Research ArticleClinical Studies

Comparison Between FOLFIRINOX and nal-IRI/FL as Second-line Treatment After Gemcitabine Plus Nab-paclitaxel for Pancreatic Cancer

TOMOHISA OTSU, YOSHIKUNI INOKAWA, HIDEKI TAKAMI, MASAMICHI HAYASHI, KEISUKE KURIMOTO, NOBUTAKE TANAKA, HARUYOSHI TANAKA, DAI SHIMIZU, NORIFUMI HATTORI, MITSURO KANDA, CHIE TANAKA, GORO NAKAYAMA and YASUHIRO KODERA
Anticancer Research August 2022, 42 (8) 3889-3894; DOI: https://doi.org/10.21873/anticanres.15882

Abstract

Background/Aim: The regimen of nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (Nal-IRI/FL) was approved in Japan as second-line chemotherapy after gemcitabine-based treatment for pancreatic ductal adenocarcinoma (PDAC) in 2020. We examined the difference in outcome between patients treated with second-line folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) and those treated with nal-IRI/FL after first-line gemcitabine and nab-paclitaxel (GnP). Patients and Methods: The outcomes of 34 patients with PDAC who received second-line FOLFIRINOX (n=21) or nal-IRI/FL (n=13) after GnP at our Department from January 2016 to June 2021 were reviewed retrospectively. Results: Patient backgrounds did not differ between the groups. Dose reduction was more frequently required for treatment with FOLFIRINOX than with nal-IRI/FL (86% vs. 46%, p=0.022). Pegfilgrastim and aprepitant were used more frequently in the FOLFIRINOX group (both p<0.01). Progression-free survival (5.9 vs. 8.3 months) and overall survival (9.1 vs. 11.2 months) did not differ significantly between the groups. The frequency of grade 3 (Common Terminology Criteria for Adverse Events) or higher adverse events was similar between the groups. All-grade peripheral neuropathy was more common in the FOLFIRINOX group (100% vs. 77%, p=0.048). Conclusion: FOLFIRINOX and nal-IRI/FL as second-line therapy after GnP provided similar prognoses, although supportive treatment and dose reduction were more frequently required for FOLFIRINOX.

Key Words:

Despite significant advancements in diagnostic technology and multidisciplinary treatment, the prognosis of pancreatic cancer remains poor, and the 5-year survival rate after diagnosis is approximately 10% for all stages. In the US alone, pancreatic cancer led to an estimated 60,430 new cases and 48,220 deaths in 2021 (1).

For patients with metastatic pancreatic cancer who have a good general condition, gemcitabine and nab-paclitaxel (GnP) (2) or folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) (3) are usually chosen as the standard first-line treatment. There is little evidence supporting the use of various second-line treatments (4, 5). Following disease progression, the Japanese pancreatic cancer guidelines recommend 5-fluorouracil (5-FU)-containing regimens after gemcitabine-containing regimens or vice versa (6). Both nab-paclitaxel and oxaliplatin cause peripheral neuropathy; hence, patients who receive chemotherapy for a long time often require dose reduction of these agents to prevent treatment interruption.

Nanoliposomal irinotecan (nal-IRI) is an intravenous liposomal formulation of the topoisomerase I inhibitor irinotecan. It is indicated for use in combination with 5-FU and leucovorin for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC) after disease progression following gemcitabine-based therapy. The NAPOLI-1 randomized phase III study revealed that nal-IRI/FL achieved significantly better overall survival (OS) than 5-FU and leucovorin combination therapy in patients with metastatic pancreatic cancer after treatment with gemcitabine-based therapy (7). The improved survival outcomes and safety profiles of nal-IRI in Asian patients were also demonstrated by subgroup analysis of the NAPOLI-1 study (8).

The nal-IRI/FL regimen was approved in Japan as second-line chemotherapy for PDAC after gemcitabine-based treatment in June 2020. Therefore, in Japan there are currently two choices for second-line chemotherapy after first-line gemcitabine and nab-paclitaxel (GnP) for patients with a good performance status: FOLFIRINOX and nal-IRI/FL. However, the survival benefits and adverse events (AEs) of these regimens are unclear (9). We assessed the differences in the efficacy and safety of second-line FOLFIRINOX and nal-IRI/FL after first-line GnP in patients with PDAC.

Patients and Methods

Patients. In total, the outcomes of 34 patients with PDAC who received FOLFIRINOX (n=21) or nal-IRI/FL (n=13) after GnP at the Department of Gastroenterological Surgery (Surgery II), Nagoya University Hospital (Nagoya, Japan) from January 2016 to June 2021 were reviewed retrospectively. Patients who received gemcitabine-based chemotherapy without nab-paclitaxel (e.g. gemcitabine alone or gemcitabine plus S-1) as the first-line treatment were excluded. The clinical background, treatment details, efficacy, progression-free survival (PFS), OS, and AEs were compared between the groups. Regarding follow-up, patients underwent computed tomography every 2-3 months, tumor marker examination every month, and physical examination, evaluation of AEs based on Common Terminology Criteria for Adverse Events version 5.0 (10), and blood testing every consultation. The efficacy of therapy was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 (11). The Review Board of Nagoya University approved the sample collection protocol (protocol number: 2021-0131), and written informed consent for clinical data use was obtained from all patients included in this study.

Treatment. FOLFIRINOX consisted of a 2-h intravenous infusion of oxaliplatin at a dose of 85 mg/m2, followed by a 2-h infusion of L-leucovorin at a dose of 200 mg/m2, a 90-min infusion of irinotecan at a dose of 180 mg/m2, and a 400 mg/m2 bolus of fluorouracil with a continuous infusion of fluorouracil at 2,400 mg/m2 over 46 h every 2 weeks. Nal-IRI/FL consisted of a 90-min intravenous infusion of 70 mg/m2 nal-IRI, followed by a 2-h infusion of 200 mg/m2 L-leucovorin and a continuous 46-h infusion of fluorouracil at 2,400 mg/m2 every 2 weeks. Pegfilgrastim or aprepitant was used at the discretion of the attending doctors. Dose reduction was conducted according to the guide for appropriate use (3, 12).

Statistical analysis. Clinicopathological variables were analyzed using the chi-square test or Fisher’s exact test. PFS was defined as the time from starting of second-line therapy to the first documentation of disease progression. OS was defined as the time from starting second-line therapy to death from any cause. The associations of the chemotherapy regimen and other histopathological factors with PFS and OS were evaluated by the log-rank test. A value of p<0.05 was considered statistically significant. Statistical analyses were performed using JMP Pro software program, version 15 (SAS Institute, Cary, NC, USA).

Results

Patient characteristics. The clinical characteristics of the 34 included patients are summarized in Table I. Twenty-one patients were treated with FOLFIRINOX, and 13 patients were treated with nal-IRI/FL. Background variables such as age, sex, the GnP duration, history of pancreatic resection, tumor location, levels of carbohydrate antigen 19-9 (CA19-9) and Duke pancreatic monoclonal antigen type 2 (DUPAN-2), and the rate of peripheral sensory neuropathy did not differ between the groups before second-line therapy (Table I).

View this table:
Table I.

Clinical characteristics of the groups treated in the second line with folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX), or nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL).

Treatment details. Dose reduction was required more frequently under treatment with FOLFIRINOX than under nal-IRI/FL (86% vs. 46%, p=0.022). Supportive treatment for neutropenia with pegfilgrastim was more frequently used in the FOLFIRINOX group than in the nal-IRI/FL group (90% vs. 23%, p<0.001). Supportive treatment for nausea with aprepitant was used more commonly in the FOLFIRINOX group than in the nal-IRI/FL group (90% vs. 38%, p=0.002). The median number of treatment courses was lower for the FOLFIRINOX group, albeit without significance [6.0 (range=1-51) vs. 9.0 (range=1-19), p=0.961; Table II). The median relative dose intensities (RDIs) of irinotecan/nal-IRI and continuous 5-FU did not differ between the groups (irinotecan: 0.72 (range=0.43-1) vs. nal-IRI: 0.8 (range=0.51-1), p=0.722; 5-FU, FOLFIRINOX: 0.72 (range=0.38-1) vs. nal-IRI/FL: 0.86 (range=0.3-1), p=0.683; see Table III). The third-line treatments used in both groups are presented in Table IV. Best supportive care was the most frequent third-line treatment in both groups.

View this table:
Table II.

Dose reduction, supportive therapy, and courses for the groups treated in the second line with folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) (n=21), or nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL) (n=13).

View this table:
Table III.

Relative dose intensity (median, with range) of agents used in second-line therapy with folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX), and nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL).

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Table IV.

Treatment post progression (third-line) of patients treated with folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) (n=21), and nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL) (n=13) in the second line.

Efficacy. The disease control rate (56% vs. 80%, p=0.55) and response rate (17% vs. 20%) were equivalent between the FOLFIRINOX and nal-IRI/FL groups (Table V). PFS (5.9 vs. 8.3 months, p=0.744) and OS (9.1 vs. 11.2 months, p=0.333) were also similar between the groups (Figure 1). In addition, OS from the start of first-line GnP treatment also did not differ between the FOLFIRINOX and nal-IRI/FL groups (18.3 vs. 19.4 months, p=0.734; see Figure 2).

View this table:
Table V.

Antitumor effect of second-line folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) (n=21), and nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL) (n=13).

Figure 1.
Figure 1.

Kaplan–Meier curves of progression-free (A) and overall (B) survival from the initiation of second-line therapy with folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) (FFX; n=21), or nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL) (n=13).

Figure 2.
Figure 2.

Kaplan–Meier curve of overall survival from the initiation of first-line therapy for groups treated in the second line with folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) (FFX; n=21), or nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL) (n=13).

AEs. AEs were compared between the two treatment groups. Regarding hematological toxicities, the rates of neutropenia, leukopenia, anemia, and thrombocytopenia did not differ between the groups. Concerning non-hematological toxicity, only the rate of peripheral sensory neuropathy was significantly higher in the FOLFIRINOX-treated group (100% vs. 73%, p=0.048; Table VI). The rates of other AEs such as anorexia, nausea, vomiting, diarrhea, dysgeusia, and aspartate aminotransferase and alanine aminotransferase elevation were equivalent between the groups.

View this table:
Table VI.

Adverse events by Common Terminology Criteria for Adverse Events (8) experienced by patients treated with second-line folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) (n=21), and nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI/FL) (n=13).

Discussion

This retrospective study revealed that nal-IRI/FL and FOLFIRINOX were associated with equivalent characteristics and survival outcomes in patients with unresectable PDAC previously treated with GnP. However, the FOLFIRINOX-treated group had a significantly higher rate of peripheral neuropathy and more frequently required supportive treatments such as pegfilgrastim and aprepitant. The rate of dose reduction was also higher for the FOLFIRINOX group than for the nal-IRI/FL group, whereas the rates of hematological and gastrointestinal toxicity were similar. These results indicate that FOLFIRINOX tended to require more complex management for AEs than nal-IFI/FL despite conferring a similar prognosis.

Few reports have compared FOLFIRINOX and nal-IRI/FL in the second-line treatment of recurrent or metastatic PDAC. Park et al. reported a multicenter retrospective analysis of FOLFIRINOX and nal-IRI/FL after gemcitabine-based therapy in Korea (13). The study revealed similar outcomes for the treatments. The subgroup analysis illustrated that younger age was associated with better OS following FOLFIRINOX, whereas older age was associated with better survival following nal-IRI/FL. Although AEs were manageable with both regimens, the frequencies of neutropenia and peripheral neuropathy were higher with FOLFIRINOX. The authors concluded that various first-line gemcitabine-based regimens might have affected the outcome (13).

At our Institution, we use pegfilgrastim purposefully, especially in patients treated with FOLFIRINOX, to prevent neutropenia or febrile neutropenia. Therefore, our data revealed a lower rate of neutropenia (grade 3 or higher) in the FOLFIRINOX-treated group than observed in the Korean study (10.0% vs. 47.2%). Moreover, no cases of febrile neutropenia occurred during second-line treatment in this study. Guidance recommendations indicate that patients receiving chemotherapy with a risk of febrile neutropenia ≥20% should be administered pegfilgrastim or short-acting granulocyte colony-stimulating factor in all cycles (14). Sasaki et al. demonstrated that prophylactic pegfilgrastim reduced the frequency of grade 3-4 neutropenia and maintained the RDI, but they did not observe a reduction of febrile neutropenia with FOLFIRINOX (15). The RDI of irinotecan/nal-IRI and infusional 5-FU were equivalent between the groups in our study, although the FOLFIRINOX group more frequently needed supportive treatments than did the nal-IRI/FL group. Some reports described a modified FOLFIRINOX regimen featuring a reduced dose of continuous infusional 5-FU and no 5-FU bolus, resulting in similar efficacy and reduced AEs (16). We used the original FOLFIRINOX regimen because there is insufficient evidence supporting the use of the modified regimen. We were able to manage neutropenia using the original regimen by administering pegfilgrastim or reducing the dose as needed.

Peripheral sensory neuropathy is a common AE caused by chemotherapy. Concerning pancreatic cancer, nab-paclitaxel, a component of GnP (17), and oxaliplatin, a component of FOLFIRINOX (18), both induce peripheral sensory neuropathy. Peripheral sensory neuropathy induced by GnP may be associated with a longer treatment duration and longer survival (19). In this study, we used GnP in the first-line setting, and all 21 patients who received second-line FOLFIRINOX developed peripheral sensory neuropathy. Most patients developed peripheral sensory neuropathy during first-line GnP therapy (Table I), and on the commencement of second-line FOLFIRINOX, their neuropathy tended to worsen, necessitating dose reduction or withdrawal of oxaliplatin. Although the rate of all-grade peripheral sensory neuropathy was 77% in the nal-IRI/FL group, all patients had neuropathy derived from GnP at the time of initiation of second-line therapy. nal-IRI/FL can be administered safely since it is less likely to induce peripheral neuropathy.

This study had several limitations. Firstly, this was a single-center study with a small number of participants. We restricted the first-line therapy to GnP to ensure that the patients’ backgrounds were matched. Secondly, this was a retrospective study; therefore, a large-scale prospective study is needed, especially to enable a comparison in terms of efficacy data. Thirdly, the observation period of the nal-IRI/FL group was shorter than that of the FOLFIRINOX group, since we administered nal-IRI/FL after June 2020. Patients of the FOLFIRINOX group tended to be treated earlier in this study. The difference of treatment timing of the groups might have affected the outcomes. Furthermore, there is no definite standard for using supportive treatment such as pegfilgrastim and aprepitant. Finally, all patients had a good performance status and the ability to tolerate relatively high-risk chemotherapy such as GnP, FOLFIRINOX, and nal-IRI/FL.

In conclusion, both nal-IRI/FL and FOLFIRINOX led to good survival outcomes in the second-line treatment of PDAC after progression following GnP, and the safety profiles of these regimens were also equivalent and manageable. Treatment with nal-IRI/FL had lower requirements for supportive treatment and dose reduction. Furthermore, the rate of peripheral neuropathy using nal-IRI/FL was lower. These results suggest that nal-IRI/FL is more manageable than FOLFIRINOX as the second-line therapy after GnP.

Acknowledgements

The Authors thank Joe Barber Jr., PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this article.

Footnotes

  • Authors’ Contributions

    T.O., Y.I. designed the project. T.O. and Y.I. collected clinical data and analyzed them. N.T., H.T., Y.I., H.T., and M.H. did a multimodal treatment and followed up the patients. D.S., N.H., M.H., M.K., C.T., G.N, and Y.K. reviewed the article. T.O. and Y.I. wrote the article.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare.

  • Received May 19, 2022.
  • Revision received June 16, 2022.
  • Accepted June 21, 2022.

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Comparison Between FOLFIRINOX and nal-IRI/FL as Second-line Treatment After Gemcitabine Plus Nab-paclitaxel for Pancreatic Cancer
TOMOHISA OTSU, YOSHIKUNI INOKAWA, HIDEKI TAKAMI, MASAMICHI HAYASHI, KEISUKE KURIMOTO, NOBUTAKE TANAKA, HARUYOSHI TANAKA, DAI SHIMIZU, NORIFUMI HATTORI, MITSURO KANDA, CHIE TANAKA, GORO NAKAYAMA, YASUHIRO KODERA
Anticancer Research Aug 2022, 42 (8) 3889-3894; DOI: 10.21873/anticanres.15882
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