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Anal Cancer

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

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Anal Cancer

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  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 Boost 25Gy implant or 15Gy in 6F RT alone 45Gy 6 weeks 6 weeks Boost 25Gy implant or 15Gy in 6F

  5. 75 HR 0.46, p<0.001 50 having a local relapse (%) Percentage of patients 25 RT alone CMT 0 0 2 4 6 8 10 12 14 16 18 20 Time since randomisation (years) ACT I :Time to first local relapse

  6. Colostomy-free survival

  7. ACT II Factorial DesignChemoradiation Comparison MMC5FU CRT No maintenance CisP5FU CRT No maintenance versus CisP5FU CRT +Maintenance MMC 5FU CRT +Maintenance MMC N=472 CisP N=468

  8. MMC 5FU CRTNo maintenance CisP 5FU CRTNo maintenance CisP 5FU CRTMaintenance MMC 5FU CRT Maintenance ACT II Factorial DesignMaintenance Comparison No Maint N=446 versus Maint N=448

  9. Chemoradiation Regimens 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. 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

  11. 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

  12. 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

  13. Tumour Stage

  14. Response at 26 weeks P=0.66

  15. 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

  16. CR at 26 weeks

  17. PFS -free survival MMCvsCisPcomparison 74% 73%

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

  19. 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

  20. 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 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

  21. Maintenance Comparison - Overall Survival 100 85% HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21 80 84% 60 HR: 0.81, 95% CI: 0.57 to 1.13, P=0.21 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. 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

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

  24. Site of relapse The pattern was similar for PF only and PF + mets (data not shown)

  25. 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.

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

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

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

  29. 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

  30. 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)

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