1. What is the Preferable Treatment Option for T1/T2 Low Rectal Cancer? Christopher H. Crane, M.D. Program Director, GI Section Department of Radiation Oncology Department of Radiation Oncology Christopher H. Crane, M.D. Program Director, GI Section Department of Radiation Oncology Department of Radiation Oncology

2. No Disclosures

3. Complications of Radical Rectal Surgery Permanently altered bowel function –Often colostomy Urinary dysfunction from 7-68% Impotence 15-100% Retrograde ejaculation 3-35%

4. *RESPONDING PATIENTS Chemoradiation Followed by Local Excision*

5. NCDB LE Special Study (1994-96 ) Local Recurrence – T2 5- Year LERR T222%15% T2: p=0.01 You et al. Ann Surg 245(5):726-33, 2007 N=164 N=866

6. German Trial (CAO / ARO / AIO) Pre-operative vs Postoperative CXRT Significantly lower acute toxicity rate –27% vs 40%, p=0.001 LR improved with preoperative CXRT –5 yr: 6% vs 13%, p=0.001 SP higher in preoperative CXRT –39% vs 19%, p=0.006 –Subjective need for APR, not whole group Significantly lower late toxicity –14% vs 24%, p=0.01 anastamotic stricture (12% vs 4%) Diarrhea, SBO (9% vs 15%) Sauer, R NEJM, 351, 2004

7. Can Radical Surgery Be Avoided in Selected Rectal Cancer Patients?

8. CXRT / Mesorectal resection- cT3 N0 pts ypN+ according to ypT stage Crane, pESTRO 2004 ypT0 in T3 NX (including clinically node +) = 4/45 = 9% Bedrosian, J Gastroint Surg, 2004

9. Local Excision of T3 tumors after Preoperative XRT

10. Local Excision of T2 tumors after Preoperative XRT

11. Cumulative recurrence rates based on ypT Stage CXRT/LE (cT2/cT3) Modified from Table 5, Borschitz, et al Ann Surg Onc, 2008

12. Randomized Trial - T2 Rectal Cancer CXRT then TAE vs Laparoscopic Resection 40 pts 50.4 Gy + PVI 5-FU (200 mg/m 2 ) –20 TAE –20 LAP Resection One recurrence in each group (5%) Median FU 56 mo Lezoche, et al Surgical Oncology, 2005

13. Complications, CXRT / TAE Modified from Table 3, Borschitz, et al Ann Surg Onc, 2008 Wound complications do not appear to be a limitation Diverting iliostomy could be perfomed

14. Non-operative Management in Complete Responders? University of São Paulo, Brazil Pre-op Chemoradiation (50.4 Gy + FU/LV) 265 pts –Clinical CR = observation (n=71, 26%) 2 endorectal failures, 5y OS 100% –Incomplete CR / radical surgery, pCR (n=22%, 8.3%) 2 DOD, 5y OS 88% Median follow-up 57.3 months Habr-Gama, Ann Surg. 240(4):711-718, 2004

15. ACOSOG Z6041 Study Design uT2 rectal cancer (EUS- MRI) CXRT Cape (850mg/m2 bid) oxali (50 mg/m2/wk) 54 Gy Local excision T0-T2 R0: Observation T3 or R+: radical resection FollowFollow <8 cm from anal verge <4 cm size Primary Obj: 3 yr DFS in uT2N0 Chan, ASTRO 2010

16. ACOSOG Z6041 Study Design uT2 rectal cancer (EUS- MRI) CXRT Cape (650mg/m2 bid) oxali (50 mg/m2/wk) 50.4Gy Local excision T0-T2 R0: Observation T3 or R+: radical resection FollowFollow <8 cm from anal verge <4 cm size Primary Obj: 3 yr DFS in uT2N0 Chan, ASTRO 2010

17. Conclusions Neoadjuvant CRT with CAPOX 44% pCR Only 5% of patients needed radical surgery Long term follow-up is needed for LC endpoint High GI toxicity rates Chan, ASTRO 2010

18. Organ Preservation Model Locally Advanced Rectal Ca Clinical selection will affect success –Tumor size, nodal status, tumor grade, others Neoadjuvant CXRT –Endoscopic CR Full thickness local excision = excisional biopsy of tumor bed –ypT0, no further surgery Radical surgery only for non-responders: –Gross residual disease or ypT3 What about microscopic residual disease? Crane, Annals of Surg Onc, (3) p288-90, 2006

19. Response of Primary Tumor to CXRT Observing response of primary key to organ preserving strategy Predicts Control of Microscopic Mesorectal Disease Could predicting response help? –Only if it leads to personalized therapy –Increase the pool of responders Pair agents to patients –Proteomics, genomics Change agents during therapy (PET)?

20. The Message Regarding Pre-op/LE Promising strategy, especially in responding patients Better long term GI and sexual function Salvage rates of LR 50-70% –Close FU is critical Multidisciplinary team has to be on the same page