今日の臨床サポート

膵癌(化学療法)

著者: 古瀬純司 杏林大学医学部腫瘍内科学

監修: 下瀬川徹 みやぎ県南中核病院企業団

著者校正/監修レビュー済:2020/06/19
参考ガイドライン:
  1. 日本膵臓学会:膵癌診療ガイドライン 2019年版

概要・推奨   

  1. 膵癌の治療選択において、切除可能であれば、まず切除手術を検討する。
  1. 膵癌切除後の術後補助療法は、S-1が第一選択の治療であり、S-1の適応が難しい場合はゲムシタビン(GEM)が用いられる。また、切除可能膵癌の術前補助療法として、GEM+S-1を2サイクル(6週間)行うことで、全生存期間の延長が確認され、新たな推奨される治療となった。
  1. 切除不能膵癌に対する化学療法は、FOLFIRINOX療法とGEM+ナブパクリタキセル併用療法が第一選択として推奨されている。これらは有効性も高いが、副作用も強く発現する懸念がある。適切な適応と副作用対策が必要である。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
古瀬純司 : 講演料(ヤクルト本社,小野薬品,エーザイ,バイエル薬品,富士フイルム,日本イーライリリー,MSD),研究費・助成金など(アステラス製薬,アストラゼネカ,EPクルーズ,MSD,小野薬品,ジェイファーマ,大鵬薬品,メルクバイオファーマ),奨学(奨励)寄付など(大鵬薬品,小野薬品)[2021年]
監修:下瀬川徹 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 2020年3月、nanoliposomal irinotecan(一般名:イリノテカン塩酸塩水和物 リポソーム製剤)が「がん化学療法後に増悪した治癒切除不能な膵がん」に適応が承認された。2020年6月に製造販売の開始が見込まれている。

病態・疫学・診察

イントロダクション  
  1. 膵癌は膵臓から発生した悪性腫瘍であり、病理組織学的には膵管上皮から発生する浸潤性膵管癌(腺癌)が90%以上を占める。その他、内分泌腺に由来する膵内分泌腫瘍や膵管上皮から発生し、膵管内発育と粘液産生を特徴とする膵管内乳頭粘液性腫瘍(IPMN)、粘液性嚢胞腫瘍、腺房から発生する腺房細胞癌などがあるが、いずれも稀な腫瘍である。がんの統計によると、わが国における膵癌の年間罹患数は2013年で34,837人、年間死亡数は2016年で33,475人と罹患数と死亡数がほぼ同数である。切除可能例は20~30%に過ぎず、切除例、非切除例を含めた5年生存率は10%未満であり、悪性腫瘍の中でも飛びぬけて予後不良の疾患である。

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文献 

著者: Helmut Oettle, Stefan Post, Peter Neuhaus, Klaus Gellert, Jan Langrehr, Karsten Ridwelski, Harald Schramm, Joerg Fahlke, Carl Zuelke, Christof Burkart, Klaus Gutberlet, Erika Kettner, Harald Schmalenberg, Karin Weigang-Koehler, Wolf-Otto Bechstein, Marco Niedergethmann, Ingo Schmidt-Wolf, Lars Roll, Bernd Doerken, Hanno Riess
雑誌名: 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.

PMID 17227978  JAMA. 2007 Jan 17;297(3):267-77. doi: 10.1001/jama.297.・・・
著者: H Ueno, T Kosuge, Y Matsuyama, J Yamamoto, A Nakao, S Egawa, R Doi, M Monden, T Hatori, M Tanaka, M Shimada, K Kanemitsu
雑誌名: 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.

PMID 19690548  Br J Cancer. 2009 Sep 15;101(6):908-15. doi: 10.1038/sj・・・
著者: Eileen M O'Reilly
雑誌名: 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.

PMID 21342036  Expert Rev Anticancer Ther. 2011 Feb;11(2):173-7. doi: ・・・
著者: Katsuhiko Uesaka, Narikazu Boku, Akira Fukutomi, Yukiyasu Okamura, Masaru Konishi, Ippei Matsumoto, Yuji Kaneoka, Yasuhiro Shimizu, Shoji Nakamori, Hirohiko Sakamoto, Soichiro Morinaga, Osamu Kainuma, Koji Imai, Naohiro Sata, Shoichi Hishinuma, Hitoshi Ojima, Ryuzo Yamaguchi, Satoshi Hirano, Takeshi Sudo, Yasuo Ohashi, JASPAC 01 Study Group
雑誌名: 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.
PMID 27265347  Lancet. 2016 Jul 16;388(10041):248-57. doi: 10.1016/S01・・・
著者: Hiroshi Ishii, Junji Furuse, Narikazu Boku, Takuji Okusaka, Masafumi Ikeda, Shinichi Ohkawa, Akira Fukutomi, Yasuo Hamamoto, Kenichi Nakamura, Haruhiko Fukuda, JCOG Gastrointestinal Oncology Study Group
雑誌名: 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.

PMID 20185458  Jpn J Clin Oncol. 2010 Jun;40(6):573-9. doi: 10.1093/jj・・・
著者: Masafumi Ikeda, Tatsuya Ioka, Yoshinori Ito, Naohiro Yonemoto, Michitaka Nagase, Kenji Yamao, Hiroyuki Miyakawa, Hiroshi Ishii, Junji Furuse, Keiko Sato, Tosiya Sato, Takuji Okusaka
雑誌名: 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.
PMID 22677367  Int J Radiat Oncol Biol Phys. 2013 Jan 1;85(1):163-9. d・・・
著者: H A Burris, M J Moore, J Andersen, M R Green, M L Rothenberg, M R Modiano, M C Cripps, R K Portenoy, A M Storniolo, P Tarassoff, R Nelson, F A Dorr, C D Stephens, D D Von Hoff
雑誌名: J Clin Oncol. 1997 Jun;15(6):2403-13.
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.

PMID 9196156  J Clin Oncol. 1997 Jun;15(6):2403-13.
著者: Malcolm J Moore, David Goldstein, John Hamm, Arie Figer, Joel R Hecht, Steven Gallinger, Heather J Au, Pawel Murawa, David Walde, Robert A Wolff, Daniel Campos, Robert Lim, Keyue Ding, Gary Clark, Theodora Voskoglou-Nomikos, Mieke Ptasynski, Wendy Parulekar, National Cancer Institute of Canada Clinical Trials Group
雑誌名: 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.

PMID 17452677  J Clin Oncol. 2007 May 20;25(15):1960-6. doi: 10.1200/J・・・
著者: Hideki Ueno, Tatsuya Ioka, Masafumi Ikeda, Shinichi Ohkawa, Hiroaki Yanagimoto, Narikazu Boku, Akira Fukutomi, Kazuya Sugimori, Hideo Baba, Kenji Yamao, Tomotaka Shimamura, Masayuki Sho, Masayuki Kitano, Ann-Lii Cheng, Kazuhiro Mizumoto, Jen-Shi Chen, Junji Furuse, Akihiro Funakoshi, Takashi Hatori, Taketo Yamaguchi, Shinichi Egawa, Atsushi Sato, Yasuo Ohashi, Takuji Okusaka, Masao Tanaka
雑誌名: 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.

PMID 23547081  J Clin Oncol. 2013 May 1;31(13):1640-8. doi: 10.1200/JC・・・
著者: Thierry Conroy, Françoise Desseigne, Marc Ychou, Olivier Bouché, Rosine Guimbaud, Yves Bécouarn, Antoine Adenis, Jean-Luc Raoul, Sophie Gourgou-Bourgade, Christelle de la Fouchardière, Jaafar Bennouna, Jean-Baptiste Bachet, Faiza Khemissa-Akouz, Denis Péré-Vergé, Catherine Delbaldo, Eric Assenat, Bruno Chauffert, Pierre Michel, Christine Montoto-Grillot, Michel Ducreux, Groupe Tumeurs Digestives of Unicancer, PRODIGE Intergroup
雑誌名: 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.).

PMID 21561347  N Engl J Med. 2011 May 12;364(19):1817-25. doi: 10.1056・・・
著者: Daniel D Von Hoff, Thomas Ervin, Francis P Arena, E Gabriela Chiorean, Jeffrey Infante, Malcolm Moore, Thomas Seay, Sergei A Tjulandin, Wen Wee Ma, Mansoor N Saleh, Marion Harris, Michele Reni, Scot Dowden, Daniel Laheru, Nathan Bahary, Ramesh K Ramanathan, Josep Tabernero, Manuel Hidalgo, David Goldstein, Eric Van Cutsem, Xinyu Wei, Jose Iglesias, Markus F Renschler
雑誌名: 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.).

PMID 24131140  N Engl J Med. 2013 Oct 31;369(18):1691-703. doi: 10.105・・・
著者: John P Neoptolemos, Deborah D Stocken, Helmut Friess, Claudio Bassi, Janet A Dunn, Helen Hickey, Hans Beger, Laureano Fernandez-Cruz, Christos Dervenis, François Lacaine, Massimo Falconi, Paolo Pederzoli, Akos Pap, David Spooner, David J Kerr, Markus W Büchler, European Study Group for Pancreatic Cancer
雑誌名: N Engl J Med. 2004 Mar 18;350(12):1200-10. doi: 10.1056/NEJMoa032295.
Abstract/Text BACKGROUND: The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results.
METHODS: In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation.
RESULTS: The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors.
CONCLUSIONS: Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.

Copyright 2004 Massachusetts Medical Society
PMID 15028824  N Engl J Med. 2004 Mar 18;350(12):1200-10. doi: 10.1056・・・
著者: B Chauffert, F Mornex, F Bonnetain, P Rougier, C Mariette, O Bouché, J F Bosset, T Aparicio, L Mineur, A Azzedine, P Hammel, J Butel, N Stremsdoerfer, P Maingon, L Bedenne
雑誌名: 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.

PMID 18467316  Ann Oncol. 2008 Sep;19(9):1592-9. doi: 10.1093/annonc/m・・・
著者: Pascal Hammel, Florence Huguet, Jean-Luc van Laethem, David Goldstein, Bengt Glimelius, Pascal Artru, Ivan Borbath, Olivier Bouché, Jenny Shannon, Thierry André, Laurent Mineur, Benoist Chibaudel, Franck Bonnetain, Christophe Louvet, LAP07 Trial Group
雑誌名: 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.

PMID 27139057  JAMA. 2016 May 3;315(17):1844-53. doi: 10.1001/jama.201・・・
著者: C G Moertel, S Frytak, R G Hahn, M J O'Connell, R J Reitemeier, J Rubin, A J Schutt, L H Weiland, D S Childs, M A Holbrook, P T Lavin, E Livstone, H Spiro, A Knowlton, M Kalser, J Barkin, H Lessner, R Mann-Kaplan, K Ramming, H O Douglas, P Thomas, H Nave, J Bateman, J Lokich, J Brooks, J Chaffey, J M Corson, N Zamcheck, J W Novak
雑誌名: Cancer. 1981 Oct 15;48(8):1705-10.
Abstract/Text One-hundred-ninety-four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with high-dose (6000 rads) radiation therapy alone, to moderate-dose (4000 rads) radiation + 5-fluorouracil (5-FU), and to high-dose radiation plus 5-FU. Median survival with radiation alone was only 51/2 months from date of diagnosis. Both 5-FU-containing treatment regimens produced a highly significant survival improvement when compared with radiation alone. Forty percent of patients treated with the combined regimens were still living at one year compared with 10% of patients treated with radiation only. Survival differences between 4000 rads plus 5-FU and 6000 rads plus 5-FU were not significant with an overall median survival of ten months. Significant prognostic variables, in addition to treatment, were pretreatment performance status and pretreatment CEA level.

PMID 7284971  Cancer. 1981 Oct 15;48(8):1705-10.
著者: H Ishii, S Okada, K Tokuuye, H Nose, T Okusaka, M Yoshimori, H Nagahama, M Sumi, Y Kagami, H Ikeda
雑誌名: Cancer. 1997 Apr 15;79(8):1516-20.
Abstract/Text BACKGROUND: Radiotherapy plus bolus 5-fluorouracil (5-FU) is generally accepted as the standard treatment for locally advanced pancreatic carcinoma. To intensify the antitumor effect of chemotherapy, the authors administered protracted 5-FU infusion with concurrent radiotherapy. The aim of this study was to determine the feasibility and effectiveness of this combined therapy.
METHODS: Twenty patients, all of whom had histologically confirmed exocrine pancreatic carcinoma that was nonresectable but confined to the pancreatic region, were enrolled in a Phase II trial of protracted 5-fluorouracil infusion (200 mg/m2/day) with concurrent radiotherapy (50.4 gray in 28 fractions over 5.5 weeks). Chemotherapy began on the first day of radiation and continued through the entire radiation course. Thereafter, weekly infusions (500 mg/m2) were administered until disease progression.
RESULTS: Of the 20 patients, 17 (85%) completed the scheduled course of chemoradiotherapy. Grade 3 or worse toxicity, graded according to World Health Organization criteria, was observed in 4 patients (20%). Two patients (10%) achieved partial response, and disease remained stable in 16 patients (80%). After the completion of combined therapy, serum CA 19-9 levels were reduced by more than 50% in 10 of 12 patients (83%) who had pretreatment CA 19-9 levels of 100 U/mL or greater. The median progression free survival and 1-year progression free survival rate were 4.9 months and 29.5%, respectively. The median overall survival and 1-year overall survival rate were 10.3 months and 41.8%, respectively.
CONCLUSIONS: This treatment showed moderate activity against locally advanced pancreatic carcinoma and was accompanied by an acceptable toxicity level.

PMID 9118032  Cancer. 1997 Apr 15;79(8):1516-20.
著者: T Okusaka, Y Ito, H Ueno, M Ikeda, Y Takezako, C Morizane, Y Kagami, H Ikeda
雑誌名: Br J Cancer. 2004 Aug 16;91(4):673-7. doi: 10.1038/sj.bjc.6602001.
Abstract/Text Gemcitabine has been reported to be a potent radiosensitiser in human pancreatic cell lines. This study was conducted to evaluate the efficacy and toxicity of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. In all, 42 patients with pancreatic cancer that was unresectable but confined to the pancreatic region were treated with external-beam radiation (50.4 Gy in 28 fractions over 5.5 weeks) and weekly gemcitabine (250 mg m(-2), 30-min infusion). Maintenance gemcitabine (1000 mg m(-2) weekly x 3 every 4 weeks) was initiated 1 month after the completion of the chemoradiotherapy and continued until disease progression or unacceptable toxicity. Of the 42 patients, 38 (90%) completed the scheduled course of chemoradiotherapy. The major toxicity was leucopenia and anorexia. There was one death attributed to duodenal bleeding and sepsis. The median survival time was 9.5 months and the 1-year survival rate was 28%. The median progression-free survival time was 4.4 months. In 35 patients with documented disease progression at the time of analysis, 34 (97%) showed distant metastasis as the cause of the initial disease progression. The chemoradiotherapy used in this study has a moderate activity against locally advanced pancreatic cancer and an acceptable toxicity profile. Future investigations for treatment with more systemic effects are warranted.

PMID 15226765  Br J Cancer. 2004 Aug 16;91(4):673-7. doi: 10.1038/sj.b・・・
著者: Junji Furuse, Taira Kinoshita, Mitsuhiko Kawashima, Hiroshi Ishii, Michitaka Nagase, Masaru Konishi, Toshio Nakagohri, Kazuto Inoue, Takashi Ogino, Hiroshi Ikeda, Yasushi Maru, Masahiro Yoshino
雑誌名: Cancer. 2003 Mar 1;97(5):1346-52. doi: 10.1002/cncr.11165.
Abstract/Text BACKGROUND: Chemoradiotherapy is widely used for patients with locally advanced pancreatic carcinoma. The purpose of this study was to clarify the efficacy and feasibility of chemoradiotherapy with more intensive radiotherapy in these patients, using a combination of intraoperative radiotherapy (IORT), conformal external-beam radiaotherapy (EBRT), and protracted 5-fluorouracil (5-FU).
METHODS: Thirty patients with unresectable locally advanced pancreatic carcinoma were enrolled in this Phase II study. The treatment consisted of IORT (25 grays [Gy]), followed by EBRT (40 Gy in 20 fractions, 5 times per week), and concurrent protracted 5-FU infusion (200 mg/m(2)), beginning 2-4 weeks after IORT. The authors evaluated the efficacy and adverse effects of this treatment by following up patients for 12.0-28.1 months. Survival from the date of IORT was calculated using the Kaplan-Meier method.
RESULTS: In 11 of the 30 patients, metastatic spread was detected in the abdominal cavity at laparotomy. The full EBRT dose was administered in 28 of the 30 patients. Of the remaining 2 patients, EBRT was terminated at 8 Gy due to progression of brain metastasis and another patient did not receive EBRT or chemotherapy due to massive ascites after IORT. The overall response rate for primary pancreatic tumor on dynamic computed tomography scan was 23.3% (7 partial responses). Grade 3 or 4 toxicity (according to the National Cancer Institute Common Toxicity Criteria) was observed in 15 of the 28 patients who received the full irradiation dose (53.6%). These included anorexia, nausea, emesis, fatigue, leukopenia, and/or elevation of transaminase levels. There were no directly treatment-related deaths, but 1 patient died of hepatic failure related to late effects of irradiation after 25.6 months. The median survival time of the 30 patients was 7.8 months and the 2-year survival rate was 8.1%. The median survival time of the 19 patients without metastatic spread in the abdominal cavity was 12.9 months and that of the 11 patients with metastatic spread was 5.8 months.
CONCLUSIONS: The present regimen of chemoradiotherapy is not superior to conventional chemoradiotherapy (EBRT and 5-FU) for patients with locally advanced pancreatic carcinoma.

Copyright 2003 American Cancer Society.
PMID 12599244  Cancer. 2003 Mar 1;97(5):1346-52. doi: 10.1002/cncr.111・・・
著者: Takuji Okusaka, Masafumi Ikeda, Akira Fukutomi, Tatsuya Ioka, Junji Furuse, Shinichi Ohkawa, Hiroyuki Isayama, Narikazu Boku
雑誌名: 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.
PMID 25117729  Cancer Sci. 2014 Oct;105(10):1321-6. doi: 10.1111/cas.1・・・
著者: Hideki Ueno, Masafumi Ikeda, Makoto Ueno, Nobumasa Mizuno, Tatsuya Ioka, Yasushi Omuro, Takako Eguchi Nakajima, Junji Furuse
雑誌名: 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.

PMID 26842789  Cancer Chemother Pharmacol. 2016 Mar;77(3):595-603. doi・・・
著者: Masato Ozaka, Hiroshi Ishii, Tosiya Sato, Makoto Ueno, Masafumi Ikeda, Kazuhiro Uesugi, Naohiro Sata, Kouichirou Miyashita, Nobumasa Mizuno, Kunihiro Tsuji, Takuji Okusaka, Junji Furuse
雑誌名: 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.

PMID 29633005  Cancer Chemother Pharmacol. 2018 Jun;81(6):1017-1023. d・・・
著者: Uwe Pelzer, Ingo Schwaner, Jens Stieler, Mathias Adler, Jörg Seraphin, Bernd Dörken, Hanno Riess, Helmut Oettle
雑誌名: 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.
PMID 21565490  Eur J Cancer. 2011 Jul;47(11):1676-81. doi: 10.1016/j.e・・・
著者: Helmut Oettle, Hanno Riess, Jens M Stieler, Gerhard Heil, Ingo Schwaner, Jörg Seraphin, Martin Görner, Matthias Mölle, Tim F Greten, Volker Lakner, Sven Bischoff, Marianne Sinn, Bernd Dörken, Uwe Pelzer
雑誌名: 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.
PMID 24982456  J Clin Oncol. 2014 Aug 10;32(23):2423-9. doi: 10.1200/J・・・
著者: Andrea Wang-Gillam, Chung-Pin Li, György Bodoky, Andrew Dean, Yan-Shen Shan, Gayle Jameson, Teresa Macarulla, Kyung-Hun Lee, David Cunningham, Jean F Blanc, Richard A Hubner, Chang-Fang Chiu, Gilberto Schwartsmann, Jens T Siveke, Fadi Braiteh, Victor Moyo, Bruce Belanger, Navreet Dhindsa, Eliel Bayever, Daniel D Von Hoff, Li-Tzong Chen, NAPOLI-1 Study Group
雑誌名: 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.
PMID 26615328  Lancet. 2016 Feb 6;387(10018):545-557. doi: 10.1016/S01・・・

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