RECTAL CANCER The (neo)adjuvant story Mark Rother MD FRCPC Medical Oncologist Peel Regional Cancer Center Credit Valley Hospital Case • 62 year old man (father of your life long best friend) has rectal bleeding • You get him in to see a GI specialist and a colonoscopy finds a non obstructing adenocarcinoma 6 cms from anal verge • CT Thorax/Abd/Pelvis – No mets • Your friend calls you for advice on the next step? He has been reading up! • He thinks his Dad will need surgery, chemo and radiation based on his reading • He finds it all very confusing but knows you are an expert in GI oncology and will clarify it for him and his dad. Questions? • More Tests- MRI? EUS? Role of PET/CT? • Surgery- When? What type? Who should do it? • Radiation- Before/After surgery? Long protracted or intensive short type? With chemo or without? • Chemotherapy- What type? How long for? New drugs? Clinical trials? Must he get a PICC? OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Postoperative chemotherapy after neoadjuvant CRT Future Approaches OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Postoperative chemotherapy after neoadjuvant CRT Future Approaches Rectal Cancer • Estimated 6000 new cases per year in Canada (30% of colorectal cancer) • Local and Systemic Relapse Risk • Prototype of a multimodality approach – Surgery – Radiation – Chemotherapy Definition- Rectal Cancer • Discriminating between colon and rectal cancer is critical • Colon is 150 cm long but rectum is about the last 12-15 cm • Anatomically, the upper boundary of the rectum is located at the rectosigmoid junction, slightly below the sacral promontory. On clinical grounds, the peritoneal reflection is the more important landmark Definition - Rectal Cancer • In the post-operative setting the location of the tumour relative to the peritoneal reflection should be part of the surgical and pathological report • Identification of rectal tumours prior to surgery is generally obtained by measuring the distance between the inferior edge of the tumour and the anal verge(12-15cm) Adjuvant therapy • Adjuvant therapy needs to address the local and systemic recurrence risk • Under-treatment : pelvic recurrences and complications • Over-treatment : therapy related complications - bowel, bladder and sexual dysfunction Challenges in Adjuvant Therapy for Rectal Cancer • Data from randomized trials limited. • Debate on pre vs post op radiation and radiation dose and schedule is confusing • Chemotherapy concurrently with XRT-What and How? • Decisions on adjuvant chemo if received pre-op therapy. OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Postoperative chemotherapy after neoadjuvant CRT Future Approaches OLDER APPROACH TO RECTAL CANCER (but still commonly done) • Surgical resection • Pathology assessment and risk estimation • Treatment based on TMN • Post operative Chemoradiation 1990 NCI Consensus Statement • Combined postoperative chemotherapy and radiation improves local control and survival in patients with stage II and III rectal cancer and is recommended: – GITSG – NCCTG-MAYO JAMA 1990: 264:1444-1450 1990 NCI Consensus Statement GITSG (227) NEJM 1985 Surgery/5FU/mCCNU/RT NCCTG (204) NEJM 1991 Surgery/5FU/mCCNU/RT LR 11% OS 56% LR 14% OS 58% Surgery/5FU/mCCNU LR 21% OS 46% Surgery/RT LR 25% OS 48% Surgery/RT LR 20% OS 43% Surgery LR 24% OS 32% NCCTG Intergroup Study • 660 patients with resected stage II/III rectal cancer O’Connell NEJM 1994 NCCTG Intergroup Trial 2x2 study design: PVI 5-FU vs bolus(with rads) - Improved PFS (p=0.02) - Improved OS (p=.01) MeCCNU: no benefit O’Connell NEJM 1994 Intergroup 0114 : Post-operative CT – CRT- CT Bolus 5FU II III R Bolus 5FU-Levamisole Bolus 5FU-Leucovorin Bolus 5FU-Leucovorin-Levamisole Tepper et al. JCO 2002 CP1050909-25 Intergroup 0114 -OS by treatment arm Tepper, J.E. et al. J Clin Oncol; 20:1744-1750 2002 Intergroup 0144: Post operative CT – CRT - CT b5FU – XRT+PVI5FU – b5FU II III R PVI5FU – XRT+PVI5FU – PVI5FU b5FU/LV – XRT+b5FU/LV – b5FU/LV Smalley, JCO2006 Intergroup 0144 - Overall survival and relapse-free survival Smalley, S. R. et al. J Clin Oncol; 24:3542-3547 2006 Advantages of Postoperative Treatment • Accurate pathologic staging • Shorter delay to definitive surgery • Potentially less surgical morbidity? – Not complicated by prior XRT-chemo Long-Term Effects of Postoperative Chemoradiation Surgery alone Chemoradiation # BMs/day 2 (1-7) 7 (1-20) Nocturnal BMs 18% 46% Continence 93% 44% 5% 53% Antidiarrheals OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Postoperative chemotherapy after neoadjuvant CRT Future Approaches Swedish Rectal Cancer Study Preop RT (25 Gy in 5 fractions) R LR 11%, 5yr OS 58% Immediate surgery LR 27%, 5yr OS 48% NEJM 1997 Dutch Colorectal Group (NEJM 2001) Preop RT + TME (25 Gy in 5 fractions) R LR 5.6% TME alone LR 10.9% Kapiteijn NEJM 2001 MRC CR-07 (NCIC CO-16) Lancet 2009; 373: 821–28 Lancet 2009; 373: 821–28 MRC CR07 Lancet 2009; 373: 821–28 MRC CR07 What about Short-course XRT? • 2500 cGy in 5 fractions • Northern Europe approach • No concurrent chemo(5FU) radiosensitizer • Surgery within a 1-2 weeks • No downstaging(not for T4 or concern re CRM) • Concerns re long term bowel function • Studies ongoing with 6 week delay(?downstaging)-Stockholm lll OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Postoperative chemotherapy after neoadjuvant CRT Future Approaches Preoperative Chemoradiotherapy •North American/Southern Europe approach •For patients with locally advanced disease -T3/T4 or N+ •More protracted RT course 5-6 weeks(45-50.4 cGy) •Concurrent 5FU based chemotherapy •Followed by Surgery 4 - 6 weeks later Bosset NEJM 2006 Bosset NEJM 2006 Polish Study Results • 25/5 vs Chemoradiation Therapy • pCR 1% vs. 19% • Similar SSS,DFS,OS • Similar late toxicity • Await similar design TROG study TROG Study-ASCO 2010 OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Postoperative chemotherapy after neoadjuvant CRT Future Approaches • INT- 0147 - terminated prematurely due to poor accrual • NSABP R-03 - terminated prematurely due to poor accrual • German Trial- CAO/ARO/AIO 94 - completed accrual Volume 351:1731-1740 October 2004 Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group Results -Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group • 421 receive preoperative and 402 receive postoperative chemoradiotherapy. • The overall five-year survival rates were 76 percent and 74 percent (P=0.80). • The five-year incidence of local relapse 6 percent for preoperative and 13 percent in the postoperative group (P=0.006). • Grade 3 or 4 acute toxicity occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001) Sauer NEJM 2004 Sauer NEJM 2004 Sauer NEJM 2004 Sauer NEJM 2004 Sphincter Preserving Surgery ITT Analysis Postoper. RCT n= 394 Pre-randomization: “APR Necessary“ Sphincter preserved APR actually done Preoper. RCT n = 405 85 17/85 (20%) 85-17= 68 109 p = 0.004 43/109 (39%) 109-43= 66 German Rectal Study Conclusions • Preop CRT significantly improves local control • Preop CRT improves sphincter preservation in low-lying tumours • Preop CRT reduced acute and chronic toxicity • Preop CRT should be the standard adjuvant treatment in cT3/4 or cN+ rectal cancer CAVEAT • 18% of tumours in the post operative group were overstaged clinically (i.e. Stage 1 on pathology) • Mandates excellent preoperative radiologic assessment Preoperative Rectal Staging Accurate preoperative local tumor staging is critical in directing patient management All modalities remain poor in assessment of regional lymph node involvement CT still the workhorse for distant metastatic disease, complications/sequelae and surveillance OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Postoperative chemotherapy after neoadjuvant CRT Future Approaches 5FU as a radiosensitizer • Improves local control, pCR (FFCD,EORTC) • Potentially improves control at distant sites (treats micro metastasis earlier) • PVI is the optimal schedule Capecitabine as a Radiosensitizer? • Mimics infusional 5FU • Convenient versus PVI • Intratumoral thymidine phosphorylase activity upregulated with XRT Oral vs Infusional 5FU N PCR (%) SSS (%) Phase2, UFT 400mg/m2/d X 5/7 – S – 5FU/LVX4 (1) 94 9% 25% Phase1 – RP2D Capecitabine 825mg/m2 BID X 7/7 (2) 36 -- -- Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (3) 53 24% 59% Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (4) 95 12% 74% Matched-Pair Analysis (PVI vs Capecitabine) (5) 89/89 12%/21% 70%/78% Similar OS 1 – Fernandez, JCO2004 2 – Dunst, JCO 2002 3 – DePaoli, Ann Oncol 2006 4 – Kim, IJROBP 2005 5 – Das, IJROBP, 2006 Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemo-radiotherapy for locally advanced rectal cancer: Long term results of a randomized phase III trial R. Hofheinz, F. Wenz, S. Post, on behalf of the German MARGIT study Study Design Mar 2002-July2005 Post-Op Treatment Post July 2005 After Publication of Sauer Trial Neoadjuvant Treatment Arms Added Overall survival (OS) Primary endpoint (Median Follow-up 52 mon.) Disease free survival (DFS) Secondary endpoint (Median Follow-up 52 mon.) NSABP-R04 No Oxaliplatin Oxaliplatin 1200 pts 5FU Capecitabine ***Capecitabine is 825 mg /m2 bid for 5/7(Rad days) Roh et al ASCO 2011 NSABP-R04 Roh et al ASCO 2011 NSABP-R04 Roh et al ASCO 2011 5FU-Oxaliplatin-XRT •Over 15 phase I/II trials have demonstrated pCR rates ranging from 20-40% (compared to 10-20% expected with XRT+5-FU) •Increased likelihood for sphincter preservation? •More efficacious systemic therapy for micrometastases given preoperatively? NSABP-R04 Roh et al ASCO 2011 NSABP-R04 Pathologic Complete Response by Treatment Oxaliplatin vs None Sphincter Saving Surgery by Treatment Oxaliplatin vs None Roh et al ASCO 2011 STAR TRIAL Aschele C et al. J Clin Oncol July 2011 STAR TRIAL RESULTS 5-FU CRT 5-FU/Oxal CRT p-value Path CR 16% 16% 0.94 Gr 3-4 toxicity Any Diarrhea 8% 4% 24% 15% <0.0001 <0.0001 0.5% 36% <0.0001 Grade 2-3 neurosensory Aschele C et al. J Clin Oncol July 2011 ACCORD 12/0405-Prodige 2 Eligibility • T3-4, N0-2, M0 resectable (or T2 distal anterior) rectal cancer, DRE accessible R CAPE/RT45 RT 45 Gy x 5 wks CAPE 800 mg/m2 BID/day* CAPOX/RT50 RT 50 Gy x 5 wks CAPE 800 mg/m2 BID/day* OXA 50 mg/m2 weekly (6 weeks) *Except weekend Total Mesorectal Excision (TME) Adjuvant chemotherapy (Center discretion) Gerard JP et al. J Clin Oncol 2010;28(10):1638-44. ACCORD 12 TRIAL RESULTS CAP/RT CAPOX/RT p-value Path CR 14% 19% 0.11 Gr 3-4 toxicity Any Diarrhea Neuropathy 11% 3% 0.4% 25% 13% 5% <0.001 <0.001 <0.002 Standard of care remains 5-FU based neoadjuvant CRT without oxaliplatin. Gerard JP et al. J Clin Oncol 2010;28(10):1638-44. OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Postoperative chemotherapy after neoadjuvant CRT Future Approaches Decline in the rates of local failure:1980-2010 The war we are winning 35 Local failure (%) 30 25 20 15 10 5 0 sx only sx RT sx CTRT CTRT TME Distant metastases (%) Deline in the rates of distant failures: 1980-2010 The war we are losing 40 35 30 25 20 15 10 5 0 sx only sx RT sx CTRT CTRT TME Postoperative chemotherapy in Rectal Cancer (no preoperative treatment in these studies) (NCCTG 794751, 864751; NSABP R01, R02; INT 0114) n=3791 CT No CT Gunderson, L. L. et al. J Clin Oncol; 22:1785-1796 2004 Postoperative chemotherapy in Rectal Cancer QUASAR STUDY-Rectal Cohort(29%) n=948 Recurrence free survival Overall survival Lancet 2007 Lancet 2007; 370: 2020–29; 370: 2020–29 Postoperative chemotherapy in Rectal Cancer ECOG 3201 5FU/LV Stage II/II Rectal Cancer R FOLFOX4 Preop or Postop CRT (MD Choice) FOLFIRI Closed at 225 of planned 3150 Bosset NEJM 2006 Bosset NEJM 2006 Who benefits from post operative 5FU? (ypT downsized) Collette, L. et al. J Clin Oncol; 25:4379-4386 2007 Postoperative chemotherapy after neoadjuvant CRT 5FU/FA: -Only trend in EORTC study(negative)-Only level 1 study to date -Standard in postoperative CRT era-QUASAR,INT 0114/0144 Xeloda: -Only extrapolation from stage 3 colon cancer(X-ACT) FOLFOX: -Only extrapolation from stage 3 colon cancer(MOSAIC,CO7) Postoperative chemotherapy after neoadjuvant CRT • All patients should get some chemo regardless of ypT ypN statusplan set preoperatively • Duration should be 4 months • Choice of Xeloda vs FOLFOX individualized • If no downstaging- FOLFOX? • If short-course preop-XRT – 6 months STUDIES OF CHEMOTHERAPY IN RECTAL CANCER Pre-op: STAR( 5FU +/- OXALIPLATIN)-Published JCO 2011 ACCORD(XELODA +/- OXALIPLATIN)- Published JCO 2010 NASBP R-04( 5FU vs. XELODA +/- OXALIPLATIN)-ASCO 2011 Post-op: SCRIPT (XELODA vs. Nil)-Closed for accrual issues CHRONICLE (XELOX vs. Nil)- Closed for accrual issues E5204 (FOLFOX +/-AVASTIN)- Closed for accrual issues Pre and Post-op: CAO/ARO/AIO 04(5FU+/-Oxaliplatin---PRE/POST)- report 2011 PETACC-6(XELODA +/- OXALIPATIN---PRE/POST)-ongoing SCRIPT STUDY Operable Rectal Cancer-Clinical Stage2/3 ↓ Preop CRT/5 day rads ↓ TME surgery ↓ Randomization Observation Capecitabine CLOSED DUE TO POOR ACCRUAL CHRONICLE STUDY CLOSED DUE TO POOR ACCRUAL ECOG 5204 Phase III Trial (NCIC CRC.4) mFOLFOX6 X 12 Stage II/III R mFOLFOX6 + Bev X 12 Accrual: 2100 planned- CLOSED DUE TO ACCRUAL -2009 CAO/ARO/AIO 04 Rodel et al ASCO 2011 CAO/ARO/AIO 04 Rodel et al ASCO 2011 CAO/ARO/AIO 04 Rodel et al ASCO 2011 CAO/ARO/AIO 04 Conclusion Rodel et al ASCO 2011 PETACC 6 ONGOING OVERVIEW • • • • • • • • Introduction Postoperative Chemoradiation Preoperative Radiotherapy(no chemo) Preoperative Chemoradiation Preoperative vs Postoperative Chemoradiation Optimizing Preoperative Chemoradiation Post operative adjuvant chemotherapy Future Approaches Newer approaches-Phase 2 Newer approaches-Phase 2 Newer approaches-Phase 2 EXPERT trial Newer approaches-Phase 2 Newer approaches-Phase 2 Newer approaches-Phase 2 Newer approaches-Phase 2 Newer approaches-Phase 2 Newly diagnosed clinical stage II or III rectal adenocarinoma FOLFOX + Bev FOLFOX + Bev x 4 FOLFOX x 2 Patients with progressive or stable disease XRT + 5-FU Patients with clinical regression Surgery* *Post-operative treatment at discretion of physician. FOLFOX x 6 recommended; no post-operative Bev provided. Schrag D et al. Proc ASCO 2010;Abstract 3511. Newer approaches-Phase 2 • 31 patients with Stage II/III (no T4) rectal • 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 Schrag D et al. Proc ASCO 2010;Abstract 3511. CALGB Phase II/III “PROSPECT” study Newer approaches-Phase 2 SUMMARY APPROACH TO RECTAL CANCER-2011 • Accurate preoperative imaging -MRI Staging • Multidisciplinary Tumour Board discussion • Use of preoperative radiation with or without chemotherapy • Surgical concept of TME resections • Pathologists “auditing” the surgical procedure -TME quality, CRM, nodal recovery • Postoperative chemotherapy Questions