Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer? Assigned Viewpoint: PRO Great Debates Symposium New York City, NY Deb Schrag MD Dana Farber Cancer Institute Harvard Medical School March 27th 2015

CAVEAT LOCUTOR The standard of care for locally advanced rectal cancer is chemoradiation Neoadjuvant chemo is an investigational strategy This is a post-prandial debate I need to keep you awake

The Efficacy of neoadjuvant chemotherapy without radiation has not yet been established in the context of controlled clinical trials

Objective Persuade you that a trial to compare neoadjuvant chemoradiation to neoadjuvant chemo with selective radiation is a priority Describe the rationale for neoadjuvant chemotherapy Describe trials evaluating neoadjuvant chemo Pilot/Phase II experience Phase III trials in progress

Current Rectal Cancer Treatment Paradigm 5-6 weeks recovery 4-6 weeks recovery 5.5 Weeks of CMT TME Rectal Surgery Adjuvant ChemoRx 16-19 weeks until start of systemic chemotherapy 72

Dutch Trial: Pre-op XRT and TME vs. TME Alone 1805 eligible pts, T1-3 (54% T1-2, 56% I-II) Outcome TME Pre-op XRT LR at 4 years 11% 6% Rx Mortality 3% 4% OS 82% Radiation Decreases LR Rate Even with Good Surgery Kapiteijn NEJM 245 2001

German Trial RCT of Pre vs. Post Op Chemo RT Pre-Op 394 Post-op 405 P value Local Recurrence 6% 13% .006 Distant Recurrence 30% 34% NS Grade 3-4 Toxicity 27% 40% <0.05 Overall Survival 3-yr 76% 74% Sphincter Preservation 39% 19% Sauer et al: NEJM 2004 Preop ChemoRT is preferable to Postop

Why Question Use of Neoadjuvant XRT? Pelvic radiation causes short and long-term morbidity Each treatment modality has improved since the current treatment paradigm was established Better imaging Widespread availability of MRI to characterize T stage and Circumferential radial margin (CRM) Better surgery Diffusion of modern TME techniques Better systemic chemotherapy—adjuvant FOLFOX More screen detected rectal cancers---within stage migration to smaller tumors

Experience with Neoadjuvant Chemo in Stage IV Rectal Cancer and Patients with Contraindications to XRT Patients with stage IV rectal cancer High response rate and conversion to resectability--omitting the preop XRT Clinical experience treatment rectal cancer without XRT in “special cases” Stage II-III RC in Prostate and GYN Cancer survivors Women seeking fertility/childbearing preservation Men and women very concerned about sexual function

Challenges Arising from Neoadjuvant ChemoXRT Rectal Treatment Paradigm Distant disease is the primary site of recurrence/site of death in rectal cancer Undertreatment risk: Node+ pts don’t complete post-op systemic chemo Overtreatment risk: Node- pts may get unnecessary rx Myelosuppression and impaired chemo tolerance after pelvic XRT Met rectal pts get less chemo, have inferior survival compared to met colon pts

Restaging post CAPOX Restaging Post Chemo/RT UK Phase II of Induction CAPOX, then ChemoRT: MRI demonstrates high clinical response rates Restaging post CAPOX Restaging Post Chemo/RT (n=68) (n=68) CR 3 (4%) 14 (21%) PR 57 (84%) 52 (77%) SD 8 (12%) 2 (3%) ORR 88% 97% Chau et al ASCO 2005

Pilot Study of Neoadjuvant Chemo with Selective Use of XRT 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 32 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

Pilot Studies of Neoadjuvant Chemo without routine use of XRT Study N Cohort Bad Risk Features Rx R0 Rate pCR% Ishii (2010) 26 T3-4 Any N 12% T4 IFL 100% 3.8% Fernandez Martos (2012) 28 T3 Middle 3rd >2mm from MRF Excluded CAPOX-Bev 96.4% 14.3% Uehara (2013) 32 T3,T4, N2 CRM at risk 57% T4 84.3% 12.5% Schrag (2014) T2N1 T3N0 T3N1 FOLFOX-Bev 25%

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

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 310 patients accrued to date…

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

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

Study Schema with Suggested Post-op Regimens “Standard Arm” 5FUCMT TME FOLFOX x 8* Response 20% FOLFOX x 6* RANDOMIZE 1:1 TME FOLFOX x 6 “Selective Arm” 5FUCMT TME Response <20% *Post-op chemo is suggested; # of cycles & regimen may be modified (modification is not a protocol violation)

PROSPECT: Study Endpoints Primary Outcomes: Randomized Phase II Component R0 Resection Rate Time to local recurrence (TLR) Phase III Component: Co-primary endpoints Disease free survival (DFS)

PROSPECT: Inclusion Criteria Biopsy proven rectal adenocarcinoma at age 18+ Candidate for sphincter sparing surgery according to TME experienced surgeon at presentation Standard treatment would be combined modality neoadjuvant chemoradiation 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

PROSPECT: Exclusion Criteria Clinical T4 tumors Bulky clinical N2 disease (estimated from imaging) 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

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 Re-evaluation in selective arm: Proctoscopy/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

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

Treatment Considerations Balancing 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 and MD discretion

Randomized Phase II Study of Neoadjuvant Chemo without XRT: Bacchus Trial (MRC UK) Study in progress NCT 01650428 “poor prognosis”-pT3bT3c or T3d FOLFOX/Bev vs. FOLFOXIRI/bev x6 Response assessed by PET/CT after 3 cycles of rx Primary endpoint: pathologic CR rate at surgery

Neoadjuvant Chemo Phase III Trial in Progress: Sun Yat Sen Trial FOWARC: NCT01211210 China 3 arm Phase II/III for all pre-op locally advanced rectal cancers ChemoRT FOLFOX then chemoRT FOLFOX Primary outcome is DFS at 3 years

Conclusions Neoadjuvant chemotherapy strategies are an investigational approach for patients with resectable rectal CA amenable to sphincter sparing TME Patients with threatened margins are inappropriate candidates for selective use of XRT Induction FOLFOX merits consideration for pts who can’t have XRT due to prior therapy with stage IV disease amenable to R0 resection with suspected metastatic disease Please enroll clinical stage II/III rectal cancer patients in PROSPECT to help address this “great debate”

THANK YOU Questions?