Phase II trial of five fractions of radiotherapy followed by four cycles of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma: Report of an interim response analysis.

Abstract

e14003 Background: Preoperative radiotherapy (RT) with 5FU chemotherapy (CT) is a standard of care for cT3-4 rectal cancer. Multi-institution trials incorporating additional cytotoxic agents have resulted in increased morbidity with little benefit. We evaluate a template that seeks to (1) include the known benefits of preoperative RT on local response/control, (2) provide for preoperative multi-drug CT, (3) avoid the morbidity of concurrent RT and multi-drug CT, (4) keep the surgery within 4 weeks of where it would be with conventionally fractionated RT. Methods: Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed by a surgeon to be candidates for extirpative surgery, provided the response to preoperative treatment was sufficient. Preoperative treatment consisted of 5 fractions of pelvic RT (25 Gy to involved mesorectum, 20 Gy to elective nodes) followed by a 2 week rest, followed by 4 cycles of bi-weekly mFOLFOX6. Surgery was 4-9 weeks after completion of preoperative treatment. Postoperative CT was at the discretion of the treating medical oncologist, but another 6-8 cycles of FOLFOX was recommended. The principal objectives are to demonstrate that this regimen can achieve T stage down staging (ypT < cT) and acute grade 3+ gastrointestinal (GI) morbidity equal to or better than historical controls. Results: Accrual opened November 2009. To date 36 patients have enrolled, with 6 cases experiencing grade 3 acute GI morbidity. Twenty-five cases (all cT3, 18 cN+, 3cM1) have had sufficient time to proceed to surgery. Two were inevaluable: one withdrew consent prior to CT and one received no surgery due to progression of distant disease (with local response). Of the 23 evaluable cases, all had R0 resections, 18 (78%) had ypT0-2 residual disease (6 ypT0 (26%), 4 ypT1, 8 ypT2), 19 (83%) were ypN0. Conclusions: Interim analysis shows that 5 fractions of preoperative RT followed by 4 cycles of FOLFOX is effective in eliciting tumor response. This template preserves the known benefits of radiation therapy on local control while allowing incorporation of full-dose multi-agent chemotherapy.