The optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin C (MMC) or Cisplatin (CisP) with or without Maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II Dr Rob Glynne-Jones on behalf of the NCRI ACT II Trial Management Group and Investigators ASCO, Chicago, June 2012. Abstract ID: 4004 Cancer Research UK grant number: C444/A628 ISRCTN number: 26715889 Funder Sponsor
ACT II Objectives To evaluate in a factorial design whether chemoradiation using CisP or MMC produces a higher complete response rate maintenance therapy (5FU/CisP) will improve local control /prolong survival by preventing or delaying disease dissemination Accrual - 940 patients randomised Jun 01 Dec 08 Median follow-up - 5 years
ACT II Factorial Design Chemoradiation Comparison MMC 5FU CRT No maintenance MMC 5FU CRT +Maintenance versus CisP 5FU CRT No maintenance CisP 5FU CRT +Maintenance MMC N=472 CisP N=468
ACT II Factorial Design Maintenance Comparison MMC 5FU CRT No maintenance CisP 5FU CRT No maintenance No Maint N=446 versus MMC 5FU CRT Maintenance CisP 5FU CRT Maintenance Maint N=448
Chemoradiation Regimens RT week 5FU MMC 1 2 3 4 5 1000mg/m 2 d1-4 & 29-32 24 hour continuous iv infusion 12mg/m 2 d1 only iv bolus, max single dose 20 mg 6 RT week 5FU CisP 1 2 3 4 5 1000mg/m 2 d1-4 & 29-32 24 hour continuous iv infusion 60mg/m 2 d1 & 29 iv infusion 6
ACT II Response Assessments From start of CRT 11 weeks - ie 4 wks after end of CRT DRE +/- EUA 18 weeks - ie 10-11 weeks post CRT and pre-maintenance DRE +/- EUA 26 weeks - ie post maintenance 4 wks DRE +/- EUA plus abdo-pelvic CT scan, chest X-ray
ACT II Radiotherapy 50.4 Gy 28 daily fractions 5 ½ weeks Two-phase technique Both phases planned simultaneously
Tumour Stage MMC (472) CisP (468) T stage T1 T2 49% (232) 54% (254) T3 T4 48% (225) 44% (205) TX 15 13 N Stage Node negative 63% (297) 62% (290) Node positive 32% (150) 33% (155) NX 25 23
Response at 26 weeks Patients with response data (863) MMC (432/472) CisP (431/468) CR primary 90% 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
Missed Response Assessment at 26 weeks Reason excluded N = 77 Death 23 Progression /salvage surgery 8 Too unwell 5 Assessment inconclusive 2 Did not attend 12 Not assessed 25 Not known 2
CR at 26 weeks Difference (95% CI) P value MMC CisP 83% (358/432) No Maint 82% (337/409) 84% (362/431) Maint 85% (348/410) +1% (-3.8 to 6.1) p =0.66 +3% (-2.6 to 7.5) p = 0.34
Timing of CR Assessment (691 pts with data at all 3 time-points) Wk Pts with CR CR rate% MMC CisP 11 426 65.2 58.1 18 526 75.4 76.9 26 584 84.1 85.0 Absolute risk difference 7.1% (-0.1, +14.5) p=0.05 1.5% (-7.9, +4.8) p=0.64 0.9% (-6.3, +4.5) p=0.74 HR (95% CI) (CR vs not CR) PFS OS 0.71 (0.53, 0.95) p=0.02 0.52 (0.38, 0.71) p<0.001 0.21 (0.15, 0.29) p<0.001 0.70 (0.49, 0.99) p=0.046 0.48 (0.34, 0.70) p<0.001 0.21 (0.15, 0.31) p<0.001
ACT II Compliance & Toxicity Radiotherapy 92% MMC vs 90% CisP - total dose 50.4Gy ~3% >7 d 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
PFS -free survival MMC vs CisP comparison 74% 73%
PFS-free survival CR vs Not CR week 11 80% 72%
PFS free-survival CR vs Not CR week 26 83% 45%
Overall Survival CR vs Not CR week 26 93% 61%
ACT II Conclusions Excellent CR rate at 6 months - 83% v 84% 60% of pts not in CR at 11 weeks achieved CR at 26 weeks. We recommend assessment at 26 weeks in future trials
NCCN Guidelines for follow-up version 2, 2012 - www.nccn.org Re-evaluation with DRE at 8-12 weeks after CRT Classify as CR or persistent disease or progressive disease Persistent disease - watch closely for 4 weeks to see if further regression Progressive disease - requires histologic confirmation
ACT II 59 Participating Sites Aberdeen Royal Infirmary Maidstone General Hospital Royal Shrewsbury Hospital Addenbrookes Hospital Mount Vernon Hospital Royal South Hants Hospital King's Lynn New Cross Hospital Royal Surrey County Hospital Peterborough Ninewells Hospital Royal Sussex County Hospital Beatson Oncology Centre North Middlesex Hospital Scunthorpe General Belvoir Park Hospital North Staffordshire Royal Infirmary Singleton Hospital Berkshire Cancer Centre North Wales Cancer Treatment Centre St Bartholomew's Bristol Oncology Centre Northampton General Hospital St Georges Hospital Charing Cross Hospital Milton Keynes St Mary's Hospital Cheltenham General Hospital Nottingham City Hospital St Thomas' Hospital Christie Hospital Princess Royal Hospital Diana Princes of Wales Hosp Churchill Hospital Queen Elizabeth Hospital Torbay Hospital Clatterbridge Centre for Oncology Birmingham Heartlands University College Hospital Cookridge Hospital Good Hope Velindre Hospital Cumberland Infirmary Walsall Walsgrave Hospital Derbyshire Royal Infirmary Raigmore Hospital Warwick Derriford Hospital Royal Cornwall Hospital Western General Hospital Ipswich Hospital Royal Devon & Exeter Hospital Weston Park Hospital James Cook University Hospital Royal Marsden Lincoln County Hospital Royal Preston Hospital