This retrospective study investigated mFFX therapy in patients with GnP-refractory MPC. The patients demonstrated an objective response rate of 10.6%, disease control rate of 56.7%, and median PFS and OS of 3.9 and 7.0 months, respectively. The median OS time after the start of the first-line therapy was 15.9 months. After exploring the independent variables associated with survival in this setting, we identified the CEA level and GPS as independent prognostic factors. This study also showed that the median PFS and OS of patients in good general condition with these good prognostic factors were 7.6 and 14.7 months, respectively.
Regarding second-line chemotherapy for GEM-refractory PC, a prematurely discontinued randomized clinical trial (RCT) by the German CONKO-study group provided evidence on the benefit of second-line chemotherapy compared with best supportive care . In a recent NAPOLI-1 phase III trial, significant improvements in both PFS and OS were observed in patients with MPC after previous GEM-based therapy and irinotecan liposomal injection combined with 5-FU/l-leucovorin, indicating a new treatment option for this population . The NAPOLI-1 study showed a median PFS and OS of 3.1 and 6.1 months, respectively, for a combination of 5-FU and liposomal irinotecan. Oxaliplatin combination therapy in this setting has also been investigated by three RCTs, with different and confounding results (CONKO-003, PANCREOX, and SOX [S-1 plus oxaliplatin])  . In a recent large phase III GRAPE trial comparing S-1 plus leucovorin and S-1 in patients with a good performance status and Alb ≥ 3.5 g/dL, the median PFS and OS were 2.8 and 7.9 months, respectively . Meanwhile, in our study, the median PFS and OS for patients with Alb ≥ 3.5 g/dL were 5.1 and 9.5 months, respectively. Sequential therapies with FFX and GnP have been tested because FFX and GnP are more effective as first-line therapy than GEM alone. A prospective cohort study in France evaluated second-line GnP after first-line FFX in 57 patients and showed a median PFS and OS of 5.1 months and 8.8 months, respectively, and a median OS of 18 months since the start of first-line FFX . Although comparisons among these previous studies are difficult, their findings led us to suggest that mFFX in selected patients may be effective and promising as a second-line treatment after failure of GnP.
As the FFX regimen has demonstrated better survival benefits than GEM as a first-line treatment, several prospective and retrospective studies evaluated FFX after failure of GEM-based chemotherapy, demonstrating median PFS time and OS times of 2.8-5.8 and 8.4-9.8 months    . These results suggest the promising clinical efficacy of the FFX regimen as a second-line treatment. Because FFX is a potentially highly toxic combination of drugs with serious side effects, two of the above studies, which are prospective phase II trial conducted by two Korean groups, reduced the dosage of both irinotecan (120-135 mg/m2) and oxaliplatin (60 -65 mg/m2). Despite the dose reduction, these studies showed a promising efficacy of the regimen for patients with PC after failure of GEM-based chemotherapy. In these studies, most of the patients received GEM monotherapy or GEM plus erlotinib as a first-line treatment. In our study, we evaluated the efficacy and tolerability of mFFX after failure of first-line GnP and found the RDIs of oxaliplatin and irinotecan to be 80.0% and 77.2%, respectively. Prospective studies are needed to better define the doses of mFFX and to determine the efficacy and risks of mFFX after failure of GnP.
Our study also found that grade 3-4 toxicities occurred in 57 patients (54.8%) and consisted mainly of hematological adverse effects (grade 3-4 neutropenia, 42.3%; febrile neutropenia, 5.8%). Although these incidences of hematologic toxicities are relatively higher than those reported for second-line chemotherapy regimens in previous studies such as the NAPOLI-1 and GRAPE trials and in the previous prospective French cohort treated with GnP after FFX, they are comparable with those reported for mFFX as first-line chemotherapy in Japan. In our study, most episodes of the adverse events were reversible, and the treatment was generally well tolerated. Dose reduction and cycle delay were required in about 70% of the patients in this setting. Moreover, the RDI was relatively low compared with that of mFFX as a first-line treatment in a phase II study in Japan . Although the safety profile in our study suggests that mFFX can be safely used after failure of GnP, the dosage and treatment schedule of mFFX in this setting should be more carefully evaluated in the future. Indeed, several prospective studies to evaluate FFX after failure of GEM-based therapy have reduced the initial dose of irinotecan and oxaliplatin.
One of the main concerns with sequential therapies consisting of GnP and mFFX is the risk of severe chronic PN owing to the use of nab-paclitaxel after oxaliplatin. In this study, the incidence of grade 1-2 PN was 78.8%, and that of grade 3-4 PN was 10.6%. This toxicity rate is higher than that of FFX or mFFX as first-line chemotherapy in Japan  . However, this rate is consistent with that of FFX in the ACCORD11 trial or in the previous prospective French cohort treated with GnP after FFX, and is quite lower than that in the MPACT trial   . The mechanisms of oxaliplatin and nab-paclitaxel neurotoxicity are different, and so are their mechanisms of reversibility. Nab-paclitaxel causes paresthesia and distal burning pain, but the symptoms generally improve within 2 months after treatment cessation . Oxaliplatin causes cumulative symmetric paresthesia and distal sensory decline . Therefore, despite an equivalence in toxicity grade by both drugs, the impact of oxaliplatin neurotoxicity on patients’ quality of life (QOL) may be less severe. This notion is supported by the finding that patients treated with a combination of FOLFOX and nab-paclitaxel did not develop significant neuropathy when they received fewer than 10 cycles, which is consistent with the occurrence of neuropathy in patients treated with FOLFOX alone . As for nab-paclitaxel-induced PN, the MPACT trial revealed that the median time to improvement from grade 3 to grade 2 was 21 days and that from grade 3 to grade 1 or resolution of the event was 29 days. With a median of only 6 cycles of mFFX per patient in our study, the risk of severe neurotoxicity seems limited in this study.
Subgroup analysis of the patients in this study showed that a low GPS and a low CEA level were independently associated with a good outcome. Previous reports indicated that the performance status, CA19-9 level, duration of the first-line chemotherapy, and inflammation-based prognostic score were important prognostic factors in a salvage setting [25,26]     . It is now widely accepted that the inflammation-based prognostic score, such as the GPS, is a reliable indicator of survival for many types of malignant solid tumors including PC in various settings  . Tumor markers such as CA19-9 and CEA levels were also reported as important prognostic factors in patients with advanced PC treated with chemotherapy. In our study, although the CA19-9 level and survival did not show a significant difference, patients in this setting with high CEA levels might indicate a more aggressive tumor biology. The question of whether the benefits of mFFX extend to patients even after failure of GnP is relevant because both mFFX and GnP are more intensive than GEM alone and there is no established second-line chemotherapy regimen for PC. Our prognostic model using GPS and CEA levels classified the patients into three prognostic groups (good, intermediate, and poor) and enabled stratification of patients according to both PFS and OS. The median OS times in the poor, intermediate, and good prognostic group were 5.0, 6.5, and 14.7 months, respectively. These results suggest that mFFX after failure of GnP offered no survival benefits to the poor prognostic group. Thus, the model might be useful for deciding whether mFFX is indicated for the patients with MPC in this setting.
This study has a few limitations. First, we only performed a single-center retrospective analysis, although the sample size exceeded 100 patients. Second, the patients who received treatment might have been more fit, better able to tolerate the treatment, and therefore more likely to benefit from it. Additionally, the gap between the median OS time and median PFS time in the good prognostic group was relatively large. In the good prognostic group, 28% of patients received chemotherapy after failure of second-line mFFX. In a previous meta-analysis, post-progression survival following second-line chemotherapy in patients with advanced PC previously treated with GEM was associated with subsequent chemotherapy and supportive care . The subsequent treatment and bias from selecting patients with a good general condition may explain these findings. Lastly, this study did not evaluate biomarkers and QOL. QOL is an important element of palliative chemotherapy for PC. Hence, future prospective studies of second-line mFFX following GnP are necessary to clarify treatment efficacy and QOL of patients in this context.
In conclusion, mFFX showed to be a tolerable second-line treatment for selected patients with MPC after failure of GnP therapy. Our prognostic model using GPS and CEA level might be useful for deciding whether mFFX is indicated in this setting. These findings need to be confirmed in a comparative randomized trial.