PURPOSE The brain is a common site of metastasis for patients with high-risk melanoma. Although surgery or stereotactic radiosurgery are highly effective local treatments for a small number of metastases, there is a high risk of developing additional brain metastases. The role of adjuvant whole-brain radiotherapy (WBRT) in reducing new metastases is controversial, with a lack of high-level evidence specifically for melanoma. METHODS In this randomized phase III trial, patients who had local treatment of one to three melanoma brain metastases were randomly assigned to WBRT or observation. The primary end point was distant intracranial failure within 12 months, and secondary end points included time to intracranial failure, survival, and time to deterioration in performance status. RESULTS Between April 2009 and September 2017, 215 patients were randomly assigned from 24 centers. Median follow-up was 48.1 months (range, 39.6 to 68 months). Forty-two percent of patients in the WBRT group and 50.5% of those in the observation developed distant intracranial failure within 12 months (odds ratio, 0.71; 95% CI, 0.41 to 1.23; P = .22) and the rates over the entire follow-up period were 52.0% and 57.9%, respectively (odds ratio, 0.79; 95% CI, 0.45 to 1.36; P = .39). Local failure rate was lower after WBRT (20.0% v 33.6%; P = .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died ( P = .28), with no difference in the rate of neurologic death. Median time to deterioration in performance status was 3.8 months after WBRT and 4.4 months with observation ( P = .32). WBRT was associated with more grade 1 to 2 acute toxicity. CONCLUSION After local treatment of one to three melanoma brain metastases, adjuvant WBRT does not provide clinical benefit in terms of distant intracranial control, survival, or preservation of performance status.
BackgroundBrain metastases are a common cause of death in patients with melanoma. The role of adjuvant whole brain radiotherapy (WBRT) following local treatment of intracranial melanoma metastases is controversial. The Australian and New Zealand Melanoma Trials Group (ANZMTG) and the Trans-Tasman Radiation Oncology Group (TROG) are leading the first ever single histology randomised trial investigating this question. The primary endpoint is distant intracranial failure on magnetic resonance imaging (MRI) within twelve months of randomisation. The first planned interim analysis was performed twelve months after randomisation of the 100th patient. The analysis was an opportunity to review completeness of the trial data to date.MethodsAll data received up to the end of twelve months after randomisation of the 100th patient was reviewed.ResultsReview of pathology reports confirmed that all 100 patients had stage IV melanoma and were appropriately entered into the study. Of the 47 distant intracranial events, 34 occurred in isolation (i.e. only distant failure was identified), whilst 13 were accompanied by local failure. Data review showed compliance with the protocol mandated MRI schedule and accuracy of intracranial failure reporting was very high. The Quality of Life (QoL) component of the study achieved a 91% completion rate. For the neurocognitive function (NCF) assessments, a high completion rate was maintained throughout the 12 month period. Where assessments were not performed at expected time points, valid reasons were noted. Radiotherapy quality was high. Of 50 patients who received WBRT, 32 were reviewed as per protocol design and there was only one major variation out of 308 data points reviewed (0.3%). There were minimal trial related adverse events (AEs) and no serious adverse events (SAEs). Pre-specified protocol stopping rules were not met.ConclusionsThe Data Safety Monitoring Committee (DSMC) recommended the trial continue recruitment after reviewing the unblinded data. The data provision and quality to date indicates that a reliable outcome will be obtained when the final analysis is performed. Accrual is ongoing with 156 out of 200 patients randomised to date (26th November 2014).
9500 Background: The role of adjuvant WBRT in MBMs is controversial. This trial compares WBRT with Obs after local treatment of 1-3 MBMs. Methods: The primary endpoint is distant intracranial failure (DIF) within 12 months of randomization. The a priori neurocognitive function (NCF) endpoint is Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months. Secondary endpoints include local failure (LF), overall survival (OS) and global quality of life (QoL). Analyses were conducted on intention-to-treat basis with nominal two-sided significance level 5%. Drug therapy was allowed. Effective drugs became available during trial and their impact was analysed. Results: Of 586 eligible patients (pts), 215 consented from 31 sites in 3 countries (Australia, UK and Norway) between 2009 and 2017. Eight (0.04%) who withdrew or had no data collected were excluded. 107 randomized to Obs and 100 to WBRT. Mean age 62 years, 67% males, 61% with single MBM of mean size 2cm, 67% had extracranial disease at randomization. The two arms were well matched. NCF was completed by English speakers; 50 WBRT and 70 Obs at baseline, declining to 26 and 35 respectively at 4 months. Within 12 months, 54 (50.5%) Obs had DIF compared with 42 (42.0%) WBRT pts (OR 0.71; 95%CI 0.41-1.23; p = 0.222). There was no difference in LF (p = 0.100) or OS (log-rank p = 0.861). 53% (Obs) and 59% (WBRT) pts were alive at 12 months. There was no significant between-group difference in mean intervention effect on global QoL (p = 0.083). Pts who received T-cell checkpoint inhibitors and/or mitogen-activated protein kinase (MAPK) pathway inhibitors and WBRT before or within 12 months of randomization had DIF rate 29% compared with Obs and no systemic therapy had 44%, but was not significant (p = 0.228). Obs had greater relative improvement from baseline in HVLT-R at every timepoint. At 4 months, Obs had 20.9% improvement from baseline in HVLT-R-delayed recall compared to 2.7% decline in WBRT; overall adjusted average intervention effect 23.6% (95%CI 9.0, 38.2; p = 0.0018). There was no difference in time to cognitive failure or in proportions with global cognitive impairment. Conclusion: This level one evidence shows WBRT does not improve outcomes in MBMs. This practice-changing trial justifies the recent move away from WBRT that occurred during the course of the trial. Clinical trial information: NCT01503827.
Purpose/Objective(s): Management of glioblastoma (GBM) is challenged by difficulties discriminating tumor progression from treatmentrelated 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). Materials/Methods: 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 IRBapproved 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. Results: 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 (nZ25) vs. 18.9 (range, 3.2-60.8) months for IMRT (nZ41). 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 (pZns for all). Median clinical PFS was 8.7 (range, 6.4-11.1) months; 8.9 months IMRT vs. 8.7 months PT (pZ0.065). Median RANO PFS was 8.3 (range, 5.8-11.6) months: 8.3 months IMRT vs. 6.9 months PT (pZ0.226). 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 (pZ0.35). Conclusion: 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.
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