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ACT II: The Second UK Phase III Anal Cancer Trial

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

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ACT II: The Second UK Phase III Anal Cancer Trial

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  1. ACT II: The SecondUK 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/A628ISRCTN number: 26715889 Sponsor Funder

  2. Background Standard treatment- RT + 5-FU + MMC • 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

  3. 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

  4. Factorial Design1.Chemoradiation Comparison CisP5FU CRT No maintenance MMC5FU CRTNo maintenance MMC CisP versus CisP5FU CRT Maintenance MMC5FU CRT Maintenance N=471 N=469

  5. CisP 5FU CRTNo maintenance MMC 5FU CRTNo maintenance CisP 5FU CRTMaintenance MMC 5FU CRT Maintenance Factorial Design2.Maintenance Comparison No maintenance N=446 versus Maintenance N=448

  6. Statistical Methods Sample Size 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

  7. 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

  8. 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

  9. 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 Radiotherapy50.4 Gy in 28 fractions over 5 ½ weeks (no gap)

  10. 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

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

  12. Accrual • 940 patients • Jun 2000 – Dec 2008 • 59 sites • Multi centre & National collaboration

  13. MMC No maint n=246 CisP No maint n=246 MMC Maint n=226 CisP Maint n=222 *Gender Male Female 38% 62% 38% 62% 38% 62% 37% 63% *Age <65 65 75% 25% 75% 25% 73% 27% 74% 26% *GFR <60 60 4% 96% 4% 96% 4% 96% 4% 96% Pre Rx-colostomy No Yes N/K 81% 7% 12% 76% 11% 13% 71% 14% 15% 80% 9% 12% Patient Demographics - 1 * Stratification factor

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

  15. MMC CisP Results: Grade 3 & 4 Acute Toxicity During Chemoradiation 100% P=0.17 80% 60% P<0.001 40% 20% 13.4% 24.7% 60.2% 64.6% 0 Haematological Non-haematological 2 treatment related deaths

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

  17. MMC CisP CRT ComparisonComplete Response at 6 months P=0.53 100% 94.5% 95.4% 80% 60% 40% 20% 0 MMC CisP

  18. CRT ComparisonColostomy rate at 3 years 100 80 60 P=0.26 40 20 13.7% 11.3% 0 MMC CisP Includes colostomies for toxicity and pre treatment colostomies not reversed

  19. Results: Maintenance ComparisonRecurrence 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 0 0 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

  20. 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: Sites of First Recurrence

  21. Results : Maintenance ComparisonOverall 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 0 0 1 2 3 4 5 6 7 8 Time from randomisation (years) No. at risk No Maint 446 369 278 198 125 67 19 4 Maint 448 361 278 203 138 71 22 3

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

  23. Results: Maintenance ComparisonCause 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 0 0 1 2 3 4 5 6 7 8 Time from randomisation (years) No. atrisk No Maint 446 369 278 198 125 67 19 4 Maint 448 361 278 203 138 71 22 3

  24. 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

  25. 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

  26. 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

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