Patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) are often treated with chemotherapy, radiotherapy, or both before undergoing surgery, but the optimal regimen in this setting is controversial.
Results from the Alliance A021501 study suggest the reference regimen should be neoadjuvant therapy with modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and infusional 5-fluorouracil 2,400 mg/m2 over 46 hours), according to Matthew Katz, MD, FACS, chief of the pancreatic surgery service at the University of Texas MD Anderson Cancer Center, Houston.
This regimen improved survival for patients with PDAC, relative to historical data. For patients who received mFOLFIRINOX, the overall 18-month survival rate was 66.4%. However, when this regimen was combined with hypofractionated radiotherapy, the survival benefit was significantly lower, at 47.3%.
These findings were presented at the 2021 Gastrointestinal Cancers Symposium (GICS), which was held online this year.
“ASCO guidelines recommend that preoperative therapy be administered to patients with localized pancreatic adenocarcinoma who have tumors that have a significant radiographic interface with the major mesenteric blood vessels, as these patients are at high risk for a margin-positive operation and short survival when pancreatectomy is performed de novo,” Dr. Katz explained.
Although both chemotherapy and radiotherapy are used in these patients, there is no consensus as to the best approach, he commented.
The goal of Alliance A021501 “was to define a reference preoperative regimen for future trials of preoperative therapy,” he said.
The cohort included 126 patients who were randomly assigned to receive either mFOLFIRINOX (arm A) or mFOLFIRINOX plus radiotherapy (arm B).
Patients in arm A received eight cycles of neoadjuvant mFOLFIRINOX. Patients in arm B received seven cycles of mFOLFIRINOX followed by 5 days of hypofractionated radiotherapy with either stereotactic body radiotherapy or hypofractionated image-guided radiotherapy.
In either arm, patients who did not experience disease progression underwent pancreatectomy followed by four cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and infusional 5-fluorouracil 2,400 mg/m2 over 46 hours).
The study’s primary endpoint was 18-month overall survival in comparison to a historical control of 50%. “An interim futility analysis was scheduled to be conducted following treatment of 30 patients on each arm,” Dr. Katz said. “Either arm in which 11 or fewer patients underwent [curative] R0 resection on protocol was to be declared futile and closed to further enrollment.
“With 62 evaluable patients in each arm, the final efficacy analysis was powered to detect an improvement in 18-month overall survival of 13% over the historical rate of 50%,” said Dr. Katz. “The two arms would be compared only if both were declared efficacious.”
At the interim analysis, 57% of the first 30 patients in arm A had undergone a resection, vs. 33% in arm B. Therefore, arm B was considered futile and was closed to accrual.
The median overall survival in arm A was 29.8 months. The median event-free survival was 15 months. Nearly half (49%) of patients proceeded to pancreatectomy following neoadjuvant therapy. The R0 resection rate was 88%, the pathologic complete response rate was 0%, and the 18-month overall survival rate was 93.1%.
For the patients in arm B, which had been closed to accrual, the median overall survival was 17.1 months, and the median event-free survival was 10.2 months. About one-third (35%) of patients were able to proceed to pancreatectomy. The R0 resection rate was 74%, the pathologic complete response rate was 11%, and the 18-month overall survival rate was 78.9%.
“Preoperative mFOLFIRINOX was associated with favorable overall survival relative to historical criteria in patients with borderline resectable PDAC, and mFOLFIRINOX with radiation therapy met the predefined futility boundary for R0 resection at interim analysis,” Dr. Katz concluded. “Therefore, mFOLFIRINOX represents a reference perioperative regimen for patients with borderline resectable PDAC.”