今日の臨床サポート

小細胞肺癌(初期)

著者: 駄賀晴子 大阪市立総合医療センター

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:2021/06/02
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
患者向け説明資料

概要・推奨   

  1. 臨床病期I、IIA期(第8版)の小細胞肺癌LD症例では手術療法+薬物療法で良好な成績が報告されており、手術を含む治療が推奨されるCJG推奨度2)
  1. 小細胞肺癌LD症例において薬物療法単独よりも薬物療法と放射線療法の併用療法を行うことで生存の延長が示されており、薬物療法に放射線療法を併用することが推奨されるS/CSJG推奨度1)
  1. 小細胞肺癌LD症例における薬物療法と放射線療法は、同時併用による生存の改善が示されており、早期同時併用が推奨されるS/CSJG推奨度1)
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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:
駄賀晴子 : 講演料(中外製薬)[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 悪性胸膜中皮腫・胸腺腫瘍含む」 に基づき確認を行った(変更なし)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 小細胞肺癌とは、肺癌の一種で、他のがん細胞と比較すると細胞が小さいためにそのような名前がつけられている。肺癌全体の約15%を占める。
  1. 喫煙との関連が高く、特に重喫煙者に多く認められる。
  1. 非小細胞肺癌と比較すると、腫瘍の増殖速度が速く、早期に血行性・リンパ行性遠隔転移を起こす。
  1. 肺門部が好発部位だが、末梢発生もまれではなく、原発巣が比較的小さな時期よりリンパ節転移が認められることが多い。
  1. 抗利尿ホルモン不適合分泌症候群(SIADH)やクッシング症候群、ランバート・イートン症候群などの腫瘍随伴症候群を伴うことがある。
  1. 小細胞肺癌の病期診断には、TNM分類に加えて限局型(limited disease、LD)と進展型(extensive disease、ED)の分類が使用されることが多く、頻度はLDが30~40%、EDが60~70%である。
  1. 治療は放射線療法、薬物療法が主体となる。
  1. 小細胞肺癌は進行が速いため、疑われた場合は速やかに確定診断と病期診断を行い、できるだけ早く治療を開始する。
問診・診察のポイント  
問診のポイント:
  1. 小細胞肺癌はさまざまな症状を呈することが多いため、全身症状を含めた問診が必要となる。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: T Lad, S Piantadosi, P Thomas, D Payne, J Ruckdeschel, G Giaccone
雑誌名: Chest. 1994 Dec;106(6 Suppl):320S-323S.
Abstract/Text Three hundred twenty-eight patients with limited stage small cell lung cancer were enrolled in a trial to evaluate surgical treatment for such patients responding to chemotherapy. Cyclophosphamide, doxorubicin, and vincristine were administered every 21 days for five cycles. Patients achieving at least partial response who had confirmation of pure small cell histologic features by pathology review and who were fit enough for thoracotomy were randomized to undergo or not to undergo pulmonary resection. All randomized patients received radiotherapy to the chest and brain. Two hundred seventeen (66%) of the patients achieved objective response (90 complete response; 127 partial response). One hundred forty-six patients were randomized (66% of responders, 44% of all patients): 70 to surgery and 76 to no surgery. Results of surgery were 83% resection rate, 19% pathologic complete remission rate, and 9% with residual non-small cell histologic features only, for a total of 28% eradication of small cell lung cancer. The survival curves for the two arms are not different (log rank p = 0.78). Median survivals were 12 months for all enrolled patients and 16 months for those who were randomized. Actuarial 2-year survival is 20%. The results of this trial do not support the addition of pulmonary resection to the multimodality treatment of small cell lung cancer.

PMID 7988254  Chest. 1994 Dec;106(6 Suppl):320S-323S.
著者: F A Shepherd, R J Ginsberg, G A Patterson, W K Evans, R Feld
雑誌名: J Thorac Cardiovasc Surg. 1989 Feb;97(2):177-86.
Abstract/Text Seventy-two patients with limited small cell lung cancer were identified as candidates for adjuvant operation after chemotherapy. All patients received preoperative chemotherapy with cyclophosphamide, doxorubicin HCl (Adriamycin), and vincristine, or the epipodophyllotoxin derivative VP-16 and cisplatin. The rate of response to chemotherapy was 80% (complete response 38% and partial response 42%). After chemotherapy, 57 patients (79.1%) were candidates for adjuvant surgical resection, but only 38 underwent thoracotomy. Eight required a pneumonectomy, 25 a lobectomy, and five patients had no resection. Postoperative pathologic study revealed only small cell lung cancer for 29 patients, mixed and non-small cell lung cancer for two, non-small cell lung cancer for four, and no residual tumor in three patients. Pathologic staging revealed seven patients in stage I (N0), nine in stage II (N1), and 22 in stage III. The median survival time for the 38 surgical patients was 91 weeks and projected 5-year survival rate 36%. Patients with pathologic stage I disease had significantly longer survival times (median not reached) than did patients in stage II or stage III (median survival 69 and 52 weeks, respectively). Within the group not undergoing operation, 19 patients responded to therapy and were eligible for adjuvant surgical resection, but did not undergo thoracotomy (10 patients were randomized to radiation only, and nine patients refused operation). Their median survival of 51 weeks was inferior to that of the 38 surgical patients (p = 0.049). Adjuvant surgical resection after chemotherapy resulted in long-term survival and cure for a significant proportion of patients with pathologic stage I disease. A significant improvement in survival could not be documented for patients in stages II and III. Intensive pretreatment investigation including mediastinoscopy is essential to exclude patients who will not benefit from adjuvant surgical resection.

PMID 2536868  J Thorac Cardiovasc Surg. 1989 Feb;97(2):177-86.
著者: Ryosuke Tsuchiya, Kenji Suzuki, Yukito Ichinose, Yoh Watanabe, Tsutomu Yasumitsu, Naoki Ishizuka, Harubumi Kato
雑誌名: J Thorac Cardiovasc Surg. 2005 May;129(5):977-83. doi: 10.1016/j.jtcvs.2004.05.030.
Abstract/Text OBJECTIVE: Indications for surgical intervention for very limited small cell lung cancer have not yet been determined. The objective of this study is to determine whether resection followed by cisplatin and etoposide is feasible.
METHODS: From September 1991 through December 1996, 62 patients with completely resected small cell lung cancer who were less than 76 years of age from 17 centers were entered in the trial. Of 62 patients, 61 were eligible, with a median follow-up of 65 months. Chemotherapy consisted of 4 cycles of cisplatin (100 mg/m 2 , day 1) and etoposide (100 mg/m 2 , days 1-3). There were 49 (80%) male patients, 44 with clinical stage I disease, 10 with stage II disease, and 6 with stage IIIa disease.
RESULTS: Forty-two (69%) patients received 4 cycles of cisplatin and etoposide. No treatment-associated mortality was noted. Median survival time was not reached in patients with pathologic stage I disease, was 449 days in patients with stage II disease, and was 712 days in patients with stage IIIa disease. Three-year survival was 61% overall, 68% in patients with clinical stage I disease, 56% in patients with stage II disease, and 13% in patients with stage IIIa disease ( P = .02). Recurrence was noted in 26 (43%) patients overall. Local failure was noted in 6 (10%) patients. Locoregional recurrence tends to be found more frequently in patients with stage IIIA disease. Distant failure was found in 21 (34%) patients overall. Brain metastasis was found in 15% of the patients.
CONCLUSION: Major lung resection followed by postoperative cisplatin and etoposide is feasible, with a favorable survival profile. Because nodal metastasis appears to be a major prognostic factor, preoperative evaluation of nodal status remains a major concern.

PMID 15867769  J Thorac Cardiovasc Surg. 2005 May;129(5):977-83. doi: ・・・
著者: Malcolm V Brock, Craig M Hooker, James E Syphard, William Westra, Li Xu, Anthony J Alberg, David Mason, Stephen B Baylin, James G Herman, Rex C Yung, Julie Brahmer, Charles M Rudin, David S Ettinger, Stephen C Yang
雑誌名: J Thorac Cardiovasc Surg. 2005 Jan;129(1):64-72. doi: 10.1016/j.jtcvs.2004.08.022.
Abstract/Text OBJECTIVE: Although resection is not the standard of care in treating small cell lung cancer, new platinum drugs and modern staging have allowed the role of surgery to be reevaluated.
METHODS: We reviewed our institutional experience of 1415 patients with small cell lung cancer from 1976 to 2002 among whom 82 (6%) underwent surgery with curative intent.
RESULTS: Median age at surgery was 62 years, and small cell lung cancer of mixed morphology represented 14 of 82 (17%). Treatment consisted of surgery alone in 11% of cases (9/82), surgery with neoadjuvant therapy in 22% (18/82), and surgery with adjuvant therapy in 55% (45/82). Prophylactic cranial irradiation was given to 23% (19/82). The 5-year survival of the entire cohort was 42%. The 5-year survival of patients receiving adjuvant chemotherapy (n = 41) was significantly different according to whether patients had received platinum or nonplatinum regimens (68% vs 32.2%, P = .04). Among patients with stage I disease who received adjuvant chemotherapy (n = 24), the 5-year survivals for patients receiving platinum and nonplatinum chemotherapy were 86% and 42%, respectively ( P < .02). If patients who received either neoadjuvant or adjuvant therapy (n = 56) were considered, the 5-year survival was significantly better for platinum than for nonplatinum chemotherapy (62% vs 36%, P = .05). The 5-year survival was also better for those undergoing lobectomies (n = 52) than for those with limited resections (n = 15, 50% vs 20%, P = .03). Survival outcomes also differed by gender, with female patients having a 5-year survival advantage over male patients (60% vs 28%, P = .004).
CONCLUSION: These results support a reevaluation of the role of surgery in the multimodality therapy for small cell lung cancer, which currently includes only radiotherapy and chemotherapy.

PMID 15632826  J Thorac Cardiovasc Surg. 2005 Jan;129(1):64-72. doi: 1・・・
著者: J P Pignon, R Arriagada, D C Ihde, D H Johnson, M C Perry, R L Souhami, O Brodin, R A Joss, M S Kies, B Lebeau
雑誌名: N Engl J Med. 1992 Dec 3;327(23):1618-24. doi: 10.1056/NEJM199212033272302.
Abstract/Text BACKGROUND: In spite of 16 randomized trials conducted during the past 15 years, the effect of thoracic radiotherapy on the survival of patients with limited small-cell lung cancer remains controversial. The majority of these trials did not have enough statistical power to detect a difference in survival of 5 to 10 percent at five years. This meta-analysis was designed to evaluate the hypothesis that thoracic radiotherapy contributes to a moderate increase in overall survival in limited small-cell lung cancer.
METHODS: We collected individual data on all patients enrolled before December 1988 in randomized trials comparing chemotherapy alone with chemotherapy combined with thoracic radiotherapy. Trials that included only patients with extensive disease were excluded.
RESULTS: The meta-analysis included 13 trials and 2140 patients with limited disease. A total of 433 patients with extensive disease were excluded. Overall, 1862 of 2103 patients who could be evaluated died; the median follow-up period for the surviving patients was 43 months. The relative risk of death in the combined-therapy group as compared with the chemotherapy group was 0.86 (95 percent confidence interval, 0.78 to 0.94; P = 0.001), corresponding to a 14 percent reduction in the mortality rate. The benefit in terms of overall survival at three years (+/- SD) was 5.4 +/- 1.4 percent. Indirect comparison of early with late radiotherapy and of sequential with non-sequential radiotherapy did not reveal any optimal time for treatment. There was a trend toward a larger reduction in mortality among younger patients: the relative risk of death in the combined-therapy as compared with the chemotherapy group ranged from 0.72 for patients less than 55 years old (95 percent confidence interval, 0.56 to 0.93) to 1.07 (0.70 to 1.64) for patients over 70.
CONCLUSIONS: Thoracic radiotherapy moderately improves survival in patients with limited small-cell lung cancer who are treated with combination chemotherapy. Identification of the optimal combination of chemotherapy and radiotherapy will require further trials.

PMID 1331787  N Engl J Med. 1992 Dec 3;327(23):1618-24. doi: 10.1056/・・・
著者: P Warde, D Payne
雑誌名: J Clin Oncol. 1992 Jun;10(6):890-5.
Abstract/Text PURPOSE: Our main purpose was to determine whether the addition of thoracic radiation therapy to systemic chemotherapy improves 2-year survival, improves local (intrathoracic) tumor control, and affects treatment-related mortality in patients with limited-stage small-cell carcinoma of the lung.
DESIGN: Eleven randomized trials addressing this issue were identified using a computerized literature search (Medline and Cancerline) and by polling senior investigators in the field. A meta-analysis was then performed and the results of the trials were analyzed in two ways, the odds ratio (OR) (Peto) method and the risk difference method (Dersimonian and Laird).
RESULTS: The overall OR for benefit of thoracic radiation on 2-year survival (ie, the odds of surviving 2 years among patients allocated to radiation compared with the odds of surviving 2 years among patients allocated to control) is 1.53 (95% confidence interval [CI], 1.30 to 1.76; chi 2 = 12.76; P less than .001). The risk difference method showed that radiation therapy improved 2-year survival by 5.4% (95% CI, 1.1% to 9.7%). Local control results were available for only nine studies, the OR for treatment benefit is 3.02 (95% CI, 2.80 to 3.24; chi 2 = 101.48; P less than .0001), and intrathoracic tumor control was improved by 25.3% (95% CI, 16.5% to 34.1%). The OR for excess treatment-related deaths in the thoracic radiation-treated patients was 2.54 (95% CI, 1.90 to 3.18; chi 2 = 8.24; P less than .01). The risk difference for treatment-related deaths was 1.2% (95% CI, -0.6% to 3.0%).
CONCLUSIONS: This meta-analysis shows a small but significant improvement in survival and a major improvement in tumor control in the thorax in patients receiving thoracic radiation therapy. However, this is achieved at the cost of a small increase in treatment-related mortality.

PMID 1316951  J Clin Oncol. 1992 Jun;10(6):890-5.
著者: Minoru Takada, Masahiro Fukuoka, Masaaki Kawahara, Takahiko Sugiura, Akira Yokoyama, Soichiro Yokota, Yutaka Nishiwaki, Koshiro Watanabe, Kazumasa Noda, Tomohide Tamura, Haruhiko Fukuda, Nagahiro Saijo
雑誌名: J Clin Oncol. 2002 Jul 15;20(14):3054-60.
Abstract/Text PURPOSE: To evaluate the optimal timing for thoracic radiotherapy (TRT) in limited-stage small-cell lung cancer (LS-SCLC), the Lung Cancer Study Group of the Japan Clinical Oncology Group conducted a phase III study in which patients were randomized to sequential TRT or concurrent TRT.
PATIENTS AND METHODS: We treated 231 patients with LS-SCLC. TRT consisted of 45 Gy over 3 weeks (1.5 Gy twice daily), and the patients were randomly assigned to receive either sequential or concurrent TRT. All patients received four cycles of cisplatin plus etoposide every 3 weeks (sequential arm) or 4 weeks (concurrent arm). TRT was begun on day 2 of the first cycle of chemotherapy in the concurrent arm and after the fourth cycle in the sequential arm.
RESULTS: Concurrent radiotherapy yielded better survival than sequential radiotherapy (P =.097 by log-rank test). The median survival time was 19.7 months in the sequential arm versus 27.2 months in the concurrent arm. The 2-, 3-, and 5-year survival rates for patients who received sequential radiotherapy were 35.1%, 20.2%, and 18.3%, respectively, as opposed to 54.4%, 29.8% and 23.7%, respectively, for the patients who received concurrent radiotherapy. Hematologic toxicity was more severe in the concurrent arm. However, severe esophagitis was infrequent in both arms, occurring in 9% of the patients in the concurrent arm and 4% in the sequential arm.
CONCLUSION: This study strongly suggests that cisplatin plus etoposide and concurrent radiotherapy is more effective for the treatment of LS-SCLC than cisplatin plus etoposide and sequential radiotherapy.

PMID 12118018  J Clin Oncol. 2002 Jul 15;20(14):3054-60.
著者: N Murray, P Coy, J L Pater, I Hodson, A Arnold, B C Zee, D Payne, E C Kostashuk, W K Evans, P Dixon
雑誌名: J Clin Oncol. 1993 Feb;11(2):336-44.
Abstract/Text PURPOSE: The importance of the timing of thoracic irradiation (TI) in the combined modality therapy of limited-stage small-cell lung cancer (SCLC) was assessed in a randomized trial.
METHODS: All 308 eligible patients received cyclophosphamide, doxorubicin, and vincristine (CAV) alternating with etoposide and cisplatin (EP) every 3 weeks for three cycles of each chemotherapy regimen. Patients randomized to early TI received 40 Gy in 15 fractions over 3 weeks to the primary site concurrent with the first cycle of EP (week 3), and late TI patients received the same radiation concurrent with the last cycle of EP (week 15). After completion of all chemotherapy and TI, patients without progressive disease received prophylactic cranial irradiation (25 Gy in 10 fractions over 2 weeks).
RESULTS: Although complete remission rates were not significantly different between the two arms, progression-free survival (P = .036) and overall survival (P = .008) were superior in the early TI arm. Patients in the late TI arm had a higher risk of brain metastases (P = .006).
CONCLUSION: The early administration of TI in the combined modality therapy of limited-stage SCLC is superior to late or consolidative TI.

PMID 8381164  J Clin Oncol. 1993 Feb;11(2):336-44.
著者: Daniel B Fried, David E Morris, Charles Poole, Julian G Rosenman, Jan S Halle, Frank C Detterbeck, Thomas A Hensing, Mark A Socinski
雑誌名: J Clin Oncol. 2004 Dec 1;22(23):4837-45. doi: 10.1200/JCO.2004.01.178.
Abstract/Text PURPOSE: We employed meta-analytic techniques to evaluate early (E) versus late (L) timing of thoracic radiation therapy (RT) in limited-stage small-cell lung cancer (LS-SCLC). In addition, we assessed the impact of radiation fractionation and chemotherapeutic regimen on timing.
METHODS: Randomized trials published after 1985 addressing timing of RT relative to chemotherapy in LS-SCLC were included. Trials were analyzed by risk ratio (RR), risk difference, and number-needed-to-treat methods.
RESULTS: Overall survival (OS) RRs for all studies were 1.17 at 2 years (95% CI, 1.02 to 1.35; P = .03) and 1.13 at 3 years (95% CI, 0.92 to 1.39; P = .2), indicating a significantly increased 2-year survival for ERT versus LRT patients and suggestive of a similar trend at 3 years. Subset analysis of studies using hyperfractionated RT revealed OS RR for ERT versus LRT of 1.44 (95% CI, 1.17 to 1.77; P = .001) and 1.39 (95% CI, 1.02 to 1.90; P = .04) at 2 and 3 years, respectively, indicating a survival benefit of ERT versus LRT. Studies using once-daily fractionation showed no difference in 2- and 3-year OS RRs for ERT compared with LRT. Studies using platinum-based chemotherapy had OS RRs of 1.30 (95% CI, 1.10 to 1.53; P = .002) and 1.35 (95% CI, 1.07 to 1.70; P = .01) at 2 and 3 years, respectively, favoring ERT. Studies using nonplatinum-based chemotherapy regimens had nonsignificant differences in OS.
CONCLUSION: A small but significant improvement in 2-year OS for ERT versus LRT in LS-SCLC was observed, similar to the benefit of adding RT to chemotherapy or prophylactic cranial irradiation. A greater difference was evident for hyperfractionated RT and platinum-based chemotherapy.

PMID 15570087  J Clin Oncol. 2004 Dec 1;22(23):4837-45. doi: 10.1200/J・・・
著者: Madelon Pijls-Johannesma, Dirk De Ruysscher, Johan Vansteenkiste, Arnold Kester, Isabelle Rutten, Philippe Lambin
雑誌名: Cancer Treat Rev. 2007 Aug;33(5):461-73. doi: 10.1016/j.ctrv.2007.03.002. Epub 2007 May 21.
Abstract/Text BACKGROUND: We undertook a systematic review and literature-based meta-analysis to determine whether the timing of chest radiotherapy may influence the survival of patients with limited stage small cell lung cancer (LS-SCLC).
OBJECTIVES: To establish the most effective way of combining chest radiotherapy with chemotherapy for patients with limited-stage small cell lung cancer in order to improve long-term survival.
MATERIALS: Eligible studies were identified according to the Cochrane Collaboration Guidelines and were randomised controlled clinical trials comparing different timing of chest radiotherapy in patients with LS-SCLC. Early chest irradiation was defined as beginning within 30 days after the start of chemotherapy.
RESULTS: Seven randomised trials were eligible. The overall survival at 2 years or at 5 years was not significantly different between early or late chest radiotherapy. When only trials were considered that used platinum chemotherapy concurrent with chest radiotherapy, significantly higher 2 and 5-year survival rates were observed when chest radiotherapy (RT) was started within 30 days after the start of chemotherapy (2-year survival: HR: 0.73, 95% CI 0.57-0.94, p=0.01; 5-year survival: HR: 0.65, 95% CI 0.45-0.93, p=0.02). This was even more pronounced when the overall treatment time of chest radiotherapy was less than 30 days. In studies that did not show a survival advantage by early chest radiation, a lower dose-intensity of chemotherapy in the early vs. late arm was observed.
CONCLUSIONS: When platinum-based chemotherapy concurrently with chest RT is used, the 2- and 5-year survival rates of patients with LS-SCLC may be in favour of early chest radiotherapy, with a significant difference if the overall treatment time of chest radiation is less than 30 days.

PMID 17513057  Cancer Treat Rev. 2007 Aug;33(5):461-73. doi: 10.1016/j・・・
著者: A T Turrisi, K Kim, R Blum, W T Sause, R B Livingston, R Komaki, H Wagner, S Aisner, D H Johnson
雑誌名: N Engl J Med. 1999 Jan 28;340(4):265-71. doi: 10.1056/NEJM199901283400403.
Abstract/Text BACKGROUND: For small-cell lung cancer confined to one hemithorax (limited small-cell lung cancer), thoracic radiotherapy improves survival, but the best ways of integrating chemotherapy and thoracic radiotherapy remain unsettled. Twice-daily accelerated thoracic radiotherapy has potential advantages over once-daily radiotherapy.
METHODS: We studied 417 patients with limited small-cell lung cancer. All the patients received four 21-day cycles of cisplatin plus etoposide. We randomly assigned these patients to receive a total of 45 Gy of concurrent thoracic radiotherapy, given either twice daily over a three-week period or once daily over a period of five weeks.
RESULTS: Twice-daily treatment beginning with the first cycle of chemotherapy significantly improved survival as compared with concurrent once-daily radiotherapy (P=0.04 by the log-rank test). After a median follow-up of almost 8 years, the median survival was 19 months for the once-daily group and 23 months for the twice-daily group. The survival rates for patients receiving once-daily radiotherapy were 41 percent at two years and 16 percent at five years. For patients receiving twice-daily radiotherapy, the survival rates were 47 percent at two years and 26 percent at five years. Grade 3 esophagitis was significantly more frequent with twice-daily thoracic radiotherapy, occurring in 27 percent of patients, as compared with 11 percent in the once-daily group (P<0.001).
CONCLUSIONS: Four cycles of cisplatin plus etoposide and a course of radiotherapy (45 Gy, given either once or twice daily) beginning with cycle 1 of the chemotherapy resulted in overall two- and five-year survival rates of 44 percent and 23 percent, a considerable improvement in survival rates over previous results in patients with limited small-cell lung cancer.

PMID 9920950  N Engl J Med. 1999 Jan 28;340(4):265-71. doi: 10.1056/N・・・
著者: Steven E Schild, James A Bonner, Thomas G Shanahan, Burke J Brooks, Randolph S Marks, Susan M Geyer, Shauna L Hillman, Gist H Farr, Henry D Tazelaar, James E Krook, Francois J Geoffroy, Muhammad Salim, Robert M Arusell, James A Mailliard, Paul L Schaefer, James R Jett
雑誌名: Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):943-51. doi: 10.1016/j.ijrobp.2004.01.055.
Abstract/Text PURPOSE: This Phase III study was performed to determine whether twice-daily (b.i.d.) radiotherapy (RT) resulted in better survival than once-daily (q.d.) RT for patients with limited-stage small-cell lung cancer (LD-SCLC).
METHODS AND MATERIALS: A total of 310 patients with LD-SCLC initially received three cycles of etoposide and cisplatin. Subsequently, the 261 patients without significant progression were randomized to two cycles of etoposide and cisplatin plus either q.d. RT (50.4 Gy in 28 fractions) or split-course b.i.d. RT (24 Gy in 16 fractions, a 2.5-week break, and 24 Gy in 16 fractions) to the chest. Patients then received a sixth cycle of etoposide and cisplatin followed by prophylactic cranial RT.
RESULTS: Follow-up ranged from 4.6 to 11.9 years (median, 7.4 years). The median survival and 5-year survival rate from randomization was 20.6 months and 21% for patients who received q.d. RT compared with 20.6 months and 22% for those who received b.i.d. RT (p = 0.68), respectively. No statistically significant differences were found in the rates of progression (p = 0.68), intrathoracic failure (p = 0.45), in-field failure (p = 0.62), or distant failure (p = 0.82) between the two treatment arms. No statistically significant difference was found in the overall rate of Grade 3 or worse (p = 0.83) or Grade 4 or worse toxicity (p = 0.95). Grade 3 or worse esophagitis (p = 0.05) was more common in the b.i.d. arm. Grade 5 toxicity occurred in 4 (3%) of 130 patients who received b.i.d. RT compared with 0 (0%) of 131 who received q.d. RT (p = 0.04).
CONCLUSION: Although this study did not demonstrate an advantage to split-course b.i.d. RT, the long-term survival was favorable, likely reflecting the positive influences of concurrent combined modality therapy and prophylactic cranial RT.

PMID 15234027  Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):943-51.・・・
著者: Corinne Faivre-Finn, Michael Snee, Linda Ashcroft, Wiebke Appel, Fabrice Barlesi, Adityanarayan Bhatnagar, Andrea Bezjak, Felipe Cardenal, Pierre Fournel, Susan Harden, Cecile Le Pechoux, Rhona McMenemin, Nazia Mohammed, Mary O'Brien, Jason Pantarotto, Veerle Surmont, Jan P Van Meerbeeck, Penella J Woll, Paul Lorigan, Fiona Blackhall, CONVERT Study Team
雑誌名: Lancet Oncol. 2017 Aug;18(8):1116-1125. doi: 10.1016/S1470-2045(17)30318-2. Epub 2017 Jun 20.
Abstract/Text BACKGROUND: Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer.
METHODS: The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up.
FINDINGS: Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35-58), median overall survival was 30 months (95% CI 24-34) in the twice-daily group versus 25 months (21-31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95-1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50-62) in the twice-daily group and 51% (45-57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI -3·2% to 13·7%]). The most common grade 3-4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3-4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3-4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group).
INTERPRETATION: Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting.
FUNDING: Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).

Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 28642008  Lancet Oncol. 2017 Aug;18(8):1116-1125. doi: 10.1016/S1・・・
著者: Stein Sundstrøm, Roy M Bremnes, Stein Kaasa, Ulf Aasebø, Reidulv Hatlevoll, Ragnar Dahle, Nils Boye, Mari Wang, Tor Vigander, Jan Vilsvik, Eva Skovlund, Einar Hannisdal, Steinar Aamdal, Norwegian Lung Cancer Study Group
雑誌名: J Clin Oncol. 2002 Dec 15;20(24):4665-72.
Abstract/Text PURPOSE: To investigate whether chemotherapy with etoposide and cisplatin (EP) is superior to cyclophosphamide, epirubicin, and vincristine (CEV) in small-cell lung cancer (SCLC).
PATIENTS AND METHODS: A total of 436 eligible patients were randomized to chemotherapy with EP (n = 218) or CEV (n = 218). Patients were stratified according to extent of disease (limited disease [LD], n = 214; extensive disease [ED], n = 222). The EP group received five courses of etoposide 100 mg/m(2) intravenously (IV) and cisplatin 75 mg/m(2) IV on day 1, followed by oral etoposide 200 mg/m(2) daily on days 2 to 4. The CEV group received five courses of epirubicin 50 mg/m(2), cyclophosphamide 1,000 mg/m(2), and vincristine 2 mg, all IV on day 1. In addition, LD patients received thoracic radiotherapy concurrent with chemotherapy cycle 3, and those achieving complete remission during the treatment period received prophylactic cranial irradiation.
RESULTS: The treatment groups were well balanced with regard to age, sex, and prognostic factors such as weight loss, and performance status. The 2- and 5-year survival rates in the EP arm (14% and 5%, P =.0004) were significantly higher compared with those in the CEV arm (6% and 2%). Among LD patients, median survival time was 14.5 months versus 9.7 months in the EP and CEV arms, respectively (P =.001). The 2- and 5-year survival rates of 25% and 10% in the EP arm compared with 8% and 3% in the CEV arm (P =.0001). For ED patients, there was no significant survival difference between the treatment arms. Quality-of-life assessments revealed no major differences between the randomized groups.
CONCLUSION: EP is superior to CEV in LD-SCLC patients. In ED-SCLC patients, the benefits of EP and CEV chemotherapy seem equivalent, with similar survival time and quality of life.

PMID 12488411  J Clin Oncol. 2002 Dec 15;20(24):4665-72.
著者: Kaoru Kubota, Toyoaki Hida, Satoshi Ishikura, Junki Mizusawa, Makoto Nishio, Masaaki Kawahara, Akira Yokoyama, Fumio Imamura, Koji Takeda, Shunichi Negoro, Masao Harada, Hiroaki Okamoto, Nobuyuki Yamamoto, Tetsu Shinkai, Hiroshi Sakai, Kaoru Matsui, Kazuhiko Nakagawa, Taro Shibata, Nagahiro Saijo, Tomohide Tamura, Japan Clinical Oncology Group
雑誌名: Lancet Oncol. 2014 Jan;15(1):106-13. doi: 10.1016/S1470-2045(13)70511-4. Epub 2013 Dec 3.
Abstract/Text BACKGROUND: Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC.
METHODS: We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on day 1) plus AHTRT (1.5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095.
FINDINGS: 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3.2 years (95% CI 2.4-4.1). In the irinotecan and cisplatin group, median overall survival was 2.8 years (95% CI 2.4-3.6); overall survival did not differ between the two groups (hazard ratio 1.09 [95% CI 0.80-1.46], one-sided stratified log-rank p=0.70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group).
INTERPRETATION: Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC.
FUNDING: National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 24309370  Lancet Oncol. 2014 Jan;15(1):106-13. doi: 10.1016/S1470・・・
著者: A Aupérin, R Arriagada, J P Pignon, C Le Péchoux, A Gregor, R J Stephens, P E Kristjansen, B E Johnson, H Ueoka, H Wagner, J Aisner
雑誌名: N Engl J Med. 1999 Aug 12;341(7):476-84. doi: 10.1056/NEJM199908123410703.
Abstract/Text BACKGROUND: Prophylactic cranial irradiation reduces the incidence of brain metastasis in patients with small-cell lung cancer. Whether this treatment, when given to patients in complete remission, improves survival is not known. We performed a meta-analysis to determine whether prophylactic cranial irradiation prolongs survival.
METHODS: We analyzed individual data on 987 patients with small-cell lung cancer in complete remission who took part in seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation. The main end point was survival.
RESULTS: The relative risk of death in the treatment group as compared with the control group was 0.84 (95 percent confidence interval, 0.73 to 0.97; P= 0.01), which corresponds to a 5.4 percent increase in the rate of survival at three years (15.3 percent in the control group vs. 20.7 percent in the treatment group). Prophylactic cranial irradiation also increased the rate of disease-free survival (relative risk of recurrence or death, 0.75; 95 percent confidence interval, 0.65 to 0.86; P<0.001) and decreased the cumulative incidence of brain metastasis (relative risk, 0.46; 95 percent confidence interval, 0.38 to 0.57; P<0.001). Larger doses of radiation led to greater decreases in the risk of brain metastasis, according to an analysis of four total doses (8 Gy, 24 to 25 Gy, 30 Gy, and 36 to 40 Gy) (P for trend=0.02), but the effect on survival did not differ significantly according to the dose. We also identified a trend (P=0.01) toward a decrease in the risk of brain metastasis with earlier administration of cranial irradiation after the initiation of induction chemotherapy.
CONCLUSIONS: Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission.

PMID 10441603  N Engl J Med. 1999 Aug 12;341(7):476-84. doi: 10.1056/N・・・
著者: A P Meert, M Paesmans, T Berghmans, B Martin, C Mascaux, F Vallot, J M Verdebout, J J Lafitte, J P Sculier
雑誌名: BMC Cancer. 2001;1:5. Epub 2001 Jun 19.
Abstract/Text PURPOSE: A systematic review of the literature was carried out to determine the role of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC).
METHODS: To be eligible, full published trials needed to deal with SCLC and to have randomly assigned patients to receive PCI or not. Trials quality was assessed by two scores (Chalmers and ELCWP).
RESULTS: Twelve randomised trials (1547 patients) were found to be eligible. Five evaluated the role of PCI in SCLC patients who had complete response (CR) after chemotherapy. Brain CT scan was done in the work-up in five studies and brain scintigraphy in six. Chalmers and ELCWP scores are well correlated (p < 0.001), with respective median scores of 32.6 and 38.8 %. This meta-analysis based on the available published data reveals a decrease of brain metastases incidence (hazard ratio (HR): 0.48; 95 % confidence interval (CI): 0.39 - 0.60) for all the studies and an improvement of survival (HR: 0.82; 95 % CI: 0.71 - 0.96) in patients in CR in favour of the PCI arm. Unfortunately, long-term neurotoxicity was not adequately described.
CONCLUSIONS: PCI decreases brain metastases incidence and improves survival in CR SCLC patients but these effects were obtained in patients who had no systematic neuropsychological and brain imagery assessments. The long-term toxicity has not been prospectively evaluated. If PCI can be recommended in patients with SCLC and CR documented by a work-up including brain CT scan, data are lacking to generalise its use to any CR situations.

PMID 11432756  BMC Cancer. 2001;1:5. Epub 2001 Jun 19.
著者: Cécile Le Péchoux, Ariane Dunant, Suresh Senan, Aaron Wolfson, Elisabeth Quoix, Corinne Faivre-Finn, Tudor Ciuleanu, Rodrigo Arriagada, Richard Jones, Rinus Wanders, Delphine Lerouge, Agnès Laplanche, Prophylactic Cranial Irradiation (PCI) Collaborative Group
雑誌名: Lancet Oncol. 2009 May;10(5):467-74. doi: 10.1016/S1470-2045(09)70101-9. Epub 2009 Apr 20.
Abstract/Text BACKGROUND: The optimum dose of prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (SCLC) is unknown. A meta-analysis suggested that the incidence of brain metastases might be reduced with higher PCI doses. This randomised clinical trial compared the effect of standard versus higher PCI doses on the incidence of brain metastases.
METHODS: Between September, 1999, and December, 2005, 720 patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy from 157 centres in 22 countries were randomly assigned to a standard (n=360, 25 Gy in 10 daily fractions of 2.5 Gy) or higher PCI total dose (n=360, 36 Gy) delivered using either conventional (18 daily fractions of 2 Gy) or accelerated hyperfractionated (24 fractions in 16 days with two daily sessions of 1.5 Gy separated by a minimum interval of 6 h) radiotherapy. All of the treatment schedules excluded weekends. Randomisation was stratified according to medical centre, age (60 years), and interval between the start of induction treatment and the date of randomisation (180 days). Eligible patients were randomised blindly by the data centre of the Institut Gustave Roussy (PCI99-01 and IFCT) using minimisation, and by the data centres of EORTC (EORTC ROG and LG) and RTOG (for CALGB, ECOG, RTOG, and SWOG), both using block stratification. The primary endpoint was the incidence of brain metastases at 2 years. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov number NCT00005062.
FINDINGS: Five patients in the standard-dose group and four in the higher-dose group did not receive PCI; nonetheless, all randomised patients were included in the effectiveness anlysis. After a median follow-up of 39 months (range 0-89 months), 145 patients had brain metastases; 82 in the standard-dose group and 63 in the higher-dose group. There was no significant difference in the 2-year incidence of brain metastases between the standard PCI dose group and the higher-dose group, at 29% (95% CI 24-35) and 23% (18-29), respectively (hazard ratio [HR] 0.80 [95% CI 0.57-1.11], p=0.18). 226 patients in the standard-dose group and 252 in the higher-dose group died; 2-year overall survival was 42% (95% CI 37-48) in the standard-dose group and 37% (32-42) in the higher-dose group (HR 1.20 [1.00-1.44]; p=0.05). The lower overall survival in the higher-dose group is probably due to increased cancer-related mortality: 189 patients in the standard group versus 218 in the higher-dose group died of progressive disease. Five serious adverse events occurred in the standard-dose group versus zero in the higher-dose group. The most common acute toxic events were fatigue (106 [30%] patients in the standard-dose group vs 121 [34%] in the higher-dose group), headache (85 [24%] vs 99 [28%]), and nausea or vomiting (80 [23%] vs 101 [28%]).
INTERPRETATION: No significant reduction in the total incidence of brain metastases was observed after higher-dose PCI, but there was a significant increase in mortality. PCI at 25 Gy should remain the standard of care in limited-stage SCLC.
FUNDING: Institut Gustave-Roussy, Association pour la Recherche sur le Cancer (2001), Programme Hospitalier de Recherche Clinique (2007). The European Organisation for Research and Treatment of Cancer (EORTC) contribution to this trial was supported by grants 5U10 CA11488-30 through 5U10 CA011488-38 from the US National Cancer Institute.

PMID 19386548  Lancet Oncol. 2009 May;10(5):467-74. doi: 10.1016/S1470・・・
著者: P A Bunn, J Crowley, K Kelly, M B Hazuka, K Beasley, C Upchurch, R Livingston, G R Weiss, W J Hicks, D R Gandara
雑誌名: J Clin Oncol. 1995 Jul;13(7):1632-41.
Abstract/Text PURPOSE: This phase III randomized trial was designed to determine if granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the hematologic toxicity and morbidity induced by chemoradiotherapy in limited-stage small-cell lung cancer (SCLC).
METHODS: This multicenter prospective trial randomized 230 patients to receive chemotherapy and radiotherapy (RT) with or without GM-CSF given on days 4 to 18 of each of six cycles. The primary end point was hematologic toxicity. Secondary end points included the following: nonhematologic toxicities; days of (1) fever, (2) antibiotics, (3) hospitalization, and (4) infection; number of transfusions; drug doses delivered; and response rates and survival.
RESULTS: There was a statistically significant increase in the frequency and duration of life-threatening thrombocytopenia (P < .001) in patients randomized to GM-CSF. GM-CSF patients had significantly more toxic deaths (P < .01), more nonhematologic toxicities, more days in hospital, a higher incidence of intravenous (IV) antibiotic usage, and more transfusions. Patients randomized to GM-CSF had higher WBC and neutrophil nadirs (P < .01), but no significant difference in the frequency of grade 4 leukopenia or neutropenia. Patients randomized to GM-CSF had a lower complete response rate (36% v 44%), but the differences were not significant (P = .29). There were no significant differences in survival (median, 14 months on GM-CSF and 17 months on no GM-CSF; P = .15).
CONCLUSION: GM-CSF, as delivered in this study, should not be included with concurrent chemoradiotherapy treatment programs for limited-stage SCLC. The simultaneous use of hematopoietic colony-stimulating factors (CSFs) and chemoradiotherapy should be performed only in experimental settings. Chemoradiotherapy programs with cisplatin and etoposide ([VP-16] PE) and simultaneous chest RT produce grade 4 neutropenia and thrombocytopenia in a small-enough proportion of patients that prophylactic hematopoietic growth factors are clinically unnecessary.

PMID 7602352  J Clin Oncol. 1995 Jul;13(7):1632-41.
著者: Martin Weinmann, Branislav Jeremic, Michael Bamberg, Carsten Bokemeyer
雑誌名: Lung Cancer. 2003 Apr;40(1):1-16.
Abstract/Text There is a general trend worldwide of an increasing incidence of elderly population. Age is the greatest risk factor for cancer; therefore, this demographic shift is a main reason for an increase of cancer incidence. Lung cancer is a typical disease of the elderly patients. Small cell lung cancer (SCLC) accounts for approximately 20% of all lung cancer cases. This review summarises the issues of treatment of SCLC in elderly. The number of randomised phase III trials concerning treatment of SCLC in elderly patients are very limited. Although currently most treatment decisions are based on lower grades of evidence, some conclusions can be drawn from the current studies. Age alone is a very uncertain prognostic criteria for outcome or tolerability of treatment. Much more important is the geriatric assessment of each individual patient. Current treatment standards for limited disease (LD)-SCLC (polychemotherapy plus local thoracic irradiation and additional prophylactic cranial irradiation in case of complete remission) seems to be also feasible for 'fit' elderly (>70 years) LD-SCLC patients with a good performance and full functional capacities. There are preliminary data indicating that a similar outcome in elderly patients can probably be achieved a with reduced number of treatment schedules (e.g. 2 instead of 4 cycles in combination with radiotherapy. Surgical resection is also feasible in selected elderly patients with very early stage SCLC, where this maybe an appropriate approach, although no phase III data are available, which demonstrated the benefit of additional surgery compared to chemotherapy alone in early stage SCLC. In patients with extensive disease-SCLC age alone does not necessarily restrict the use of multiagent regimen, although the risk of haematological toxicity seems to be higher than in the younger patients. When standard treatment is not feasible due to co-morbidity or loss of functional capacity, several alternative combination regimens are available, which appear to be slightly superior to single agent treatment, although randomised data for elderly on that issue are sparse. Carboplatin and etoposide seems currently the most appropriate two-drug combination in elderly patients, but there are a variety of active and low toxic third generation agents like taxanes, gemcitabine and vinorelbine which are active in both, non-small cell lung cancer and SCLC. For the comparison of trials in elderly patients it will be of key importance to include a comprehensive and standardised geriatric assessment in such studies.

PMID 12660002  Lung Cancer. 2003 Apr;40(1):1-16.
著者: A R Yuen, G Zou, A T Turrisi, W Sause, R Komaki, H Wagner, S C Aisner, R B Livingston, R Blum, D H Johnson
雑誌名: Cancer. 2000 Nov 1;89(9):1953-60.
Abstract/Text BACKGROUND: Elderly patients comprise a significant portion of patients with limited stage small cell lung carcinoma. However, the prognostic importance of age has been controversial, and concern for toxicity often hinders enthusiasm for offering full dose therapy.
METHODS: In this retrospective analysis of Intergroup Trial 0096, the authors compared the outcome of patients 70 years or older to those younger than 70 years. Patients received cisplatin 60 mg/m(2), Day 1 and etoposide 120 mg/m(2), Days 1-3 for 4 cycles and either once or twice daily concurrent thoracic radiotherapy to 45 grays.
RESULTS: Of 381 patients, 50 (13%) were age 70 years or older. The elderly group did not differ significantly from those younger than 70 years with respect to gender distribution, performance status, or weight loss. Severe hematologic toxicity (Grade 4-5: 61% vs. 84%; P < 0.01) and fatal toxicity (1% vs. 10%; P = 0.01) occurred more often among older patients. There were no differences in the frequency of nonhematologic toxicities. Response rate (88% vs. 80%; P = 0.11), event free survival rate (5 year, 19% vs. 16%; P = 0.18), time to local failure, and duration of response did not differ between groups. Overall survival rates (5 year, 22% vs. 16%; P = 0.05) favored those younger than 70 years. Much of the difference in overall survival rates between age groups occurred within the first 6 months on study.
CONCLUSIONS: Elderly patients had similar response and survival rates compared with those younger than 70 years. However, toxicity, particularly hematologic, was greater among the elderly. Selected older patients, such as those with a good performance status, should be considered for optimum treatment approaches.

Copyright 2000 American Cancer Society.
PMID 11064352  Cancer. 2000 Nov 1;89(9):1953-60.
著者: Steven E Schild, Philip J Stella, Burke J Brooks, Sumithra Mandrekar, James A Bonner, William L McGinnis, James A Mailliard, James E Krook, Richard L Deming, Alex A Adjei, Aminah Jatoi, James R Jett
雑誌名: Cancer. 2005 Jun 1;103(11):2349-54. doi: 10.1002/cncr.21034.
Abstract/Text BACKGROUND: A Phase III trial was conducted by the North Central Cancer Treatment Group to determine whether chemotherapy (etoposide and cisplatin) plus either twice-daily radiotherapy (BIDRT) or once-daily radiotherapy (QDRT) resulted in a better outcome for patients with limited-stage small cell lung carcinoma (LD-SCLC). No difference in survival was identified between the two arms. The current analysis examined the relation between age and outcome for patients treated during this trial.
METHODS: The current study included 263 patients with LD-SCLC and an Eastern Cooperative Oncology Group performance status of < or = 2 who were randomized to receive QDRT or split-course BIDRT. The outcomes of the 209 (79%) younger patients (age < 70 years old) were compared with the 54 (21%) elderly patients (age > or = 70 years old).
RESULTS: Elderly patients presented with significantly greater weight loss and poorer performance status. The 2-year and 5-year survival rates were 48% and 22% for younger patients compared with 33% and 17% for older patients (P = 0.14). One specific toxicity (i.e., Grade > or = 4 pneumonitis [according to National Cancer Institute Common Toxicity Criteria]) occurred in 0% of those patients age < 70 years compared with 6% of older patients (P = 0.008). Grade 5 toxicity occurred in 1 of 209 (0.5%) patients age < 70 years compared with 3 of 54 (5.6%) older patients (P = 0.03).
CONCLUSIONS: Despite having more weight loss, poorer performance status, increased pulmonary toxicity, and more deaths due to treatment, survival was not found to be significantly worse in older individuals. Fit elderly patients with LD-SCLC can receive combined-modality therapy with the expectation of relatively favorable long-term survival. Future research should focus on ways to decrease toxicity especially in the elderly.

PMID 15852407  Cancer. 2005 Jun 1;103(11):2349-54. doi: 10.1002/cncr.2・・・
著者: B Jeremic, Y Shibamoto, L Acimovic, S Milisavljevic
雑誌名: Cancer. 1998 Mar 1;82(5):836-41.
Abstract/Text BACKGROUND: It is not clear how well elderly patients with limited small cell lung carcinoma tolerate intensive chemotherapy, and they have often been treated with palliative intent. As an alternative strategy, the authors designed and employed a short term combination regimen consisting of carboplatin and etoposide with accelerated hyperfractionated radiotherapy.
METHODS: Seventy-five patients ages > or = 70 years with a Karnofsky performance status of > or = 60 and no other major medical problems, were enrolled in this study and 72 were evaluable. The protocol consisted of intravenous carboplatin (400 mg/m2) given on Days 1 and 29, oral etoposide (50 mg/m2) given on Days 1-21 and 29-49, and accelerated hyperfractionated radiation at a dose of 1.5 gray (Gy) administered twice daily (total dose, 45 Gy) starting on Day 1.
RESULTS: The median follow-up period was 61 months. The response rate was 75%, and complete response was observed in 57% of the patients. The median survival time was 15 months, and the 2- and 5-year survival rates were 32% and 13%, respectively. Acute Grade 3 leukopenia, thrombocytopenia, and esophagitis were observed in 8.3%, 11%, and 2.8% of the patients, respectively. Only one patient experienced Grade 4 acute toxicity (thrombocytopenia). No late toxicity of Grade 3 or higher was observed.
CONCLUSIONS: This combined treatment program was tolerable and produced promising long term results. Elderly patients should not universally be treated with palliative intent. Further studies exploring a potentially more effective regimen are warranted.

PMID 9486571  Cancer. 1998 Mar 1;82(5):836-41.
著者: Takehito Shukuya, Toshiaki Takahashi, Hideyuki Harada, Akira Ono, Hiroaki Akamatsu, Tetsuhiko Taira, Hirotsugu Kenmotsu, Tateaki Naito, Haruyasu Murakami, Masahiro Endo, Kazuhisa Takahashi, Nobuyuki Yamamoto
雑誌名: Jpn J Clin Oncol. 2013 Feb;43(2):176-83. doi: 10.1093/jjco/hys197. Epub 2012 Dec 5.
Abstract/Text BACKGROUND: As clinical trials for limited-disease small-cell lung cancer often exclude elderly patients due to comorbidities and a decline in organ function, the most suitable treatment for limited-disease small-cell lung cancer patients aged 75 years or older still remains unclear.
METHODS: From July 2002 to June 2011, 20 consecutive patients aged 75 years or older, with Stage II to IIIB limited-disease small-cell lung cancer, were scheduled to be treated with concurrent or sequential chemoradiotherapy at the Shizuoka Cancer Center. We reviewed the medical charts of the patients and evaluated their characteristics, treatment compliance, toxicity and antitumor efficacy.
RESULTS: Five patients were treated with concurrent chemoradiotherapy and the other 15 patients were scheduled to be treated with sequential chemoradiotherapy. Of these 15 patients, 12 were treated with four cycles of etoposide (80 mg/m(2), days 1-3, q3-4w) plus carboplatin (area under the curve 5, day 1, q3-4w), followed by thoracic radiotherapy. Of the five patients treated with concurrent chemoradiotherapy, discontinuation of chemotherapy/thoracic radiotherapy occurred in two patients due to toxicity and they suffered a prolonged decrease in performance status. Of the 12 patients treated with etoposide plus carboplatin followed by sequential thoracic radiotherapy, the response rate, median progression-free survival and median overall survival time were 91%, 244 and 601 days.
CONCLUSIONS: These results suggest that concurrent chemoradiotherapy is not feasible for all limited-disease small-cell lung cancer patients aged 75 years or older. The alternative of four cycles of etoposide plus carboplatin followed by thoracic radiotherapy is a candidate for the standard treatment of limited-disease small-cell lung cancer patients in this age group. A further trial is warranted to develop and evaluate the optimal treatment for elderly patients with limited-disease small-cell lung cancer.

PMID 23225910  Jpn J Clin Oncol. 2013 Feb;43(2):176-83. doi: 10.1093/j・・・
著者: J L Pujol, L Carestia, J P Daurès
雑誌名: Br J Cancer. 2000 Jul;83(1):8-15. doi: 10.1054/bjoc.2000.1164.
Abstract/Text Chemotherapy is the backbone of small-cell lung cancer therapy. However, optimal drug combinations and schedules remain to be defined and there is hitherto no world-wide accepted standard regimen. Cisplatin, an alkylating agent with high putative toxicity is currently widely used although its effectiveness in this disease has not been established firmly. We conducted a meta-analysis of published data reporting trials randomizing a cisplatin-containing regimen versus a regimen without this alkylating agent in order to determine possible differences in survival response and toxicity. Nineteen trials have been identified in medical literature (4054 evaluable patients). Ten trials randomized patients to receive a cisplatin-etoposide regimen versus a regimen without any of these two drugs. A subgroup analysis was, therefore, carried out in the nine remaining trials that randomly allocated patients between two regimens differing in the absence or presence of cisplatin, whereas etoposide was given (or not given) in both arms (1579 evaluable patients). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death and the increase in probability of being responders to chemotherapy. There was no significant difference between the cisplatin-containing regimen and the regimen without this drug when the risk of toxic-death was taken into account with respective probabilities of 3.1 and 2.7% (NS). Patients randomized in a cisplatin-containing regimen had an increase in probability of being responders with an OR of 1.35, 95% confidence interval (CI) of 1.18-1.55; P < 10(-5) corresponding to an increase of objective (partial plus complete) response rate from 0.62 to 0.69 (a result taking into account a significant heterogeneity). Patients treated with a cisplatin-containing regimen benefited from a significant reduction of risk of death at 6 months and 1 year with respective OR 0.87, 95% CI 0.75-0.98, P = 0.03, and or 0.80, 95% CI 0.69-0.93, P = 0.002 (no statistical heterogeneity). This corresponded to a significant increase in the probability of survival of 2.6% and 4.4% at 6 months and 1 year respectively. The meta-analysis restricted to the subset of nine trials without etoposide treatment imbalance reached similar conclusions. A cisplatin-containing regimen yields a higher response rate and probability of survival than does a chemotherapy containing others alkylating agents without a perceptible increase in risk of toxic-death.

PMID 10883661  Br J Cancer. 2000 Jul;83(1):8-15. doi: 10.1054/bjoc.200・・・
著者: C Mascaux, M Paesmans, T Berghmans, F Branle, J J Lafitte, F Lemaitre, A P Meert, P Vermylen, J P Sculier, European Lung Cancer Working Party (ELCWP)
雑誌名: Lung Cancer. 2000 Oct;30(1):23-36.
Abstract/Text PURPOSE: Cisplatin (CDDP) and etoposide (VP16) are considered major standard cytotoxic drugs for small cell lung cancer (SCLC). The present systematic review had as its objective the evaluation of their role, as components of chemotherapy regimens, on survival.
METHODS: Published randomised clinical trials (from 1980 to 1998) were selected comparing, in SCLC patients, chemotherapy regimens, given as first-line therapy. One arm (the experimental arm) had to include CDDP and/or VP16, while another had to omit the same drug(s). Trials quality was assessed by two published scores (Chalmers and European Lung Cancer Working Party (ELCWP)). For each individual trial, the hazard ratio (HR) of the survival distributions was estimated on the basis of reported statistics or, if not available, by extracting, from the survival graphical representations, the data required to construct the difference between expected and observed numbers of events as calculated in the log-rank statistic. A combined hazard ratio was obtained by the Peto method (a value < 1 meaning a benefit for CDDP and/or VP16).
RESULTS: Thirty-six trials eligible for our systematic review were identified, classified into four groups (I-IV): group I, 1 trial testing a CDDP-based regimen (without VP16) against another arm not including either CDDP or VP16; group II, 17 trials testing a VP16-based regimen (without CDDP) against a regimen without VP16 and CDDP; group III, nine trials comparing a regimen including CDDP and VP16 with a regimen using neither drug; and, finally, group IV, nine trials comparing a regimen based on both drugs with a regimen based on VP16 only. Overall, Chalmers and ELCWP scores correlated well (r(S) = 0.76, P < 0. 001) and had respective median scores of 50.3 and 63.7%. The number of eligible patients did not have a significant impact on the scores as well as the trials group, the trial positivity (a positive trial defined as showing itself a statistically significant survival benefit for the experimental regimen), overall or in categories, and the year of publication. Combined hazard ratios with 95% confidence intervals were: 0.70 (0.41-1.21) for group I, 0.72 (0.67-0.78) for II, 0.57 (0.51-0.64) for III, and 0.74 (0.66-0.83) for IV, showing a survival benefit in favour of regimens including etoposide alone or in combination with cisplatin, justifying with high significance levels the use of each of these drugs. Overall survival benefits could also be shown for regimens including CDDP (HR = 0.61; confidence interval (CI), 0.57-0.66), as well as for those including VP16 (HR = 0. 65; CI, 0.61-0.69). Robustness of these results has to be confirmed with appropriate randomised trials.

PMID 11008007  Lung Cancer. 2000 Oct;30(1):23-36.
著者: H Okamoto, K Watanabe, Y Nishiwaki, K Mori, Y Kurita, I Hayashi, M Masutani, K Nakata, S Tsuchiya, H Isobe, N Saijo
雑誌名: J Clin Oncol. 1999 Nov;17(11):3540-5.
Abstract/Text PURPOSE: The target area under the plasma-concentration-versus-time curve (AUC)-based dosing of carboplatin using Calvert's formula is expected to result in more acceptable toxicity and greater efficacy in elderly patients with small-cell lung cancer (SCLC) than the body surface area-based dosing strategy. This phase II study was designed to determine the toxicity and efficacy of carboplatin based on Calvert's formula plus the standard dose of intravenous etoposide for elderly patients with SCLC.
PATIENTS AND METHODS: Carboplatin, dosed to a target AUC of 5 x (24-hour creatinine clearance + 25), was given intravenously on day 1 and etoposide 100 mg/m(2) was given intravenously on days 1, 2, and 3. Patients aged >/= 70 years old with a performance status of 0 to 2 were eligible.
RESULTS: Thirty-six patients were enrolled onto the study. The patient characteristics were as follows: median age, 73 years; limited disease (LD), 16 patients; and extensive disease (ED), 20 patients. Grades 3 and 4 leukopenia occurred in 57% and 3% of patients, and grades 3 and 4 thrombocytopenia occurred in 40% and 11% of patients, respectively. There was one treatment-related death due to hemoptysis. Other toxicities were relatively mild. There were two complete responses and 25 partial responses, for a response rate of 75%. The median survival time was 10.8 months (LD, 11.6 months; ED, 10.1 months), and the 1-year survival rate was 47%.
CONCLUSION: This carboplatin/etoposide combination chemotherapy is an active and relatively nontoxic regimen in elderly patients with SCLC, which suggests that the combination may be suitable for randomized controlled trials.

PMID 10550152  J Clin Oncol. 1999 Nov;17(11):3540-5.
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: Gregory M M Videtic, Larry W Stitt, A Rashid Dar, Walter I Kocha, Anna T Tomiak, Pauline T Truong, Mark D Vincent, Edward W Yu
雑誌名: J Clin Oncol. 2003 Apr 15;21(8):1544-9. doi: 10.1200/JCO.2003.10.089.
Abstract/Text PURPOSE: To determine the impact of continued smoking by patients receiving chemotherapy (CHT) and radiotherapy (RT) for limited-stage small-cell lung cancer (LSCLC) on toxicity and survival.
PATIENTS AND METHODS: A retrospective review was carried out on 215 patients with LSCLC treated between 1989 and 1999. Treatment consisted of six cycles of alternating cyclophosphamide, doxorubicin, vincristine and etoposide, cisplatin (EP). Thoracic RT was concurrent with EP (cycle 2 or 3) only. Patients were known smokers, with their smoking status recorded at the start of chemoradiotherapy (CHT/RT). RT interruption during concurrent CHT/RT was used as the marker for treatment toxicity.
RESULTS: Of 215 patients, smoking status was recorded for 186 patients (86.5%), with 79 (42%) continuing to smoke and 107 (58%) abstaining during CHT/RT. RT interruptions were recorded in 38 patients (20.5%), with a median duration of 5 days (range, 1 to 18 days). Median survival for former smokers was greater than for continuing smokers (18 v 13.6 months), with 5-year actuarial overall survival of 8.9% versus 4%, respectively (log-rank P =.0017). Proportion of noncancer deaths was comparable between the two cohorts. Continuing smokers did not have a greater incidence of toxicity-related treatment breaks (P =.49), but those who continued to smoke and also experienced a treatment break had the poorest overall survival (median, 13.4 months; log-rank P =.0014).
CONCLUSION: LSCLC patients who continue to smoke during CHT/RT have poorer survival rates than those who do not. Smoking did not have an impact on the rate of treatment interruptions attributed to toxicity.

PMID 12697879  J Clin Oncol. 2003 Apr 15;21(8):1544-9. doi: 10.1200/JC・・・
著者: A Parsons, A Daley, R Begh, P Aveyard
雑誌名: BMJ. 2010 Jan 21;340:b5569. Epub 2010 Jan 21.
Abstract/Text OBJECTIVE: To systematically review the evidence that smoking cessation after diagnosis of a primary lung tumour affects prognosis.
DESIGN: Systematic review with meta-analysis.
DATA SOURCES: CINAHL (from 1981), Embase (from 1980), Medline (from 1966), Web of Science (from 1966), CENTRAL (from 1977) to December 2008, and reference lists of included studies.
STUDY SELECTION: Randomised controlled trials or observational longitudinal studies that measured the effect of quitting smoking after diagnosis of lung cancer on prognostic outcomes, regardless of stage at presentation or tumour histology, were included.
DATA EXTRACTION: Two researchers independently identified studies for inclusion and extracted data. Estimates were combined by using a random effects model, and the I(2) statistic was used to examine heterogeneity. Life tables were used to model five year survival for early stage non-small cell lung cancer and limited stage small cell lung cancer, using death rates for continuing smokers and quitters obtained from this review.
RESULTS: In 9/10 included studies, most patients studied were diagnosed as having an early stage lung tumour. Continued smoking was associated with a significantly increased risk of all cause mortality (hazard ratio 2.94, 95% confidence interval 1.15 to 7.54) and recurrence (1.86, 1.01 to 3.41) in early stage non-small cell lung cancer and of all cause mortality (1.86, 1.33 to 2.59), development of a second primary tumour (4.31, 1.09 to 16.98), and recurrence (1.26, 1.06 to 1.50) in limited stage small cell lung cancer. No study contained data on the effect of quitting smoking on cancer specific mortality or on development of a second primary tumour in non-small cell lung cancer. Life table modelling on the basis of these data estimated 33% five year survival in 65 year old patients with early stage non-small cell lung cancer who continued to smoke compared with 70% in those who quit smoking. In limited stage small cell lung cancer, an estimated 29% of continuing smokers would survive for five years compared with 63% of quitters on the basis of the data from this review.
CONCLUSIONS: This review provides preliminary evidence that smoking cessation after diagnosis of early stage lung cancer improves prognostic outcomes. From life table modelling, the estimated number of deaths prevented is larger than would be expected from reduction of cardiorespiratory deaths after smoking cessation, so most of the mortality gain is likely to be due to reduced cancer progression. These findings indicate that offering smoking cessation treatment to patients presenting with early stage lung cancer may be beneficial.

PMID 20093278  BMJ. 2010 Jan 21;340:b5569. Epub 2010 Jan 21.

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