Vera P, Thureau S, Le Tinier F, Chaumet-Riffaud P, Hapdey S, Kolesnikov-Gauthier H, Martin E, Berriolo-Riedinger A, Pourel N, Broglia JM, Boissellier P, Guillemard S, Salem N, Brenot-Rossi I, Le Péchoux C, Berthold C, Giroux-Leprieur E, Moreau D, Guillerm S, Benali K, Tessonnier L, Audigier-Valette C, Lerouge D, Quak E, Massabeau C, Courbon F, Moisson P, Larrouy A, Modzelewski R, Gouel P, Ghazzar N, Langlais A, Amour E, Zalcman G, and Giraud P
Background: Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [ 18 F]fluorodeoxyglucose ([ 18 F]FDG)-PET results., Methods: In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [ 18 F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m 2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m 2 intravenously once every 3 weeks and vinorelbine 30 mg/m 2 intravenously on day 1 and 60 mg/m 2 orally [or 30 mg/m 2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m 2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m 2 intravenously and vinorelbine 20 mg/m 2 intravenously on day 1 and 40 mg/m 2 orally (or 20 mg/m 2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing., Findings: From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [ 18 F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment)., Interpretation: A thoracic radiotherapy boost, based on interim [ 18 F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [ 18 F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC., Funding: Programme Hospitalier de Recherche Clinique National 2014., Competing Interests: Declaration of interests EM declared payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Varian Medical Systems, AstraZeneca, MSD, Janssen, and Sanofi; support for attending meetings or travel, or both, from Ipsen, Janssen, and AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca and Janssen. IB-R declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis 3A and Curium; payment for expert testimony from Curium; and support for attending meetings or travel, or both, from Novartis 3A. CLP declares payment or honoraria to her institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca and Amgen; support for attending meetings or travel, or both, paid to her institution from Janssen and Roche; and participation on a data safety monitoring board or advisory board paid to her institution for AstraZeneca, Varian, MSD, and Roche. EG-L declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, and Takeda; and support for attending meetings or travel, or both, from Takeda, MSD, AstraZeneca, and Roche. CA-V declares support for attending meetings or travel, or both, from Roche, Sanofi, MSD, BMS, Lilly, Pfizer, AstraZeneca, Janssen, and Abbvie; and participation on a data safety monitoring board or advisory board for Roche, Sanofi, MSD, BMS, Lilly, Pfizer, AstraZeneca, Janssen, and Abbvie. ALan and EA are employees of the French Intergroup (Intergroupe Francophone de Cancérologie Thoracique). GZ declares consulting fees paid to his institution from AstraZeneca, BMS, Takeda, and Roche; payment or honoraria to his institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Inventiva, BMS, and Pfizer; support for attending meetings or travel, or both, from Roche, BMS, Abbvie, Pfizer, and AstraZeneca; and receipt of equipment, materials, drugs, medical writing, gifts, or other services to his institution by Foundation Roche. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. 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