The management of patients with brain metastases has become a major issue due to the increasing frequency and complexity of the diagnostic and therapeutic approaches. In 2014, the European Association of NeuroOncology (EANO) created a multidisciplinary Task Force to draw evidence-based guidelines for patients with brain metastases from solid tumors. Here, we present these guidelines, which provide a consensus review of evidence and recommendations for diagnosis by neuroimaging and neuropathology, staging, prognostic factors, and different treatment options. Specifically, we addressed options such as surgery, stereotactic radiosurgery/stereotactic fractionated radiotherapy, whole-brain radiotherapy, chemotherapy and targeted therapy (with particular attention to brain metastases from non-small cell lung cancer, melanoma and breast and renal cancer), and supportive care. Key wordsbrain metastases | chemotherapy | neuroimaging | neuropathology | stereotactic radiosurgery/stereotactic fractionated radiotherapy | supportive care | surgery | targeted therapy | whole-brain radiation therapy

Immune checkpoint inhibitors (ICPI), such as ipilimumab [anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody] and nivolumab or pembrolizumab [anti-programmed cell death protein-1 (PD-1) antibodies], improve survival in several cancer types. Since inhibition of CTLA-4 or PD-1 leads to non-selective activation of the immune system, immune-related adverse events (irAEs) are frequent. Enterocolitis is a common irAE, currently managed with corticosteroids and, if necessary, anti-tumor necrosis factor-α therapy. Such a regimen carries a risk of serious side-effects including infections, and may potentially imply impaired antitumor effects. Vedolizumab is an anti-integrin α4β7 antibody with gut-specific immunosuppressive effects, approved for Crohn’s disease and ulcerative colitis. We report a case series of seven patients with metastatic melanoma or lung cancer, treated with vedolizumab off-label for ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October 2016. Clinical, laboratory, endoscopic, and histologic data were analyzed. Patients initially received corticosteroids but were steroid-dependent and/or partially refractory. One patient was administered infliximab but was refractory. The median time from onset of enterocolitis to start of vedolizumab therapy was 79 days. Following vedolizumab therapy, all patients but one experienced steroid-free enterocolitis remission, with normalized fecal calprotectin. This was achieved after a median of 56 days from vedolizumab start, without any vedolizumab-related side-effects noted. The patient in whom vedolizumab was not successful, due to active ulcerative colitis, received vedolizumab prophylactically. This is the first case series to suggest that vedolizumab is an effective and well-tolerated therapeutic for steroid-dependent or partially refractory ICPI-induced enterocolitis. A larger prospective study to evaluate vedolizumab in this indication is warranted.

Summary: Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5-fluorouracil (5-FU). The underlying pathophysiologic mechanism remains unclear but clinical data suggest that the endothelium of coronary arteries may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5-FU and support the hypothesis that a thrombogenic effect of 5-FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5-FU-induced cardiotoxicity. In the present study we evaluate the role of antithrombotic treatment with dalteparin as protection against the thrombogenic effect of 5-FU on the vascular endothelium in a rabbit model. The effects on the vascular endothelium of 5-FU, dalteparin, and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endothelium was seen in 5-FU-treated animals, often leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5-FU was partly reversible. The combination of 5-FU and dalteparin gave lower scores on Day 3 because of less evidence of thrombotic events. However, the reversibility of the endothelial damage was poorer in this group, as well as in the group that received dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5-FU, secondary to its direct toxic effect on the vascular endothelium. However, the study indicates that dalteparin per se has a toxic effect on the endothelium that is different from that of 5-FU.

Cardiotoxicity is a serious side effect of cancer treatment with the commonly used drug 5-fluorouracil (5-FU). The pathophysiology of this is unclear. Experimental studies show a thrombogenic effect of 5-FU, secondary to a direct toxic effect on the endothelium, possibly mediated by radical generation. Probucol is a lipid-lowering drug with strong antioxidant properties. The aim of this study was to evaluate the possibility of using probucol treatment to protect against the toxicity of 5-FU on vascular endothelium of the central artery in the ears of rabbits. Five groups of rabbits were treated with 1) 5-FU, 2) saline, 3) probucol high-dose and saline, 4) probucol high-dose and 5-FU, 5) probucol low-dose and 5-FU. Damage to the arterial endothelium was evaluated by scanning electron microscopy. Damage to the endothelium in 5-FU + probucol-treated animals was minimal and comparable to that of the control group. Intima disruption or thrombus formation was seen with 5-FU only. The results of the study indicate that treatment with probucol prevents 5-FU-induced endothelial injury.

LBA2002 Background: Despite treatment advances, survival of elderly GBM patients (pts) is usually < 12 months. Hypofractionated RT is advocated in order to shorten treatment time, and chemotherapy has been proposed as an alternative to RT. In a randomized trial we compared two different RT schedules with single-agent TMZ chemotherapy. Methods: Newly diagnosed GBM pts age ≥ 60 years with PS 0-2, were randomized to either standard RT (60 Gy in 2 Gy fractions over 6 weeks) or hypofractionated RT (34 Gy in 3,4 Gy fractions over 2 weeks) or 6 cycles of chemotherapy with TMZ (200 mg/m2 day 1-5 every 28 days). Follow-up including quality of life, symptom checklist, and steroid dosing was completed at 6 weeks, 3 months, and 6 months after start of treatment. The primary study end point was overall survival (OS). Results: A total of 342 pts were included. 291 pts were randomized between the 3 treatment options, 51 pts between hypofractionated RT and TMZ. Median age was 70 years (range 60-88), 59% were male and 72% had undergone tumor resection, the remaining 28% had a diagnostic biopsy only. Performance status was 0-1 for 75% of pts. Survival data are available for 334 pts (98%), with 11 pts (3%) being alive. There was no significant difference in OS between the three treatment arms, with median survival being 8 months for TMZ, 7.5 months for hypofractionated RT and 6 months for 6 weeks RT (p=0.14). Conclusions: Elderly patients with GBM have a short survival. Time-consuming therapy that does not offer longer survival should therefore be avoided. Our study showed no advantage of standard 6 weeks RT compared to hypofractionated RT over 2 weeks or 6 cycles of TMZ chemotherapy. These results indicate that standard RT should no longer be offered to the elderly pt population with GBM. Exclusive TMZ chemotherapy may be an alternative to RT. Subgroup analyses and determination of molecular markers is ongoing. Whether outcome could be improved by concomitant chemoradiotherapy is subject of ongoing clinical trials. [Table: see text]

Background: Disulfiram (DSF) is a well-tolerated, inexpensive, generic drug that has been in use to treat alcoholism since the 1950s. There is now independent preclinical data that supports DSF as an anticancer agent, and experimental data suggest that copper may increase its anti-neoplastic properties. There is also some clinical evidence that DSF is a promising anticancer agent in extracranial cancers. In glioblastoma, DSF induced O 6-methylguanine methyltransferase (MGMT) inhibition may increase response to alkylating chemotherapy. A recent phase I study demonstrated the safety of DSF in glioblastoma patients when DSF was administered at doses below 500 mg/day together with chemotherapy. We plan to assess the effects of DSF combined with nutritional copper supplement (DSF-Cu) as an adjuvant to alkylating chemotherapy in glioblastoma treatment. Methods: In an academic, industry independent, multicenter, open label randomized controlled phase II/III trial with parallel group design (1:1) we will assess the efficacy and safety of DSF-Cu in glioblastoma treatment. The study will include 142 patients at the time of first recurrence of glioblastoma where salvage therapy with alkylating chemotherapy is planned. Patients will be randomized to treatment with or without DSF-Cu. Primary end-point is survival at 6 months. Secondary end-points are overall survival, progression free survival, quality of life, contrast enhancing tumor volume and safety. Discussion: There is a need to improve the treatment of recurrent glioblastoma. Results from this randomized controlled trial with DSF-Cu in glioblastoma will serve as preliminary evidence of the future role of DSF-Cu in glioblastoma treatment and a basis for design and power estimations of future studies. In this publication we provide rationale for our choices and discuss methodological issues. Trial registration: The study underwent registration in EudraCT 2016-000167-16 (Date: 30.03.2016,) and Clinicaltrials.gov NCT02678975 (Date: 31.01.2016) before initiating the study.

Background: Multidisciplinary team (MDT) meetings provide treatment recommendations based on available information and collective decision-making in teams with complementary professions, disciplines and skills. We aimed to map ancillary medical and nonmedical patient information during case presentations and case discussions in MDT meetings in cancer care. Methods: Through a nonparticipant, observational approach, we mapped verbal information on medical, nonmedical and patient-related characteristics and classified these based on content. Data were collected from 336 case discussions in three MDTs for neuro-oncology, sarcoma and hepato-biliary cancer. Results: Information on physical status was presented in 48.2% of the case discussions, psychological status in 8.9% and comorbidity in 48.5% of the cases. Nonmedical factors, such as family relations, occupation, country of origin and abode were referred to in 3.6–7.7% of the cases, and patient preferences were reported in 4.2%. Conclusions: Provision of information on comorbidities in half of the cases and on patient characteristics and treatment preferences in <10% of case discussions suggest a need to define data elements and develop reporting standards to support robust MDT decision-making.

The aim was to evaluate volume, diffusion, and perfusion metrics for better presurgical differentiation between high-grade gliomas (HGG), low-grade gliomas (LGG), and metastases (MET). For this retrospective study, 43 patients with histologically verified intracranial HGG (n = 18), LGG (n = 10), and MET (n = 15) were chosen. Preoperative magnetic resonance data included pre- and post-gadolinium contrast-enhanced T1-weighted fluid-attenuated inversion recover, cerebral blood flow (CBF), cerebral blood volume (CBV), fractional anisotropy, and apparent diffusion coefficient maps used for quantification of magnetic resonance biometrics by manual delineation of regions of interest. A binary logistic regression model was applied for multiparametric analysis and receiver operating characteristic (ROC) analysis. Statistically significant differences were found for normalized-ADC-tumor (nADC-T), normalized-CBF-tumor (nCBF-T), normalized-CBV-tumor (nCBV-T), and normalized-CBF-edema (nCBF-E) between LGG and HGG, and when these metrics were combined, HGG could be distinguished from LGG with a sensitivity and specificity of 100%. The only metric to distinguish HGG from MET was the normalized-ADC-E with a sensitivity of 68.8% and a specificity of 80%. LGG can be distinguished from MET by combining edema volume (Vol-E), Vol-E/tumor volume (Vol-T), nADC-T, nCBF-T, nCBV-T, and nADC-E with a sensitivity of 93.3% and a specificity of 100%. The present study confirms the usability of a multibiometric approach including volume, perfusion, and diffusion metrics in differentially diagnosing brain tumors in preoperative patients and adds to the growing body of evidence in the clinical field in need of validation and standardization.