Martin K. Nicholas

Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma

PURPOSE We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. PATIENTS AND METHODS One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. RESULTS In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade > or = 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). CONCLUSION Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab

Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma.

Corticosteroid Use in Patients with Glioblastoma at First or Second Relapse Treated with Bevacizumab in the BRAIN Study

BACKGROUND Vascular endothelial growth factor inhibitors have corticosteroid-sparing effects in patients with high-grade gliomas. We assessed corticosteroid use in patients with recurrent glioblastoma treated with bevacizumab (BEV) in the BRAIN study (J Clin Oncol 2009;27:4733-4740). METHODS BRAIN was a phase II, multicenter, randomized, noncomparative trial of BEV alone (n = 85) or in combination with irinotecan (CPT-11) (n = 82) in adults with recurrent glioblastoma. Median corticosteroid dose for patients who used corticosteroids at baseline was summarized by treatment arm; the percentage of patients who had sustained (≥50% corticosteroid dose reduction for ≥50% of time on study drug) or complete (discontinuation of corticosteroid for ≥25% of time on study drug) reduction in corticosteroid dose overall and by objective response and progression-free survival was calculated. The incidence of corticosteroid-related adverse events was summarized. RESULTS In each treatment group, 50% of patients were using systemic corticosteroids at baseline. The majority of those experienced a reduction in dose while receiving BEV-based therapy. Thirteen (30.2%) BEV and 20 (46.5%) BEV + CPT-11 patients had a sustained reduction of corticosteroid dose; 7 (16.3%) BEV and 9 (20.9%) BEV + CPT-11 patients had a complete reduction of corticosteroid dose. The majority of patients who had an objective response or progression-free survival >6 months experienced corticosteroid dose reduction. Approximately 64% of patients who used corticosteroids while receiving BEV-based therapy experienced infection. CONCLUSION BEV may have corticosteroid-sparing effects in patients with recurrent glioblastoma. Corticosteroid reduction may positively affect patient health-related quality of life. Given the exploratory nature of the analyses in a noncomparative study, these results should be interpreted cautiously.

Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.

Suppressor and cytolytic cell function in multiple sclerosis. Effects of cyclosporine A and interleukin 2.

Patients with progressive multiple sclerosis (MS) demonstrated persistent reductions in levels of concanavalin A (Con A)-induced suppressor activity and heightened levels of in vitro pokeweed mitogen (PWM)-induced IgG secretion. The reduced Con A suppressor activity could not be reversed by addition of interleukin 2 (IL-2). Cyclosporine A (CsA) treatment did not alter the defect in Con A-induced suppressor activity, but did markedly inhibit T8+ cell-mediated alloantigen directed cytolytic activity; this latter defect was reversible by in vitro addition of IL-2. CsA-treated patients did not differ from placebo-treated patients with regard to levels of PWM-induced IgG secretion or proliferative responses of their mononuclear cells to Con A. The results indicate that CsA treatment of MS patients reduces cytolytic function from baseline normal values, but does not alter aberrant suppressor cell function.

Prevention of neural allograft rejection in the mouse following in vivo depletion of L3T4+ but not LYT-2+ T-lymphocytes

Publisher Summary This chapter examines the prevention of neural allograft rejection in a mouse following an in vivo depletion of L3T4 + but not LYT-2 + T-lymphocytes. In the experiment described in the chapter, a mouse model for fetal neural transplantation as a means of determining the degree of immunological privilege afforded neural tissue following transplantation to the central nervous system (CNS). Although L3T4 + T-cells consistently outnumbered LYT-2 + T-cells in isolates from neural allograft, the relative numbers of LYT-2 + cells increased with time such that the L3T4:LYT-2 ratio decreased from 5.2 at 1 month after transplantation to 2.2 at 4 months after transplantation. This suggested a possible role for the LYT-2 T-lymphocyte late in the rejection process. The success of T-cell depletion in vivo was established using flow cytometry. The results of a blinded histological evaluation of transplants from the 4 treatment groups are presented in the chapter.

Leptomeningeal carcinomatosis in esophageal cancer: a case series and systematic review of the literature.

The aim of this study was to more clearly define the clinical course of leptomeningeal carcinomatosis due to esophageal cancer. A single institution retrospective case series was conducted. Additionally, a systematic review of the literature was performed. We present a large case series (n = 7) of leptomeningeal carcinomatosis due to esophageal cancer. Our case series and systematic review of the literature report similar findings. In our series, we report a predominance of male patients (86%) with adenocarcinoma histology (77%). Variable onset of leptomeningeal involvement of esophageal cancer in relation to the original diagnosis of the primary disease (5 months to 3 years and 11 weeks) was noted. Disease progresses quickly and overall survival is poor, measured in weeks (2.5-16 weeks) from the diagnosis of leptomeningeal involvement. Four of our patients initiated whole-brain radiation therapy with only two completing the course prior to clinical deterioration. Our patient with the longest survival (16 weeks) received intrathecal topotecan and oral temozolomide. Leptomeningeal carcinomatosis secondary to esophageal cancer has a poor prognosis. A clearly beneficial treatment modality is lacking.

A phenotypic analysis of T lymphocytes isolated from the brains of mice with allogeneic neural transplants

Publisher Summary This chapter describes the phenotypic analysis of T cells isolated from the brains of mice with iso- and allogeneic intraventricular neural transplants. The chapter indicates the preponderance of MHC class II restricted T lymphocytes in most neural allografts when mice differ completely at the MHC and at mH loci. Depletion of class II-restricted T cells in host mice permits the survival of fully histoincompatible orthotopic skin grafts, while depletion of class I-restricted cells does not. Although, class II-restricted cells are often functionally defined as helper cells, they can clearly effect cytotoxic functions as well, an activity, which predominates in the class I-restricted subset. The target(s) of the immune response observed in intraventricular allografts is unknown. While class I antigen expression on neurons can be induced in vitro with interferons, class II antigen expression has not been convincingly demonstrated. This relative resistance to inducible MHC antigen expression may confer selective privilege to neurons, especially if class II MHC restriction proves to play a pivitol role in the rejection process.

Update in the treatment of high-grade gliomas

Advances in the molecular classification of high-grade gliomas are laying the groundwork for potential changes in the treatment of high-grade gliomas. Currently, a combined modality approach involving surgery, radiation therapy, and chemotherapy is most often used in the treatment of high-grade gliomas. The authors review recent advances in the treatment of these primary brain tumors.

Association between hospital volume and receipt of treatment and survival in patients with glioblastoma

The relation between hospital volume and outcomes for patients with glioblastoma is unknown. We undertook this study to determine the effect of hospital volume on treatment received and its effect on survival in patients with glioblastoma. We included patients from the National Cancer Database diagnosed with a glioblastoma from 2006 to 2013. Hospital volume was calculated by examining the treating facilities average number of cases per year and grouping them into tertiles: (low < 9.25, medium 9.26–23.88, and high ≥ 23.39). Treatment was defined as receiving any type of therapeutic surgery, radiation or chemotherapy. Using regression models we examined the relation between hospital volume to treatment received and survival with adjustment for clinical, socioeconomic and institutional factors. The study included 68,726 patients of which 91.8% received treatment. Among patients diagnosed at low volume facilities, 90.1% received treatment versus 94.2% in high volume facilities (p < 0.0001). Compared to low volume centers, the odds ratio of receiving any treatment was 1.01 (CI 95% CI: 0.95–1.09) and 1.43 (95% CI: 1.31–1.55) for medium volume and high volume facilities, respectively. On multivariate analysis for survival among those who received treatment, the hazard of mortality was decreased at high volume (HR 0.92, 95% CI 0.89–0.94) facilities compared to low volume facilities. Patients diagnosed with glioblastoma at a high volume facility (≥23.39 cases per year) have an increased likelihood of receiving treatment. Furthermore, glioblastoma patients may significantly improve their survival by choosing to receive care at a high-volume hospital.