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RECTAL CANCER The (neo)adjuvant story

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

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RECTAL CANCER The (neo)adjuvant story

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  1. RECTAL CANCERThe (neo)adjuvant story Mark Rother MD FRCPC Medical Oncologist Peel Regional Cancer Center Credit Valley Hospital

  2. 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

  3. 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.

  4. 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?

  5. OVERVIEW • Introduction • Postoperative Chemoradiation • Preoperative Radiotherapy(no chemo) • Preoperative Chemoradiation • Preoperative vs Postoperative Chemoradiation • Optimizing Preoperative Chemoradiation • Postoperative chemotherapy after neoadjuvant CRT • Future Approaches

  6. OVERVIEW • Introduction • Postoperative Chemoradiation • Preoperative Radiotherapy(no chemo) • Preoperative Chemoradiation • Preoperative vs Postoperative Chemoradiation • Optimizing Preoperative Chemoradiation • Postoperative chemotherapy after neoadjuvant CRT • Future Approaches

  7. 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

  8. 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

  9. 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)

  10. 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

  11. 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.

  12. OVERVIEW • Introduction • Postoperative Chemoradiation • Preoperative Radiotherapy(no chemo) • Preoperative Chemoradiation • Preoperative vs Postoperative Chemoradiation • Optimizing Preoperative Chemoradiation • Postoperative chemotherapy after neoadjuvant CRT • Future Approaches

  13. OLDER APPROACH TO RECTAL CANCER(but still commonly done) • Surgical resection • Pathology assessment and risk estimation • Treatment based on TMN • Post operative Chemoradiation

  14. 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

  15. 1990 NCI Consensus Statement

  16. NCCTG Intergroup Study 660 patients with resected stage II/III rectal cancer O’Connell NEJM 1994

  17. 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

  18. Intergroup 0114 : Post-operative CT – CRT- CT Bolus 5FU II III Bolus 5FU-Levamisole R Bolus 5FU-Leucovorin Bolus5FU-Leucovorin-Levamisole Tepper et al. JCO 2002 CP1050909-25

  19. Intergroup 0114 -OS by treatment arm Tepper, J.E. et al. J Clin Oncol; 20:1744-1750 2002

  20. Intergroup 0144: Post operative CT – CRT - CT b5FU – XRT+PVI5FU – b5FU II III PVI5FU – XRT+PVI5FU – PVI5FU R b5FU/LV – XRT+b5FU/LV – b5FU/LV Smalley, JCO2006

  21. Intergroup 0144 - Overall survival and relapse-free survival Smalley, S. R. et al. J Clin Oncol; 24:3542-3547 2006

  22. Advantages of Postoperative Treatment Accurate pathologic staging Shorter delay to definitive surgery Potentially less surgical morbidity? Not complicated by prior XRT-chemo

  23. Long-Term Effects of Postoperative Chemoradiation

  24. OVERVIEW • Introduction • Postoperative Chemoradiation • Preoperative Radiotherapy(no chemo) • Preoperative Chemoradiation • Preoperative vs Postoperative Chemoradiation • Optimizing Preoperative Chemoradiation • Postoperative chemotherapy after neoadjuvant CRT • Future Approaches

  25. 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

  26. 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

  27. MRC CR-07 (NCIC CO-16) Lancet 2009; 373: 821–28

  28. Lancet 2009; 373: 821–28

  29. MRC CR07 Lancet 2009; 373: 821–28

  30. MRC CR07

  31. 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

  32. OVERVIEW • Introduction • Postoperative Chemoradiation • Preoperative Radiotherapy(no chemo) • Preoperative Chemoradiation • Preoperative vs Postoperative Chemoradiation • Optimizing Preoperative Chemoradiation • Postoperative chemotherapy after neoadjuvant CRT • Future Approaches

  33. 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

  34. Bosset NEJM 2006

  35. Bosset NEJM 2006

  36. PolishStudy Results 25/5 vsChemoradiation Therapy pCR 1% vs. 19% Similar SSS,DFS,OS Similar late toxicity Await similar design TROG study

  37. TROG Study-ASCO 2010

  38. OVERVIEW • Introduction • Postoperative Chemoradiation • Preoperative Radiotherapy(no chemo) • Preoperative Chemoradiation • Preoperative vs Postoperative Chemoradiation • Optimizing Preoperative Chemoradiation • Postoperative chemotherapy after neoadjuvant CRT • Future Approaches

  39. 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

  40. Preoperative versus Postoperative Chemoradiotherapy for Rectal CancerRolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group Volume 351:1731-1740 October 2004

  41. Results -Preoperative versus Postoperative Chemoradiotherapy for Rectal CancerRolf 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

  42. Sauer NEJM 2004 Sauer NEJM 2004

  43. Sauer NEJM 2004

  44. Sphincter Preserving Surgery ITT Analysis Postoper. RCT Preoper. RCT n= 394 n = 405 85 109 17/85 (20%) 43/109 (39%) 85-17= 68 109-43= 66 Pre-randomization: “APR Necessary“ Sphincter preserved p = 0.004 APR actually done

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