hemithoracic irradiation with proton therapy in malignant pleural mesothelioma

Conditions: Malignant Pleural Mesothelioma

Summary: phase iii randomised-controlled trial for patients with unilateral malignant pleural mesothelioma (mpm).

study design: randomised phase iii clinical trial for patients with unilateral mpm. primary endpoint: progression free survival (pfs) and overall survival (os), defined as the time from randomisation to the date of progression and death from any cause. secondary endpoints: safety and tolerability, health related quality of life (qol): euroqol eq-5d-3l, locoregional control. randomisation and stratification: 1:1 randomisation. patients with be stratified for histology (epithelioid versus non-epithelioid), potential pbt centre (uclh or the christie) , laterality (left or right sided) and time since diagnosis (\ 1 year) treatment: experimental arm: patients in the experimental arm will receive pbt to the hemithorax to a dose of 50gy in 25 fractions with a boost to 60gy for the visible tumour (gross tumour volume-gtv). treatment is given daily monday-friday over 5 weeks. following completion of treatment in the experimental arm patients will have 2 years of follow-up from time of randomisation at the local recruiting/referring centre. control arm: the patients in the control arm would be under standard of care surveillance i.e. "watch and wait", with no treatment or other intervention. patients will have 2 years of follow-up from time of randomisation at the local recruiting/referring centre. if the disease progresses, the patient will receive soc treatment i.e. immunotherapy with nivolumab and ipilimumab, or chemotherapy at the clinician's discretion. statistical analysis plan: the sample size is 148 patients (74 patients per arm). this is to detect a os hazard ratio of 0.58, equivalent to an improvement in 2-year os from 30% to 50%, with 85% power and 5% two-sided alpha. recruitment to complete in 3 years across 20 uk centres with 2 years of additional follow-up and up to 5% dropout. interim analyses for os efficacy will be performed when 50, 75 and 110 patients have been randomised at around 1.5, 2.0 and 2.5 years respectively. using a fixed-sequence approach, a difference for os will only be tested if the co-primary endpoint of pfs is statistically significant (p\ 85% power to detect a pfs hazard ratio of 0.58 accounting for up to 10% dropout.

Eligibility criteria:
inclusion criteria: * patients ≥18 years of age, with histologically (biopsy) confirmed mpm * n0 or n1 and m0 disease * written informed consent * patient and responsible clinician opt for active surveillance and deferral of systemic anti-cancer therapy until clinical or radiological progression * who performance status 0-1 * disease confined to one hemithorax based on ct assessment * adequate pulmonary function: * ≥ 40% predicted post-fev1; * ≥ 40% predicted dlco/tlco * agreement to travel to either proton beam therapy centres (i.e. uclh or the christie) if randomised to arm 2 * agreement to be followed up at a local hit-meso trial site exclusion criteria: * presence of metastatic or contralateral disease * prior thoracic radiotherapy, chemotherapy, immunotherapy for mpm * prior radical surgery for mpm (extrapleural pneumonectomy or extended pleurectomy decortication or pleurectomy decortication) * initial systemic therapy or surgery is required and the patient and responsible clinician do not opt for active surveillance * involvement of contralateral or supraclavicular lymph nodes * t4 disease with clear invasion of the myocardium * n2 and/or m1 disease * presence of new effusion that is not amenable to drainage * who performance status ≥ 2 * women who are pregnant or breast feeding * history of other malignancy; exception: (a) subjects who have been successfully treated and are disease-free for 3 years, (b) a history of treated non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) cll in stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal therapy.

Keywords: proton beam therapy