A randomized controlled phase III study comparing hadrontherapy with carbon ions versus conventional radiotherapy – including photon and proton therapy – for the treatment of radioresistant tumors: the ETOILE trial

Abstract

Background Some cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy. Methods The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas. In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France. The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted. To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study. Discussion So far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors. Trial registration ClinicalTrials.gov identifier: NCT02838602. Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.

Chondrosarcoma Resistance to Radiation Therapy: Origins and Potential Therapeutic Solutions

“…Indeed, there are only two randomized trials currently recruiting patients. The first one, the French ETOILE trial (NCT02838602) [ 113 ], aims to compare the best radiotherapy, at the investigator site (IMRT or ideally proton therapy), with carbon therapy, delivered at CNAO. Poor prognosis, inoperable, or macroscopically incompletely resected (R2) radioresistant cancers, including chondrosarcoma ≥ grade II, are eligible, though skull base chondrosarcomas are excluded.…”

The rationale for a carbon ion radiation therapy facility in Australia

“…Clinicaltrials.gov 124 lists 67 trials involving CIRT, seven of which are Phase III. These include comparisons to XRT, surgery or PBT and are for pelvic sarcomas (PROSPER), 125 radioresistant tumours (ACC and sarcomas) (ETOILE), 126 locally advanced pancreatic cancer (CIPHER), 50,62 sacral chordoma (SACRO), 62 glioblastoma 50,62 and skull-base chordomas (HIT-1) and chondrosarcomas (CSP12C). 42 Some were paused by Covid restrictions and only three are currently actively recruiting, ETOILE (comparing CIRT to XRT) and the two Heidelberg Ion Therapy Centre (HIT) skull-base studies (CIRT to PBT).…”

Particle Therapy: Clinical Applications and Biological Effects

“…Despite the controversy, C-ion options remain highly relevant. The nosological emphasis is placed on head-and-neck tumors and other radioresistant cancers in relapse [72,73]. Despite the sound theoretical grounds for the use of C-ions, corresponding preclinical and clinical evidence is still insufficient.…”