今日の臨床サポート

非小細胞肺癌(進行期)

著者: 藤村至 岩手医科大学 医学部 内科学講座 呼吸器内科分野

著者: 前門戸任 岩手医科大学 医学部 内科学講座 呼吸器内科分野

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
薬価収載情報:2022年4月20日 ルマケラス錠 120mg(ソトラシブ 抗悪性腫瘍剤/KRAS G12C阻害剤)

概要・推奨   

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:
藤村至 : 特に申告事項無し[2022年]
前門戸任 : 講演料(アストラゼネカ,小野薬品工業,BMS,中外製薬,ファイザー,武田薬品工業,日本イーライリリー,ノバルティス,日本ベーリンガー),研究費・助成金など(ノバルティス,小野薬品工業),奨学(奨励)寄付など(中外製薬)[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.  可能な限り様々なエビデンスに基づいた改定を心がけた

病態・疫学・診察

定義  
  1. 「転移性肺癌Metastatic lung cancer」は同側肺内を除いた遠隔臓器に1つ以上の結節ができる状態と定義され、 TNM分類(第8版)の「Stage Ⅳ」に該当する[1]
  1. 現在のTNM分類第8版は2016年に発表された[2]。第7版との違いをそれぞれT,N,M毎に述べる。
  1. T 分類では最大径の分類基準が第7版には無かった「1㎝と4㎝」が追加、細分化され1,2,3,4,5,7 cm となった。また、CT 上の最大径は充実成分径に変更されている。その他、気管分岐部に浸潤が及ばない主気管支浸潤肺癌は従来の期間分岐部から2㎝未満でT2→T3となる分類を撤廃し、気管分岐部からの距離に関わらずT2 とした。片肺の完全無気肺・肺炎の存在もT3 から T2 に変更された。横隔膜直接浸潤はT3 → T4に再分類された。縦隔胸膜のみの浸潤は T 分類変更要素にはされなくなった。
  1. N 分類は変更されなかったが、T1-2aN1M0 がIIA(第7 版)→IIB(第8版)、T3N2M0がIIIA(第7版)→IIIB(第8版)、T3~4N3M0 がIIIB(第7版)→ IIIC(第8版で新設)に再分類された。
  1. M分類ではM1b(第7版)→ M1b(胸腔外の1 臓器単発転移)+ M1c(多発転移)と第8版で再分割された。
  1. 結果として病期分類は、IA期がIA1、IA2、IA3期に分かれ, IIIC期が新設され、IV期がIVA(M1aおよびM1b)、IVB 期(M1c)に分かれた。これらの再分類によって第8版は各病期分類に有意さを保ったまま、第7版より細やかに肺癌の生命予後を予測できるようになった。
 
利用可能なデータベース全体を用いたTNM分類

a.第7版のグループ分けによる臨床病期別の全生存率
b.第8版のグループ分けによる臨床病期別の全生存率
※MST=median survival time

出典

img1:  The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer.
 
 J Thorac Oncol. 2016 Jan;11(1):39-51. do・・・
 
  1. 「高齢者」の定義は75歳以上とされる。 日本の臨床試験では75歳以上が除外されることが多いものの、70歳以上の高齢者を対象とした試験において多くが75歳以上であったことが根拠とされている[3]
  1. 機能障害に応じて患者を分類し、治療の有効性を比較して患者予後を評価する試みは古くから存在してきた[4][5]。Eastern Cooperative Oncology Group(ECOG)の Performance Status(PS)は1982年に発表され[6]、Karnofsky Performance Status (KPS) スケールより単純でありながら生存予後の予測能は十分保たれていた[7]。PSは上昇するにつれてmedian overall survival (OS)が下がることが分かっており[8]、PS0と比較すると、PS1, PS2, PS>3で予後が分かれる[9]。免疫チェックポイント阻害薬で治療を行った非小細胞肺癌患者のPSが2以上かどうかは重要な予後予測因子である可能性が示唆された[10]。また、高齢者でもPSが1であるか2であるかで予後予測に違いがでる結果も報告されている[11]。本邦の肺癌診療ガイドラインもPS0-1, PS2, PS>3で方針が変わってくる[3]
 
Eastern Cooperative Oncology Group(ECOG)の Performance Status(PS)

参考文献:Am J Clin Oncol. 1982;5(6): 649–56.
※ピクトグラムはhttps: //pictogram2.com/より一部改変
 

出典

img1:  著者提供
 
 
 
  1. COPDや在宅酸素療法導入状態の患者のPSは慎重に判断する必要がある。
  1. StageⅠであってもKarnofsky Performance Status (KPS) score<80に対する定位放射線照射療法の全生存期間はKPS≧80に比して長くないことが報告されており[12]、呼吸機能の低下に伴うスコアの低下が一因であった。
 
疫学  
  1. 2019年にがんで死亡した人は376,425人(男性220,339人, 女性156,086人)で、そのうち、肺癌が男性では53,338人で第一位, 女性では22,056人で第二位と報告され2017年の報告と同様の傾向が続いている。罹患率は前回参照した2017年のデータのままであり、男性は横ばいで推移しているが、女性は増加傾向である[13]

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

まずは15日間無料トライアル
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

J Vansteenkiste, D De Ruysscher, W E E Eberhardt, E Lim, S Senan, E Felip, S Peters, ESMO Guidelines Working Group
Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol. 2013 Oct;24 Suppl 6:vi89-98. doi: 10.1093/annonc/mdt241. Epub 2013 Jul 16.
Abstract/Text
PMID 23860613
Peter Goldstraw, Kari Chansky, John Crowley, Ramon Rami-Porta, Hisao Asamura, Wilfried E E Eberhardt, Andrew G Nicholson, Patti Groome, Alan Mitchell, Vanessa Bolejack, International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions, International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Advisory Boards and Participating Institutions
The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer.
J Thorac Oncol. 2016 Jan;11(1):39-51. doi: 10.1016/j.jtho.2015.09.009.
Abstract/Text The IASLC Staging and Prognostic Factors Committee has collected a new database of 94,708 cases donated from 35 sources in 16 countries around the globe. This has now been analysed by our statistical partners at Cancer Research And Biostatistics and, in close collaboration with the members of the committee proposals have been developed for the T, N, and M categories of the 8th edition of the TNM Classification for lung cancer due to be published late 2016. In this publication we describe the methods used to evaluate the resultant Stage groupings and the proposals put forward for the 8th edition.

Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.
PMID 26762738
M M Oken, R H Creech, D C Tormey, J Horton, T E Davis, E T McFadden, P P Carbone
Toxicity and response criteria of the Eastern Cooperative Oncology Group.
Am J Clin Oncol. 1982 Dec;5(6):649-55.
Abstract/Text
PMID 7165009
Raymond W Jang, Valerie B Caraiscos, Nadia Swami, Subrata Banerjee, Ernie Mak, Ebru Kaya, Gary Rodin, John Bryson, Julia Z Ridley, Lisa W Le, Camilla Zimmermann
Simple prognostic model for patients with advanced cancer based on performance status.
J Oncol Pract. 2014 Sep;10(5):e335-41. doi: 10.1200/JOP.2014.001457. Epub 2014 Aug 12.
Abstract/Text PURPOSE: Providing survival estimates is important for decision making in oncology care. The purpose of this study was to provide survival estimates for outpatients with advanced cancer, using the Eastern Cooperative Oncology Group (ECOG), Palliative Performance Scale (PPS), and Karnofsky Performance Status (KPS) scales, and to compare their ability to predict survival.
METHODS: ECOG, PPS, and KPS were completed by physicians for each new patient attending the Princess Margaret Cancer Centre outpatient Oncology Palliative Care Clinic (OPCC) from April 2007 to February 2010. Survival analysis was performed using the Kaplan-Meier method. The log-rank test for trend was employed to test for differences in survival curves for each level of performance status (PS), and the concordance index (C-statistic) was used to test the predictive discriminatory ability of each PS measure.
RESULTS: Measures were completed for 1,655 patients. PS delineated survival well for all three scales according to the log-rank test for trend (P < .001). Survival was approximately halved for each worsening performance level. Median survival times, in days, for each ECOG level were: EGOG 0, 293; ECOG 1, 197; ECOG 2, 104; ECOG 3, 55; and ECOG 4, 25.5. Median survival times, in days, for PPS (and KPS) were: PPS/KPS 80-100, 221 (215); PPS/KPS 60 to 70, 115 (119); PPS/KPS 40 to 50, 51 (49); PPS/KPS 10 to 30, 22 (29). The C-statistic was similar for all three scales and ranged from 0.63 to 0.64.
CONCLUSION: We present a simple tool that uses PS alone to prognosticate in advanced cancer, and has similar discriminatory ability to more complex models.

Copyright © 2014 by American Society of Clinical Oncology.
PMID 25118208
Tomoya Kawaguchi, Minoru Takada, Akihito Kubo, Akihide Matsumura, Shimao Fukai, Atsuhisa Tamura, Ryusei Saito, Yosihito Maruyama, Masaaki Kawahara, Sai-Hong Ignatius Ou
Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: a comprehensive analysis of 26,957 patients with NSCLC.
J Thorac Oncol. 2010 May;5(5):620-30. doi: 10.1097/JTO.0b013e3181d2dcd9.
Abstract/Text BACKGROUND: Performance status (PS) is an important factor in determining survival outcome in non-small cell lung cancer (NSCLC) but is generally confounded by stage, age, gender, and smoking status. We investigated the prognostic significance of PS taking into account these important factors.
METHODS: Retrospective analysis of registry database of the National Hospital Study Group for Lung Cancer (NHSGLC) between 1990 and 2005. Univariate analysis was performed using Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards model to identify independent prognostic factors.
RESULTS: A total of 26,957 patients with NSCLC were analyzed of which 12,613 patients (46.8%) had World Health Organization (WHO) PS = 0, 8,137 patients were never smokers (30.2%), and most of them were females (72.7%). The majority of PS = 0 patients presented with stage I disease (56.9%). Patients with PS = 0 constituted the group with the highest proportion of never smokers (36.7%). There was a significant difference in the median overall survival (OS) between patients with PS = 0 and PS = 1 (51.5 months versus 15.4 months, respectively; p < 0.0001) and among patients with various PS within individual American Joint Committee on Cancer stage (all p values <0.0001). Never smokers had significantly improved median OS than ever smokers (30.0 months versus 19.0 months, respectively; p < 0.0001). Multivariate analysis demonstrated good PS, never smoker (versus ever smoker; hazard ratio = 0.935, 95% confidence interval: 0.884-0.990; p = 0.0205), early stage, female gender, squamous cell carcinoma histology, and treatment were all as independent favorable prognostic factors.
CONCLUSIONS: PS and smoking status are independent prognostic factors for OS in NSCLC.

PMID 20354456
Jean-Paul Sculier, Kari Chansky, John J Crowley, Jan Van Meerbeeck, Peter Goldstraw, International Staging Committee and Participating Institutions
The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition.
J Thorac Oncol. 2008 May;3(5):457-66. doi: 10.1097/JTO.0b013e31816de2b8.
Abstract/Text PURPOSE: To identify, in the international staging database of the International Association for the Study of Lung Cancer, those prognostic factors that were significant and independent of clinical stage.
MATERIAL AND METHODS: From the data submitted to the staging data base concerning 100,869 patients, cases were selected for which all the following variables were available: clinical stage, age, gender, performance status (PS), and histologic cell types. For non-small cell lung cancer (NSCLC), 12,428 patients were assessable, and for SCLC, 6609 patients were available for this study. Methods used were Cox regression analyses and recursive partitioning and amalgamation analyses.
RESULTS: PS appeared to be a very important prognostic factor for survival in addition to clinical stage. Age and gender were other independent significant variables; For NSCLC and SCLC separately, recursive partitioning and amalgamation allowed the identification of four groups of patients with differing prognoses. In advanced NSCLC (stage IIIB / IV), some routine laboratory tests (mainly white blood cells and hypercalcaemia) were also found to be significant prognostic variables. In SCLC, albumin was an independent biologic prognostic factor.
CONCLUSION: In addition to stage, PS and, to a lesser extent, age and gender seem to be important prognostic factors for survival in lung cancer. Although this data was obtained from the largest series ever used for such an analysis in lung cancer, these prognostic factors and models require confirmation in the prospective study already planned by the International Association for the Study of Lung Cancer Lung Cancer Staging Project.

PMID 18448996
Filippo G Dall'Olio, Ilaria Maggio, Maria Massucci, Veronica Mollica, Benedetta Fragomeno, Andrea Ardizzoni
ECOG performance status ≥2 as a prognostic factor in patients with advanced non small cell lung cancer treated with immune checkpoint inhibitors-A systematic review and meta-analysis of real world data.
Lung Cancer. 2020 Jul;145:95-104. doi: 10.1016/j.lungcan.2020.04.027. Epub 2020 May 6.
Abstract/Text OBJECTIVES: ICIs have been approved and are routinely administered regardless of performance status (PS), despite randomized clinical trials of ICIs alone or combined with chemotherapy or target therapy enrolled patients with ECOG PS 0 or 1, while patients with ECOG PS 2 or more were excluded.
MATERIALS AND METHODS: We carried out a meta-analysis of available clinical studies exploring the prognostic impact of PS ≥ 2 on Overall Survival (OS), Progression Free Survival (PFS) or Overall Response Rate (ORR) in patients with non small cell lung cancer (NSCLC) treated with immunotherapy (any line).
RESULTS: We reviewed 19 studies, comprising 3600 NSCLC patients, 757 of whom with ECOG PS > 1 (average 21.0%, range 6.0-48.6%). In the overall population PS ≥ 2 resulted in worse OS, PFS and ORR (OS pooled hazard ratio of 2.72; 95% CI: 2.03-3.63; I2 72.70%, p < 0.001; PFS pooled hazard ratio of 2.39; 95% CI 1.81-3.15, p < 0.0001; I2 73.03%; ORR pooled odds ratio 0.25; 95% CI 0.11-0.56, p 0.001; I2 0.00%).
CONCLUSION: ECOG PS ≥ 2 retains an important prognostic validity in patients treated with ICI similar, in terms of effect size, to that reported for chemotherapy in NSCLC. The high level of heterogeneity for OS and PFS analysis (but not for ORR), not completely explained by the different proportion of ECOG 3-4 patients (ranging from 0% to 50% of the PS ≥ 2 population), could be the result of both patient heterogeneity within the PS 2 population and the subjectivity of ECOG PS assessment. Whether poorer PS is also a predictor of lower immunotherapy efficacy remains still to be demonstrated.

Copyright © 2020 Elsevier B.V. All rights reserved.
PMID 32417680
Apar Kishor Ganti, Xiaofei Wang, Thomas E Stinchcombe, Yinpeng Wang, Jeffrey Bradley, Harvey J Cohen, Karen Kelly, Rebecca Paulus, Suresh S Ramalingam, Everett E Vokes, Herbert Pang
Clinical prognostic model for older patients with advanced non-small cell lung cancer.
J Geriatr Oncol. 2019 Jul;10(4):555-559. doi: 10.1016/j.jgo.2019.02.007. Epub 2019 Feb 21.
Abstract/Text BACKGROUND: Older patients with non-small cell lung cancer (NSCLC) are often not prescribed standard therapy. It is important to know which older patients would be candidates for aggressive therapy based on their prognosis, and to develop a model that can help determine prognosis.
METHODS: Data on older patients (≥70 years) enrolled on 38 NCI cooperative group trials of advanced NSCLC from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise selection. We derived a prognostic score using the estimated Cox PH regression coefficient. We then calculated the area under receiver operating characteristic (ROC) curve of survival in the testing set.
RESULTS: The final analysis included 1467 patients, who were randomly divided into a training (n = 963) and a testing set (n = 504). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS = 1) + 8 (if PS = 2) + 11 (if initial stage = IV) + 4 (if weight loss). Patients were classified into two prognostic groups: good (0-8) and poor (≥9). The median survival in the two groups in the testing set were 13.15 (95% CI, 10.82-15.91) and 8.52 months (95% CI, 7.5-9.63), respectively. The model had area under the 1-year and 2-year ROCs (0.6 and 0.65, respectively) that were higher than existing models.
CONCLUSIONS: Male gender, poor performance status, distant metastases and recent weight loss predict for poor overall survival (OS) in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC.

Copyright © 2019. Published by Elsevier Ltd.
PMID 30797707
Aiko Koba, Kazuhiko Hayashi, Osamu Suzuki, Yoshifumi Kawaguchi, Kazuhiko Ogawa, Masashi Chatani
Stereotactic body radiotherapy feasibility for patients with peripheral stage I lung cancer and poor pulmonary function.
Oncol Lett. 2020 Mar;19(3):2515-2521. doi: 10.3892/ol.2020.11333. Epub 2020 Jan 22.
Abstract/Text The aim of the present study was to evaluate the toxicity and investigate the prognostic factors of stereotactic body radiotherapy (SBRT) for peripheral stage I lung cancer in patients with poor pulmonary function. Data from 95 patients with stage I lung cancer with poor pulmonary function treated using SBRT at Osaka Rosai Hospital were retrospectively analyzed. Poor pulmonary function was defined as the forced expiratory volume %/sec (FEV1/FVC) <70% or percentage of vital capacity (%VC) <80% during pretreatment spirometry testing. The median FEV1/FVC and %VC of the patients were 59.1 and 78.8%, respectively. The most commonly prescribed dose of SBRT was 50 Gy in four fractions (68 patients, 72%). The median follow-up period was 34 months. Four patients developed adverse effects of grade ≥3, one patient developed grade 5 radiation pneumonitis, one grade 5 hemoptysis, one grade 3 radiation pneumonitis and one grade 3 chest wall pain. The 3-year local control and overall survival (OS) rates were 78.8 and 59.9%, respectively. Univariate analysis revealed that Karnofsky performance status (KPS) significantly predicted OS (P=0.037). Thus, SBRT in patients with stage I lung cancer with poor pulmonary function may be effective with acceptable toxicity. A KPS score ≥80 indicated good prognosis.

Copyright © 2020, Spandidos Publications.
PMID 32194753
Abstract/Text BACKGROUND: This guideline is intended to provide an evidence-based approach to the initial evaluation of patients with known or suspected lung cancer. It also includes an assessment of the impact of timeliness of care and multidisciplinary teams on outcome.
METHODS: The applicable current medical literature was identified by a computerized search and evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee of the American College of Chest Physicians. Data sources included MEDLINE and the Cochrane Database of Systematic Reviews.
RESULTS: Initial evaluation should include a thorough history and physical examination; CT imaging; pulmonary function tests; and hemoglobin, electrolyte, liver function, and calcium levels. Additional testing for distant metastases and paraneoplastic syndromes should be determined on the basis of these results. Paraneoplastic syndromes may have an adverse impact on cancer treatment, so they should be controlled rapidly with the goal of proceeding with definitive cancer treatment in a timely manner. Although the relationship between timeliness of care and survival is difficult to quantify, efforts to deliver timely care are reasonable and should be balanced with the need to attend to other dimensions of health-care quality (eg, safety, effectiveness, efficiency, equality, consistency with patient values and preferences). Quality care will require multiple disciplines. Although it is difficult to assess the impact, we suggest that a multidisciplinary team approach to care be used, particularly for patients requiring multimodality therapy.
CONCLUSIONS: The initial evaluation of patients with lung cancer should include a thorough history and physical examination, pulmonary function tests, CT imaging, basic laboratory tests, and selective testing for distant metastases and paraneoplastic syndromes.

PMID 23649435
Pu-Yuan Xing, Yi-Xiang Zhu, Le Wang, Zhou-Guang Hui, Shang-Mei Liu, Jian-Song Ren, Ye Zhang, Yan Song, Cheng-Cheng Liu, Yun-Chao Huang, Xian-Zhen Liao, Xiao-Jing Xing, De-Bin Wang, Li Yang, Ling-Bin Du, Yu-Qin Liu, Yong-Zhen Zhang, Yun-Yong Liu, Dong-Hua Wei, Kai Zhang, Ju-Fang Shi, You-Lin Qiao, Wan-Qing Chen, Jun-Ling Li, Min Dai, LuCCRES Group
What are the clinical symptoms and physical signs for non-small cell lung cancer before diagnosis is made? A nation-wide multicenter 10-year retrospective study in China.
Cancer Med. 2019 Jul;8(8):4055-4069. doi: 10.1002/cam4.2256. Epub 2019 May 31.
Abstract/Text BACKGROUND: Most lung cancer patients are diagnosed after the onset of symptoms. However, whether the symptoms of lung cancer were independently associated with the diagnosis of lung cancer is unknown, especially in the Chinese population.
METHODS: We conducted a 10 years (2005-2014) nationwide multicenter retrospective clinical epidemiology study of lung cancer patients diagnosed in China. As such, this study focused on nonsmall cell lung cancer (NSCLC). We calculated the odds ratios (ORs) for variables associated with the symptoms and physical signs using multivariate unconditional logistic regressions.
RESULTS: A total of 7184 lung cancer patients were surveyed; finally, 6398 NSCLC patients with available information about their symptoms and physical signs were included in this analysis. The most common initial symptom and physical sign was chronic cough (4156, 65.0%), followed by sputum with blood (2110, 33.0%), chest pain (1146, 17.9%), shortness of breath (1090, 17.0%), neck and supraclavicular lymphadenectasis (629, 9.8%), weight loss (529, 8.3%), metastases pain (378, 5.9%), fatigue (307, 4.8%), fever (272, 4.3%), and dyspnea (270, 4.2%). Patients with squamous carcinoma and stage III disease were more likely to present with chronic cough (P < 0.0001) and sputum with blood (P < 0.0001) than patients with other pathological types and clinical stages, respectively. Metastases pain (P < 0.0001) and neck and supraclavicular lymphadenectasis (P = 0.0006) were more likely to occur in patients with nonsquamous carcinoma than in patients with other carcinomas. Additionally, patients with stage IV disease had a higher percentage of chest pain, shortness of breath, dyspnea, weight loss, and fatigue than patients with other stages of disease. In multivariable logistic analyses, compared with patients with adenocarcinoma, patients with squamous carcinoma were more likely to experience symptoms (OR = 2.885, 95% confidence interval [CI] 2.477-3.359) but were less likely to present physical signs (OR = 0.844, 95% CI 0.721-0.989). The odds of having both symptoms and physical signs were higher in patients with late-stage disease than in those with early-stage disease (P < 0.0001).
CONCLUSIONS: The symptoms and physical signs of lung cancer were associated with the stage and pathological diagnosis of NSCLC. Patients with squamous carcinoma were more likely to develop symptoms, but not signs, than patients with adenocarcinoma. The more advanced the stage at diagnosis, the more likely that symptoms or physical signs are to develop. Further prospective cohort studies are needed to explore these results.

© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PMID 31150167
Bruno Giometto, Wolfgang Grisold, Roberta Vitaliani, Francesc Graus, Jérôme Honnorat, Guido Bertolini, PNS Euronetwork
Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers.
Arch Neurol. 2010 Mar;67(3):330-5. doi: 10.1001/archneurol.2009.341.
Abstract/Text BACKGROUND: Paraneoplastic neurologic syndrome (PNS) represents the remote effects of cancer on the nervous system. Diagnostic criteria for the syndrome were published by the PNS Euronetwork and form the basis of a database to collect standardized clinical data from patients with PNS.
OBJECTIVES: To analyze various types of PNS, frequent tumor and antibody associations, clinical characteristics of individual syndromes, and possible therapeutic and prognostic strategies.
DESIGN: Prospective case series and database study.
SETTING: Twenty European centers. Patients Patients were recruited from January 1, 2000, to December 31, 2008.
MAIN OUTCOME MEASURES: Based on diagnostic criteria published by the PNS Euronetwork consortium, clinical characteristics of classic PNS and several other less well-characterized syndromes associated with cancer were assessed.
RESULTS: Data from 979 patients were analyzed, representing the largest PNS investigation to date. The findings elucidate the clinical evolution of paraneoplastic cerebellar syndrome according to the onconeural antibodies present, the heterogeneity and prognosis of dysautonomic disorders, and the clinical variability of paraneoplastic limbic encephalitis.
CONCLUSION: The study results confirm that PNS influences oncologic patient survival. Tumors are the main cause of death, but some types of PNS (such as dysautonomia) have a poorer prognosis than malignant neoplasms.

PMID 20212230
Rowena Yip, Kunwei Li, Li Liu, Dongming Xu, Kathleen Tam, David F Yankelevitz, Emanuela Taioli, Betsy Becker, Claudia I Henschke
Controversies on lung cancers manifesting as part-solid nodules.
Eur Radiol. 2018 Feb;28(2):747-759. doi: 10.1007/s00330-017-4975-9. Epub 2017 Aug 23.
Abstract/Text PURPOSE: Summarise survival of patients with resected lung cancers manifesting as part-solid nodules (PSNs).
METHODS: PubMed/MEDLINE and EMBASE databases were searched for all studies/clinical trials on CT-detected lung cancer in English before 21 December 2015 to identify surgically resected lung cancers manifesting as PSNs. Outcome measures were lung cancer-specific survival (LCS), overall survival (OS), or disease-free survival (DFS). All PSNs were classified by the percentage of solid component to the entire nodule diameter into category PSNs <80% or category PSNs ≥80%.
RESULTS: Twenty studies reported on PSNs <80%: 7 reported DFS and 2 OS of 100%, 6 DFS 96.3-98.7%, and 11 OS 94.7-98.9% (median DFS 100% and OS 97.5%). Twenty-seven studies reported on PSNs ≥80%: 1 DFS and 2 OS of 100%, 19 DFS 48.0%-98.0% (median 82.6%), and 16 reported OS 43.0%-98.0% (median DFS 82.6%, OS 85.5%). Both DFS and OS were always higher for PSNs <80%.
CONCLUSION: A clear definition of the upper limit of solid component of a PSN is needed to avoid misclassification because cell-types and outcomes are different for PSN and solid nodules. The workup should be based on the size of the solid component.
KEY POINTS: • Lung cancers manifesting as PSNs are slow growing with high cure rates. • Upper limits of the solid component are important for correct interpretation. • Consensus definition is important for the management of PSNs. • Median disease-free-survival (DFS) increased with decreasing size of the nodule.

PMID 28835992
Heber MacMahon, David P Naidich, Jin Mo Goo, Kyung Soo Lee, Ann N C Leung, John R Mayo, Atul C Mehta, Yoshiharu Ohno, Charles A Powell, Mathias Prokop, Geoffrey D Rubin, Cornelia M Schaefer-Prokop, William D Travis, Paul E Van Schil, Alexander A Bankier
Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017.
Radiology. 2017 Jul;284(1):228-243. doi: 10.1148/radiol.2017161659. Epub 2017 Feb 23.
Abstract/Text The Fleischner Society Guidelines for management of solid nodules were published in 2005, and separate guidelines for subsolid nodules were issued in 2013. Since then, new information has become available; therefore, the guidelines have been revised to reflect current thinking on nodule management. The revised guidelines incorporate several substantive changes that reflect current thinking on the management of small nodules. The minimum threshold size for routine follow-up has been increased, and recommended follow-up intervals are now given as a range rather than as a precise time period to give radiologists, clinicians, and patients greater discretion to accommodate individual risk factors and preferences. The guidelines for solid and subsolid nodules have been combined in one simplified table, and specific recommendations have been included for multiple nodules. These guidelines represent the consensus of the Fleischner Society, and as such, they incorporate the opinions of a multidisciplinary international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists. Changes from the previous guidelines issued by the Fleischner Society are based on new data and accumulated experience. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on March 13, 2017.

PMID 28240562
M E J Callister, D R Baldwin, A R Akram, S Barnard, P Cane, J Draffan, K Franks, F Gleeson, R Graham, P Malhotra, M Prokop, K Rodger, M Subesinghe, D Waller, I Woolhouse, British Thoracic Society Pulmonary Nodule Guideline Development Group, British Thoracic Society Standards of Care Committee
British Thoracic Society guidelines for the investigation and management of pulmonary nodules.
Thorax. 2015 Aug;70 Suppl 2:ii1-ii54. doi: 10.1136/thoraxjnl-2015-207168.
Abstract/Text
PMID 26082159
J H Austin, N L Müller, P J Friedman, D M Hansell, D P Naidich, M Remy-Jardin, W R Webb, E A Zerhouni
Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society.
Radiology. 1996 Aug;200(2):327-31. doi: 10.1148/radiology.200.2.8685321.
Abstract/Text
PMID 8685321
David M Hansell, Alexander A Bankier, Heber MacMahon, Theresa C McLoud, Nestor L Müller, Jacques Remy
Fleischner Society: glossary of terms for thoracic imaging.
Radiology. 2008 Mar;246(3):697-722. doi: 10.1148/radiol.2462070712. Epub 2008 Jan 14.
Abstract/Text Members of the Fleischner Society compiled a glossary of terms for thoracic imaging that replaces previous glossaries published in 1984 and 1996 for thoracic radiography and computed tomography (CT), respectively. The need to update the previous versions came from the recognition that new words have emerged, others have become obsolete, and the meaning of some terms has changed. Brief descriptions of some diseases are included, and pictorial examples (chest radiographs and CT scans) are provided for the majority of terms.

(c) RSNA, 2008.
PMID 18195376
M Remy-Jardin, J Remy, F Giraud, L Wattinne, B Gosselin
Computed tomography assessment of ground-glass opacity: semiology and significance.
J Thorac Imaging. 1993 Fall;8(4):249-64. doi: 10.1097/00005382-199323000-00001.
Abstract/Text Among the computed tomography (CT) signs of parenchymal lung disease, the ground-glass pattern is the one most difficult to diagnose and most influenced by CT technique. Ground-glass opacity may result from changes in the airspaces or interstitial tissues in acute or chronic infiltrative lung disease. It may also be seen as a consequence of increased capillary blood volume in redistribution of blood flow due to airway disease, emphysema, or pulmonary thromboembolism. Definition of this sign on high-resolution CT (HRCT) images, its various HRCT patterns, and potential pitfalls in its recognition are described with special attention to optimal HRCT technique.

PMID 8246323
Chang Min Park, Jin Mo Goo, Hyun Ju Lee, Chang Hyun Lee, Eun Ju Chun, Jung-Gi Im
Nodular ground-glass opacity at thin-section CT: histologic correlation and evaluation of change at follow-up.
Radiographics. 2007 Mar-Apr;27(2):391-408. doi: 10.1148/rg.272065061.
Abstract/Text The popularization of computed tomography (CT) in clinical practice and the introduction of mass screening for early lung cancer with the use of CT have increased the frequency of findings of subtle nodules or nodular ground-glass opacity. Nodular ground-glass opacity may be observed in malignancies such as bronchioloalveolar carcinoma and adenocarcinoma, as well as in their putative precursors, such as atypical adenomatous hyperplasia. Nodular ground-glass opacity also may be seen in the presence of benign conditions, including focal interstitial fibrosis, inflammation, and hemorrhage. The persistence of nodular ground-glass opacity over time may be strongly suggestive of an early-stage malignancy, especially if the lesion increases in size or includes a solid component that increases in its extent. Persistent nodular ground-glass opacity also may remain stable in size but show increased attenuation. The more extensive the solid portions of the lesion, the higher the probability of malignancy and the poorer the prognosis. An awareness of the clinical setting, in addition to familiarity with the thin-section CT features of nodular ground-glass opacity at initial and follow-up imaging over several months, can help identify malignancy and achieve an accurate diagnosis. A meticulous evaluation of those CT features, and their correlation with specific histopathologic characteristics, also may enable a more accurate prognosis in cases of neoplastic disease.

(c) RSNA, 2007.
PMID 17374860
S L Primack, T E Hartman, K S Lee, N L Müller
Pulmonary nodules and the CT halo sign.
Radiology. 1994 Feb;190(2):513-5. doi: 10.1148/radiology.190.2.8284408.
Abstract/Text PURPOSE: To determine whether the "halo sign" at computed tomography (CT) could be used to differentiate hemorrhagic from nonhemorrhagic pulmonary nodules.
MATERIALS AND METHODS: CT scans of 12 patients with hemorrhagic pulmonary nodules and of a control group of 10 patients with nonhemorrhagic pulmonary nodules were randomized and reviewed by two chest radiologists. Nodules were considered hemorrhagic if a surrounding halo of ground-glass attenuation was present.
RESULTS: Nodules were correctly identified as either hemorrhagic or nonhemorrhagic by both observers in 19 of the 22 cases (86%). Eight of the 12 patients with hemorrhagic nodules had an infectious process including invasive aspergillosis, candidiasis, cytomegalovirus, herpes simplex virus, or coccidioidomycosis. Four of 12 patients with hemorrhagic nodules had a noninfectious cause including Wegener granulomatosis, metastatic angiosarcoma, and Kaposi sarcoma.
CONCLUSION: Most hemorrhagic pulmonary nodules have a characteristic CT appearance consisting of a central area of soft-tissue attenuation with a surrounding halo of ground-glass attenuation that allows distinction from nonhemorrhagic nodules.

PMID 8284408
Ha Young Kim, Young Mog Shim, Kyung Soo Lee, Joungho Han, Chin A Yi, Yoon Kyung Kim
Persistent pulmonary nodular ground-glass opacity at thin-section CT: histopathologic comparisons.
Radiology. 2007 Oct;245(1):267-75. doi: 10.1148/radiol.2451061682.
Abstract/Text PURPOSE: To retrospectively compare pure pulmonary ground-glass opacity (GGO) nodules observed on thin-section computed tomography (CT) images with histopathologic findings.
MATERIALS AND METHODS: The institutional review board approved this study and waived informed consent. Histopathologic specimens were obtained from 53 GGO nodules in 49 patients. CT scans were assessed in terms of nodule size, shape, contour, internal characteristics, and the presence of a pleural tag. The findings obtained were compared with histopathologic results. Differences in thin-section CT findings according to histopathologic diagnoses were analyzed by using the Kruskal-Wallis test or Fisher exact test.
RESULTS: Of 53 nodules in 49 patients (20 men, 29 women; mean age, 54 years; range, 29-78 years), 40 (75%) proved to be broncholoalveolar cell carcinoma (BAC) (n=36) or adenocarcinoma with predominant BAC component (n=4), three (6%) atypical adenomatous hyperplasia, and 10 (19%) nonspecific fibrosis or organizing pneumonia. No significant differences in morphologic findings on thin-section CT scans were found among the three diseases (all P>0.05). A polygonal shape (25%, 10 of 40 nodules) and a lobulated or spiculated margin (45%, 18 of 40) in BAC or adenocarcinoma with predominant BAC component were caused by interstitial fibrosis or infiltrative tumor growth. A polygonal shape and a lobulated or spiculated margin were observed in two (20%) and three (30%) of 10 nodules, respectively, in organizing pneumonia/fibrosis were caused by granulation tissue aligned in a linear manner in perilobular regions with or without interlobular septal thickening.
CONCLUSION: About 75% of persistent pulmonary GGO nodules are attributed to BAC or adenocarcinoma with predominant BAC component, and at thin-section CT, these nodules do not manifest morphologic features that distinguish them from other GGO nodules with different histopathologic diagnoses.

Copyright (c) RSNA, 2007.
PMID 17885195
Masao Nakata, Hideyuki Saeki, Ichiro Takata, Yoshihiko Segawa, Hiroshi Mogami, Koichi Mandai, Kenji Eguchi
Focal ground-glass opacity detected by low-dose helical CT.
Chest. 2002 May;121(5):1464-7. doi: 10.1378/chest.121.5.1464.
Abstract/Text OBJECTIVE: Focal ground-glass opacity (GGO) has been detected increasingly by low-dose helical CT. Although focal GGO suggests in situ neoplastic lesion in the peripheral lung, it remains controversial how to manage these lesions. The purpose of this study was to evaluate the pathologic and radiologic characteristics of focal GGO in order to develop a standard of treatment for these lesions.
PATIENTS: Forty-three patients with persistent focal GGO < or = 2 cm in size from January 1998 to September 2000 were studied. Thoracoscopic lung biopsy was performed consecutively for persistent focal GGO following a several-month observation period (mean, 3.7 months).
RESULTS: The histologic diagnoses were bronchioloalveolar carcinoma (BAC) in 23 patients, adenocarcinoma with mixed subtypes in 11 patients, and atypical adenomatous hyperplasia (AAH) in 9 patients. None of 34 carcinoma patients had lymph node involvement. All of 17 lesions > or = 1 cm in size were malignant. GGO with solid components on high-resolution CT were highly associated with adenocarcinoma (malignant rate, 93.3%).
CONCLUSIONS: Persistent focal GGO after observation for several months was a finding of early adenocarcinoma or its precursor. Especially, lesions > or = 1 cm in size or GGO with solid component were significant signs of malignancy. We concluded lung biopsy should be attempted for persistent focal GGO.

PMID 12006429
Ryu Nakajima, Tomoyuki Yokose, Ryutaro Kakinuma, Kanji Nagai, Yutaka Nishiwaki, Atsushi Ochiai
Localized pure ground-glass opacity on high-resolution CT: histologic characteristics.
J Comput Assist Tomogr. 2002 May-Jun;26(3):323-9. doi: 10.1097/00004728-200205000-00001.
Abstract/Text PURPOSE: The aim of this study is to assess the histologic characteristics in cases of localized pure ground-glass opacity (LPGGO) that do not exhibit consolidation on high-resolution CT (HRCT) images.
METHOD: Twenty surgically resected lesions from 20 consecutive cases were retrospectively investigated. Each of the 20 lesions had exhibited LPGGO on HRCT images. The HRCT images and histopathologic findings were examined for correlations.
RESULTS: The areas of LPGGO had a maximum diameter of 2.0-24 mm on the HRCT images. Histopathology of the LPGGO lesions resulted in diagnosis of fibrosis (n = 3; 15%), atypical adenomatous hyperplasia (n = 5; 25%), bronchioloalveolar carcinoma (n = 10; 50%), and adenocarcinoma with stromal invasion (n = 2; 10%). Nonaerogenous components corresponding to solid components without normal alveolar septal destruction were pathologically observed in 15 of the 20 lesions. The diameter of the nonaerogenous components varied between 0.2 and 2.0 mm.
CONCLUSION: Because 10% of LPGGO lesions include invasive disease, patients with LPGGO should undergo pathologic examination for confirmation.

PMID 12016356
William D Travis, Elisabeth Brambilla, Andrew G Nicholson, Yasushi Yatabe, John H M Austin, Mary Beth Beasley, Lucian R Chirieac, Sanja Dacic, Edwina Duhig, Douglas B Flieder, Kim Geisinger, Fred R Hirsch, Yuichi Ishikawa, Keith M Kerr, Masayuki Noguchi, Giuseppe Pelosi, Charles A Powell, Ming Sound Tsao, Ignacio Wistuba, WHO Panel
The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification.
J Thorac Oncol. 2015 Sep;10(9):1243-1260. doi: 10.1097/JTO.0000000000000630.
Abstract/Text The 2015 World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification. The most significant changes in this edition involve (1) use of immunohistochemistry throughout the classification, (2) a new emphasis on genetic studies, in particular, integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients, (3) a new classification for small biopsies and cytology similar to that proposed in the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (4) a completely different approach to lung adenocarcinoma as proposed by the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (5) restricting the diagnosis of large cell carcinoma only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories, (6) reclassifying squamous cell carcinomas into keratinizing, nonkeratinizing, and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemistry proof of squamous differentiation, (7) grouping of neuroendocrine tumors together in one category, (8) adding NUT carcinoma, (9) changing the term sclerosing hemangioma to sclerosing pneumocytoma, (10) changing the name hamartoma to "pulmonary hamartoma," (11) creating a group of PEComatous tumors that include (a) lymphangioleiomyomatosis, (b) PEComa, benign (with clear cell tumor as a variant) and

(c) PEComa, malignant, (12) introducing the entity pulmonary myxoid sarcoma with an EWSR1-CREB1 translocation, (13) adding the entities myoepithelioma and myoepithelial carcinomas, which can show EWSR1 gene rearrangements, (14) recognition of usefulness of WWTR1-CAMTA1 fusions in diagnosis of epithelioid hemangioendotheliomas, (15) adding Erdheim-Chester disease to the lymphoproliferative tumor, and (16) a group of tumors of ectopic origin to include germ cell tumors, intrapulmonary thymoma, melanoma and meningioma.
PMID 26291008
S Kawakami, S Sone, S Takashima, F Li, Z G Yang, Y Maruyama, T Honda, M Hasegawa, J C Wang
Atypical adenomatous hyperplasia of the lung: correlation between high-resolution CT findings and histopathologic features.
Eur Radiol. 2001;11(5):811-4. doi: 10.1007/s003300000790.
Abstract/Text We describe herein the CT features of atypical adenomatous hyperplasia (AAH) of the lung and its histopathological characteristics. Among 17,919 individuals screened for lung cancer by CT scanning, ten AAH nodules were detected in nine asymptomatic subjects. On high-resolution CT, the lesions measured from 6 x 6 mm to 15 x 17 mm and their CT number ranged from -500 to -760 HU. The AAHs appeared as round nodules with smooth and distinct borders and showed a ground-glass opacity. Plain chest radiographs failed to identify all lesions. Histopathologically, AAH lesions showed atypical epithelial cell proliferation along slightly thickened alveolar septa. Whereas it is often easy to differentiate these nodules from inflammatory and benign lung lesions, histopathological examination remains at present the only method to differentiate AAH from lung cancers.

PMID 11372613
M Noguchi, A Morikawa, M Kawasaki, Y Matsuno, T Yamada, S Hirohashi, H Kondo, Y Shimosato
Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
Cancer. 1995 Jun 15;75(12):2844-52. doi: 10.1002/1097-0142(19950615)75:12<2844::aid-cncr2820751209>3.0.co;2-#.
Abstract/Text BACKGROUND: Although there are many reported prognostic indicators for pulmonary adenocarcinoma, the clinicopathologic characteristics and prognostic factors of early stage adenocarcinoma have not been evaluated fully, except for several studies of nonmucinous and sclerosing bronchioloalveolar carcinoma.
METHOD: Two hundred thirty-six surgically resected small peripheral adenocarcinomas measuring 2 cm or less in greatest dimension were reviewed using a simple histologic classification of six types based on tumor growth patterns.
RESULTS: Type A (localized bronchioloalveolar carcinoma [LBAC]) (n = 14) revealed replacement growth of alveolar-lining epithelial cells with a relatively thin stroma. In type B (LBAC with foci of structural collapse of alveoli) (n = 14), fibrotic foci due to alveolar collapse were observed in tumors of LBAC. Type C (LBAC with foci of active fibroblastic proliferation) (n = 141) was the largest group in this study, and foci of active fibroblastic proliferation were evident. Type D (poorly differentiated adenocarcinoma), type E (tubular adenocarcinoma) and type F (papillary adenocarcinoma with a compressive growth pattern) (n = 61) showed compressive and expanding growth. Types A and B showed no lymph node metastasis and the most favorable prognosis (100% 5-year survival) of the six types.
CONCLUSION: Histologic types A and B are thought to be in situ peripheral adenocarcinoma, whereas type C appears to be an advanced stage of types A and B. Conversely, types D, E, and F are small advanced adenocarcinomas with a less favorable prognosis.

PMID 7773933
William D Travis, Elisabeth Brambilla, Masayuki Noguchi, Andrew G Nicholson, Kim R Geisinger, Yasushi Yatabe, David G Beer, Charles A Powell, Gregory J Riely, Paul E Van Schil, Kavita Garg, John H M Austin, Hisao Asamura, Valerie W Rusch, Fred R Hirsch, Giorgio Scagliotti, Tetsuya Mitsudomi, Rudolf M Huber, Yuichi Ishikawa, James Jett, Montserrat Sanchez-Cespedes, Jean-Paul Sculier, Takashi Takahashi, Masahiro Tsuboi, Johan Vansteenkiste, Ignacio Wistuba, Pan-Chyr Yang, Denise Aberle, Christian Brambilla, Douglas Flieder, Wilbur Franklin, Adi Gazdar, Michael Gould, Philip Hasleton, Douglas Henderson, Bruce Johnson, David Johnson, Keith Kerr, Keiko Kuriyama, Jin Soo Lee, Vincent A Miller, Iver Petersen, Victor Roggli, Rafael Rosell, Nagahiro Saijo, Erik Thunnissen, Ming Tsao, David Yankelewitz
International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.
J Thorac Oncol. 2011 Feb;6(2):244-85. doi: 10.1097/JTO.0b013e318206a221.
Abstract/Text INTRODUCTION: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies.
METHODS: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach.
RESULTS: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤ 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized.
CONCLUSIONS: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

PMID 21252716
Myrna C B Godoy, Bradley Sabloff, David P Naidich
Subsolid pulmonary nodules: imaging evaluation and strategic management.
Curr Opin Pulm Med. 2012 Jul;18(4):304-12. doi: 10.1097/MCP.0b013e328354a5f2.
Abstract/Text PURPOSE OF REVIEW: Given the higher rate of malignancy of subsolid pulmonary nodules and the considerably lower growth rate of ground-glass nodules (GGNs), dedicated standardized guidelines for management of these nodules have been proposed, including long-term low-dose computed tomography (CT) follow-up (≥3 years). Physicians must be familiar with the strategic management of subsolid pulmonary nodules, and should be able to identify imaging features that suggest invasive adenocarcinoma requiring a more aggressive management.
RECENT FINDINGS: Low-dose CT screening studies for early detection of lung cancer have increased our knowledge of pulmonary nodules, and in particular our understanding of the strong although imperfect correlation of the subsolid pulmonary nodules, including pure GGNs and part-solid nodules, with the spectrum of preinvasive to invasive lung adenocarcinoma. Serial CT imaging has shown stepwise progression in a subset of these nodules, characterized by increase in size and density of pure GGNs and development of a solid component, the latter usually indicating invasive adenocarcinoma.
SUMMARY: There is close correlation between the CT features of subsolid nodules (SSNs) and the spectrum of lung adenocarcinoma. Standardized guidelines are suggested for management of SSNs.

PMID 22575798
Hisao Asamura, Tomoyuki Hishida, Kenji Suzuki, Teruaki Koike, Kenichi Nakamura, Masahiko Kusumoto, Kanji Nagai, Hirohito Tada, Tetsuya Mitsudomi, Masahiro Tsuboi, Taro Shibata, Haruhiko Fukuda, Japan Clinical Oncology Group Lung Cancer Surgical Study Group
Radiographically determined noninvasive adenocarcinoma of the lung: survival outcomes of Japan Clinical Oncology Group 0201.
J Thorac Cardiovasc Surg. 2013 Jul;146(1):24-30. doi: 10.1016/j.jtcvs.2012.12.047. Epub 2013 Feb 8.
Abstract/Text OBJECTIVE: The study objective was to evaluate the long-term survival of patients with radiographically determined noninvasive lung adenocarcinomas.
METHODS: A prospective, multi-institutional study on image diagnosis to define early (noninvasive) adenocarcinomas of the lung (Japan Clinical Oncology Group 0201) has shown that a consolidation/tumor ratio on thin-section computed tomography 0.25 or less in cT1a (≤2.0 cm) could be used as a better radiologic criterion for a noninvasive pathology than a consolidation/tumor ratio 0.50 or less in cT1a-b (≤3.0 cm). From the prognostic viewpoints, these criteria were evaluated for 545 patients with adenocarcinoma who underwent lobectomy and lymph node dissection.
RESULTS: The subjects consisted of 233 men and 312 women with a median age of 62 years. The median follow-up period among overall patients was 7.1 years (range, 0-8.5 years). The overall and relapse-free 5-year survivals of the overall patients were 90.6% and 84.7%, respectively. When a consolidation/tumor ratio 0.5 or less in cT1a-b was used as a cutoff, the 5-year overall survivals of radiologic noninvasive (121 patients, 22.2%) and invasive (424 patients, 77.8%) adenocarcinomas were 96.7% and 88.9%, respectively, and the difference was statistically significant (P < .001, log-rank test). With the use of a consolidation/tumor ratio 0.25 or less in cT1a, the 5-year overall survivals of radiologic noninvasive (35 patients, 12.1%) and invasive (254 patients, 87.9%) adenocarcinomas were 97.1% and 92.4%, respectively, and the difference was not statistically significant (P = .259).
CONCLUSIONS: The radiologic criteria of a consolidation/tumor ratio 0.25 or less in cT1a (≤2.0 cm) and 0.50 in cT1a-b (≤3.0 cm) were both able to define a homogeneous group of patients with an excellent prognosis before surgery.

Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
PMID 23398645
Kenichi Nakamura, Hisashi Saji, Ryu Nakajima, Morihito Okada, Hisao Asamura, Taro Shibata, Shinichiro Nakamura, Hirohito Tada, Masahiro Tsuboi
A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L).
Jpn J Clin Oncol. 2010 Mar;40(3):271-4. doi: 10.1093/jjco/hyp156. Epub 2009 Nov 22.
Abstract/Text A Phase III study was started in Japan to evaluate the non-inferiority in overall survival of segmentectomy compared with lobectomy in patients with small-sized (diameter
PMID 19933688
Yoshihisa Kobayashi, Chiara Ambrogio, Tetsuya Mitsudomi
Ground-glass nodules of the lung in never-smokers and smokers: clinical and genetic insights.
Transl Lung Cancer Res. 2018 Aug;7(4):487-497. doi: 10.21037/tlcr.2018.07.04.
Abstract/Text Pulmonary ground-glass nodules (GGNs) are hazy radiological findings on computed tomography (CT). GGNs are detected more often in never-smokers. Retrospective and prospective studies have revealed that approximately 20% of pure GGNs and 40% of part-solid GGNs gradually grow or increase their solid components, whereas others remain stable for years. Most persistent or growing GGNs are lung adenocarcinomas or their preinvasive lesions. To distinguish GGNs with growth from those without growth, GGNs should be followed for at least 5 years. Lesion size and smoking history are predictors of GGN growth. Genetic analyses of resected GGNs have suggested that EGFR mutations are also predictors for growth but a subset of KRAS- or BRAF-mutated GGNs may undergo spontaneous regression because the frequencies of KRAS or BRAF mutations decrease with the advance of pathological invasiveness. Although lobectomy is the standard surgical procedure for lung cancer, limited surgery such as wedge resection or segmentectomy for lung cancers ≤2 cm with consolidation/tumor ratio ≤0.25 can be a viable alternative based on the recent clinical trial. Further genetic analyses and clinical trials can contribute to elucidation of the biological aspects of preinvasive adenocarcinoma and the development of less invasive management strategies for patients with GGNs.

PMID 30225212
Annette McWilliams, Martin C Tammemagi, John R Mayo, Heidi Roberts, Geoffrey Liu, Kam Soghrati, Kazuhiro Yasufuku, Simon Martel, Francis Laberge, Michel Gingras, Sukhinder Atkar-Khattra, Christine D Berg, Ken Evans, Richard Finley, John Yee, John English, Paola Nasute, John Goffin, Serge Puksa, Lori Stewart, Scott Tsai, Michael R Johnston, Daria Manos, Garth Nicholas, Glenwood D Goss, Jean M Seely, Kayvan Amjadi, Alain Tremblay, Paul Burrowes, Paul MacEachern, Rick Bhatia, Ming-Sound Tsao, Stephen Lam
Probability of cancer in pulmonary nodules detected on first screening CT.
N Engl J Med. 2013 Sep 5;369(10):910-9. doi: 10.1056/NEJMoa1214726.
Abstract/Text BACKGROUND: Major issues in the implementation of screening for lung cancer by means of low-dose computed tomography (CT) are the definition of a positive result and the management of lung nodules detected on the scans. We conducted a population-based prospective study to determine factors predicting the probability that lung nodules detected on the first screening low-dose CT scans are malignant or will be found to be malignant on follow-up.
METHODS: We analyzed data from two cohorts of participants undergoing low-dose CT screening. The development data set included participants in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). The validation data set included participants involved in chemoprevention trials at the British Columbia Cancer Agency (BCCA), sponsored by the U.S. National Cancer Institute. The final outcomes of all nodules of any size that were detected on baseline low-dose CT scans were tracked. Parsimonious and fuller multivariable logistic-regression models were prepared to estimate the probability of lung cancer.
RESULTS: In the PanCan data set, 1871 persons had 7008 nodules, of which 102 were malignant, and in the BCCA data set, 1090 persons had 5021 nodules, of which 42 were malignant. Among persons with nodules, the rates of cancer in the two data sets were 5.5% and 3.7%, respectively. Predictors of cancer in the model included older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Our final parsimonious and full models showed excellent discrimination and calibration, with areas under the receiver-operating-characteristic curve of more than 0.90, even for nodules that were 10 mm or smaller in the validation set.
CONCLUSIONS: Predictive tools based on patient and nodule characteristics can be used to accurately estimate the probability that lung nodules detected on baseline screening low-dose CT scans are malignant. (Funded by the Terry Fox Research Institute and others; ClinicalTrials.gov number, NCT00751660.).

PMID 24004118
Kiyomi Furuya, Kotaro Yasumori, Sadanori Takeo, Ikuo Sakino, Noriko Uesugi, Seiya Momosaki, Toru Muranaka
Lung CT: Part 1, Mimickers of lung cancer--spectrum of CT findings with pathologic correlation.
AJR Am J Roentgenol. 2012 Oct;199(4):W454-63. doi: 10.2214/AJR.10.7262.
Abstract/Text OBJECTIVE: The purpose of this article is to describe CT findings of miscellaneous pulmonary conditions that mimic lung cancers, especially primary cancers, to improve diagnosis of pulmonary lesions. Brief descriptions of patient clinical information and pathologic findings will be included and correlated with imaging findings in actual cases.
CONCLUSION: A wide variety of pulmonary conditions present imaging features that mimic those of primary lung cancers and are difficult to differentiate from cancer. Awareness of these conditions with an understanding of their pathologic background and careful attention to the clinical information will help achieve correct diagnoses.

PMID 22997395
Tanmay S Panchabhai, Carol Farver, Kristin B Highland
Lymphocytic Interstitial Pneumonia.
Clin Chest Med. 2016 Sep;37(3):463-74. doi: 10.1016/j.ccm.2016.04.009. Epub 2016 Jun 25.
Abstract/Text Lymphocytic interstitial pneumonia (LIP) is a rare lung disease on the spectrum of benign pulmonary lymphoproliferative disorders. LIP is frequently associated with connective tissue diseases or infections. Idiopathic LIP is rare; every attempt must be made to diagnose underlying conditions when LIP is diagnosed. Computed tomography of the chest in patients with LIP may reveal ground-glass opacities, centrilobular and subpleural nodules, and randomly distributed thin-walled cysts. Demonstrating polyclonality with immunohistochemistry is the key to differentiating LIP from lymphoma. The 5-year mortality remains between 33% and 50% and is likely to vary based on the underlying disease process.

Copyright © 2016 Elsevier Inc. All rights reserved.
PMID 27514593
R L Kradin, P W Spirn, E J Mark
Intrapulmonary lymph nodes. Clinical, radiologic, and pathologic features.
Chest. 1985 May;87(5):662-7. doi: 10.1378/chest.87.5.662.
Abstract/Text The clinical, radiographic, and pathologic material from ten patients with intrapulmonary lymph nodes was analyzed, along with information from all previously reported cases. In our series the median age was 56 years, and 80 percent (eight) of the patients were men. All patients are or were cigarette smokers. Sixty percent (six) had a history of exposure to either asbestos, nonfibrous silicates, or both. There were no characteristic symptoms attributable to the intrapulmonary lymph nodes. Forty percent (four) had an unexplained pulmonary nodule or nodules on the chest roentgenogram, which prompted further diagnostic studies, including thoracotomy, to rule out a malignant neoplasm. Radiographically, in our cases and in the literature, almost all cases of intrapulmonary lymph nodes are subpleural, inferior to the level of the carina, and less than 2.0 cm in diameter. Thirty-five percent are multiple. Pathologically, in our cases, all intrapulmonary lymph nodes were markedly anthracotic, and 60 percent were additionally silicotic. Although their histogenesis is uncertain, intrapulmonary lymph nodes are probably hyperplastic lymphoid nodules related to inhalation of irritant dusts and attendant distortion of local lymphatic vessels. Precise clinical and radiographic analysis correlated carefully with cytologic and histologic material obtained by percutaneous needle biopsy should obviate exploratory thoracotomy in most instances.

PMID 3987379
Chang Min Park, Jin Mo Goo, Hyun Ju Lee, Chang Hyun Lee, Doo Hyun Chung, Eun Ju Chun, Jung-Gi Im
Focal interstitial fibrosis manifesting as nodular ground-glass opacity: thin-section CT findings.
Eur Radiol. 2007 Sep;17(9):2325-31. doi: 10.1007/s00330-007-0596-z. Epub 2007 Feb 14.
Abstract/Text The purpose of this study was to describe the thin-section computed tomographic (CT) features of focal interstitial fibrosis manifesting as nodular ground-glass opacity (GGO) and its changes during follow-up. The thin-section CT findings of pathologically proven focal interstitial fibrosis manifesting as nodular GGO were retrospectively evaluated in nine patients (five women and four men; mean age, 59.3 years; age range, 34-81 years). The thin-section CT findings of each lesion were analyzed for multiplicity, location, shape, margin characteristics, pleural retraction or vascular convergence, size and internal attenuation, lesion internal features and lesion changes on follow-up CT scans (mean 90 days, range 5 to 215 days). All lesions manifested as a solitary nodular GGO (100%), and seven of the nine lesions (77.8%) were located in the upper lobe. Focal interstitial fibrosis was round or oval in shape in five cases (55.6%), complex in shape in three cases (33.3%) and polygonal in one case (11.1%). Lesion margins were smooth in five patients (55.6%), irregular in three (33.3%) and spiculated in one (11.1%). Pleural retraction or vascular convergence was present in two patients (22.2%). Lesions measured 4.8 mm to 25.5 mm (mean, 11.5 mm) and had attenuations ranging from -151 to -699 HU (mean, -514.7 HU). Eight (88.9%) manifested as pure nodular GGOs and one as mixed GGO with a spiculated margin. In all patients, no lesion changes were observed in follow-up CT scans. Focal interstitial fibrosis manifesting as nodular GGO usually presents as a solitary nodule with pure GGO on thin-section CT, which does not change significantly during follow-up.

PMID 17429642
S Novello, F Barlesi, R Califano, T Cufer, S Ekman, M Giaj Levra, K Kerr, S Popat, M Reck, S Senan, G V Simo, J Vansteenkiste, S Peters, ESMO Guidelines Committee
Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
Ann Oncol. 2016 Sep;27(suppl 5):v1-v27. doi: 10.1093/annonc/mdw326.
Abstract/Text
PMID 27664245
Chia-I Shen, Hsu-Ching Huang, Chi-Lu Chiang, Yung-Hung Luo, Tsu-Hui Shiao, Chao-Hua Chiu
Effects of different brain surveillance strategies on outcomes for patients with EGFR-mutant metastatic lung adenocarcinoma under targeted therapy.
Lung Cancer. 2019 Dec;138:52-57. doi: 10.1016/j.lungcan.2019.10.001. Epub 2019 Oct 11.
Abstract/Text OBJECTIVES: Brain metastasis (BM) is common in patients with epidermal growth factor receptor (EGFR)-mutant lung cancer. However, the brain surveillance strategy during treatment in advanced lung cancer patients varies, and the impact on clinical outcome is unclear. Here we aimed to evaluate the effect of different brain surveillance strategies on the clinical characteristics and treatment outcome in patients with EGFR-mutant lung adenocarcinoma treated with first-line EGFR tyrosine kinase inhibitors (EGFR-TKIs).
MATERIALS AND METHODS: This is a retrospective observational study conducted in a medical center in an area with high prevalence of EGFR mutation. Patients with initially diagnosed stage IV EGFR-mutant lung adenocarcinoma were included. Patients undergoing regular brain magnetic resonance imaging (MRI) every 3-6 months were categorized in the regular follow-up (RFU) group, and the rest were categorized in the liberal follow-up (LFU) group. Clinical outcomes were collected and analyzed.
RESULTS: A total of 310 patients were included, and 43.5% initially had brain metastases. Patients in the LFU group were significantly older than those in the RFU group (median age: 67 vs 62, p < 0.001). The overall survival and time-to-treatment failure of patients with initial EGFR-TKIs treatment showed no statistical difference between the two groups. However, the intracranial progression free survival was significantly shorter in the RFU group than in the LFU group (p = 0.009). The risk of mortality was similar in the LFU and RFU groups. There was no difference in the intracranial progression patterns and cause of death between the two groups.
CONCLUSIONS: For EGFR-mutant lung adenocarcinoma patients who used EGFR-TKIs as the frontline therapy, regular or liberal brain MRI follow-up showed no significant impact on the outcome, irrespective of initial brain metastasis.

Copyright © 2019 Elsevier B.V. All rights reserved.
PMID 31634655
B J Hudson, M B Crawford, J J Curtin
Brain imaging in lung cancer patients without symptoms of brain metastases: a national survey of current practice in England.
Clin Radiol. 2015 Jun;70(6):610-3. doi: 10.1016/j.crad.2015.02.007. Epub 2015 Mar 10.
Abstract/Text AIM: To determine current practice regarding brain imaging for newly diagnosed lung cancer patients without symptoms of brain metastases.
MATERIALS AND METHODS: A survey questionnaire was sent by e-mail to all the lung cancer lead clinicians in England currently on the National Cancer Intelligence Network database. The survey asked whether brain imaging was used in new lung cancer patients without symptoms or signs to suggest brain metastases; and if so, which patient subgroups were imaged according to cell type, stage of disease, and intention to treat, and which techniques were used to image these patients. Responses were received between February and May 2014.
RESULTS: Fifty-nine of 154 centres replied to the survey (38%). Thirty of the 59 centres (51%) did not image the brain in these patients. Twenty-nine of the 59 (49%) centres imaged the brain in at least certain subgroups. Of those centres that did image the brain 21 (72%) used CT as the first-line imaging technique and six (20%) used MRI. Twenty-five of 59 (42%) centres stated that the 2011 NICE guidelines had led to a change in their practice.
CONCLUSION: There is wide variation in practice regarding brain imaging in this patient group in England, with no brain imaging at all in approximately half of centres and a spectrum of imaging in the other half. When the brain is imaged, CT is the technique most commonly used. The 2011 NICE guidelines have led to some change in practice but not to national uniformity.

Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
PMID 25766968
Antonin Levy, Corinne Faivre-Finn, Baktiar Hasan, Eleonora De Maio, Anna S Berghoff, Nicolas Girard, Laurent Greillier, Sylvie Lantuéjoul, Mary O'Brien, Martin Reck, Anne-Marie C Dingemans, Silvia Novello, Thierry Berghmans, Benjamin Besse, Lizza Hendriks, Young Investigators EORTC Lung Cancer Group (YI EORTC LCG)
Diversity of brain metastases screening and management in non-small cell lung cancer in Europe: Results of the European Organisation for Research and Treatment of Cancer Lung Cancer Group survey.
Eur J Cancer. 2018 Apr;93:37-46. doi: 10.1016/j.ejca.2018.01.067. Epub 2018 Feb 21.
Abstract/Text BACKGROUND: Brain metastases (BM) are frequent in non-small cell lung cancer (NSCLC) patients, but there is a lack of evidence-based management of this patient group. We aimed to capture a snapshot of routine BM management in Europe to identify relevant research questions for future clinical trials.
METHODS: An EORTC Lung Cancer Group (LCG) online survey containing questions on NSCLC BM screening and treatment was distributed between 16/02/17 and 15/06/17 to worldwide EORTC LCG members, and through several European scientific societies in the thoracic oncology field.
RESULTS: A total of 462 European physician responses (394 institutions) were analysed (radiation oncologist: 53% [n = 247], pulmonologist: 26% [n = 119], medical oncologist: 18% [n = 84]; 84% with >5 years' experience in NSCLC). Italy (18%, n = 85), Netherlands (15%, n = 68), UK (14%, n = 66), and France (12%, n = 55) contributed most. 393 physicians (85%) screened neurologically asymptomatic patients for BM at diagnosis (52% using magnetic resonance imaging). Most often screened patients were those with a driver mutation (MUT+; 51%, n = 234), stage III (63%, n = 289), and IV (43%, n = 199). 158 physicians (34%) used a prognostic classification to guide initial treatment decisions, and in 50%, lowest prognostic-score threshold to receive treatment differed between MUT+ and non-driver mutation (MUT-) patients. MUT+ patients with >4 BM were more likely to receive stereotactic radiosurgery (SRS) compared with MUT- (27% versus. 21%; p < 0.01). Most physicians (90%) had access to SRS. After single BM surgery, 50% systematically prescribed SRS or WBRT, and 45% only in case of incomplete resection. The preferred treatment in neurologically asymptomatic treatment-naive patients diagnosed with >5 BM was systemic treatment (79%). Of all, 45%/49% physicians stated that all tyrosine kinase inhibitors and immune checkpoint blockers were discontinued (timing varied) during SRS/WBRT, respectively. Drugs most often continued during SRS/WBRT were erlotinib (44%/40%), gefitinib (39%/34%), afatinib (29%/25%), crizotinib (33%/26%) and anti-PD-(L)-1 (28%/22%).
CONCLUSION: BM management is highly variable in Europe: screening is not uniform, prognostic classifications are not often used and MUT+ NSCLC patients generally receive more intensive local treatment. Prospective assessment of BM management in MUT+ NSCLC patients is required.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29477100
Ramón Rami-Porta
Future Perspectives on the TNM Staging for Lung Cancer.
Cancers (Basel). 2021 Apr 17;13(8). doi: 10.3390/cancers13081940. Epub 2021 Apr 17.
Abstract/Text Since its conception by Pierre Denoix in the mid-20th century, the tumor, node, and metastasis (TNM) classification has undergone seven revisions. The North American database managed by Clifton Mountain was used to inform the 2nd to the 6th editions, and an international database collected by the International Association for the Study of Lung Cancer, promoted by Peter Goldstraw, was used to inform the 7th and the 8th editions. In these two latest editions, it was evident that the impact of tumor size was much greater than it was suggested in previous editions; that the amount of nodal disease had prognostic relevance; and that the number and location of the distant metastases had prognostic implications. However, the TNM classification is not the only prognostic factor. Data are being collected now to inform the 9th edition of the TNM classification, scheduled for publication in 2024. Patient-, environment-, and tumor-related factors, including biomarkers (genetic biomarkers, copy number alterations, and protein alterations) are being collected to combine them in prognostic groups to enhance the prognosis provided by the mere anatomic extent of the tumor, and to offer a more personalized prognosis to an individual patient. International collaboration is essential to build a large and detailed database to achieve these objectives.

PMID 33920510
Seung Hyeun Lee
Chemotherapy for Lung Cancer in the Era of Personalized Medicine.
Tuberc Respir Dis (Seoul). 2019 Jul;82(3):179-189. doi: 10.4046/trd.2018.0068. Epub 2018 Dec 20.
Abstract/Text Although recent advances in molecular targeted therapy and immuno-oncology have revolutionized the landscape of lung cancer therapeutics, cytotoxic chemotherapy remains an essential component of lung cancer treatment. Extensive evidence has demonstrated the clinical benefit of chemotherapy, either alone or in combination with other treatment modalities, on survival and quality of life of patients with early and advanced lung cancer. Combinational approaches with other classes of anti-neoplastic agents and new drug-delivery systems have revealed promising data and are areas of active investigation. Chemotherapy is recommended as a standard of care in patients that have progressed after tyrosine kinase inhibitors or immune checkpoint inhibitors. Chemotherapy remains the fundamental means of lung cancer management and keeps expanding its clinical implication. This review will discuss the current position and future role of chemotherapy, and specific consideration for its clinical application in the era of precision medicine.

Copyright©2019. The Korean Academy of Tuberculosis and Respiratory Diseases.
PMID 30841023
Venus Sosa Iglesias, Lorena Giuranno, Ludwig J Dubois, Jan Theys, Marc Vooijs
Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting?
Front Oncol. 2018;8:267. doi: 10.3389/fonc.2018.00267. Epub 2018 Jul 24.
Abstract/Text Drug resistance is a major cause for therapeutic failure in non-small cell lung cancer (NSCLC) leading to tumor recurrence and disease progression. Cell intrinsic mechanisms of resistance include changes in the expression of drug transporters, activation of pro-survival, and anti-apoptotic pathways, as well as non-intrinsic influences of the tumor microenvironment. It has become evident that tumors are composed of a heterogeneous population of cells with different genetic, epigenetic, and phenotypic characteristics that result in diverse responses to therapy, and underlies the emergence of resistant clones. This tumor heterogeneity is driven by subpopulations of tumor cells termed cancer stem cells (CSCs) that have tumor-initiating capabilities, are highly self-renewing, and retain the ability for multi-lineage differentiation. CSCs have been identified in NSCLC and have been associated with chemo- and radiotherapy resistance. Stem cell pathways are frequently deregulated in cancer and are implicated in recurrence after treatment. Here, we focus on the NOTCH signaling pathway, which has a role in stem cell maintenance in non-squamous non-small lung cancer, and we critically assess the potential for targeting the NOTCH pathway to overcome resistance to chemotherapeutic and targeted agents using both preclinical and clinical evidence.

PMID 30087852
Roberto Ruiz-Cordero, Walter Patrick Devine
Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer.
Surg Pathol Clin. 2020 Mar;13(1):17-33. doi: 10.1016/j.path.2019.11.002.
Abstract/Text Lung cancer is the leading cause of cancer mortality. It is classified into different histologic subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma (commonly referred as non-small cell lung cancer) and small cell lung cancer. Comprehensive molecular characterization of lung cancer has expanded our understanding of the cellular origins and molecular pathways affected in each of these subtypes. Many of these genetic alterations represent potential therapeutic targets for which drugs are constantly under development. This article discusses the molecular characteristics of the main lung cancer subtypes and discusses the current guidelines and novel targeted therapies, including checkpoint immunotherapy.

Copyright © 2019 Elsevier Inc. All rights reserved.
PMID 32005431
Wendy A Cooper, David C L Lam, Sandra A O'Toole, John D Minna
Molecular biology of lung cancer.
J Thorac Dis. 2013 Oct;5 Suppl 5:S479-90. doi: 10.3978/j.issn.2072-1439.2013.08.03.
Abstract/Text Lung cancers are characterised by abundant genetic diversity with relatively few recurrent mutations occurring at high frequency. However, the genetic alterations often affect a common group of oncogenic signalling pathways. There have been vast improvements in our understanding of the molecular biology that underpins lung cancer in recent years and this has led to a revolution in the diagnosis and treatment of lung adenocarcinomas (ADC) based on the genotype of an individual's tumour. New technologies are identifying key and potentially targetable genetic aberrations not only in adenocarcinoma but also in squamous cell carcinoma (SCC) of the lung. Lung cancer mutations have been identified in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), BRAF and the parallel phosphatidylinositol 3-kinase (PI3K) pathway oncogenes and more recently in MEK and HER2 while structural rearrangements in ALK, ROS1 and possibly rearranged during transfection (RET) provide new therapeutic targets. Amplification is another mechanism of activation of oncogenes such as MET in adenocarcinoma, fibroblastgrowth factor receptor 1 (FGFR1) and discoidin domain receptor 2 (DDR2) in SCC. Intriguingly, many of these genetic alternations are associated with smoking status and with particular racial and gender differences, which may provide insight into the mechanisms of carcinogenesis and role of host factors in lung cancer development and progression. The role of tumour suppressor genes is increasingly recognised with aberrations reported in TP53, PTEN, RB1, LKB11 and p16/CDKN2A. Identification of biologically significant genetic alterations in lung cancer that lead to activation of oncogenes and inactivation of tumour suppressor genes has the potential to provide further therapeutic opportunities. It is hoped that these discoveries may make a major contribution to improving outcome for patients with this poor prognosis disease.

PMID 24163741
Roy S Herbst, Daniel Morgensztern, Chris Boshoff
The biology and management of non-small cell lung cancer.
Nature. 2018 Jan 24;553(7689):446-454. doi: 10.1038/nature25183.
Abstract/Text Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.

PMID 29364287
Pasi A Jänne, James Chih-Hsin Yang, Dong-Wan Kim, David Planchard, Yuichiro Ohe, Suresh S Ramalingam, Myung-Ju Ahn, Sang-We Kim, Wu-Chou Su, Leora Horn, Daniel Haggstrom, Enriqueta Felip, Joo-Hang Kim, Paul Frewer, Mireille Cantarini, Kathryn H Brown, Paul A Dickinson, Serban Ghiorghiu, Malcolm Ranson
AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.
N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817.
Abstract/Text BACKGROUND: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations.
METHODS: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy.
RESULTS: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients.
CONCLUSIONS: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).

PMID 25923549
Tony S Mok, Yi-Long Wu, Myung-Ju Ahn, Marina C Garassino, Hye R Kim, Suresh S Ramalingam, Frances A Shepherd, Yong He, Hiroaki Akamatsu, Willemijn S M E Theelen, Chee K Lee, Martin Sebastian, Alison Templeton, Helen Mann, Marcelo Marotti, Serban Ghiorghiu, Vassiliki A Papadimitrakopoulou, AURA3 Investigators
Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer.
N Engl J Med. 2017 Feb 16;376(7):629-640. doi: 10.1056/NEJMoa1612674. Epub 2016 Dec 6.
Abstract/Text BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown.
METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival.
RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%).
CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).

PMID 27959700
Misty Dawn Shields, Julian A Marin-Acevedo, Bruna Pellini
Immunotherapy for Advanced Non-Small Cell Lung Cancer: A Decade of Progress.
Am Soc Clin Oncol Educ Book. 2021 Mar;41:1-23. doi: 10.1200/EDBK_321483.
Abstract/Text The treatment paradigm for patients with advanced non-small cell lung cancer has substantially changed with the discovery of immunotherapy. The incorporation of immunotherapy into treatment algorithms has resulted in better outcomes for patients, with fewer side effects compared with classic chemotherapeutic agents. Multiple treatment options are now available for patients with advanced non-small cell lung cancer, ranging from single-agent immunotherapy to quadruple therapy, which involves dual immune checkpoint inhibitor plus chemotherapy or immune checkpoint inhibitor plus chemotherapy plus anti-vascular endothelial growth factor drugs. This article will review landmark studies that have led to U.S. Food and Drug Administration approval of immunotherapy agents alone or in combination with chemotherapy or other immunotherapy drugs to treat advanced non-small cell lung cancer.

PMID 33979196
Thomas J Lynch, Daphne W Bell, Raffaella Sordella, Sarada Gurubhagavatula, Ross A Okimoto, Brian W Brannigan, Patricia L Harris, Sara M Haserlat, Jeffrey G Supko, Frank G Haluska, David N Louis, David C Christiani, Jeff Settleman, Daniel A Haber
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.
Abstract/Text BACKGROUND: Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown.
METHODS: We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells.
RESULTS: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib.
CONCLUSIONS: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

Copyright 2004 Massachusetts Medical Society
PMID 15118073
J Guillermo Paez, Pasi A Jänne, Jeffrey C Lee, Sean Tracy, Heidi Greulich, Stacey Gabriel, Paula Herman, Frederic J Kaye, Neal Lindeman, Titus J Boggon, Katsuhiko Naoki, Hidefumi Sasaki, Yoshitaka Fujii, Michael J Eck, William R Sellers, Bruce E Johnson, Matthew Meyerson
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
Science. 2004 Jun 4;304(5676):1497-500. doi: 10.1126/science.1099314. Epub 2004 Apr 29.
Abstract/Text Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.

PMID 15118125
William Pao, Vincent Miller, Maureen Zakowski, Jennifer Doherty, Katerina Politi, Inderpal Sarkaria, Bhuvanesh Singh, Robert Heelan, Valerie Rusch, Lucinda Fulton, Elaine Mardis, Doris Kupfer, Richard Wilson, Mark Kris, Harold Varmus
EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. doi: 10.1073/pnas.0405220101. Epub 2004 Aug 25.
Abstract/Text Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

PMID 15329413
J C Ruckdeschel, D M Finkelstein, D S Ettinger, R H Creech, B A Mason, R A Joss, S Vogl
A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer.
J Clin Oncol. 1986 Jan;4(1):14-22. doi: 10.1200/JCO.1986.4.1.14.
Abstract/Text Between October 1981 and June 1983, the Eastern Cooperative Oncology Group (ECOG) conducted a prospectively randomized trial (EST 1581) of the four most active chemotherapy regimens for metastatic non-small-cell lung cancer (NSCLC). Four hundred eighty-six good performance status patients (PS 0 or 1; 81%) were randomized to receive cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); mitomycin, vinblastine, and cisplatin (MVP); etoposide and cisplatin (VP-P); or vindesine and cisplatin (VDA-P). All regimens were administered in the doses and schedules originally reported. Complete response (CR) plus partial response (PR) rates for the four regimens were CAMP, 17%; MVP, 31%; VP-P, 20%; and VDA-P, 25%. The response rate for MVP was significantly higher in patients with squamous and adenocarcinoma histologies, but there was no impact on median survival (overall, 24.5 weeks). The duration of response did not differ by treatment as previously suggested for VDA-P. There were 15 CRs (CAMP, one; MVP, six; VP-P, two; VDA-P, six), and 12 patients have survived more than 2 years. Toxicity was significant with 20 treatment-related deaths. CAMP was significantly less toxic than the other regimens (P less than .001). VDA-P demonstrated significantly more life-threatening (seven) and lethal (three) episodes of nephrotoxicity (P less than .001) despite an aggressive hydration program that in itself caused significant morbidity. Analysis of the toxicity data showed, however, that most of the severe toxicity occurred in the 19% of patients who were initially PS 2, suggesting that they are not appropriate candidates for trials of new agents or combinations. None of these regimens can be recommended as a standard therapy for metastatic NSCLC.

PMID 3510278
P Marino, A Preatoni, A Cantoni, G Buccheri
Single-agent chemotherapy versus combination chemotherapy in advanced non-small cell lung cancer: a quality and meta-analysis study.
Lung Cancer. 1995 Aug;13(1):1-12. doi: 10.1016/0169-5002(95)00477-i.
Abstract/Text STUDY OBJECTIVE: To estimate the quality of the studies and to compare single-agent with combination chemotherapy in advanced non-small cell lung cancer.
DESIGN: Identification of published randomized trials and extraction of essential results directly from the published reports.
MEASUREMENTS AND RESULTS: Survival probability at 1 year, as estimated from the published survival curves, has been considered as the end-point of interest. Quality scoring of the studies has also been performed. Arithmetical calculation, concerning the estimation of quantities necessary for the meta-analysis of the literature, has been addressed. The estimated pooled Odds Ratio of death was 0.8, with 95% confidence interval of 0.6-1.0, thus favoring combination chemotherapy.
CONCLUSIONS: The results of our meta-analysis favor combination chemotherapy. They must, however, be considered in the light of their clinical relevance and of the balance between quality of life, toxicity and costs of chemotherapy.

PMID 8528635
J K Weick, J Crowley, R B Natale, B L Hom, S Rivkin, C A Coltman, S A Taylor, R B Livingston
A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study.
J Clin Oncol. 1991 Jul;9(7):1157-62. doi: 10.1200/JCO.1991.9.7.1157.
Abstract/Text Six hundred eighty assessable patients with measureable stage III M1, non-small-cell lung cancer (NSCLC) were randomized to one of five treatment arms including cisplatin, etoposide (VP-16) +/- methylglyoxal bisguanylhydrazone (MGBG; PVp, PVpM); cisplatin, vinblastine (PVe); or PVe alternating with vinblastine, mitomycin (PVeMi); or fluorouracil, vincristine, mitomycin/cyclophosphamide, doxorubicin, cisplatin (FOMi/CAP). The overall response rate was 20% with 3% complete responses and 17% partial remissions. The duration of these responses was not statistically different by treatment regimen and varied from 2.7 months to 5.0 months. The overall median survival for all patients was 5.3 months and is not different by treatment. Toxicity was greater in PVpM. The similarity of results for response, duration of response, and survival does not establish the superiority of any of these platinum-based regimens for standard clinical usage.

PMID 1646292
R J Gralla, E Cvitkovic, R B Golbey
cis-Dichlorodiammineplatinum(II) in non-small cell carcinoma of the lung.
Cancer Treat Rep. 1979 Sep-Oct;63(9-10):1585-8.
Abstract/Text The role of cis-dichlorodiammineplatinum(II) (cis-platinum) as a single agent in non-small cell lung cancer has not been clearly defined, and extensive phase II studies have not been conducted. However, objective responses were noted in several early clinical trials. A review of these reports, including combinations with conventional agents, shows 15 partial responses among 100 patients. Results are presented on a new protocol using high-dose cis-platinum with mannitol-induced diuresis combined with cyclophosphamide and Adriamycin. An overall partial response rate of 28% was observed, including a 38% response rate in good performance status patients, with a median survival of 16 months in responding patients. Data from recent combination protocols do not define the activity of cis-platinum as a single agent, but suggest that it may be useful in non-small cell carcinoma of the lung.

PMID 498158
Nasser Hanna, Frances A Shepherd, Frank V Fossella, Jose R Pereira, Filippo De Marinis, Joachim von Pawel, Ulrich Gatzemeier, Thomas Chang Yao Tsao, Miklos Pless, Thomas Muller, Hong-Liang Lim, Christopher Desch, Klara Szondy, Radj Gervais, Shaharyar, Christian Manegold, Sofia Paul, Paolo Paoletti, Lawrence Einhorn, Paul A Bunn
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy.
J Clin Oncol. 2004 May 1;22(9):1589-97. doi: 10.1200/JCO.2004.08.163.
Abstract/Text PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy.
PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m(2) intravenously (i.v.) day 1 with vitamin B(12), folic acid, and dexamethasone or docetaxel 75 mg/m(2) i.v. day 1 with dexamethasone every 21 days. The primary end point was overall survival.
RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P =.105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P <.001), febrile neutropenia (12.7% v 1.9%; P <.001), neutropenia with infections (3.3% v 0.0%; P =.004), hospitalizations for neutropenic fever (13.4% v 1.5%; P <.001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P =.092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P <.001) and all grade alopecia (37.7% v 6.4%; P <.001) compared with patients receiving pemetrexed.
CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.

PMID 15117980
F A Shepherd, J Dancey, R Ramlau, K Mattson, R Gralla, M O'Rourke, N Levitan, L Gressot, M Vincent, R Burkes, S Coughlin, Y Kim, J Berille
Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.
J Clin Oncol. 2000 May;18(10):2095-103. doi: 10.1200/JCO.2000.18.10.2095.
Abstract/Text PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.
PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m(2) (49 patients) or 75 mg/m(2) (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks.
RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7. 1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P <.001), as was median survival (7.0 v 4.6 months; log-rank test, P =.047). The difference was more significant for docetaxel 75 mg/m(2) patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P =.010; 1-year survival, 37% v 11%; chi(2) test, P =.003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m(2), three of whom died, and in one patient treated with docetaxel 75 mg/m(2). Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups.
CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m(2), the benefits of docetaxel therapy outweigh the risks.

PMID 10811675
Martin Reck, Delvys Rodríguez-Abreu, Andrew G Robinson, Rina Hui, Tibor Csőszi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O'Brien, Suman Rao, Katsuyuki Hotta, Ticiana A Leal, Jonathan W Riess, Erin Jensen, Bin Zhao, M Catherine Pietanza, Julie R Brahmer
Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50.
J Clin Oncol. 2021 Jul 20;39(21):2339-2349. doi: 10.1200/JCO.21.00174. Epub 2021 Apr 19.
Abstract/Text PURPOSE: We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS).
METHODS: Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point.
RESULTS: Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure.
CONCLUSION: Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.

PMID 33872070
David S Ettinger, Douglas E Wood, Dara L Aisner, Wallace Akerley, Jessica R Bauman, Ankit Bharat, Debora S Bruno, Joe Y Chang, Lucian R Chirieac, Thomas A D'Amico, Thomas J Dilling, Jonathan Dowell, Scott Gettinger, Matthew A Gubens, Aparna Hegde, Mark Hennon, Rudy P Lackner, Michael Lanuti, Ticiana A Leal, Jules Lin, Billy W Loo, Christine M Lovly, Renato G Martins, Erminia Massarelli, Daniel Morgensztern, Thomas Ng, Gregory A Otterson, Sandip P Patel, Gregory J Riely, Steven E Schild, Theresa A Shapiro, Aditi P Singh, James Stevenson, Alda Tam, Jane Yanagawa, Stephen C Yang, Kristina M Gregory, Miranda Hughes
NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021.
J Natl Compr Canc Netw. 2021 Mar 2;19(3):254-266. doi: 10.6004/jnccn.2021.0013. Epub 2021 Mar 2.
Abstract/Text The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

PMID 33668021
D Planchard, S Popat, K Kerr, S Novello, E F Smit, C Faivre-Finn, T S Mok, M Reck, P E Van Schil, M D Hellmann, S Peters
Correction to: "Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up".
Ann Oncol. 2019 May;30(5):863-870. doi: 10.1093/annonc/mdy474. Epub 2019 Dec 4.
Abstract/Text
PMID 31987360
Sandra Zelman Lewis, Rebecca Diekemper, Doreen J Addrizzo-Harris
Methodology for development of guidelines for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
Chest. 2013 May;143(5 Suppl):41S-50S. doi: 10.1378/chest.12-2344.
Abstract/Text BACKGROUND: The objective was to develop high-quality and comprehensive evidence-based guidelines on the diagnosis and management of lung cancer.
METHODS: A carefully crafted panel of lung cancer experts, methodologists, and other specialists was assembled and reviewed for relevant conflicts of interest. The American College of Chest Physicians guideline methodology was used. Population, intervention, comparator, outcome (PICO)-based key questions and defined criteria for eligible studies were developed to inform the search strategies, subsequent evidence summaries, and recommendations. Research studies, systematic reviews, and meta-analyses, where they existed, were assessed for quality and summarized to inform the recommendations.
RESULTS: Each recommendation was developed with supporting evidence and the consensus of the writing committees. Controversial recommendations were identified for further consultation by the entire panel, with anonymous voting to achieve consensus.
CONCLUSIONS: The final recommendations can be trusted by health-care providers, patients, and other stakeholders since they are based on the current evidence in these areas and were developed with trustworthy processes for guideline development.

PMID 23649432
Nasser H Hanna, Andrew G Robinson, Sarah Temin, Sherman Baker, Julie R Brahmer, Peter M Ellis, Laurie E Gaspar, Rami Y Haddad, Paul J Hesketh, Dharamvir Jain, Ishmael Jaiyesimi, David H Johnson, Natasha B Leighl, Pamela R Moffitt, Tanyanika Phillips, Gregory J Riely, Rafael Rosell, Joan H Schiller, Bryan J Schneider, Navneet Singh, David R Spigel, Joan Tashbar, Gregory Masters
Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update.
J Clin Oncol. 2021 Mar 20;39(9):1040-1091. doi: 10.1200/JCO.20.03570. Epub 2021 Feb 16.
Abstract/Text PURPOSE: To provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) with driver alterations. A guideline update for systemic therapy for patients with stage IV NSCLC without driver alterations was published separately.
METHODS: The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel updated recommendations based on a systematic review of randomized controlled trials (RCTs) from December 2015 to January 2020 and meeting abstracts from ASCO 2020.
RESULTS: This guideline update reflects changes in evidence since the previous update. Twenty-seven RCTs, 26 observational studies, and one meta-analysis provide the evidence base (total 54). Outcomes of interest included efficacy and safety. Additional literature suggested by the Expert Panel is discussed.
RECOMMENDATIONS: All patients with nonsquamous NSCLC should have the results of testing for potentially targetable mutations (alterations) before implementing therapy for advanced lung cancer, regardless of smoking status recommendations, when possible, following other existing high-quality testing guidelines. Most patients should receive targeted therapy for these alterations: Targeted therapies against ROS-1 fusions, BRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions should be offered to patients, either as initial or second-line therapy when not given in the first-line setting. New or revised recommendations include the following: Osimertinib is the optimal first-line treatment for patients with activating epidermal growth factor receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M); alectinib or brigatinib is the optimal first-line treatment for patients with anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the guideline includes recommendations regarding RET, MET, and NTRK alterations. Chemotherapy is still an option at most stages.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

PMID 33591844
Nasser H Hanna, Bryan J Schneider, Sarah Temin, Sherman Baker, Julie Brahmer, Peter M Ellis, Laurie E Gaspar, Rami Y Haddad, Paul J Hesketh, Dharamvir Jain, Ishmael Jaiyesimi, David H Johnson, Natasha B Leighl, Tanyanika Phillips, Gregory J Riely, Andrew G Robinson, Rafael Rosell, Joan H Schiller, Navneet Singh, David R Spigel, Janis O Stabler, Joan Tashbar, Gregory Masters
Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update.
J Clin Oncol. 2020 May 10;38(14):1608-1632. doi: 10.1200/JCO.19.03022. Epub 2020 Jan 28.
Abstract/Text PURPOSE: The aim of this work is to provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) without driver alterations. A guideline update for patients with stage IV NSCLC with driver alterations will be published separately.
METHODS: The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel made updated recommendations based on a systematic review of randomized controlled trials from December 2015 to 2019.
RESULTS: This guideline update reflects changes in evidence since the previous guideline update. Five randomized controlled trials provide the evidence base. Additional literature suggested by the Expert Panel is discussed.
RECOMMENDATIONS: Recommendations apply to patients without driver alterations in epidermal growth factor receptor or ALK. For patients with high programmed death ligand 1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%) and non-squamous cell carcinoma (non-SCC), the Expert Panel recommends single-agent pembrolizumab. Additional treatment options include pembrolizumab/carboplatin/pemetrexed, atezolizumab/carboplatin/paclitaxel/bevacizumab, or atezolizumab/carboplatin/nab-paclitaxel. For most patients with non-SCC and either negative (0%) or low positive (1% to 49%) PD-L1, the Expert Panel recommends pembrolizumab/carboplatin/pemetrexed. Additional options are atezolizumab/carboplatin/nab-paclitaxel, atezolizumab/carboplatin/paclitaxel/bevacizumab, platinum-based two-drug combination chemotherapy, or non-platinum-based two-drug therapy. Single-agent pembrolizumab is an option for low positive PD-L1. For patients with high PD-L1 expression (TPS ≥ 50%) and SCC, the Expert Panel recommends single-agent pembrolizumab. An additional treatment option is pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel). For most patients with SCC and either negative (0%) or low positive PD-L1 (TPS 1% to 49%), the Expert Panel recommends pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel) or chemotherapy. Single-agent pembrolizumab is an option in select cases of low positive PD-L1. Recommendations are conditional on the basis of histology, PD-L1 status, and/or the presence or absence of contraindications. Additional information is available at www.asco.org/lung-cancer-guidelines.

PMID 31990617
Nasser Hanna, David Johnson, Sarah Temin, Sherman Baker, Julie Brahmer, Peter M Ellis, Giuseppe Giaccone, Paul J Hesketh, Ishmael Jaiyesimi, Natasha B Leighl, Gregory J Riely, Joan H Schiller, Bryan J Schneider, Thomas J Smith, Joan Tashbar, William A Biermann, Gregory Masters
Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update.
J Clin Oncol. 2017 Oct 20;35(30):3484-3515. doi: 10.1200/JCO.2017.74.6065. Epub 2017 Aug 14.
Abstract/Text Purpose Provide evidence-based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC). Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of randomized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence-Based Care's update of a previous ASCO search. Results This guideline update reflects changes in evidence since the previous guideline update. Fourteen randomized controlled trials provide the evidence base; earlier phase trials also informed recommendation development. Recommendations New or revised recommendations include the following. Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma (without positive markers, eg, EGFR/ALK /ROS1), if the patient has high programmed death ligand 1 (PD-L1) expression, pembrolizumab should be used alone; if the patient has low PD-L1 expression, clinicians should offer standard chemotherapy. All other clinical scenarios follow 2015 recommendations. Regarding second-line treatment in patients who received first-line chemotherapy, without prior immune checkpoint therapy, if NSCLC tumor is positive for PD-L1 expression, clinicians should use single-agent nivolumab, pembrolizumab, or atezolizumab; if tumor has negative or unknown PD-L1 expression, clinicians should use nivolumab or atezolizumab. All immune checkpoint therapy is recommended alone plus in the absence of contraindications. For patients who received a prior first-line immune checkpoint inhibitor, clinicians should offer standard chemotherapy. For patients who cannot receive immune checkpoint inhibitor after chemotherapy, docetaxel is recommended; in patients with nonsquamous NSCLC, pemetrexed is recommended. In patients with a sensitizing EGFR mutation, disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy, and T790M mutation, osimertinib is recommended; if NSCLC lacks the T790M mutation, then chemotherapy is recommended. Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib, or if they previously received crizotinib, they may be offered chemotherapy.

PMID 28806116
Andrea Bezjak, Sarah Temin, Gregg Franklin, Giuseppe Giaccone, Ramaswamy Govindan, Melissa L Johnson, Andreas Rimner, Bryan J Schneider, John Strawn, Christopher G Azzoli
Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline.
J Clin Oncol. 2015 Jun 20;33(18):2100-5. doi: 10.1200/JCO.2014.59.2360. Epub 2015 May 5.
Abstract/Text PURPOSE: The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on external-beam radiotherapy for patients with locally advanced non-small-cell lung cancer (NSCLC). Because of its relevance to the American Society of Clinical Oncology (ASCO) membership, ASCO endorsed the guideline after applying a set of procedures and a policy that are used to critically examine and endorse guidelines developed by other guideline development organizations.
METHODS: The ASTRO guideline was reviewed by ASCO content experts for clinical accuracy and by ASCO methodologists for developmental rigor. On favorable review, an ASCO expert panel was convened and endorsed the guideline. The ASCO guideline approval body, the Clinical Practice Guideline Committee, approved the final endorsement.
RESULTS: The recommendations from the ASTRO guideline, published in Practical Radiation Oncology, are clear, thorough, and based on the most relevant scientific evidence. The ASCO Endorsement Panel endorsed the guideline and added qualifying statements.
RECOMMENDATIONS: For curative-intent treatment of locally advanced NSCLC, concurrent chemoradiotherapy improves local control and overall survival compared with sequential chemotherapy followed by radiation. The standard dose-fractionation of radiation is 60 Gy given in 2-Gy once-daily fractions over 6 weeks. There is no role for the routine use of induction therapy before chemoradiotherapy. Current data fail to support a clear role for consolidation therapy after chemoradiotherapy; however, consolidation therapy remains an option for patients who did not receive full systemic chemotherapy doses during radiotherapy. Important questions remain about the ideal concurrent chemotherapy regimen and optimal management of patients with resectable stage III disease.

© 2015 by American Society of Clinical Oncology.
PMID 25944914
Francesco Facchinetti, Giulia Mazzaschi, Fausto Barbieri, Francesco Passiglia, Francesca Mazzoni, Rossana Berardi, Claudia Proto, Fabiana Letizia Cecere, Sara Pilotto, Vieri Scotti, Sabrina Rossi, Alessandro Del Conte, Emanuele Vita, Chiara Bennati, Andrea Ardizzoni, Giulio Cerea, Maria Rita Migliorino, Elisa Sala, Andrea Camerini, Alessandra Bearz, Elisa De Carlo, Francesca Zanelli, Giorgia Guaitoli, Marina Chiara Garassino, Lucia Pia Ciccone, Giulia Sartori, Luca Toschi, Filippo Gustavo Dall'Olio, Lorenza Landi, Elio Gregory Pizzutilo, Gabriele Bartoli, Cinzia Baldessari, Silvia Novello, Emilio Bria, Diego Luigi Cortinovis, Giulio Rossi, Antonio Rossi, Giuseppe Luigi Banna, Roberta Camisa, Massimo Di Maio, Marcello Tiseo
First-line pembrolizumab in advanced non-small cell lung cancer patients with poor performance status.
Eur J Cancer. 2020 May;130:155-167. doi: 10.1016/j.ejca.2020.02.023. Epub 2020 Mar 25.
Abstract/Text BACKGROUND: Pembrolizumab is the first-line standard of care for advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumour proportion score (TPS) ≥ 50%. Eastern Cooperative Oncology Group performance status (PS) 2 patients may receive pembrolizumab, despite the absence of sustaining evidence.
PATIENTS AND METHODS: GOIRC-2018-01 is a multicentre, retrospective, observational study. PS 2 NSCLC patients with a PD-L1 TPS ≥50% receiving first-line pembrolizumab from June 2017 to December 2018 at 21 Italian institutions were included. Clinical-pathological characteristics were correlated with disease response and survival outcomes; adverse events were recorded. The primary objective was 6-months progression-free rate (6-months PFR).
RESULTS: One hundred fifty-three patients (median age 70 years) were enrolled. At a median follow-up of 18.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.4 (95% confidence interval, 95% CI, 1.6-2.5) and 3.0 months (95% CI 2.4-3.5), respectively. 6-months PFR was 27% (95% CI 21-35%). Patients with a PS 2 determined by comorbidities (n = 41) had significantly better outcomes compared with disease burden-induced PS 2 (n = 112). Indeed, 6-months PFR was 49% versus 19%, median PFS 5.6 versus 1.8 months and OS 11.8 versus 2.8 months, respectively. Additional potential prognostic factors (radiotherapy, antibiotics, steroids received before pembrolizumab) correlated with clinical outcomes. The determinant of PS 2 resulted the only factor independently impacting on both PFS and OS. No toxicity issues emerged.
CONCLUSIONS: Outcomes of PS 2 NSCLC patients with PD-L1 TPS ≥50% receiving first-line pembrolizumab were globally dismal but strongly dependent on the reason conditioning the poor PS itself.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32220780
Kaname Nosaki, Hideo Saka, Yukio Hosomi, Paul Baas, Gilberto de Castro, Martin Reck, Yi-Long Wu, Julie R Brahmer, Enriqueta Felip, Takeshi Sawada, Kazuo Noguchi, Shi Rong Han, Bilal Piperdi, Debra A Kush, Gilberto Lopes
Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.
Lung Cancer. 2019 Sep;135:188-195. doi: 10.1016/j.lungcan.2019.07.004. Epub 2019 Jul 8.
Abstract/Text OBJECTIVES: Most lung cancer diagnoses occur in elderly patients, who are underrepresented in clinical trials. We present a pooled analysis of safety and efficacy in elderly patients (≥75 years) who received pembrolizumab (a programmed death 1 inhibitor) for advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1)‒positive tumors.
METHODS: The pooled analysis included patients aged ≥18 years with advanced NSCLC with PD-L1-positive tumors from the KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894) studies. In KEYNOTE-010, patients were randomized to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel, as second- or later-line therapy. In KEYNOTE-024 and KEYNOTE-042, patients were randomized to first-line pembrolizumab 200 mg Q3W or platinum-based chemotherapy. Overall survival (OS) was estimated by the Kaplan-Meier method, and safety data were summarized in elderly patients (≥75 years).
RESULTS: The analysis included 264 elderly patients with PD-L1-positive tumors (PD-L1 tumor proportion score [TPS] ≥1%); among these, 132 had PD-L1 TPS ≥ 50%. Pembrolizumab improved OS among elderly patients with PD-L1 TPS ≥ 1% (hazard ratio [HR], 0.76 [95% CI, 0.56-1.02]) and PD-L1 TPS ≥ 50% (HR, 0.40 [95% CI, 0.25-0.64]). Pembrolizumab as first-line therapy also improved OS among elderly patients with PD-L1 TPS ≥ 50% (from KEYNOTE-024 and KEYNOTE-042) compared with chemotherapy (HR, 0.41 [95% CI, 0.23‒0.73]). Pembrolizumab was associated with fewer treatment-related adverse events (AEs) in elderly patients (overall, 68.5% vs 94.3%; grade ≥3, 24.2% vs 61.0%) versus chemotherapy. Immune-mediated AEs and infusion reactions were more common with pembrolizumab versus chemotherapy (overall, 24.8% vs 6.7%; grade 3‒4: 9.4% vs 0%; no grade 5 events).
CONCLUSIONS: In this pooled analysis of elderly patients with advanced NSCLC with PD-L1‒positive tumors, pembrolizumab improved OS versus chemotherapy, with a more favorable safety profile. Outcomes with pembrolizumab in patients ≥75 years were comparable to those in the overall populations in the individual studies.

Copyright © 2019 Elsevier B.V. All rights reserved.
PMID 31446994
Mark G Kris, Bruce E Johnson, Lynne D Berry, David J Kwiatkowski, A John Iafrate, Ignacio I Wistuba, Marileila Varella-Garcia, Wilbur A Franklin, Samuel L Aronson, Pei-Fang Su, Yu Shyr, D Ross Camidge, Lecia V Sequist, Bonnie S Glisson, Fadlo R Khuri, Edward B Garon, William Pao, Charles Rudin, Joan Schiller, Eric B Haura, Mark Socinski, Keisuke Shirai, Heidi Chen, Giuseppe Giaccone, Marc Ladanyi, Kelly Kugler, John D Minna, Paul A Bunn
Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
JAMA. 2014 May 21;311(19):1998-2006. doi: 10.1001/jama.2014.3741.
Abstract/Text IMPORTANCE: Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
OBJECTIVES: To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival.
DESIGN, SETTING, AND PARTICIPANTS: From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival.
INTERVENTIONS: Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies.
MAIN OUTCOMES AND MEASURES: Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival.
RESULTS: From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score-adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006).
CONCLUSIONS AND RELEVANCE: Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01014286.

PMID 24846037
Christopher G Azzoli, Sherman Baker, Sarah Temin, William Pao, Timothy Aliff, Julie Brahmer, David H Johnson, Janessa L Laskin, Gregory Masters, Daniel Milton, Luke Nordquist, David G Pfister, Steven Piantadosi, Joan H Schiller, Reily Smith, Thomas J Smith, John R Strawn, David Trent, Giuseppe Giaccone, American Society of Clinical Oncology
American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer.
J Clin Oncol. 2009 Dec 20;27(36):6251-66. doi: 10.1200/JCO.2009.23.5622. Epub 2009 Nov 16.
Abstract/Text The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy.

PMID 19917871
Abstract/Text UNLABELLED: Evidence suggests that platinum-based regimens confer a better survival in patients with non-small cell lung carcinoma (NSCLC). However, evidence is lacking regarding the specific effects of cisplatin or carboplatin when compared to non-platinum-based doublets.
METHODS: Meta-analysis of all randomized trials comparing non-platinum-based with platinum-based doublet regimens given as first-line treatment for NSCLC. Relative risks were calculated for all outcomes ascertained. Sensitivity analysis, using methodological quality of the trials and different measures of effect, was undertaken.
RESULTS: Seventeen trials, comprising 4920 patients were included. The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (RR=1.08, 95% CI 1.01-1.16, p=0.03), better partial response (RR=1.11, 95% CI 1.02-1.21, p=0.02), with a higher risk of anemia, nausea, and neurotoxicity. Cisplatin-based doublet regimens improved survival at 1 year (RR=1.16, 95% CI 1.06-1.27, p=0.001), complete response (RR=2.29, 95% CI 1.08-4.88, p=0.03), partial response (RR=1.19, 95% CI 1.07-1.32, p=0.002) with an increased risk of anemia, neutropenia, neurotoxicity and nausea. Conversely, carboplatin-based doublet regimens did not increase survival rate at 1 year (RR=0.95, 95% CI 0.85-1.07, p=0.43). There was a statistically significant difference between the effect of cisplatin compared to carboplatin (p=0.05). Carboplatin-based doublet regimen included a higher risk of anemia and thrombocytopenia, but no increased nausea and/or vomiting, contrarily to cisplatin. Sensitivity analyses showed that the results were robust to the exclusion of lesser quality trials and the choice of the measure of effect.
CONCLUSION: We provide additional evidence that cisplatin, but not carboplatin-based doublet regimens are associated with a slightly better survival compared to non-platinum-based doublet regimens. Side effects of cisplatin- and carboplatin-based regimens differ between each other and when compared to non-platinum doublets. Although this analysis has limitations, it may provide valuable information to clinicians when choosing the appropriate regimen for patients with non-small cell lung cancer.

PMID 17720276
Yu Yang Soon, Martin R Stockler, Lisa M Askie, Michael J Boyer
Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials.
J Clin Oncol. 2009 Jul 10;27(20):3277-83. doi: 10.1200/JCO.2008.19.4522. Epub 2009 May 26.
Abstract/Text PURPOSE: To determine if it is preferable to extend chemotherapy beyond a standard number of cycles in patients receiving first-line chemotherapy for advanced non-small-cell lung cancer.
METHODS: We searched biomedical literature databases and conference proceedings for randomized controlled trials (RCTs) comparing a defined number of cycles with continuation of the same chemotherapy until disease progression, a larger defined number of cycles of identical chemotherapy, and a defined number of cycles of identical initial chemotherapy followed by additional cycles of an alternative chemotherapy. Meta-analysis was performed using the fixed effect model. The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), adverse events (AE), and health-related quality of life (HRQL).
RESULTS: We found 13 RCTs including 3,027 patients. Extending chemotherapy improved PFS substantially (hazard ratio [HR], 0.75; 95% CI, 0.69 to 0.81; P < .00001) and OS modestly (HR, 0.92; 95% CI, 0.86 to 0.99; P = .03). Subgroup analysis revealed that effects on PFS were greater for trials extending chemotherapy with third-generation regimens rather than older regimens (HR, 0.70 interaction v 0.92 interaction; P = .003). Extending chemotherapy was associated with more frequent AE in all trials where it was reported and impaired HRQL in two of seven trials.
CONCLUSION: Extending chemotherapy, particularly with a third-generation regimen, improved PFS substantially, but OS less so. Future trials should test extending treatment with more effective and/or better-tolerated agents.

PMID 19470938
Antonio Rossi, Paolo Chiodini, Jong-Mu Sun, Mary E R O'Brien, Christian von Plessen, Fernando Barata, Keunchil Park, Sanjay Popat, Bengt Bergman, Barbara Parente, Ciro Gallo, Cesare Gridelli, Francesco Perrone, Massimo Di Maio
Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data.
Lancet Oncol. 2014 Oct;15(11):1254-62. doi: 10.1016/S1470-2045(14)70402-4. Epub 2014 Sep 14.
Abstract/Text BACKGROUND: Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy.
METHODS: All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics.
FINDINGS: Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients-568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months [95% CI 8·98-10·69] in patients assigned to six cycles vs 8·68 months [8·03-9·54] in those assigned to fewer cycles; hazard ratio [HR] 0·94 [95% CI 0·83-1·07], p=0·33) with slight heterogeneity between trials (p=0·076; I(2)=56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82-6·87) in patients assigned to six cycles and 5·33 months (4·90-5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68-0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia.
INTERPRETATION: Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients.
FUNDING: None.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 25232001
Wolfgang Schuette, Thomas Blankenburg, Wolf Guschall, Ina Dittrich, Michael Schroeder, Hans Schweisfurth, Assaad Chemaissani, Christian Schumann, Nikolas Dickgreber, Tabea Appel, Dieter Ukena
Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin.
Clin Lung Cancer. 2006 Mar;7(5):338-43. doi: 10.3816/clc.2006.n.016.
Abstract/Text PURPOSE: The combination of paclitaxel with carboplatin is effective in advanced-stage non-small cell lung cancer (NSCLC). This phase III study was designed to compare the efficacy and tolerability of a weekly versus an every-3-week schedule in the first-line treatment of advanced-stage NSCLC.
PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive paclitaxel 100 mg/m2 and carboplatin at an area under the curve of 2 once weekly for 6-8 weeks (arm A) or paclitaxel 200 mg/m2 and carboplatin at an area under the curve of 6 on day 1 every 21 days (arm B).
RESULTS: A total of 883 patients received >or= 1 chemotherapy cycle and were included in the results. The objective response rates observed (complete response plus partial response) were 38% for arm A and 33% for arm B. Median times to progression and median survival times were 6.1 months and 8.9 months in arm A and 7.2 months and 9.5 months in arm B, respectively. There were no significant differences between treatment arms. The chemotherapy was well tolerated in both schedules. However, grade 3/4 sensory neuropathy occurred more frequently with the every-3-week schedule (9.1% vs. 4.4%), whereas grade 3/4 diarrhea occurred more frequently with the weekly schedule (4.2% vs. 1.1%).
CONCLUSION: In terms of response and survival, paclitaxel/carboplatin administered once weekly is comparable with the every-3-week schedule. Toxicity differences should be considered when choosing the appropriate schedule for the individual.

PMID 16640806
Chandra P Belani, Suresh Ramalingam, Michael C Perry, Renato V LaRocca, David Rinaldi, Preston S Gable, William J Tester
Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer.
J Clin Oncol. 2008 Jan 20;26(3):468-73. doi: 10.1200/JCO.2007.13.1912.
Abstract/Text PURPOSE: To compare the efficacy and safety of weekly paclitaxel in combination with carboplatin administered every 4 weeks to the standard regimen of paclitaxel and carboplatin administered every 3 weeks for the treatment of patients with advanced non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: Four hundred forty-four patients with previously untreated stage IIIB/IV NSCLC were randomly assigned to either arm 1 (n = 223), paclitaxel 100 mg/m(2) weekly for 3 of 4 weeks with carboplatin area under the curve (AUC) = 6 mg/mL x min on day 1 of each 4 week cycle, or arm 2 (n = 221), paclitaxel 225 mg/m(2) and carboplatin AUC = 6 on day 1 of each 3-week cycle. After four cycles of therapy, patients in both treatment arms were eligible to continue weekly paclitaxel (70 mg/m(2), 3 of 4 weeks) as maintenance therapy until unacceptable toxicity or disease progression.
RESULTS: The objective response rate was 27.6% for arm 1 and 19.2% for arm 2. Median time to progression (TTP) was 18.4 and median survival (MS) was 38.6 weeks for arm 1. For arm 2, the median TTP and MS were 16.7 weeks and 42.9 weeks respectively. Grade 3/4 anemia was more common with arm 1, although grade 2/3 neuropathy and arthralgia were less common. The remainder of the toxicities were similar between the two arms.
CONCLUSION: All efficacy parameters were similar between the two treatment arms. The favorable nonhematologic toxicity profile of arm 1 makes this an alternative treatment option for patients with advanced NSCLC.

PMID 18202422
Martin Reck, Delvys Rodríguez-Abreu, Andrew G Robinson, Rina Hui, Tibor Csőszi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O'Brien, Suman Rao, Katsuyuki Hotta, Melanie A Leiby, Gregory M Lubiniecki, Yue Shentu, Reshma Rangwala, Julie R Brahmer, KEYNOTE-024 Investigators
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.
N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8.
Abstract/Text BACKGROUND: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).
METHODS: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.
RESULTS: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).
CONCLUSIONS: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).

PMID 27718847
Tony S K Mok, Yi-Long Wu, Iveta Kudaba, Dariusz M Kowalski, Byoung Chul Cho, Hande Z Turna, Gilberto Castro, Vichien Srimuninnimit, Konstantin K Laktionov, Igor Bondarenko, Kaoru Kubota, Gregory M Lubiniecki, Jin Zhang, Debra Kush, Gilberto Lopes, KEYNOTE-042 Investigators
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
Lancet. 2019 May 4;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7. Epub 2019 Apr 4.
Abstract/Text BACKGROUND: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.
METHODS: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894.
FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.
INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.
FUNDING: Merck Sharp & Dohme.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30955977
Roy S Herbst, Giuseppe Giaccone, Filippo de Marinis, Niels Reinmuth, Alain Vergnenegre, Carlos H Barrios, Masahiro Morise, Enriqueta Felip, Zoran Andric, Sarayut Geater, Mustafa Özgüroğlu, Wei Zou, Alan Sandler, Ida Enquist, Kimberly Komatsubara, Yu Deng, Hiroshi Kuriki, Xiaohui Wen, Mark McCleland, Simonetta Mocci, Jacek Jassem, David R Spigel
Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC.
N Engl J Med. 2020 Oct 1;383(14):1328-1339. doi: 10.1056/NEJMoa1917346.
Abstract/Text BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known.
METHODS: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden.
RESULTS: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden.
CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32997907
Non-Small Cell Lung Cancer Collaborative Group
Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer.
Cochrane Database Syst Rev. 2010 May 12;(5):CD007309. doi: 10.1002/14651858.CD007309.pub2. Epub 2010 May 12.
Abstract/Text BACKGROUND: Since our individual patient data (IPD) meta-analysis of supportive care and chemotherapy for non-small cell lung cancer (NSCLC), published in 1995, many trials have been completed. We have carried out an updated IPD meta-analysis to assess newer regimens and determine conclusively the effect of chemotherapy.
OBJECTIVES: To assess the effect on survival of supportive care and chemotherapy versus supportive care alone in advanced NSCLC.
SEARCH STRATEGY: All randomised controlled trials (RCTs), published or unpublished. We searched bibliographic databases, trials registers, conference proceedings and reference lists of relevant trials. Searches were completed to November 2009.
SELECTION CRITERIA: Trials had to have commenced accrual on or after 1 January 1965 and should have included patients with NSCLC who had received either chemotherapy and supportive care or supportive care alone. Patients should have not received any previous chemotherapy or had any prior malignancy.
DATA COLLECTION AND ANALYSIS: For trials included in 1995 we sought updated follow up. For new trials we sought survival and baseline characteristics for all patients. We combined results from RCTs to calculate individual and pooled hazard ratios (HRs).
MAIN RESULTS: We obtained data on 2714 patients from 16 RCTs. There were 1293 deaths among 1399 patients assigned supportive care and chemotherapy and 1240 among 1315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR = 0.77; 95% CI 0.71 to 0.83, P < 0.0001), equivalent to a relative increase in survival of 23%, an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29% or an absolute increase in median survival of 1.5 months (from 4.5 months to six months). There was no clear evidence that this effect was influenced by the drugs used (P = 0.63) or whether they were used as single agents or in combination (P = 0.40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = 0.77). There was no clear evidence of a difference in the relative effect of chemotherapy across patient subgroups. Quality of life could not be formally assessed.
AUTHORS' CONCLUSIONS: All trials were of good methodological quality with no risk of bias. This meta-analysis of chemotherapy in the supportive care setting demonstrates that chemotherapy improves overall survival in all patients with advanced NSCLC. Patients who are fit enough and wish to receive it should be offered chemotherapy.

PMID 20464750
Leena Gandhi, Delvys Rodríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven F Powell, Susanna Y-S Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Rina Hui, Edward B Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E Gray, John Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M Catherine Pietanza, Marina C Garassino, KEYNOTE-189 Investigators
Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.
N Engl J Med. 2018 May 31;378(22):2078-2092. doi: 10.1056/NEJMoa1801005. Epub 2018 Apr 16.
Abstract/Text BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.
RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.
CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).

PMID 29658856
Martin Reck, Tony S K Mok, Makoto Nishio, Robert M Jotte, Federico Cappuzzo, Francisco Orlandi, Daniil Stroyakovskiy, Naoyuki Nogami, Delvys Rodríguez-Abreu, Denis Moro-Sibilot, Christian A Thomas, Fabrice Barlesi, Gene Finley, Anthony Lee, Shelley Coleman, Yu Deng, Marcin Kowanetz, Geetha Shankar, Wei Lin, Mark A Socinski, IMpower150 Study Group
Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.
Lancet Respir Med. 2019 May;7(5):387-401. doi: 10.1016/S2213-2600(19)30084-0. Epub 2019 Mar 25.
Abstract/Text BACKGROUND: The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups.
METHODS: IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing.
FINDINGS: Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17·0-NE) with ABCP (34 of 400) and 18·7 months (95% CI 13·4-NE) with BCP (45 of 400; hazard ratio [HR] 0·61 [95% CI 0·29-1·28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17·5 months [95% CI 11·7-NE] with BCP [32 of 400]; HR 0·31 [95% CI 0·11-0·83]) and in the intention-to-treat population (19·8 months [17·4-24·2] vs 14·9 months [13·4-17·1]; HR 0·76 [0·63-0·93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13·3 months [11·6-NE] with ABCP [52 of 400] vs 9·4 months [7·9-11·7] with BCP [57 of 400]; HR 0·52 [0·33-0·82]). Median overall survival was 21·4 months (95% CI 13·8-NE) with ACP versus 18·7 months (95% CI 13·4-NE) with BCP in EGFR-positive patients (HR 0·93 [95% CI 0·51-1·68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0·90 [95% CI 0·47-1·74]), in the intention-to-treat population (HR 0·85 [0·71-1·03]), or in patients with baseline liver metastases (HR 0·87 [0·57-1·32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.
INTERPRETATION: Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.
FUNDING: F. Hoffmann-La Roche, Genentech.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30922878
Matthew D Hellmann, Luis Paz-Ares, Reyes Bernabe Caro, Bogdan Zurawski, Sang-We Kim, Enric Carcereny Costa, Keunchil Park, Aurelia Alexandru, Lorena Lupinacci, Emmanuel de la Mora Jimenez, Hiroshi Sakai, Istvan Albert, Alain Vergnenegre, Solange Peters, Konstantinos Syrigos, Fabrice Barlesi, Martin Reck, Hossein Borghaei, Julie R Brahmer, Kenneth J O'Byrne, William J Geese, Prabhu Bhagavatheeswaran, Sridhar K Rabindran, Ravi S Kasinathan, Faith E Nathan, Suresh S Ramalingam
Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.
N Engl J Med. 2019 Nov 21;381(21):2020-2031. doi: 10.1056/NEJMoa1910231. Epub 2019 Sep 28.
Abstract/Text BACKGROUND: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC.
METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more.
RESULTS: Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.
CONCLUSIONS: First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31562796
Shirish Gadgeel, Delvys Rodríguez-Abreu, Giovanna Speranza, Emilio Esteban, Enriqueta Felip, Manuel Dómine, Rina Hui, Maximilian J Hochmair, Philip Clingan, Steven F Powell, Susanna Yee-Shan Cheng, Helge G Bischoff, Nir Peled, Francesco Grossi, Ross R Jennens, Martin Reck, Edward B Garon, Silvia Novello, Belén Rubio-Viqueira, Michael Boyer, Takayasu Kurata, Jhanelle E Gray, Jing Yang, Tuba Bas, M Catherine Pietanza, Marina C Garassino
Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer.
J Clin Oncol. 2020 May 10;38(14):1505-1517. doi: 10.1200/JCO.19.03136. Epub 2020 Mar 9.
Abstract/Text PURPOSE: In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680).
METHODS: Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis.
RESULTS: As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups.
CONCLUSION: First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

PMID 32150489
Mark A Socinski, Robert M Jotte, Federico Cappuzzo, Francisco Orlandi, Daniil Stroyakovskiy, Naoyuki Nogami, Delvys Rodríguez-Abreu, Denis Moro-Sibilot, Christian A Thomas, Fabrice Barlesi, Gene Finley, Claudia Kelsch, Anthony Lee, Shelley Coleman, Yu Deng, Yijing Shen, Marcin Kowanetz, Ariel Lopez-Chavez, Alan Sandler, Martin Reck, IMpower150 Study Group
Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
N Engl J Med. 2018 Jun 14;378(24):2288-2301. doi: 10.1056/NEJMoa1716948. Epub 2018 Jun 4.
Abstract/Text BACKGROUND: The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy.
METHODS: We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group.
RESULTS: In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines.
CONCLUSIONS: The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143 .).

PMID 29863955
Martin Reck, Thomas Wehler, Francisco Orlandi, Naoyuki Nogami, Carlo Barone, Denis Moro-Sibilot, Mikhail Shtivelband, Jose Luis González Larriba, Jeffrey Rothenstein, Martin Früh, Wei Yu, Yu Deng, Shelley Coleman, Geetha Shankar, Hina Patel, Claudia Kelsch, Anthony Lee, Elisabeth Piault, Mark A Socinski
Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell Lung Cancer.
J Clin Oncol. 2020 Aug 1;38(22):2530-2542. doi: 10.1200/JCO.19.03158. Epub 2020 May 27.
Abstract/Text PURPOSE: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) demonstrated survival benefit versus bevacizumab, carboplatin, and paclitaxel (BCP) in chemotherapy-naïve nonsquamous non-small-cell lung cancer (NSCLC). We present safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in nonsquamous NSCLC.
METHODS: Patients were randomly assigned to receive atezolizumab, carboplatin, and paclitaxel (ACP), ABCP, or BCP. Coprimary end points were overall survival and investigator-assessed progression-free survival. The incidence, nature, and severity of adverse events (AEs) were assessed. PROs, a secondary end point, were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core 30 and EORTC QLQ-Lung Cancer 13.
RESULTS: Overall, 400 (ACP), 393 (ABCP), and 394 (BCP) patients were safety evaluable (ie, intention-to-treat population that received one or more doses of any study treatment). More patients had grade 3/4 treatment-related AEs during the induction versus maintenance phase (ACP, 40.5% v 8.2%; ABCP, 48.6% v 21.2%; BCP, 44.7% v 11.1%). During induction, the incidence of serious AEs (SAEs) was 28.3%, 28.5%, and 26.4% in the ACP, ABCP, and BCP arms, respectively. During maintenance, SAE incidences were 20.0%, 26.3%, and 13.0%, respectively. Completion rates of the PRO questionnaires were > 88% at baseline and remained ≥ 70% throughout most study visits. Across arms, patients on average reported no clinically meaningful worsening of global health status or physical functioning scores through cycle 13. Patients across arms rated common symptoms with chemotherapy and immunotherapy similarly.
CONCLUSION: ABCP seems tolerable and manageable versus ACP and BCP in first-line nonsquamous NSCLC. Treatment tolerability differed between induction and maintenance phases across treatment arms. PROs reflect a minimal treatment burden (eg, health-related quality of life, symptoms) with each regimen.

PMID 32459597
Howard West, Michael McCleod, Maen Hussein, Alessandro Morabito, Achim Rittmeyer, Henry J Conter, Hans-Georg Kopp, Davey Daniel, Steven McCune, Tarek Mekhail, Alona Zer, Niels Reinmuth, Ahad Sadiq, Alan Sandler, Wei Lin, Tania Ochi Lohmann, Venice Archer, Lijia Wang, Marcin Kowanetz, Federico Cappuzzo
Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
Lancet Oncol. 2019 Jul;20(7):924-937. doi: 10.1016/S1470-2045(19)30167-6. Epub 2019 May 20.
Abstract/Text BACKGROUND: Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer.
METHODS: IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFRwt and ALKwt) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781.
FINDINGS: Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2-23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4-23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0-21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0-18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64-0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2-7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4-5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54-0·77]; p<0·0001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group.
INTERPRETATION: IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer.
FUNDING: F. Hoffmann-La Roche.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31122901
Scott J Antonia, Augusto Villegas, Davey Daniel, David Vicente, Shuji Murakami, Rina Hui, Takayasu Kurata, Alberto Chiappori, Ki H Lee, Maike de Wit, Byoung C Cho, Maryam Bourhaba, Xavier Quantin, Takaaki Tokito, Tarek Mekhail, David Planchard, Young-Chul Kim, Christos S Karapetis, Sandrine Hiret, Gyula Ostoros, Kaoru Kubota, Jhanelle E Gray, Luis Paz-Ares, Javier de Castro Carpeño, Corinne Faivre-Finn, Martin Reck, Johan Vansteenkiste, David R Spigel, Catherine Wadsworth, Giovanni Melillo, Maria Taboada, Phillip A Dennis, Mustafa Özgüroğlu, PACIFIC Investigators
Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.
N Engl J Med. 2018 Dec 13;379(24):2342-2350. doi: 10.1056/NEJMoa1809697. Epub 2018 Sep 25.
Abstract/Text BACKGROUND: An earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival.
METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary end points were progression-free survival (as assessed by blinded independent central review) and overall survival. Secondary end points included the time to death or distant metastasis, the time to second progression, and safety.
RESULTS: Of the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events.
CONCLUSIONS: Durvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

PMID 30280658
Luis Paz-Ares, Tudor-Eliade Ciuleanu, Manuel Cobo, Michael Schenker, Bogdan Zurawski, Juliana Menezes, Eduardo Richardet, Jaafar Bennouna, Enriqueta Felip, Oscar Juan-Vidal, Aurelia Alexandru, Hiroshi Sakai, Alejo Lingua, Pamela Salman, Pierre-Jean Souquet, Pedro De Marchi, Claudio Martin, Maurice Pérol, Arnaud Scherpereel, Shun Lu, Thomas John, David P Carbone, Stephanie Meadows-Shropshire, Shruti Agrawal, Abderrahim Oukessou, Jinchun Yan, Martin Reck
First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.
Lancet Oncol. 2021 Feb;22(2):198-211. doi: 10.1016/S1470-2045(20)30641-0. Epub 2021 Jan 18.
Abstract/Text BACKGROUND: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit.
METHODS: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706.
FINDINGS: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.
INTERPRETATION: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.
FUNDING: Bristol Myers Squibb.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 33476593
Isamu Okamoto, Hiroshi Nokihara, Shogo Nomura, Seiji Niho, Shunichi Sugawara, Hidehito Horinouchi, Koichi Azuma, Yasuto Yoneshima, Haruyasu Murakami, Yukio Hosomi, Shinji Atagi, Tomohiro Ozaki, Atsushi Horiike, Yuka Fujita, Hiroaki Okamoto, Masahiko Ando, Nobuyuki Yamamoto, Yuichiro Ohe, Kazuhiko Nakagawa
Comparison of Carboplatin Plus Pemetrexed Followed by Maintenance Pemetrexed With Docetaxel Monotherapy in Elderly Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.
JAMA Oncol. 2020 May 1;6(5):e196828. doi: 10.1001/jamaoncol.2019.6828. Epub 2020 May 14.
Abstract/Text Importance: Few clinical trials have been specifically designed for elderly patients with advanced non-small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit.
Objective: To determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC.
Design, Setting, and Participants: This open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019.
Interventions: Patients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks.
Main Outcomes and Measures: The primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model.
Results: Of the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority = .003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed.
Conclusion and Relevance: Carboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC.
Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460.

PMID 32163097
Makoto Maemondo, Akira Inoue, Shunichi Sugawara, Toshiyuki Harada, Yuji Minegishi, Kazuhiro Usui, Koji Miwa, Naoto Morikawa, Mariko Kambe, Kenji Ube, Kana Watanabe, Osamu Ishimoto, Tomohiro Sakakibara, Akihiko Gemma, Toshihiro Nukiwa
Randomized phase II trial comparing carboplatin plus weekly paclitaxel and docetaxel alone in elderly patients with advanced non-small cell lung cancer: north japan lung cancer group trial 0801.
Oncologist. 2014 Apr;19(4):352-3. doi: 10.1634/theoncologist.2013-0411. Epub 2014 Mar 28.
Abstract/Text BACKGROUND: Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial.
METHODS: Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m²) (CP regimen) or to single-agent docetaxel (60 mg/m²). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile.
RESULTS: Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%-69%) and 24% (95% confidence interval: 11%-37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CP arm were generally moderate. One treatment-related death was observed in the docetaxel arm.
CONCLUSION: The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC.

PMID 24682465
Elisabeth Quoix, Gérard Zalcman, Jean-Philippe Oster, Virginie Westeel, Eric Pichon, Armelle Lavolé, Jérôme Dauba, Didier Debieuvre, Pierre-Jean Souquet, Laurence Bigay-Game, Eric Dansin, Michel Poudenx, Olivier Molinier, Fabien Vaylet, Denis Moro-Sibilot, Dominique Herman, Jaafar Bennouna, Jean Tredaniel, Alain Ducoloné, Marie-Paule Lebitasy, Laurence Baudrin, Silvy Laporte, Bernard Milleron, Intergroupe Francophone de Cancérologie Thoracique
Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.
Lancet. 2011 Sep 17;378(9796):1079-88. doi: 10.1016/S0140-6736(11)60780-0. Epub 2011 Aug 8.
Abstract/Text BACKGROUND: Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC.
METHODS: In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415.
FINDINGS: 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]).
INTERPRETATION: Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered.
FUNDING: Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21831418
Shinzoh Kudoh, Koji Takeda, Kazuhiko Nakagawa, Minoru Takada, Nobuyuki Katakami, Kaoru Matsui, Tetsu Shinkai, Toshiyuki Sawa, Isao Goto, Hiroshi Semba, Takashi Seto, Masahiko Ando, Taroh Satoh, Naruo Yoshimura, Shunichi Negoro, Masahiro Fukuoka
Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904).
J Clin Oncol. 2006 Aug 1;24(22):3657-63. doi: 10.1200/JCO.2006.06.1044.
Abstract/Text PURPOSE: Docetaxel has shown activity in elderly patients with advanced non-small-cell lung cancer (NSCLC). This randomized phase III trial evaluated the efficacy and safety of docetaxel versus vinorelbine (the current standard treatment) in elderly patients.
PATIENTS AND METHODS: Chemotherapy-naïve patients age 70 years or older with stage IIIB/IV NSCLC and performance status 2 or lower were eligible. Patients randomly received docetaxel 60 mg/m2 (day 1) or vinorelbine 25 mg/m2 (days 1 and 8) every 21 days for four cycles. The primary end point was overall survival. Overall disease-related symptom improvement was assessed using an eight-item questionnaire.
RESULTS: In total, 182 patients were enrolled. Median age was 76 years (range, 70 years to 86 years). There was no statistical difference in median overall survival with docetaxel versus vinorelbine (14.3 months v 9.9 months; hazard ratio, 0.780; 95% CI, 0.561 to 1.085; P = .138). There was a significant difference in median progression-free survival (5.5 months v 3.1 months; P < .001). Response rates were also significantly improved with docetaxel versus vinorelbine (22.7% v 9.9%; P = .019). The most common grade 3 to 4 toxicities were neutropenia (82.9% for docetaxel; 69.2% for vinorelbine; P = .031) and leukopenia (58.0% for docetaxel; 51.7% for vinorelbine). Other toxicities were mild and generally well tolerated. Docetaxel improved overall disease-related symptoms over vinorelbine (odds ratio, 1.86; 95% CI, 1.09 to 3.20).
CONCLUSION: Docetaxel improved progression-free survival, response rate, and disease-related symptoms versus vinorelbine. Overall survival was not statistically significantly improved at this time. Docetaxel monotherapy may be considered as an option in the standard treatment of elderly patients with advanced NSCLC.

PMID 16877734
Abstract/Text BACKGROUND: Vinorelbine, a semisynthetic vinca alkaloid, represents a well-tolerated treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC). We explored the quality of life (QoL) of such patients in a multicenter randomized trial that compared vinorelbine treatment with supportive care alone.
METHODS: Eligible patients were 70 years of age or older, had stage IV or IIIB NSCLC that was ineligible for radiotherapy, and had a performance status of 0-2 (a status of fully active to a status of capable of all self-care but unable to work). Vinorelbine was given intravenously on days 1 and 8 of a 21-day treatment cycle, for a total of six cycles. QoL was evaluated with European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-LC13, and the QoL data were analyzed by fitting a linear mixed model for each QoL scale. Survival curves were plotted and were compared with the Mantel-Haenszel test. Relative hazards of death and 95% confidence intervals (CIs) were estimated by the Cox model.
RESULTS: Investigators, blinded to the results, stopped the trial early because of a low enrollment rate. (From April 1996 to November 1997, 191 of the 350 targeted patients were randomly assigned.) Data from 161 patients have been analyzed. Vinorelbine-treated patients scored better than control patients on QoL functioning scales, and they reported fewer lung cancer-related symptoms but reported worse toxicity-related symptoms. There was a statistically significant (two-sided P = .03) survival advantage for patients receiving vinorelbine; median survival increased from 21 to 28 weeks in the vinorelbine-treated group. The relative hazard of death for vinorelbine-treated patients was 0.65 (95% CI = 0.45-0.93).
CONCLUSION: Vinorelbine improves survival of elderly patients with advanced NSCLC and possibly improves overall QoL.

PMID 9890172
Yang-Gun Suh, Jaeho Cho
Local ablative radiotherapy for oligometastatic non-small cell lung cancer.
Radiat Oncol J. 2019 Sep;37(3):149-155. doi: 10.3857/roj.2019.00514. Epub 2019 Sep 30.
Abstract/Text In metastatic non-small cell lung cancer (NSCLC), the role of radiotherapy (RT) has been limited to palliation to alleviate the symptoms. However, with the development of advanced RT techniques, recent advances in immuno-oncology therapy targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) and targeted agents for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation allowed new roles of RT in these patients. Within this metastatic population, there is a subset of patients with a limited number of sites of metastatic disease, termed as oligometastasis that can achieve long-term survival from aggressive local management. There is no consensus on the definition of oligometastasis; however, most clinical trials define oligometastasis as having 3 to 5 metastatic lesions. Recent phase II randomized clinical trials have shown that ablative RT, including stereotactic ablative body radiotherapy (SABR) and hypofractionated RT, to primary and metastatic sites improved progression-free survival (PFS) and overall survival (OS) in patients with oligometastatic NSCLC. The PEMBRO-RT study, a randomized phase II study comparing SABR prior to pembrolizumab therapy and pembrolizumab therapy alone, revealed that the addition of SABR improved the overall response, PFS, and OS in patients with advanced NSCLC. The efficacy of RT in oligometastatic lung cancer has only been studied in phase II studies; therefore, large-scale phase III studies are needed to confirm the benefit of local ablative RT in patients with oligometastatic NSCLC. Local intensified RT to primary and metastatic lesions is expected to become an important treatment paradigm in the near future in patients with metastatic lung cancer.

PMID 31591862
Rosemary Stevens, Fergus Macbeth, Elizabeth Toy, Bernadette Coles, Jason F Lester
Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer.
Cochrane Database Syst Rev. 2015 Jan 14;1:CD002143. doi: 10.1002/14651858.CD002143.pub4. Epub 2015 Jan 14.
Abstract/Text BACKGROUND: Palliative radiotherapy to the chest is often used in patients with lung cancer, but radiotherapy regimens are more often based on tradition than research results. This is an update of a Cochrane review first published in 2001 and previously updated in 2006.
OBJECTIVES: The two objectives of this review were:1. To assess the effects of different palliative radiotherapy regimens on improving thoracic symptoms in patients with locally advanced or metastatic non-small cell lung cancer who are not suitable for radical RT given with curative intent.2. To assess the effects of radiotherapy dose on overall survival in patients with locally advanced or metastatic non-small cell lung cancer who are not suitable for radical RT given with curative intent.
SEARCH METHODS: The electronic databases MEDLINE (1966 - Jan 2014), EMBASE and the Cochrane Central Register of Controlled Trials, reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished.Two authors (FM and RS) independently identified all studies that may be suitable for inclusion in the review.We updated the search up to January 2014.
SELECTION CRITERIA: Randomised controlled clinical trials comparing different regimens of palliative thoracic radiotherapy in patients with non-small cell lung cancer.
DATA COLLECTION AND ANALYSIS: The reviewers assessed search results independently and possible studies were highlighted and the full text obtained. Data were extracted and attempts were made to contact the original authors for missing information.The primary outcome measure was improvement in major thoracic symptoms (degree and duration). Secondary outcome measures were short and long term toxicities, effect on quality of life and overall survival.Patient reported outcomes were reported descriptively. Quantitative data such as survival and toxicity were analysed as dichotomous variables and reported using relative risks (RR).For this update of the review a meta-analysis of the survival data was carried out.
MAIN RESULTS: Fourteen randomised controlled trials (3576 patients) were included, with no new studies added in this update.There were important differences in the doses of radiotherapy investigated, the patient characteristics including disease stage and performance status and the outcome measures.The doses of RT investigated ranged from 10 Gy in 1 fraction (10Gy/1F) to 60 Gy/30F over six weeks, with a total of 19 different dose/ fractionation regimens.Potential biases were identified in some studies. Methods of randomisation, assessment of symptoms and statistical methods used were unclear in some papers. Withdrawal and drop-outs were accounted for in all but one study.All 13 studies that investigated symptoms reported that major thoracic symptoms improved following RT.There is no strong evidence that any regimen gives greater palliation. Higher dose regimens may give more acute toxicity and some regimens are associated with an increased risk of radiation myelitis. Variation in reporting of toxicities, in particular the absence of clear grading, means results of the meta-analysis should be treated with caution.Meta-analysis of overall survival broken down by performance status, a key variable, is included in this update. Further information was sought from all the original authors if stratified data was not included in the original publication. Three published studies contained sufficient data and seven authors were able to provide further information which represented 1992 patients (56% of all patients). The absence of data for nearly half of the patients has affected the quality of evidence.The meta-analysis showed no significant difference in 1-year overall survival between regimens with fewer radiotherapy fractions compared with regimens with more when patients were stratified by performance status. The results of the meta-analysis of 1-year overall survival for patients with good performance status (WHO performance status 0-1) showed moderately high heterogeneity and a summary result was not thought meaningful. The results of 1-year overall survival for patients with poor performance status was RR 0.96 (95% CI 0.91 to 1.02; moderate quality of evidence).
AUTHORS' CONCLUSIONS: Radiotherapy for patients with incurable non-small cell lung cancer can improve thoracic symptoms. Care should be taken with the dose to the spinal cord to reduce the risk of radiation myelopathy. The higher dose, more fractionated palliative radiotherapy regimens do not provide better or more durable palliation and their use to prolong survival is not supported by strong evidence. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.

PMID 25586198
Stephen Lutz, Tracy Balboni, Joshua Jones, Simon Lo, Joshua Petit, Shayna E Rich, Rebecca Wong, Carol Hahn
Palliative radiation therapy for bone metastases: Update of an ASTRO Evidence-Based Guideline.
Pract Radiat Oncol. 2017 Jan - Feb;7(1):4-12. doi: 10.1016/j.prro.2016.08.001. Epub 2016 Aug 5.
Abstract/Text PURPOSE: The purpose is to provide an update the Bone Metastases Guideline published in 2011 based on evidence complemented by expert opinion. The update will discuss new high-quality literature for the 8 key questions from the original guideline and implications for practice.
METHODS AND MATERIALS: A systematic PubMed search from the last date included in the original Guideline yielded 414 relevant articles. Ultimately, 20 randomized controlled trials, 32 prospective nonrandomized studies, and 4 meta-analyses/pooled analyses were selected and abstracted into evidence tables. The authors synthesized the evidence and reached consensus on the included recommendations.
RESULTS: Available literature continues to support pain relief equivalency between single and multiple fraction regimens for bone metastases. High-quality data confirm single fraction radiation therapy may be delivered to spine lesions with acceptable late toxicity. One prospective, randomized trial confirms both peripheral and spine-based painful metastases can be successfully and safely palliated with retreatment for recurrence pain with adherence to published dosing constraints. Advanced radiation therapy techniques such as stereotactic body radiation therapy lack high-quality data, leading the panel to favor its use on a clinical trial or when results will be collected in a registry. The panel's conclusion remains that surgery, radionuclides, bisphosphonates, and kyphoplasty/vertebroplasty do not obviate the need for external beam radiation therapy.
CONCLUSION: Updated data analysis confirms that radiation therapy provides excellent palliation for painful bone metastases and that retreatment is safe and effective. Although adherence to evidence-based medicine is critical, thorough expert radiation oncology physician judgment and discretion regarding number of fractions and advanced techniques are also essential to optimize outcomes when considering the patient's overall health, life expectancy, comorbidities, tumor biology, anatomy, previous treatment including prior radiation at or near current site of treatment, tumor and normal tissue response history to local and systemic therapies, and other factors related to the patient, tumor characteristics, or treatment.

Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
PMID 27663933
May N Tsao, Dirk Rades, Andrew Wirth, Simon S Lo, Brita L Danielson, Laurie E Gaspar, Paul W Sperduto, Michael A Vogelbaum, Jeffrey D Radawski, Jian Z Wang, Michael T Gillin, Najeeb Mohideen, Carol A Hahn, Eric L Chang
Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline.
Pract Radiat Oncol. 2012 Jul-Sep;2(3):210-225. doi: 10.1016/j.prro.2011.12.004. Epub 2012 Jan 30.
Abstract/Text PURPOSE: To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases.
METHODS AND MATERIALS: Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management.
RESULTS: The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation). Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3). Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3). Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3). It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful.
CONCLUSIONS: Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone).

Copyright © 2012 American Society for Radiation Oncology. All rights reserved.
PMID 25925626
Meysam Yousefi, Tayyeb Bahrami, Arash Salmaninejad, Rahim Nosrati, Parisa Ghaffari, Seyed H Ghaffari
Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options.
Cell Oncol (Dordr). 2017 Oct;40(5):419-441. doi: 10.1007/s13402-017-0345-5. Epub 2017 Sep 18.
Abstract/Text BACKGROUND: Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies.
CONCLUSIONS: The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

PMID 28921309
A J Schoenfeld, K C Arbour, H Rizvi, A N Iqbal, S M Gadgeel, J Girshman, M G Kris, G J Riely, H A Yu, M D Hellmann
Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.
Ann Oncol. 2019 May 1;30(5):839-844. doi: 10.1093/annonc/mdz077.
Abstract/Text BACKGROUND: Concurrent programmed death-ligand-1 (PD-(L)1) plus osimertinib is associated with severe immune related adverse events (irAE) in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Now that PD-(L)1 inhibitors are routinely used as adjuvant and first-line treatments, sequential PD-(L)1 inhibition followed by osimertinib use may become more frequent and have unforeseen serious toxicity.
METHODS: We identified patients with EGFR-mutant NSCLC who were treated with PD-(L)1 blockade and EGFR- tyrosine kinase inhibitors (TKIs), irrespective of drug or sequence of administration (total n = 126). Patient records were reviewed to identify severe (NCI-CTCAE v5.0 grades 3-4) toxicity.
RESULTS: Fifteen percent [6 of 41, 95% confidence interval (CI) 7% to 29%] of all patients treated with sequential PD-(L)1 blockade followed later by osimertinib developed a severe irAE. Severe irAEs were most common among those who began osimertinib within 3 months of prior PD-(L)1 blockade (5 of 21, 24%, 95% CI 10% to 45%), as compared with >3-12 months (1 of 8, 13%, 95% CI 0% to 50%), >12 months (0 of 12, 0%, 95% CI 0% to 28%). By contrast, no severe irAEs were identified among patients treated with osimertinib followed by PD-(L)1 (0 of 29, 95% CI 0% to 14%) or PD-(L)1 followed by other EGFR-TKIs (afatinib or erlotinib, 0 of 27, 95% CI 0% to 15%). IrAEs occurred at a median onset of 20 days after osimertinib (range 14-167 days). All patients with irAEs required steroids and most required hospitalization.
CONCLUSION: PD-(L)1 blockade followed by osimertinib is associated with severe irAE and is most frequent among patients who recently received PD-(L)1 blockade. No irAEs were observed when osimertinib preceded PD-(L)1 blockade or when PD-(L)1 was followed by other EGFR-TKIs. This association appears to be specific to osimertinib, as no severe irAEs occurred with administration of other EGFR-TKIs.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PMID 30847464
Yasuo Oshima, Tetsuya Tanimoto, Koichiro Yuji, Arinobu Tojo
EGFR-TKI-Associated Interstitial Pneumonitis in Nivolumab-Treated Patients With Non-Small Cell Lung Cancer.
JAMA Oncol. 2018 Aug 1;4(8):1112-1115. doi: 10.1001/jamaoncol.2017.4526.
Abstract/Text Importance: Nivolumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now the standard-of-care therapies in non-small cell lung cancer (NSCLC). Although EGFR-TKIs are well understood and have well-defined safety profiles, our experience with immune checkpoint inhibitors is still growing, particularly regarding the use of combinations of different classes of antitumor agents, including both the concomitant and sequential use of such agents.
Objective: To determine whether nivolumab increases EGFR-TKI-associated interstitial pneumonitis (IP).
Design, Setting, and Participants: A database study of 20 516 participants with NSCLC in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, performed between April 2015 and March 2017.
Main Outcomes and Measures: We compared the incidence of EGFR-TKI-associated IP in patients receiving and not receiving nivolumab treatment.
Results: The mean (SD) age of participants treated with EGFR-TKI, with and without nivolumab, was 64.4 (15.5) and 68.9 (11.8) years, respectively, and the proportion of men was 40.0% and 53.8%, respectively. Of the 20 516 participants with NSCLC, 985 cases (4.80%; 95% CI, 4.51-5.10) developed IP. Of 5777 patients treated with EGFR-TKI, 265 developed IP (4.59%; 95% CI, 4.06-5.16). Of 70 patients treated with both EGFR-TKI and nivolumab, 18 developed IP (25.7%; 95% CI, 16.0-37.6). The adjusted odds ratio for an interaction between EGFR-TKI and nivolumab was 4.31 (95% CI, 2.37-7.86; P < .001), suggesting the existence of an interaction. When we further stratified the patients by treatment with and without nivolumab, the odds ratio of EGFR-TKI-associated IP in cases with and without nivolumab treatment was 5.09 (95% CI, 2.87-9.03) and 1.22 (95% CI, 1.00-1.47), respectively.
Conclusions and Relevance: We found a higher proportion of reports of IP for nivolumab in combination with EGFR-TKI vs treatment with either drug alone. Owing to the limitations of this study, the results warrant further confirmation. However, careful consideration should be given to the possibility of an increased risk of IP when EGFR-TKI is administered in combination with nivolumab, including concomitant and sequential use, and careful monitoring for IP is recommended.

PMID 29327061
G R Oxnard, J C-H Yang, H Yu, S-W Kim, H Saka, L Horn, K Goto, Y Ohe, H Mann, K S Thress, M M Frigault, K Vishwanathan, D Ghiorghiu, S S Ramalingam, M-J Ahn
TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.
Ann Oncol. 2020 Apr;31(4):507-516. doi: 10.1016/j.annonc.2020.01.013. Epub 2020 Jan 24.
Abstract/Text BACKGROUND: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody].
PATIENTS AND METHODS: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks).
RESULTS: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively.
CONCLUSION: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated.
CLINICAL TRIALS NUMBER: NCT02143466.

Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.
PMID 32139298
Benjamin C Creelan, Tammie C Yeh, Sang-We Kim, Naoyuki Nogami, Dong-Wan Kim, Laura Q M Chow, Shintaro Kanda, Rosemary Taylor, Weifeng Tang, Mei Tang, Helen K Angell, Martine P Roudier, Marcelo Marotti, Don L Gibbons
A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer.
Br J Cancer. 2021 Jan;124(2):383-390. doi: 10.1038/s41416-020-01099-7. Epub 2020 Oct 5.
Abstract/Text BACKGROUND: EGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advanced EGFRm NSCLC was evaluated.
METHODS: This Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19del EGFRm. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy.
RESULTS: From dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9-80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5-15.2) and median response duration was 9.2 months (95% CI: 3.7-14.0).
CONCLUSIONS: Durvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients with EGFRm NSCLC.

PMID 33012782
Bobbak Vahid, Paul E Marik
Pulmonary complications of novel antineoplastic agents for solid tumors.
Chest. 2008 Feb;133(2):528-38. doi: 10.1378/chest.07-0851.
Abstract/Text Antineoplastic agent-induced pulmonary toxicity is an important cause of respiratory failure. Although the incidence of antineoplastic agent-induced pulmonary toxicity seems to be low, more cases can be expected, with increasing numbers of patients receiving the new generations of antineoplastic agents. Antineoplastic agents have previously been associated with bronchospasm, hypersensitivity reactions, venous thromboembolism, and pulmonary hemorrhage. Physicians should be aware of the clinical and radiographic presentations of the pulmonary toxicities associated with the newer antineoplastic agents. The approach to diagnosis, risk factors, and possible mechanisms of antineoplastic agent-induced pulmonary toxicity are discussed in this article.

PMID 18252919
Xiao Ding, Wei Ji, Junling Li, Xiangru Zhang, Luhua Wang
Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer.
Radiat Oncol. 2011 Mar 6;6:24. doi: 10.1186/1748-717X-6-24. Epub 2011 Mar 6.
Abstract/Text BACKGROUND: Radiation recall pneumonitis (RRP) describes a rare reaction in previously irradiated area of pulmonary tissue after application of triggering agents. RRP remains loosely characterized and poorly understood since it has so far only been depicted in 8 cases in the literature. The objective of the study is to disclose the general characteristics of RRP induced by chemotherapy after thoracic irradiation for lung cancer, and to draw attention to the potential toxicity even after a long time interval from the previous irradiation.
METHODS: Medical records were reviewed. RRP induced by chemotherapy was diagnosed by the history of chemotherapy after radiotherapy, clinical presentation and radiographic abnormalities including ground-glass opacity, attenuation, or consolidation changes within the radiation field, plus that radiographic examination of the thorax before showed no radiation pneumonitis. RRP was graded according to Common Terminology Criteria for Adverse Events version 3.0. The characteristics of the 12 RRP cases were analyzed.
RESULTS: Twelve patients were diagnosed of RRP, of who 8 received taxanes. The median time interval between end of radiotherapy and RRP, between end of radiotherapy and beginning of chemotherapy, and between beginning of chemotherapy and RRP was 95 days, 42 days and 47 days, respectively. Marked symptomatic and radiographic improvement was observed in the 12 patients after withdrawal of chemotherapy and application of systemic corticosteroids. Seven patients were rechallenged with chemotherapy, of whom four with the same kind of agents, and showed no recurrence with steroid cover.
CONCLUSIONS: Doctors should pay attention to RRP even after a long time from the previous radiotherapy or after several cycles of consolidation chemotherapy. Taxanes are likely to be associated with radiation recall more frequently. Withdrawal of causative agent and application of steroids are the treatment of choice. Patients may be rechallenged safely with steroid cover and careful observation, which needs to be validated.

PMID 21375774
Vyshak A Venur, Manmeet S Ahluwalia
Targeted Therapy in Brain Metastases: Ready for Primetime?
Am Soc Clin Oncol Educ Book. 2016;35:e123-30. doi: 10.1200/EDBK_100006.
Abstract/Text Brain metastasis is a serious complication of cancer that causes significant morbidity for patients. Over the last decade, numerous new driver somatic mutations have been recognized and targeted therapies are changing the landscape of treatment in lung cancer, breast cancer, and melanoma, which are also the three most common cancers that result in brain metastases. The common actionable mutations include the EGFR mutation and anaplastic lymphoma kinase (ALK) translocations in non-small cell lung cancer, the HER2 mutation in breast cancer, and the BRAF mutation in melanoma. However, most of the early trials with targeted agents excluded patients with brain metastases. With a better understanding of the biology, several recent trials of targeted therapy that focus on brain metastases have been reported and others are ongoing. Novel agents with better penetration across the blood-brain barrier are currently being investigated for patients with brain metastases. In this review, we discuss the current state of use and future directions of targeted therapies in brain metastases.

PMID 27249714
Todd M Bauer, Alice T Shaw, Melissa L Johnson, Alejandro Navarro, Justin F Gainor, Holger Thurm, Yazdi K Pithavala, Antonello Abbattista, Gerson Peltz, Enriqueta Felip
Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer.
Target Oncol. 2020 Feb;15(1):55-65. doi: 10.1007/s11523-020-00702-4.
Abstract/Text BACKGROUND: Lorlatinib is a potent, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) designed to penetrate the blood-brain barrier.
OBJECTIVE: We report the cumulative incidence of central nervous system (CNS) and non-CNS progression with lorlatinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) previously treated with ALK TKIs.
PATIENTS AND METHODS: In an ongoing phase II study (NCT01970865), 198 patients with ALK-positive NSCLC with ≥ 1 prior ALK TKI were enrolled into expansion cohorts (EXP) based on treatment history. Patients received lorlatinib 100 mg once daily. Patients were analyzed for progressive disease, categorized as CNS or non-CNS progression, by independent central review. Cumulative incidence probabilities were calculated adopting a competing risks approach.
RESULTS: Fifty-nine patients received crizotinib as their only prior ALK TKI (EXP2-3A); cumulative incidence rates (CIRs) of CNS and non-CNS progression were both 22% at 12 months in patients with baseline CNS metastases (n = 37), and CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients without baseline CNS metastases [43% vs. 9% (n = 22)]. In patients who received ≥ 1 prior second-generation ALK TKI [EXP3B-5 (n = 139)], CIR of non-CNS progression at 12 months was higher versus that for CNS progression in patients both with and without baseline CNS metastases (35% vs. 23% (n = 94) and 55% vs. 12% (n = 45), respectively).
CONCLUSIONS: Lorlatinib showed substantial intracranial activity in patients with pretreated ALK-positive NSCLC, with or without baseline CNS metastases, whose disease progressed on crizotinib or second-generation ALK TKIs. CLINICALTRIALS.
GOV IDENTIFIER: NCT01970865.

PMID 32060867
C Dodson, T J Richards, D A Smith, N H Ramaiya
Tyrosine Kinase Inhibitor Therapy for Brain Metastases in Non-Small-Cell Lung Cancer: A Primer for Radiologists.
AJNR Am J Neuroradiol. 2020 May;41(5):738-750. doi: 10.3174/ajnr.A6477. Epub 2020 Mar 26.
Abstract/Text Treatment options for patients who develop brain metastases secondary to non-small-cell lung cancer have rapidly expanded in recent years. As a key adjunct to surgical and radiation therapy options, systemic therapies are now a critical component of the oncologic management of metastatic CNS disease in many patients with non-small-cell lung cancer. The aim of this review article was to provide a guide for radiologists, outlining the role of systemic therapies in metastatic non-small-cell lung cancer, with a focus on tyrosine kinase inhibitors. The critical role of the blood-brain barrier in the development of systemic therapies will be described. The final sections of this review will provide an overview of current imaging-based guidelines for therapy response. The utility of the Response Assessment in Neuro-Oncology criteria will be discussed, with a focus on how to use the response criteria in the assessment of patients treated with systemic and traditional therapies.

© 2020 by American Journal of Neuroradiology.
PMID 32217548
Patrick G Morris, Anne S Reiner, Olga Rosenvald Szenberg, Jennifer L Clarke, Katherine S Panageas, Hector R Perez, Mark G Kris, Timothy A Chan, Lisa M DeAngelis, Antonio M Omuro
Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy.
J Thorac Oncol. 2012 Feb;7(2):382-5. doi: 10.1097/JTO.0b013e3182398e4f.
Abstract/Text INTRODUCTION: Leptomeningeal metastasis (LM), or leptomeningeal carcinomatosis, is a devastating complication of non-small cell lung cancer (NSCLC), and the optimal therapeutic approach remains challenging. A retrospective review was carried out to assess the impact of whole brain radiotherapy (WBRT), intrathecal therapy (IT), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on outcomes.
METHODS: Patients with newly diagnosed LM from NSCLC from January 2002 to December 2009 were identified through institutional databases and medical records reviewed. Survival was assessed by Kaplan-Meier and landmark analyses by administered treatment to minimize selection bias.
RESULTS: We identified 125 patients (45 men, 80 women) with LM from NSCLC, median age 59 years (range, 28-87 years). Almost all (123 [98%]) patients have died and median overall survival was 3.0 months (95% confidence interval, 2.0-4.0). No differences in survival were seen between patients who were treated with WBRT (n =46) and those who were not (n =59, p =0.84) in a landmark analysis. In the seven patients selected to receive IT chemotherapy, median survival was 18 months (range, 5-33 months) and appeared superior to those not selected for this treatment (p =0.001) in a landmark analysis. The median survival of the nine patients with known EGFR mutations (all of whom received TKIs at some point) was 14 months (range, 1-28 months).
CONCLUSIONS: This retrospective study, the largest published series, demonstrates the poor survival of LM from NSCLC. In this study, survival was not improved by WBRT. The survival of patients selected for IT chemotherapy and those with EGFR mutations treated with TKIs highlights the importance of developing novel agents.

PMID 22089116
Pengyu Kong, Jinglong Yan, Donghui Liu, Ye Ji, Yufu Wang, Jinpeng Zhuang, Jincai Wang, Xiaowei Hu, Xiaolong Yue
Skeletal-related events and overall survival of patients with bone metastasis from nonsmall cell lung cancer - A retrospective analysis.
Medicine (Baltimore). 2017 Dec;96(51):e9327. doi: 10.1097/MD.0000000000009327.
Abstract/Text Because of improving treatments and survival, 40% to 58% of patients with bone metastases from nonsmall cell lung cancer (NSCLC) will suffer from at least one skeletal-related event (SRE), affecting their quality of life, but the natural history of SRE is poorly understood. The study aimed to examine the factors involved in SRE-free survival (SRS) and overall survival (OS) of patients with NSCLC and bone metastases.This was a retrospective study of 211 patients with bone metastasis from NSCLC and treated at the Tumor Hospital Affiliated to Harbin Medical University between January 2007 and January 2012. OS and SRS were evaluated by the Kaplan-Meier method. The factors associated with SRS and OS were examined using multivariate Cox analyses.The 1 year OS was 55.9% and the median OS was 30 months (range, 1-98 months). Multivariate analyses showed that clinical staging at initial diagnosis (P < .001) and SRE (P = .033) were independently associated with OS, and clinical staging at initial diagnosis (P = .009), bone pain (P = .008), primary tumor radiotherapy (P < .001), and chemotherapy (P = .031) were independently associated with SRS. Stage I, II, and III patients under biphosphonate therapy fared better than those without biphosphonate treatment, but there was no difference for stage IV patients.The identification of factors associated with OS and SRS of patients with NSCLC and bone metastases should provide new clues for a better management of these patients.

Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
PMID 29390509
Go Saito, Takahiro Ebata, Tsukasa Ishiwata, Shunichiro Iwasawa, Ichiro Yoshino, Yuichi Takiguchi, Koichiro Tatsumi
Risk factors for skeletal-related events in non-small cell lung cancer patients treated with bone-modifying agents.
Support Care Cancer. 2021 Jul;29(7):4081-4088. doi: 10.1007/s00520-020-05880-5. Epub 2021 Jan 6.
Abstract/Text PURPOSE: The risk factors for skeletal-related events (SREs) among non-small cell lung cancer (NSCLC) patients during treatment with bone-modifying agents (BMAs) are not yet well-understood.
METHODS: The medical records of 238 consecutive NSCLC patients treated with BMAs, including zoledronic acid and denosumab, at the Chiba University Hospital from 2012 to 2016 were reviewed in the present study. SREs were defined as either pathologic fractures, spinal cord compression, the need for bone irradiation or surgery, or hypercalcemia. The risk factors for earlier occurrence of the first SRE from the time of the first bone metastasis diagnosis after the initiation of BMA treatment were identified.
RESULTS: Of the 238 included patients, 92% (n = 220) had a performance status (PS) of 0-2 at diagnosis of bone metastasis. Forty-eight (20%) patients developed at least one SRE. The most common first SRE was the need for bone irradiation surgery (n = 27, 56%). Significant risk factors included poor PS (hazard ratio [HR]: 4.36; p = .024), male sex (HR: 2.17; p = .022), and the use of zoledronic acid (HR: 1.91; p = .032). The overall survival (OS) from the first bone metastasis diagnosis was 394 days (95% confidence interval [CI]: 331-465). The OS of patients with PS 3 and 4 at the diagnosis of bone metastasis (median: 36 days; 95% CI: 13-50) was significantly (p < 0.0001) shorter than that of patients with PS 0-2 (median: 411 days; 95% CI: 354-558) (HR: 4.53; 95% CI: 2.62-7.35).
CONCLUSIONS: Careful observation is needed for patients with the identified risk factors, which include poor PS and male sex, despite the BMA treatment.

PMID 33404803
Xiao-Tian Wu, Jian-Wei Zhou, Long-Ci Pan, Ting Ge
Clinical features and prognostic factors in patients with bone metastases from non-small cell lung cancer.
J Int Med Res. 2020 May;48(5):300060520925644. doi: 10.1177/0300060520925644.
Abstract/Text OBJECTIVE: To investigate the clinical features and evaluate the prognostic factors in patients with bone metastases from non-small cell lung cancer (NSCLC).
METHODS: We retrospectively investigated 356 patients with NSCLC with bone metastases from January 2012 to December 2017. The overall survival (OS) and 1-year survival rate were calculated by Kaplan-Meier analysis and compared by univariate analysis using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model.
RESULTS: A total of 694 sites of bone metastases were determined among the 356 patients. The most common site of bone metastases was the ribs. The median OS was 12.5 months and the 1-year survival was 50.8% in the overall population. Univariate analysis revealed that histological type, number of bone metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), bisphosphonate therapy, and serum calcium, lactate dehydrogenase, and alkaline phosphatase were significantly correlated with prognosis. Multivariate analysis identified multiple bone metastases, ECOG PS ≥2, lactate dehydrogenase ≥225 U/L, and alkaline phosphatase ≥140 U/L as independent negative prognostic factors.
CONCLUSION: Multiple bone metastases, high ECOG PS, and high serum alkaline phosphatase and lactate dehydrogenase are independent negative prognostic factors for bone metastases from NSCLC.

PMID 32425092
Miguel Martin, Richard Bell, Hugues Bourgeois, Adam Brufsky, Ingo Diel, Alexandru Eniu, Lesley Fallowfield, Yasuhiro Fujiwara, Jacek Jassem, Alexander H G Paterson, Diana Ritchie, Günther G Steger, Alison Stopeck, Charles Vogel, Michelle Fan, Qi Jiang, Karen Chung, Roger Dansey, Ada Braun
Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid.
Clin Cancer Res. 2012 Sep 1;18(17):4841-9. doi: 10.1158/1078-0432.CCR-11-3310. Epub 2012 Aug 14.
Abstract/Text PURPOSE: Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL).
EXPERIMENTAL DESIGN: Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy-general).
RESULTS: Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59-0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70-0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels.
CONCLUSIONS: Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer.

©2012 AACR.
PMID 22893628
Julian Downward
Targeting RAS and PI3K in lung cancer.
Nat Med. 2008 Dec;14(12):1315-6. doi: 10.1038/nm1208-1315.
Abstract/Text
PMID 19057554
Xin Yan, Xuan Tian, Zhiqiang Wu, Weidong Han
Impact of Age on the Efficacy of Immune Checkpoint Inhibitor-Based Combination Therapy for Non-small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.
Front Oncol. 2020;10:1671. doi: 10.3389/fonc.2020.01671. Epub 2020 Sep 23.
Abstract/Text Background: Despite the acknowledged benefits of immune checkpoint inhibitor (ICI)-based combination therapy (either with other checkpoint inhibitors, chemotherapy, targeted therapy, or radiotherapy), little is known about the impact of age on the efficacy of ICI -based combination therapy in non-small-cell lung cancer (NSCLC) patients. We conducted a systematic review and meta-analysis to investigate the differences in the benefits of ICI-based combination therapy for NSCLC by age (cut-off age, 65 years). Methods: We systematically searched randomized controlled trials (RCTs) of ICI plus other therapies including other ICIs, chemotherapies, targeted therapies, or radiotherapies, in the PubMed, Embase, and Cochrane databases with available hazard ratios (HRs) and 95% confidence intervals (CIs) for death and disease progression according to patient age. The search deadline was May 25, 2020. First, we calculated the pooled HRs of younger and older patients based on the HRs from each trial. Second, we assessed the pooled ratio of HRs reported in older patients to the HRs reported in younger patients for progression or death by the random-effects model. An estimated pooled HR ratio was lower than 1 indicating a better effect in older patients and higher than 1 indicating a better effect in younger patients. Results: A total of 10 eligible RCTs were included in our meta-analysis. The pooled HR for overall survival (OS) comparing ICI combined with other therapies to non-ICI regimens was 0.67 (95%CI 0.58-0.78) for younger patients and 0.79 (95%CI 0.70-0.90) for older patients. The pooled HRs ratio for OS reported in older patients compared to younger patients was 1.16 (95%CI 0.99-1.34), indicating no statistically significant difference between younger and older patients. Consistent with the findings related to OS, the analysis also demonstrated that ICI-based immunotherapy could significantly prolong progression-free survival (PFS) in younger and older patients (HR = 0.55; 95% CI 0.47-0.66, and HR = 0.64; 95% CI 0.57-0.71). The same results could also be observed in the pooled HRs ratio for PFS (HR = 1.15, 95%CI 0.91-1.46) indicating comparable efficacy of ICI-based combination therapy in younger and older patients with NSCLC. Conclusion: ICI-based combination therapy vs. non-ICI treatment had comparable efficacy in younger and older NSCLC patients with a cut-off age of 65 years.

Copyright © 2020 Yan, Tian, Wu and Han.
PMID 33072551

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから