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. 2024 Mar 1;10(3):352-359.
doi: 10.1001/jamaoncol.2023.6033.

Accelerated Hypofractionated Chemoradiation Followed by Stereotactic Ablative Radiotherapy Boost for Locally Advanced, Unresectable Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial

Trudy C Wu  1 , Elaine Luterstein  2 , Beth K Neilsen  1 , Jonathan W Goldman  3 , Edward B Garon  3 , Jay M Lee  4 , Carol Felix  1 , Minsong Cao  1 , Stephen E Tenn  1 , Daniel A Low  1 , Patrick A Kupelian  5 , Michael L Steinberg  1 , Percy Lee  1   6
Affiliations

Accelerated Hypofractionated Chemoradiation Followed by Stereotactic Ablative Radiotherapy Boost for Locally Advanced, Unresectable Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial

Trudy C Wu et al. JAMA Oncol. .

Abstract

Importance: Intrathoracic progression remains the predominant pattern of failure in patients treated with concurrent chemoradiation followed by a consolidation immune checkpoint inhibitor for locally advanced, unresectable non-small cell lung cancer (NSCLC).

Objective: To determine the maximum tolerated dose (MTD) and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy (SABR) boost.

Design, setting, and participants: This was an early-phase, single-institution, radiation dose-escalation nonrandomized controlled trial with concurrent chemotherapy among patients with clinical stage II (inoperable/patient refusal of surgery) or III NSCLC (American Joint Committee on Cancer Staging Manual, seventh edition). Patients were enrolled and treated from May 2011 to May 2018, with a median patient follow-up of 18.2 months. Patients advanced to a higher SABR boost dose if dose-limiting toxic effects (any grade 3 or higher pulmonary, gastrointestinal, or cardiac toxic effects, or any nonhematologic grade 4 or higher toxic effects) occurred in fewer than 33% of the boost cohort within 90 days of follow-up. The current analyses were conducted from January to September 2023.

Intervention: All patients first received 4 Gy × 10 fractions followed by an adaptive SABR boost to residual metabolically active disease, consisting of an additional 25 Gy (low, 5 Gy × 5 fractions), 30 Gy (intermediate, 6 Gy × 5 fractions), or 35 Gy (high, 7 Gy × 5 fractions) with concurrent weekly carboplatin/paclitaxel.

Main outcome and measure: The primary outcome was to determine the MTD.

Results: Data from 28 patients (median [range] age, 70 [51-88] years; 16 [57%] male; 24 [86%] with stage III disease) enrolled across the low- (n = 10), intermediate- (n = 9), and high- (n = 9) dose cohorts were evaluated. The protocol-specified MTD was not exceeded. The incidences of nonhematologic acute and late (>90 days) grade 3 or higher toxic effects were 11% and 7%, respectively. No grade 3 toxic effects were observed in the intermediate-dose boost cohort. Two deaths occurred in the high-dose cohort. Two-year local control was 74.1%, 85.7%, and 100.0% for the low-, intermediate-, and high-dose cohorts, respectively. Two-year overall survival was 30.0%, 76.2%, and 55.6% for the low-, intermediate-, and high-dose cohorts, respectively.

Conclusions and relevance: This early-phase, dose-escalation nonrandomized controlled trial showed that concurrent chemoradiation with an adaptive SABR boost to 70 Gy in 15 fractions with concurrent chemotherapy is a safe and effective regimen for patients with locally advanced, unresectable NSCLC.

Trial registration: ClinicalTrials.gov Identifier: NCT01345851.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Goldman reported grants from AstraZeneca and Merck and personal fees from AstraZeneca outside the submitted work. Dr Garon reported personal fees from AbbVie, ABL Bio, Arcus, AstraZeneca, Atreca, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Seagen, Sensei, Summit, Synthekine, Xilio, and Zymeworks; grants from ABL Bio, ArriVent, AstraZeneca, Bristol Myers Squibb, Daiichi Sanyko, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, Novartis, Regeneron, and Synthekine; sponsored independent medical education from Daiichi Sankyo and Ipsen; and travel fees from A2 Bio and Novartis outside the submitted work. Dr J. Lee reported serving on the advisory board for or as consultant with AstraZeneca, Bristol Myers Squibb, Foundation Medicine Institute, Genentech, IDEOlogy Health, Merck, Novartis, Regeneron Pharmaceuticals, and Roche; research support from Bristol Myers Squibb, Genentech, Novartis, and Roche; serving on the steering committees for Genentech and Novartis; serving in the speaker’s bureau for AstraZeneca, Bristol Myers Squibb, DAVA Oncology, ecancer, Genentech, Medscape, Roche, and Targeted Oncology; stock in Moderna; and patents through the University of California, Los Angeles. Dr Cao reported grants from Varian Medical System and personal fees from Varian Medical System and ViewRay outside the submitted work. Dr Low reported grants from Varian, personal fees from ViewRay and TAE Life Sciences, serving as a founder of Pulmonum LLC, and stock in Triplet State outside the submitted work. Dr Kupelian reported employment with Varian during the conduct of the study. Dr Steinberg reported personal fees from Viewray outside the submitted work. Dr P. Lee reported personal fees from AstraZeneca, Genentech, and Roche, as well as nonfinancial support from Varian and Viewray outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Flow Diagram
4DCT indicates 4-dimensional computed tomography; FDG-PET/CT, 18F-fludeoxyglucose–positron emission tomography/computed tomography; NSCLC, non–small cell lung cancer; RT, radiotherapy.
Figure 2.
Figure 2.. Toxic Effects Stratified by Boost Cohort
Int indicates intermediate.
Figure 3.
Figure 3.. Kaplan-Meier Curves Stratified by Boost Cohort
Int indicates intermediate; RT, radiotherapy.
See this image and copyright information in PMC

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