Concurrent whole brain radiotherapy and bortezomib for brain metastasis

Abstract

BackgroundSurvival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis.MethodsA phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects.ResultsTwenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023).ConclusionsConcurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.

Clinical Observation of Whole Brain Radiotherapy Concomitant with Targeted Therapy for Brain Metastasis in Non-small Cell Lung Cancer Patients with Chemotherapy Failure

“…Medium PFS and OS in patients with EGFR mutation were 8.2 months and 11.2 months respectively, slightly higher than those of whole patients, whereas they were 4.6 months and 9.3 months in patients with KRAS mutation respectively, lower than those of whole patients, indicating that KRAS mutation could induce drug-tolerance of EGFR-TKI and antagonistic factor of radiotherapy. Additionally, the less mutation cases or the heterogeneity of gene mutations in primary tumor and metastasis of lung cancer might be the reason why EGFR and KRAS mutations were not related with survival (Lao et al, 2013).…”

Radiation Therapy for Solitary Plasmacytoma and Multiple Myeloma: Guidelines From the International Lymphoma Radiation Oncology Group

“…Combined treatment gave an improved serologic response (decrease of monoclonal protein) with a trend to significance (P Z .08). However, one should be cautious of a combination of abdominal RT and concurrent bortezomib owing to case reports of gastrointestinal toxicity (60, 61), although larger studies of bortezomib in combination with RT to the brain or other metastatic sites (in solid tumors) indicate that it is generally safe aside from predictable myelosuppression (62,63).…”

Establishment of a Human iPSC- and Nanofiber-Based Microphysiological Blood–Brain Barrier System

“…In this study, we used PTX and BTZ as model drugs, which are widely used as anticancer drugs to treat primary and metastatic brain cancer. 44,45 Both PTX and BTZ have limited penetration capacities through the BBB. 46,47 We thus conducted a triculture BBB model consisting of hiPSC-ECs and hiPSC-Astro with U87MG cells, as shown in Figure 5A.…”