the management of anal cancer dr c. m. mclean edinburgh cancer centre 2010

1. The Management of Anal CancerDr C. M. McLeanEdinburgh Cancer Centre 2010

3. Pathology Anal Canal Malignant epithelial tumours Squamous cell -keratinising Squamous cell -non keratinising(basaloid/cloacogenic) Adenocarcinoma -rectal type or anal gland Small cell Undifferentiated Anal Margin Squamous cell/basal cell /Bowens /Pagets

4. TNM staging Tis Ca insitu T1 <2cm T2 2-5cm T3 >5cm T4 involving adjacent organs M0 no mets M1 distant mets Canal N0 no regional LN N1 perirectal LN N2 unilateral internal iliac or inguinal LN N3 bilateral internal iliac or inguinal nodes Margin N0 no regional nodes N1 regional nodes

5. Lymphatic and metastatic spread Based on surgical series 26% of patients have involved nodes, but 50% of palpable nodes are reactive hyperplasia Lymph node involvement is directly related to the degree of involvement of the sphincter muscles Extrapelvic metastases at presentation is rare - 8% Locoregional recurrence 30%

6. Anal cancer Uncommon in western countries- but rising Median age 60-65yrs approx 300 cases per annum in the U.K demography changing- occurring in the younger age group and immunocompromised link between sexual behaviour many parallels between anal cancer and cervical cancer

7. Anal Intraepithelial Neoplasia Like cervical cancer, anal cancer has an in situ change- intraepithelial neoplasia (AIN) occurs most commonly in the transitional zone. AIN1 nuclear abnormalities in lower third of epithelium AIN2 effect lower two thirds AIN3 full thickness and microvascular invasion of the basement membrane Atypical squamous cells,condylomata and AIN are all manifestations of HPV infection

8. Anal Intraepithelial Neoplasia and HIV Prevalence of anal cytological abnormalities in Edinburgh 30% in HIV+ve homosexuals 4.7% in HIV �ve homosexuals 0% in heterosexual males Increase risk if CD4 count <500 x 106/l

9. Management of AIN In immuno-competent patients AIN does not usually progress to invasive cancer. - AIN1 and 2 can be managed by anoscopy at 6 monthly intervals and if 3 consecutive examinations show no cytological progression then discharge - AIN3 requires excision and ongoing anoscopy. Small lesions can be treated with trichloroacetic acid Immunocompromised patients carry significant risk of progression to invasion - monitor CD 4 counts and 6 monthly anoscopy

10. Anal Cancer and HIV increase in incidence of anal cancer in homosexual men with AIDS in other AIDS cohorts eg drug abusers/ haemophiliacs anal cancer is rarely seen immunocompetence leads to progression of AIN toxicity of treatment is greater pretreatment CD4 levels < 200 is associated with increased toxicity

11. Evolving management of anal cancer APR was treatment of choice until 1980�s Radiotherapy alone was in vogue in 1930�s but was associated with unacceptable morbidity Nigro et al 1974 - used combined chemoradiation for preoperative downstaging - 30Gy in 15# with mitomycin-C and 5FU - first 3 patients had had a pathological CR at surgery studies began to demonstrate local control rates of 61-87% without surgery

12. Chemoradiation vs RT alone EORTC 1987-1994 110 pts randomised RT vs chemoRT 45Gy/25# mitomycin C 15 mg/m2 d 1 5FU 750 mg/m2 d 1-5 UKCCCR 1987-1991 577 patients randomised 45Gy/20-25# gap 6/52 boost 15Gy in 6# or 25Gy in 2-3 days by implant mitomycin C 12 mg/m2 d 1 5FU 1000 mg/m2 d 1-4 and #21-25

13. Chemoradiation studies cont

14. UKCCCR TRIAL (ACT I) At 5 years 50% were dead Of disease failures only 58% were suitable for salvage surgery 33% of patients undergoing salvage surgery developed metastatic disease distant met rate in RT group 38% vs 26% in CMT group ? Could chemotherapy add a systemic effect as well as a radiosensitising effect

15. What chemotherapy? RTOG (3)- RT+5FU vs RT + Mitomycin C/5FU 5yr colostomy free survival no difference (p=0.17) 5 yr overall survival improved for mitomycin-C 67% vs 50% (p=0.006) role of cisplatin in combination with RT and adjuvantly (ACT II) RTOG 98-11 neoadjuvant chemotherapy with Mitomycin- C or cisplatin

16. Neoadjuvant chemotherapy RTOG 98-11 682 patients randomised between 2 cycles of 5-FU (1000 mg/m2 x4 + mitomycin-C 10 mg/m2 d 1,29, 57, 85 chemoRT starting day 57 OR 2cycles of 5-FU (1000 mg/m2 x4 + cisplatin 75 mg/m2 d1,29,57,85 chemoRT starting day 57 End point of study � DFS and secondary end point OS, colostomy free survival at 2 years and local recurrence

17. Results of neoadjuvant chemo 634 analysable patients HR for DFS 1.15 (95%CI 0.87-1.5 p=0.33) ie no difference between the 2 groups O.S no different Colostomy rate higher in the cisplatin arm suggesting that cisplatin may be inferior to mitomycin -C

18. ACT II (2x2 factorial design) Epidermoid anal cancer staged by EUA and CT GFR >50ml/min RANDOMISATION RT+5FU+MMC RT+5FU+ MMC RT+5FU+CDDP RT+5FU+CDDP No maintenance Maintenance No Maintenance Maintenance therapy therapy therapy therapy Patients with progressive/persistent disease following initial chemoradiation or maintenance chemotherapy should be considered for salvage surgery

22. ACT11 Results 940 patients recruited Median age 58 years T1/T2 50%, T3/T4 43% Node �ve 62% Median FU 3years Complete response rate MMC 94%, Cisp 95% p=0.53 Gd3/4 haematological toxicities MMC 25%, cisp 13% p<0.01 ( but no increase in neutropenic sepsis) Non haematological toxicities 61%vs 65% Recurrence free survival 75%

23. EXTRA Phase II trial Phase II multicentre trial Same RT dose and technique as in ACTII Mitomycin C 12mg/m2 day 1, capecitabine 825mg/m2 b.d on radiotherapy days (5 days per week) End points CR at 4 weeks, 6 month local control and toxicity 31 patients, 14 male, 17female Compliance 60%with chemo, 81%with RT Acceptable toxicity (no treatment related deaths) 77% CR, 16% PR Median FU 14/12, 3 locoregional relapses Capecitabine should be considered in further randomised studies

24. Elderly/frail patients cont. 16 patients (median age 81yrs) 30Gy in 15# (3cm margins on the tumour) 5FU 600mg/m2 days 1-4 1pt grade 3 skin toxicity Local control rate 73% 13/16 patients alive at 16 months

25. What radiotherapy? Dose - bearing in mind Nigro�s original dose was 30Gy/15# - report of acceptable local control in elderly and poor P.S patients Gap � at last we have got rid of it! Involved nodal irradiation? Is it correct to use the same technique for a T1 N0 tumour as a T4 N2 tumour

26. Prophylactic nodal irradiation? Group from Lyon in a retrospective study of 243 cases of node negative anal cancer treated without prophylactic inguinal nodal RT found an incidence of nodal relapse to be 6.4% for T1/T2 tumours Small retrospective study from Guys and St Thomas� Hospital - 30 patients with node negative disease (clinical examination and imaging) underwent involved field RT alone, median FU 41 months.4 patients relapsed, 2 locally, 1 in inguinal region, 1 in liver � all were salvaged surgically and remain disease free Role of PET scanning, sentinel node biopsy??

27. Toxicity Impact on bowel function Bladder function Sexual Function � impotence and vaginal stenosis Chronic skin toxicity Osteoradionecrosis

28. SUMMARY Chemoradiation is the standard of care for sqamous cell carcinoma of anus. Results have improved significantly over the last decade (DFS ACT I 52%, ACT II 75%) Future trial need to examine RT technique, can we reduce the field in earlier tumours. What chemotherapy? Role of PET in staging/ response to RT (earlier salvage surgery)