Pancreatic cancer (PC) accounts for 4.5% of all cancer-related deaths and is one of the deadliest cancers with 5-year survival rates of <5%. The chemotherapeutic regimen FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) is widely used in the management of metastatic PC (MPC), but its benefit in locally advanced PC (LAPC) is less well defined. The purpose of this meta-analysis was to assess the efficacy of FOLFIRINOX as a first-line chemotherapy regimen for LAPC.

Investigators systematically searched PubMed, EMBASE, and the Cochrane Library for studies dated up to January 1, 2020 that focused on the effectiveness of FOLFIRINOX in patients with LAPC. To be included in the meta-analysis, studies had to be randomized, controlled trials, cohort studies, or clinical controlled studies; had to include at least one patient with LAPC; had to incorporate confirmation of the diagnosis of LAPC by imaging or pathology prior to chemotherapy; and had to use FOLFIRINOX as first-line therapy. Case reports, reviews, conference abstracts, republications, studies that lacked data on resection rate or R0 resection rate (i.e., microscopically margin-negative resection), those with insufficient data on the outcome of interest, and those that were not published in English were excluded from analysis.

The primary outcomes of this meta-analysis were the rates of resection and R0 resection after first-line FOLFIRINOX treatment for LAPC. The secondary outcomes were the rates of response, median overall survival (OS), median progression-free survival (PFS), and grade 3 to 4 adverse events.

Twenty-one studies were included in the meta-analysis, which represented 1,013 patients. Of these studies, 17 were retrospective cohort studies, three were prospective cohort studies, and one was a phase II multicenter study.

Of the 1,013 patients included in these studies, 75 had borderline resectable PC, 270 had MPC, 653 had LAPC, and 15 had tumor recurrence. Overall, 51% of study subjects were male and median age in the studies ranged from 58 to 67 years. Of the 653 patients with LAPC, data were available for analysis for 648 patients. Of these patients, 29% (n =190) had undergone surgical resection after first-line folfirinox chemotherapy +/- radiotherapy, and the pooled resection rate was 26%. About three-quarters of LAPC patients who underwent surgical resection achieved R0 resection, and the pooled R0 resection rate was 88%.

Subgroup analyses of the rate of surgical resection and R0 resection were performed based on the median number of cycles of FOLFIRINOX administered.  However, no statistically significant differences were observed. OS ranged from 10.0 to 32.7 months with median PFS of 3.0 to 25.3 months, depending on the study. The objective response rate (ORR) ranged from a low of 17.2% to a high of 55.6% with pooled ORR of 34%.

About 90% of the studies reported on the occurrence of grade 3 to 4 adverse events. Among the 875 patients treated with FOLFIRINOX for whom data were available, there were 570 grade 3 or 4 adverse events or 65.1 event per 100 patients. The most common grade 3 to 4 adverse hematological events were neutropenia (20% pooled rates per 100 patients [PR100P]), febrile neutropenia (7% PR100P), and thrombocytopenia (6% PR100P). The most common grade 3 to 4 adverse nonhematological events were fatigue (9% PR100P), nausea/vomiting (7% PR100P), and diarrhea (10% PR100P). Despite the severity of these events, the majority were manageable with the use of either systemic treatments or chemotherapy dose reductions.

The authors stated that the ORR of 34% associated with FOLFIRINOX is much higher than the ORR of 9.4% seen with gemcitabine and that the combination may have advantages over gemcitabine in survival outcomes. However, they cautioned that the sample sizes of the included trials were small; over 80% of trials were retrospective; much heterogeneity was present among the studies; criteria differed between the studies in diagnosing LAPC; details were limited on treatment protocols (including indications for dose reductions); and neither the ethnicity nor dietary practices of study patients were identified.

Pharmacists managing patients with LAPC are faced with limited options. This study sheds light on the possible usefulness of a folfirinox -based neoadjuvant therapeutic regimen for patients with LAPC.

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