Two different preoperative chemotherapy regimens for pancreatic cancer failed to improve survival as compared with historical outcomes with adjuvant therapy, a randomized trial showed.
A modified FOLFIRINOX regimen and the combination of gemcitabine and nab-paclitaxel (Abraxane) led to 2-year overall survival (OS) of 47-48%, which did not differ significantly from the a priori target of 40%. Patients in both treatment arms had a median OS of about 2 years. The gemcitabine regimen was associated with a moderately longer disease-free interval after resection.
Toxicity was consistent with prior experience for both chemotherapy regimens, Davendra P.S. Sohal, MD, MPH, of the University of Cincinnati, and coauthors reported in JAMA Oncology.
“We demonstrate the feasibility of multidisciplinary treatment using perioperative chemotherapy for patients with resectable pancreatic cancer,” the authors concluded. “We establish key clinical outcome metrics in this setting, using the two most active chemotherapy regimens for pancreatic cancer. We also reveal the challenges in quality control that serve as lessons for the future conduct of trials in this setting.”
“To our knowledge, this is the first time the two front-line chemotherapy regimens for pancreatic cancer have been tested in one study,” they added. “The present study was not designed for a between-arm comparison; nonetheless, the two arms resulted in very similar outcomes. Prior to this study, cross-trial comparisons in metastatic disease suggested that FOLFIRINOX might be more efficacious at the cost of increased toxic effects.”
The findings add another chapter to the ongoing effort to identify therapies that improve outcomes in pancreatic cancer. The findings also contrast with recent studies suggesting that preoperative chemotherapy improves survival as compared with historical results with adjuvant therapy.
Two years ago, a randomized trial of adjuvant therapy showed that a modified (m)FOLFIRINOX regimen (fluorouracil, leucovorin, irinotecan, and oxaliplatin) improved the disease-free interval by almost 9 months as compared with gemcitabine alone. The author of an accompanying editorial questioned whether preoperative chemotherapy might lead to further improvement in survival for a disease that can be systemic at diagnosis. By that time, the American Society of Clinical Oncology already recommended preoperative chemotherapy for borderline-resectable disease.
Last year, a propensity-matched analysis showed that preoperative mFOLFIRINOX significantly improved objective response rate (ORR) and subsequent rate of surgery as compared with gemcitabine/nab-paclitaxel.
Prior studies included limited prospective data on neoadjuvant therapy for resectable disease, Sohal and coauthors noted. To address that issue, they undertook a prospective investigation of the feasibility and clinical utility of neoadjuvant and adjuvant chemotherapy for resectable pancreatic cancer.
The Southwest Oncology Group S1505 trial enrolled patients with pancreatic ductal adenocarcinoma that was considered resectable by intergroup criteria. They were randomized to perioperative chemotherapy with mFOLFIRINOX or gemcitabine/nab-paclitaxel — 12 weeks of preoperative therapy, followed by restaging and resection in the absence of disease progression, and then 12 weeks of postoperative treatment. The primary outcome was 2-year OS determined by pick-the-winner design based on a prespecified 40% threshold for efficacy from historical data.
Data analysis included 102 randomized patients. The study population had a median age of about 65, and men accounted for about 60% of the patients. More than 60% of patients had a Zubrod Performance Score of 0, and more than 80% had tumors of the pancreas head. About 85% of the patients completed preoperative chemotherapy.
Subsequently, 40 patients in the mFOLFIRINOX arm and 33 in the gemcitabine/nab-paclitaxel arm underwent resection. The principal reasons for not having surgery were chemotherapy-associated toxicity, clinical deterioration, and patient refusal. Following surgery, 31 patients randomized to mFOLFIRINOX and 31 to gemcitabine/nab-paclitaxel started adjuvant chemotherapy, and 27 (49%) and 19 (40%) completed all treatment.
Neither arm of the trial significantly exceeded the threshold for 2-year OS: 47% for mFOLFIRINOX (95% CI 31-61%, P=0.15) and 48% for gemcitabine/nab-paclitaxel (95% CI 31-63%, P=0.14). Median OS was 23.2 months with mFOLFIRINOX and 23.6 months with gemcitabine/nab-paclitaxel. Other outcomes also did not differ significantly between the arms:
- Objective response: 9% vs 21%
- R0 resection: 85% in each arm
- Node-negative resection: 40% vs 45%
- Pathologic complete or major response: 25% vs 42%
- Median disease-free survival from resection: 10.9 vs 14.2 months
The most common grade 3/4 adverse events were hematologic toxicities, fatigue, diarrhea, nausea, and neuropathy, none of which exceeded expected rates.
The authors cited the challenge of determining resectability as a key issue encountered during the trial. The intergroup criteria used in the trial comprise objective anatomical findings, as opposed to subjective descriptors used in the past. Nonetheless, a third of the first 76 patients evaluated for the trial were ineligible, as were a fourth of 70 subsequent patients evaluated by central review.
“While the debate on the exact definition is beyond the scope of the present study, there is consensus that resectability definition is associated with outcomes and should be approached meticulously,” they noted.
The study was supported by the National Cancer Institute.
Sohal disclosed relationships with Perthera, Incyte, and Ability Pharma.