The Apparent Complete Response- Ian Geh
- 1. Dukes' Club Annual Meeting, Kenilworth. 24-26 February 2012 What's New in Rectal Cancer? The Apparent Complete Response Ian Geh Consultant Clinical Oncologist Queen Elizabeth Hospital & Heartlands Hospital Birmingham, UK Ian.Geh@uhb.nhs.uk
- 2. Preoperative Radiotherapy Schedules for Rectal Cancer Long Course Pre-operative Radiotherapy 6-12 weeks Surgery phase I 45Gy in 25F; (phase II 5.4Gy 3F) Short Course Pre-operative Radiotherapy (SCPRT) Max 10 days Surgery 25Gy in 5F
- 3. Preoperative Radiotherapy Schedules for Rectal Cancer Long Course Pre-operative Radiotherapy 6-12 weeks Surgery phase I 45Gy in 25F; (phase II 5.4Gy 3F) Long Course Pre-operative Chemoradiotherapy (CRT) capecitabine 825 mg/m2 6-12 weeks Surgery phase I 45Gy in 25F; (phase II 5.4Gy 3F)
- 4. Addition of Radiotherapy to Surgery Non-TME Surgery TME Surgery EORTC RT (5 wks) FFCD EORTC German CRT (5 wks) FFCD Polish NSABP R-03 Australasian Dutch MRC CR07 SCPRT (1 wk) Swedish Polish Australasian Dutch Surgery Swedish MRC CR07 Post op CRT NSABP R-03 German
- 5. Local Recurrence Non-TME Surgery TME Surgery 17% RT (5 wks) - 17% 9% 6% CRT (5 wks) 8% 16% 11% 4% 6% 5% SCPRT (1 wk) 11% 11% 7% 11% Surgery 27% 11% Post op CRT 11% 13%
- 6. pCR in Resected Patients Non-TME Surgery TME Surgery 5% RT (5 wks) - 4% 14% 8% CRT (5 wks) 11% 16% 15% ns 1% 0% SCPRT (1 wk) 0% 1% ns 2% Surgery - - Post op CRT - -
- 7. Radical Resection for Rectal Cancer: One Size Fits All? • How do we achieve best results at the minimum price? Locally advanced cancers Early rectal cancer • Postoperative morbidity & mortality Most units 2-5% High risk groups • Permanent stoma 10-30% Variation between surgeons, units & networks Higher rates in socially deprived regions • Long-term sequelae Sphincter and sexual function Second cancers
- 8. What happens if there is no tumour? • Pathological complete response (pCR) What does this mean? Was surgery necessary? • Microscopic foci of residual disease What does this mean? Would pCR occur if I waited longer?
- 9. Significance of pCR Following Preoperative RT • Measure of efficacy of preoperative RT 3-4% from RT alone 10-30% from CRT
- 10. Significance of pCR Following Preoperative RT • Measure of efficacy of preoperative RT 3-4% from RT alone 10-30% from CRT • Associated with improved outcomes
- 12. Significance of pCR Following Preoperative RT • Measure of efficacy of preoperative RT 3-4% from RT alone 10-30% from CRT • Associated with improved outcomes • Can we abandon surgery if pCR achieved?
- 13. Nigro et al. Dis Colon Rectum 1974; 17: 354-6
- 14. Preoperative CRT in Anal Cancer CRT: 30 Gy in 15 fractions over 3 weeks mitomycin C (d1) & 5FU (d1-4, 29-32) Surgery: 4-6 weeks later no. pCR % APR 12 7 58 Local excision 14 14 100 No biopsy 2 - total 81% Nigro et al 1983
- 15. Mitomycin/5FU CRT in Anal Cancer No. CvM T3-4 Gy Boost LRC CFS OS UKCCCR 295 65% 51% 45 15-20 61% - 65% EORTC 51 100% 77% 45 15-20 68% 72% 70% RTOG 87-04 146 100% 47% 45 ±9 - 80% 80% RTOG 98-11 322 100% 26% 36-45 ±10-14 75% 90% 84% Birmingham 133 68% 54% 30 20-25 84% 60% 81%
- 16. Radiotherapy Instead of Surgery Habr-Gama et al. Reassess 8 wks Ann Surg 2004 No residual Long disease: course Follow up 265 CRT Resectable 50.4 Gy rectal ca in 28 F 0-7 cm Clinical 5FU/FA Residual d1-3 Disease: d36-38 Resection
- 17. Radiotherapy Instead of Surgery Habr-Gama et al. Reassess 8 wks Follow up schedule: Ann Surg 2004 No residual Long disease: DRE, proctoscopy, CEA course Follow up Y1 monthly 265 CRT Y2 2 monthly Resectable 50.4 Gy rectal ca in 28 F Y3 6 monthly 0-7 cm Clinical 5FU/FA CT abdo / pelvis Residual d1-3 Disease: 6 monthly d36-38 Resection
- 18. Radiotherapy Instead of Surgery Habr-Gama et al. Reassess 8 wks Ann Surg 2004 No residual Remains clear at 12 m Long disease: Stage 0 course Follow up 265 CRT Resectable 50.4 Gy rectal ca in 28 F 194 (73%) 0-7 cm yp st 0 (pCR) Clinical 5FU/FA Residual d1-3 Disease: d36-38 yp stage I – III Resection
- 19. Radiotherapy Instead of Surgery Habr-Gama et al. Reassess 8 wks 71 (27%) Ann Surg 2004 No residual Stage 0 71 (27%) Long disease: If clear at 12 m course Follow up 265 CRT Resectable 50.4 Gy Total stage 0 93 (35%) rectal ca in 28 F 194 (73%) 0-7 cm pCR (stage 0) 22 (8%) Clinical 5FU/FA Residual d1-3 Disease: yp stage I – III d36-38 Resection 172 (65%) Stage 0 group: 10y OS 98%, DFS 84%, 2 LRs
- 20. Recent Series of Non-Operative Management No. cCR LR (%) Brazil (Habr-Gama 2004) 265 71 (27%) 2 (3%) Mt Vernon (Hughes 2010) - 10 6 (60%) MSK (Smith 2012) 311 32 (10%) 6 (19%) Exeter (Dalton 2011) 49 12 (24%) 0 (0%) Holland (Maas 2011) 192 21 (11%) 1 (5%) Marsden (Yu 2011) - 19 9 (47%)
- 21. Factors Influencing pCR Following Preoperative RT • Size and stage of tumour Locally advanced (T3-4) tumours Early (T1-2) tumours • Timing of surgery following completion of preoperative RT • Thoroughness of pathologist Will he find the needle in the haystack? • Radiotherapy & chemotherapy
- 22. Factors Influencing pCR Following Preoperative RT • Size and stage of tumour Locally advanced (T3-4) tumours vs early (T1-2) tumours No. Selection for CRT pCR Birmingham 267 CRM threatened 7% German 2004 421 uT3/4 or N1 8% FFCD 2006 375 non selective 11% EORTC 2006 506 non selective 14% ACOSOG 2010 94 T2 44% Bujko 2009 44 mainly T1/T2 54%
- 23. Factors Influencing pCR Following Preoperative RT • Timing of surgery following completion of preoperative RT Longer duration results in better tumour response and pathological downstaging Does this translate to better outcomes? Could outcomes be worse? NCRI 6 vs 12 Week Trial
- 24. Factors Influencing pCR Following Preoperative RT • Thoroughness of pathological examination Will he find the needle in the haystack? Lack of standardisation of definition of pCR
- 25. Obliterated vein Fibrosis and previous site of vascular invasion
- 28. Standardisation of Definition of pCR Consensus from CORE II Trial; • Take 5 blocks from site of tumour, if no residual tumour; • Embed whole of suspicious area, if no residual tumour; • Take 3 levels through each block, if no residual tumour; • Defined as pCR
- 29. Factors Influencing pCR Following Preoperative RT • Radiotherapy & chemotherapy Optimal RT dose & fractionation Interaction between RT and chemotherapy; • choice of chemotherapy drug(s) • optimal scheduling of chemotherapy
- 30. Systematic Review of Preoperative CRT Trials 64 Phase II-III Trials (4372 pts) No. Adjusted 95% CI p= pCR mean Use of second drug 1280 0.17 0.13-0.23 0.001 Delivery of 5FU / equiv. 929 0.20 0.16-0.24 0.03 Radiation dose <45 Gy 481 0.09 0.05-0.14 0.02 Sanghera et al. Clin Oncol 2008
- 31. Addition of Oxaliplatin to Fluoropyrimidines: Trials 5FU Capecitabine NSABP R-04 NSABP R-04 CAO/ARO/AIO-04 PETACC-6 No Oxaliplatin STAR-01 ACCORD 12 German MARGIT German MARGIT NSABP R-04 NSABP R-04 Oxaliplatin CAO/ARO/AIO-04 PETACC-6 STAR-01 ACCORD 12
- 32. Addition of Oxaliplatin to Fluoropyrimidines: pCR Rates 5FU Capecitabine 19% 22% 13% No Oxaliplatin 14% 16% 14% 5% 19% 21% Oxaliplatin 17% 19% 16%
- 33. NCRI Aristotle Trial R 460 CRT 45 Gy 25F TME A Capecitabine Surgery MRI Defined N Locally D Advanced O Rectal M AdenoCa I CRT 45 Gy 25F 460 TME S Irinotecan Surgery E Capecitabine Tumour at / beyond fascia Very low tumour (levator / sphincter / anal canal involved)
- 34. UK Perspective • Standard of care is different from USA and most of Europe • pCR rates depend on MDT 'threshold' to give CRT; any T3? any N1? CRM threatened only? • CRT reserved for locally VERY advanced rectal cancers • Very few patients with clinical CR
- 35. Clinical Complete Response Not Achieved • Proceed with planned surgery; % with pCR % with residual tumour?
- 37. Clinical Complete Response Achieved • Proceed with planned surgery; % with pCR % with residual tumour? • Wait and watch; Optimum follow up strategy and for how long? How salvageable are recurrences? % cured? – NCRI Wait and Watch Trial
- 38. Future Developments • Early rectal cancers Higher pCR rates Balancing number of patients at risk of 'overtreatment' • Better predictive tools of pCR • Better CRT regimens
- 39. Summary • pCR is the key to progress for non-surgical treatment • Outcomes of 'true pCRs' are excellent irrespective of surgical management • Challenges of non-surgical management – management of early stage cancers – achieving a suitable compromise for patient – successful salvage of failures
- 40. Mark Davies "I have never lived my life on what ifs and maybes and I wasn't going to sacrifice my bum on an off chance."