ACT II: The Second UK Phase III Anal Cancer Trial A randomised trial of chemoradiation using mitomycin of cisplatin, with or without maintenance cisplatin/5-FU in squamous cell carcinoma of the anus. Professor Roger James on behalf of the NCRI ACT II Trial Management Group and Investigators ASCO, Florida, May 2009. Abstract ID: LBA 4009 (30894) Cancer Research UK grant number: C444/A628 ISRCTN number: 26715889 Sponsor Funder

Background Standard treatment - RT + 5-FU + MMC Research questions UKCCCR ACT 1 EORTC 22861 RTOG 87-04/ECOG 1289 Research questions 1. Concurrent chemoradiotherapy Different chemotherapy – RTOG 98-11 / ACT II /EORTC Increase RT dose – ACCORD 3 2. Additional therapy Neoadjuvant chemotherapy – RTOG 98-11 & ACCORD 3 Maintenance chemotherapy – ACT II Do think you need to set the scene first

Objectives To evaluate in a factorial design Whether chemoradiation using Cisplatin or Mitomycin produces a higher complete response rate Whether maintenance therapy will improve local control or prolong survival 3

Factorial Design 1. Chemoradiation Comparison MMC 5FU CRT No maintenance CisP 5FU CRT No maintenance MMC versus CisP MMC 5FU CRT Maintenance CisP 5FU CRT Maintenance N=471 N=469

Factorial Design 2. Maintenance Comparison No maintenance N=446 MMC 5FU CRT No maintenance CisP 5FU CRT No maintenance versus Maintenance N=448 MMC 5FU CRT Maintenance CisP 5FU CRT Maintenance

Statistical Methods Sample Size Analysis Target sample size ~950 patients CRT Comparison 5% increase of CR rate from 90% to 95% - CisP arm Maintenance Comparison decrease of recurrence from 25% to 17.5% - maintenance arm Each with 80% power, p<0.05 Analysis 905/940 patients evaluable Median follow-up 3 yrs Intention to Treat 6

Primary 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 7

Entry Criteria Histologically confirmed No evidence of metastases Fit for all possible treatments and consent Minimum GFR > 50 ml/min GFR <60 confirmed by EDTA clearance /other isotopic method Normal blood counts, LTF’s Adequate Cardiac function No contraindications to treatment Known HIV positive patients not eligible 8

Radiotherapy 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

Chemoradiation Treatment 1 2 3 4 5 6 RT week 1000mg/m2 d1-4 & 29-32 24 hour continuous iv infusion 5FU 12mg/m2 d1 only iv bolus, max single dose 20 mg MMC 1 2 3 4 5 6 RT week 1000mg/m2 d1-4 & 29-32 24 hour continuous iv infusion 5FU 60mg/m2 d1 & 29 iv infusion CisP 10

Maintenance Treatment Starts 4 wks after end of primary CRT 1 2 3 4 Week 1000mg/m2 d1-4 & 29-32 24 hour continuous iv infusion 5FU 60mg/m2 d1 & 29 iv infusion CisP 11

Accrual 940 patients Jun 2000 – Dec 2008 59 sites Multi centre & National collaboration We do need this slide in – only one with no of pts entered and duration of accrual 12

Patient Demographics - 1 * Stratification factor   MMC No maint n=246 CisP Maint n=226 n=222 *Gender Male Female 38% 62% 37% 63% *Age <65 65 75% 25% 73% 27% 74% 26% *GFR <60 60 4% 96% Pre Rx-colostomy No Yes N/K 81% 7% 12% 76% 11% 13% 71% 14% 15% 80% 9% Pre treatment colos not stratification factor could delete row and add info to colos at 3 yrs slide - 10% of pts had pre treatment colostomies

Patient Demographics - 2 * Stratification factor   MMC No maint n=246 CisP Maint n=226 n=222 *Site Canal Margin N/K 80% 16% 4% 81% 15% 83% 14% * T1 T2 T3 T4 11% 41% 29% 13% 6% 10% 39% 31% 7% 30% * Node +ve Node -ve 63% 8% 61% 9%

Results: Grade 3 & 4 Acute Toxicity During Chemoradiation 100% P=0.17 80% 60% P<0.001 MMC CisP 40% 1 cardiac 5-FU death 1 neutropaenic sepsis – not picked up and acted on in time – subject of internal enquiry – cross sites 20% 24.7% 13.4% 60.2% 64.6% Haematological Non-haematological 2 treatment related deaths

Results: Grade 3 & 4 Acute Toxicity During Maintenance by Prior Chemoradiation 100% 80% 60% Prior MMC P=0.38 Prior CisP 40% P=0.81 11.7% 9.1% 3.3% 2.9% 20% 0% Haematological Non Haematological

CRT Comparison Complete Response at 6 months 100% 94.5% 95.4% 80% MMC CisP 60% 40% 20% MMC CisP

CRT Comparison Colostomy rate at 3 years 100 80 60 P=0.26 40 20 13.7% 11.3% MMC CisP Includes colostomies for toxicity and pre treatment colostomies not reversed

Results: Maintenance Comparison Recurrence Free Survival Event is progression, recurrence or death 100 HR: 0.94, 95% CI: 0.72 to 1.24, P=0.67 75% 80 75% 60 Recurrence-free survival (%) 40 No Maint - 103 events 20 Maint - 100 events 1 2 3 4 5 6 7 8 Time from randomisation (years) No. at risk No Maint 472 346 263 183 116 67 19 4 Maint 468 345 251 183 132 61 16 1

Results: Sites of First Recurrence   MMC n=472 CisP n=468 No Maint n=446 Maint n=448 Local only 21 (4%) 28 (6%) 24 (5%) 23 (5%) Loco-regional 18 (4%) 25 (5%) 24 (5%) 19 (4%) Loco-regional & distant 11 (3%) 8 (2%) 7 (2%) 11 (3%) Any loco-regional 50 (11%) 61 (13%) 55 (12%) 53 (12%) Extra-pelvic only 21 (4%) 10 (2%) 16 (4%) 14 (3%) Missing 1 (<1%) 1 (<1%) 1 (<1%) 1 (<1%) Total recurrences 72 72 72 68

Results : Maintenance Comparison Overall Survival 100 85% HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21 80 84% 60 Overall survival (%) 40 No Maint - 74 events 20 Maint - 60 events 1 2 3 4 5 6 7 8 No. at risk Time from randomisation (years) No Maint 446 369 278 198 125 67 19 4 Maint 448 361 278 203 138 71 22 3

Results: Maintenance Comparison Causes of death   No Maint n=446 Maint n=448 Anal cancer 52 44 All treatment-related* 3 2 New cancer 5 Other 11 8 Unknown Total 74 60 * Chemoradiation: 3, 2 Chemotherapy, 1 Radiotherapy. Salvage surgery: 2

Results: Maintenance Comparison Cause Specific Survival 100 HR: 0.84, 95% CI: 0.57 to 1.26, P=0.41 80 60 Cause Specific Survival (%) 40 No Maint - 52 events 20 Maint - 44 events 1 2 3 4 5 6 7 8 No. at risk Time from randomisation (years) No Maint 446 369 278 198 125 67 19 4 Maint 448 361 278 203 138 71 22 3

NCRI ACT II Trial – Conclusions CRT comparison No evidence for superior CR rate with cisplatin Increased haematological toxicity in MMC pts No statistically significant difference in colostomy rate Maintenance comparison Preliminary data - follow-up ongoing No statistically significant difference in RFS, OS or cause specific survival Compared with other trials ACT I Comparable patients Better disease control and survival – less toxicity Lower RT dose, No gap, no second MMC & lower CisP dose RTOG 98-11 Comparable patients but no T1’s Less grade 3/4 toxicity Disease control and survival using CisP better 24

NCRI ACT II Trial – Conclusions Overall Largest ever trial in anal cancer Changed UK standard of care Comparable (or better) results to others Dose - 50.4Gy, no gap Single dose of MMC low frequency of grade 3/4 haematological and non-haematological toxicity Would leave this in have deleted sentence comparing with ACT 1 Info for comparison with other trials ACT I Comparable patients Better disease control and survival – less toxicity Lower RT dose, No gap, no second MMC & lower CisP dose RTOG 98-11 Comparable patients but no T1’s Less grade 3/4 toxicity Disease control and survival using CisP better 25

Acknowledgements To all patients participating in the trial To all site staff at the 59 UK sites To coordinating centre staff at the Cancer Research UK & UCL Cancer Trials Centre To members of the Data Monitoring Committee Trial Steering Committee Again leave in for acknowledgements 26