今日の臨床サポート

非小細胞肺癌(初期)

著者: 内野順治 京都府立医科大学大学院医学研究科 呼吸器内科学

著者: 髙山浩一 京都府立医科大学大学院医学研究科 呼吸器内科学

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:2021/01/20
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
患者向け説明資料

概要・推奨   

  1. 非小細胞肺癌の術前病期診断(縦隔リンパ節転移)に際し、PET、PET/CTは臨床上有用である。非小細胞肺癌の治療前評価にPET/CTは推奨される(スクリーニングでは推奨されない)(推奨度2)
  1. 非小細胞肺癌の術前病期診断(縦隔リンパ節転移)に際し、縦隔鏡検査前に非侵襲的な超音波内視鏡下縦隔リンパ節生検を行うことで診断精度は向上する(推奨度2)
  1. FDG-PET/CT(あるいはFDG-PET)は、骨シンチグラフィーあるいはMRI検査と比較して肺癌骨転移診断の感度・特異度とも優れている。癌診療においてPET/CT検査は必要不可欠なものとなりつつある(推奨度2)
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
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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:
内野順治 : 未申告[2021年]
髙山浩一 : 未申告[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. 定期レビューを行った(変更なし)。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 2017年の肺癌死亡数は男性5万3,002人、女性2万1,118人に上り、部位別総死亡数は男性では1位、女性では大腸癌(結腸癌+直腸癌)に次ぎ2位である。
  1. 年齢階級別では75歳以上の高齢者の死亡率上昇が著しい。
  1. 病理学的には、現在のところ、非小細胞癌85%強、小細胞癌10%強程度であるが、小細胞癌の割合は減少傾向にある一方で腺癌は増加傾向にある。
  1. 最も重要な危険因子は喫煙だが、慢性閉塞性肺疾患やアスベストなどへの職業的曝露も肺癌リスクを高める。
  1. 病理学的な組織診断と病期診断に加えて、年齢、合併症などの患者背景を考慮し、手術、放射線療法、化学療法の適応を決定する。
問診・診察のポイント  
  1. 肺癌に特徴的な症状はないが、多くの場合、長引く咳嗽、血痰、呼吸困難、嗄声、胸痛などの胸部症状などで医療機関を受診し発見される。

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文献 

著者: Michael K Gould, Ware G Kuschner, Chara E Rydzak, Courtney C Maclean, Anita N Demas, Hidenobu Shigemitsu, Jo Kay Chan, Douglas K Owens
雑誌名: Ann Intern Med. 2003 Dec 2;139(11):879-92.
Abstract/Text PURPOSE: To compare the diagnostic accuracy of computed tomography (CT) and positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) for mediastinal staging in patients with non-small-cell lung cancer and to determine whether test results are conditionally dependent (the sensitivity and specificity of FDG-PET depend on the presence or absence of enlarged mediastinal lymph nodes on CT).
DATA SOURCES: Computerized search of MEDLINE, EMBASE, BIOSIS, and CancerLit through March 2003 and reference lists of retrieved studies and review articles.
STUDY SELECTION: Studies in any language that examined FDG-PET for mediastinal staging in patients with known or suspected non-small-cell lung cancer, enrolled at least 10 participants (including at least 5 participants with mediastinal metastasis), and provided enough data to permit calculation of sensitivity and specificity for identifying lymph node involvement.
DATA EXTRACTION: One reviewer (of non-English-language studies) or 2 reviewers (of English-language studies) independently evaluated studies for inclusion, rated methodologic quality, and abstracted relevant data.
DATA SYNTHESIS: Thirty-nine studies met inclusion criteria. Methodologic quality varied, but few aspects of study quality affected diagnostic accuracy. The authors constructed summary receiver-operating characteristic curves for CT and FDG-PET. Positron emission tomography with 18-fluorodeoxyglucose was more accurate than CT for identifying lymph node involvement (P < 0.001). For CT, median sensitivity and specificity were 61% (interquartile range, 50% to 71%) and 79% (interquartile range, 66% to 89%), respectively. For FDG-PET, median sensitivity and specificity were 85% (interquartile range, 67% to 91%) and 90% (interquartile range, 82% to 96%), respectively. Fourteen studies provided information about the conditional test performance of CT and FDG-PET. Positron emission tomography with 18-fluorodeoxyglucose was more sensitive but less specific when CT showed enlarged lymph nodes (median sensitivity, 100% [interquartile range, 90% to 100%]; median specificity, 78% [interquartile range, 68% to 100%]) than when CT showed no lymph node enlargement (median sensitivity, 82% [interquartile range, 65% to 100%]; median specificity, 93% [interquartile range, 92% to 100%]; P = 0.002).
CONCLUSIONS: Positron emission tomography with 18-fluorodeoxyglucose is more accurate than CT for mediastinal staging. Positron emission tomography with 18-fluorodeoxyglucose is more sensitive but less specific when CT shows enlarged mediastinal lymph nodes.

PMID 14644890  Ann Intern Med. 2003 Dec 2;139(11):879-92.
著者: Barbara Fischer, Ulrik Lassen, Jann Mortensen, Søren Larsen, Annika Loft, Anne Bertelsen, Jesper Ravn, Paul Clementsen, Asbjørn Høgholm, Klaus Larsen, Torben Rasmussen, Susanne Keiding, Asger Dirksen, Oke Gerke, Birgit Skov, Ida Steffensen, Hanne Hansen, Peter Vilmann, Grete Jacobsen, Vibeke Backer, Niels Maltbaek, Jesper Pedersen, Henrik Madsen, Henrik Nielsen, Liselotte Højgaard
雑誌名: N Engl J Med. 2009 Jul 2;361(1):32-9. doi: 10.1056/NEJMoa0900043.
Abstract/Text BACKGROUND: Fast and accurate staging is essential for choosing treatment for non-small-cell lung cancer (NSCLC). The purpose of this randomized study was to evaluate the clinical effect of combined positron-emission tomography and computed tomography (PET-CT) on preoperative staging of NSCLC.
METHODS: We randomly assigned patients who were referred for preoperative staging of NSCLC to either conventional staging plus PET-CT or conventional staging alone. Patients were followed until death or for at least 12 months. The primary end point was the number of futile thoracotomies, defined as any one of the following: a thoracotomy with the finding of pathologically confirmed mediastinal lymph-node involvement (stage IIIA [N2]), stage IIIB or stage IV disease, or a benign lung lesion; an exploratory thoracotomy; or a thoracotomy in a patient who had recurrent disease or death from any cause within 1 year after randomization.
RESULTS: From January 2002 through February 2007, we randomly assigned 98 patients to the PET-CT group and 91 to the conventional-staging group. Mediastinoscopy was performed in 94% of the patients. After PET-CT, 38 patients were classified as having inoperable NSCLC, and after conventional staging, 18 patients were classified thus. Sixty patients in the PET-CT group and 73 in the conventional-staging group underwent thoracotomy (P=0.004). Among these thoracotomies, 21 in the PET-CT group and 38 in the conventional-staging group were futile (P=0.05). The number of justified thoracotomies and survival were similar in the two groups.
CONCLUSIONS: The use of PET-CT for preoperative staging of NSCLC reduced both the total number of thoracotomies and the number of futile thoracotomies but did not affect overall mortality. (ClinicalTrials.gov number, NCT00867412.)

2009 Massachusetts Medical Society
PMID 19571281  N Engl J Med. 2009 Jul 2;361(1):32-9. doi: 10.1056/NEJM・・・
著者: Donna E Maziak, Gail E Darling, Richard I Inculet, Karen Y Gulenchyn, Albert A Driedger, Yee C Ung, John D Miller, Chu-Shu Gu, Kathryn J Cline, William K Evans, Mark N Levine
雑誌名: Ann Intern Med. 2009 Aug 18;151(4):221-8, W-48. Epub 2009 Jul 6.
Abstract/Text BACKGROUND: Among patients with early-stage non-small cell lung cancer (NSCLC), preoperative imaging tests are important in defining surgical candidates.
OBJECTIVE: To assess whether whole-body positron emission tomography and computed tomography (PET-CT) plus cranial imaging correctly upstages cancer in more patients with NSCLC than does conventional staging plus cranial imaging.
DESIGN: Randomized clinical trial with recruitment from June 2004 to August 2007. The centralized, computer-generated, variable block size randomization scheme was stratified by treatment center and cancer stage. Participants, health care providers, and outcome assessors were not blinded to imaging modality assignment.
SETTING: 8 hospitals and 5 PET-CT centers in academic institutions.
PATIENTS: Eligible patients were older than 18 years; had histologic or cytologic proof of stage I, II, or IIIA NSCLC on the basis of chest radiography and thoracic CT; and had a tumor considered to be resectable.
INTERVENTION: PET-CT or conventional staging (abdominal CT and bone scan). All patients also had cranial imaging using CT or magnetic resonance imaging.
MEASUREMENTS: The primary outcome was correct upstaging, thereby avoiding stage-inappropriate surgery. Secondary outcomes were incorrect upstaging and incorrect understaging.
RESULTS: 170 patients were assigned to PET-CT and 167 to conventional staging. Eight patients (3 who had PET-CT and 5 who had conventional staging) did not have planned surgery. Disease was correctly upstaged in 23 of 167 PET-CT recipients and 11 of 162 conventional staging recipients (13.8% vs. 6.8%; difference, 7.0 percentage points [95% CI, 0.3 to 13.7 percentage points]), thereby sparing these patients from surgery. Disease was incorrectly upstaged in 8 PET-CT recipients and 1 conventional staging recipient (4.8% vs. 0.6%; difference, 4.2 percentage points [CI, 0.5 to 8.6 percentage points]), and it was incorrectly understaged in 25 and 48 patients, respectively (14.9% vs. 29.6%; difference, 14.7 percentage points [CI, 5.7 to 23.4 percentage points]). At 3 years, 52 patients who had PET-CT and 57 patients who had conventional staging had died. Limitation: The relatively small sample and the fact that some patients did not have planned surgery limited the ability to determine precise differences in clinical outcomes that were attributable to testing strategies.
CONCLUSION: Preoperative staging with PET-CT and cranial imaging identifies more patients with mediastinal and extrathoracic disease than conventional staging, thereby sparing more patients from stage-inappropriate surgery, but the strategy also incorrectly upstaged disease in more patients.

PMID 19581636  Ann Intern Med. 2009 Aug 18;151(4):221-8, W-48. Epub 20・・・
著者: Jouke T Annema, Jan P van Meerbeeck, Robert C Rintoul, Christophe Dooms, Ellen Deschepper, Olaf M Dekkers, Paul De Leyn, Jerry Braun, Nicholas R Carroll, Marleen Praet, Frederick de Ryck, Johan Vansteenkiste, Frank Vermassen, Michel I Versteegh, Maud Veseliç, Andrew G Nicholson, Klaus F Rabe, Kurt G Tournoy
雑誌名: JAMA. 2010 Nov 24;304(20):2245-52. doi: 10.1001/jama.2010.1705.
Abstract/Text CONTEXT: Mediastinal nodal staging is recommended for patients with resectable non-small cell lung cancer (NSCLC). Surgical staging has limitations, which results in the performance of unnecessary thoracotomies. Current guidelines acknowledge minimally invasive endosonography followed by surgical staging (if no nodal metastases are found by endosonography) as an alternative to immediate surgical staging.
OBJECTIVE: To compare the 2 recommended lung cancer staging strategies.
DESIGN, SETTING, AND PATIENTS: Randomized controlled multicenter trial (Ghent, Leiden, Leuven, Papworth) conducted between February 2007 and April 2009 in 241 patients with resectable (suspected) NSCLC in whom mediastinal staging was indicated based on computed or positron emission tomography.
INTERVENTION: Either surgical staging or endosonography (combined transesophageal and endobronchial ultrasound [EUS-FNA and EBUS-TBNA]) followed by surgical staging in case no nodal metastases were found at endosonography. Thoracotomy with lymph node dissection was performed when there was no evidence of mediastinal tumor spread.
MAIN OUTCOME MEASURES: The primary outcome was sensitivity for mediastinal nodal (N2/N3) metastases. The reference standard was surgical pathological staging. Secondary outcomes were rates of unnecessary thoracotomy and complications.
RESULTS: Two hundred forty-one patients were randomized, 118 to surgical staging and 123 to endosonography, of whom 65 also underwent surgical staging. Nodal metastases were found in 41 patients (35%; 95% confidence interval [CI], 27%-44%) by surgical staging vs 56 patients (46%; 95% CI, 37%-54%) by endosonography (P = .11) and in 62 patients (50%; 95% CI, 42%-59%) by endosonography followed by surgical staging (P = .02). This corresponded to sensitivities of 79% (41/52; 95% CI, 66%-88%) vs 85% (56/66; 95% CI, 74%-92%) (P = .47) and 94% (62/66; 95% CI, 85%-98%) (P = .02). Thoracotomy was unnecessary in 21 patients (18%; 95% CI, 12%-26%) in the mediastinoscopy group vs 9 (7%; 95% CI, 4%-13%) in the endosonography group (P = .02). The complication rate was similar in both groups.
CONCLUSIONS: Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00432640.

PMID 21098770  JAMA. 2010 Nov 24;304(20):2245-52. doi: 10.1001/jama.20・・・
著者: Xinhua Qu, Xiaolu Huang, Weili Yan, Lianming Wu, Kerong Dai
雑誌名: Eur J Radiol. 2012 May;81(5):1007-15. doi: 10.1016/j.ejrad.2011.01.126. Epub 2011 Feb 26.
Abstract/Text BACKGROUND AND PURPOSE: Lung cancer is the most common cause of cancer related death among both men and women worldwide. The skeleton is the most common site of cancer metastasis. Early detection is crucial for prognosis. To evaluate and compare the capability for bone metastasis assessment of [(18)F] fluoro-2-d-glucose positron emission tomography with computed tomography ((18)FDG-PET-CT), [(18)F] fluoro-2-d-glucose positron emission tomography ((18)FDG-PET), magnetic resonance imaging (MRI) and bone scintigraphy (BS) in lung cancer patients, a meta-analysis is preformed.
METHODS: We searched MEDLINE, OVID, EMBASE and the Cochrane Library for studies evaluating diagnosis validity of (18)FDG-PET-CT, (18)FDG-PET, MRI and BS between January 1990 and August 2010. Meta-analysis methods were used to pool sensitivity, specificity, diagnostic odd ratios (DORs) and to construct a summary receiver-operating characteristic curve (SROC).
RESULTS: A total of 17 articles (9 (18)FDG-PET-CT studies, 9 (18)FDG-PET studies, 6 MRI studies and 16 BS studies) that included 2940 patients who fulfilled all of the inclusion criteria were considered for inclusion in the analysis. The pooled sensitivity for the detection of bone metastasis in lung cancer using (18)FDG-PET-CT, (18)FDG-PET, MRI and BS were 0.92 (95% CI, 0.88-0.95), 0.87 (95% CI, 0.81-0.92), 0.77 (95% CI, 0.65-0.87) and 0.86 (95% CI, 0.82-0.89), respectively. The pooled specificity for the detection of bone metastasis from lung cancer using (18)FDG-PET-CT, (18)FDG-PET, MRI and BS were 0.98 (95% CI, 0.97-0.98), 0.94 (95% CI, 0.92-0.96), 0.92 (95% CI, 0.88-0.95), 0.88 (95% CI, 0.86-0.89), respectively. The pooled DORs estimates for (18)FDG-PET-CT 449.17 were significantly higher than for (18)FDG-PET (118.25, P<0.001), MRI (38.27, P<0.001) and BS (63.37, P<0.001). The pooled sensitivity of BS was not correlated with the prevalence of bone metastasis.
CONCLUSION: The results showed that both (18)FDG-PET-CT and (18)FDG-PET were better imaging methods for diagnosing bone metastasis from lung cancer than MRI and BS. (18)FDG-PET-CT has higher diagnostic value (sensitivity, specificity and DORs) for diagnosing bone metastasis from lung cancer than any other imaging methods.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
PMID 21354739  Eur J Radiol. 2012 May;81(5):1007-15. doi: 10.1016/j.ej・・・
著者: R J Ginsberg, L V Rubinstein
雑誌名: Ann Thorac Surg. 1995 Sep;60(3):615-22; discussion 622-3.
Abstract/Text BACKGROUND: It has been reported that limited resection (segment or wedge) is equivalent to lobectomy in the management of early stage (T1-2 N0) non-small cell lung cancer.
METHODS: A prospective, multiinstitutional randomized trial was instituted comparing limited resection with lobectomy for patients with peripheral T1 N0 non-small cell lung cancer documented at operation. Analysis included locoregional and distant recurrence rates, 5-year survival rates, perioperative morbidity and mortality, and late pulmonary function assessment.
RESULTS: There were 276 patients randomized, with 247 patients eligible for analysis. There were no significant differences for all stratification variables, selected prognostic factors, perioperative morbidity, mortality, or late pulmonary function. In patients undergoing limited resection, there was an observed 75% increase in recurrence rates (p = 0.02, one-sided) attributable to an observed tripling of the local recurrence rate (p = 0.008 two-sided), an observed 30% increase in overall death rate (p = 0.08, one-sided), and an observed 50% increase in death with cancer rate (p = 0.09, one-sided) compared to patients undergoing lobectomy (p = 0.10, one-sided was the predefined threshold for statistical significance for this equivalency study).
CONCLUSIONS: Compared with lobectomy, limited pulmonary resection does not confer improved perioperative morbidity, mortality, or late postoperative pulmonary function. Because of the higher death rate and locoregional recurrence rate associated with limited resection, lobectomy still must be considered the surgical procedure of choice for patients with peripheral T1 N0 non-small cell lung cancer.

PMID 7677489  Ann Thorac Surg. 1995 Sep;60(3):615-22; discussion 622-・・・
著者: H Nakamura, N Kawasaki, M Taguchi, K Kabasawa
雑誌名: Br J Cancer. 2005 Mar 28;92(6):1033-7. doi: 10.1038/sj.bjc.6602414.
Abstract/Text Extent of resection needed to treat lung cancer has long been an issue. The sole randomised controlled trial, reported by the Lung Cancer Study Group, advised against limited resection as standard surgery even for small peripheral non-small-cell lung cancers (< or =3 cm), because of frequent local recurrences. Elsewhere, conflicting results have been reported from different institutions. We therefore conducted a meta-analysis of reported studies to compare survival of stage I patients between limited resection and standard lobectomy. A MEDLINE web search for computer-archived bibliographic data yielded 14 articles suitable for analysis. Combined survival differences (survival rate with lobectomy minus that with limited resection) at 1, 3, and 5 years after resection according to the DerSimonian-Laird random effects model were 0.7% (95% CI, -0.8 to 2.1; P=0.3659), 1.9% (95% CI, -3.7 to 7.4; P=0.5088), and 3.6% (95% CI, -0.4 to 10.5; P=0.3603), respectively. None of these survival differences were significant, indicating that survival after limited resection for stage I lung cancer was comparable to that after lobectomy. However, since interstudy heterogeneity was detected, caution is required in interpretation of the results.

PMID 15756281  Br J Cancer. 2005 Mar 28;92(6):1033-7. doi: 10.1038/sj.・・・
著者: Koichi Yoshikawa, Noriaki Tsubota, Ken Kodama, Hiroyoshi Ayabe, Toshihiko Taki, Takashi Mori
雑誌名: Ann Thorac Surg. 2002 Apr;73(4):1055-8; discussion 1058-9.
Abstract/Text BACKGROUND: Minimal resection of small lung tumors is still controversial. This study was conducted to clarify whether this type of operation is acceptable.
METHODS: From January 1992 to December 1994, 73 patients were registered in a multiinstitutional trial of limited resection for peripheral lung tumors less than 2 cm in diameter. The operative procedure consisted of extended segmentectomy in which the cut line of the lung was beyond the burdened segment, confirming N0 disease by intraoperative lymph node examination of frozen sections. The operation was changed to other procedures if the report was positive.
RESULTS: All the patients were observed more than 5 years. There were no perioperative deaths and no major complications. A total of 55 patients were finally enrolled in this study. Ten patients died postoperatively, 4 of lung cancer and the remaining 6 died of other diseases, with no signs of recurrence. The 5-year survival rate, excluding these 6 patients, was 91.8%; for all patients including those who died it was 81.8%. A total of 18 patients were not included in this study for various reasons. The decrease in forced vital capacity was 11.3% +/- 9.8% compared with the preoperative value.
CONCLUSIONS: Extended segmentectomy is an alternative method as a standard operation for patients with small peripheral lung tumors, and the loss of lung function is minimal. However, patient selection must be strict, with intraoperative pathologic examination, and a wide margin to the lesion beyond the burdened segment is mandatory.

PMID 11996240  Ann Thorac Surg. 2002 Apr;73(4):1055-8; discussion 1058・・・
著者: K Kodama, M Higashiyama, H Yokouchi, K Takami, K Kuriyama, M Mano, T Nakayama
雑誌名: Lung Cancer. 2001 Jul;33(1):17-25.
Abstract/Text OBJECTIVE: This study was undertaken to investigate the value of the ground-glass opacity (GGO) area found on high-resolution computed tomography (HRCT) scanning as a preoperative prognostic indicator.
PATIENTS AND METHODS: We studied 104 patients with small-sized lung adenocarcinoma, 20 mm or less in diameter, between 1995 and 1999. Three independent radiologists semi-quantitatively scored the extent of GGO on HRCT as greater than or less than 50%. Three independent pathologists semi-quantitatively scored the extent of the bronchioloalveolar carcinoma (BAC) component of the tumor on histologic examination as greater than or less than 50%. As no relapse occurred in patients with GGO greater than 50%, multivariate analysis of this prognostic factor was not possible.
RESULTS: Fifty patients were scored as having both BAC and GGO greater than 50%, 36 as both BAC and GGO less than 50%, and 16 as BAC greater than 50% and GGO less than 50%. In only two patients (1.9%), BAC less than 50% was overestimated on HRCT as GGO greater than 50%. The sensitivity and specificity of GGO to BAC were 76 and 95%, respectively. The 3 year-relapse-free survival rates in each group of 52 patients with GGO greater than and less than 50% were 100 and 72%, respectively, after a median follow-up of 24 months. Univariate analysis indicated that both GGO and BAC areas were significantly correlated with cancer relapse (P=0.005 and P=0.002). The multivariate analysis revealed an independent prognostic influence of the BAC area on relapse-free survival (P=0.015, relative risk=0.07).
CONCLUSIONS: To date there has been no relapse among the 52 patients with GGO greater than 50%. This novel classification based on the semiquantitative analysis of GGO area on HRCT should become an useful independent preoperative indicator when deciding on operative procedure, and to predict the potential of relapse in patients with small adenocarcinoma arising from the peripheral lung.

PMID 11429192  Lung Cancer. 2001 Jul;33(1):17-25.
著者: T Aoki, Y Tomoda, H Watanabe, H Nakata, T Kasai, H Hashimoto, M Kodate, T Osaki, K Yasumoto
雑誌名: Radiology. 2001 Sep;220(3):803-9.
Abstract/Text PURPOSE: To evaluate the prognostic importance of thin-section computed tomographic (CT) findings of peripheral lung adenocarcinomas.
MATERIALS AND METHODS: The subjects were 127 patients with adenocarcinomas smaller than 3 cm in largest diameter who underwent at least a lobectomy with hilar and mediastinal lymphadenectomy. The margin characteristics of nodules and the extent of ground-glass opacity (GGO) within the nodules at preoperative thin-section CT were analyzed retrospectively. Regional lymph node metastasis (LNM) and vessel invasion (VI) were histologically examined in surgical specimens. Survival curves were calculated according to the Kaplan-Meier method.
RESULTS: The frequencies of LNM (4% [1 of 24]) and VI (13% [three of 24]) in adenocarcinomas with GGO components of more than 50% were significantly lower than those with GGO components of less than 10% (LNM, P <.05; VI, P <.01). The patients with GGO components of more than 50% showed a significantly better prognosis than those with GGO components less than 50% (P <.05). All 17 adenocarcinomas smaller than 2 cm with GGO components of more than 50% were free of LNM and VI, and all these patients are alive without recurrence. Coarse spiculation and thickening of bronchovascular bundles around the tumors were observed more frequently in tumors with LNM or VI than in those without LNM or VI (P <.01).
CONCLUSION: Thin-section CT findings of peripheral lung adenocarcinomas correlate well with histologic prognostic factors.

PMID 11526285  Radiology. 2001 Sep;220(3):803-9.
著者: Kenji Suzuki, Hisao Asamura, Masahiko Kusumoto, Haruhiko Kondo, Ryosuke Tsuchiya
雑誌名: Ann Thorac Surg. 2002 Nov;74(5):1635-9.
Abstract/Text BACKGROUND: The number of peripherally located lung cancers with an excellent prognosis has been increasing, possibly due to the introduction of computed tomography for lung cancer screening in Japan. The concept of peripherally located "early lung cancer" remains controversial.
METHODS: A retrospective study was conducted on 1,540 lung cancers resected at our institute between May 1992 and December 2000. The sizes of solid attenuation and ground glass opacity were evaluated radiologically and the relationships between radiologic findings and clinicopathologic features were investigated to define peripheral early lung cancer.
RESULTS: Sixty-nine (4.4%) lung cancers showed a large ground glass opacity component on thin-section computed tomographic scan. The maximum tumor dimension ranged from 6 to 41 mm, and all tumors were clinical stage I. Forty-seven patients were diagnosed as having bronchioloalveolar carcinoma pathologically. None of the tumors showed lymph node involvement or lymphatic invasion. Only two showed vascular invasion, but all were pathologic stage I disease. Most of the lung cancers that showed pure ground glass opacity were bronchioloalveolar carcinoma.
CONCLUSIONS: Peripheral lung nodules with a large ground glass opacity component on thin-section computed tomographic scan, which do not disappear during follow-up, tend to be bronchioloalveolar carcinomas or minimally invasive adenocarcinomas of the lung. These findings warrant a feasibility study of limited surgical resection for such lung tumors.

PMID 12440622  Ann Thorac Surg. 2002 Nov;74(5):1635-9.
著者: Kenji Suzuki, Teruaki Koike, Takashi Asakawa, Masahiko Kusumoto, Hisao Asamura, Kanji Nagai, Hirohito Tada, Tetsuya Mitsudomi, Masahiro Tsuboi, Taro Shibata, Haruhiko Fukuda, Harubumi Kato, Japan Lung Cancer Surgical Study Group (JCOG LCSSG)
雑誌名: J Thorac Oncol. 2011 Apr;6(4):751-6. doi: 10.1097/JTO.0b013e31821038ab.
Abstract/Text PURPOSE: Pathological noninvasiveness needs to be precisely predicted in preoperative radiological examinations of patients with early lung cancer for the application of limited surgery.
PATIENTS AND METHODS: Patients with clinical T1N0M0 peripheral lung cancer were recruited. Radiological findings of the main tumor were evaluated as to ground-glass opacity with thin-section computed tomography. The primary end point was specificity, i.e., the proportion of patients with radiologically diagnosed invasive lung cancer to patients with pathologically diagnosed invasive lung cancer. The precision-based planned sample size was 450. We expected that the lower limit of the 95% confidence interval (CI) for specificity should be satisfied in ≥97% of patients.
RESULTS: We enrolled 811 patients from 31 institutions between December 2002 and May 2004. The primary end point was evaluated in 545 patients. The specificity and sensitivity for the diagnosis of pathologically diagnosed invasive cancer were 96.4% (161/167, 95% CI: 92.3-98.7%) and 30.4% (115/378, 95% CI: 25.8-35.3%), respectively, i.e., a negative result. Nevertheless, the specificity for lung adenocarcinoma ≤2.0 cm with ≤0.25 consolidation to the maximum tumor diameter was 98.7% (95% CI: 93.2-100.0%), and this criterion could be used to radiologically define early adenocarcinoma of the lung.
CONCLUSIONS: Although our predetermined criterion for specificity was not statistically confirmed, radiological diagnosis of noninvasive lung cancer with a thin-section computed tomography scan corresponded well with pathological invasiveness. Radiological noninvasive peripheral lung adenocarcinoma could be defined as an adenocarcinoma ≤2.0 cm with ≤0.25 consolidation.

PMID 21325976  J Thorac Oncol. 2011 Apr;6(4):751-6. doi: 10.1097/JTO.0・・・
著者: N P Rowell, C J Williams
雑誌名: Cochrane Database Syst Rev. 2001;(2):CD002935. doi: 10.1002/14651858.CD002935.
Abstract/Text BACKGROUND: In general, surgery is believed to offer the best prospects for cure for early stage non-small cell lung cancer (NSCLC). In spite of the intention to consider all patients with stage I-II disease for surgery, there are those who, although technically operable, either refuse surgery or are considered inoperable because of insufficient respiratory reserve, cardiovascular disease or general frailty. This group may therefore be considered "medically inoperable". Some respiratory physicians refer these patients for radical radiotherapy whilst others believe that radiotherapy has little to offer and adopt a watch policy, referring patients for palliative radiotherapy only when they become symptomatic. Although there is little evidence from randomised trials to support the use of radical radiotherapy for stage I/II NSCLC, it is the perception of most clinical oncologists (radiotherapists) that patients should receive radical, as opposed to palliative, treatment (COIN 1999).
OBJECTIVES: To determine the effectiveness and the morbidity of radical radiotherapy for medically inoperable NSCLC.
SEARCH STRATEGY: Randomised trials were sought by electronic searching the Cochrane Clinical Trials Register and both randomised and non-randomised trials sought by searching Medline and Excerpta Medica (Embase). Further studies were identified from references cited in those papers already identified by electronic searching.
SELECTION CRITERIA: Studies of patients of any age with stage I/II NSCLC receiving radiotherapy at a dose greater than 40Gy in 20 fractions over four weeks or its radiobiological equivalent.
DATA COLLECTION AND ANALYSIS: Two randomised and thirty-five non-randomised studies were identified. One randomised and nine non-randomised studies did not meet the selection criteria and were not included in the review.
MAIN RESULTS: In the randomised trial comparing two radiotherapy schedules, two-year survival was superior following continuous hyperfractionated accelerated radiotherapy (CHART; 37%) compared to 60Gy in 30 fractions over six weeks (24%). There were 26 non-randomised retrospective studies including an estimated 2003 patients, in which overall survival results varied between 33-72% at two years, 17-55% at three years and 0-42% at five years. The proportion of deaths not due to cancer was 11-43%. Cancer-specific survival was between 54-93% at two years, 22-56% at three years and 13-39% at five years. Complete response rates were 33-61% and local failure rates between 6-70%. Distant metastases developed in approximately 25% of patients. Better response rates and survival were seen in those with smaller tumours and in those receiving higher doses though the reasons for prescribing higher doses were not clearly stated. Worse outcome was seen in those with prior weight loss or poor performance status. Assessment of treatment-related morbidity and effects on quality of life and symptom control were inconclusive because of the lack of prospective evaluation and paucity of data.
REVIEWER'S CONCLUSIONS: There were no randomised trials that compared a policy of immediate radical radiotherapy with palliative radiotherapy given when patients develop symptoms. In the absence of such trials, radical radiotherapy appears to result in a better survival than might be expected had treatment not been given. A substantial, though variable, proportion of patients died during follow-up from causes other than cancer. The optimal radiation dose and treatment technique (particularly with respect to mediastinal irradiation) remain uncertain.

PMID 11406051  Cochrane Database Syst Rev. 2001;(2):CD002935. doi: 10.・・・
著者: K Morita, N Fuwa, Y Suzuki, M Nishio, K Sakai, Y Tamaki, H Niibe, M Chujo, S Wada, T Sugawara, M Kita
雑誌名: Radiother Oncol. 1997 Jan;42(1):31-6.
Abstract/Text PURPOSE: In order to obtain the standard treatment results of medically inoperable non-small cell lung cancer (NSCLC) in Stage I in the post-CT scan era, a retrospective analysis of patients who were treated by radical radiotherapy was performed.
METHODS AND MATERIALS: 149 cases treated between 1980 and 1989 were accumulated from ten large hospitals in Japan. All patients received a total dose of 55-75 Gy (mean 64.7 Gy) with conventional fractionation. For evaluation of treatment results, complete response (CR) rate, median survival period and long-termed survival rates were used.
RESULTS: The median survival of the all cases was 27.2 months and the actuarial 3- and 5-year survival rates were 34.2% and 22.2%, respectively. CR was obtained in 57 cases (38%). The CR rate was strongly correlated with the long-term survival (5-year survival rate in CR group: 35.1% compared with PR + NC group: 14.1% (P < 0.0001)). The size of tumor was also of prognostic importance. In 116 patients who died within 5 years after treatment, 66 patients (57%) died of local tumor regrowth.
CONCLUSION: Although the medically inoperable NSCLC patients in Stage I should be offered curative radiation therapy, development of some new steps to increase the CR rate and local control rate is urgently needed.

PMID 9132823  Radiother Oncol. 1997 Jan;42(1):31-6.
著者: Robert Timmerman, Rebecca Paulus, James Galvin, Jeffrey Michalski, William Straube, Jeffrey Bradley, Achilles Fakiris, Andrea Bezjak, Gregory Videtic, David Johnstone, Jack Fowler, Elizabeth Gore, Hak Choy
雑誌名: JAMA. 2010 Mar 17;303(11):1070-6. doi: 10.1001/jama.2010.261.
Abstract/Text CONTEXT: Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management.
OBJECTIVE: To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer.
DESIGN, SETTING, AND PATIENTS: Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non-small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 1(1/2) and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009.
MAIN OUTCOME MEASURES: The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival.
RESULTS: A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported.
CONCLUSION: Patients with inoperable non-small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.

PMID 20233825  JAMA. 2010 Mar 17;303(11):1070-6. doi: 10.1001/jama.201・・・
著者: Janneke P C Grutters, Alfons G H Kessels, Madelon Pijls-Johannesma, Dirk De Ruysscher, Manuela A Joore, Philippe Lambin
雑誌名: Radiother Oncol. 2010 Apr;95(1):32-40. doi: 10.1016/j.radonc.2009.08.003. Epub 2009 Sep 3.
Abstract/Text PURPOSE: To provide a comparison between radiotherapy with photons, protons and carbon-ions in the treatment of Non-Small-Cell Lung Cancer (NSCLC), performing a meta-analysis of observational studies.
METHODS: Eligible studies on conventional radiotherapy (CRT), stereotactic radiotherapy (SBRT), concurrent chemoradiation (CCR), proton therapy and carbon-ion therapy were searched through a systematic review. To obtain pooled estimates of 2- and 5-year disease-specific and overall survival and the occurrence of severe adverse events for each treatment modality, a random effects meta-analysis was carried out. Pooled estimates were corrected for effect modifiers.
RESULTS: Corrected pooled estimates for 2-year overall survival in stage I inoperable NSCLC ranged from 53% for CRT to 74% for carbon-ion therapy. Five-year overall survival for CRT (20%) was statistically significantly lower than that for SBRT (42%), proton therapy (40%) and carbon-ion therapy (42%). However, caution is warranted due to the limited number of patients and limited length of follow-up of the particle studies.
CONCLUSION: Survival rates for particle therapy were higher than those for CRT, but similar to SBRT in stage I inoperable NSCLC. Particle therapy may be more beneficial in stage III NSCLC, especially in reducing adverse events.

Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
PMID 19733410  Radiother Oncol. 2010 Apr;95(1):32-40. doi: 10.1016/j.r・・・
著者: Giorgio V Scagliotti, Roldano Fossati, Valter Torri, Lucio Crinò, Giuseppe Giaccone, Giovanni Silvano, Massimo Martelli, Maurizia Clerici, Francesco Cognetti, Maurizio Tonato, Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer-Lung Cancer Cooperative Group Investigators
雑誌名: J Natl Cancer Inst. 2003 Oct 1;95(19):1453-61.
Abstract/Text BACKGROUND: Surgery is the primary treatment for patients with stage I, II, or IIIA non-small-cell lung cancer (NSCLC). However, long-term survival of NSCLC patients after surgery alone is largely unsatisfactory, and the role of adjuvant chemotherapy in patient survival has not yet been established.
METHODS: Between January 1994 and January 1999, 1209 patients with stage I, II, or IIIA NSCLC were randomly assigned to receive mitomycin C (8 mg/m2 on day 1), vindesine (3 mg/m2 on days 1 and 8), and cisplatin (100 mg/m2 on day 1) every 3 weeks for three cycles (MVP group; n = 606) or no treatment (control group; n = 603) after complete resection. Randomization was stratified by investigational center, tumor size, lymph-node involvement, and the intention to perform radiotherapy. The primary endpoint was overall survival and secondary endpoints were progression-free survival and toxicity associated with adjuvant treatment. Survival curves were analyzed using the log-rank test. All statistical tests were two-sided.
RESULTS: After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in overall survival (hazard ratio = 0.96, 95% confidence interval = 0.81 to 1.13; P =.589) or progression-free survival (hazard ratio = 0.89, 95% confidence interval = 0.76 to 1.03; P =.128). Only 69% of patients received the three planned cycles of MVP. Grades 3 and 4 neutropenia occurred in 16% and 12%, respectively, of patients in the MVP arm. Radiotherapy was completed by 65% of patients in the MVP arm and by 82% of patients in the control group. In the multivariable analysis, only disease stage and sex were associated with survival.
CONCLUSION: This randomized trial failed to prospectively confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC. Given the poor compliance with the MVP regimen used in this study, future studies should explore more effective treatments.

PMID 14519751  J Natl Cancer Inst. 2003 Oct 1;95(19):1453-61.
著者: D Waller, M D Peake, R J Stephens, N H Gower, R Milroy, M K B Parmar, R M Rudd, S G Spiro
雑誌名: Eur J Cardiothorac Surg. 2004 Jul;26(1):173-82. doi: 10.1016/j.ejcts.2004.03.041.
Abstract/Text OBJECTIVES: The non-small cell lung cancer (NSCLC) meta-analysis suggested a survival benefit for cisplatin-based chemotherapy when given in addition to surgery, radical radiotherapy or 'best supportive care'. However, it included many small trials and trials with differing eligibility criteria and chemotherapy regimens. The aim of the Big Lung Trial was therefore to run a large pragmatic trial to confirm the survival benefits seen in the meta-analysis.
METHODS: In the surgery setting, a total of 381 patients were randomised to chemotherapy (C, 192 patients) or no chemotherapy (NoC, 189 patients). C was three 3-weekly cycles of cisplatin/vindesine, mitomycin/ifosfamide/cisplatin, mitomycin/vinblastine/cisplatin or vinorelbine/cisplatin.
RESULTS: Chemotherapy was given before surgery in 3% of patients whilst 97% received adjuvant chemotherapy. Baseline characteristics were: median age 61 years, 69% male, 48% squamous cell, 93% WHO PS 0-1, 27% stage I, 38% stage II, and 34% stage III. Complete resection was achieved in approximately 95% of patients. In the C group, 13% received no chemotherapy, 21% one or two cycles, and 64% all three cycles of their prescribed chemotherapy (60% of the latter with no delays or modification). 30% had grade 3/4 toxicity, mainly haematological, nausea/vomiting and neutropenic fever, and six patients were reported as having a treatment-related death. 198 (52%) of patients have died, but there is currently no evidence of a benefit in overall survival to the C group: HR 1.02 (95% CI 0.77-1.35), P = 0.90).
CONCLUSIONS: This trial has failed to observe a survival benefit with adjuvant chemotherapy following complete resection of stage I-III NSCLC. However, the hazard ratio and 95% confidence intervals are consistent with the previously reported meta-analysis and two large recently reported trials, which suggest a small survival benefit with cisplatin-based chemotherapy.

PMID 15200998  Eur J Cardiothorac Surg. 2004 Jul;26(1):173-82. doi: 10・・・
著者: Rodrigo Arriagada, Bengt Bergman, Ariane Dunant, Thierry Le Chevalier, Jean-Pierre Pignon, Johan Vansteenkiste, International Adjuvant Lung Cancer Trial Collaborative Group
雑誌名: N Engl J Med. 2004 Jan 22;350(4):351-60. doi: 10.1056/NEJMoa031644.
Abstract/Text BACKGROUND: On the basis of a previous meta-analysis, the International Adjuvant Lung Cancer Trial was designed to evaluate the effect of cisplatin-based adjuvant chemotherapy on survival after complete resection of non-small-cell lung cancer.
METHODS: We randomly assigned patients either to three or four cycles of cisplatin-based chemotherapy or to observation. Before randomization, each center determined the pathological stages to include, its policy for chemotherapy (the dose of cisplatin and the drug to be combined with cisplatin), and its postoperative radiotherapy policy. The main end point was overall survival.
RESULTS: A total of 1867 patients underwent randomization; 36.5 percent had pathological stage I disease, 24.2 percent stage II, and 39.3 percent stage III. The drug allocated with cisplatin was etoposide in 56.5 percent of patients, vinorelbine in 26.8 percent, vinblastine in 11.0 percent, and vindesine in 5.8 percent. Of the 932 patients assigned to chemotherapy, 73.8 percent received at least 240 mg of cisplatin per square meter of body-surface area. The median duration of follow-up was 56 months. Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (44.5 percent vs. 40.4 percent at five years [469 deaths vs. 504]; hazard ratio for death, 0.86; 95 percent confidence interval, 0.76 to 0.98; P<0.03). Patients assigned to chemotherapy also had a significantly higher disease-free survival rate than those assigned to observation (39.4 percent vs. 34.3 percent at five years [518 events vs. 577]; hazard ratio, 0.83; 95 percent confidence interval, 0.74 to 0.94; P<0.003). There were no significant interactions with prespecified factors. Seven patients (0.8 percent) died of chemotherapy-induced toxic effects.
CONCLUSIONS: Cisplatin-based adjuvant chemotherapy improves survival among patients with completely resected non-small-cell lung cancer.

Copyright 2004 Massachusetts Medical Society
PMID 14736927  N Engl J Med. 2004 Jan 22;350(4):351-60. doi: 10.1056/N・・・
著者: Timothy Winton, Robert Livingston, David Johnson, James Rigas, Michael Johnston, Charles Butts, Yvon Cormier, Glenwood Goss, Richard Inculet, Eric Vallieres, Willard Fry, Drew Bethune, Joseph Ayoub, Keyue Ding, Lesley Seymour, Barbara Graham, Ming-Sound Tsao, David Gandara, Kenneth Kesler, Todd Demmy, Frances Shepherd, National Cancer Institute of Canada Clinical Trials Group, National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators
雑誌名: N Engl J Med. 2005 Jun 23;352(25):2589-97. doi: 10.1056/NEJMoa043623.
Abstract/Text BACKGROUND: We undertook to determine whether adjuvant vinorelbine plus cisplatin prolongs overall survival among patients with completely resected early-stage non-small-cell lung cancer.
METHODS: We randomly assigned patients with completely resected stage IB or stage II non-small-cell lung cancer to vinorelbine plus cisplatin or to observation. The primary end point was overall survival; principal secondary end points were recurrence-free survival and the toxicity and safety of the regimen.
RESULTS: A total of 482 patients underwent randomization to vinorelbine plus cisplatin (242 patients) or observation (240); 45 percent of the patients had pathological stage IB disease and 55 percent had stage II, and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. In both groups, the median age was 61 years, 65 percent were men, and 53 percent had adenocarcinomas. Chemotherapy caused neutropenia in 88 percent of patients (including grade 3 febrile neutropenia in 7 percent) and death from toxic effects in two patients (0.8 percent). Nonhematologic toxic effects of chemotherapy were fatigue (81 percent of patients), nausea (80 percent), anorexia (55 percent), vomiting (48 percent), neuropathy (48 percent), and constipation (47 percent), but severe (grade 3 or greater) toxic effects were uncommon (<10 percent). Overall survival was significantly prolonged in the chemotherapy group as compared with the observation group (94 vs. 73 months; hazard ratio for death, 0.69; P=0.04), as was relapse-free survival (not reached vs. 46.7 months; hazard ratio for recurrence, 0.60; P<0.001). Five-year survival rates were 69 percent and 54 percent, respectively (P=0.03).
CONCLUSIONS: Adjuvant vinorelbine plus cisplatin has an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected early-stage non-small-cell lung cancer.

Copyright 2005 Massachusetts Medical Society.
PMID 15972865  N Engl J Med. 2005 Jun 23;352(25):2589-97. doi: 10.1056・・・
著者: Jean-Yves Douillard, Rafael Rosell, Mario De Lena, Francesco Carpagnano, Rodryg Ramlau, Jose Luis Gonzáles-Larriba, Tomasz Grodzki, Jose Rodrigues Pereira, Alain Le Groumellec, Vito Lorusso, Claude Clary, Antonio J Torres, Jabrail Dahabreh, Pierre-Jean Souquet, Julio Astudillo, Pierre Fournel, Angel Artal-Cortes, Jacek Jassem, Leona Koubkova, Patricia His, Marcello Riggi, Patrick Hurteloup
雑誌名: Lancet Oncol. 2006 Sep;7(9):719-27. doi: 10.1016/S1470-2045(06)70804-X.
Abstract/Text BACKGROUND: Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC.
METHODS: 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m(2) vinorelbine plus 100 mg/m(2) cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737.
FINDINGS: 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17-108] vs 59% [17-100]). After a median follow-up of 76 months (range 43-116), median survival was 65.7 months (95% CI 47.9-88.5) in the chemotherapy group and 43.7 (35.7-52.3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0.80 [95% CI 0.66-0.96]; p=0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%).
INTERPRETATION: Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.

PMID 16945766  Lancet Oncol. 2006 Sep;7(9):719-27. doi: 10.1016/S1470-・・・
著者: NSCLC Meta-analyses Collaborative Group, R Arriagada, A Auperin, S Burdett, J P Higgins, D H Johnson, T Le Chevalier, C Le Pechoux, M K B Parmar, J P Pignon, R L Souhami, R J Stephens, L A Stewart, J F Tierney, H Tribodet, J van Meerbeeck
雑誌名: Lancet. 2010 Apr 10;375(9722):1267-77. doi: 10.1016/S0140-6736(10)60059-1. Epub 2010 Mar 24.
Abstract/Text BACKGROUND: Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy.
METHODS: We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat.
FINDINGS: The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0.86, 95% CI 0.81-0.92, p<0.0001), with an absolute increase in survival of 4% (95% CI 3-6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0.88, 95% CI 0.81-0.97, p=0.009), representing an absolute improvement in survival of 4% (95% CI 1-8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup.
INTERPRETATION: The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy.
FUNDING: UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Copyright 2010 Elsevier Ltd. All rights reserved.
PMID 20338627  Lancet. 2010 Apr 10;375(9722):1267-77. doi: 10.1016/S01・・・
著者: Harubumi Kato, Yukito Ichinose, Morio Ohta, Enjo Hata, Noriaki Tsubota, Hirohito Tada, Yoh Watanabe, Hiromi Wada, Masahiro Tsuboi, Nobuyuki Hamajima, Mitsuo Ohta, Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy
雑誌名: N Engl J Med. 2004 Apr 22;350(17):1713-21. doi: 10.1056/NEJMoa032792.
Abstract/Text BACKGROUND: In a previous phase 3 trial of adjuvant chemotherapy after resection of non-small-cell lung cancer, a combination of uracil and tegafur (often referred to as UFT) taken orally was shown to prolong survival. A subgroup analysis disclosed that most patients who benefited had pathological stage I adenocarcinoma.
METHODS: We randomly assigned patients with completely resected pathological stage I adenocarcinoma of the lung to receive either oral uracil-tegafur (250 mg of tegafur per square meter of body-surface area per day) for two years or no treatment. Randomization was performed with stratification according to the pathological tumor category (T1 vs. T2), sex, and age. The primary end point was overall survival.
RESULTS: From January 1994 through March 1997, 999 patients were enrolled. Twenty patients were found to be ineligible and were excluded from the analysis after randomization; 491 patients were assigned to receive uracil-tegafur and 488 were assigned to observation. The median duration of follow-up for surviving patients was 73 months. The difference in overall survival between the two groups was statistically significant in favor of the uracil-tegafur group (P=0.04 by a stratified log-rank test). Grade 3 toxic effects occurred in 10 of the 482 patients (2 percent) who actually received uracil-tegafur.
CONCLUSIONS: Adjuvant chemotherapy with uracil-tegafur improves survival among patients with completely resected pathological stage I adenocarcinoma of the lung.

Copyright 2004 Massachusetts Medical Society
PMID 15102997  N Engl J Med. 2004 Apr 22;350(17):1713-21. doi: 10.1056・・・
著者: Chikuma Hamada, Fumihiro Tanaka, Mitsuo Ohta, Shigefumi Fujimura, Ken Kodama, Munehisa Imaizumi, Hiromi Wada
雑誌名: J Clin Oncol. 2005 Aug 1;23(22):4999-5006. doi: 10.1200/JCO.2005.09.017.
Abstract/Text PURPOSE: Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non-small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC.
METHODS: Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis.
RESULTS: Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001).
CONCLUSION: This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.

PMID 16051951  J Clin Oncol. 2005 Aug 1;23(22):4999-5006. doi: 10.1200・・・
著者: Chikuma Hamada, Masahiro Tsuboi, Mitsuo Ohta, Shigefumi Fujimura, Ken Kodama, Munehisa Imaizumi, Hiromi Wada
雑誌名: J Thorac Oncol. 2009 Dec;4(12):1511-6. doi: 10.1097/JTO.0b013e3181bbf1f2.
Abstract/Text BACKGROUND: The Seventh Edition of the Tumor, Node, Metastasis Classification of Malignant Tumors in non-small cell lung cancer (NSCLC) proposes a more detailed classification of primary tumor diameter. Stage IA T1 disease is subdivided into two groups: T1a disease (tumor diameter, < or = 2 cm) and T1b disease (tumor diameter, >2 to < or = 3 cm). Tegafur-uracil (UFT) improves survival in patients with stage I NSCLC. However, whether it is effective in patients with T1 disease (stage IA) remains controversial.
METHODS: Data from a 2005 meta-analysis of UFT were reanalyzed to evaluate the effectiveness of UFT according to T1a and T1b tumors as proposed by the new tumor, node, metastasis classification in patients who had T1 tumors with no lymph-node metastasis.
RESULTS: Data from 1269 patients were analyzed: 670 (52.8%) had T1a tumors and 599 (47.2%) had T1b tumors. In the surgery-alone group, survival rates at 5 years were 85% in patients with T1a tumors and 82% in those with T1b tumors after surgery alone and 87% in patients with T1a tumors and 88% in those with T1b tumors after surgery followed by adjuvant treatment with UFT. In patients with T1b tumors, the survival rate was significantly higher in the UFT group than in the surgery-alone group (hazard ratio = 0.62; 95% confidence interval, 0.42-0.90; log-rank p = 0.011). The hazard ratio for death in the UFT group when compared with the surgery-alone group was 0.84 for those with T1a disease (95% confidence interval, 0.58-1.23). The results of a test for interaction between treatment response and T1 subgroup were not significant (p = 0.30).
CONCLUSIONS: UFT significantly improves survival in patients with stage IA T1b NSCLC compared with surgery alone.

PMID 19875974  J Thorac Oncol. 2009 Dec;4(12):1511-6. doi: 10.1097/JTO・・・

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