Abstract
BackgroundBorderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined.MethodsIn Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33–40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy will undergo pancreatectomy and will subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, bolus 5-fluorouracil 400 mg/m2, and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The primary analysis will compare the 18-month overall survival rate of each arm to a historical control rate of 50%. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site.DiscussionThis study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials.Trial registrationClinicalTrials.gov: NCT02839343, registered July 14, 2016.
Highlights
Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo
Given that complete microscopic (R0) resection represents a requisite component of curative treatment for patients with pancreatic ductal adenocarcinomas (PDAC), preoperative treatment regimens designed to both optimize surgical outcomes and to select appropriate patients for pancreatectomy are increasingly being administered to patients with borderline resectable cancers in an attempt to maximize the likelihood for long-term survival
In Alliance for Clinical Oncology Trial A021101, a recently-published, prospective pilot trial, we showed that this paradigm of multimodality therapy can be implemented effectively in a multi-institutional setting; among 22 patients with borderline resectable PDAC who initiated treatment, 15 (68%) underwent pancreatectomy and the overall survival rate of all accrued patients at 18 months was 50% [7]
Summary
Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. Patients first receive 2 to 4 months of systemic chemotherapy followed by a conventionally fractionated course of radiation therapy given over 5–6 weeks with a radiosensitizing fluoropyrimidine or gemcitabine Patients who complete this multimodality regimen without evidence of disease progression undergo pancreatectomy with curative intent; those who progress systemically prior to the intended operation are treated with non-surgical palliative therapies. This approach leverages theoretical benefits associated with systemic chemotherapy (e.g., systemic antitumor activity for micrometastatic disease known to exist in almost all patients), radiation therapy (e.g., “sterilization” of surgical margins) and time (e.g., patient selection) in an attempt to maximize systemic control, local control, and overall survival. In Alliance for Clinical Oncology Trial A021101, a recently-published, prospective pilot trial, we showed that this paradigm of multimodality therapy can be implemented effectively in a multi-institutional setting; among 22 patients with borderline resectable PDAC who initiated treatment, 15 (68%) underwent pancreatectomy and the overall survival rate of all accrued patients at 18 months was 50% [7]
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