By Jennifer Lubell
Preoperative neoadjuvant modified FOLFIRINOX is associated with favorable overall survival (OS) rates in patients with borderline resectable pancreatic cancer, relative to historical data. But combining this therapy with hypofractionated radiation therapy (RT) was not as successful.
Matthew Katz, MD, chief of the Pancreatic Surgery Service at the University of Texas MD Anderson Cancer Center, presented this research (Abstract 377) at the American Society of Clinical Oncology’s 2021 Gastrointestinal Cancers Symposium.
ASCO guidelines recommend preoperative therapy in patients with localized pancreatic adenocarcinoma whose tumors have a significant radiographic interface with the major mesenteric blood vessels. “These patients are at high risk for a margin-positive operation and short survival when pancreatectomy is performed de novo,” Dr. Katz said. Systemic chemotherapy and radiation therapy are often used in these patients, yet “the optimal regimen in this setting is controversial.”
The aim of the Alliance A021501 study “was to define a reference preoperative regimen for future trials of preoperative therapy. We sought to evaluate one regimen that included RT and one that did not,” Dr. Katz said.
A two-stage registration process helped ensure quality assurance during the trial. Investigators enrolled patients with centrally reviewed borderline resectable pancreatic cancer into two cohorts, enrolling a total of 126 patients to either a modified FOLFIRINOX regimen in Arm A or a modified FOLFIRINOX plus radiation therapy regimen in Arm B. Patients, on average, were in their early 60s and most identified as white.
Prior to anticipated pancreatectomy, Arm A patients received eight cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours). Arm B patients received seven cycles of mFOLFIRINOX followed by 5 days of hypofractionated radiation, using either stereotactic body radiotherapy or hypofractionated image guided radiotherapy.
Patients who underwent pancreatectomy in either arm were assigned to receive four cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2,400 mg/m2 over 46 hours) following surgery. In Arm A, 49% of patients had this procedure, compared to 35% in Arm B. Overall, 31% of patients in Arm A and 18% of patients in Arm B completed all therapy in the trial.
Investigators defined the proportion of evaluable patients alive 18 months following randomization divided by the total number of evaluable patients, as the primary endpoint. For each arm, they compared this rate 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.”
An arm was declared as “efficacious” and as a reference regimen for future studies if 36 patients were alive 18 months following randomization.
The modified FOLFIRINOX regimen (Arm A) had an 18-month OS rate of 66.4% (95% CI, 55.6-79.2), which was noticeably higher than what was seen with the radiation therapy regimen (Arm B), which had a rate of 47.3% (95% CI: 35.8 – 62.5).
Additionally, the median OS for patients who received only the modified FOLFIRINOX regimen was 29.8 months, compared with 17.1 months in the radiation therapy group.
In Arm A, 39 patients were alive 18 months following randomization “and thus the mFOLFIRINOX regimen was declared efficacious,” Dr. Katz said. Arm B, the group receiving radiation therapy, closed prematurely prior to full accrual at interim analysis and did not meet this metric.
The results show that modified FOLFIRINOX represents a reference preoperative regimen for patients with borderline resectable pancreatic adenocarcinoma, Dr. Katz concluded.
Both arms experienced dose reductions and delays during preoperative chemotherapy. During preoperative treatment, 57% of patients in Arm A and 64% in Arm B experienced at least one Grade 3 or greater AE during chemotherapy. Grade 4 AEs were less common in both arms.
Following pancreatectomy, 9% in Arm A and 16% of patients in Arm B developed a post-operative pancreatic fistula or abscess. Resections took place in about a third of the operations; in Arm A, the resection rate was 49% compared with 35% in Arm B.
Three patients across both arms died within 90 days of surgery.