Proton Therapy Reirradiation in Difficult-to-Treat Recurrent Glioblastoma

Abstract

To report preliminary results of re-irradiation with proton therapy (PT) with or without chemotherapy (CHT) in difficult-to-treat recurrent glioblastoma (rGBM): patients (pts) were selected for PT due to the large tumor size or proximity to dose-limiting organs at risk that previously had received near-maximum dose tolerance during the first radiation course. Between January 2015 and January 2017 twenty pts with rGBM were re-irradiated with PT. All pts had been previously treated with Stupp regimen. Fifteen (75%) were re-irradiated at first relapse/progression, five at the second/third one. Six patients (30%) were re-irradiated after partial tumor resection. Median age and Karnofsky performance status at re-irradiation were 56 years and 90%, respectively. Median time between prior radiotherapy and PT was 13 months. Target definition was based on CT, MR, and 18F-DOPA PET imaging. Gross Tumor Volume (GTV) included any area of contrast enhancement after contrast medium administration plus any pathological PET uptake regions. Clinical Target Volume (CTV) was generated by adding to GTV a 3-mm uniform margin manually corrected in proximity of anatomical barriers. Median CTV volume was 47 cc (range, 13-153 cc). All pts received 36 GyRBE in 18 fractions. PT was delivered with or without chemotherapy as follows: four (20%) pts (Group 1) also received concomitant TMZ (75 mg/m2/die, 7 days/week); 3 (15%) pts (Group 2) also received concomitant (as above) and adjuvant TMZ (150-200 mg/m2/die, 5 days/month); 5 (25%) pts (Group 3) received PT only; 8 (40%) pts (Group 4) received PT followed by CHT (different regimens/drugs). All pts were treated with active pencil beam scanning PT. Registered side effects were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment response was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria. Survival and progression-free survival after re-irradiation were calculated from initiation of PT until tumor progression or death (by any cause), using the Kaplan Meier method. All pts completed the treatment without breaks. There were no grade 3 or higher acute toxicities. One pts developed TMZ-related grade 1 neutropenia. There were no grade 3 or higher late toxicities. During follow-up three pts (15%) developed radionecrosis (diagnosed at imaging) with mild symptoms controlled with steroids. The median progression-free survival (PFS) was 6.3 months, while 6-month PFS rate was 60%. The median PFS was 6.8, 4.3, 5.4, and 5.5 for Group 1-2-3-4, respectively. Median overall survival (OS) after PT was 10.7 months. PT re-irradiation of difficult-to-treat rGBM showed to be feasible and safe even with concomitant and adjuvant chemotherapy administration. Despite the small number of patients of this series and the retrospective nature of the study PFS and OS rates are promising and deserve further evaluation in a larger pts sample to assess the most effective strategy.