Purpose We aimed to develop a hippocampal vascular injury surrogate marker for early prediction of late neurocognitive dysfunction in patients receiving brain radiotherapy (RT). Methods and Materials 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. Patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8-Gy fractions). Six dynamic-contrast enhanced MRI scans were performed from pre-RT to 18-month post-RT, and quantified for vascular parameters related to blood-brain barrier permeability, Ktrans, and the fraction of blood plasma volume, Vp. The temporal changes in the means of hippocampal Ktrans and Vp after starting RT were modeled by integrating the dose effects with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampi was correlated with neurocognitive dysfunction 6 and 18-months post-RT. Results The Ktrans mean increased significantly from pre-RT to 1-month post-RT (p<0.0004), which significantly depended on sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females correlated significantly with changes in memory function at 6 (r = −0.95, p<0.0006) and 18-months (r = −0.88, p<0.02) post-RT. Conclusions The early hippocampal vascular dose-response could be a predictor of late neurocognitive dysfunction. A personalized hippocampus sparing strategy may be considered in the future.

Purpose Using conventional MRI for target definition, glioblastomas may receive inadequate radiation dose coverage of the nonenhanced hypercellular subvolume. This study aimed to develop a technique to identify the hypercellular components of GB by using high b-value DWI and to investigate its relationships with the prescribed 95%- isodose volume (PDV) and progression-free survival (PFS). Methods Twenty-one patients with glioblastoma underwent chemoradiotherapy post-resection/biopsy. RT treatment planning was based upon conventional MRI. Pre-RT DWIs were acquired in 3 orthogonal directions with b-values of 0, 1000, and 3000 s/mm2. Hypercellularity volume (HCV) was defined on the high b-value (3000 s/mm2) DWI by a threshold method. “Nonenhanced” signifies regions not covered by the Gd-enhanced gross tumor volume (GTV-Gd) on T1-weighted images. The PDV was used to evaluate spatial coverage of the HCV by the dose plan. Association between HCV and PFS or other clinical covariates were assessed using univariate proportional hazards regression models. Results HCVs and nonenhanced HCVs varied 0.58-67 cc (median: 9.8cc) and 0.15-60 cc (median: 2.5cc), respectively. Fourteen patients had incomplete dose coverage of the HCV, of which 6 patients had 1+ cc HCV missed by the 95%-PDV (range: 1.01–25.4cc). Of the 15 patients who progressed, 5 progressed earlier, within 6 months post-RT, and 10 patients after. Pre-RT HCVs within recurrent GTVs-Gd were 78% (range: 65–89%) for the 5 earliest progressions but lower, 53% (range: 0–85%), for the later progressions. HCV and nonenhanced HCV were significant negative prognostic indicators for PFS (p < 0.002 and p < 0.01, respectively). The hypercellularity subvolume not covered by the 95%-PDV was a significant negative predictor for PFS (p < 0.05). Conclusions High b-value DWI identifies the hypercellular components of GB and could aid in RT target volume definition. Future studies will allow us to investigate the role of high b-value DWI in identifying radiation boost volumes and diagnosing progression.

BACKGROUND: Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. SIGNIFICANCE: Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial.

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