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Treatment of Localized Rectal Cancer: Missteps and Next Steps

Treatment of Localized Rectal Cancer: Missteps and Next Steps. Hagen Kennecke, MD, MHA, FRCPC BC Cancer Agency – Vancouver Centre Atlantic Canada Oncology Group Symposium June 24, 2011. OBJECTIVES. Briefly review advances in rectal cancer therapy over the past 2 decades.

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Treatment of Localized Rectal Cancer: Missteps and Next Steps

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  1. Treatment of Localized Rectal Cancer:Missteps and Next Steps Hagen Kennecke, MD, MHA, FRCPC BC Cancer Agency – Vancouver Centre Atlantic Canada Oncology Group Symposium June 24, 2011

  2. OBJECTIVES • Briefly review advances in rectal cancer therapy over the past 2 decades. • Evaluate recent phase III trials of chemoradiation in rectal cancer. • Consider the Status Quo of stage II/III disease. • Describe current and planned trials.

  3. STEPS FORWARD in RECTAL CANCER: Radiation • 1970s-80s: • Trials of Radiation vs. Surgery alone • Meta-analysis of 22 RCTs • Peri-op XRT reduces LRR by 46% (pre-op) and 37% (post-op) • No impact on OS, 62 vs 63% (p=0.06) • 1990: Post-operative chemoradiation becomes standard CCCG, Lancet, 2001

  4. STEPS FORWARD: Surgery 1990s: Total Mesorectal Excision established as superior surgical modality: ”en bloc resection of tumor and nodes by sharp dissection through mesorectal fascial planes” • 2001: • Radiation reduces LocoRegional Relapse (LRR)even when TME is done. Kapitejn NEJM 2001

  5. 5 Year Risk: Rectal vs. Colon Ca BC Cancer Agency study of stage II/III colorectal cancer. Improvement in both rectal and colon ca Greater improvement for rectal cancer 5Y survival of colon and rectal cancer similar in modern era Renouf ASCO 2008

  6. STEPS FORWARD in RECTAL CANCER: Radiation 2001-2010 • Pre-operative chemoradiation is more effective and less toxic (acute and chronic) than Post-Operative Chemoradiation • Peri-operative chemotherapy with 5-FU reduces LRR by 50% versus Radiation alone…but does not reduce Distant Relapse. • Adding Oxaliplatin to 5-FU/Radiation does not improve pathological response rate (pCR) and increases acute toxicity. • Capecitabine is equivalent to infusional 5-FU with radiation. Bosset NEJM 06,Sauer NEJM 04 Aschele ASCO 2009, Gerard ASCO 2009, Roh ASCO 2011

  7. Pre- vs Post-operative Chemoradiation. • Significant reduction in LRR • No difference in DISTANT Relapse Sauer NEJM 2004

  8. The Impact of Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Patients with Carcinoma of the Rectum: NSABP R-04 MS Roh, GA Yothers, MJ O’Connell, RW Beart, HC Pitot, AF Shields, DS Parda, S Sharif, CJ Allegra, NJ Petrelli, JC Landry, DP Ryan, A Arora, TL Evans, GS Soori, L Chu, RV Landes, M Mohiuddin, S Lopa, N Wolmark ASCO June 4, 2011

  9. NSABP R-04Primary Aims • Compare the rate of local-regional relapse in patients receiving preoperative capecitabine with RT to patients receiving preoperative continuous infusional 5-FU with RT • Compare the rate of local-regional relapse in patients receiving preoperative oxaliplatin with those not receiving preoperative oxaliplatin

  10. Gastrointestinal Toxicity5-FU or CAPE vs addition of Oxaliplatin

  11. Sphincter Saving Surgery by Treatment 5-FU vs Capecitabine

  12. Sphincter Saving Surgery by Treatment Oxaliplatin vs. None

  13. Pathologic Complete Response by Treatment5-FU vs Capecitabine

  14. Pathologic Complete Response by Treatment Oxaliplatin vs. None

  15. NSABP R-04CONCLUSIONS • Administration of capecitabine with preoperative RT achieved rates similar to CVI 5-FU for • Surgical downstaging • Sphincter saving surgery • Pathologic complete response • Addition of oxaliplatin did not improve outcomes and added significant toxicity • Longer follow up will be needed to assess local-regional tumor relapse, DFS and OS

  16. Status Quo for Resectable Stage II/III Rectal Ca: • Pre-operative tumor staging: • Endorectal US or Pelvic MRI • Pre-operative Radiation/Chemoradiation: • For tumors ≤ 12 cm • Capecitabine or Inf 5-FU if Long Course Radiation • Post-operative chemotherapy: • Clinical or Pathologic stage? • Stage II: Capecitabine or 5-FU/Leucovorin • Stage III: FOLFOX – evidence?

  17. Outcomes of Stage II/III Rectal Cancer • Low Locoregional relapse rates: 6-8% • However, 50-70% with LRR also have Distant Relapse • Poor Disease Free Survival Rates: • 5-Year DFS in modern trials: 56-74% • DISTANT RELAPSE is the major issue

  18. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-FU and oxaliplatin versus 5-FU alone in locally advanced rectal cancer: First results of CAO/ARO/AIO-04 C. Rödel, H. Becker, R. Fietkau, U. Graeven, W. Hohenberger, C. Hess, T. Hothorn, M. Lang-Welzenbach, T. Liersch, L. Staib, C. Wittekind, R. Sauer German Rectal Cancer Study Group

  19. Phase III: CAO/ARO/AIO-04

  20. Main Inclusion Criteria • Carcinoma of rectum • Within 12 cm above anal verge • ECOG PS 0-2 • cT3/4 and/or cN+, cM0 • Staging: EUS+CT and/or MRI

  21. Study Endpoints • Primary: Disease-free survival • 3y-DFS: 75% to 82% • 80% power, alpha error: 0.05 • Sample size: 1200 patients • Main secondary: • Toxicity and compliance • R0 resection rate • pCR rate and Tumor Regression (TRG)

  22. Compliance Adjuvant Chemotherapy

  23. Current Questions in Rectal Cancer: HOW CAN WE REDUCE DISTANT RELPASE? • Give systemic therapy BEFORE radiation? • Will this increase % patients treated and dose intensity? • Get the chemotherapy in earlier • Better systemic therapy WITH radiation– • STAR, ACCORD negative so far, R04 Pending • Many phase II trials, pending • Give oxaliplatin Post-Operatively – PETTAC pending, many already do this

  24. Should biologics be added to chemoradiotherapy ? • Cetuximab: • Phase II evidence of Cetuximab plus CAPOX and XRT • Disappointing pCR of 9% • Bevacizumab: • Phase I: Bev + 5-FU + XRT safe • Phase II: 10+ ongoing trials including A-CORRECT DID WE TAKE TWO STEPS FORWARD (OX PLUS BEV) AND NOW NEED TO TAKE ONE STEP BACK?

  25. Radiation Issues • Acute Toxicity: Diarrhoea, Fistula, APR Woundhealing • Chronic Toxicity: 5 Y Incontinence: XRT 62 % vs. no XRT 38% 5 Y Severe Incontinence: XRT 14% vs. no XRT 5% • Lack of effect on distant disease Peeters JCO 05, Bosset NEJM 06,Gerard JCO 06, Sauer NEJM 04

  26. Routine versus selective radiation for resectable rectal cancer: Ph III Study • Phase III MRC trial, 4 countries, 1350 patients with operable rectal cancer. • Standard Arm: • Pre-op XRT 25Gy/5 • Experimental Arm: • No Pre-op XRT • Post-op chemoXRT 45Gy/25 only if + CRM Lancet 2009

  27. RESULTS • Patients similar in both arms • 22% of pts with + CRM did NOT get XRT • Adjuvant chemotherapy: • Stage II : PRE 18% Post 18% • Stage III : PRE 84% Post 87% • Outcomes: • HR of 0.4 decrease in LR, Pre vs Post-OP XRT • 3 year LR 6.2% versus 10.6% • 3 year DFS 77% versus 71%

  28. Neo-adjuvant FOLFOX-bev without radiation for locally advanced rectal ca • 31 patients with Stage II/III (no T4) rectal • Neo-adjuvant FOLFOX-Bev x 3 months • 27/27 patients had regression and proceeded to surgery with no XRT • 27 had R0 resection and 7/27 (26%) pCR • One pt with 14/14 nodes offered post-op XRT • Is this worth pursuing? Schrag ASCO GI 2010

  29. CALGB Phase II/III ProposalApproved by NCI GI Steering Committee Sx XRT 50.4/30 + Cap Clinical T3N0/1 Rectal Cancer Planned surgery: LAR Phase III Primary Endpoint = Locoregional RFS And DFS R Sx Pre-OP FOLFOX x6 XRT 50.4/30 ONLY if Progression Repeat MRI

  30. CONCLUSIONS • Significant advancements in LR Therapy. • Distant Relapse must be reduced. • Some concerns about Radiation Toxicity. • Strategies needed to address both these issues!

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