Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery

Joe Y Chang, Reza J Mehran, Lei Feng, Vivek Verma, Zhongxing Liao, James W Welsh, Steven H Lin, Michael S O'Reilly, Melenda D Jeter, Peter A Balter, Stephen E McRae, Donald Berry, John V Heymach, Jack A Roth, STARS Lung Cancer Trials Group, Mara Antonoff, Wayne Hofstetter, Ravi Rajaram, David Rice, Boris Sepesi, Stephen Swisher, Ara Vaporciyan, Garrett Walsh, Craig DeGraaf, Arlene Correa, Aileen Chen, Saumil Gandhi, Ritsuko Komaki, Percy Lee, Quynh-Nhu Nguyen, Matthew Ning, Song Gao, Julianne Pollard-Larkin, Paige Nitsch, Ramaswamy Sadagopan, Xiaochun Wang, Joe Y Chang, Reza J Mehran, Lei Feng, Vivek Verma, Zhongxing Liao, James W Welsh, Steven H Lin, Michael S O'Reilly, Melenda D Jeter, Peter A Balter, Stephen E McRae, Donald Berry, John V Heymach, Jack A Roth, STARS Lung Cancer Trials Group, Mara Antonoff, Wayne Hofstetter, Ravi Rajaram, David Rice, Boris Sepesi, Stephen Swisher, Ara Vaporciyan, Garrett Walsh, Craig DeGraaf, Arlene Correa, Aileen Chen, Saumil Gandhi, Ritsuko Komaki, Percy Lee, Quynh-Nhu Nguyen, Matthew Ning, Song Gao, Julianne Pollard-Larkin, Paige Nitsch, Ramaswamy Sadagopan, Xiaochun Wang

Abstract

Background: A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND).

Methods: This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0-2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov, NCT02357992.

Findings: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87% (79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84% (76-93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable analysis.

Interpretation: Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended.

Funding: Varian Medical Systems and US National Cancer Institute (National Institutes of Health).

Conflict of interest statement

Declaration of interests JYC reports grants from Varian Medical Systems and Bristol Myers Squibb; consulting fees from AstraZeneca and Legion Healthcare Partner; honoraria from Varian Medical Systems; is a shareholder of Global Oncology One; and is chair of the American Radium Society Thoracic Appropriate Use Criteria Committee and Proton Therapy Co-operative Group Thoracic Committee. RJM reports grants from Genprex. JWW reports research funding from Artidis, Alkermes, Checkmate Pharmaceuticals, GlaxoSmithKline, Mavu Pharma, Nanobiotix, RefleXion, Bristol Myers Squibb, and Takeda; clinical trial sponsored research from Varian Medical Systems, Merck, Bristol Myers Squibb, China Medical Tribune, and RefleXion; patents or royalties from MolecularMatch; leadership roles in Healios, MolecularMatch; speakers' bureau for Roche-Ventana and US Oncology; consulting or advisory roles for Alpine Immune Sciences, Artidis, AstraZeneca, Checkmate Pharmaceuticals, GI Innovation, Genentech, Incyte, Mavu Pharma, Legion Healthcare Partners, MolecularMatch, Nanobiotix, Nanorobotix, OncoResponse, RefleXion, China Medical Tribune, Merck, Aileron Therapeutics, and Roche-Ventana; stock or ownership in Checkmate Pharmaceuticals, Welsh DV8, Healios, Mavu Pharma, Legion Healthcare Partners, MolecularMatch, Nanorobotix, OncoResponse, and RefleXion; and honoraria from Welsh DV8, Nanobiotix, OncoResponse, RefleXion, Korean Society of Radiology, Varian Medical Systems, Aileron Therapeutics, and Roche-Ventana. SHL reports grants from Beyond Spring Pharmaceuticals, IntraOp, STCube Pharmaceuticals, and Nektar Therapeutics; consulting fees from XRAD Therapeutics; and advisory board membership for AstraZeneca, Beyond Spring Pharmaceuticals, and STCube Pharmaceuticals.PAB reports grants from Varian Medical Systems and Raysearch Laboratories. DB reports being co-owner of Berry Consultants. JVH reports grants from AstraZeneca, GlaxoSmithKline, and Spectrum; royalties or licenses from Spectrum; consulting fees from AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda, Mirati Therapeutics, Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche, and Leads Biolabs; and honoraria from PeerView, MJH Events, and Nexus Oncology. JAR reports grants from Varian Medical Systems; consulting fees, patents, stock options, and advisory board membership for Genprex; and advisory board membership for the VALOR trial. All other authors declare no competing interests.