Transcript STEPS FORWARD in RECTAL CANCER: Radiation
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.
Evaluate recent phase III trials of chemoradiation in rectal cancer.
Consider the Status Quo of stage II/III disease.
Describe current and planned trials.
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
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 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 1990 1995/ 1996 2001/ 2002 Rectal Cancer 44% 59% 62% Colon Cancer 54% 62% 66% Renouf ASCO 2008
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
Pre- vs Post-operative Chemoradiation.
Significant reduction in LRR No difference in DISTANT Relapse Sauer NEJM 2004
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
NSABP R-04
Primary 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
Gastrointestinal Toxicity
5-FU or CAPE vs addition of Oxaliplatin
Sphincter Saving Surgery by Treatment
5-FU vs Capecitabine
Sphincter Saving Surgery by Treatment
Oxaliplatin vs. None
Pathologic Complete Response by Treatment
5-FU vs Capecitabine
Pathologic Complete Response by Treatment
Oxaliplatin vs. None
NSABP R-04
CONCLUSIONS • • • 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
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?
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
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
Phase III: CAO/ARO/AIO-04
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
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)
Compliance Adjuvant Chemotherapy
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
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?
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
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
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%
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
CALGB Phase II/III Proposal Approved by NCI GI Steering Committee
Clinical T3N0/1 Rectal Cancer Planned surgery: LAR
R
Sx
XRT 50.4/30 + Cap
Phase III Primary Endpoint = Locoregional RFS And DFS
Pre-OP FOLFOX x6
Repeat MRI
XRT 50.4/30 ONLY if Progression
Sx
CONCLUSIONS
Significant advancements in LR Therapy.
Distant Relapse must be reduced.
Some concerns about Radiation Toxicity.
Strategies needed to address both these issues!