Phase I Trial to Assess Feasibility of Administering the Novel Radiation Therapy Schedule
tumor, Tumor, ®, toxicity, SRS, Cancer
ADVERSE EVENT, TUMOR, TUMOR, DISEASE, BRAIN TUMOR, CAVITY, ONCOLOGY, CANCER
Recurrent GBM patients (based on contemporary pathologic grading systems) who were previously treated with definitive neurosurgical biopsy or resection followed by RT with or without systemic therapy, deemed appropriate for re-irradiation, at least 18 years old and with a Karnofsky Performance Status of at least 70 were eligible for this feasibility study, which was approved by the Dana-Farber Cancer Institute Institutional Review Board (DF 18-105; NCT03557372). Exclusion criteria were either more than one prior course of RT to the local site of progressive disease, RT to the local site of progressive disease within 3 months of the anticipated start of re-irradiation, brainstem or optic structures involvement, and no radiologically definable tumor cavity. There were no limits on the number of prior relapses or use of prior therapies (other than the stated exclusion criteria relating to prior RT), including bevacizumab. Written informed consent was received from all patients prior to participation. Subjects were permitted to receive bevacizumab, but not other therapies, concurrent with re-irradiation. All subjects enrolled underwent a CT simulation with rigid stereotactic immobilization using the QFix Encompass™ SRS Fibreplast® System. The Gross Tumor Volume was defined using CT and contrast-enhanced MRI obtained prior to the initiation of re-irradiation. In postsurgical cases where no residual enhancing tumor was noted, the postoperative resection cavity was contoured as the Gross Tumor Volume. Treatment of subclinical disease through a Clinical Target Volume was not performed in any patient treated given the re-treatment setting of this cohort, though the protocol did allow an optional Clinical Target Volume expansion of up to 5 mm for lesions <3.5 cm in maximal diameter or for lesions not previously irradiated. A Planning Target Volume (PTV) was generated using a margin of 2–3 mm with daily pretreatment kV and cone-beam CT imaging to confirm setup accuracy.External beam radiation treatment plans were optimized using inverse planning (Varian Eclipse Version 15.6) using the Volumetric Arc Therapy technique. Sequential plans were generated to deliver a schedule of 7 fractions of 3.96 Gy (QD) followed by 9 fractions of 1.0 Gy (TID) based on pre-defined coverage (The primary endpoint was the successful completion of schedule administration, defined as administering the TID fractions within 1 h of the prescribed times and the QD fractions within 24 h of the prescribed times. These time windows for schedule adherence were based on sensitivity analyses (Subjects were assessed with a physical and neurologic examination, toxicity assessments (Common Terminology Criteria for Adverse Events (CTCAE) v4.0), and patient-reported outcome measures (MDASI-BT: M. D. Anderson Symptom Inventory—Brain Tumor survey) at baseline and at 4-weeks post-treatment. Routine MRI surveillance imaging, toxicity assessment, and subsequent clinical follow-up were performed in conjunction with Radiation Oncology and Neuro-Oncology treatment teams every 1–3 months per standard of care. Radiographic response to treatment was assessed using a combination of standard MRI, advanced imaging (diffusion-weighted imaging, perfusion), and clinical assessment using the Response Assessment in Neuro-Oncology (RANO) working group methodology.