Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related death in the U.S., and its incidence is increasing (CA Cancer J Clin 2017;67(1):7-30, CA Cancer J Clin 2012;62(2):118-128). Surgical resection presents the only chance of cure; but, unfortunately, the minority of patients present at an early stage (CA Cancer J Clin 2017;67(1):7-30).
The basis of management of patients with advanced disease is palliative chemotherapy; patients with very good performance status are candidates for treatment with gemcitabine- or 5-fluorouracil (5FU)-based combination therapy. The combinations of gemcitabine with nanoparticle albumin-bound (nab)-paclitaxel and 5FU with oxaliplatin and irinotecan (FOLFIRINOX) have been found to improve overall survival compared to gemcitabine monotherapy, but the risk of adverse events is substantial (N Engl J Med 2011;364(19):1817-1825, N Engl J Med 2013;369(18):1691-1703).
Approximately 25-45 percent of patients with advanced PDAC in everyday clinical practice are candidates for FOLFIRINOX and gemcitabine/nab-paclitaxel therapy, respectively, based on the ACCORD 11/PRODIGE 4 and MPACT trials entry criteria (Am J Clin Oncol 2015; doi:10.1097/COC.0000000000000193).
Treatments for Pancreatic Adenocarcinoma
Nab-paclitaxel is a novel formulation of paclitaxel with a more favorable hematologic toxicity profile but a higher risk of neurotoxicity (J Clin Oncol 2005;23(31):7794-7803). Weekly nab-paclitaxel administration at a dose of 125 mg/m2 in combination with gemcitabine at a dose of 1,000 mg/m2 is the standard regimen for advanced PDAC (N Engl J Med 2013;369(18):1691-1703), but retrospective evidence supports that biweekly administration every 28 days or weekly administration every 21 days (days 1 and 8 of a 21-day cycle) at the same doses can have comparable efficacy and an improved toxicity profile compared to the regimen tested in the MPACT trial (Ther Adv Med Oncol 2017;9(2):75-82, Annals of Oncology 2016:27(suppl 6):666P).
Further, an ad hoc analysis of the MPACT trial supports the notion that longer medication exposure with appropriate dose reductions and delays is associated with improved outcomes (J Gastrointest Oncol 2016;7(3):469-478). In the contrary, sequential administration of gemcitabine (24 hours after nab-paclitaxel infusion) may improve overall and progression-free survival, but to the cost of more hematologic toxicity, need for growth factor support, and fatigue (J Clin Oncol 2017;35(4 suppl):342).
Similar to the OPTIMOX strategy in metastatic colorectal cancer, nab-paclitaxel discontinuation upon development of significant neurotoxicity while gemcitabine is continued with potential re-introduction of nab-paclitaxel upon resolution of neurotoxicity or disease progression is an option that may delay initiation of second-line therapy. This “OPTINAB” strategy has not been extensively evaluated in prospective clinical trials. Evidence from small patient series is reassuring in terms of preserved efficacy, but it is unclear if this strategy is superior to discontinuing all therapy (chemo holiday) (Cancer Chemother Pharmacol 2017;80(2):371-375).
The rationale of the 5FU bolus/5FU continuous infusion regimen developed by De Gramont et al. (J Clin Oncol 1997;15(2):808-815) is to enhance efficacy through induction of DNA damage followed by DNA repair inhibition (J Natl Cancer Inst 1993;85(23):193719-193744). It is the basis for most gastrointestinal cancer 5FU-based regimens in modern clinical practice, including FOLFIRINOX for PDAC. The need for 5FU bolus/leucovorin infusion is debatable in the current era or more potent DNA damaging agents like oxaliplatin and irinotecan.
Further, addition of low-dose leucovorin (20 mg/m2 weekly by IV infusion) to 5FU by continuous infusion appears to have similar efficacy, but a worse gastrointestinal adverse events profile in patients with metastatic colorectal cancer (J Clin Oncol 1995;13(6):1303-1311). Thus, it is reasonable to omit 5FU bolus/leucovorin from FOLFIRINOX in patients with PDAC, as well minimize toxicity and maximize treatment exposure. Modifications (i.e., omission of 5FU bolus, 5FU bolus and irinotecan dose reductions, use of scheduled hematopoietic growth factor support) of the original FOLFIRINOX regimen have been prospectively evaluated patients with advanced PDAC (Pancreas 2013;42(8):1311-1315, Br J Cancer 2016;114(7):737-743). The efficacy of this modified FOLFIRINOX regimen appears preserved and the rate of adverse events—particularly neutropenia, fatigue, and vomiting—decreased compared to historical controls. Oxaliplatin (rather than irinotecan) dose modifications and discontinuation (similar to OPTIMOX strategy in metastatic colorectal cancer) after a set number of cycles also seems reasonable based on inconsistent reports from clinical trials regarding the activity for oxaliplatin plus 5FU regimens in the second-line setting compared to 5FU as single agent (J Clin Oncol 2016;34(32):3914-3920, J Clin Oncol 2014;32(23):2423-2429).
On the contrary, nanoliposomal irinotecan plus 5FU is more active compared to 5FU alone in the second-line setting (Lancet 2016;387(10018):545-557). Conventional irinotecan and oxaliplatin have been directly compared as second-line therapy, both in combination with 5FU (Br J Cancer 2009;101(10):1658-1663). Overall survival appears equivalent between the two groups (6-month survival rate was 27% in the irinotecan-containing arm vs. 30% in the oxaliplatin-containing arm; disease-control rate was 23% vs. 17%, respectively). It should be noted that the statistical design of this study does not inform the clinician on what the most active regimen is (the study was powered to select the regimen with the highest observed overall survival for further development, irrespective of the actual difference between protocols).
In addition, while a modified FOLFOX6 regimen was used in the oxaliplatin arm (with the continuous 5FU infusion dose decreased to 2000 mg/m2), a modified FOLFIRI3 regimen was used in the irinotecan arm. The total irinotecan dose in this regimen is lower than in the most commonly FOLFIRI used regimen in the U.S. (140 mg/m2 vs. 180 mg/m2) and is also administered as split dose on days 1 and 3 after the end of the continuous 5FU infusion. In the absence of a deleterious germline (or somatic) BRCA1/2 mutation, oxaliplatin may be the least active of the three agents in the combination.
In summary, gemcitabine-nab-paclitaxel and FOLFIRINOX chemotherapy have improved outcomes when used as first-line therapy in patients with advanced PDAC and excellent performance status. The toxicity of the two regimens necessitates early treatment modifications for most patients. To expand the eligible population, upfront modifications may be required. The ideal modified regimen—if it exists—is currently unknown; prospective studies should try to answer this important clinical question.
CHRISTOS FOUNTZILAS, MD, is a Medical Oncologist in the Gastrointestinal Medical Oncology Department at Roswell Park Cancer Institute, Buffalo, N.Y.