Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

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Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response. Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors. http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg .

Radionecrosis is a well-characterized effect of stereotactic radiosurgery (SRS) and is occasionally associated with serious neurologic sequelae. Here, we investigated the incidence of and clinical variables associated with the development of radionecrosis and related radiographic changes after SRS for brain metastases in a cohort of patients with long-term follow up. 271 brain metastases treated with single-fraction linear accelerator-based SRS were analyzed. Radionecrosis was diagnosed either pathologically or radiographically. Univariate and multivariate Cox regression was performed to determine the association between radionecrosis and clinical factors available prior to treatment planning. After median follow up of 17.2 months, radionecrosis was observed in 70 (25.8 %) lesions, including 47 (17.3 %) symptomatic cases. 22 of 70 cases (31.4 %) were diagnosed pathologically and 48 (68.6 %) were diagnosed radiographically. The actuarial incidence of radionecrosis was 5.2 % at 6 months, 17.2 % at 12 months and 34.0 % at 24 months. On univariate analysis, radionecrosis was associated with maximum tumor diameter (HR 3.55, p < 0.001), prior whole brain radiotherapy (HR 2.21, p = 0.004), prescription dose (HR 0.56, p = 0.02) and histology other than non-small cell lung, breast or melanoma (HR 1.85, p = 0.04). On multivariate analysis, only maximum tumor diameter (HR 3.10, p < 0.001) was associated with radionecrosis risk. This data demonstrates that with close imaging follow-up, radionecrosis after single-fraction SRS for brain metastases is not uncommon. Maximum tumor diameter on pre-treatment MR imaging can provide a reliable estimate of radionecrosis risk prior to treatment planning, with the greatest risk among tumors measuring >1 cm.

Purpose/Objective To evaluate local control following surgical resection and postoperative stereotactic radiosurgery (SRS) for brain metastases. Methods and Materials Forty-nine patients (50 lesions) were enrolled and available for analysis. Eligibility criteria included histologically confirmed malignancy with 1 or 2 intraparenchymal brain metastases, age ≥18, and KPS ≥70. Cox proportional hazard regression model was used to test for significant association between clinical factors and overall survival (OS). Competing risks regression models, as well as cumulative incidence functions, were fit using the method of Fine and Gray in order to assess the association between clinical factors and both local failure (LF, recurrence within surgical cavity or SRS target), and regional failure (RF, intracranial metastasis outside of treated volume). Results The median follow-up was 12.0 months (mos, range: 1.0–94.1 mos). Following surgical resection, 39 patients with 40 lesions were treated a median of 31 days (range: 7–56 days) later with SRS to the surgical bed to a median dose of 1800 cGy (range: 1500–2200 cGy). Of the 50 lesions, 15 (30%) demonstrated LF after surgery. The cumulative LF and RF rates were 22% and 44% at 12 mos. Patients who went on to receive SRS had significantly lower incidence of LF (p=0.008). Other factors associated with improved local control includes NSCLC histology (p=0.048), tumor diameter <3 cm (p=0.010), and deep parenchymal tumors (p=0.036). Large tumors (≥3 cm) with superficial dural/pial involvement showed the highest risk for LF (53.3% at 12 mos). Large, superficial lesions treated with SRS had 54.5% LF. Infratentorial lesions were at higher risk of developing RF compared to supratentorial lesions (p <0.001). Conclusions Postoperative SRS is associated with high local control, especially for deep brain metastases <3 cm. Tumors ≥3 cm with superficial dural/pial involvement demonstrate the highest risk in LF.

Context Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options. Case A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL. Molecular Evaluation Both prospective clinical sequencing with Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation. Conclusion Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.

Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR ¼ 2.6, P ¼ 0.02), and likely preceded the acquisition of alkylating therapyassociated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAFmutant gliomas, response to agents targeting the RAF/MEK/ ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

In recent years, accelerated partial breast irradiation (APBI) has been considered an alternative to whole breast irradiation for patients undergoing breast-conserving therapy. APBI delivers higher doses of radiation in fewer fractions to the post-lumpectomy tumor bed with a 1-2 cm margin, targeting the area at the highest risk of local recurrence while sparing normal breast tissue. However, there are inherent challenges in defining accurate target volumes for APBI. Studies have shown that significant interobserver variation exists among radiation oncologists defining the lumpectomy cavity, which raises the question of how to improve the accuracy and consistency in the delineation of tumor bed volumes. The combination of standardized guidelines and surgical clips significantly improves an observer's ability in delineation, and it is the standard in multiple ongoing external-beam APBI trials. However, questions about the accuracy of the clips to mark the lumpectomy cavity remain, as clips only define a few points at the margin of the cavity. This paper reviews the techniques that have been developed so far to improve target delineation in APBI delivered by conformal external beam radiation therapy, including the use of standardized guidelines, surgical clips or fiducial markers, pre-operative computed tomography imaging, and additional imaging modalities, including magnetic resonance imaging, ultrasound imaging, and positron emission tomography/computed tomography. Alternatives to post-operative APBI, future directions, and clinical recommendations were also discussed.