SUMMARYBackgroundAfter brain metastasis resection, whole-brain radiation therapy (WBRT) decreases local recurrence but may cause cognitive decline. We performed this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved local tumor tumor-free recurrence rates compared to surgical resection alone as an alternative to the need for immediate WBRT.MethodsThe main entry criteria for the study included patients >3 years of age, with a Karnofsky Performance Score ≥ 70, who were able to undergo an MRI scan and who had a complete resection of 1–3 brain metastases (the maximum diameter of the resection cavity had to be ≤4cm). Patients were assigned randomly to either SRS treatment of the resection cavity (within 30 days of surgery) or observation (OBS). Patients were stratified by histology, tumor size, and number of metastases. Patients were recruited at a single tertiary cancer center. The primary endpoint was time to local recurrence in the resection cavity assessed by blinded central review of brain MRI scans in the intention-to-treat population. The trial was registered at clinicaltrials.gov (Trial NCT00950001, status: closed to new participants).FindingsBetween 8/13/2009 and 2/16/2016, 132 patients were randomized to OBS (N=68) or SRS (N=64), with 128 patients available for analysis. We stratified by metastasis size (maximum diameter of ≥3 cm vs. <3 cm), histology (melanoma vs. other), and number of metastases (one vs. two or three). The 12-month local tumor recurrence-free rate was 43% (OBS) (95% CI 31%–59%) and 72% (SRS) (95% CI 60%–87%) (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.24–0.88, p=0.015).InterpretationThis prospective randomized trial of patients undergoing surgical resection for 1–3 brain metastases indicates that SRS administered to the resection cavity significantly lowers local recurrence compared to observation alone. Thus, the use of SRS after brain metastasis resection is an alternative to WBRT.

Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma and metastatic colorectal cancer. Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that cetuximabresistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin, heparinbinding EGF and b-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and resensitization to cetuximab. In addition, expression of a nuclear localization sequence-tagged EGFR in cetuximab-sensitive cells increased resistance to cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with cetuximab-resistant tumors with inhibitors of SFKs in combination with cetuximab.

Background and Purpose-RTOG 0933 is a phase II clinical trial of hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) to prevent radiation-induced neurocognitive decline. By quantifying baseline incidence of perihippocampal or hippocampal metastases, we sought to estimate the risk of developing metastases in the hippocampal avoidance region (the hippocampus plus 5mm margin).

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The findings indicate that binge pattern exposure to ethanol during adolescence enhances responsiveness to the memory-impairing effects of ethanol in adulthood.