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A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407)

Open AccessPublished:January 09, 2023DOI:https://doi.org/10.1016/j.ejca.2022.12.014

      Highlights

      • Pancreatic cancer is one of the most fatal cancers worldwide.
      • We compared the efficacy of mFOLFIRINOX with that of GnP in LAPC.
      • mFOLFIRINOX and GnP achieved similar efficacy.
      • Both regimens showed better 1-year survival than gemcitabine monotherapy.
      • GnP demonstrated better DCR and CA19-9 response and mild gastrointestinal toxicity.

      Abstract

      Aim

      We compared the efficacy of modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) with that of gemcitabine plus nab-paclitaxel (GnP) for locally advanced pancreatic cancer (LAPC).

      Methods

      Patients with untreated LAPC were randomly assigned (1:1) to receive mFOLFIRINOX or GnP. One-year overall survival (OS) was the primary endpoint. The major secondary end-points included progression-free survival (PFS), response rate (RR), carbohydrate antigen 19-9 (CA19-9) response, and adverse events. The sample size was 124 patients to select a more effective regimen with a minimum probability of 0.85 and to examine the null hypothesis of the 1-year OS <53%.

      Results

      Of the 126 patients enrolled from 29 institutions, 125 were deemed eligible. The 1-year OS was 77.4% (95% CI, 64.9–86.0) and 82.5% (95% CI, 70.7–89.9) in the mFOLFIRINOX and GnP arms, respectively. The median PFS was 11.2 (95% CI, 9.9–15.9) and 9.4 months (95% CI, 7.4–12.8) in the mFOLFIRINOX and GnP arms, respectively. The RR and CA19-9 response rate were 30.9% (95% CI, 19.1–44.8) and 57.1% (95% CI, 41.0–72.3) and 42.1% (95% CI 29.1–55.9) and 85.0% (95% CI, 70.2–94.3) in the mFOLFIRINOX and GnP arms, respectively. Grade 3–4 diarrhoea and anorexia were predominant in the mFOLFIRINOX arm.

      Conclusion

      GnP was considered the candidate for a subsequent phase III trial because of its better RR, CA19-9 response, and mild gastrointestinal toxicities. Both regimens displayed higher efficacy in the 1-year survival than in the historical data of gemcitabine monotherapy.

      Keywords

      1. Introduction

      Pancreatic cancer is one of the most fatal cancers, with a 5-year overall survival (OS) < 5% [
      • Kamisawa T.
      • Wood L.D.
      • Itoi T.
      • Takaori K.
      Pancreatic cancer.
      ]. Approximately 80% of pancreatic cancers are unresectable, with locally advanced disease or distant metastasis at diagnosis [
      • Vincent A.
      • Herman J.
      • Schulick R.
      • Hruban R.H.
      • Goggins M.
      Pancreatic cancer.
      ]. Advanced pancreatic cancer is an unresectable state without metastases owing to vascular involvement. Clinicians recommend both chemoradiotherapy and chemotherapy as the standard treatments for locally advanced pancreatic cancer (LAPC) [
      ,
      • Okusaka T.
      • Nakamura M.
      • Yoshida M.
      • et al.
      Clinical practice guidelines for pancreatic cancer 2019 from the Japan Pancreas Society: a Synopsis.
      ]; for chemotherapy, researchers recommended gemcitabine monotherapy for patients with LAPC, with a median survival of 8.7–15.0 months and a 1-year OS of 5364% [
      • Ishii H.
      • Furuse J.
      • Boku N.
      • et al.
      Phase II study of gemcitabine chemotherapy alone for locally advanced pancreatic carcinoma: JCOG0506.
      ,
      • Ueno H.
      • Ioka T.
      • Ikeda M.
      • et al.
      Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study.
      ].
      Combination chemotherapies, such as 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) [
      • Conroy T.
      • Desseigne F.
      • Ychou M.
      • et al.
      FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
      ], and gemcitabine plus nab-paclitaxel (GnP) [
      • Von Hoff D.D.
      • Ervin T.
      • Arena F.P.
      • et al.
      Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
      ], demonstrated a marked survival advantage over gemcitabine monotherapy for metastatic pancreatic cancer. Moreover, FOLFIRINOX and GnP have been used in LAPC because of their efficacy. FOLFIRINOX-treated patients with LAPC had a median survival of 24.2 months in a meta-analysis [
      • Suker M.
      • Beumer B.R.
      • Sadot E.
      • et al.
      FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis.
      ]. A single-arm phase II study of GnP for LAPC displayed a median OS of 18.8 months [
      • Philip P.A.
      • Lacy J.
      • Portales F.
      • et al.
      Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study.
      ]. However, no randomised controlled trials have directly compared FOLFIRINOX and GnP in locally advanced diseases.
      Despite the promising efficacy of FOLFIRINOX, the majority of patients require dose reduction because of severe toxicities [
      • Okusaka T.
      • Ikeda M.
      • Fukutomi A.
      • et al.
      Phase II study of FOLFIRINOX for chemotherapy-naive Japanese patients with metastatic pancreatic cancer.
      ]. Therefore, researchers have modified the FOLFIRINOX treatment regimen; they reduced the dose of irinotecan and eliminated 5-fluorouracil bolus. Its efficacy was comparable to that of the original FOLFIRINOX, besides tolerable toxicity in patients [
      • Ozaka M.
      • Ishii H.
      • Sato T.
      • et al.
      A phase II study of modified FOLFIRINOX for chemotherapy-naive patients with metastatic pancreatic cancer.
      ]. Therefore, modified FOLFIRINOX (mFOLFIRINOX) has been selected as a candidate regimen for further clinical trials.
      We conducted a selection design randomised phase II study to determine the preferable chemotherapy regimen for a subsequent phase III trial comparing chemotherapy with chemoradiotherapy for patients with LAPC. In addition, we aimed to compare the efficacy of mFOLFIRINOX or GnP against that historically reported for gemcitabine monotherapy. This trial (JCOG1407) had been registered with UMIN000023143 at the UMIN Clinical Trials Registry and jRCTs031180085 at the Japan Registry of Clinical Trials.

      2. Materials and methods

      2.1 Study design and patients

      This multicentre, open-label, randomised phase II study was conducted across 29 Japanese hospitals participating in the Hepatobiliary and Pancreatic Oncology Group of Japan Clinical Oncology Group (JCOG). The eligibility criteria were as follows: (1) aged 20–75 years; (2) with histologically or cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma; (3) no distant metastases and no ascites/pleural effusion; (4) T4 (tumour involving the celiac axis or superior mesenteric artery) or T3 with an invasion to the common hepatic artery, proper hepatic artery, or an extensive portal vein involvement according to the Union for International Cancer Control-‘Tumor’, ‘Nodes’, ‘Metastases’ classification (7th edition); (5) Eastern Cooperative Oncology Group performance status of 0 or 1; (6) no diarrhoea; (7) no peripheral sensory/motor neuropathy; (8) no prior surgical resection for pancreatic cancer; (9) no prior anti-cancer chemotherapy or radiotherapy for any malignancy; (10) uridine diphosphate glucuronosyltransferase (UGT) 1A1 genotype of either ∗6/∗6, ∗28/∗28, or ∗6/∗28; (11) sufficient organ function; and (12) the provision of written informed consent. The main exclusion criteria were as follows: synchronous or metachronous (within 5 years) malignancies, active infection, receiving continuous systemic corticosteroids or immunosuppressants, and severe pulmonary disease, cardiac disease. Borderline resectable is defined by superior mesenteric vein (SMV), portal vein (PV) invasion alone, or arterial invasion, according to 7th edition of the Classification of Pancreatic Carcinoma (classification according to UICC 7th edition) (supplement 1).
      The study protocol was approved by the JCOG Protocol Review Committee and the Institutional Review Board of each participating hospital. This study was performed in accordance with the international ethical recommendations of the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects.

      2.2 Procedures

      The mFOLFIRINOX arm was subjected to a 2-h i.v. injection (IV) each of 85 mg/m2 oxaliplatin and 200 mg/m2 l-leucovorin and a 1.5-h IV of 150 mg/m2 irinotecan, followed by a continuous IV of 2400 mg/m2 5-fluorouracil over 46 h. This regimen was repeated every 2 weeks until disease progression, unacceptable toxicity, or patient refusal. The GnP arm was subjected to 30-min IV each of 125 mg/m2 nab-paclitaxel and 1000 mg/m2 gemcitabine on days 1, 8, and 15, which was repeated every 4 weeks until disease progression, unacceptable toxicity, or patient refusal. Enhanced computed tomography (CT) or magnetic resonance imaging (MRI), chest X-ray, and serum tumour marker levels (carcinoembryonic antigen and carbohydrate antigen [CA] 19-9) were evaluated every 8 weeks until disease progression or death. We performed physical and laboratory examinations on day 1 of the subsequent treatment courses in the mFOLFIRINOX arm and on days 1, 8, and 15 of the treatment courses in the GnP arm. There were no restrictions on the subsequent treatment. A primary tumour could be resected when patients were considered to have resectable tumours owing to remarkable tumour responses to chemotherapy. In these patients, we terminated the treatment protocol on surgery day.

      2.3 Outcomes

      The 1-year OS of all eligible patients was the primary end-point. OS was defined as the number of days from the date of randomisation to the date of death from any cause, and data were censored on the last day the patient was alive. The secondary end-points included progression-free survival (PFS), distant metastasis-free survival, response rate (RR) in patients with target lesions, CA19-9 response, adverse events, treatment-related deaths, early death, grade 4 non-haematological toxicity, and dose intensity. PFS was defined as the days from the date of randomisation to the documented date of disease progression or death from any cause. The distant metastasis-free survival was defined as the days from the date of randomisation to the documented date of metastatic disease or death from any cause. We assessed the CA19-9 response for patients with a pretreatment CA19-9 level >100 U/mL, and a positive response was defined as a >50% reduction from the pretreatment level [
      • Ishii H.
      • Okada S.
      • Sato T.
      • et al.
      CA 19-9 in evaluating the response to chemotherapy in advanced pancreatic cancer.
      ]. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 4.0. We evaluated the tumour response using the Response Evaluation Criteria in Solid Tumors version 1.1. No central review was performed.

      2.4 Random assignment

      After confirming the eligibility criteria, we performed patient registration with the JCOG Data Center using a web-based system. We used the minimisation method with a random component to randomly assign the patients to the mFOLFIRINOX or GnP arms in a 1:1 ratio, using the institution and CA19-9 (<1000 U/mL vs. ≥1000 U/mL) as the stratification factors.

      2.5 Statistical analysis

      This study was performed to determine the more promising chemotherapy regimen between mFOLFIRINOX and GnP for patients with LAPC. We assumed that the proportion of the 1-year survival for gemcitabine monotherapy would be 53% based on the 1-year survival data from the GEST trial of gemcitabine monotherapy [
      • Ueno H.
      • Ioka T.
      • Ikeda M.
      • et al.
      Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study.
      ], whereas that of mFOLFIRINOX or GnP would be >63%. According to Simon's selection design [
      • Simon R.
      • Wittes R.E.
      • Ellenberg S.S.
      Randomized phase II clinical trials.
      ] (pick-the-winner design), 106 patients had ≥85% probability of selecting more effective chemotherapy. A sample size of 120 patients was required to maintain 80% power for the hypothesis that the 1-year survival is expected to be 70%, with a threshold value of 53% and a one-sided alpha of 5%. Therefore, the planned sample size was 124 patients, assuming that few patients were ineligible or lost to the follow-up. We estimated the OS, PFS, and distant metastasis-free survival using the Kaplan–Meier method. Hazard ratios (HR) of the treatment effects were estimated by the unstratified Cox regression model. All statistical analyses were performed at the JCOG Data Center using SAS version 9.4.

      3. Results

      3.1 Patient characteristics

      Between July 2016 and August 2019, we enrolled and randomly assigned 126 patients to the mFOLFIRINOX (62 patients) or GnP arm (64 patients) at 29 centres across Japan (Fig. 1). One patient in the GnP arm was identified as ineligible in a site visit audit because of no baseline creatinine clearance. Thus, 125 patients (62 in the mFOLFIRINOX arm and 63 in the GnP arm) were enrolled. Table 1 summariases the baseline patient characteristics, which were balanced between the arms. The resectability status included approximately 10% of borderline resectable (BR) and 90% of unresectable-locally advanced (UR-LA) cancer. Of all the patients, 50% and 56% had a family history of malignancy in the mFOLFIRINOX and GnP arms, respectively.
      Fig. 1
      Fig. 1CONSORT diagram: The flow chart of patients with locally advanced pancreatic cancer receiving mFOLFIRINOX vs. GnP
      CONSORT, Consolidated Standards of Reporting Trials; mFOLFIRINOX, modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; and GnP, gemcitabine plus nab-paclitaxel.
      Table 1Baseline characteristics (all eligible patients).
      mFOLFIRINOX (N = 62)GnP (N = 63)
      Median Age, Years (Range)66 (44–75)66 (47–75)
      Sex
       Male36 (58)38 (59)
       Female26 (42)25 (41)
      ECOG performance status
       046 (74)45 (71)
       116 (26)18 (29)
      Tumour location
       Head39 (63)34 (54)
       Body20 (32)27 (43)
       Tail3 (5)2 (3)
      Carbohydrate antigen 19-9 (U/mL)
       <100047 (75)45 (71)
       >100015 (25)18 (29)
      Nodal status
       cN046 (74)53 (84)
       cN116 (26)10 (16)
      Resectability status
       BR7 (11)6 (10)
       UR-LA55 (89)57 (90)
      Vascular involvement
       CA28 (45)36 (57)
       SMA40 (65)41 (65)
       CHA35 (56)39 (62)
       PHA17 (27)20 (32)
       PV21 (34)22 (35)
      Family history31 (50)35 (56)
      Pancreatic cancer57
      Ovarian cancer01
      Breast cancer73
      Prostate cancer33
      N (%) unless otherwise stated.
      Abbreviations: FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; mFOLFIRINOX, modified FOLFIRINOX; GnP, gemcitabine plus nab-paclitaxel; ECOG: Eastern Cooperative Oncology Group; BR, borderline resectable; UR-LA, unresectable-locally advanced; CA, celiac artery; SMA, superior mesenteric artery; CHA, common hepatic artery; PHA, proper hepatic artery; and PV, portal vein.

      3.2 Treatment

      All patients received the protocol treatment in both arms and terminated the protocol treatment at the cut-off date of October 06, 2021. The median dose intensity during 48 weeks of oxaliplatin, irinotecan, and 5-fluorouracil administration was 76.9% (range: 53.4–99.5), 75.3% (range: 53.3–100), and 85.5% (range: 49.5–99.9) in the mFOLFIRINOX arm, respectively, whereas that of gemcitabine and nab-paclitaxel were 79.8% (range: 34.9–99.5) and 72.2% (range: 33.4–97.9) in the GnP arm, respectively.

      3.3 Efficacy

      With the data cut-off date of October 2021, the median duration of follow-up was 22.2 months (interquartile range 14.1–29.9). Of all patients, 91 had died (44 in the mFOLFIRINOX arm; 47 in the GnP arm). The proportion of the 1-year OS was 77.4% (95% CI, 64.9–86.0) and 82.5% (95% CI, 70.7–89.9) in the mFOLFIRINOX and GnP arms (HR, 1.096; 95% CI, 0.726–1.654, Fig. 2A), respectively. The proportion of the 2-year OS was 46.2% (95% CI, 33.4–58.0) and 41.3 (95% CI, 29.1–53.0) in the mFOLFIRINOX and GnP arms, respectively. The median OS was 23.0 (95% CI, 19.3–29.3) and 21.3 months (95% CI, 18.2–24.1) in the mFOLFIRINOX and GnP arms, respectively. The median PFS was 11.2 (95% CI, 9.9–15.9) and 9.4 months (95% CI, 7.4–12.8) in the mFOLFIRINOX and GnP arms, respectively (HR, 1.359; 95% CI, 0.939–1.968, Fig. 2B). The median distant metastasis-free survival was 17.4 (95% CI, 12.3–22.1) and 13.3 months (95% CI, 9.3–16.9) in the mFOLFIRINOX and GnP arms, respectively (HR, 1.254; 95% CI, 0.853–1.844, Fig. 2C). Table 2 summarises the tumour response data of the patients with measurable lesions. The RR was 30.9% (95% CI, 19.1–44.8) and 42.1% (95% CI, 29.1–55.9) in the mFOLFIRINOX and GnP arms, respectively. The disease control rate (DCR, complete response (CR) + partial response (PR) + stable disease (SD)) was 87.3% (95% CI, 73.3–93.5) and 96.5% (95% CI, 87.9–99.6) in the mFOLFIRINOX and GnP arms, respectively. We assessed the CA19-9 response rate in 42 and 40 patients in the mFOLFIRINOX and GnP arms, respectively. The CA19-9 response rate was 57.1% (95% CI, 41.0–72.3) and 85.0% (95% CI, 70.2–94.3) in the mFOLFIRINOX and GnP arms, respectively.
      Fig. 2
      Fig. 2(A) Overall survival (primary end-point) (B) progression-free survival, and (C) distant metastasis-free survival.
      Table 2Best tumour (patients with measurable lesions) and CA19-9 responses.
      mFOLFIRINOX (N = 55)GnP (N = 57)
      Response
       Complete response1 (1.8)0
       Partial response16 (29.1)24 (42.1)
       Stable disease31 (56.4)31 (54.4)
       Progressive disease5 (9.1)1 (1.8)
       Not evaluable2 (3.6)1 (1.8)
      Response rate17 (30.9)24 (42.1)
      Disease control rate48 (87.3)55
      CA19-9 > 100 U/mL4240
      CA19-9 response rate24 (57.1)34 (85.0)
      We assessed CA19-9 response for patients with a pretreatment CA19-9 level >100 U/mL, and a positive response was defined as >50% reduction from the pretreatment level. N (%) unless otherwise stated.
      Abbreviations: FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; mFOLFIRINOX, modified FOLFIRINOX; GnP, gemcitabine plus nab-paclitaxel; and CA19-9, carbohydrate antigen 19-9.

      3.4 Safety

      We assessed the toxicity in the safety population (62 patients in the FOLFIRINOX arm; 63 patients in the GnP arm). Table 3 summarises the haematological and non-haematological toxicities. Any grade nausea (mFOLFIRINOX vs. GnP: 58.1% vs. 30.2%) and vomiting (24.2% vs. 12.7%) were predominant in the mFOLFIRINOX arm. Moreover, grade 3 or 4 diarrhoea (17.7% vs. 1.6%) and anorexia (16.1% vs. 6.3%) were predominant in the mFOLFIRINOX arm. By contrast, grade 3 or 4 peripheral sensory neuropathy (25.8% vs. 36.5%), decreased white blood cells (22.6% vs. 44.4%), and decreased neutrophil count (59.7% vs. 79.4%) were predominant in the GnP arm. Febrile neutropenia occurred in five (8.1%) and three patients (4.8%) in the mFOLFIRINOX and GnP arms, respectively. We observed grade 4 non-haematological adverse events in four and three patients in the mFOLFIRINOX and GnP arms, respectively, regardless of their relation to treatments. No treatment-related deaths occurred in both arms.
      Table 3A summary of the adverse events (safety analysis set).
      mFOLFIRINOX (N = 62)GnP (N = 63)
      All gradeGrade 3–4All gradeGrade 3–4
      Decreased white blood cells36 (58.1)14 (22.6)52 (82.5)28 (44.4)
      Decreased neutrophil count56 (90.3)37 (59.7)61 (96.8)50 (79.4)
      Anaemia43 (69.4)7 (11.3)54 (85.7)12 (19.0)
      Decreased platelet count54 (87.1)2 (3.2)59 (93.7)2 (3.2)
      Febrile neutropenia5 (8.1)5 (8.1)3 (4.8)3 (4.8)
      Diarrhoea33 (53.2)11 (17.7)25 (39.7)1 (1.6)
      Anorexia42 (67.7)10 (16.1)37 (58.7)4 (6.3)
      Nausea36 (58.1)3 (4.8)19 (30.2)4 (6.3)
      Vomiting15 (24.2)2 (3.2)8 (12.7)2 (3.2)
      Fatigue28 (45.2)3 (4.8)39 (61.9)0
      Increased aspartate aminotransferase47 (75.8)7 (11.3)47 (74.6)8 (12.7)
      Increased alanine aminotransferase50 (80.6)8 (12.9)51 (81.0)10 (15.9)
      Peripheral sensory neuropathy46 (74.2)16 (25.8)46 (73.0)23 (36.5)
      The grades of adverse events were defined according to the Common Terminology Criteria for Adverse Events (version 4.0). N (%) unless otherwise stated.
      Abbreviations: FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; mFOLFIRINOX, modified FOLFIRINOX; and GnP, gemcitabine plus nab-paclitaxel.

      3.5 Reasons for treatment termination and second-line chemotherapy

      The protocol treatment was terminated for the following reasons: disease progression in 17 and 29 patients in the mFOLFIRINOX and GnP arms, respectively, or adverse events or refusal associated with adverse events in 37 and 27 patients in the mFOLFIRINOX and GnP arms, respectively. Second-line chemotherapy was administered to 51 and 47 patients in the mFOLFIRINOX and GnP arms, respectively. GnP and mFOLFIRINOX were the most common second-line regimens for 21 and 14 patients in the mFOLFIRINOX and GnP arms, respectively. Five patients in both arms who had positively responded to chemotherapy underwent conversion surgery (mFOLFIRINOX arm vs. GnP arm: 8.1% vs. 7.8%).

      4. Discussion

      This randomised phase II trial was performed to select a regimen from mFOLFIRINOX or GnP as a promising candidate for a subsequent phase III study. The 1-year OS of the primary end-point was marginally better in the GnP arm than that in the mFOLFIRINOX arm, whereas the 2-year OS was marginally better in the mFOLFIRINOX arm than that in the GnP arm in patients with LAPC. Which of the two regimens is more promising must be considered comprehensively in light of other efficacy measures or toxicities. GnP displayed better efficacy in the RR, DCR, and CA19-9 response and milder gastrointestinal toxicity, thus leading to better termination of the protocol treatment than mFOLFIRINOX. Consequently, we considered GnP as the more promising regimen for a subsequent phase III study. GnP demonstrated higher RR; thus, patients with LAPC displayed considerable shrinkage of the primary tumour in terms of the possibility of additional treatments, such as surgical resection or chemoradiotherapy. An equal number of patients underwent surgical resection or chemoradiotherapy in both groups. SWOG1505 was conducted in a different patient population with resectable disease [
      • Sohal D.P.S.
      • Duong M.
      • Ahmad S.A.
      • et al.
      Efficacy of perioperative chemotherapy for resectable pancreatic adenocarcinoma: a Phase 2 randomized clinical trial.
      ]. However, it is the only other published randomised trial directly comparing these regimens. Similar to SWOG1505, this study also found higher response rate with GnP though no differences in resection rate or survival.
      Grade 3 or 4 neutropenia tended to be predominant in the GnP arm, thereby suggesting it may be attributed to differences in the frequency of laboratory examinations. Febrile neutropenia was comparable and manageable in both arms. By contrast, grade 3 or 4 diarrhoea and anorexia were predominant in the mFOLFIRINOX arm. Treatment termination owing to adverse events was predominant in the mFOLFIRINOX arm. This difference in tolerability was based on the comparison of well-conditioned patients selected for UGT1A1 and aged under 75 years, thus deeming GnP a feasible treatment.
      Moreover, we intended to examine the efficacy of mFOLFIRINOX and GnP using the historical data on gemcitabine monotherapy [
      • Ishii H.
      • Furuse J.
      • Boku N.
      • et al.
      Phase II study of gemcitabine chemotherapy alone for locally advanced pancreatic carcinoma: JCOG0506.
      ,
      • Ueno H.
      • Ioka T.
      • Ikeda M.
      • et al.
      Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study.
      ]. Both mFOLFIRINOX and GnP significantly exceeded the threshold 1-year survival of 53%, thus suggesting both treatments were considered standard chemotherapy regimens for LAPC, despite no direct comparison with gemcitabine monotherapy. The same trend was reported in the PRODIGE 29-UCGI 26(NEOPAN) comparing FOLFIRINOX and Gem [
      • Ducreux M.P.
      • Desgrippes R.
      • Rinaldi Y.
      • et al.
      1296MO PRODIGE 29-UCGI 26(NEOPAN): a phase III randomised trial comparing chemotherapy with folfirinox or gemcitabine in locally advanced pancreatic carcinoma (LAPC).
      ].
      mFOLFIRINOX and GnP are often used for LAPC as the initial chemotherapies, with an intention to conversion surgery because of their high response rates [
      • Kunzmann V.
      • Siveke J.T.
      • Algül H.
      • et al.
      Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial.
      ]. Approximately 10% of the prospectively enrolled patients could undergo conversion surgery [
      • Suker M.
      • Beumer B.R.
      • Sadot E.
      • et al.
      FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis.
      ]. In this study, conversion surgery was performed in approximately 8% of the patients in both arms, thus warranting further investigation, including the importance of the PFS and distant metastasis-free survival. The PFS Kaplan–Meier curve for the mFOLFIRINOX arm was initially below that for the GnP arm; thereafter, the curves crossed at 6 months. Hence, there may be subgroups with or without sensitivity to mFOLFIRINOX, considering the unfavourable aspect of mFOLFIRINOX as initial chemotherapy.
      Chemoradiotherapy has also been developed for LAPC. However, overall survival in this study group was better than in the chemoradiation groups in the SCALOP study [
      • Mukherjee Somnath
      • Hurt Christopher N.
      • Bridgewater John
      • et al.
      Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial.
      ], LAP07 [
      • Pascal Hammel
      • Huguet Florence
      • Jean-Luc van Laethem
      • et al.
      Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 Months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial.
      ], and CONKO-007 [
      • Fietkau Rainer
      • Ghadimi Michael
      • Grützmann Robert
      • et al.
      Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: first results of the CONKO-007 trial.
      ], and it remains to be seen whether chemoradiation is more effective for LAPC than FFX or GnP.
      Germline BReast CAncer gene 1/2 and Partner and localiser of BRCA2 mutations, due to homologous recombination deficiency, have been established as the predictive biomarkers for platinum sensitivity [
      • Golan T.
      • Kanji Z.S.
      • Epelbaum R.
      • et al.
      Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.
      ]. One limitation of this study was that we did not examine these genome screenings. These mutations are observed in 10–15% of pancreatic cancers [
      • Smith A.L.
      • Wong C.
      • Cuggia A.
      • et al.
      Reflex testing for germline BRCA1, BRCA2, PALB2, and ATM mutations in pancreatic cancer: mutation prevalence and clinical outcomes from two Canadian research registries.
      ,
      • Singhi A.D.
      • George B.
      • Greenbowe J.R.
      • et al.
      Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers.
      ]; thus, they can be good targets for FOLFIRINOX, thereby warranting further investigation.
      In conclusion, mFOLFIRINOX and GnP displayed comparable efficacy and safety for LAPC. We considered GnP as the candidate for the subsequent phase III trial because of its better RR, DCR, and CA19-9 response and mild gastrointestinal toxicities.

      Funding

      This work was supported by Health and Labour Sciences Research Grants for Clinical Cancer Research [H26-081] from the Ministry of Health, Labour and Welfare of Japan, AMED under Grant Numbers JP16ck0106084, JP19ck0106354, and JP21ck0106625 and by the National Cancer Center Research and Development Fund (26-A-4, 29-A-3, and 2020-J-3).

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
      MO reports grants and non-financial support from the Ministry of Health, Labor, and Welfare, Japan and grants from the Japan Agency for Medical Research and Development (AMED), during the study as well as personal fees from Taiho Pharmaceutical, Yakult Honsha, MSD, Ono Pharmaceutical, Nihon Servier, Bayer, and Pfizer outside the submitted work. KN reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as grants from Delta-Fly Pharma and personal fees from Eisai, Yakult, AstraZeneca, and Ono. SK reports grants and non-financial support from the Ministry of Health, Labor, and Welfare, Japan and grants and non-financial support from Japan AMED, during the study as well as personal fees from Bayer Yakuhin, Chugai Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Taiho Pharmaceutical, Takeda, Yakult Honsha outside of the submitted work. AO reports grants and non-financial support from the Ministry of Health, Labor, and Welfare, Japan and grants and non-financial support from Japan AMED, during the study. HI reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. TT reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. HI reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as personal fees from Yakult Honsha, Taiho Pharmaceutical, Eli Lilly Japan, Teijin Pharma, Ono Pharmaceutical, Chugai Pharmaceutical, Novartis, and Incyte Biosciences Japan outside the submitted work. JM reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. HK reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. TK reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. TO reports non-financial support from the Ministry of Health, Labor, and Welfare, Japan and non-financial support from Japan AMED, during the study as well as grants from AstraZeneca, Bristol Myers Squibb, MSD KK, Eisai, Syneos, Ep-CRSU, and Incyte, and personal fees from AstraZeneca, MSD KK, Incyte, Eisai, Taiho Pharmaceutical, Eli Lilly Japan KK, Yakult Honsha, Ono Pharmaceutical, Pfizer Japan Inc, Daiichi Sankyo, Nihon Servier, Nippon Shinyaku, Chugai Pharmaceutical, Meiji Seika Pharma, Elmedix, and Johnson & Johnson KK outside the submitted work. MI reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as grants from Chugai Pharmaceutical, Yakult Honsha, Nihon Servier, Chiome Bioscience, Bayer, Ono Pharmaceutical, Bristol Myers Squibb, Eisai, Merck Serono, Delta-Fly Pharma, MSD, J-Pharma, Pfizer, ASLAN Pharmaceuticals, Eli Lilly Japan, Takeda, AstraZeneca, and Merus N.V, and personal fees from Chugai Pharmaceutical, Yakult Honsha, Nihon Servier, Bristol Myers Squibb, Taiho Pharmaceutical, Bayer, Eisai, MSD, Astellas, Sumitomo Dainippon, Otsuka Pharmaceutical, GlaxoSmithKline, Eli Lilly Japan, Takeda, AstraZeneca, AbbVie, and Abbott Japan outside the submitted work. NS reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Shionogi, and Teijin Pharma and personal fees from Taiho Pharmaceutical, Eisai Chugai Pharmaceutical, Takeda Pharmaceutical. HM reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. EM reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. NO reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as personal fees from Taiho Pharmaceutical, Eli Lilly Japan, Kyowa Hakko Kirin, Eisai, Bayer Yakuhin, Chugai Pharmaceutical, Takeda, GlaxoSmithKline, and Ono Pharmaceutical outside of the submitted work. NM reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as grants from Yakult Honsha, AstraZeneca, Novartis, ASLAN Pharmaceuticals, Incyte, Ono Pharmaceutical, Seagen, MSD, Taiho Pharmaceutical, NanoCarrier, Eisai, and Dainippon Sumitomo Pharma and personal fees from Yakult Honsha, AstraZeneca, Novartis, FUJIFILM Toyama Chemical, and MSD outside the submitted work. TY reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. YK reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as grants from Taiho Pharmaceutical Co., Ltd. Chugai Pharmaceutical CO., LTD. Nippon Kayaku Co. Ltd., ONO P Pharmaceutical CO., LTD., Nippon Zoki Pharmaceutical Co., Ltd., Shionogi & CO., LTD., EPS Holdings, Inc., IQVIA Services Japan K.K., Astellas Pharma Inc., Eisai Co., Ltd., MSD, Yakult Honsha Co., Ltd., and Daiichi Sankyo COMPANY, LIMITED and personal fees from ONO Pharmaceutical CO., LTD., Chugai Pharmaceutical CO., LTD., TAIHO Pharmaceutical Co., Ltd., and Daiichi Sankyo COMPANY, LIMITED. AT reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. KK reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. MF reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as grants from Astellas, Merck biopharma, Incyte Biosciences Japan, MSD, Eisai, Ono, J-Pharma, Yakult, and Taiho and personal fees from MSD, Yakult, Ono, NIHON SERVIER, Daiichi-sankyo, and Taiho outside the submitted work. NF reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. AK reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. YT reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. HT reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. HF reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study. MU reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study as well as grants from Taiho Pharmaceutical, AstraZeneca, Merck Biopharma, MSD, Astellas Pharma, Eisai, Ono Pharmaceutical, Incyte, Chugai Pharmaceutical, Delta-Fly Pharma, and Daiichi Sankyo and personal fees from Taiho Pharmaceutical, AstraZeneca, Merck Biopharma, MSD, Nihon Servier, Eisai, Ono Pharmaceutical, Incyte, and Chugai Pharmaceutical outside the submitted work. JF reports grants from the Ministry of Health, Labor, and Welfare, Japan and grants from Japan AMED, during the study, as well as grants from Ono Pharmaceutical, MSD, Merck Biopharma, J-Pharma, Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Yakult Honsha, Eisai, Daiichi Sankyo, Mochida Pharmaceutical, Sanofi, Sumitomo Dainippon, Bayer, Astellas, and Incyte Japan and personal fees from Fujifilm, Mudi Pharma, OncoTherapy Science, Merck Biopharma, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Chugai Pharmaceutical, Astellas, AstraZeneca, Takara Bio, Delta-Fly Pharma, Incyte Japan, Bayer, Eisai, Eli Lilly Japan, Yakult Honsha, Novartis, Pfizer, Takeda Pharmaceutical, Sanofi, Mylan EPD, EA Pharma, Kyowa Hakko Kirin, Daiichi Sankyo, Teijin Pharma, and Servier outside the submitted work.

      CRediT author statement

      Masato Ozaka: Conceptualisation, Methodology, Formal analysis, Investigation, Resources, Writing - Original Draft. Kohei Nakachi: Investigation, Resources, Writing - Review & Editing. Satoshi Kobayashi: Investigation, Resources, Writing - Review & Editing. Akihiro Ohba: Investigation, Resources, Writing - Review & Editing. Hiroshi Imaoka: Investigation, Resources, Writing - Review & Editing. Takeshi Terashima: Investigation, Resources, Writing - Review & Editing. Hiroshi Ishii: Investigation, Resources, Writing - Review & Editing. Junki Mizusawa: Methodology, Formal analysis, Data Curation, Writing - Review & Editing. Hiroshi Katayama: Methodology, Formal analysis, Data Curation, Writing - Review & Editing. Tomoko Kataoka: Methodology, Formal analysis, Data Curation, Writing - Review & Editing. Takuji Okusaka: Investigation, Resources, Writing - Review & Editing. Masafumi Ikeda: Investigation, Resources, Writing - Review & Editing. Naoki Sasahira: Investigation, Resources, Writing - Review & Editing. Haruo Miwa: Investigation, Resources, Writing - Review & Editing. Eishiro Mizukoshi: Investigation, Resources, Writing - Review & Editing. Naohiro Okano: Investigation, Resources, Writing - Review & Editing. Nobumasa Mizuno: Investigation, Resources, Writing - Review & Editing. Tomohisa Yamamoto: Investigation, Resources, Writing - Review & Editing. Yoshito Komatsu: Investigation, Resources, Writing - Review & Editing. Akiko Todaka: Investigation, Resources, Writing - Review & Editing. Ken Kamata: Investigation, Resources, Writing - Review & Editing. Masayuki Furukawa: Investigation, Resources, Writing - Review & Editing. Nao Fujimori: Investigation, Resources, Writing - Review & Editing. Akio Katanuma: Investigation, Resources, Writing - Review & Editing. Yukiko Takayama: Investigation, Resources, Writing - Review & Editing. Hidetaka Tsumura: Investigation, Resources, Writing - Review & Editing. Haruhiko Fukuda: Methodology, Formal analysis, Data Curation, Writing - Review & Editing. Makoto Ueno: Conceptualisation, Methodology, Formal analysis, Investigation, Resources, Writing - Review & Editing. Junji Furuse: Conceptualisation, Methodology, Formal analysis, Investigation, Resources, Writing - Review & Editing, Project.

      Acknowledgements

      The authors sincerely appreciate the participation of the patients and their families. The authors are grateful to the members of the Japan Clinical Oncology Group Data Center and Operations Office for their support in preparing the manuscript and for the support in data management.

      Appendix A. Supplementary data

      The following are the supplementary data to this article.

      References

        • Kamisawa T.
        • Wood L.D.
        • Itoi T.
        • Takaori K.
        Pancreatic cancer.
        Lancet. 2016; 388: 73-85https://doi.org/10.1016/S0140-6736(16)00141-0
        • Vincent A.
        • Herman J.
        • Schulick R.
        • Hruban R.H.
        • Goggins M.
        Pancreatic cancer.
        Lancet. 2011; 378: 607-620https://doi.org/10.1016/S0140-6736(10)62307-0
      1. NCCN clinical practice guideline in Oncology (NCCN Guidelines®) Pancreatic adenocarcinoma version. 1.2022;2022. NCCN.org, 2022
        • Okusaka T.
        • Nakamura M.
        • Yoshida M.
        • et al.
        Clinical practice guidelines for pancreatic cancer 2019 from the Japan Pancreas Society: a Synopsis.
        Pancreas. 2020; 49: 326-335https://doi.org/10.1097/MPA.0000000000001513
        • Ishii H.
        • Furuse J.
        • Boku N.
        • et al.
        Phase II study of gemcitabine chemotherapy alone for locally advanced pancreatic carcinoma: JCOG0506.
        Jpn J Clin Oncol. 2010; 40: 573-579https://doi.org/10.1093/jjco/hyq011
        • Ueno H.
        • Ioka T.
        • Ikeda M.
        • et al.
        Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study.
        J Clin Oncol. 2013; 31: 1640-1648https://doi.org/10.1200/JCO.2012.43.3680
        • Conroy T.
        • Desseigne F.
        • Ychou M.
        • et al.
        FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
        N Engl J Med. 2011; 364: 1817-1825https://doi.org/10.1056/NEJMoa1011923
        • Von Hoff D.D.
        • Ervin T.
        • Arena F.P.
        • et al.
        Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
        N Engl J Med. 2013; 369: 1691-1703https://doi.org/10.1056/NEJMoa1304369
        • Suker M.
        • Beumer B.R.
        • Sadot E.
        • et al.
        FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis.
        Lancet Oncol. 2016; 17: 801-810https://doi.org/10.1016/S1470-2045(16)00172-8
        • Philip P.A.
        • Lacy J.
        • Portales F.
        • et al.
        Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study.
        Lancet Gastroenterol Hepatol. 2020; 5: 285-294https://doi.org/10.1016/S2468-1253(19)30327-9
        • Okusaka T.
        • Ikeda M.
        • Fukutomi A.
        • et al.
        Phase II study of FOLFIRINOX for chemotherapy-naive Japanese patients with metastatic pancreatic cancer.
        Cancer Sci. 2014; 105: 1321-1326https://doi.org/10.1111/cas.12501
        • Ozaka M.
        • Ishii H.
        • Sato T.
        • et al.
        A phase II study of modified FOLFIRINOX for chemotherapy-naive patients with metastatic pancreatic cancer.
        Cancer Chemother Pharmacol. 2018; 81: 1017-1023https://doi.org/10.1007/s00280-018-3577-9
        • Ishii H.
        • Okada S.
        • Sato T.
        • et al.
        CA 19-9 in evaluating the response to chemotherapy in advanced pancreatic cancer.
        Hepato-Gastroenterology. 1997; 44: 279-283
        • Simon R.
        • Wittes R.E.
        • Ellenberg S.S.
        Randomized phase II clinical trials.
        Cancer Treat Rep. 1985; 69: 1375-1381
        • Sohal D.P.S.
        • Duong M.
        • Ahmad S.A.
        • et al.
        Efficacy of perioperative chemotherapy for resectable pancreatic adenocarcinoma: a Phase 2 randomized clinical trial.
        JAMA Oncol. 2021 March 1; 7: 421-427https://doi.org/10.1001/jamaoncol.2020.7328
        • Ducreux M.P.
        • Desgrippes R.
        • Rinaldi Y.
        • et al.
        1296MO PRODIGE 29-UCGI 26(NEOPAN): a phase III randomised trial comparing chemotherapy with folfirinox or gemcitabine in locally advanced pancreatic carcinoma (LAPC).
        Ann Oncol. 2022; 33: S592-S598https://doi.org/10.1016/annonc/annonc1067
        • Kunzmann V.
        • Siveke J.T.
        • Algül H.
        • et al.
        Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial.
        Lancet Gastroenterol Hepatol. 2021; 6: 128-138https://doi.org/10.1016/S2468-1253(20)30330-7
        • Mukherjee Somnath
        • Hurt Christopher N.
        • Bridgewater John
        • et al.
        Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial.
        Lancet Oncol. 2013; 14: 317-326https://doi.org/10.1016/S1470-2045(13)70021-4
        • Pascal Hammel
        • Huguet Florence
        • Jean-Luc van Laethem
        • et al.
        Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 Months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial.
        JAMA. 2016; 315: 1844-1853https://doi.org/10.1001/jama.2016.4324
        • Fietkau Rainer
        • Ghadimi Michael
        • Grützmann Robert
        • et al.
        Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: first results of the CONKO-007 trial.
        J Clin Oncol. 2022; 40: 4008https://doi.org/10.1200/JCO.2022.40.16_suppl.4008
        • Golan T.
        • Kanji Z.S.
        • Epelbaum R.
        • et al.
        Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.
        Br J Cancer. 2014; 111: 1132-1138https://doi.org/10.1038/bjc.2014.418
        • Smith A.L.
        • Wong C.
        • Cuggia A.
        • et al.
        Reflex testing for germline BRCA1, BRCA2, PALB2, and ATM mutations in pancreatic cancer: mutation prevalence and clinical outcomes from two Canadian research registries.
        JCO Precis Oncol. 2018; 2: 1-16https://doi.org/10.1200/PO.17.00098
        • Singhi A.D.
        • George B.
        • Greenbowe J.R.
        • et al.
        Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers.
        Gastroenterology. 2019; 156: 2242-2253.e4https://doi.org/10.1053/j.gastro.2019.02.037