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

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 Rectal Cancer

Colon Cancer

1990 44% 54%

1995/1996

59% 62%

2001/2002

62% 66%

Renouf ASCO 2008

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

Pre- vs Post-operative Chemoradiation.

Significant reduction in LRRNo 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-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

Gastrointestinal Toxicity5-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 Treatment5-FU vs Capecitabine

Pathologic Complete Response by Treatment Oxaliplatin vs. None

• 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

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

Carcinoma of rectumWithin 12 cm above anal

vergeECOG PS 0-2cT3/4 and/or cN+, cM0Staging: EUS+CT and/or MRI

Main Inclusion Criteria

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

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 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

CONCLUSIONS Significant advancements in LR Therapy.

Distant Relapse must be reduced.

Some concerns about Radiation Toxicity.

Strategies needed to address both these issues!