Brown, Paul D.

Abstract Background: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising low intensity alternating electric fields. TTFields has demonstrated efficacy in non-small cell lung cancer (NSCLC) in in vitro and in vivo models, and in a Phase I/II clinical study. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. This prospective, multicenter study [NCT02831959] investigated the efficacy, safety and neurocognitive outcomes of TTFields in NSCLC patients with brain metastases. Methods: NSCLC patients (N=270) with 1-10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays and allows normal daily activities. Patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Patients in the control arm are allowed to cross over to TTFields arm at the time of second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2-10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1-4 and 5-10 brain metastases; bi-monthly intracranial progression rate from 2-12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. Citation Format: Minish P Mehta, Vinai Gondi, Manmeet Ahluwalia, Paul D. Brown. Phase III METIS study: Tumor Treating Fields (150 kHz) and radiosurgery for supra- and/or infratentorial brain metastases (1-10) from non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT172.

Background Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit. Methods We describe a single-center multidisciplinary experience in managing PC patients over a 22-year period and review previously published PC series. Results Seventeen patients were identified. Median age at PC diagnosis was 44 years (range 16–82 years), and the median time from PA to PC transformation was 5 years (range 1–29 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervous system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest PFS in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year survival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy. Conclusions PC management benefits from multidisciplinary care and multimodality therapy. TMZ-based regimens were associated with high survival rates and long disease control.

2009 Background: NRG CC001, a phase III trial of WBRT plus memantine (WBRT+M) with or without HA, sought to evaluate the neuro-protective effects of lowering the hippocampal radiation dose. Methods: Patients (pts) with BM were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module and analyzed using mixed effects models and t-tests. Results: From 7/2016 to 3/2018, 518 pts were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted hazard ratio (HR) = 0.74, p = 0.02) due to lower risk of deterioration in executive function at 4 mos (p = 0.01) and encoding (p = 0.049) and consolidation (p = 0.02) at 6 mos. Age≤61 predicted lower NCF failure risk (HR = 0.60, p = 0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p = 0.036), difficulty speaking (p = 0.049) and problems remembering things (p = 0.013) at 6 mos favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p = 0.011) and symptom interference (p = 0.008) at 6 mos. Treatment arms did not differ in toxicity, overall survival, or intracranial progression. Conclusions: HA during WBRT+M for BM better preserves NCF and patient-reported symptoms, while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute. Clinical trial information: NCT02360215.

Abstract Background Radiographic leptomeningeal disease (LMD) develops in up to 30% of patients following postoperative stereotactic radiosurgery (SRS) for brain metastases. However, the clinical relevancy of this finding and outcomes after various salvage treatments are not known. Methods Patients with brain metastases, of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. LMD pattern was categorized as nodular (nLMD) or classical (“sugarcoating,” cLMD). Results The study cohort was 147 patients. Most patients (60%) were symptomatic at LMD presentation, with cLMD more likely to be symptomatic than nLMD (71% vs. 51%, P = 0.01). Salvage therapy was whole brain radiotherapy (WBRT) alone (47%), SRS (27%), craniospinal radiotherapy (RT) (10%), and other (16%), with 58% receiving a WBRT-containing regimen. WBRT was associated with lower second LMD recurrence compared with focal RT (40% vs 68%, P = 0.02). Patients with nLMD had longer median overall survival (OS) than those with cLMD (8.2 vs 3.3 mo, P < 0.001). On multivariable analysis for OS, pattern of initial LMD (nodular vs classical) was significant, but type of salvage RT (WBRT vs focal) was not. Conclusions Nodular LMD is a distinct pattern of LMD associated with postoperative SRS that is less likely to be symptomatic and has better OS outcomes than classical “sugarcoating” LMD. Although focal RT demonstrated increased second LMD recurrence compared with WBRT, there was no associated OS detriment. Focal cranial RT for nLMD recurrence after surgery and SRS for brain metastases may be a reasonable alternative to WBRT.

Abstract The finding that most grades II and III gliomas harbor isocitrate dehydrogenase (IDH) mutations conveying a relatively favorable and fairly similar prognosis in both tumor grades highlights that these tumors represent a fundamentally different entity from IDH wild-type gliomas exemplified in most glioblastoma. Herein we review the most recent developments in molecular neuropathology leading to reclassification of these tumors based upon IDH and 1p/19q status, as well as the potential roles of methylation profiling and deletional analysis of cyclin-dependent kinase inhibitor 2A and 2B. We discuss the epidemiology, clinical manifestations, benefit of surgical resection, and neuroimaging features of lower-grade gliomas as they relate to molecular subtype, including advanced imaging techniques such as 2-hydroxyglutarate magnetic resonance spectroscopy and amino acid PET scanning. Recent, ongoing, and planned studies of radiation therapy and both cytotoxic and targeted chemotherapies are summarized, including both small molecule and immunotherapy approaches specifically targeting the mutant IDH protein.

Abstract Primary spinal cord tumors represent a hetereogeneous group of central nervous system malignancies whose management is complex given the relatively uncommon nature of the disease and variety of tumor subtypes, functional neurologic deficits from the tumor, and potential morbidities associated with definitive treatment. Advances in neuroimaging; integration of diagnostic, prognostic, and predictive molecular testing into tumor classification; and developments in neurosurgical techniques have refined the current role of radiotherapy in the multimodal management of patients with primary spinal cord tumors, and corroborated the need for prospective, multidisciplinary discussion and treatment decision making. Radiotherapeutic technological advances have dramatically improved the entire continuum from treatment planning to treatment delivery, and the development of stereotactic radiosurgery and proton radiotherapy provides new radiotherapy options for patients treated in the definitive, adjuvant, or salvage setting. The objective of this comprehensive review is to provide a contemporary overview of the management of primary intradural spinal cord tumors, with a focus on radiotherapy.

Abstract Background This study evaluated the association between health-related quality of life (HRQOL) and cognition in patients receiving memantine for prevention of cognitive dysfunction during whole-brain radiotherapy (WBRT). Methods Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine, 20 mg per day, within 3 days of initiating radiotherapy, for 24 weeks. The Functional Assessment of Cancer Therapy-Brain module (FACT-Br) and Medical Outcomes Scale-Cognitive Functioning Scale (MOS-C) were completed in coordination with serial standardized tests of cognitive function. Results Of the 508 eligible patients, 442 (87%) consented to participate in the HRQOL portion and contributed to baseline analyses. Evaluable patients at 24 weeks (n = 246) included surviving patients completing FACT-Br, MOS-C, and objective cognitive assessments (n = 146, 59%) and patients alive at time of missed assessment (n = 100, 41%). Baseline cognitive function correlated significantly with FACT-Br and MOS-C self-reports. All domains of objective cognitive function showed declines over time. Neither FACT-Br nor MOS-C differed between the treatment arms. Emotional and functional well-being subscales of the FACT improved over time while the remainder of the FACT-Br domains remained stable. MOS-C scores declined over time. Conclusion Baseline cognitive function correlated significantly with FACT-Br and MOS-C scores. No by-arm differences in HRQOL were observed despite differences in objective cognitive function. Patient attrition and poor testing compliance remain significant problems in studies of cognitive function of brain metastases patients and further effort is needed to improve compliance with testing and sensitivity of patient-reported measures.