Treatment of Localized Rectal Cancer: Missteps and Next Steps
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Treatment of Localized Rectal Cancer:Missteps and Next Steps
Hagen Kennecke, MD, MHA, FRCPCBC Cancer Agency – Vancouver Centre
Atlantic Canada Oncology Group Symposium
June 24, 2011
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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.
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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
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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
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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
Cohort Rectal Cancer
Colon Cancer
1990 44% 54%
1995/1996
59% 62%
2001/2002
62% 66%
Renouf ASCO 2008
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STEPS FORWARD in RECTAL CANCER:
Radiation2001-2010
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
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Pre- vs Post-operative Chemoradiation.
Significant reduction in LRRNo difference in DISTANT Relapse
Sauer NEJM 2004
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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
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NSABP R-04Primary Aims
1. Compare the rate of local-regional relapse in patients receiving preoperative capecitabine with RT to patients receiving preoperative continuous infusional 5-FU with RT
2. Compare the rate of local-regional relapse in patients receiving preoperative oxaliplatin with those not receiving preoperative oxaliplatin
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Gastrointestinal Toxicity5-FU or CAPE vs addition of Oxaliplatin
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Sphincter Saving Surgery by Treatment
5-FU vs Capecitabine
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Sphincter Saving Surgery by Treatment
Oxaliplatin vs. None
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Pathologic Complete Response by Treatment5-FU vs Capecitabine
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Pathologic Complete Response by Treatment Oxaliplatin vs. None
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• 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
NSABP R-04CONCLUSIONS
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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?
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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
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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
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Phase III: CAO/ARO/AIO-04
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Carcinoma of rectumWithin 12 cm above anal
vergeECOG PS 0-2cT3/4 and/or cN+, cM0Staging: EUS+CT and/or MRI
Main Inclusion Criteria
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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)
Study Endpoints
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Compliance Adjuvant Chemotherapy
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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
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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?
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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
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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
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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%
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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
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CALGB Phase II/III ProposalApproved by NCI GI Steering Committee
ClinicalT3N0/1Rectal Cancer
Planned surgery: LAR
R
Pre-OPFOLFOX
x6
Phase III Primary Endpoint =Locoregional RFSAnd DFS
XRT 50.4/30 +
Cap
XRT 50.4/30ONLY if Progression
Sx
Sx
Repeat MRI
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CONCLUSIONS Significant advancements in LR Therapy.
Distant Relapse must be reduced.
Some concerns about Radiation Toxicity.
Strategies needed to address both these issues!