今日の臨床サポート

非小細胞肺癌(初期)

著者: 金永学 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:2022/09/28
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 2021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(T因子)おいて、胸部造影CTは必須である(推奨度1)
  1. 非小細胞肺癌の術前病期診断(N因子)に際し、PET/CTは臨床上有用であり、行うことが推奨される(推奨度2)
  1. 非小細胞肺癌の術前病期診断(M因子)のために、PET/CTと頭部造影MRIを行うよう推奨する(推奨度2)
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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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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:
金永学 : 未申告[2022年]
髙山浩一 : 未申告[2022年]
監修:高橋和久 : 講演料(アストラゼネカ(株),MSD(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(杏林製薬(株),サノフィ(株),大鵬薬品工業(株),中外製薬(株),帝人ファーマ(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))[2022年]

改訂のポイント:
  1. 構成も含めた全体的なレビューを行い、最新ガイドラインに基づく知見反映を行ったほか、その他の部分についても適宜加筆修正を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 2021年の予測肺癌死亡数は男性5万2,600人、女性2万2,300人に上り、部位別総死亡数は男性では1位、女性では大腸癌に次ぐ2位である。
  1. 肺癌診断時における病期(ステージ)は、I期が38.0%、II期が7.1%、III期が25.5%、IV期が27.8%である。このように進行期に発見される患者が比較的多いことが肺癌の予後が不良であることの一因である。肺癌の予後を改善するためには、治療法の開発のみならず、いかにして早期に発見するかが重要である。
  1. 喫煙は肺癌の最大の危険因子であり、禁煙は最も有効な肺癌予防法である。
  1. 病理学的には非小細胞癌が約85%、小細胞癌が約15%である。喫煙率の低下に伴い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. 病理学的な組織診断と病期診断に加えて、年齢や合併症などの患者背景を考慮し、手術、放射線療法、薬物療法の適応を決定する。
問診・診察のポイント  
  1. 肺癌に特異的な症状は存在しないが、長引く咳嗽、血痰、呼吸困難、胸痛などの胸部症状などのいわゆる呼吸器症状を主訴として医療機関を受診し発見されることが多い。

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文献 

Mia Schmidt-Hansen, David R Baldwin, Elise Hasler, Javier Zamora, Víctor Abraira, Marta Roqué I Figuls
PET-CT for assessing mediastinal lymph node involvement in patients with suspected resectable non-small cell lung cancer.
Cochrane Database Syst Rev. 2014 Nov 13;(11):CD009519. doi: 10.1002/14651858.CD009519.pub2. Epub 2014 Nov 13.
Abstract/Text BACKGROUND: A major determinant of treatment offered to patients with non-small cell lung cancer (NSCLC) is their intrathoracic (mediastinal) nodal status. If the disease has not spread to the ipsilateral mediastinal nodes, subcarinal (N2) nodes, or both, and the patient is otherwise considered fit for surgery, resection is often the treatment of choice. Planning the optimal treatment is therefore critically dependent on accurate staging of the disease. PET-CT (positron emission tomography-computed tomography) is a non-invasive staging method of the mediastinum, which is increasingly available and used by lung cancer multidisciplinary teams. Although the non-invasive nature of PET-CT constitutes one of its major advantages, PET-CT may be suboptimal in detecting malignancy in normal-sized lymph nodes and in ruling out malignancy in patients with coexisting inflammatory or infectious diseases.
OBJECTIVES: To determine the diagnostic accuracy of integrated PET-CT for mediastinal staging of patients with suspected or confirmed NSCLC that is potentially suitable for treatment with curative intent.
SEARCH METHODS: We searched the following databases up to 30 April 2013: The Cochrane Library, MEDLINE via OvidSP (from 1946), Embase via OvidSP (from 1974), PreMEDLINE via OvidSP, OpenGrey, ProQuest Dissertations & Theses, and the trials register www.clinicaltrials.gov. There were no language or publication status restrictions on the search. We also contacted researchers in the field, checked reference lists, and conducted citation searches (with an end-date of 9 July 2013) of relevant studies.
SELECTION CRITERIA: Prospective or retrospective cross-sectional studies that assessed the diagnostic accuracy of integrated PET-CT for diagnosing N2 disease in patients with suspected resectable NSCLC. The studies must have used pathology as the reference standard and reported participants as the unit of analysis.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted data pertaining to the study characteristics and the number of true and false positives and true and false negatives for the index test, and they independently assessed the quality of the included studies using QUADAS-2. We calculated sensitivity and specificity with 95% confidence intervals (CI) for each study and performed two main analyses based on the criteria for test positivity employed: Activity > background or SUVmax ≥ 2.5 (SUVmax = maximum standardised uptake value), where we fitted a summary receiver operating characteristic (ROC) curve using a hierarchical summary ROC (HSROC) model for each subset of studies. We identified the average operating point on the SROC curve and computed the average sensitivities and specificities. We checked for heterogeneity and examined the robustness of the meta-analyses through sensitivity analyses.
MAIN RESULTS: We included 45 studies, and based on the criteria for PET-CT positivity, we categorised the included studies into three groups: Activity > background (18 studies, N = 2823, prevalence of N2 and N3 nodes = 679/2328), SUVmax ≥ 2.5 (12 studies, N = 1656, prevalence of N2 and N3 nodes = 465/1656), and Other/mixed (15 studies, N = 1616, prevalence of N2 to N3 nodes = 400/1616). None of the studies reported (any) adverse events. Under-reporting generally hampered the quality assessment of the studies, and in 30/45 studies, the applicability of the study populations was of high or unclear concern.The summary sensitivity and specificity estimates for the 'Activity > background PET-CT positivity criterion were 77.4% (95% CI 65.3 to 86.1) and 90.1% (95% CI 85.3 to 93.5), respectively, but the accuracy estimates of these studies in ROC space showed a wide prediction region. This indicated high between-study heterogeneity and a relatively large 95% confidence region around the summary value of sensitivity and specificity, denoting a lack of precision. Sensitivity analyses suggested that the overall estimate of sensitivity was especially susceptible to selection bias; reference standard bias; clear definition of test positivity; and to a lesser extent, index test bias and commercial funding bias, with lower combined estimates of sensitivity observed for all the low 'Risk of bias' studies compared with the full analysis.The summary sensitivity and specificity estimates for the SUVmax ≥ 2.5 PET-CT positivity criterion were 81.3% (95% CI 70.2 to 88.9) and 79.4% (95% CI 70 to 86.5), respectively.In this group, the accuracy estimates of these studies in ROC space also showed a very wide prediction region. This indicated very high between-study heterogeneity, and there was a relatively large 95% confidence region around the summary value of sensitivity and specificity, denoting a clear lack of precision. Sensitivity analyses suggested that both overall accuracy estimates were marginally sensitive to flow and timing bias and commercial funding bias, which both lead to slightly lower estimates of sensitivity and specificity.Heterogeneity analyses showed that the accuracy estimates were significantly influenced by country of study origin, percentage of participants with adenocarcinoma, (¹⁸F)-2-fluoro-deoxy-D-glucose (FDG) dose, type of PET-CT scanner, and study size, but not by study design, consecutive recruitment, attenuation correction, year of publication, or tuberculosis incidence rate per 100,000 population.
AUTHORS' CONCLUSIONS: This review has shown that accuracy of PET-CT is insufficient to allow management based on PET-CT alone. The findings therefore support National Institute for Health and Care (formally 'clinical') Excellence (NICE) guidance on this topic, where PET-CT is used to guide clinicians in the next step: either a biopsy or where negative and nodes are small, directly to surgery. The apparent difference between the two main makes of PET-CT scanner is important and may influence the treatment decision in some circumstances. The differences in PET-CT accuracy estimates between scanner makes, NSCLC subtypes, FDG dose, and country of study origin, along with the general variability of results, suggest that all large centres should actively monitor their accuracy. This is so that they can make reliable decisions based on their own results and identify the populations in which PET-CT is of most use or potentially little value.

PMID 25393718
Ozcan Birim, A Pieter Kappetein, Theo Stijnen, Ad J J C Bogers
Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer.
Ann Thorac Surg. 2005 Jan;79(1):375-82. doi: 10.1016/j.athoracsur.2004.06.041.
Abstract/Text A systematic review was undertaken to select studies that compared the accuracy of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography with computed tomographic imaging in detecting mediastinal lymph node metastases in patients with nonsmall cell lung cancer. Two authors selected relevant articles according to predefined criteria. With a meta-analytic method, summary receiver operating characteristic curves were constructed. The point on the receiver operating characteristic curve with equal sensitivity and specificity for 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography was Q* = 0.90 (95% confidence interval [CI], 0.86 to 0.95). For computed tomography it was 0.70 (95% CI, 0.65 to 0.75). The difference was highly significant (p < 0.0001). We conclude that 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography is more accurate than computed tomography in detecting mediastinal lymph node metastases.

PMID 15620991
Michael K Gould, Ware G Kuschner, Chara E Rydzak, Courtney C Maclean, Anita N Demas, Hidenobu Shigemitsu, Jo Kay Chan, Douglas K Owens
Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis.
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
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
Preoperative staging of lung cancer with combined PET-CT.
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
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
Positron emission tomography in staging early lung cancer: a randomized trial.
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
W De Wever, S Ceyssens, L Mortelmans, S Stroobants, G Marchal, J Bogaert, J A Verschakelen
Additional value of PET-CT in the staging of lung cancer: comparison with CT alone, PET alone and visual correlation of PET and CT.
Eur Radiol. 2007 Jan;17(1):23-32. doi: 10.1007/s00330-006-0284-4. Epub 2006 May 9.
Abstract/Text Integrated positron emission tomography (PET) and computed tomography (CT) is a new imaging modality offering anatomic and metabolic information. The purpose was to evaluate retrospectively the accuracy of integrated PET-CT in the staging of a suggestive lung lesion, comparing this with the accuracy of CT alone, PET alone and visually correlated PET-CT. Fifty patients undergoing integrated PET-CT for staging of a suggestive lung lesion were studied. Their tumor, node, metastasis (TNM) statuses were determined with CT, PET, visually correlated PET-CT and integrated PET-CT. These TNM stages were compared with the surgical TNM status. Integrated PET-CT was the most accurate imaging technique in the assessment of the TNM status. Integrated PET-CT predicted correctly the T status, N status, M status and TNM status in, respectively, 86%, 80%, 98%, 70% versus 68%, 66%,88%, 46% with CT, 46%, 70%, 96%, 30% with PET and 72%, 68%, 96%, 54% with visually correlated PET-CT. T status and N status were overstaged, respectively, in 8% and 16% with integrated PET-CT, in 20% and 28% with CT, in 16% and 20% with PET, in 12% and 20% with visually correlated PET-CT and understaged in 6% and 4% with integrated PET-CT, versus 12% and 6% with CT, 38% and 10% with PET and 12% with visually correlated PET-CT. Integrated PET-CT improves the staging of lung cancer through a better anatomic localization and characterization of lesions and is superior to CT alone and PET alone. If this technique is not available, visual correlation of PET and CT can be a valuable alternative.

PMID 16683115
Gerald Antoch, Jörg Stattaus, Andre T Nemat, Simone Marnitz, Thomas Beyer, Hilmar Kuehl, Andreas Bockisch, Jörg F Debatin, Lutz S Freudenberg
Non-small cell lung cancer: dual-modality PET/CT in preoperative staging.
Radiology. 2003 Nov;229(2):526-33. doi: 10.1148/radiol.2292021598. Epub 2003 Sep 25.
Abstract/Text PURPOSE: To determine the accuracy of dual-modality positron emission tomographic (PET)-computed tomographic (CT) imaging, as compared with PET alone and CT alone, in the staging of non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: Twenty-seven patients with NSCLC underwent staging with combined fluorine 18 fluorodeoxyglucose PET and CT. CT, PET, and coregistered PET/CT images were evaluated separately by two different physicians for each imaging modality, and disease stage was determined by using TNM and American Joint Committee on Cancer staging systems. Histopathologic results served as the reference standard. The statistical significance of differences among CT, PET, and PET/CT was determined by using the McNemar test.
RESULTS: Overall tumor stage was correctly classified as 0-IV with CT in 19 patients, with PET in 20 patients, and with PET/CT in 26 patients. PET/CT findings when compared with PET findings led to a treatment change for four patients (15%) and when compared with CT findings led to a treatment change for five patients (19%). Differences in the accuracy of overall tumor staging between PET/CT and CT (P =.008) and between PET/CT and PET (P =.031) were significant. Primary tumor stage was correctly determined in more patients with PET/CT than with either PET alone or CT alone. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of regional lymph node staging, respectively, were 89%, 94%, 89%, 94%, and 93%, with PET/CT; 89%, 89%, 80%, 94%, and 89% with PET; and 70%, 59%, 50%, 77%, and 63% with CT. Fourteen distant metastases were detected in four patients with CT, four were detected in two patients with PET, and 17 were detected in four patients with PET/CT.
CONCLUSION: Use of dual-modality PET/CT significantly increases the number of patients with correctly staged NSCLC and thus has a positive effect on treatment.

Copyright RSNA, 2003
PMID 14512512
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)
A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201).
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
H Nakamura, N Kawasaki, M Taguchi, K Kabasawa
Survival following lobectomy vs limited resection for stage I lung cancer: a meta-analysis.
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
Morihito Okada, Teruaki Koike, Masahiko Higashiyama, Yasushi Yamato, Ken Kodama, Noriaki Tsubota
Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study.
J Thorac Cardiovasc Surg. 2006 Oct;132(4):769-75. doi: 10.1016/j.jtcvs.2006.02.063.
Abstract/Text OBJECTIVE: At present, even when early-stage, small-sized non-small cell lung cancers are being increasingly detected, lesser resection has not become the treatment of choice. We sought to compare sublobar resection (segmentectomy or wedge resection) with lobar resection to test which one is the appropriate procedure for such lesions.
METHODS: From 1992 to 2001, a nonrandomized study was performed in 3 institutes for patients with a peripheral cT1N0M0 non-small cell lung cancer of 2 cm or less who were able to tolerate a lobectomy. The results of the sublobar resection group enrolled preoperatively (n = 305) were compared with those of the lobar resection group (n = 262).
RESULTS: Except for distribution of tumor location, there were no significant differences in any variable, patient characteristics, curability, pathologic stage, morbidity, or recurrence rate. Median follow-up was more than 5 years. Disease-free and overall survivals were similar in both groups with 5-year survivals of 85.9% and 89.6% for the sublobar resection group and 83.4% and 89.1% for the lobar resection group, respectively. Multivariate analysis confirmed that the recurrence rate and prognosis associated with sublobar resection were not inferior to those obtained with lobar resection. Postoperative lung function was significantly better in patients who underwent sublobar resection.
CONCLUSIONS: Sublobar resection should be considered as an alternative for stage IA non-small cell lung cancers 2 cm or less, even in low-risk patients. These results could lay the foundation for starting randomized controlled trials anew, which would bring great changes of lung cancer surgery in this era of early detection of lung cancer.

PMID 17000286
Hisashi Saji, Morihito Okada, Masahiro Tsuboi, Ryu Nakajima, Kenji Suzuki, Keiju Aokage, Tadashi Aoki, Jiro Okami, Ichiro Yoshino, Hiroyuki Ito, Norihito Okumura, Masafumi Yamaguchi, Norihiko Ikeda, Masashi Wakabayashi, Kenichi Nakamura, Haruhiko Fukuda, Shinichiro Nakamura, Tetsuya Mitsudomi, Shun-Ichi Watanabe, Hisao Asamura, West Japan Oncology Group and Japan Clinical Oncology Group
Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.
Lancet. 2022 Apr 23;399(10335):1607-1617. doi: 10.1016/S0140-6736(21)02333-3.
Abstract/Text BACKGROUND: Lobectomy is the standard of care for early-stage non-small-cell lung cancer (NSCLC). The survival and clinical benefits of segmentectomy have not been investigated in a randomised trial setting. We aimed to investigate if segmentectomy was non-inferior to lobectomy in patients with small-sized peripheral NSCLC.
METHODS: We conducted this randomised, controlled, non-inferiority trial at 70 institutions in Japan. Patients with clinical stage IA NSCLC (tumour diameter ≤2 cm; consolidation-to-tumour ratio >0·5) were randomly assigned 1:1 to receive either lobectomy or segmentectomy. Randomisation was done via the minimisation method, with balancing for the institution, histological type, sex, age, and thin-section CT findings. Treatment allocation was not concealed from investigators and patients. The primary endpoint was overall survival for all randomly assigned patients. The secondary endpoints were postoperative respiratory function (6 months and 12 months), relapse-free survival, proportion of local relapse, adverse events, proportion of segmentectomy completion, duration of hospital stay, duration of chest tube placement, duration of surgery, amount of blood loss, and the number of automatic surgical staples used. Overall survival was analysed on an intention-to-treat basis with a non-inferiority margin of 1·54 for the upper limit of the 95% CI of the hazard ratio (HR) and estimated using a stratified Cox regression model. This study is registered with UMIN Clinical Trials Registry, UMIN000002317.
FINDINGS: Between Aug, 10, 2009, and Oct 21, 2014, 1106 patients (intention-to-treat population) were enrolled to receive lobectomy (n=554) or segmentectomy (n=552). Patient baseline clinicopathological factors were well balanced between the groups. In the segmentectomy group, 22 patients were switched to lobectomies and one patient received wide wedge resection. At a median follow-up of 7·3 years (range 0·0-10·9), the 5-year overall survival was 94·3% (92·1-96·0) for segmentectomy and 91·1% for lobectomy (95% CI 88·4-93·2); superiority and non-inferiority in overall survival were confirmed using a stratified Cox regression model (HR 0·663; 95% CI 0·474-0·927; one-sided p<0·0001 for non-inferiority; p=0·0082 for superiority). Improved overall survival was observed consistently across all predefined subgroups in the segmentectomy group. At 1 year follow-up, the significant difference in the reduction of median forced expiratory volume in 1 sec between the two groups was 3·5% (p<0·0001), which did not reach the predefined threshold for clinical significance of 10%. The 5-year relapse-free survival was 88·0% (95% CI 85·0-90·4) for segmentectomy and 87·9% (84·8-90·3) for lobectomy (HR 0·998; 95% CI 0·753-1·323; p=0·9889). The proportions of patients with local relapse were 10·5% for segmentectomy and 5·4% for lobectomy (p=0·0018). 52 (63%) of 83 patients and 27 (47%) of 58 patients died of other diseases after lobectomy and segmentectomy, respectively. No 30-day or 90-day mortality was observed. One or more postoperative complications of grade 2 or worse occurred at similar frequencies in both groups (142 [26%] patients who received lobectomy, 148 [27%] who received segmentectomy).
INTERPRETATION: To our knowledge, this study was the first phase 3 trial to show the benefits of segmentectomy versus lobectomy in overall survival of patients with small-peripheral NSCLC. The findings suggest that segmentectomy should be the standard surgical procedure for this population of patients.
FUNDING: National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Copyright © 2022 Elsevier Ltd. All rights reserved.
PMID 35461558
Jan Nyman, Andreas Hallqvist, Jo-Åsmund Lund, Odd-Terje Brustugun, Bengt Bergman, Per Bergström, Signe Friesland, Rolf Lewensohn, Erik Holmberg, Ingmar Lax
SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC.
Radiother Oncol. 2016 Oct;121(1):1-8. doi: 10.1016/j.radonc.2016.08.015. Epub 2016 Sep 3.
Abstract/Text BACKGROUND: Stereotactic body radiotherapy (SBRT) has been introduced for small lung tumors due to excellent local control and few side effects, even though there are no comparative studies. SPACE (Stereotactic Precision And Conventional radiotherapy Evaluation) is the first randomized phase II trial comparing SBRT and conventional fractionated radiotherapy (3DCRT).
METHODS: Patients with stage I medically inoperable NSCLC were randomized to receive SBRT to 66Gy in 3 fractions (one week) or 3DCRT to 70Gy (7weeks). Patients were followed to assess efficacy, toxicity and HRQL.
FINDINGS: Between 2007 and 2011, 102 patients were randomized. Mean age 74 (57-86), 60% women, the vast majority (92%) had COPD or cardiovascular comorbidity. The SBRT arm included more patients with T2-tumors (p=0.02) and male gender (p=0.35). The median follow-up was 37months with a 1-, 2- and 3-year PFS of: SBRT: 76%, 53%, 42% and 3DCRT: 87%, 54% 42%, HR=0.85 (95% CI 0.52-1.36) with no difference between the groups and no difference in OS (HR=0.75, 95% CI 0.43-1.30). At the end of the study 70% of SBRT patients had not progressed compared to 59% (3DCRT, p=0.26). Toxicity was low with no grade 5 events. Pneumonitis of any grade was observed in 19% (SBRT) and 34% (3DCRT, p=0.26), and esophagitis in 8% and 30% respectively (p=0.006). HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with 3DCRT experienced worse dyspnea (p=0.01), chest pain (p=0.02) and cough (>10 points difference).
INTERPRETATION: There was no difference in PFS and OS between SBRT and conventionally treated patients despite an imbalance of prognostic factors. We observed a tendency of an improved disease control rate in the SBRT group and they experienced better HRQL and less toxicity. SBRT is convenient for patients and should be considered standard treatment for patients with inoperable stage I NSCLC.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
PMID 27600155
David Ball, G Tao Mai, Shalini Vinod, Scott Babington, Jeremy Ruben, Tomas Kron, Brent Chesson, Alan Herschtal, Marijana Vanevski, Angela Rezo, Christine Elder, Marketa Skala, Andrew Wirth, Greg Wheeler, Adeline Lim, Mark Shaw, Penelope Schofield, Louis Irving, Benjamin Solomon, TROG 09.02 CHISEL investigators
Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial.
Lancet Oncol. 2019 Apr;20(4):494-503. doi: 10.1016/S1470-2045(18)30896-9. Epub 2019 Feb 12.
Abstract/Text BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is widely used to treat inoperable stage 1 non-small-cell lung cancer (NSCLC), despite the absence of prospective evidence that this type of treatment improves local control or prolongs overall survival compared with standard radiotherapy. We aimed to compare the two treatment techniques.
METHODS: We did this multicentre, phase 3, randomised, controlled trial in 11 hospitals in Australia and three hospitals in New Zealand. Patients were eligible if they were aged 18 years or older, had biopsy-confirmed stage 1 (T1-T2aN0M0) NSCLC diagnosed on the basis of 18F-fluorodeoxyglucose PET, and were medically inoperable or had refused surgery. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and the tumour had to be peripherally located. Patients were randomly assigned after stratification for T stage and operability in a 2:1 ratio to SABR (54 Gy in three 18 Gy fractions, or 48 Gy in four 12 Gy fractions if the tumour was <2 cm from the chest wall) or standard radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2·5 Gy fractions, depending on institutional preference) using minimisation, so no sequence was pre-generated. Clinicians, patients, and data managers had no previous knowledge of the treatment group to which patients would be assigned; however, the treatment assignment was subsequently open label (because of the nature of the interventions). The primary endpoint was time to local treatment failure (assessed according to Response Evaluation Criteria in Solid Tumors version 1.0), with the hypothesis that SABR would result in superior local control compared with standard radiotherapy. All efficacy analyses were based on the intention-to-treat analysis. Safety analyses were done on a per-protocol basis, according to treatment that the patients actually received. The trial is registered with ClinicalTrials.gov (NCT01014130) and the Australia and New Zealand Clinical Trials Registry (ACTRN12610000479000). The trial is closed to new participants.
FINDINGS: Between Dec 31, 2009, and June 22, 2015, 101 eligible patients were enrolled and randomly assigned to receive SABR (n=66) or standard radiotherapy (n=35). Five (7·6%) patients in the SABR group and two (6·5%) in the standard radiotherapy group did not receive treatment, and a further four in each group withdrew before study end. As of data cutoff (July 31, 2017), median follow-up for local treatment failure was 2·1 years (IQR 1·2-3·6) for patients randomly assigned to standard radiotherapy and 2·6 years (IQR 1·6-3·6) for patients assigned to SABR. 20 (20%) of 101 patients had progressed locally: nine (14%) of 66 patients in the SABR group and 11 (31%) of 35 patients in the standard radiotherapy group, and freedom from local treatment failure was improved in the SABR group compared with the standard radiotherapy group (hazard ratio 0·32, 95% CI 0·13-0·77, p=0·0077). Median time to local treatment failure was not reached in either group. In patients treated with SABR, there was one grade 4 adverse event (dyspnoea) and seven grade 3 adverse events (two cough, one hypoxia, one lung infection, one weight loss, one dyspnoea, and one fatigue) related to treatment compared with two grade 3 events (chest pain) in the standard treatment group.
INTERPRETATION: In patients with inoperable peripherally located stage 1 NSCLC, compared with standard radiotherapy, SABR resulted in superior local control of the primary disease without an increase in major toxicity. The findings of this trial suggest that SABR should be the treatment of choice for this patient group.
FUNDING: The Radiation and Optometry Section of the Australian Government Department of Health with the assistance of Cancer Australia, and the Cancer Society of New Zealand and the Cancer Research Trust New Zealand (formerly Genesis Oncology Trust).

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30770291
Janneke P C Grutters, Alfons G H Kessels, Madelon Pijls-Johannesma, Dirk De Ruysscher, Manuela A Joore, Philippe Lambin
Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis.
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
Abstract/Text OBJECTIVES: To determine the effectiveness of radical radiotherapy in medically inoperable stage I/II non-small cell lung cancer (NSCLC) and the extent of treatment related morbidity.
METHODS: Randomised trials were sought by electronically searching the Cochrane Clinical Trials Register, and both randomised and non-randomised trials were sought by searching Medline and Excerpta Medica (Embase). Further studies were identified from references cited in those papers already identified by electronic searching. The studies included were those of patients of any age with stage I/II NSCLC receiving radiotherapy at a dose of >40 Gy in 20 fractions over 4 weeks or its radiobiological equivalent.
RESULTS: Two randomised and 35 non-randomised studies were identified. One randomised and nine non-randomised studies did not meet the selection criteria, leaving one randomised and 26 non-randomised studies for analysis. In the randomised trial 2 year survival was higher following continuous hyperfractionated accelerated radiotherapy (CHART; 37%) than following 60 Gy in 30 fractions over 6 weeks (24%). An estimated 2003 patients were included in the 26 non-randomised studies; overall survival was 22-72% at 2 years, 17-55% at 3 years, and 0-42% at 5 years. Following treatment, 11-43% of patients died from causes other than cancer. Cancer specific survival was 54-93% at 2 years, 22-56% at 3 years, and 13-39% at 5 years. Complete response rates were 33-61% and local failure rates were 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 although the reasons for prescribing higher doses were not clearly stated. The outcome was worse 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.
CONCLUSIONS: No randomised trials 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 11462066
Abstract/Text BACKGROUND: Surgical resection remains the treatment of choice for patients with stage I nonsmall cell lung carcinoma. However, there is a group of patients who are medically inoperable and are treated with radiotherapy alone. This review summarizes findings from published series of radiotherapy for patients with medically inoperable Stage I lung carcinoma.
METHODS: A literature search was used to identify studies of treatment with radiotherapy alone for patients with medically inoperable Stage I nonsmall cell lung carcinoma. Ten studies that utilized megavoltage irradiation to doses of >55 gray (Gy) in conventional fractionation were selected for analysis.
RESULTS: Radiotherapy doses were similar throughout the series, with a median dose of 60-66 Gy. However, treatment volumes varied considerably, from small "postage stamp" fields to comprehensive lymph node coverage. Averaging the results of these studies showed that approximately 15% of patients will be long term survivors, 25% will die of intercurrent disease, 30% will die of distant metastatic disease and 30% will die after local failure only. Eight of ten series report Grade 3-5 complications occurring in <2% of patients. Analysis of treatment factors affecting survival revealed a consistent benefit of higher radiotherapy doses in terms of local control or disease free survival. No benefit from prophylactic lymph node irradiation was demonstrated.
CONCLUSIONS: Despite the infirm nature of patients with medically inoperable Stage I lung carcinoma, the majority will ultimately die of uncontrolled lung carcinoma. Because complications are uncommon after doses of 60-66 Gy, trials of dose escalation to limited fields are indicated for patients with medically inoperable nonsmall cell carcinoma in an attempt to improve overall survival.

PMID 9452258
Xueying Qiao, Owe Tullgren, Ingmar Lax, Florin Sirzén, Rolf Lewensohn
The role of radiotherapy in treatment of stage I non-small cell lung cancer.
Lung Cancer. 2003 Jul;41(1):1-11. doi: 10.1016/s0169-5002(03)00152-1.
Abstract/Text Most information on results with radiotherapy (RT) for stage I non-small cell lung cancer (NSCLC) is based on retrospective studies on RT-treated inoperable NSCLC cases. Thus, the role of RT for stage I NSCLC, as a curative modality, has not yet been established. A literature search for studies on stage I non-small cell lung carcinoma (NSCLC) treated by RT alone resulted in 18 papers published between 1988 and 2000. The majority of stage I patients received RT treatment because they were medically inoperable. The main contraindications for surgery were grave impairment of pulmonary function and serious cardiovascular disease. Local recurrence was the most common reason for treatment failure (median value 40%) but varied highly between the studies, ranging from 6.4 to 70%. In contrast with local recurrence, regional failure was not a major problem (0-3.2%). Generally, smaller tumour size, low T-stage and increased dose had a favourable impact on local control and increased local control was followed by increased survival. No serious treatment complications were recorded in the majority of these studies. Overall treatment results were, however, disappointing. The median survival in these studies ranged from 18 to 33 months. The 3- and 5-year overall survival was 34+/-9 and 21+/-8% (mean value+/-1 S.E.), respectively. The cause-specific survival at 3 and 5 years was 39+/-10 and 25+/-9% (mean value+/-1 S.E.), respectively. Dose escalation, in a setting with conformal RT using involved field or stereotactic RT, should be the focus of developmental therapeutic strategies with inoperable stage I NSCLC to improve local control and survival.

PMID 12826306
K Morita, N Fuwa, Y Suzuki, M Nishio, K Sakai, Y Tamaki, H Niibe, M Chujo, S Wada, T Sugawara, M Kita
Radical radiotherapy for medically inoperable non-small cell lung cancer in clinical stage I: a retrospective analysis of 149 patients.
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
Shaan Dudani, Xiaofu Zhu, Daniel W Yokom, Andrew Yamada, Cheryl Ho, Jason R Pantarotto, Natasha B Leighl, Tinghua Zhang, Paul Wheatley-Price
Radical Treatment of Stage II Non-small-cell Lung Cancer With Nonsurgical Approaches: A Multi-institution Report of Outcomes.
Clin Lung Cancer. 2018 Jan;19(1):e11-e18. doi: 10.1016/j.cllc.2017.06.007. Epub 2017 Jun 21.
Abstract/Text INTRODUCTION: Standard management of stage II non-small-cell lung cancer (NSCLC) is surgery, often followed by adjuvant chemotherapy. However, some patients do not undergo surgery for various reasons. We examined outcomes in this defined patient group.
METHODS: We reviewed the records of patients with stage II NSCLC treated nonsurgically with curative intent from 2002 to 2012 across 3 academic cancer centers. Data collected included demographics, comorbidities, staging, treatments, and survival. The primary endpoint was overall survival (OS). We assessed factors associated with treatment choice and OS.
RESULTS: A total of 158 patients were included: the median age was 74 years (range, 50-91 years), 44% were female, and 68% had a performance status of 0 to 1. The stage II groupings of the patients were T2b-T3 N0 in 55% and N1 in 45%. The most common reasons for inoperability were inadequate pulmonary reserve (27%) and medical comorbidities (24%). All patients received radical radiotherapy (RT) (median, 60 Gy [range, 48-75 Gy]). Seventy-three percent received RT alone; 24% received concurrent and 3% sequential chemoradiotherapy (CRT). In multivariate analyses, CRT was less likely in older patients (≥ 70 years) (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.11-0.70; P = .006) and in patients with higher (> 5) Charlson comorbidity scores (OR, 0.34; 95% CI, 0.13-0.90; P = .03) or normal (< 10 × 109/L) white blood cell counts (OR, 0.26; 95% CI, 0.09-0.73; P = .01). At the time of our analysis, 74% have died. The median OS was 22.9 months (range, 17.1-26.6 months). Patients who had undergone CRT had a significantly longer median OS than those receiving RT alone (39.1 vs. 20.5 months; P = .0019), confirmed in multivariate analysis (hazard ratio, 0.38; 95% CI, 0.21-0.69; P = .001).
CONCLUSION: Nonsurgical approaches to management of stage II NSCLC are varied. Treatment with CRT was associated with significantly longer survival compared with RT alone. A randomized trial may be warranted.

Copyright © 2017 Elsevier Inc. All rights reserved.
PMID 28711384
Yi-Long Wu, Masahiro Tsuboi, Jie He, Thomas John, Christian Grohe, Margarita Majem, Jonathan W Goldman, Konstantin Laktionov, Sang-We Kim, Terufumi Kato, Huu-Vinh Vu, Shun Lu, Kye-Young Lee, Charuwan Akewanlop, Chong-Jen Yu, Filippo de Marinis, Laura Bonanno, Manuel Domine, Frances A Shepherd, Lingmin Zeng, Rachel Hodge, Ajlan Atasoy, Yuri Rukazenkov, Roy S Herbst, ADAURA Investigators
Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer.
N Engl J Med. 2020 Oct 29;383(18):1711-1723. doi: 10.1056/NEJMoa2027071. Epub 2020 Sep 19.
Abstract/Text BACKGROUND: Osimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown.
METHODS: In this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation-positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety.
RESULTS: A total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted.
CONCLUSIONS: In patients with stage IB to IIIA EGFR mutation-positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32955177
Enriqueta Felip, Nasser Altorki, Caicun Zhou, Tibor Csőszi, Ihor Vynnychenko, Oleksandr Goloborodko, Alexander Luft, Andrey Akopov, Alex Martinez-Marti, Hirotsugu Kenmotsu, Yuh-Min Chen, Antonio Chella, Shunichi Sugawara, David Voong, Fan Wu, Jing Yi, Yu Deng, Mark McCleland, Elizabeth Bennett, Barbara Gitlitz, Heather Wakelee, IMpower010 Investigators
Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
Lancet. 2021 Oct 9;398(10308):1344-1357. doi: 10.1016/S0140-6736(21)02098-5. Epub 2021 Sep 20.
Abstract/Text BACKGROUND: Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients.
METHODS: IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting).
FINDINGS: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%).
INTERPRETATION: IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC.
FUNDING: F Hoffmann-La Roche and Genentech.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 34555333
Abstract/Text OBJECTIVE: To evaluate the effect of cytotoxic chemotherapy on survival in patients with non-small cell lung cancer.
DESIGN: Meta-analysis using updated data on individual patients from all available randomised trials, both published and unpublished.
SUBJECTS: 9387 patients (7151 deaths) from 52 randomised clinical trials.
MAIN OUTCOME MEASURE: Survival.
RESULTS: The results for modern regimens containing cisplatin favoured chemotherapy in all comparisons and reached conventional levels of significance when used with radical radiotherapy and with supportive care. Trials comparing surgery with surgery plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death, equivalent to an absolute benefit of 5% at five years). Trials comparing radical radiotherapy with radical radiotherapy plus chemotherapy gave a hazard ratio of 0.87 (13% reduction in the risk of death; absolute benefit of 4% at two years), and trials comparing supportive care with supportive care plus chemotherapy 0.73 (27% reduction in the risk of death; 10% improvement in survival at one year). The essential drugs needed to achieve these effects were not identified. No difference in the size of effect was seen in any subgroup of patients. In all but the radical radiotherapy setting, older trials using long term alkylating agents tended to show a detrimental effect of chemotherapy. This effect reached conventional significance in the adjuvant surgical comparison.
CONCLUSION: At the outset of this meta-analysis there was considerable pessimism about the role of chemotherapy in non-small cell lung cancer. These results offer hope of progress and suggest that chemotherapy may have a role in treating this disease.

PMID 7580546
Jean-Pierre Pignon, Hélène Tribodet, Giorgio V Scagliotti, Jean-Yves Douillard, Frances A Shepherd, Richard J Stephens, Ariane Dunant, Valter Torri, Rafael Rosell, Lesley Seymour, Stephen G Spiro, Estelle Rolland, Roldano Fossati, Delphine Aubert, Keyue Ding, David Waller, Thierry Le Chevalier, LACE Collaborative Group
Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.
J Clin Oncol. 2008 Jul 20;26(21):3552-9. doi: 10.1200/JCO.2007.13.9030. Epub 2008 May 27.
Abstract/Text PURPOSE: Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy.
PATIENTS AND METHODS: Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial.
RESULTS: With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin.
CONCLUSION: Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.

PMID 18506026

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