A Phase I Study of Short-Course Accelerated Whole Brain Radiation Therapy for Multiple Brain Metastases

Object Multiple brain metastases are a common health problem, frequently found in patients with cancer. The prognosis, even after treatment with whole-brain radiation therapy (WBRT), is poor, with an average expected survival time of less than 6 months. Investigators at numerous centers have evaluated the role of stereotactic radiosurgery in retrospective case series of patients harboring solitary or multiple tumors. Tumor resection is used mainly for patients with large tumors that cause acute neurological syndromes. The authors conducted a randomized trial in which they compared radiosurgery combined with WBRT with WBRT alone. Methods Twenty-seven patients were randomized (14 to recieve WBRT alone and 13 to receive WBRT combined with radiosurgery). The rate of local failure at 1 year was 100% after WBRT alone but only 8% in patients in whom boost radiosurgery was performed. The median time to local failure was 6 months after WBRT alone (95% confidence interval (CI) 3.5–8.5) in comparison to 36 months (95% CI 15.6–57) after WBRT and radiosurgery (p = 0.0005). The median time to the development of any brain failure was improved in the combined modality group (p = 0.002). Survival was shown to be related to the extent of extracranial disease (p = 0.02). Conclusions Combined WBRT and radiosurgery for the treatment of patients with two to four brain metastases significantly improves control of brain disease. Whole-brain radiation therapy alone does not provide lasting and effective care when treating most patients. Surgical resection remains important for patients with large symptomatic tumors and in whom limited extracranial disease has been demonstrated.

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TRLS-07. BRAINSTORM: OUTCOMES FROM A MULTI-INSTITUTIONAL PHASE I/II STUDY OF RRx-001 IN COMBINATION WITH WHOLE BRAIN RADIATION THERAPY FOR PATIENTS WITH BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.040 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i9-i10

Author(s):

Michelle Kim ◽

Hemant Parmar ◽

Matthew Schipper ◽

Theresa Devasia ◽

Madhava Aryal ◽

...

Keyword(s):

Radiation Therapy ◽

Brain Metastases ◽

Phase I ◽

Tumor Volume ◽

Whole Brain Radiation Therapy ◽

Whole Brain ◽

Dce Mri ◽

Whole Brain Radiation ◽

Dose Levels ◽

Brain Radiation

Abstract INTRODUCTION: To determine the recommended Phase II dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases, and to assess whether quantitative changes in perfusion MRI after RRx-001 correlate with response. METHODS AND MATERIALS: Five centers participated in this phase I/II trial of RRx-001 given once pre-WBRT then twice weekly during WBRT (30 Gy/10 fractions). Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose-escalation was managed by the Time-to-Event Continual Reassessment Model (TITE-CRM). Correlative DCE-MRI was performed in a subset of patients and linear mixed models used to correlate change in 24-hour T1, Ktrans (capillary permeability) and Vp (plasma volume) with change in tumor volume. RESULTS: Between 2015–2017, 31 patients were enrolled. Two patients dropped out prior to any therapy and 7 were treated with concurrent temozolomide following a study amendment. Median age was 60 years (range, 30–76) and 17 were male. The most common tumor types were melanoma (58%) and non-small cell lung cancer (20%). No dose-limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia in 6.9% (2/29). The median intracranial response rate was 46% (95%CI 24–68) and median overall survival was 5.2 months (95%CI 4.5–9.4). No neurologic deaths occurred. Among 10 evaluable patients undergoing DCE-MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 month and 4 months (p≤0.01). CONCLUSION: The addition of RRx-001 to WBRT is safe and well-tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, and in the absence of a dose response, the recommended Phase 2 dose is 10 mg administered twice weekly. A reduction in Vp by DCE-MRI 24 hours after RRx-001 suggests anti-angiogenic activity that is associated with longer-term tumor response.

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