The present study prospectively investigated the safety and efficacy of an attenuated dose of FOLFIRINOX as a second-line therapy for advanced pancreatic cancer and showed encouraging length of progression-free survival and overall survival, but was accompanied by significant toxicity.
Although several analyses on the efficacy and safety of modified doses of FOLFIRINOX have been performed, conclusive evidence is still lacking. Ghorani et al. [16] retrospectively analyzed data from their single-center experience in the United Kingdom with modified FOLFIRINOX for chemotherapy-naïve advanced pancreatic cancer. The treatment regimen consisted of oxaliplatin 85 mg/m2, irinotecan 130–135 mg/m2, folinic acid 400 mg/m2, and 5-FU infusion 2400 mg/m2 over 46 h, administered every 14 days. Their study included 15 patients with stage IV disease and indicated 47% ORR, with median PFS and OS of 7.2 and 9.3 months, respectively. The authors reported grade 3 or 4 neutropenia in 5.6% of their patients and non-hematologic adverse events (grade 3 or 4 vomiting: 27.8%). Blazer et al. [17] and Lakatos et al. [18] tested modified FOLFIRINOX in patients with locally advanced disease. Dose intensities varied between the research groups, but these studies reported a relatively low rate of adverse events along with meaningful disease control.
Umemura et al. [19] used a modified dose of FOLFIRINOX to treat a small group of patients with unresectable locally advanced or metastatic pancreatic cancer who failed on gemcitabine- and S-1-based therapies. The authors designed the modified regimen with oxaliplatin 75 mg/m2, irinotecan 150 mg/m2, folinic acid 320 mg/m2, 5-FU bolus 320 mg/m2, and 5-FU infusion 1920 mg/m2 administered every 21 days. After a total of 114 cycles were delivered in 13 patients, the ORR obtained was 30.8% with no CR, and median PFS and OS were 137 and 176 days, respectively. Five patients (38.5%) experienced grade 3 or 4 neutropenia, but febrile neutropenia did not occur. The other common grade 3 or 4 adverse events were anorexia, vomiting, and diarrhea (3, 1, and 1 patients, respectively). The incidence of grade 3–4 diarrhea in clinical trials in the Republic of Korea has been low compared with that reported in Western trials. Similar incidence is reported in Japanese patients. Ethnic differences in the activity of enzymes that metabolize irinotecan appear to be the cause. In a phase II trial of modified FOLFIRI.3 compared with modified FOLFOX as a second-line treatment for advanced pancreatic cancer conducted by Yoo et al. [11] in Korea, irinotecan dose was 140 mg/m2 every 2 weeks, and grade 3–4 diarrhea was observed in 7% of 31 patients. Kobayashi et al. [20] reported no occurrence of grade 3–4 diarrhea in 18 Japanese patients who were enrolled in a prospective phase I/II study of FOLFIRINOX as a second-line treatment for metastatic pancreatic cancer. The phase I trial was a dose-finding study for irinotecan in combination with fixed-dose 5-FU, leucovorin and oxaliplatin. As a result, an irinotecan dose of 100 mg/m2 was recommended. This finding is consistent with the frequent dose reduction of irinotecan in this study. The results of those two trials are very similar to those of the current study.
In a small retrospective analysis of salvage treatment with FOLFIRINOX, Lee et al. [13] reported a DCR of 55.6%, with median PFS and OS of 2.8 and 8.4 months, respectively. These findings are similar to the outcomes obtained with our attenuated dose of FOLFIRINOX, although the FOLFIRINOX regimen reported by Lee et al. consisted of the same dose as that of the original PRODIGE/ACCORD 11 trial. Clinical outcomes of several studies with modified FOLFIRINOX as a frontline treatment appeared not to be inferior to those of the original dose [21, 22]. In the CONKO-003 trial, which confirmed the survival benefit of salvage chemotherapy described above, the median OS was 5.9 and 3.3 months, and time to progression was 2.9 and 2.0 months (OFF versus FF, respectively). The efficacy of OFF regimen was not significantly different from that of our attenuated FOLFIRINOX in terms of PFS but tends to be inferior in terms of OS. In this previous study, 25% of the subjects received third-line therapy, similarly to our series of patients. The results of a few single-arm studies with irinotecan, fluorouracil, and leucovorin (FOLFIRI) as a second-line chemotherapy for pancreatic cancer have also been published. Zaniboni et al. [10] reported that 36% of patients showed DCR, with median PFS and OS of 3.2 and 5 months, respectively, using a FOLFIRI regimen in the GISCAD multicenter phase II study. Yoo et al. [12] stated that DCR was achieved in 23% of patients, with a median OS of 3.9 months in response to their modified FOLFIRI.3 chemotherapy in a randomized phase II study. These outcomes suggest the need for a triple combination of drugs for gemcitabine-refractory pancreatic cancer, despite concerns regarding their higher toxicity.
Attenuated FOLFIRINOX therapy in our study achieved a meaningful OS benefit, although the ORR fell short of our expectations. However, this dose-modified FOLFIRINOX regimen did not reduce toxicity either. Forty-one percent prevalence of grade 3 toxicities or neutropenia and an event of treatment-related mortality still leave concerns regarding the safety of this regimen. The small size of the study population for subgroup analysis, the absence of biomarker evaluation, and the lack of an assessment of the quality of life are also limitations of the present study. There is increasing interest in the feasibility and safety of FOLFIRINOX as a second-line treatment. Before initiation of our study, gemcitabine-based front-line therapy was doubted for its survival benefit because only modest effects were observed when gemcitabine in combination with erlotinib was compared with gemcitabine alone.
Recently, a new regimen of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine was shown to be superior to gemcitabine alone for OS as a front-line treatment in a randomized phase III study; thus, nab-paclitaxel plus gemcitabine is becoming one of the most widely used options as a first-line treatment [23,24,25,26]. Accordingly, the importance of salvage chemotherapy, which involves neither gemcitabine nor taxane, is increasing.
The higher DCR and longer OS observed in the current study justify the triple combination of FOLFIRINOX over doublet regimens such as FOLFIRI or FOLFOX, even in heavily pretreated pancreatic cancer patients. To date, only a handful of regimens apart from FOLFIRINOX could obtain a median OS beyond 8 months from initiation of second-line therapy for advanced pancreatic cancer [26]. Based on these findings, a phase III trial to confirm the survival benefits of modified FOLFIRINOX as a second-line treatment for advanced pancreatic cancer is being planned.