C. A. Helis1, H. Zarabi2, G. Russell3, M. C. LeCompte4, W. Liu5, J. A. Hattangadi-Gluth6, L. M. Halasz7, S. G. Soltys8, S. E. Braunstein9, T. J. C. Wang10, W. Shi11, C. Shen12, J. E. Mignano13, A. H. Masters14, L. R. Kleinberg15, J. Huang16, A. B. Hopper6, A. B. Barbour17, M. A. Salans18, and M. D. Chan19; 1Alexander T. Augusta Military Medical Center, Fort Belvoir, VA, 2Department of Neurosurgery, Temple University Hospital, Philadelphia, PA, 3Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, 4Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 5Washington University School of Medicine in St. Louis, Department of Radiation Oncology, St. Louis, MO, 6Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 7Department of Radiation Oncology, University of Washington/ Fred Hutchinson Cancer Center, Seattle, WA, 8Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 9Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 10Department of Radiation Oncology, Columbia University Medical Center, New York, NY, 11Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, 12Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, 13Tufts Medical Center, Department of Radiation Oncology, Boston, MA, 14Department of Radiation Oncology, University of Louisville, Louisville, KY, 15Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, 16Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, 17Department of Radiation Oncology, University of Washington - Fred Hutchinson Cancer Center, Seattle, WA, 18University of California San Francisco, San Francisco, CA, 19Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC
Purpose/Objective(s):Reirradiation (reRT) is a treatment option for recurrent high grade glioma (HGG). However, the ideal treatment regimen and patient selection criteria remain unclear. Materials/
Methods: A retrospective review of patients with recurrent HGG who received fractionated reRT (>3 fractions) was performed at 12 institutions. The Kaplan-Meier Method was used to estimate overall survival (OS). Cox proportional hazards regression models were used to identify factors associated with OS. Toxicity outcomes were assessed using logistic regression. Significance was assumed if p<0.05. SAS (version 9.4, Cary, NC, USA) was used for all analyses. Results: 482 eligible patients were identified. 336 (69.7%) had glioblastoma (GBM), with the remainder having Grade 3 gliomas. At reRT, the median age was 53.1 years (IQR 41.7-62.7 years) and the median KPS was 80 (IQR 70-90). 196 patients (51.0%) received reRT for their initial recurrence, 122 (30.0%) had IDH-mutant tumors, and 161 (46.4%) had MGMT methylation. The median dose at reRT was 47 Gy BED10 (IQR 47-53). 192 (44.4%) and 116 (26.9%) received concurrent temozolomide (TMZ) and bevacizumab (BEV), respectively. Median OS was 9.8 months, with a 1 year survival rate of 40.5%. In a multivariate Cox proportional hazards model, dose > 47.25 Gy BED10 (equivalent to 35 Gy in 10 fractions) was associated with improved OS (HR 0.59, p <0.01). Benefits to dose escalation were seen in both IDH-mutant (median OS 21.3 vs 11.3 months, p = 0.01) and IDH-wild type tumors (median OS 10.2 vs 6.5 months, p < 0.01), and in tumors with (median OS 13.3 vs 6.5 months, p < 0.01) and without MGMT methylation (median OS 9.6 vs 6.5 months, p < 0.01). In addition to dose, statistically significant predictors of OS in the multivariate model were glioblastoma histology (HR 1.98, 95% p < 0.01), tumor diameter > 5 cm (HR 1.47, p < 0.01), a window of < 12 months between RT courses (HR 1.88, p < 0.01), and an increasing number of recurrences prior to reRT (HR 1.25, p< 0.01 per recurrence). 107 patients (25.1%) developed Grade 2 or greater adverse radiation effects (ARE), including both pseudoprogression and radionecrosis. On univariate analysis, only one variable showed prognostic significance-patients with T2 FLAIR abnormality intentionally targeted at reRT were less likely to develop Grade 2 or greater ARE (HR 0.41, 95% p < 0.01). Receipt of BEV was not associated with development of Grade 2 or greater ARE (HR 0.67, p = 0.15) Conclusion: Doses greater than the BED-equivalent of 35 Gy in 10 fractions are associated with improved survival at reRT for recurrent HGG. This benefit to dose escalation is particularly profound in IDH-mutant tumors and in MGMT-methylated tumors. Increased dose was not associated with an increase in Grade 2 or greater ARE. Factors that can potentially guide optimal patient selection for reRT include histology (non-GBM), a tumor diameter of < 5cm, an interval of at least 12 months between RT courses, and a small number of recurrences.
