Catherine Maurice

Eosinophilic Fasciitis and Acute Encephalopathy Toxicity from Pembrolizumab Treatment of a Patient with Metastatic Melanoma

The patterns and kinetics of toxicity with anti–PD-1 agents are emerging. The incidence of grade 3 or above toxicities is low. We identify an idiosyncratic toxicity, eosinophilic fasciitis, that requires particular clinical vigilance to enable diagnosis and management. Anti–PD-1 inhibitors have significant activity in metastatic melanoma. Responses often occur early and may be sustained. The optimal duration of treatment with these agents is unknown. Here, we report the case of a 51-year-old woman treated with pembrolizumab, as part of the Keynote-001 trial, as first-line treatment for metastatic disease. She experienced a complete response after 13.8 months of treatment with no adverse events. One month after the last drug infusion and 18 months from starting treatment, the patient presented with eosinophilic fasciitis. She then developed acute confusion and weakness, thought to be due to intracranial vasculitis. High-dose steroids were initiated with resolution of the fasciitis. Aspirin was commenced for presumed vasculitis with resolution of the neurologic symptoms. To our knowledge, there are no previous reports of eosinophilic fasciitis or cerebral vasculitis due to anti–PD-1 agents. This case demonstrates that toxicity may occur in association with pembrolizumab treatment after a prolonged period of treatment without toxicity. Future trials should explore the optimal duration of treatment with pembrolizumab. Cancer Immunol Res; 4(3); 175–8. ©2016 AACR.

Subacute CNS demyelination after treatment with nivolumab for melanoma

Checkpoint blockade carries risks of immune-related adverse effects, but frequency and severity are unknown. A patient is described who received anti–CTLA-4 (ipilimumab), and then anti–PD-1 (nivolumab). The patient developed lethal subacute and progressive CNS demyelination. Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell–rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors. Cancer Immunol Res; 3(12); 1299–302. ©2015 AACR.

Bevacizumab in Recurrent High-Grade Gliomas: A Canadian Retrospective Study

BACKGROUND Bevacizumab has been used in recurrent glioblastoma (rGBM) since 2010 in Canada. Given its cost, potential toxicities, and unclear efficacy, further studies are required to better define suitable candidates for therapy. METHODS A single-center retrospective review of patients started on bevacizumab for rGBM from 2012 to 2015 was performed. Patient demographics, tumor characteristics, treatment regimen, and dates of clinical progression and death were collected. Overall survival (OS) and progression-free survival (PFS) were used as clinical outcomes and estimates. Radiological response was assessed using modified Response Assessment in Neuro-Oncology criteria. RESULTS A total of 80 patients were included. There were 67 reported deaths, and the median OS was 9.2 months (95% confidence interval [CI 95%]=7.0-10.1 months), with a 12-month OS of 31% (CI 95%=21.9-43.5%). Some 79 patients were included for analysis of clinical progression, among whom 61 had documented clinical progression. The median clinical PFS was 4.6 months (CI 95%=3.8-6.4 months), and the 6-month clinical PFS was 39% (CI 95%=29.0-52.9%). Addition of chemotherapy did not improve clinical outcomes. A total of 68 patients were included for radiological progression analysis, with 58 radiological progressions. The median radiological PFS was 5.8 months (CI 95%=4.2-6.7 months), and the 6-month radiological PFS was 46% (CI 95%=35.6-60.0%). CONCLUSIONS This is the first reported Canadian experience with bevacizumab for rGBM. Our clinical outcomes are consistent with published data from multicenter phase II and III trials on bevacizumab in rGBM. More research is required to determine which subtype(s) of patients with rGBM could benefit from bevacizumab upon recurrence.

Cognitive rehabilitation for brain tumor survivors: A pilot study.

140 Background: Brain tumor survivors often face unique challenges from chronic cognitive deficits such as memory problems or executive dysfunction. Cognitive rehabilitation is a relatively new field. With few well-controlled studies in cancer patients, oncology and supportive care teams lack accessible, reliable tools to address cognitive dysfunction. This pilot study evaluated the feasibility and potential efficacy of two behavioral interventions for brain tumor survivors. METHODS We compared two programs, each with 8 individual treatment sessions and daily homework. Goal Management Training (GMT) is a neuroscience-based integration of mindfulness and strategy training. The Brain Health Workshop (BHW) offers supportive psychoeducation about living with a brain tumor. Using a prospective randomized design, 6 brain tumor patients (with chronic cognitive dysfunction, ≥ 3 months post-radiation or surgery) were enrolled in GMT or BHW and completed a battery of measures at baseline and post-training. Composite scores were calculated by domain, with objective tests of attention, processing speed, memory, and executive functioning, and subjective measures of coping, mood, behavioral regulation and cognitive symptoms. Patient feedback was obtained in post-training qualitative interviews. RESULTS All patients (Table 1) completed all study activities. Analyses of group differences in composite change scores showed greater improvement in executive functions and greater attainment of pre-training functional goals in the GMT group (ps < .05). The BHW group showed a trend toward greater improvement in mood and behavioral regulation that did not reach statistical significance. Patients in both groups reported satisfaction with their program and continued, frequent (daily to every other day) use of their new knowledge following training. CONCLUSIONS This pilot study demonstrated the feasibility of cognitive rehabilitation for brain tumor survivors between 1 and 8 years post-diagnosis. Results suggest unique benefits of each intervention that will be further explored in a larger clinical trial. [Table: see text].

A critical balance: Managing coagulation in patients with glioma

ABSTRACT Cancer-associated thrombosis, including both arterial and venous thromboembolism (VTE), is a significant source of morbidity and mortality in patients with glioma. This risk is highest in the immediate postoperative period and is increased by chemotherapy, radiation, and corticosteroids. Systemic anticoagulation with low molecular weight heparin is the treatment of choice in both the therapeutic and prophylactic settings. However, these patients are also at risk of intracranial hemorrhage, a potentially catastrophic complication of anticoagulation, and this risk must be carefully balanced against the risk of VTE. In this review we outline the incidence, pathophysiology and management of thrombosis in patients with glioma, with a focus on clinical considerations including perioperative management, chemotherapy-induced thrombocytopenia, and end-of-life management.

HCP-17RETROSPECTIVE ANALYSIS OF PNEUMOCYSTIS JIROVECI IN BRAIN TUMOR PATIENTS

Pneumocystis jiroveci pneumonia (PCP) can be a highly lethal infection in patients with HIV or other immunodeficiencies, with a mortality rate estimated at 50%. The use of corticosteroids has been associated with 80-94% of PCP cases in the non-HIV population. In two-thirds of cases, the infection clinically presents during the tapering of steroids, likely reflecting an infection that is unmasked as the patient regains the ability to mount an immune response. The precise influence of dose and duration of corticosteroid treatment regarding susceptibility to PCP infection remains a controversial question. Some studies suggest that patients with brain tumors on steroids for more than 5 weeks are at high risk of PCP, especially during the tapering period. Generally, patients who receive steroid treatment for more than 4 weeks at a dose equivalent to 20 mg of prednisone per day are considered for PCP prophylaxis at most cancer centres, but there is variability across institutions. At the Pencer Brain Tumor Centre at Princess Margaret, there is no established protocol regarding PCP prophylaxis in glioma patients on corticosteroids, as it is felt that the incidence of PCP is rare and side effects of prophylaxis can impact patients overall well being during treatment. Retrospective assessment of our cohort of patients with primary brain tumors from January 1st 2008 to December 31st 2013 will help determine the incidence of PCP infection in this population in the absence of prophylaxis and will allow evaluation of factors associated with PCP infection, including the dose and the duration of corticosteroid treatment, CD4 count and systemic therapy. We will also determine the proportion of patients who needed to stop their PCP prophylaxis due to side effects and the correlation between PCP infections and the duration/dose of steroid treatment. Results will be available for the SNO meeting.

CN-14RETROSPECTIVE ANALYSIS OF ISCHEMIC CEREBRAL STROKES IN PATIENTS DIAGNOSED WITH A GLIOBLASTOMA DURING THE COURSE OF A BEVACIZUMAB TREATMENT

Bevacizumab is an anti-vascular endothelial growth factor approved in the treatment of recurrent glioblastoma. It prolongs progression-free survival, improes radiologic response and contributes to reduce the dose of dexamethasone required to control peritumoral edema. Arterial and venous thromboembolic events represent significant toxicities related to the use of angiogenesis inhibitors. Various mechanisms could be implicated in bevacizumab-related strokes, as cardioembolic, lacunar stroke related to hypertension, deep venous thrombosis passing through a patent foramen ovale, pro-coagulant effect of the underlying glioblastoma and radiation-induced damages on peritumoral vessels. The characterization of the risk factors and stroke mechanisms is primordial since bevacizumab is currently used in the treatment of glioblastoma and VEGF receptor tyrosine-kinase inhibitors are actually in clinical trials for malignant gliomas. The prevention and optimal treatment of strokes depend on a precise description of the pathophysiological mechanisms involved. This retrospective study is performed with the collaboration of Roche to evaluate in detail risk factors and stroke mechanisms in the population of patients diagnosed with a glioblastoma who presented an ischemic cerebral stroke during the course of a bevacizumab treatment. The impact of the stroke on the overall survival and the location of the infarct in relation to the tumor emplacement will also be evaluated. This project will be completed in time for the SNO meeting, since we received the official approval from Roche and the ethics committee of Princess Margaret Hospital.