岸和田昌之、伊佐地秀司：3-3 診断 膵癌の病期分類（膵癌取扱い規約第7版）. 藤井努、川井学編. 新世代の膵癌診療・治療バイブル. MCメディカ出版, 2017; 93-101.
日本膵臓学会編：膵癌取扱い規約 第7版、金原出版、2016.
James D Brierley, Mary K Gospodarowicz, Christian Wittekind編、UICC日本委員会TNM委員会訳：TNM悪性腫瘍の分類 第8版 日本語版、金原出版、2017.
Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H.
Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.
JAMA. 2007 Jan 17;297(3):267-77. doi: 10.1001/jama.297.3.267.
Abstract/Text
CONTEXT: The role of adjuvant therapy in resectable pancreatic cancer is still uncertain, and no recommended standard exists.
OBJECTIVE: To test the hypothesis that adjuvant chemotherapy with gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more.
DESIGN, SETTING, AND PATIENTS: Open, multicenter, randomized controlled phase 3 trial with stratification for resection, tumor, and node status. Conducted from July 1998 to December 2004 in the outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled into 2 groups.
INTERVENTION: Patients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1, 8, and 15 every 4 weeks (n = 179), or observation ([control] n = 175).
MAIN OUTCOME MEASURES: Primary end point was disease-free survival, and secondary end points were overall survival, toxicity, and quality of life. Survival analysis was based on all eligible patients (intention-to-treat).
RESULTS: More than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (95% confidence interval, 6.1-7.8; P<.001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, 17-23.4; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank).
CONCLUSIONS: Postoperative gemcitabine significantly delayed the development of recurrent disease after complete resection of pancreatic cancer compared with observation alone. These results support the use of gemcitabine as adjuvant chemotherapy in resectable carcinoma of the pancreas.
TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN34802808.
Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S, Doi R, Monden M, Hatori T, Tanaka M, Shimada M, Kanemitsu K.
A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer.
Br J Cancer. 2009 Sep 15;101(6):908-15. doi: 10.1038/sj.bjc.6605256. Epub 2009 Aug 18.
Abstract/Text
BACKGROUND: This multicentre randomised phase III trial was designed to determine whether adjuvant chemotherapy with gemcitabine improves the outcomes of patients with resected pancreatic cancer.
METHODS: Eligibility criteria included macroscopically curative resection of invasive ductal carcinoma of the pancreas and no earlier radiation or chemotherapy. Patients were randomly assigned at a 1 : 1 ratio to either the gemcitabine group or the surgery-only group. Patients assigned to the gemcitabine group received gemcitabine at a dose of 1000 mg m(-2) over 30 min on days 1, 8 and 15, every 4 weeks for 3 cycles.
RESULTS: Between April 2002 and March 2005, 119 patients were enrolled in this study. Among them, 118 were eligible and analysable (58 in the gemcitabine group and 60 in the surgery-only group). Both groups were well balanced in terms of baseline characteristics. Although heamatological toxicity was frequently observed in the gemcitabine group, most toxicities were transient, and grade 3 or 4 non-heamatological toxicity was rare. Patients in the gemcitabine group showed significantly longer disease-free survival (DFS) than those in the surgery-only group (median DFS, 11.4 versus 5.0 months; hazard ratio=0.60 (95% confidence interval (CI): 0.40-0.89); P=0.01), although overall survival did not differ significantly between the gemcitabine and surgery-only groups (median overall survival, 22.3 versus 18.4 months; hazard ratio=0.77 (95% CI: 0.51-1.14); P=0.19).
CONCLUSION: The current results suggest that adjuvant gemcitabine contributes to prolonged DFS in patients undergoing macroscopically curative resection of pancreatic cancer.
O'Reilly EM.
Adjuvant therapy for pancreas adenocarcinoma: where are we going?
Expert Rev Anticancer Ther. 2011 Feb;11(2):173-7. doi: 10.1586/era.10.232.
Abstract/Text
Evaluation of: Neoptolemos JP, Stocken DD, Bassi C et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs. gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304(10), 1073-1081 (2010). Over the last decade, adjuvant therapy in the treatment of resected pancreas adenocarcinoma has had its value established. Such treatment incrementally increases 5-year survivorship and delays time to tumor recurrence. The backbone of adjuvant therapy is the single-agent gemcitabine, based primarily on results from the Charité Onkologie Clinical (CONKO)-001 study. Based on the combined results of the European Study Group for Pancreas Cancer (ESPAC)-1 and ESPAC-3 trials, Neoptolemos and colleagues have established both bolus 5-fluorouracil and leucovorin and gemcitabine as standard options for resected pancreatic cancer. Gemcitabine remains the main standard therapy based on its ease of administration and a more favorable toxicity profile; however, there is now a clearly validated alternate option of 5-fluororuacil and leucovorin based on the results of ESPAC-3. Moving forward, the integration of novel cytotoxic and targeted agents into adjuvant therapy, along with refining the role of neoadjuvant therapy for patients with resectable pancreas cancer, will hopefully accrue a more substantial improvement in outcome for patients with resected pancreas adenocarcinoma.
Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group.
Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01).
Lancet. 2016 Jul 16;388(10041):248-57. doi: 10.1016/S0140-6736(16)30583-9. Epub 2016 Jun 2.
Abstract/Text
BACKGROUND: Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival.
METHODS: We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I-III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m(2), intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0.87 with a non-inferiority margin of 1.25 (power 80%; one-sided type I error 2.5%). This trial is registered at UMIN CTR (UMIN000000655).
FINDINGS: 385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0.57 (95% CI 0.44-0.72, pnon-inferiority<0.0001, p<0.0001 for superiority), associated with 5-year overall survival of 24.4% (18.6-30.8) in the gemcitabine group and 44.1% (36.9-51.1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group.
INTERPRETATION: Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients.
FUNDING: Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Ishii H, Furuse J, Boku N, Okusaka T, Ikeda M, Ohkawa S, Fukutomi A, Hamamoto Y, Nakamura K, Fukuda H; JCOG Gastrointestinal Oncology Study Group.
Phase II study of gemcitabine chemotherapy alone for locally advanced pancreatic carcinoma: JCOG0506.
Jpn J Clin Oncol. 2010 Jun;40(6):573-9. doi: 10.1093/jjco/hyq011. Epub 2010 Feb 25.
Abstract/Text
OBJECTIVE: Chemoradiotherapy with 5-fluorouracil has been accepted as a standard care for locally advanced pancreatic cancer; however, it has not been shown to be superior to chemotherapy alone in the gemcitabine era. The present multicentre phase II study was conducted to evaluate the efficacy and safety of Gem monotherapy against locally advanced pancreatic cancer in comparison with the historical data of chemoradiotherapy with 5-fluorouracil.
METHODS: Eligibility criteria included patients with histologically proven locally advanced pancreatic cancer, all lesions encompassed by a square of 15 cm on one side, no prior treatment, good performance status and adequate organ function. Gemcitabine was given intravenously at a dose of 1000 mg/m(2) over 30 min on days 1, 8 and 15, repeated every 4 weeks. The primary endpoint was %1-year survival. Expected and threshold %1-year survival were 40 and 25%, respectively.
RESULTS: Between January 2006 and February 2007, 50 locally advanced pancreatic cancer patients were registered. The major grade 3-4 adverse events were neutropaenia (62%), thrombocytopaenia (18%), fatigue (12%) and infection-biliary tree (12%). Haematological toxicity was mostly transient and there was no episode of infection with grade 3-4 neutropaenia. Up to the final follow-up in February 2009, the median overall survival was 15.0 months with a %1-year survival of 64.0%.
CONCLUSIONS: Gemcitabine monotherapy demonstrated far better survival than historical data for chemoradiotherapy with 5-fluorouracil with mild toxicities. Gemcitabine could be consider as a standard treatment for locally advanced pancreatic cancer.
Ikeda M, Ioka T, Ito Y, Yonemoto N, Nagase M, Yamao K, Miyakawa H, Ishii H, Furuse J, Sato K, Sato T, Okusaka T.
A multicenter phase II trial of S-1 with concurrent radiation therapy for locally advanced pancreatic cancer.
Int J Radiat Oncol Biol Phys. 2013 Jan 1;85(1):163-9. doi: 10.1016/j.ijrobp.2012.03.059. Epub 2012 Jun 5.
Abstract/Text
PURPOSE: The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiation therapy for locally advanced pancreatic cancer (PC).
METHODS AND MATERIALS: Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma or adenosquamous carcinoma, who had no previous therapy were enrolled. Radiation therapy was delivered through 3 or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. S-1 was administered orally at a dose of 80 mg/m2 twice daily on the day of irradiation during radiation therapy. After a 2- to 8-week break, patients received a maintenance dose of S-1 (80 mg/m2/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of disease progression or unacceptable toxicity. The primary efficacy endpoint was survival, and the secondary efficacy endpoints were progression-free survival, response rate, and serum carbohydrate antigen 19-9 (CA19-9) response; the safety endpoint was toxicity.
RESULTS: Of the 60 evaluable patients, 16 patients achieved a partial response (27%; 95% confidence interval [CI], 16%-40%). The median progression-free survival period, overall survival period, and 1-year survival rate of the evaluable patients were 9.7 months (95% CI, 6.9-11.6 months), 16.2 months (95% CI, 13.5-21.3 months), and 72% (95%CI, 59%-82%), respectively. Of the 42 patients with a pretreatment serum CA19-9 level of ≥100 U/ml, 34 (81%) patients showed a decrease of greater than 50%. Leukopenia (6 patients, 10%) and anorexia (4 patients, 7%) were the major grade 3-4 toxicities with chemoradiation therapy.
CONCLUSIONS: The effect of S-1 with concurrent radiation therapy in patients with locally advanced PC was found to be very favorable, with only mild toxicity.
Copyright © 2013 Elsevier Inc. All rights reserved.
Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD.
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.
J Clin Oncol. 1997 Jun;15(6):2403-13. doi: 10.1200/JCO.1997.15.6.2403.
Abstract/Text
PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer.
PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival.
RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated.
CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group.
Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.
J Clin Oncol. 2007 May 20;25(15):1960-6. doi: 10.1200/JCO.2006.07.9525. Epub 2007 Apr 23.
Abstract/Text
PURPOSE: Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.
PATIENTS AND METHODS: Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival.
RESULTS: A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; P = .038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; P = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2.
CONCLUSION: To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.
Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, Fukutomi A, Sugimori K, Baba H, Yamao K, Shimamura T, Sho M, Kitano M, Cheng AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A, Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi Y, Okusaka T, Tanaka M.
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 May 1;31(13):1640-8. doi: 10.1200/JCO.2012.43.3680. Epub 2013 Apr 1.
Abstract/Text
PURPOSE: The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival.
PATIENTS AND METHODS: The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle).
RESULTS: In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group.
CONCLUSION: Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup.
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
N Engl J Med. 2011 May 12;364(19):1817-25. doi: 10.1056/NEJMoa1011923.
Abstract/Text
BACKGROUND: Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer.
METHODS: We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival.
RESULTS: The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001).
CONCLUSIONS: As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF.
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
N Engl J Med. 2013 Oct 31;369(18):1691-703. doi: 10.1056/NEJMoa1304369. Epub 2013 Oct 16.
Abstract/Text
BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer.
METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate.
RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days.
CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).
日本膵臓学会 膵癌診療ガイドライン改訂委員会編：膵癌診療ガイドライン2022年版 第6版.金原出版.2022.
Ozaka M, Nakachi K, Kobayashi S, Ohba A, Imaoka H, Terashima T, Ishii H, Mizusawa J, Katayama H, Kataoka T, Okusaka T, Ikeda M, Sasahira N, Miwa H, Mizukoshi E, Okano N, Mizuno N, Yamamoto T, Komatsu Y, Todaka A, Kamata K, Furukawa M, Fujimori N, Katanuma A, Takayama Y, Tsumura H, Fukuda H, Ueno M, Furuse J; Hepatobiliary and Pancreatic Oncology Group of Japan Clinical Oncology Group (JCOG).
A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407).
Eur J Cancer. 2023 Mar;181:135-144. doi: 10.1016/j.ejca.2022.12.014. Epub 2022 Dec 27.
Abstract/Text
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.
Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Choné L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Breysacher G, Di Fiore F, Cripps C, Kavan P, Texereau P, Bouhier-Leporrier K, Khemissa-Akouz F, Legoux JL, Juzyna B, Gourgou S, O'Callaghan CJ, Jouffroy-Zeller C, Rat P, Malka D, Castan F, Bachet JB; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group.
FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer.
N Engl J Med. 2018 Dec 20;379(25):2395-2406. doi: 10.1056/NEJMoa1809775.
Abstract/Text
BACKGROUND: Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer.
METHODS: We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety.
RESULTS: At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis).
CONCLUSIONS: Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).
Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer.
Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.
Lancet. 2017 Mar 11;389(10073):1011-1024. doi: 10.1016/S0140-6736(16)32409-6. Epub 2017 Jan 25.
Abstract/Text
BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer.
METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434.
FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group.
INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.
FUNDING: Cancer Research UK.
Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.
Satoi Satoi S, Unno M, Motoi F, et al: The effect of neoadjuvant chemotherapy with gemcitabine and S-1 for resectable pancreatic cancer (randomized phase II/III trial; Prep-02/JSAP-05). ASCO2019 abstr 4126.
Chauffert B, Mornex F, Bonnetain F, Rougier P, Mariette C, Bouché O, Bosset JF, Aparicio T, Mineur L, Azzedine A, Hammel P, Butel J, Stremsdoerfer N, Maingon P, Bedenne L.
Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study.
Ann Oncol. 2008 Sep;19(9):1592-9. doi: 10.1093/annonc/mdn281. Epub 2008 May 7.
Abstract/Text
BACKGROUND: The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC) is uncertain.
PATIENTS AND METHODS: One hundred and nineteen patients with LAPC, World Health Organization performance status of zero to two were randomly assigned to either the induction CHRT group (60 Gy, 2 Gy/fraction; concomitant 5-fluorouracil infusion, 300 mg/m(2)/day, days 1-5 for 6 weeks; cisplatin, 20 mg/m(2)/day, days 1-5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m(2) weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m(2) weekly, 3/4 weeks) was given in both arms until disease progression or toxicity.
RESULTS: Overall survival was shorter in the CHRT than in GEM arm [median survival 8.6 (99% confidence interval 7.1-11.4) and 13 months (8.7-18.1), P = 0.03]. One-year survival was, respectively, 32% and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3-4 toxic effects were recorded in the CHRT arm, both during induction (36 versus 22%) and maintenance (32 versus 18%).
CONCLUSION: This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone.
Loehrer PJ, Powell ME, Cardenes HR, Wagner L, Brell JM, Ramanathan RK, Crane CH, Alberts SR, Benson AB. A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201. J Clin Oncol [Internet]. American Society of Clinical Oncology; 2008 May 20 [cited 2019 Aug 7];26(15_suppl):4506–4506. Available from: http://ascopubs.org/doi/10.1200/jco.2008.26.15_suppl.4506
Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group.
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 May 3;315(17):1844-53. doi: 10.1001/jama.2016.4324.
Abstract/Text
IMPORTANCE: In locally advanced pancreatic cancer, the role of chemoradiotherapy is controversial and the efficacy of erlotinib is unknown.
OBJECTIVES: To assess whether chemoradiotherapy improves overall survival of patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine-based induction chemotherapy and to assess the effect of erlotinib on survival.
DESIGN, SETTING, AND PARTICIPANTS: In LAP07, an international, open-label, phase 3 randomized trial, 449 patients were enrolled between 2008 and 2011. Follow-up ended in February 2013.
INTERVENTIONS: In the first randomization, 223 patients received 1000 mg/m2 weekly of gemcitabine alone and 219 patients received 1000 mg/m2 of gemcitabine plus 100 mg/d of erlotinib. In the second randomization involving patients with progression-free disease after 4 months, 136 patients received 2 months of the same chemotherapy and 133 underwent chemoradiotherapy (54 Gy plus capecitabine).
MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival from the date of the first randomization. Secondary outcomes were the effect of erlotinib and quality assurance of radiotherapy on overall survival, progression-free survival of gemcitabine-erlotinib and erlotinib maintenance with gemcitabine alone at the second randomization, and toxic effects.
RESULTS: A total of 442 of the 449 patients (232 men; median age, 63.3 years) enrolled underwent the first randomization. Of these, 269 underwent the second randomization. Interim analysis was performed when 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group), reaching the early stopping boundaries for futility. With a median follow-up of 36.7 months, the median overall survival from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5-18.5 months) and chemoradiotherapy at 15.2 months (95% CI, 13.9-17.3 months; hazard ratio [HR], 1.03; 95% CI, 0.79-1.34; P = .83). Median overall survival from the date of the first randomization for the 223 patients receiving gemcitabine was 13.6 months (95% CI, 12.3-15.3 months) and was 11.9 months (95% CI, 10.4-13.5 months) for the 219 patients receiving gemcitabine plus erlotinib (HR, 1.19; 95% CI, 0.97-1.45; P = .09; 188 deaths vs 191 deaths). Chemoradiotherapy was associated with decreased local progression (32% vs 46%, P = .03) and no increase in grade 3 to 4 toxicity, except for nausea.
CONCLUSIONS AND RELEVANCE: In this open-label, randomized trial involving patients with locally advanced pancreatic cancer with disease controlled after 4 months of induction chemotherapy, there was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00634725.
Ioka T, Fukutomi A, Mizusawa J, Katayama H, Nakamura S, Ito Y, Hiraoka N, Ueno M, Ikeda M, Sugimori K, Shimizu K, Okusaka T, Ozaka M, Yanagimoto H, Nakamori S, Azuma T, Hosokawa A, Sata N, Mine T, Furuse J. Randomized phase II study of S-1 and concurrent radiotherapy with versus without induction chemotherapy of gemcitabine for locally advanced pancreatic cancer (LAPC): Final analysis of JCOG1106. Ann Oncol [Internet]. Narnia; 2016 Oct 1 [cited 2019 Aug 7];27(suppl_6). Available from: http://academic.oup.com/annonc/article/doi/10.1093/annonc/mdw371.13/2799368/Randomized-phase-II-study-of-S1-and-concurrent
Okusaka T, Ikeda M, Fukutomi A, Ioka T, Furuse J, Ohkawa S, Isayama H, Boku N.
Phase II study of FOLFIRINOX for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.
Cancer Sci. 2014 Oct;105(10):1321-6. doi: 10.1111/cas.12501. Epub 2014 Sep 29.
Abstract/Text
The FOLFIRINOX combination of chemotherapy drugs had not been fully evaluated for Japanese pancreatic cancer patients. Therefore, we carried out a phase II study to examine the efficacy and safety of FOLFIRINOX in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer. FOLFIRINOX (i.v. infusion of 85 mg/m(2) oxaliplatin, 180 mg/m(2) irinotecan, and 200 mg/m(2) l-leucovorin, followed by a bolus of 400 mg/m(2) fluorouracil and a 46-h continuous infusion of 2400 mg/m(2) fluorouracil) was given every 2 weeks. The primary endpoint was the response rate. The 36 enrolled patients received a median of eight (range, 1-25) treatment cycles. The response rate was 38.9% (95% confidence interval [CI], 23.1-56.5); median overall survival, 10.7 months (95% CI, 6.9-13.2); and median progression-free survival, 5.6 months (95% CI, 3.0-7.8). Major grade 3 or 4 toxicities included neutropenia (77.8%), febrile neutropenia (22.2%), thrombocytopenia (11.1%), anemia (11.1%), anorexia (11.1%), diarrhea (8.3%), nausea (8.3%), elevated alanine aminotransferase levels (8.3%), and peripheral sensory neuropathy (5.6%). Febrile neutropenia occurred only during the first cycle. There were no treatment-related deaths. FOLFIRINOX can be a standard regimen showing favorable efficacy and acceptable toxicity profile in chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
Ueno H, Ikeda M, Ueno M, Mizuno N, Ioka T, Omuro Y, Nakajima TE, Furuse J.
Phase I/II study of nab-paclitaxel plus gemcitabine for chemotherapy-naive Japanese patients with metastatic pancreatic cancer.
Cancer Chemother Pharmacol. 2016 Mar;77(3):595-603. doi: 10.1007/s00280-016-2972-3. Epub 2016 Feb 3.
Abstract/Text
PURPOSE: Efficacy and safety of nab-paclitaxel plus gemcitabine have not been clarified in Japanese patients with metastatic pancreatic cancer. No pharmacokinetic profile of co-administration of nab-paclitaxel and gemcitabine has been reported. We conducted a phase I/II study of the efficacy, safety, and pharmacokinetics in Japanese patients with metastatic pancreatic cancer.
METHODS: The patients were administered 125 mg/m(2) nab-paclitaxel followed by 1000 mg/m(2) gemcitabine on day 1, 8, and 15 every 4 weeks. Treatment was continued until disease progression, unacceptable adverse events, or withdrawal of consent, whichever occurred first. The primary endpoints were tolerability in phase I and overall response rate according to RECIST in phase II.
RESULTS: A total of 34 patients were enrolled. At the time of 1-year follow-up analysis since the last patient enrollment, the objective response rate by independent review committee was 58.8% (20 of 34 patients; 95% confidence interval [CI], 40.7-75.4%). The median progression-free survival and median overall survival were 6.5 months (95% CI, 5.1-8.3) and 13.5 months (95% CI, 10.6--not reached), respectively. Main adverse drug reactions of grade 3 or higher were neutropenia (70.6%), leukopenia (55.9%), anemia (14.7%), lymphocytopenia (14.7%), thrombocytopenia (14.7%), and peripheral sensory neuropathy (11.8%). There were no treatment-related deaths and no marked differences in pharmacokinetics of combined paclitaxel and gemcitabine in historical comparison between co-administration and monotherapies.
CONCLUSIONS: Nab-paclitaxel plus gemcitabine regimen showed highly promising efficacy with manageable safety profile under careful observation and with appropriate supportive care in Japanese patients with metastatic pancreatic cancer.
CLINICAL TRIAL NUMBER: JapicCTI-121987.
Ozaka M, Ishii H, Sato T, Ueno M, Ikeda M, Uesugi K, Sata N, Miyashita K, Mizuno N, Tsuji K, Okusaka T, Furuse J.
A phase II study of modified FOLFIRINOX for chemotherapy-naïve patients with metastatic pancreatic cancer.
Cancer Chemother Pharmacol. 2018 Jun;81(6):1017-1023. doi: 10.1007/s00280-018-3577-9. Epub 2018 Apr 9.
Abstract/Text
BACKGROUND: We evaluated the efficacy and safety of a modified FOLFIRINOX regimen for chemotherapy-naïve patients with metastatic pancreatic cancer.
METHODS: Patients with untreated metastatic pancreatic cancer (MPC) received modified FOLFIRINOX (intravenous oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, 5-FU infusion 2400 mg/m2 over 46 h, no bolus 5-FU). The primary endpoints were overall survival and the incidence of grade 3 or higher neutropenia. No patients received prophylactic pegfilgrastim.
RESULTS: Sixty-nine pts. were enrolled from 39 institutions in Japan. The median overall survival was 11.2 months [95% confidence interval (CI) 9.0-]. The median progression-free survival was 5.5 months (95% CI 4.1-6.7). The response rate was 37.7% (95% CI 26.3-50.2), and the disease control rate was 78.3% (95% CI 66.7-87.3). The incidence of grade 3 or higher neutropenia was 47.8%. Serious adverse events occurred in six patients (8.7%). All AE proportions were less than those in the previous Japanese full-dose phase II study. One patient died due to interstitial pneumonia related to treatment.
CONCLUSION: This is the first prospective study of modified FOLFIRINOX in Asia. Modified FOLFIRINOX in this study has an improved safety profile with maintained efficacy in MPC without prophylactic pegfilgrastim.
Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algül H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL.
Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.
N Engl J Med. 2019 Jul 25;381(4):317-327. doi: 10.1056/NEJMoa1903387. Epub 2019 Jun 2.
Abstract/Text
BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population.
METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review.
RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event.
CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).
Copyright © 2019 Massachusetts Medical Society.
Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H.
Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.
Eur J Cancer. 2011 Jul;47(11):1676-81. doi: 10.1016/j.ejca.2011.04.011. Epub 2011 May 10.
Abstract/Text
BACKGROUND: Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy.
METHODS: In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200mg/m(2) followed by 5-fluorouracil 2g/m(2) (24h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m(2) on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy.
RESULTS: After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively.
INTERPRETATION: Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, Bischoff S, Sinn M, Dörken B, Pelzer U.
Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial.
J Clin Oncol. 2014 Aug 10;32(23):2423-9. doi: 10.1200/JCO.2013.53.6995. Epub 2014 Jun 30.
Abstract/Text
PURPOSE: To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid-modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy.
PATIENTS AND METHODS: A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status.
RESULTS: Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001).
CONCLUSION: Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.
© 2014 by American Society of Clinical Oncology.
Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group.
Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial.
Lancet. 2016 Feb 6;387(10018):545-557. doi: 10.1016/S0140-6736(15)00986-1. Epub 2015 Nov 29.
Abstract/Text
BACKGROUND: Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population.
METHODS: We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506.
FINDINGS: Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).
INTERPRETATION: Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population.
FUNDING: Merrimack Pharmaceuticals.
Copyright © 2016 Elsevier Ltd. All rights reserved.
