The Apparent Complete Response- Ian Geh

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Presentation given by Ian Geh, Queen Elizabeth Hospital & Heartlands Hospital, at the Dukes' Club AGM.

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The Apparent Complete Response- Ian Geh

  1. 1. Dukes Club Annual Meeting, Kenilworth. 24-26 February 2012 Whats 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. 2. Preoperative Radiotherapy Schedules for Rectal CancerLong 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 Surgery25Gy in 5F
  3. 3. Preoperative Radiotherapy Schedules for Rectal CancerLong 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. 4. Addition of Radiotherapy to Surgery Non-TME Surgery TME Surgery EORTCRT (5 wks) FFCD EORTC GermanCRT (5 wks) FFCD Polish NSABP R-03 Australasian Dutch MRC CR07SCPRT (1 wk) Swedish Polish Australasian DutchSurgery Swedish MRC CR07Post op CRT NSABP R-03 German
  5. 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. 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. 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. 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. 9. Significance of pCR Following Preoperative RT• Measure of efficacy of preoperative RT 3-4% from RT alone 10-30% from CRT
  10. 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
  11. 11. 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?
  12. 12. Nigro et al. Dis Colon Rectum 1974; 17: 354-6
  13. 13. Preoperative CRT in Anal CancerCRT: 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 58Local excision 14 14 100No biopsy 2 - total 81%Nigro et al 1983
  14. 14. Mitomycin/5FU CRT in Anal Cancer No. CvM T3-4 Gy Boost LRC CFS OSUKCCCR 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%
  15. 15. Radiotherapy Instead of SurgeryHabr-Gama et al. Reassess 8 wksAnn Surg 2004 No residual Long disease: course Follow up 265 CRTResectable 50.4 Gyrectal ca in 28 F0-7 cm Clinical 5FU/FA Residual d1-3 Disease: d36-38 Resection
  16. 16. Radiotherapy Instead of SurgeryHabr-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 monthlyResectable 50.4 Gyrectal ca in 28 F Y3 6 monthly0-7 cm Clinical 5FU/FA CT abdo / pelvis Residual d1-3 Disease: 6 monthly d36-38 Resection
  17. 17. Radiotherapy Instead of SurgeryHabr-Gama et al. Reassess 8 wksAnn Surg 2004 No residual Remains clear at 12 m Long disease: Stage 0 course Follow up 265 CRTResectable 50.4 Gyrectal 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
  18. 18. Radiotherapy Instead of SurgeryHabr-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 CRTResectable 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
  19. 19. 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%)
  20. 20. 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
  21. 21. 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%
  22. 22. 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
  23. 23. 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
  24. 24. Obliterated veinFibrosis and previous site of vascular invasion
  25. 25. 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
  26. 26. 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
  27. 27. Systematic Review of Preoperative CRT Trials64 Phase II-III Trials (4372 pts) No. Adjusted 95% CI p= pCR meanUse of second drug 1280 0.17 0.13-0.23 0.001Delivery of 5FU / equiv. 929 0.20 0.16-0.24 0.03Radiation dose <45 Gy 481 0.09 0.05-0.14 0.02Sanghera et al. Clin Oncol 2008
  28. 28. Addition of Oxaliplatin to Fluoropyrimidines: Trials 5FU Capecitabine NSABP R-04 NSABP R-04 CAO/ARO/AIO-04 PETACC-6No Oxaliplatin STAR-01 ACCORD 12 German MARGIT German MARGIT NSABP R-04 NSABP R-04Oxaliplatin CAO/ARO/AIO-04 PETACC-6 STAR-01 ACCORD 12
  29. 29. Addition of Oxaliplatin to Fluoropyrimidines: pCR Rates 5FU Capecitabine 19% 22% 13%No Oxaliplatin 14% 16% 14% 5% 19% 21%Oxaliplatin 17% 19% 16%
  30. 30. 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 CapecitabineTumour at / beyond fasciaVery low tumour (levator / sphincter / anal canal involved)
  31. 31. 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
  32. 32. Clinical Complete Response Not Achieved• Proceed with planned surgery; % with pCR % with residual tumour?
  33. 33. 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
  34. 34. Future Developments• Early rectal cancers Higher pCR rates Balancing number of patients at risk of overtreatment• Better predictive tools of pCR• Better CRT regimens
  35. 35. 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
  36. 36. Mark Davies"I have never lived mylife on what ifs andmaybes and I wasntgoing to sacrifice mybum on an off chance."

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