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!