Prospective Phase II Randomized Trial Comparing Proton Therapy Vs. IMRT for Newly Diagnosed GBM: Secondary Analysis Comparison of Progression Free Survival Between Clinical Radiological Assessment Vs. Response Assessment in Neuro-Oncology (RANO)

Management of glioblastoma (GBM) is challenged by difficulties discriminating tumor progression from treatment-related changes. There may also be differential imaging changes or response according to treatment modality, proton or photon. The objective of this study was to compare tumor progression based on clinical radiological assessment and on Response Assessment in Neuro-Oncology (RANO) criteria between patients treated with proton radiotherapy (PT) vs. photon intensity modulated radiotherapy (IMRT). Eligible patients were enrolled on a prospective phase II trial and had baseline and follow-up imaging beyond 12 weeks from treatment completion. This secondary analysis was done under an IRB-approved protocol. Clinical progression was determined on radiological reports, often described as radiographic findings of increased enhancement on post-contrast T1 or increased FLAIR signal, in combination with clinical alteration of treatment. A single blinded observer applied RANO criteria to determine the RANO-based tumor progression. Time to progression (TTP) and progression free survival (PFS) were determined for clinical and RANO-based assessments and compared between PT and IMRT patient cohorts. Ninety patients were enrolled and 66 were evaluable for this analysis, with median follow-up of 19.8 (range, 3.2-65.1) months; median of 22.6 (range, 3.4-65.1) months for PT (n=25) vs. 18.9 (range, 3.2-60.8) months for IMRT (n=41). There were no differences in sociodemographic characteristics between arms. Median TTP were 7.9 months for clinical (8.1 months IMRT, 6.3 months PT) and 7.2 months (7.3 months IMRT, 5.7 months PT) by RANO criteria (p=ns for all). Median clinical PFS was 8.7 (range, 6.4-11.1) months; 8.9 months IMRT vs. 8.7 months PT (p=0.065). Median RANO PFS was 8.3 (range, 5.8-11.6) months: 8.3 months IMRT vs. 6.9 months PT (p=0.226). There were 14 discrepant cases: 3 patients had progression based on clinical but not RANO criteria, and 11 patients had progression based on RANO but not clinical criteria. Overall survival was not significantly different between the two arms, with median survival of 22.6 months for PT and 19.5 months for IMRT (p=0.35). Based on this secondary analysis of a randomized trial of PT vs. IMRT for GBM, there was no difference in tumor progression relative to treatment technique used. There was no statistical difference in PFS noted between clinical and RANO based assessments; however, RANO criteria identified progression more often than clinical assessment, and TTP was shortened with the use of RANO criteria alone. Further development of tumor assessment tools that improve consistency and accuracy of determining tumor progression are needed to guide therapeutic trials in GBM.