Eudocia C. Quant

Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that has efficacy in recurrent malignant gliomas, particularly in combination with irinotecan. However, responses are rarely durable. Continuation of bevacizumab in combination with another chemotherapeutic agent may demonstrate some activity. In this article we present a retrospective review of 54 patients with recurrent malignant gliomas who progressed on a bevacizumab-containing regimen and were then treated with an alternate bevacizumab-containing regimen. All patients received intravenous bevacizumab (5-10 mg/kg) every 2 weeks alone or in combination with an additional chemotherapeutic agent, such as irinotecan. There was no limit on the number of prior therapies. Clinical characteristics and outcomes were reviewed. Tumor progression was determined by a combination of clinical status and radiographic changes. Patients were 33 men, 21 women (median age, 50 years; range, 23-72 years) with a median KPS score of 80 prior to the first bevacizumab-containing regimen and 70 prior to the second regimen; median prior chemotherapy regimens including the first bevacizumab-containing regimen was 3 (range, 2-5). Median progression-free survival (PFS) on the first bevacizumab-containing regimen was 124 days (95% confidence interval [CI], 87-154 days); 6-month (6M)-PFS was 33%. Median PFS on the second bevacizumab-containing regimen was 37.5 days (95% CI, 34-42 days); 6M-PFS was 2%. Ten patients on the first regimen and 12 patients on the second regimen suffered grade 3/4 toxicities. Those patients with malignant gliomas who progressed despite a bevacizumab-containing regimen rarely responded to the second bevacizumab-containing chemotherapeutic regimen. In such patients, alternate therapies should be considered.

Medical therapies for meningiomas

Meningiomas are the most common primary brain tumor in adults. Although the majority of these tumors can be effectively treated with surgery and radiation therapy, an important subset of patients have inoperable tumors, or develop recurrent disease after surgery and radiotherapy, and require some form of medical therapy. There are increasing numbers of studies evaluating various medical therapies but the results remain disappointing. Chemotherapies and hormonal therapies have been generally ineffective, although somatostatin analogues may have therapeutic potential. There is also increasing interest in targeted molecular therapies. Agents inhibiting platelet derived growth factor receptors and epidermal growth factor receptors have shown little efficacy, but molecular agents inhibiting vascular endothelial growth factor receptors appear to have some promise. As with other tumors, advances in the medical therapies for meningiomas will require improved understanding of the molecular pathogenesis of these tumors, more predictive preclinical models, and efficient mechanisms for conducting clinical trials, given the small population of eligible patients.

The benefits of steroids versus steroids plus antivirals for treatment of Bell’s palsy: a meta-analysis

Objective To determine whether steroids plus antivirals provide a better degree of facial muscle recovery in patients with Bell’s palsy than steroids alone. Design Meta-analysis. Data sources PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies published in all languages from 1984 to January 2009. Additional studies were identified from cited references. Selection criteria Randomised controlled trials that compared steroids with the combination of steroids and antivirals for the treatment of Bell’s palsy were included in this study. At least one month of follow-up and a primary end point of at least partial facial muscle recovery, as defined by a House-Brackmann grade of at least 2 (complete palsy is designated a grade of 6) or an equivalent score on an alternative recognised scoring system, were required. Review methods Two authors independently reviewed studies for methodological quality, treatment regimens, duration of symptoms before treatment, length of follow-up, and outcomes. Odds ratios with 95% confidence intervals were calculated and pooled using a random effects model. Results Six trials were included, a total of 1145 patients; 574 patients received steroids alone and 571 patients received steroids and antivirals. The pooled odds ratio for facial muscle recovery showed no benefit of steroids plus antivirals compared with steroids alone (odds ratio 1.50, 95% confidence interval 0.83 to 2.69; P=0.18). A one study removed analysis showed that the highest quality studies had the greatest effect on the lack of difference between study arms shown by the odds ratio. Subgroup analyses assessing causes of heterogeneity defined a priori (time from symptom onset to treatment, length of follow-up, and type of antiviral studied) showed no benefit of antivirals in addition to that provided by steroids. Conclusions Antivirals did not provide an added benefit in achieving at least partial facial muscle recovery compared with steroids alone in patients with Bell’s palsy. This study does not, therefore, support the routine use of antivirals in Bell’s palsy. Future studies should use improved herpes virus diagnostics and newer antivirals to assess whether combination therapy benefits patients with more severe facial paralysis at study entry.

Response Assessment in Neuro-Oncology

Accuracy and reproducibility in determining response to therapy and tumor progression can be difficult to achieve for nervous system tumors. Current response criteria vary depending on the pathology and have several limitations. Until recently, the most widely used criteria for gliomas were “Macdonald criteria,” based on two-dimensional tumor measurements on neuroimaging studies. However, the Response Assessment in Neuro-Oncology (RANO) Working Group has published new recommendations in high-grade gliomas and is working on recommendations for other nervous system tumors. This article reviews current response criteria for high-grade glioma, low-grade glioma, brain metastasis, meningioma, and schwannoma.

Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors

Agents targeting the vascular endothelial growth factor (VEGF) pathway are being used with increasing frequency in patients with recurrent high-grade glioma. The effect of more than one antiangiogenic therapy given in succession has not been established. We reviewed the efficacy of bevacizumab, a VEGF-A monoclonal antibody, in patients who progressed following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKi). Seventy-three patients with recurrent high-grade gliomas received VEGF R-TKi (cediranib, sorafenib, pazopanib, or sunitinib) as part of phase I or II clinical trials. Twenty-four of these patients with glioblastoma progressed and received bevacizumab-containing regimens immediately after R-TKi. Those who stopped R-TKi therapy for reasons other than disease progression, or received a treatment that did not include bevacizumab, were excluded from the analysis. The efficacy of bevacizumab-containing regimens in these 24 patients was evaluated. During R-TKi therapy, 6 of 24 patients (25%) had a partial response (PR) to treatment. The 6-month progression-free survival (APF6) was 16.7% and median time-to-progression (TTP) was 14.3 weeks. Grade III/IV toxicities were seen in 13 of 24 patients (54%). Subsequently with bevacizumab salvage therapy, 5 of 24 patients (21%) had a PR, the APF6 was 12.5%, and the median TTP was 8 weeks. Five of 24 patients had grade III/IV toxicities (21%). The median overall survival (OS) from the start of R-TKi therapy was 9.2 months (range: 2.8-34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3-28.9+). Bevacizumab retains modest activity in high-grade glioma patients who progress on R-TKi. However, the APF6 of 12.5% in this cohort of patients indicates that durable tumor control is not achieved for most patients.

Response assessment challenges in clinical trials of gliomas.

Accurate, reproducible criteria for determining tumor response and progression after therapy are critical for optimal patient care and effective evaluation of novel therapeutic agents. Currently, the most widely used criteria for determining treatment response in gliomas is based on two-dimensional tumor measurements using neuroimaging studies (Macdonald criteria). In recent years, the limitation of these criteria, which only address the contrast-enhancing component of the tumor, have become increasingly apparent. This review discusses challenges that have emerged in assessing response in patients with gliomas and approaches being introduced to address them.

Recurrent high-grade glioma.

Opinion statementOpinions vary on the best treatment options for recurrent high-grade glioma. Some argue that bevacizumab should become standard of care for patients with recurrent glioblastoma, especially in light of recent FDA approval for this indication. However, this opinion is not uniformly accepted. Age, performance status, histology, tumor size and location, O6-methylguanine-DNA methyltransferase (MGMT) methylation status for glioblastoma, 1p/19q status for oligodendroglial tumors, and the number and types of prior therapies are important considerations. In addition, recurrent disease must be distinguished from “pseudoprogression” due to treatment effects. Enrollment in a clinical trial is the optimal choice for most patients with recurrent high-grade glioma after failure of radiation therapy and temozolomide. For patients who are ineligible or do not have access to clinical trials, then either bevacizumab monotherapy or bevacizumab in combination with a second agent such as irinotecan is recommended. Involved-field external beam radiation should be considered for patients with anaplastic gliomas who have not received radiation. For patients with anaplastic astrocytoma who progress after radiotherapy, temozolomide may be used. For patients with anaplastic oligodendroglioma who progress after radiotherapy, PCV chemotherapy and temozolomide are options. Oligodendroglial tumors with 1p/19q deletions are more likely to respond to treatment. In the past, carmustine was commonly used to treat recurrent high-grade glioma, but the utility of carmustine in the modern era is unknown because most studies were performed prior to the widespread use of temozolomide. High-precision re-irradiation such as stereotactic radiosurgery is another option in high-grade glioma, especially for patients with poor bone marrow reserve or inability to tolerate chemotherapy, but there is a paucity of studies with adequate controls. Surgery may be useful as adjuvant treatment for patients with symptoms due to mass effect or for patients requiring definitive histopathology, but it generally should be combined with another treatment modality. Emerging therapies, including dose-intense temozolomide regimens, targeted molecular inhibitors, other antiangiogenic therapies, viral gene therapies, immunotherapies, and convection-enhanced delivery of targeted immunotoxins, are still under investigation.

Salvage stereotactic radiosurgery for breast cancer brain metastases: outcomes and prognostic factors.

Salvage stereotactic radiosurgery (SRS) is often considered in breast cancer patients previously treated for brain metastases. The goal of this study was to analyze clinical outcomes and prognostic factors for survival in the salvage setting.

Novel Medical Therapeutics in Glioblastomas, Including Targeted Molecular Therapies, Current and Future Clinical Trials

The prognosis for glioblastoma is poor despite optimal therapy with surgery, radiation, and chemotherapy. New therapies that improve survival and quality of life are needed. Research has increased our understanding of the molecular pathways important for gliomagenesis and disease progression. Novel agents have been developed against these targets, including receptor tyrosine kinases, intracellular signaling molecules, epigenetic abnormalities, and tumor vasculature and microenvironment. This article reviews novel therapies for glioblastoma, with an emphasis on targeted agents.

Neurological Complications of Hematopoietic Stem Cell Transplantation

Complications following hematopoietic stem cell transplantation have long been recognized. The causes are numerous, including chemoradiotoxicity, medication toxicity, metabolic abnormalities, organ failure, graft versus host disease, infection, pancytopenia, and platelet dysfunction. This chapter summarizes the disorders affecting the nervous system associated with hematopoietic stem cell transplantation. As the number of transplants performed annually increases, potential neurologic complications are being seen with increasing frequency.