1. Anal Cancer Rob Glynne-Jones Mount Vernon Cancer Centre on behalf of NCRI anal cancer subgroup

2. Aim to discuss The EORTC trials in anal cancer US and UK trials What we have learnt so far Where do we go from here?

3. Randomised trials UKCCR ACT 1 CRT vs RT EORTC 22861 CRT vs RT RTOG 8704/ECOG Role of MMC RTOG 98-11 Role of NACT/cisplat ACCORD-03 Role of NACT cisplat/ RT dose CRUK ACT 2 Role of cisplat vs MMC + maintenance 5FU/cisplat EORTC Role of 5FU vs CDDP/MMC 22011-40014 not extended to phase III

4. UKCCCR Anal Cancer Trial (ACT 1) CMT – 45Gy + Mitomycin C 5FU RT alone 45Gy Boost 25Gy implant or 15Gy in 6F Boost 25Gy implant or 15Gy in 6F 6 weeks

5. ACT I :Time to first local relapse 75 50 25 0 Percentage of patients having a local relapse (%) 02468101214161820 Time since randomisation (years) RT alone CMT HR 0.46, p<0.001

6. Colostomy-free survival

9. ACT II Factorial Design Chemoradiation Comparison MMC 5FU CRT No maintenance CisP 5FU CRT No maintenance MMC 5FU CRT +Maintenance CisP 5FU CRT +Maintenance MMC N=472 CisP N=468 versus

10. MMC 5FU CRT No maintenance CisP 5FU CRT No maintenance MMC 5FU CRT Maintenance CisP 5FU CRT Maintenance No Maint N=446 Maint N=448 versus ACT II Factorial Design Maintenance Comparison

11. Chemoradiation Regimens 12345 RT week 5FU MMC 12345 RT week 5FU CisP 1000mg/m 2 d1-4 & 29-32 24 hour continuous iv infusion 12mg/m 2 d1 only iv bolus, max single dose 20 mg 60mg/m 2 d1 & 29 iv infusion 1000mg/m 2 d1-4 & 29-32 24 hour continuous iv infusion 6 6

12. ACT II Endpoints Chemoradiation (CRT) comparison Primary Endpoints Complete response rate at 6 months Acute Toxicity (CTC Grade 3 & 4) Maintenance comparison Primary Endpoint Recurrence Free Survival Both comparisons Secondary Endpoints Colostomy Rate Cause-specific & Overall survival

13. 50.4 Gy in 28 fractions over 5 ½ weeks (no gap) Phase I 30.6 Gy in 17 fractions Parallel opposed 3cm below inf. tumour (or margin) Anal bolus Phase II GTV + 3cm 19.8Gy in 11 fractions N0 groins Planned volume (canal) Direct field (margin only) N+ groins all GTV +3cm Anal bolus

14. Mean Doses Received PTV primary 51.37Gy ± 0.84 (95% CI) PTV inguinal nodes 51.41Gy ± 1.54 Uninvolved inguinal 36.53Gy ± 3.38 Uninvolved external iliac 34.28Gy + 5.63 Femoral heads 47.32Gy ± 3.45 Aggarwal A, et al., Radiother Oncol. 2012 Jun;103(3):341-6

15. Tumour Stage MMC (472) CisP (468) T stage T1 T2 49% (232)54% (254) T3 T4 48% (225)44% (205) TX 1513 N Stage Node negative 63% (297)62% (290) Node positive 32% (150)33% (155) NX 2523

16. Response at 26 weeks Patients with response data (863) MMC (432/472) CisP (431/468) CR primary 90% CR N0 83% (358) 84% (362) CR N+ 3% (15)3% (12) CR Nx 4% (18)3% (12) PR 3% (14)6% (24) SD 1% (5)1% (6) PD 5% (22)3% (15) P=0.66

17. ACT II Compliance & Toxicity Radiotherapy –92% MMC vs 90% CisP - total dose 50.4Gy –~3% >7 days interruptions Chemotherapy - weeks 1 & 5 –75% MMC vs 72% CisP full dose weeks 1 & 5 Acute toxicity –58% MMC vs 60% CisP Grade 3 –13% MMC vs 12% CisP Grade 4 –71% MMC vs 72% CisP combined Grade 3/4

18. CR at 26 weeks Difference (95% CI)P value MMCCisP 83% (358/432) 84% (362/431) +1% (-3.8 to 6.1)p =0.66 No MaintMaint 82% (337/409) 85% (348/410) +3% (-2.6 to 7.5)p = 0.34

19. PFS -free survival MMC vs CisP comparison 73% 74%

20. Overall Survival CR vs Not CR week 26 93% 61%

21. ACT II – Conclusions Excellent CR rate at 6 months - 83% v 84% - no difference MMC/Cisp No difference in colostomy rate No difference in PFS 60% of pts not in CR at 11 weeks achieved CR at 26 weeks. We recommend assessment at 26 weeks in future trials

22. Maintenance Comparison- Recurrence Free Survival Event is progression, recurrence or death 0 20 40 60 80 100 Recurrence-free survival (%) Maint 46834525118313261161 47234626318311667194No Maint No. at risk 012345678 Time from randomisation (years) No Maint - 103 events Maint - 100 events HR: 0.94, 95% CI: 0.72 to 1.24, P=0.67 75%

23. 0 20 40 60 80 100 Overall survival (%) 44836127820313871223Maint 44636927819812567194 No Maint No. at risk 012345678 Time from randomisation (years) HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21 84% 85% No Maint - 74 events Maint - 60 events Maintenance Comparison - Overall Survival HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21

24. ACT II – Conclusions 2 Maintenance comparison Preliminary data shown 2009 Median follow-up now 5 years No evidence of any difference in PFS, cause specific survival or overall survival

25. ACT II Timing of pelvic recurrences (93% in years 1-3) Year 1 Year 2 Year 3

26. Site of relapse Number% total relapses PELVIC NO METS13364% PELVIC WITH METS3014% DISTANT METS ONLY 4622% TOTAL CRUDE PF (WITH OR WITHOUT METS) 16378% TOTAL RELAPSES209 The pattern was similar for PF only and PF + mets (data not shown)

27. ACCORD- 03 Locally advanced >4cm or N1 anal canal Therapeutic intensification –Induction chemotherapy –High dose radiotherapy Primary endpoint: colostomy-free-survival(CFS). Secondary endpoint : QoL, local control (LC), overall survival (OS), and cancer-specific survival.

28. ACCORD 03 70% 82% 77% 73% 5 years CFS

29. RTOG 9811 Time to Colostomy Cisplat MMC RTOG 9811 Ajani JA et al JAMA 2008

30. MMC Cisplatin RTOG 9811 Ajani JA et al JAMA 2008 RTOG 9811 Disease Free Survival

31. Thoughts No longer feasible to think that one size fits all in anal cancer We improved overall 3 year DFS from 54% (ACT I) to 74% (ACT II) We took 7 years to do ACT II We probably need international collaboration for next studies

32. Radiotherapy strategies which need exploring (1) Optimization of radiotherapy (optimal dose/fractionation/concomitant boost/brachytherapy) (2) Optimal field sizes (3) Evaluation of new radiosensitization protocols (oxaliplatin, irinotecan, taxanes). (4) Optimization of radiotherapy techniques (IMRT/VMAT/Brachytherapy)