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 28 th 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 1990Current 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 preop rx in USAIn 2004, German study (Sauer NEJM) demonstrated superiority of preoperative rather than post operative XRT in terms of QOL/local recurrence—drift to preop rx in USA Neoadjuvant XRT may be overtreatment in some casesNeoadjuvant XRT may be overtreatment in some cases Pelvic radiation causes short and long-term morbidityPelvic radiation causes short and long-term morbidity Chemo, surgery and imaging techniques have each improved since tri-modality paradigm establishedChemo, 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 survivalLandmark 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 cancerPatients with stage IV rectal cancer Start with palliative chemo RT?Start with palliative chemo RT? Start with palliative resection?Start with palliative resection? Start with systemic chemotherapy?Start with systemic chemotherapy? High response rate and conversion to resectability-- omitting the preop XRTHigh response rate and conversion to resectability-- omitting the preop XRT Chemotherapy without XRTChemotherapy without XRT Stage II-III RC in Prostate and GYN Cancer survivorsStage II-III RC in Prostate and GYN Cancer survivors Women seeking fertility preservationWomen seeking fertility preservation Men and women concerned about sexual healthMen and women concerned about sexual health

4. Challenges Arising from Neoadjuvant ChemoXRT Rectal Treatment Paradigm Rectal patients succumb to metastatic dxRectal patients succumb to metastatic dx Met Rectal patients previously treated with pelvic XRT don’t tolerate sustained myelosuppressive Rx wellMet Rectal patients previously treated with pelvic XRT don’t tolerate sustained myelosuppressive Rx well Node+ pts often drop out of post op adjuvant rxNode+ pts often drop out of post op adjuvant rx Node- pts may get unnecessary rxNode- pts may get unnecessary rx Met Rectal pts seem to get less chemo, end up having slightly inferior survival than colon ptsMet 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?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 presentationSingle 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 marginXRT planned if no response or any positive margin Of 30 participants, none required preoperative XRTOf 30 participants, none required preoperative XRT With more than 4 years median follow up:With more than 4 years median follow up: 1 post-op death, 2 cancer deaths1 post-op death, 2 cancer deaths No local recurrences No local recurrences 4 recurrences, all with metastases to lung4 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 XRTAll 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 XRTPatients 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 XRTPatients 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!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. PROSPECT N1048-CALGB81001-ACOSOGZ6052 Full protocol available on CTSU Website (www.ctsu.org) Endorsed by SWOG, ECOG, NCIC, RTOG, NSABP An 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 www.ctsu.org

8. PROSPECT: N1048 Objective: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 TMETo 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: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 RecurrencesRandomized 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 metPhase III component built in and will include 644 additional patients if stopping criteria are not met

10. Chemo per primary MD TME5FUCMT* Chemo per primary MD TME “Selective Arm” Response  20% “Standard Arm” PROSPECT: Study Schema Response <20% RANDOMIZE 1:1 5FUCMT*TME Chemo per primary MD FOLFOX x 6 *5FUCMT = infusional or oral 5FU + radiation therapy

11. PROSPECT: Study Endpoints Primary Outcomes: Randomized Phase II ComponentRandomized Phase II Component R0 Resection RateR0 Resection Rate Time to local recurrence (TLR)Time to local recurrence (TLR) Phase III Component: Co-primary endpointsPhase III Component: Co-primary endpoints Time to local recurrence (TLR)Time to local recurrence (TLR) Disease free survival (DFS)Disease free survival (DFS) Secondary Outcomes: Pathologic complete response rate (Pcr)Pathologic complete response rate (Pcr) Overall survival (OS)Overall survival (OS) Quality of life (QOL)Quality of life (QOL) Clinician and patient reported treatment toxicityClinician and patient reported treatment toxicity Molecular correlates of response to neoadjuvant therapyMolecular correlates of response to neoadjuvant therapy Adverse Event (AE) ProfilesAdverse Event (AE) Profiles Rates of receiving 5FUCMTRates of receiving 5FUCMT

12. PROSPECT: Inclusion Criteria Biopsy proven rectal adenocarcinoma at age 18+Biopsy proven rectal adenocarcinoma at age 18+ Distal end of tumor located 5-12 cm from anal vergeDistal end of tumor located 5-12 cm from anal verge Candidate for sphincter sparing surgery according to TME experienced surgeon at presentationCandidate for sphincter sparing surgery according to TME experienced surgeon at presentation Standard treatment would be combined modality neoadjuvant chemoradiation followed by curative TMEStandard treatment would be combined modality neoadjuvant chemoradiation followed by curative TME Baseline Clinical staging: T2N1, T3N0, T3N1Baseline Clinical staging: T2N1, T3N0, T3N1 Proctoscopy by primary surgeonProctoscopy by primary surgeon MRI or ERUS (MRI preferred)MRI or ERUS (MRI preferred) CT scan of Chest/Abdomen/PelvisCT scan of Chest/Abdomen/Pelvis

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

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

15. Radiation in the Intervention Arm is Used Selectively Criteria for Delivery of XRT in Selective Arm:Criteria for Delivery of XRT in Selective Arm: Preoperative 5FUCMT is to be administered if:Preoperative 5FUCMT is to be administered if: Evidence of clinical progression during pre-op FOLFOXEvidence of clinical progression during pre-op FOLFOX Restaging reveals rectal tumor response is an estimated <20%Restaging reveals rectal tumor response is an estimated <20% Unable to tolerate FOLFOXx6 at or above dose level-2Unable to tolerate FOLFOXx6 at or above dose level-2 Patient withdraws consentPatient withdraws consent Postoperative 5FUCMT is recommended if:Postoperative 5FUCMT is recommended if: TME pathology is T4TME pathology is T4 TME pathology has any positive margin (R1 or R2 resection)TME pathology has any positive margin (R1 or R2 resection) Surgeon’s self assessment is that TME was incompleteSurgeon’s self assessment is that TME was incomplete Surgical/Path QA report indicates incomplete TMESurgical/Path QA report indicates incomplete TME

16. Treatment Considerations Balancing Consistency vs. Flexibility RadiationRadiation IMRT is allowedIMRT is allowed Short course radiotherapy is not allowedShort course radiotherapy is not allowed SurgerySurgery Surgeon must be willing to submit photos of the first TME specimen for credentialingSurgeon must be willing to submit photos of the first TME specimen for credentialing Laparascopic and robotic assisted approaches are allowedLaparascopic and robotic assisted approaches are allowed Sensitizing Chemotherapy with RadiationSensitizing Chemotherapy with Radiation May give capecitabine or infusional 5FUMay give capecitabine or infusional 5FU Postoperative ChemotherapyPostoperative Chemotherapy FOLFOX is suggested, but regimen may be tailored to patient’s tolerance of preoperative treatmentFOLFOX is suggested, but regimen may be tailored to patient’s tolerance of preoperative treatment Regimen is at the discretion of the primary MDRegimen 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)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 preferredDFS 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 eitherThe selective 5FUXRT arm will be favored if it has either superior DFS compared to the treat-all armsuperior DFS compared to the treat-all arm non-inferior DFS AND non-inferior TLRnon-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 TMENeoadjuvant 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 trialXRT 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 XRTPatients with threatened margins are inappropriate candidates for selective use of XRT Induction FOLFOX for ptsInduction FOLFOX for pts who can’t have XRT due to prior therapywho can’t have XRT due to prior therapy with stage IV disease amenable to R0 resectionwith stage IV disease amenable to R0 resection With suspected metastatic diseaseWith suspected metastatic disease

19. THANK YOU Questions?Questions?

20. Study Component Contact Information Alliance Protocol Coordinator jtaylor1@uchicago.edu PI PI deb_schrag@dfci.harvard.edu Statistics Sargent.Daniel@mayo.edu Shi.Qian@mayo.edu Surgical Oncology afichera@surgery.bsd.uchicago.edu weiser1@mskcc.org Radiation Oncology hmamon@lroc.harvard.edu Medical Oncology saltzl@mskcc.org mcwilliams.robert@mayo.edu Radiology gollubm@mskcc.org Pathology wendy.frankel@osumc.edu Correlative Science solitd@mskcc.org Quality of Life PROCTCAE templel@mskcc.org basche@mskcc.org Please Contact Study Team Members with any suggestions or concerns