The Impact of Tumor Treating Fields on Glioblastoma Progression Patterns.

PURPOSE: Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed GBM. METHODS AND MATERIALS: Magnetic resonance images of 428 newly diagnosed GBM patients who participated in the pivotal EF-14 trial were reviewed, and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields-treated patients were created, and TTFields intensity distributions were calculated using a finite element method. The TTFields dose was calculated within regions of the tumor bed and normal brain, and its relationship with progression was determined. RESULTS: Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at greater distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared with normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of the enhancing tumor that returned to normal was significantly higher than in the areas of the normal brain that progressed to enhancing tumor. CONCLUSIONS: There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize the TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression.

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma.

PURPOSE: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies. EXPERIMENTAL DESIGN: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically. RESULTS: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation). CONCLUSIONS: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings. Clin Cancer Res; 22(15); 3860-75. ©2016 AACR.

A feasibility study to assess the integration of a pharmacist into neurooncology clinic.

OBJECTIVE: A multidisciplinary approach is increasingly used in NeuroOncology clinics. Although this model has several advantages, patients report feeling overwhelmed by the complexity of their treatment protocol and staff feel rushed because each provider must evaluate the patient within the limited clinic hours. We hypothesized that the presence of a pharmacist in clinic could address these concerns by (1) reviewing all treatment protocols and side-effect management with patients, (2) being available to address questions outside of clinic and (3) answering staff related medication questions. METHODS: The pharmacist met with consenting patients at the initial clinic visit and followed up by telephone two additional times. The pharmacist was available to answer questions outside of clinic hours. Surveys were developed and given to patient and staff to evaluate their experience. RESULTS: Over 4 months, 13 patients were enrolled. The pharmacist interacted with each patient an average of 9 times with 55% of interactions occurring outside scheduled visits and two-thirds of pharmacist interventions directly involving patient care. A total of 85% of patients and staff responded to the evaluation survey and 90% of respondents indicated that the pharmacist should remain part of the NeuroOncology team. Patients reported less stress related to their treatment and clinical staff experienced improved clinical efficiency directly as a result of the presence of the pharmacist. CONCLUSION: Based on these results, a clinical pharmacist should become a permanent member of the outpatient NeuroOncology clinic.

Palmar-plantar hyperpigmentation with capecitabine in adjuvant colon cancer.

BACKGROUND: Capecitabine (XELODA) is a chemotherapeutic agent used widely in the treatment of adjuvant/metastatic colon cancer and metastatic breast cancer. It is usually well tolerated; however, one of the major side effects, hand-foot syndrome (HFS), can be quite disabling. Hyperpigmentation is currently not part of the grading system of HFS, but may be a marker of developing toxicity. CASE REPORT: Here, we describe three patients treated with adjuvant capecitabine for colon cancer (a 49-year-old East Indian man, a 58-year-old Asian woman, and a 54-year-old Aboriginal man) who developed moderate to severe HFS requiring delay and dose reduction. In every case, toxic side effects were preceded by hyperpigmented macules on the hands and feet. CONCLUSION: Hyperpigmentation of the hands and feet is a rare side effect with capecitabine chemotherapy and appeared to predict impending grade 2 HFS in our patients. Clinicians and health care workers in oncology should be aware of this potential side effect; however, further investigation is required to determine whether or not palmar-plantar hyperpigmentation should be included in the spectrum of HFS. Hyperpigmentation may also be more common in the non-Caucasian populations but more research is required to determine the ethnic distribution of this finding.