Tumor treating field therapy in combination with bevacizumab for the treatment of recurrent glioblastoma.

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill. Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone. This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting. Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab. Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis. By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients. Bevacizumab however failed to prolong overall survival in a recent phase III trial. A pivotal phase III trial (EF-11) demonstrated comparable overall survival between physicians' choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm. There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy, but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the treated patients.

Status migrainosus as a potential stressor leading to takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy is a form of non-ischemic cardiomyopathy that may be acutely precipitated by stress. A number of neurologic conditions have been implicated in precipitating this disease such as subarachnoid hemorrhage, stroke, and seizures. Its association with status migrainosus, however, has never been described before. CASE: We report a case of a 25-year-old female presenting with status migrainosus followed by takotsubo cardiomyopathy. Supportive management was instituted in this patient and she made an excellent recovery. CONCLUSION: The intense pain associated with migraine may have acted as a stressor, thereby precipitating takotsubo cardiomyopathy. To our knowledge, this is the first reported case demonstrating a relationship between status migrainosus and takotsubo cardiomyopathy.

Bevacizumab for the treatment of surgically unresectable cervical cord hemangioblastoma: a case report.

INTRODUCTION: Hemangioblastomas are highly vascular tumors that can arise within the central nervous system as well as other organ systems within the body. They can arise sporadically or as part of von Hippel-Lindau syndrome. Those arising in critical locations within the central nervous system can be difficult to resect surgically and therefore pose a significant challenge and result in morbidity and even mortality. Hemangioblastomas express high levels of vascular endothelial growth factor that drives angiogenesis and tumor progression. We hypothesized that bevacizumab through its inhibitory effect on vascular endothelial growth factor will result in hemangioblastoma tumor regression as well as a meaningful clinical response. CASE PRESENTATION: We present the case of a 51-year-old Caucasian man with surgically unresectable cervical cord hemangioblastoma presenting with progressive weakness leading to quadriparesis. He was treated with bevacizumab and his follow up magnetic resonance imaging scans showed marked tumor regression. After only six cycles of intravenous bevacizumab (10mg/kg every two weeks), he started ambulating after being wheelchair bound. He is currently still receiving treatment almost two years after initiation of bevacizumab. CONCLUSIONS: We have shown for the first time that bevacizumab can result in significant tumor regression and a sustained clinical improvement in a patient with an otherwise unresectable spinal cord hemangioblastoma. This novel approach can be immensely useful for patients with difficult to resect hemangioblastomas or those with multiple lesions such as in von Hippel-Lindau syndrome.

Temozolomide: The evidence for its therapeutic efficacy in malignant astrocytomas.

INTRODUCTION: Malignant gliomas are a heterogeneous group of primary central nervous system neoplasms that represent less than 2% of all cancers yet carry a significant burden to society. They are frequently associated with considerable and progressive neurological disability and are ultimately intractable to all forms of treatment. Temozolomide (TMZ) is a new second generation DNA alkylating agent that has become part of malignant astrocytoma management paradigms because of its proven efficacy, ease of administration, and favorable toxicity profile. AIMS: To review the role of TMZ in the management of malignant astrocytomas (World Health Organization grades III and IV) including newly diagnosed (n) and recurrent (r) anaplastic astrocytomas (AA) and glioblastomas. EVIDENCE REVIEW: A series of pivotal clinical trials have established a role for TMZ in the treatment of malignant astrocytomas. A large phase II trial examining the role of TMZ in rAA showed a response rate of 35%, and a 6-month progression-free survival of 46%. This led to the accelerated approval of TMZ by the FDA and the EU for the treatment of rAA. Evidence for a role of TMZ in nAA is currently limited but research is ongoing in this area. The role of TMZ in the management of glioblastoma at the time of recurrence (rGBM) is less impressive but evidence for its activity was demonstrated in two large phase II trials that led to the approval of TMZ for this indication in Europe and Canada but not in the US. A recent large prospective randomized phase III trial showed that the addition of TMZ during and after radiation therapy (RT) in newly diagnosed (nGBM) patients prolonged median overall survival by 2.5 months; perhaps more importantly, the 2-year survival rate for patients receiving TMZ and RT was 26% compared with 10% for those receiving RT alone. Concurrent TMZ with RT followed by adjuvant TMZ has become the standard of care for nGBM patients. Based on the evidence presented in this trial, TMZ received approval from the FDA and the EU for patients with nGBM in 2005. PLACE IN THERAPY: THERE IS EVIDENCE TO SUPPORT THE USE OF TMZ FOR THE FOLLOWING DISEASES IN THE ORDER OF MOST TO LEAST CONVINCING: nGBM, rAA, rGBM, and nAA. This order may quickly change as more trials are being designed and implemented, particularly with novel TMZ dosing schedules.