rate of colostomy and improve disease-free survival Intergroup RTOG Fluorouracil, mitomycin, and radiotherapy vs. fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. J. Ajani et al. JAMA

5 Regimen 1. Radiation (45-59Gy) and 5-FU (1000mg/m2/d d1-4 and 29-32) with mitomycin C (10mg/m2 d1 and 29) 2. Induction chemotherapy 5-FU (1000mg/m2/d, d1-4, 29-32) and cisplatin (75mg/m2, d1 and 29) followed by radation (45-59Gy) starting d57 with 5-FU (1000mg/m2/d, d57-60 and 85-88) and cisplatin (75mg/m2, d57 and 85) Primary Endpoint 5-y DFS Inclusion/Exclusion T2-4, any N No metastatic disease Size (N) 682 Results No difference in DFS or OS although trend towards worse outcomes for cisplatin group Worse colostomy rate in cisplatin group (19%) compared to mitomycin group (10%), p = 0.02 Toxicity Similar toxicity profile Conclusion Cisplatin-based CRT was not superior to mitomycin-based CRT Rate of colostomy was higher with cisplatin-based CRT ACT II Trial Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, openlabel, 2 2 factorial trial. RD James et al. Lancet Regimen 1. Radiation (50.4Gy/28#) and 5-FU (1000mg/m2/d d1-4 and 29-32) with mitomycin C (12mg/m2 d1), no maintenance 2. Radiation and 5-FU (1000mg/m2/d d1-4 and 29-32) with cisplatin (60mg/m2 d1 and 29), no maintenance 3. Radiation and 5-FU (1000mg/m2/d d1-4 and 29-32) with mitomycin C (12mg/m2 d1) + maintenance 5-FU (1000mg/m2/d d71-74 and d92-95) and cisplatin (60mg/m2 d71 and d92) 4. Radiation and 5-FU (1000mg/m2/d d1-4 and 29-32) with cisplatin (60mg/m2 d1 and 29) + maintenance 5-FU and cisplatin Primary Endpoint Complete response Acute toxic effects Progression-free survival Inclusion/Exclusion Any T and N No metastatic disease Size (N) 940 Results All groups essentially identical Toxicity Similar toxicity profile Conclusion Mitomycin-based CRT is still the standard of care Maintenance chemotherapy did not offer additional benefit - Other Important Published Data: o Systematic review by Spithoff et al in 2014 confirmed best evidence for radiation plus 5- FU and mitomycin(6). METASTATIC - Bottom Line General Approach:(7,8) o Currently no randomized data to support decision o Consider resection for oligometastatic disease

6 o Cisplatin and 5-FU the most commonly reported regimen o Weekly cisplatin (for less fit) - Prognosis: o Not well understood, case series reports 9-24 months - Future data: o Current trial of cisplatin plus 5-FU vs carboplatin plus weekly paclitaxel is underway D) REFERENCES 1. Canadian Cancer Society. Canadian Cancer Statistics 2015: Special topic: Predictions of the future burden of cancer in Canada. 2015; 2. Canada PHA of. Update on the recommended Human Papilllomavirus (HPV) vaccine immunization schedule Jul. 3. Castellsagué X, Bosch FX, Muñoz N, Meijer CJLM, Shah K V, de Sanjose S, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med Apr 11;346(15): Medford RJ, Salit IE. Anal cancer and intraepithelial neoplasia: epidemiology, screening and prevention of a sexually transmitted disease. CMAJ Feb 3;187(2): Spithoff K, Cummings B, Jonker D, Biagi J. Gastrointestinal Cancer Disease Site Group. Management of squamous cell cancer of the anal canal Spithoff K, Cummings B, Jonker D, Biagi JJ. Chemoradiotherapy for squamous cell cancer of the anal canal: a systematic review. Clin Oncol (R Coll Radiol) Aug;26(8): Eng C, Chang GJ, You YN, Das P, Rodriguez-Bigas M, Xing Y, et al. The role of systemic chemotherapy and multidisciplinary management in improving the overall survival of patients with metastatic squamous cell carcinoma of the anal canal. Oncotarget Nov 30;5(22): Khawandanah M, Baxley A, Pant S. Recurrent metastatic anal cancer treated with modified paclitaxel, ifosfamide, and cisplatin and third-line mitomycin/cetuximab. J Oncol Pharm Pract Jun;21(3):232 7.