title: Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by18F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).
abstract: See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant18F-misonidazole (18F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC).Methods:Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In18F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-β = 0.95).Results:Seventy-nine patients were preincluded, 54 were included, and 34 were18F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the18F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the18F-FMISO-negative patients (P= 0.004). The radiotherapy dose was not associated with DFS when adjusting for the18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported.Conclusion:Our approach results in a response rate of 40% or more, with acceptable toxicity.18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF-LITIS, University of Rouen, Rouen, France pierre.vera@chb.unicancer.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vera
authors.affiliation: Department of Radiation Oncology and Medical Physics, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF-LITIS, Rouen, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Thureau
authors.affiliation: Department of Nuclear Medicine, Hôpitaux universitaires Paris Sud Bicêtre AP-HP and University Paris Sud, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chaumet-Riffaud
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF-LITIS, University of Rouen, Rouen, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Modzelewski
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF-LITIS, University of Rouen, Rouen, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohn
authors.affiliation: University Lille, Inserm, CHU Lille, U1189-ONCO-THAI-Image Assisted Laser Therapy for Oncology, Lille, France.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Vermandel
authors.affiliation: Department of Nuclear Medicine, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF-LITIS, University of Rouen, Rouen, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hapdey
authors.affiliation: Department of Nuclear Medicine, Nantes University Hospital, Nantes, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Pallardy
authors.affiliation: Department of Radiation Oncology, Institut de Cancérologie de l'Ouest (ICO)-René Gauducheau, Nantes, France.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Mahé
authors.affiliation: Department of Nuclear Medicine, Institut de Cancérologie de l'Ouest (ICO), Nantes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lacombe
authors.affiliation: Department of Radiation Oncology, Institut régional du Cancer Montpellier (ICM), Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boisselier
authors.affiliation: Department of Nuclear Medicine, Institut régional du Cancer Montpellier (ICM), Montpellier, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Guillemard
authors.affiliation: Department of Nuclear Medicine, Brabois University Hospital, Nancy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Olivier
authors.affiliation: Department of Radiation Oncology, Institut de Cancérologie de Lorraine, Nancy, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Beckendorf
authors.affiliation: Department of Radiation Oncology, Institut Paoli Calmette, Marseille, France.
authors.forename: Naji
authors.initials: N
authors.lastname: Salem
authors.affiliation: Department of Nuclear Medicine, Institut Paoli Calmette, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charrier
authors.affiliation: Department of Radiation Oncology, Centre regional de lutte contre le cancer de Bretagne Eugène Marquis, Rennes, France.
authors.forename: Enrique
authors.initials: E
authors.lastname: Chajon
authors.affiliation: Department of Nuclear Medicine, Centre regional de lutte contre le cancer de Bretagne Eugène Marquis, Rennes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Devillers
authors.affiliation: Nicolas Aide, Nuclear Medicine and TEP Centre, Caen University Hospital and Inserm U1086 ANTICIPE, Caen, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Aide
authors.affiliation: Department of Radiation Oncology, François Baclesse Cancer Center, Caen, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Danhier
authors.affiliation: Department of Radiation Oncology, Institut Inter-Régional de Cancérologie (ILC), Centre Jean Bernard/Clinique Victor Hugo, Le Mans, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Denis
authors.affiliation: Department of Nuclear Medicine, Institut Inter-Régional de Cancérologie (ILC), Centre Jean Bernard/Clinique Victor Hugo, Le Mans, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Muratet
authors.affiliation: Radiation Oncology, Centre Georges-Francois Leclerc, Dijon, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Martin
authors.affiliation: Department of Nuclear Medicine, Centre Georges Francois Leclerc, Dijon, France.
authors.forename: Alina Berriolo
authors.initials: AB
authors.lastname: Riedinger
authors.affiliation: Department of Nuclear Medicine, Oscar Lambret Center, Lille cedex, France.
authors.forename: Helène
authors.initials: H
authors.lastname: Kolesnikov-Gauthier
authors.affiliation: Department of Radiation Oncology, Oscar Lambret Center, Lille cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Dansin
authors.affiliation: Département de Radiothérapie. Institut Universitaire du Cancer, Toulouse cedex 9, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Massabeau
authors.affiliation: Department of Nuclear Medicine, Institut Claudius Regaud, IUCT, Toulouse cedex 9, France.
authors.forename: Fredéric
authors.initials: F
authors.lastname: Courbon
authors.affiliation: Department of Radiation Oncology, CHU de Nîmes, Institut de cancérologie du Gard, Rue Henri Pujol, Nîmes, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Farcy Jacquet
authors.affiliation: Department of Nuclear Medicine, Institut régional du Cancer Montpellier (ICM), Montpellier, France.|Department of Nuclear Medicine, CHU de Nîmes, Institut de cancérologie du Gard, Nîmes, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Kotzki
authors.affiliation: Department of Nuclear Medicine, Hospices Civils de Lyon, Lyon, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Houzard
authors.affiliation: Department of Radiation Oncology, Hospices Civils de Lyon, Lyon, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Mornex
authors.affiliation: Department of Nuclear Medicine, CHU Angers, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vervueren
authors.affiliation: Department of Radiation Oncology, Institut de Cancérologie de l'Ouest, site Paul Papin, France.
authors.forename: Amaury
authors.initials: A
authors.lastname: Paumier
authors.affiliation: Department of Nuclear Medicine, Hôpital Pellegrin, CHU de Bordeaux, France; and.
authors.forename: Philippe
authors.initials: P
authors.lastname: Fernandez
authors.affiliation: Normandy University, UNIROUEN, QuantIF-LITIS EA 4108, Rouen University Hospital, Department of Pulmonology-Thoracic Oncology-Respiratory Intensive Care, Rouen, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Salaun
authors.affiliation: Department of Radiation Oncology and Medical Physics, Henri Becquerel Cancer Center and Rouen University Hospital & QuantIF-LITIS, Rouen, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Dubray
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy*; D019583:Dose Fractionation, Radiation; D005260:Female; D005602:France; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015588:Observer Variation; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D015996:Survival Rate; D016896:Treatment Outcome; D000072258:Tumor Hypoxia / Q000528:radiation effects
chemical_list: D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D008920:Misonidazole
keywords: f-misonidasole; fluoro-deoxy-D-glucose; hypoxia; lung cancer; positron emission tomography; radiotherapy dose