今日の臨床サポート

小細胞肺癌(進行期)

著者: 礒部 威 島根大学医学部内科学講座呼吸器・臨床腫瘍学

監修: 高橋和久 順天堂大学大学院

著者校正/監修レビュー済:2021/05/19
参考ガイドライン:
  1. 日本肺癌学会:肺癌診療ガイドライン2020年版 悪性胸膜中皮腫・胸腺腫瘍含む
  1. 日本肺癌学会:臨床・病理 肺癌取扱い規約 第8版

概要・推奨   

  1. 小細胞肺癌は、非小細胞肺癌に比べ、化学療法と放射線療法に対する感受性が高いものの、腫瘍の増殖・進展速度が速く、多臓器への遠隔転移の頻度が高く、特に予後不良である。外科切除や放射線化学療法の適応とならない進展型小細胞肺癌は、現時点では有効な治療薬が限られる「難治癌」である。そのため、治療に伴う有害事象を上手くコントロールし使用可能な薬剤を適正量、適正なスケジュールで投与することが重要となる。薬物療法の概要は以下のとおりである。
  1. 進展型小細胞肺癌(PS 0-2、70 歳以下)にはシスプラチン+イリノテカン(PI)療法を行うよう推奨する。〔推奨の強さ:1、エビデンスの強さ:A〕
  1. 進展型小細胞肺癌(PS 0-2、70 歳以下)にはシスプラチン+エトポシド(PE)療法を行うよう提案する。〔推奨の強さ:2、エビデンスの強さ:A〕
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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:
礒部 威 : 講演料(アストラゼネカ,第一三共,ベーリンガーインゲルハイム),研究費・助成金など(第一三共)[2021年]
監修:高橋和久 : 講演料(アストラゼネカ(株),MSD(株),中外製薬(株)),研究費・助成金など(小野薬品工業(株),中外製薬(株),ブリストル・マイヤーズスクイブ(株)),奨学(奨励)寄付など(中外製薬(株),大鵬薬品工業(株),杏林製薬(株),サノフィ(株),日本イーライリリー(株),日本ベーリンガーインゲルハイム(株),帝人ファーマ(株))[2021年]

改訂のポイント
  1. 肺癌診療ガイドライン2020年版(日本肺癌学会)の公開に基づき、進展型小細胞肺癌の治療にPt/ETP/デュルバルマブ療法を追記した。

病態・疫学・診察

定義  
  1. 小細胞肺癌とは、免疫組織化学染色で神経内分泌学的特徴を示す、細胞質の乏しい小型腫瘍細胞がびまん性に増殖し、核分裂像を多く認め、壊死巣を伴う腫瘍である。進展型小細胞肺癌は、以下の限局型小細胞肺癌と定義される範囲を超えて進展したものを指す。
  1. 限局型の定義:一側胸郭に病変が限局するもので、同側肺門、両側縦隔および両側鎖骨上窩リンパ節転移を含む。悪性胸水(細胞診陽性、あるいは細胞診陰性でも中等量以上の胸水)がある場合は進展型とする。
 
  1. 診断メモ:
  1. 日本肺癌学会の肺癌診療ガイドラインでは多くの第Ⅲ相臨床試験で採用されている定義、すなわち病変が同側胸郭内に加え、対側縦隔、対側鎖骨上窩リンパ節までに限られており悪性胸水、心嚢水を有さないものを限局型小細胞肺癌と定義付けられている。
疫学  
  1. わが国における肺癌死亡者数は年々増加してきており、悪性腫瘍による死亡原因の第1位となっている。2017年の統計では全肺癌死亡者数は74,095人/年であった。肺癌の組織型のうち、約15%が小細胞肺癌(small cell lung cancer、以下 SCLC)であるため、約11,100人が小細胞肺癌と診断され、そのうち進展型の比率は70%であることから、約7,770名が進展型小細胞肺癌と考えられる。危険因子としては、以前または現在の喫煙歴、受動喫煙、アスベスト、ヒ素、クロム、ベリリウム、ニッケルなどの物質への職業曝露、肺癌の家族歴などがある。

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文献 

著者: Kazumasa Noda, Yutaka Nishiwaki, Masaaki Kawahara, Shunichi Negoro, Takahiko Sugiura, Akira Yokoyama, Masahiro Fukuoka, Kiyoshi Mori, Koshiro Watanabe, Tomohide Tamura, Seiichiro Yamamoto, Nagahiro Saijo, Japan Clinical Oncology Group
雑誌名: N Engl J Med. 2002 Jan 10;346(2):85-91. doi: 10.1056/NEJMoa003034.
Abstract/Text BACKGROUND: Irinotecan hydrochloride, a topoisomerase I inhibitor, is effective against small-cell lung cancer. In a phase 2 study of irinotecan plus cisplatin in patients with extensive small-cell lung cancer, there was a high response rate and a promising median survival time.
METHODS: We conducted a multicenter, randomized, phase 3 study in which we compared irinotecan plus cisplatin with etoposide plus cisplatin in patients with extensive (metastatic) small-cell lung cancer.
RESULTS: The planned size of the study population was 230 patients, but enrollment was terminated early because an interim analysis found a statistically significant difference in survival between the patients assigned to receive irinotecan and cisplatin and those assigned to receive etoposide and cisplatin; as a result, only 154 patients were enrolled. The median survival was 12.8 months in the irinotecan-plus-cisplatin group and 9.4 months in the etoposide-plus-cisplatin group (P=0.002 by the unadjusted log-rank test). At two years, the proportion of patients surviving was 19.5 percent in the irinotecan-plus-cisplatin group and 5.2 percent in the etoposide-plus-cisplatin group. Severe or life-threatening myelosuppression was more frequent in the etoposide-plus-cisplatin group than in the irinotecan-plus-cisplatin group, and severe or life-threatening diarrhea was more frequent in the irinotecan-plus-cisplatin group than in the etoposide-plus-cisplatin group.
CONCLUSIONS: Irinotecan plus cisplatin is an effective treatment for metastatic small-cell lung cancer.

PMID 11784874  N Engl J Med. 2002 Jan 10;346(2):85-91. doi: 10.1056/NE・・・
著者: Nasser Hanna, Paul A Bunn, Corey Langer, Lawrence Einhorn, Troy Guthrie, Thaddeus Beck, Rafat Ansari, Peter Ellis, Michael Byrne, Mark Morrison, Subramanian Hariharan, Benjamin Wang, Alan Sandler
雑誌名: J Clin Oncol. 2006 May 1;24(13):2038-43. doi: 10.1200/JCO.2005.04.8595.
Abstract/Text PURPOSE: Etoposide and cisplatin (EP) has been a standard treatment for extensive-disease small-cell lung cancer (SCLC). An earlier phase III trial reported improved survival for patients receiving irinotecan plus cisplatin (IP) versus EP. Our trial was designed to determine if a modified weekly regimen of IP would provide superior survival with less toxicity than EP.
PATIENTS AND METHODS: The primary objective was to compare overall survival in extensive-disease SCLC patients randomly assigned to receive IP (n = 221) or EP (n = 110). Patients were randomly assigned in 2:1 ratio to cisplatin 30 mg/m2 intravenously (IV) + irinotecan 65 mg/m2 IV on days 1 and 8 every 21 days, or cisplatin 60 mg/m2 IV on day 1, and etoposide 120 mg/m2 IV on days 1 to 3 every 21 days for at least four cycles, until progressive disease, or until intolerable toxicity resulted.
RESULTS: Selected grade 3/4 toxicities for IP/EP were: neutropenia (36.2% v 86.5%; P < .01), febrile neutropenia (3.7% v 10.4%; P = .06), anemia (4.8% v 11.5%; P = .02), thrombocytopenia (4.3% v 19.2%; P < .01), vomiting (12.5% v 3.8%; P = .04), and diarrhea (21.3% v 0%; P < .01). There was no significant difference in response rates (48% v 43.6%), median time to progression (4.1 v 4.6 months), or overall survival (median survival time, 9.3 months v 10.2 months; P = .74).
CONCLUSION: Treatment with this dose and schedule of IP did not result in improved survival when compared with EP. Fewer patients receiving IP had grade 3/4 anemia, thrombocytopenia, neutropenia, and febrile neutropenia compared with patients receiving EP, but more had grade 3/4 diarrhea and vomiting.

PMID 16648503  J Clin Oncol. 2006 May 1;24(13):2038-43. doi: 10.1200/J・・・
著者: Primo N Lara, Ronald Natale, John Crowley, Heinz Josef Lenz, Mary W Redman, Jane E Carleton, James Jett, Corey J Langer, J Philip Kuebler, Shaker R Dakhil, Kari Chansky, David R Gandara
雑誌名: J Clin Oncol. 2009 May 20;27(15):2530-5. doi: 10.1200/JCO.2008.20.1061. Epub 2009 Apr 6.
Abstract/Text PURPOSE: Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC.
PATIENTS AND METHODS: Patients were randomly assigned to IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients.
RESULTS: Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia.
CONCLUSION: This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

PMID 19349543  J Clin Oncol. 2009 May 20;27(15):2530-5. doi: 10.1200/J・・・
著者: P Zatloukal, F Cardenal, A Szczesna, V Gorbunova, V Moiseyenko, X Zhang, L Cisar, J-C Soria, M Domine, M Thomas
雑誌名: Ann Oncol. 2010 Sep;21(9):1810-6. doi: 10.1093/annonc/mdq036. Epub 2010 Mar 15.
Abstract/Text BACKGROUND: This study compared irinotecan plus cisplatin (IP) with etoposide plus cisplatin (EP) in small-cell lung cancer patients with extensive disease.
PATIENTS AND METHODS: Patients were randomly assigned to receive cisplatin 80 mg/m(2) and either irinotecan 65 mg/m(2), days 1 and 8 or etoposide 100 mg/m(2), days 1-3, every 3 weeks.
RESULTS: Baseline characteristics were balanced between patients receiving IP (N = 202) or EP (N = 203). Median overall survival was nonsignificantly superior for patients receiving IP versus EP, 10.2 versus 9.7 months [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.65-1.01, P = 0.06] and 1- and 2-year survival rates were 41.9% versus 38.9% and 16.3% versus 8.2%, respectively. Noninferiority of IP versus EP was established, upper bound of the 95% CI of HR 1.01 (prespecified margin IP/EP <1.25). Overall response (39.1% versus 46.6%) and time to tumor progression (5.4 versus 6.2 months) were not superior for IP. Grade 3/4 vomiting (10.9% versus 4.4%) and diarrhea (15.4% versus 0.5%) were more common in the IP versus EP arm; grade 3/4 neutropenia was more frequent in the EP (59.6%) versus IP arm (38.1%).
CONCLUSIONS: Our data demonstrate the noninferiority of IP versus EP for survival in primarily Western patients with SCLC-ED. A meta-analysis is required to finally assess the role of irinotecan in this setting.

PMID 20231298  Ann Oncol. 2010 Sep;21(9):1810-6. doi: 10.1093/annonc/m・・・
著者: Dong-Wan Kim, Hoon-Gu Kim, Joo-Hang Kim, Keunchil Park, Hoon-Kyo Kim, Joung Soon Jang, Bong-Seog Kim, Jin-Hyoung Kang, Kyung Hee Lee, Sang-We Kim, Hun Mo Ryoo, Jin-Soo Kim, Ki Hyeong Lee, Jung Hye Kwon, Jin-Hyuk Choi, Sang Won Shin, Seokyung Hahn, Dae Seog Heo
雑誌名: Cancer Res Treat. 2019 Jan;51(1):119-127. doi: 10.4143/crt.2018.019. Epub 2018 Mar 12.
Abstract/Text PURPOSE: This randomized phase III study was designed to compare the efficacy and safety of irinote-can plus cisplatin (IP) over etoposide plus cisplatin (EP) in Korean patients with extensive-disease small-cell lung cancer (SCLC).
Materials and Methods: Patients were randomly assigned to receive IP, composed of irinotecan 65 mg/m2 intravenously on days 1 and 8+cisplatin 70 mg/m2 intravenously on day 1 every 3 weeks, or EP, composed of etoposide 100 mg/m2 intravenously on days 1, 2, 3+cisplatin 70 mg/m2 intravenously on day 1, every 3 weeks for a maximum of six cycles, until disease progression, or until unacceptable toxicity occurred. The primary endpoint was overall survival.
RESULTS: A total of 362 patients were randomized to IP (n=173) and EP (n=189) arms. There were no significant differences between IP and EP arms for the median overall survival (10.9 months vs. 10.3 months, p=0.120) and the median progression-free survival (6.5 months vs. 5.8 months, p=0.115). However, there was a significant difference in response rate (62.4% vs. 48.2%, p=0.006). The pre-planned subgroup analyses showed that IP was associated with longer overall survival in male (11.3 months vs. 10.1 months, p=0.036), < 65 years old (12.7 months vs. 11.3 months, p=0.024), and Eastern Cooperative Oncology Group performance status 0/1 (12.4 months vs. 10.9 months, p=0.040) patient groups. The severity of treatment-related adverse events such as grade 3/4 anemia, nausea and diarrhea was more frequent in patients treated with IP.
CONCLUSION: The IP chemotherapy did not significantly improve the survival compared with EP chemotherapy in Korean patients with extensive-disease SCLC.

PMID 29529858  Cancer Res Treat. 2019 Jan;51(1):119-127. doi: 10.4143/・・・
著者: Jingwei Jiang, Xiaohua Liang, Xinli Zhou, Lizhen Huang, Ruofan Huang, Zhaohui Chu, Qiong Zhan
雑誌名: J Thorac Oncol. 2010 Jun;5(6):867-73.
Abstract/Text PURPOSE: To compare the efficacy and toxicities of irinotecan/ platinum (IP) with etoposide/platinum (EP) in patients with previously untreated extensive-stage small cell lung cancer (E-SCLC).
METHODS: The PubMed database, the Cochrane Library, conference proceedings, databases of ongoing trials, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted data. The relative risk for overall response to treatment, hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios for the different types of toxicity were pooled by STATA package.
RESULTS: Six trials involving 1476 patients with previously untreated E-SCLC were ultimately analyzed. The intention-to-treatment analysis indicated that IP regimens could acquire more overall response than EP regimens (relative risk = 1.10, 95% confidence interval [CI]: 1.00 -1.21, p = 0.043). The pooled HR showed that IP could prolong OS (HR = 0.81, 95% CI: 0.66 -0.99, p = 0.044). Nevertheless, the pooled HR failed to show a favorable PFS in IP regimens (HR = 0.82, 95% CI: 0.64 -1.06, p = 0.139). IP regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than EP regimens. Treatment-related deaths were comparable between the two groups.
CONCLUSION: Although the PFS was similar from this meta-analysis, our results suggest that IP might have an advantage in overall response and OS compared with EP with less hematological toxicities. The IP regimens may be an alternative of EP regimens in the first-line treatment of E-SCLC.

PMID 20521354  J Thorac Oncol. 2010 Jun;5(6):867-73.
著者: João Paulo S N Lima, Lucas Vieira dos Santos, Emma Chen Sasse, Carmen Silvia Passos Lima, André Deeke Sasse
雑誌名: J Thorac Oncol. 2010 Dec;5(12):1986-93. doi: 10.1097/JTO.0b013e3181f2451c.
Abstract/Text INTRODUCTION: Superiority of camptothecin regimens over etoposide-both combined with platinum analogs-in extensive disease small cell lung cancer has been a matter of debate with contradictory findings in randomized trials. A systematic review was sought to elucidate this issue.
METHODS: Randomized controlled trials comparing first-line camptothecin-platinum doublets versus etoposide-platinum doublets in patients with extensive disease small cell lung cancer were searched in MEDLINE, EMBASE, LILACS, and CENTRAL databases, European Society of Medical Oncology, American Society of Clinical Oncology, and International Association for the Study of Lung Cancer meeting sites. Meta-analyses were performed using fixed-effects model. Subgroup analyses were undertaken comparing each type of camptothecin to etoposide-based regimens. The outcomes of interest were overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicities.
RESULTS: Eight studies (3086 patients) were included. The meta-analysis of topotecan regimens (TP) was not reliable due to impending heterogeneity. Meta-analysis of trials testing irinotecan combinations (IP) versus etoposide regimens (EP; 1561 patients) stated an OS improvement in favor of IP arm, though with considerable heterogeneity, whose origin seemed to be a Japanese trial. In the analyses without that study (1407 patients left), IP brought a significant improvement in OS (hazard ratio = 0.87; 95% confidence interval 0.78-0.97; p = 0.02; I = 0). IP also increased PFS (hazard ratio = 0.83; 95% confidence interval 0.73-0.95; p = 0.006; I = 0%). There was no impact in RR (absolute RR 56% with IP; 53% with EP; p = 0.17). IP caused more diarrhea (p < 0.0001) but less hematological toxicities (p < 0.001) than EP.
CONCLUSIONS: The present meta-analysis demonstrates statistically significant OS and PFS benefits of IP over EP regimens in western and eastern patients. Specific characteristics of safety profile should be taken into account when administrating IP chemotherapy.

PMID 20978445  J Thorac Oncol. 2010 Dec;5(12):1986-93. doi: 10.1097/JT・・・
著者: D Han, G Wang, L Sun, X Ren, W Shang, L Xu, S Li
雑誌名: Eur J Cancer Care (Engl). 2017 Nov;26(6). doi: 10.1111/ecc.12723. Epub 2017 Jul 13.
Abstract/Text This meta-analysis was performed to compare the effects and toxicities between irinotecan/platinum (IP) and etoposide/platinum (EP) regimens as the fist-line treatment of patients with extensive-stage small cell lung cancer (E-SCLC). A systematic search was made of MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases. Randomised clinical trials on treatment of E-SCLC with the IP regimens, compared with EP regimens, were reviewed. Studies were pooled to hazard ratio (HR), relative risk (RR) and odds ratio (OR), with 95% confidence interval (CI). Eight trials (enrolling 2089 participants) met the inclusion criteria. Overall survival (OS) and 1-year survival rate were superior in the IP group (HR 0.83; 95% CI 0.75 to 0.91 and RR 1.19; 95% CI 1.06 to 1.34). Grades 3 and 4 anaemia, leukopenia, neutropenia, thrombocytopenia and febrile neutropenia were less frequent in the IP regimens than that in the EP regimens. And grades 3 and 4 nausea/vomiting, diarrheal, anorexia and fatigue were less frequent in the EP regimens. IP combination chemotherapy achieved a superior OS and 1-year survival rate, compared with EP doublets, in patients with E-SCLC.

© 2017 John Wiley & Sons Ltd.
PMID 28707433  Eur J Cancer Care (Engl). 2017 Nov;26(6). doi: 10.1111/・・・
著者: H Okamoto, K Watanabe, H Kunikane, A Yokoyama, S Kudoh, T Asakawa, T Shibata, H Kunitoh, T Tamura, N Saijo
雑誌名: Br J Cancer. 2007 Jul 16;97(2):162-9. doi: 10.1038/sj.bjc.6603810. Epub 2007 Jun 19.
Abstract/Text We compared the efficacy and the safety of a carboplatin plus etoposide regimen (CE) vs split doses of cisplatin plus etoposide (SPE) in elderly or poor-risk patients with extensive disease small-cell lung cancer (ED-SCLC). Eligibility criteria included: untreated ED-SCLC; age >/=70 and performance status 0-2, or age <70 and PS 3. The CE arm received carboplatin area under the curve of five intravenously (IV) on day 1 and etoposide 80 mg m(-2) IV on days 1-3. The SPE arm received cisplatin 25 mg m(-2) IV on days 1-3 and etoposide 80 mg m(-2) IV on days 1-3. Both regimens were given with granulocyte colony-stimulating factor support in a 21-28 day cycle for four courses. A total of 220 patients were randomised. Median age was 74 years and 74% had a PS of 0 or 1. Major grade 3-4 toxicities were (%CE/%SPE): leucopenia 54/51, neutropenia 95/90, thrombocytopenia 56/16, infection 7/6. There was no significant difference (CE/SPE) in the response rate (73/73%) and overall survival (median 10.6/9.9 mo; P=0.54). Palliation scores were very similar between the arms. Although the SPE regimen is still considered to be the standard treatment in elderly or poor-risk patients with ED-SCLC, the CE regimen can be an alternative for this population considering the risk-benefit balance.

PMID 17579629  Br J Cancer. 2007 Jul 16;97(2):162-9. doi: 10.1038/sj.b・・・
著者: Leora Horn, Aaron S Mansfield, Aleksandra Szczęsna, Libor Havel, Maciej Krzakowski, Maximilian J Hochmair, Florian Huemer, György Losonczy, Melissa L Johnson, Makoto Nishio, Martin Reck, Tony Mok, Sivuonthanh Lam, David S Shames, Juan Liu, Beiying Ding, Ariel Lopez-Chavez, Fairooz Kabbinavar, Wei Lin, Alan Sandler, Stephen V Liu, IMpower133 Study Group
雑誌名: N Engl J Med. 2018 Dec 6;379(23):2220-2229. doi: 10.1056/NEJMoa1809064. Epub 2018 Sep 25.
Abstract/Text BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.
METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.
RESULTS: A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed.
CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).

PMID 30280641  N Engl J Med. 2018 Dec 6;379(23):2220-2229. doi: 10.105・・・
著者: Luis Paz-Ares, Mikhail Dvorkin, Yuanbin Chen, Niels Reinmuth, Katsuyuki Hotta, Dmytro Trukhin, Galina Statsenko, Maximilian J Hochmair, Mustafa Özgüroğlu, Jun Ho Ji, Oleksandr Voitko, Artem Poltoratskiy, Santiago Ponce, Francesco Verderame, Libor Havel, Igor Bondarenko, Andrzej Kazarnowicz, György Losonczy, Nikolay V Conev, Jon Armstrong, Natalie Byrne, Norah Shire, Haiyi Jiang, Jonathan W Goldman, CASPIAN investigators
雑誌名: Lancet. 2019 Nov 23;394(10212):1929-1939. doi: 10.1016/S0140-6736(19)32222-6. Epub 2019 Oct 4.
Abstract/Text BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC.
METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing.
FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.
INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received.
FUNDING: AstraZeneca.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31590988  Lancet. 2019 Nov 23;394(10212):1929-1939. doi: 10.1016/・・・
著者: Mary E R O'Brien, Tudor-Eliade Ciuleanu, Hristo Tsekov, Yaroslav Shparyk, Branka Cuceviá, Gabor Juhasz, Nicholas Thatcher, Graham A Ross, Graham C Dane, Theresa Crofts
雑誌名: J Clin Oncol. 2006 Dec 1;24(34):5441-7. doi: 10.1200/JCO.2006.06.5821.
Abstract/Text PURPOSE: For patients with small-cell lung cancer (SCLC), further chemotherapy is routinely considered at relapse after first-line therapy. However, proof of clinical benefit has not been documented.
PATIENTS AND METHODS: This study randomly assigned patients with relapsed SCLC not considered as candidates for standard intravenous therapy to best supportive care (BSC) alone (n = 70) or oral topotecan (2.3 mg/m2/d, days 1 through 5, every 21 days) plus BSC (topotecan; n = 71).
RESULTS: In the intent-to-treat population, survival (primary end point) was prolonged in the topotecan group (log-rank P = .0104). Median survival with BSC was 13.9 weeks (95% CI, 11.1 to 18.6) and with topotecan, 25.9 weeks (95% CI, 18.3 to 31.6). Statistical significance for survival was maintained in a subgroup of patients with a short treatment-free interval (< or = 60 days). Response to topotecan was 7% partial and 44% stable disease. Patients on topotecan had slower quality of life deterioration and greater symptom control. Principal toxicities with topotecan were hematological: grade 4 neutropenia, 33%; grade 4 thrombocytopenia, 7%; and grade 3/4 anemia, 25%. Comparing topotecan with BSC, infection grade 2 was 14% versus 12% and sepsis 4% versus 1%; other grade 3/4 events included vomiting 3% versus 0, diarrhea 6% versus 0, dyspnea 3% versus 9%, and pain 3% versus 6%. Toxic deaths occurred in four patients (6%) in the topotecan arm. All cause mortality within 30 days of random assignment was 13% on BSC and 7% on topotecan.
CONCLUSION: Chemotherapy with oral topotecan is associated with prolongation of survival and quality of life benefit in patients with relapsed SCLC.

PMID 17135646  J Clin Oncol. 2006 Dec 1;24(34):5441-7. doi: 10.1200/JC・・・
著者: J von Pawel, J H Schiller, F A Shepherd, S Z Fields, J P Kleisbauer, N G Chrysson, D J Stewart, P I Clark, M C Palmer, A Depierre, J Carmichael, J B Krebs, G Ross, S R Lane, R Gralla
雑誌名: J Clin Oncol. 1999 Feb;17(2):658-67. doi: 10.1200/JCO.1999.17.2.658.
Abstract/Text PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy.
PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review.
RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens.
CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.

PMID 10080612  J Clin Oncol. 1999 Feb;17(2):658-67. doi: 10.1200/JCO.1・・・
著者: John R Eckardt, Joachim von Pawel, Jean-Louis Pujol, Zsolt Papai, Elisabeth Quoix, Andrea Ardizzoni, Ruth Poulin, Alaknanda J Preston, Graham Dane, Graham Ross
雑誌名: J Clin Oncol. 2007 May 20;25(15):2086-92. doi: 10.1200/JCO.2006.08.3998.
Abstract/Text PURPOSE: Single-agent intravenous (IV) topotecan is an effective treatment for small-cell lung cancer (SCLC) after failure of first-line chemotherapy. This open-label, randomized, phase III study compared oral and IV topotecan in patients with SCLC sensitive to initial chemotherapy.
PATIENTS AND METHODS: Patients with limited- or extensive-disease SCLC, documented complete or partial response to first-line therapy, Eastern Cooperative Oncology Group performance status < or = 2, and measurable recurrent disease (WHO criteria) with a treatment-free interval of > or = 90 days were assigned to treatment with either oral topotecan 2.3 mg/m2/d on days 1 through 5 or IV topotecan 1.5 mg/m2/d on days 1 through 5 every 21 days. Primary end point was response rate as confirmed by an external reviewer blinded to treatment.
RESULTS: A total of 309 patients were randomly assigned. In intent-to-treat analysis, response rates were 18.3% with oral topotecan (n = 153) and 21.9% with IV topotecan (n = 151), with a difference (oral -IV) of -3.6% (95% CI, -12.6% to 5.5%). Median survival time was 33.0 weeks for oral and 35.0 weeks for IV topotecan; 1- and 2-year survival rates were 32.6% and 12.4% for oral topotecan, respectively, and 29.2% and 7.1% for IV topotecan, respectively. Third-line chemotherapy was similar for both groups (33% for oral; 35% for IV). Incidence of grade 4 toxicity in patients who received oral and IV topotecan was as follows: neutropenia in 47% and 64%, thrombocytopenia in 29% and 18%, grade 3 or 4 anemia in 23% and 31%, and sepsis in 3% and 3%, respectively. The most frequent nonhematologic adverse events (all grades) included nausea (43% oral; 42% IV), alopecia (26% oral; 30% IV), fatigue (31% oral; 36% IV), and diarrhea (36% oral; 20% IV).
CONCLUSION: Oral topotecan demonstrates activity and tolerability similar to IV topotecan in chemotherapy-sensitive SCLC patients and offers patients a convenient alternative to IV therapy.

PMID 17513814  J Clin Oncol. 2007 May 20;25(15):2086-92. doi: 10.1200/・・・
著者: Koichi Goto, Yuichiro Ohe, Taro Shibata, Takashi Seto, Toshiaki Takahashi, Kazuhiko Nakagawa, Hiroshi Tanaka, Koji Takeda, Makoto Nishio, Kiyoshi Mori, Miyako Satouchi, Toyoaki Hida, Naruo Yoshimura, Toshiyuki Kozuki, Fumio Imamura, Katsuyuki Kiura, Hiroaki Okamoto, Toshiyuki Sawa, Tomohide Tamura, JCOG0605 investigators
雑誌名: Lancet Oncol. 2016 Aug;17(8):1147-1157. doi: 10.1016/S1470-2045(16)30104-8. Epub 2016 Jun 14.
Abstract/Text BACKGROUND: Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer.
METHODS: We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m(2) on days 1 and 8, intravenous etoposide 60 mg/m(2) on days 1-3, and intravenous irinotecan 90 mg/m(2) on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m(2) on days 1-5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828.
FINDINGS: Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0-35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7-20·6) than in the topotecan group (12·5 months, 10·8-14·9; hazard ratio 0·67, 90% CI 0·51-0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group.
INTERPRETATION: Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer.
FUNDING: National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27312053  Lancet Oncol. 2016 Aug;17(8):1147-1157. doi: 10.1016/S1・・・
著者: Robert Jotte, Paul Conkling, Craig Reynolds, Matthew D Galsky, Leonard Klein, James F Fitzgibbons, Richard McNally, Markus F Renschler, Jennifer W Oliver
雑誌名: J Clin Oncol. 2011 Jan 20;29(3):287-93. doi: 10.1200/JCO.2010.29.8851. Epub 2010 Dec 6.
Abstract/Text PURPOSE: This phase II study evaluated the safety and efficacy of single-agent amrubicin versus topotecan in patients with small-cell lung cancer (SCLC) sensitive to first-line platinum-based chemotherapy.
PATIENTS AND METHODS: Patients were randomly assigned 2:1 to amrubicin (40 mg/m(2)/d in a 5-minute intravenous [IV] infusion, days 1 through 3, every 21 days) or topotecan (1.5 mg/m(2)/d in a 30-minute IV infusion, days 1 through 5, every 21 days). The primary efficacy end point was overall response rate (ORR) for amrubicin. Secondary end points included time to progression, median progression-free survival (PFS), and median overall survival (OS).
RESULTS: Of 76 patients enrolled, 50 patients were randomly assigned to amrubicin, and 26 patients were randomly assigned to topotecan. Amrubicin treatment resulted in a significantly higher ORR than topotecan (44% v 15%; P = .021). Median PFS and median OS were 4.5 months and 9.2 months with amrubicin and 3.3 months and 7.6 months with topotecan, respectively. Tolerability was similar with both agents. However, grade 3 or worse neutropenia and thrombocytopenia seemed to be more frequent in the topotecan group as compared with the amrubicin group (78% and 61% v 61% and 39%, respectively).
CONCLUSION: Amrubicin shows promising activity, with an ORR of 44% compared with an ORR of 15% for topotecan as second-line treatment in patients with SCLC sensitive to first-line platinum-based chemotherapy. In addition, the safety profiles were comparable; however, a trend was noted for more frequent grade 3 or worse neutropenia and thrombocytopenia in the topotecan group as compared with the amrubicin group. Additional studies are ongoing.

PMID 21135284  J Clin Oncol. 2011 Jan 20;29(3):287-93. doi: 10.1200/JC・・・
著者: Joachim von Pawel, Robert Jotte, David R Spigel, Mary E R O'Brien, Mark A Socinski, Jörg Mezger, Martin Steins, Léon Bosquée, Jeffrey Bubis, Kristiaan Nackaerts, José M Trigo, Philip Clingan, Wolfgang Schütte, Paul Lorigan, Martin Reck, Manuel Domine, Frances A Shepherd, Shaoyi Li, Markus F Renschler
雑誌名: J Clin Oncol. 2014 Dec 10;32(35):4012-9. doi: 10.1200/JCO.2013.54.5392. Epub 2014 Nov 10.
Abstract/Text PURPOSE: Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC.
PATIENTS AND METHODS: A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m(2) intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m(2) IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety.
RESULTS: Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes.
CONCLUSION: Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin.

© 2014 by American Society of Clinical Oncology.
PMID 25385727  J Clin Oncol. 2014 Dec 10;32(35):4012-9. doi: 10.1200/J・・・
著者: Akira Inoue, Shunichi Sugawara, Koichi Yamazaki, Makoto Maemondo, Toshiro Suzuki, Kazunori Gomi, Shingo Takanashi, Chieko Inoue, Minoru Inage, Hiroshi Yokouchi, Hiroshi Watanabe, Toumei Tsukamoto, Yasuo Saijo, Osamu Ishimoto, Fumihiro Hommura, Toshihiro Nukiwa
雑誌名: J Clin Oncol. 2008 Nov 20;26(33):5401-6. doi: 10.1200/JCO.2008.18.1974. Epub 2008 Oct 14.
Abstract/Text PURPOSE: Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation.
PATIENTS AND METHODS: Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m(2) on days 1 through 3) or topotecan (1.0 mg/m(2) on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile.
RESULTS: From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival.
CONCLUSION: Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.

PMID 18854562  J Clin Oncol. 2008 Nov 20;26(33):5401-6. doi: 10.1200/J・・・
著者: Nobuyuki Horita, Masaki Yamamoto, Takashi Sato, Toshinori Tsukahara, Hideyuki Nagakura, Ken Tashiro, Yuji Shibata, Hiroki Watanabe, Kenjiro Nagai, Kentaro Nakashima, Ryota Ushio, Misako Ikeda, Nobuaki Kobayashi, Masaharu Shinkai, Makoto Kudo, Takeshi Kaneko
雑誌名: Sci Rep. 2016 Jan 11;6:18999. doi: 10.1038/srep18999. Epub 2016 Jan 11.
Abstract/Text Currently, amrubicin is permitted for relapsed small-cell lung carcinoma (SCLC) only in Japan. The efficacy and adverse effects of amrubicin as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for efficacy and safety by the AMR single agent regimen as second-line chemotherapy for a patient with SCLC. Binary data were meta-analyzed with the random-model generic inverse variance method. We included nine articles consisted of 803 patients. The pooled three-, six-, and nine-month progression-free survival were 63% (95% CI 57-69%, I(2) = 53%), 28% (95% CI 21-35%, I(2) = 71%), and 10% (95% CI 6-14%, I(2) = 41%), respectively. The pooled six-, 12-, and 18-month overall survival were 69% (95% CI 61-78%, I(2) = 83%), 36% (95% CI 28-44%, I(2) = 80%), and 15% (95% CI 8-21%, I(2) = 81%), respectively. Amrubicin seemed much more beneficial for Japanese patients. However, compared to the efficacy of topotecan presented in a previous meta-analysis, amrubicin may be a better treatment option than topotecan for both Japanese and Euro-American. Adverse effects by amrubicin were almost exclusively observed to be hematological. Notably, grade III/IV neutropenia incidence was 70% and febrile neutropenia incidence was 12%.

PMID 26750506  Sci Rep. 2016 Jan 11;6:18999. doi: 10.1038/srep18999. E・・・
著者: Haruyasu Murakami, Nobuyuki Yamamoto, Taro Shibata, Koji Takeda, Yukito Ichinose, Yuichiro Ohe, Noboru Yamamoto, Yuichiro Takeda, Shinzoh Kudoh, Shinji Atagi, Miyako Satouchi, Katsuyuki Kiura, Naoyuki Nogami, Masahiro Endo, Hirokazu Watanabe, Tomohide Tamura
雑誌名: Lung Cancer. 2014 Apr;84(1):67-72. doi: 10.1016/j.lungcan.2014.01.012. Epub 2014 Jan 25.
Abstract/Text OBJECTIVES: We conducted an open-label, multicenter, single-arm study to confirm the efficacy and safety of amrubicin (AMR), a topoisomerase II inhibitor, for treating refractory small-cell lung cancer (SCLC).
PATIENTS AND METHODS: Patients with chemotherapy-refractory SCLC received 40 mg/m(2) AMR for 3 consecutive days, every 21 days. The primary endpoint was the overall response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: Between November 2009 and February 2011, 82 patients were enrolled. Each patient received a median of four treatment cycles (range, 1-22 cycles). ORR was 32.9% [P<0.0001 by the exact binomial test for the null hypothesis that ORR ≤ 10%; 95% confidence interval (CI), 22.9-44.2%]. The median PFS and OS periods were 3.5 months (95% CI, 3.0-4.3 months) and 8.9 months (95% CI, 7.6-11.3 months), respectively. Significant differences in ORR (21.4% v 45.0%; P=0.034), PFS (median, 2.9 v 5.1 months; P=0.0009), and OS (median, 7.9 v 13.1 months; P=0.0128) were observed between patients previously treated with etoposide and others. Neutropenia was the most common grade 3 or 4 adverse events (93.9%), and febrile neutropenia developed in 26.8% patients. No treatment-related death occurred.
CONCLUSIONS: AMR monotherapy can be considered an effective and safe treatment option for refractory SCLC. Previous chemotherapy with etoposide may influence AMR efficacy.

Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
PMID 24530204  Lung Cancer. 2014 Apr;84(1):67-72. doi: 10.1016/j.lungc・・・
著者: Ben Slotman, Corinne Faivre-Finn, Gijs Kramer, Elaine Rankin, Michael Snee, Matthew Hatton, Pieter Postmus, Laurence Collette, Elena Musat, Suresh Senan, EORTC Radiation Oncology Group and Lung Cancer Group
雑誌名: N Engl J Med. 2007 Aug 16;357(7):664-72. doi: 10.1056/NEJMoa071780.
Abstract/Text BACKGROUND: We conducted a randomized trial of prophylactic cranial irradiation in patients with extensive small-cell lung cancer who had had a response to chemotherapy.
METHODS: Patients between the ages of 18 and 75 years with extensive small-cell lung cancer were randomly assigned to undergo prophylactic cranial irradiation (irradiation group) or receive no further therapy (control group). The primary end point was the time to symptomatic brain metastases. Computed tomography or magnetic resonance imaging of the brain was performed when any predefined key symptom suggestive of brain metastases was present.
RESULTS: The two groups (each with 143 patients) were well balanced regarding baseline characteristics. Patients in the irradiation group had a lower risk of symptomatic brain metastases (hazard ratio, 0.27; 95% confidence interval [CI], 0.16 to 0.44; P<0.001). The cumulative risk of brain metastases within 1 year was 14.6% in the irradiation group (95% CI, 8.3 to 20.9) and 40.4% in the control group (95% CI, 32.1 to 48.6). Irradiation was associated with an increase in median disease-free survival from 12.0 weeks to 14.7 weeks and in median overall survival from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4 to 35.5) in the irradiation group and 13.3% (95% CI, 8.1 to 19.9) in the control group. Irradiation had side effects but did not have a clinically significant effect on global health status.
CONCLUSIONS: Prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs disease-free and overall survival. (ClinicalTrials.gov number, NCT00016211 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17699816  N Engl J Med. 2007 Aug 16;357(7):664-72. doi: 10.1056/N・・・
著者: Toshiaki Takahashi, Takeharu Yamanaka, Takashi Seto, Hideyuki Harada, Hiroshi Nokihara, Hideo Saka, Makoto Nishio, Hiroyasu Kaneda, Koichi Takayama, Osamu Ishimoto, Koji Takeda, Hiroshige Yoshioka, Motoko Tachihara, Hiroshi Sakai, Koichi Goto, Nobuyuki Yamamoto
雑誌名: Lancet Oncol. 2017 May;18(5):663-671. doi: 10.1016/S1470-2045(17)30230-9. Epub 2017 Mar 23.
Abstract/Text BACKGROUND: Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer.
METHODS: We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2·5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants.
FINDINGS: Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11·6 months (95% CI 9·5-13·3) in the prophylactic cranial irradiation group and 13·7 months (10·2-16·4) in the observation group (hazard ratio 1·27, 95% CI 0·96-1·68; p=0·094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six [6%] of 106 in the prophylactic cranial irradiation group vs two [2%] of 111 in the observation group), malaise (three [3%] vs one [<1%]), and muscle weakness in a lower limb (one [<1%] vs six [5%]). No treatment-related deaths occurred in either group.
INTERPRETATION: In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up.
FUNDING: The Ministry of Health, Labour and Welfare of Japan.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28343976  Lancet Oncol. 2017 May;18(5):663-671. doi: 10.1016/S147・・・

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