Is Radiation Consistently Necessary for Mid-High Rectal Cancers? Assigned Viewpoint: No

1. Is Radiation Consistently Necessary for Mid-High Rectal Cancers?Assigned Viewpoint: No Great Debates Symposium New York City, NY Deb Schrag MD Dana Farber Cancer Institute Harvard Medical School March 28th 2014

2. Background: Why Question Use of Neoadjuvant XRT? • Current standard of care for all Stage II-III rectal cancer is tri-modality therapy—has been so since 1990 • In 2004, German study (Sauer NEJM) demonstrated superiority of preoperative rather than post operative XRT in terms of QOL/local recurrence—drift to preoprx in USA • Neoadjuvant XRT may be overtreatment in some cases • Pelvic radiation causes short and long-term morbidity • Chemo, surgery and imaging techniques have each improved since tri-modality paradigm established • Landmark Dutch TME trial showed that XRT marginally improves LR rates, but not survival

3. The Plural of Anecdote Doesn’t=Data, but Does Raise Provocative Questions • Patients with stage IV rectal cancer • Start with palliative chemo RT? • Start with palliative resection? • Start with systemic chemotherapy? • High response rate and conversion to resectability--omitting the preop XRT • Chemotherapy without XRT • Stage II-III RC in Prostate and GYN Cancer survivors • Women seeking fertility preservation • Men and women concerned about sexual health

4. Challenges Arising from Neoadjuvant ChemoXRT Rectal Treatment Paradigm Rectal patients succumb to metastatic dx Met Rectal patients previously treated with pelvic XRT don’t tolerate sustained myelosuppressive Rx well Node+ pts often drop out of post op adjuvant rx Node- pts may get unnecessary rx Met Rectal pts seem to get less chemo, end up having slightly inferior survival than colon pts Why not spare the marrow for when its really needed?

5. Motivating Pilot Study Experience • Single center phase II pilot at MSKCC administered 6 cycles of induction FOLFOX+Bev to patients with clinical T2N1, T3N0, T3N1 rectal cancer who were candidates for LAR at presentation • XRT planned if no response or any positive margin • Of 30 participants, none required preoperative XRT • With more than 4 years median follow up: • 1 post-op death, 2 cancer deaths • No local recurrences • 4 recurrences, all with metastases to lung JCO Jan 2014

6. Personal Viewpoint on Stage II/III Rectal Cancer Treatment: All patients with T4 rectal cancer require XRT Patients with T2-T3 rectal cancer proximal to ~12 cm on proctoscope can safely be managed without preop XRT Patients with T2-3 distal rectal cancer requiring an APR should receive preop Chemo XRT Patients with T2-3 rectal cancer who are candidates for Low Anterior Resection (typically ~5-12cm from anal verge) should be encouraged to enroll in PROSPECT!

7. PROSPECTN1048-CALGB81001-ACOSOGZ6052Full protocol available on CTSU Website (www.ctsu.org)Endorsed by SWOG, ECOG, NCIC, RTOG, NSABPAn NCI Cooperative Group Phase II/III Trial of Neoadjuvant FOLFOX with Selective Use of Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection with Total Mesorectal Excision

8. PROSPECT: N1048 Objective: To determine if selective use of neoadjuvant XRT is a safe alternative strategy to routine use of XRT for management of locally advanced rectal cancer that is amenable to sphincter sparing TME

9. PROSPECT: Study Design • A phase II/III NCI Cooperative Group study: • Randomized phase II of 366 patients with early stopping rule if failure to complete R0 resections or if an unacceptably high rate of Local Recurrences • Phase III component built in and will include 644 additional patients if stopping criteria are not met

10. PROSPECT: Study Schema “Standard Arm” 5FUCMT* TME Chemo per primary MD Chemo per primary MD Response 20% RANDOMIZE 1:1 TME FOLFOX x 6 “Selective Arm” 5FUCMT* TME Chemo per primary MD Response <20% *5FUCMT = infusional or oral 5FU + radiation therapy

11. PROSPECT: Study Endpoints Primary Outcomes: Randomized Phase II Component R0 Resection Rate Time to local recurrence (TLR) Phase III Component: Co-primary endpoints Time to local recurrence (TLR) Disease free survival (DFS) Secondary Outcomes: Pathologic complete response rate (Pcr) Overall survival (OS) Quality of life (QOL) Clinician and patient reported treatment toxicity Molecular correlates of response to neoadjuvant therapy Adverse Event (AE) Profiles Rates of receiving 5FUCMT

12. PROSPECT: Inclusion Criteria Biopsy proven rectal adenocarcinoma at age 18+ Distal end of tumor located 5-12 cm from anal verge Candidate for sphincter sparing surgery according to TME experienced surgeon at presentation Standard treatment would be combined modality neoadjuvantchemoradiation followed by curative TME Baseline Clinical staging: T2N1, T3N0, T3N1 Proctoscopy by primary surgeon MRI or ERUS (MRI preferred) CT scan of Chest/Abdomen/Pelvis

13. PROSPECT: Exclusion Criteria Clinical T4 tumors Clinical N2 disease Defined as >=4 pelvic nodes >10mm in diameter Not a candidate for either 5FUCMT or oxaliplatin Tumor within 3mm of mesorectal fascia on MRI or CT Undiverted symptomatic bowel obstruction ECOG Performance Status of 3 or 4 Prior pelvic radiation

14. Staging/Restaging Evaluation Baseline staging is identical in both arms Restaging in selective arm is more intensive Opportunity to give XRT if poor response to FOLFOX Evaluate if rectal tumor decreased by  20% Re-evaluation in selective arm: Proctoscopy Physical exam by primary surgeon MRI of Pelvis or ERUS (same test as at baseline) If response of primary tumor is: <20%, then gets 5FUXRT 20%, then straight to OR for TME

15. Radiation in the Intervention Arm is Used Selectively Criteria for Delivery of XRT in Selective Arm: Preoperative 5FUCMT is to be administered if: Evidence of clinical progression during pre-op FOLFOX Restaging reveals rectal tumor response is an estimated <20% Unable to tolerate FOLFOXx6 at or above dose level-2 Patient withdraws consent Postoperative 5FUCMT is recommended if: TME pathology is T4 TME pathology has any positive margin (R1 or R2 resection) Surgeon’s self assessment is that TME was incomplete Surgical/Path QA report indicates incomplete TME

16. Treatment ConsiderationsBalancing Consistency vs. Flexibility Radiation IMRT is allowed Short course radiotherapy is not allowed Surgery Surgeon must be willing to submit photos of the first TME specimen for credentialing Laparascopic and robotic assisted approaches are allowed Sensitizing Chemotherapy with Radiation May give capecitabine or infusional 5FU Postoperative Chemotherapy FOLFOX is suggested, but regimen may be tailored to patient’s tolerance of preoperative treatment Regimen is at the discretion of the primary MD

17. PROSPECT: Statistical Design • The primary goal is to compare selective to routine use of pre-op 5FUXRT with respect to the co-primary endpoints of Disease Free Survival (DFS) and time to local recurrence (TLR) • DFS and TLR will be considered jointly to determine whether selective or routine use of 5FUXRT is preferred • The selective 5FUXRT arm will be favored if it has either • superior DFS compared to the treat-all arm • non-inferior DFS AND non-inferior TLR

18. Conclusions • Neoadjuvant chemotherapy strategies are an investigational approach for patients with resectable rectal CA amenable to sphincter sparing TME • XRT is a mainstay of Rx for a curable cancer 5-12 cm from the anal verge: selective approach appropriate on a trial • Patients with threatened margins are inappropriate candidates for selective use of XRT • Induction FOLFOX for pts • who can’t have XRT due to prior therapy • with stage IV disease amenable to R0 resection • With suspected metastatic disease

19. THANK YOU Questions?

20. Please Contact Study Team Members with any suggestions or concerns