Patients with borderline resectable pancreatic cancer (PDAC) are often treated with chemotherapy, radiotherapy, or both before undergoing surgery, but the optimal regimen in this setting is controversial.
New results suggest that 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 2400 mg/m2 over 46 hours).
This regimen improved survival for patients with PDAC relative to historical data, say researachers who presented results from the Alliance A021501 study.
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%.
The findings were presented at the Gastrointestinal Cancers Symposium (GICS) 2021, 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,” explained study author Matthew Katz, MD, FACS, chief of the Pancreatic Surgery Service at the University of Texas MD Anderson Cancer Center, Houston, Texas.
Although both chemotherapy and radiotherapy are used in these patients, there is no consensus as to the best approach, he commented.
The goal of the 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 an mFOLFIRINOX regimen (arm A) or an mFOLFIRINOX plus radiotherapy regimen (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 2400 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,” 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 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 duration was 15 months. Nearly half (49%) of patients proceeded to pancreatectomy following neoadjuvant therapy. The R0 resection rate was 88%, the pCR rate was 0%, and the 18-month overall survival 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%, pCR was 11%, and the 18-month overall survival rate 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,” Katz concluded. “Therefore, mFOLFIRINOX represents a reference peroperative regimen for patient with borderline resectable PDAC.”
Further Investigation Needed
The paper’s discussant, Rebecca A. Snyder, MD, MPH, of the Brody School of Medicine, East Carolina University, Greenville, North Carolina, emphasized that this study was not designed or powered to directly compare chemotherapy with chemotherapy and radiotherapy in the neoadjuvant setting.
She noted that it is surprising that the radiotherapy arm was closed early. She said that the reasons for this remain unclear, although a few possible reasons can be speculated.
“Based on multiple studies in both the adjuvant and neoadjuvant setting, including the Alliance [A021501] trial presented today, there is no convincing randomized data that radiation therapy prolongs survival in any population of unselected patients with pancreatic cancer,” said Synder.
“Certainly, follow-up questions still remain, specifically regarding the role for non-SBRT radiation in the preoperative setting, which may be answered by the ongoing PREOPANC-2 and PRODIGE 44 trials,” she said.
She added that the “addition of SBRT in the preoperative setting does not appear to be justified.”
The role of radiotherapy for subsets of patients remains unknown, and future investigation should focus on patient-centered endpoints, such as symptomatic local control rates, Synder concluded.
The study was funded by the National Institutes of Health. Katz has had a consulting or advisory role for AbbVie and Alcresta Therapeutics. Snyder has disclosed no relevant financial relationships.
Gastrointestinal Cancers Symposium (GICS) 2021: Abstract 377. Presented January 17, 2021