Prospective Phase I Dose Escalation Study for Neoadjuvant Radiosurgery for Large Brain Metastases

Abstract

Single session stereotactic radiosurgery (SRS) alone for brain metastases larger than 2cm in maximal dimension results in local control of only 50%. Surgical resection followed by SRS to the resection cavity can result in leptomeningeal failure (LMD). Neoadjuvant SRS followed by resection has been investigated as a dose de-escalation approach with good local control and without LMD. The purpose of this Phase I trial is to determine the maximum tolerated radiosurgery dose (MTD) for neoadjuvant radiosurgery for brain metastases larger than 2cm in maximal dimension. Radiosurgery dose was escalated at 3 Gy increments from currently accepted RTOG dosing; and cohorts of 2-6 patients were treated at each dose. Initially 2 patients were treated at a particular dose and followed for 4 months. If no dose-limiting toxicities (DLT) were observed the dose was escalated and a new cohort of 4 patients were treated. Patients underwent surgical resection of brain metastases within 2 weeks of SRS and were followed with brain MRIs and neurologic evaluations every 3 months. A total of 27 patients have enrolled on the trial. Median and mean follow up are 9.2 and 15.2 months, respectively. For tumor size >2.0 - 3.0 cm, 2 patients completed treatment at 18 Gy and 3 patients at 21Gy. For tumor size >3.0 - 4.0 cm, 4 patients were treated at 15 Gy and 9 patients were treated at 18 Gy and 1 patient at 21 Gy. For tumor size > 4.0 - 5.0 cm, 1 patient was treated at 12 Gy and 7 patients at 15 Gy. No DLT have occurred. MTD has not yet been met. Twenty-six patients were evaluable for acute toxicity. Twenty-two patients (85%) had no adverse events related to protocol treatment. Three patients had grade I fatigue or headaches and 1 patient had grade II fatigue possibly related to treatment. No patients have experienced radiation necrosis. 13 patients have died at time of analysis. The 6 and 12 month local control was 94.7% and 94.7%, respectively. Six and 12 month distant brain control was 71.7% and 49.6% respectively. Overall survival at 6 and 12 months was 81.5% and 54.9%, respectively. One patient developed LMD 5 months following SRS. Only one patient has received whole brain radiotherapy. There are low rates of toxicity for neoadjuvant SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size. MTD has not yet been reached. Early results demonstrate excellent local control with low risk of LMD.