Accepted Manuscript. Adjuvant Chemotherapy in Stage I Lung Cancer: Is More Better? Chuong D. Hoang, MD

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1 Accepted Manuscript Adjuvant Chemotherapy in Stage I Lung Cancer: Is More Better? Chuong D. Hoang, MD PII: S (18)31821-X DOI: /j.jtcvs Reference: YMTC To appear in: The Journal of Thoracic and Cardiovascular Surgery Received Date: 26 June 2018 Revised Date: 26 June 2018 Accepted Date: 27 June 2018 Please cite this article as: Hoang CD, Adjuvant Chemotherapy in Stage I Lung Cancer: Is More Better?, The Journal of Thoracic and Cardiovascular Surgery (2018), doi: /j.jtcvs This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 JTCVS R3 Adjuvant Chemotherapy in Stage I Lung Cancer: Is More Better? Chuong D. Hoang, MD Section of Thoracic Surgery National Cancer Institute - NIH CCR and The Clinical Center 10 Center Drive Mail code 1201, Room , Bethesda, MD (desk) (fax) chuong.hoang@nih.gov Conflict of Interests: None Contact: Same as above Central Message: Indications for adjuvant chemotherapy in resected lung cancer may evolve with ongoing refinements in the TNM staging system, particularly with greater appreciation of high-risk tumor features.

3 With the new 8 th edition TNM staging system for non-small cell lung cancer (NSCLC), there is better stratification, particularly in early stages based on objective analyses revealing distinct survival differences according to tumor size in increments of 1 cm (up to 5 cm). Now, an opportunity exists to re-examine standard-of-care practices for NSCLC based on new definitions of TNM stage. Despite resection of NSCLC, the 5-year overall survival (OS) varies from 90% in patients with pathologic stage IA1 to 41% in those with stage IIIA (1). The majority of NSCLC patients are offered adjuvant chemotherapy based on phase III trials (reported 2003 to 2006) that, when meta-analyzed in 2008, demonstrated survival benefit for patients with stage II to IIIA and a likely detrimental effect in patients with stage IA (Lung Adjuvant Cisplatin Evaluation - LACE) (2). The clinical approach to stage IB remains controversial because of confounding results. The mature reporting of CALGB 9633, the only randomized trial specifically investigating adjuvant chemotherapy in stage IB patients, indicated no OS benefit (3). However, an updated meta-analysis of over 4500 patients pooled from 16 trials with resected stage IB showed that adjuvant chemotherapy associated with a significant OS improvement (HR = 0.74, 95% CI: ) (4). The benefit was realized mostly in those patients receiving uracil and tegafur (not FDA-approved for use in USA), whereas there was no benefit associated with platinum-based chemotherapy. Lastly, a recent multivariate analysis of the National Cancer Data Base (2004 to 2011) revealed improved median and 5-year OS in patients with resected NSCLC tumors 3.1 to 3.9 cm, among other sizes comprising T2 (7 th edition TNM), who received adjuvant chemotherapy (HR = 0.77, 95% CI: , p < 0.001) (5). Following this modern trend suggesting that adjuvant chemotherapy may be beneficial in smaller NSCLC tumors, Wang and colleagues [ ] in this issue of the Journal explore the intriguing notion of adjuvant chemotherapy in the subgroup of resected NSCLC patients stage IA1-IA3 and IB stratified by lymphovascular invasion (LVI) status of the primary tumor. Their unique multidisciplinary, locoregional practice allowed adjuvant chemotherapy in stage I patients, contrary to guidelines established by LACE. Certainly, the improved recurrence-free survival and OS rates in all stage I subgroups with LVI, as reported here, will inspire other similar investigations. Thus, this study reopens the discussion on indications for adjuvant chemotherapy in resected NSCLC as well as informs about the design options of prospective trials in this area.

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