Local Delivery of Chemotherapy Directly into the Fourth Ventricle of the Brain
Local Delivery of Chemotherapy Directly into the Fourth Ventricle of the Brain: A Novel Treatment Approach for Children with Medulloblastoma and other Malignant Tumors of the Posterior Fossa
by David I. Sandberg, M.D., Director of Pediatric Neurosurgery at the University of Texas-Houston and Associate Professor at the University of Texas-MD Anderson Cancer Center and Children’s Memorial Hermann Hospital
Introduction: The Need for Improved Treatments for Children with Malignant Posterior Fossa Brain Tumors
Current treatment regimens for children with malignant brain tumors include surgical resection, radiation therapy, and intravenous chemotherapy. Unfortunately, intravenous chemotherapy must be given in high doses in order to overcome the blood-brain barrier, a fine network of capillaries which protects the brain from unwanted substances. As a result of these high chemotherapy doses, many children suffer from serious side effects and may even have organ failure or die from the toxic effects of chemotherapy. Moreover, when tumors recur, the prognosis for long-term survival is very poor in children with medulloblastoma and other fourth ventricular tumors such as atypical teratoid rhabdoid tumor (ATRT) and ependymoma. Novel treatment approaches are warranted both to improve survival rates and to minimize the side effects associated with current treatment regimens.
Local Delivery of Chemotherapy into the Fourth Ventricle – the Site of Disease Origin!
Led by David I. Sandberg, M.D., Director of Pediatric Neurosurgery at the University of Texas-Houston and Associate Professor at the University of Texas-MD Anderson Cancer Center and Children’s Memorial Hermann Hospital, a team of investigators has developed a novel approach to treat malignant fourth ventricular tumors. Over the past 7 years, Dr. Sandberg has been the principal investigator in a series of animal studies in piglets and non-human primates. These studies have demonstrated that chemotherapy can safely be administered directly into the fourth ventricle of the brain – the site of disease origin and the most common site of tumor recurrence. Local infusions of chemotherapy caused no neurological deficits or evidence of damage to the brain on MRI scans or pathology studies. Moreover, high drug levels – 100-fold higher than those achieved by intravenous infusions – can be achieved directly at the site of disease. Drug levels high enough to kill tumor cells are achieved in cerebrospinal fluid sampled from the lumbar spine as well. Thus, this treatment approach will potentially enable simultaneous treatment of tumor at the site of disease origin in the fourth ventricle as well as tumor which has spread to the spine or other regions of the brain. Moreover, intravenous drug levels are low or negligible, so children would likely be spared from the many toxic side effects caused by intravenous chemotherapy protocols. Results of these studies were reported in the Journal of Neurosurgery:Pediatrics and the Journal of Neuro-Oncology.
A New Clinical Trial – Providing Hope to Patients with Recurrent Medulloblastoma, Atypical Teratoid/ Rhabdoid Tumor, and Ependymoma
Based upon the promising animal studies performed by Dr. Sandberg and colleagues, a joint pilot clinical trial has been initiated at The University of Texas MD Anderson Children’s Cancer Hospital and Children’s Memorial Hermann Hospital. This trial has been approved by the Institutional Review Boards of both institutions and has received an IND (Investigational New Drug) exemption from the FDA (Food and Drug Administration) Eligible patients will undergo surgical resection of recurrent tumor from the posterior fossa of the brain. Simultaneously, a catheter will be inserted into the fourth ventricle of the brain. This catheter will be connected to a reservoir placed under the skin through which chemotherapy will be given. The chemotherapeutic agent used will be methotrexate, a drug which has shown promise in previous studies for malignant brain tumors when administered into fluid spaces of the brain and spine. This study will be the first time that methotrexate or any other chemotherapeutic agent has ever been given directly into the primary site of disease for fourth ventricular tumors. Chemotherapy will be given into the fourth ventricle in 3 cycles over the course of 3 months. Patients will be assessed by MRI scans as well as sampling of cerebrospinal fluid. Our hope is that this novel approach not only proves to be safe, as expected based upon the preclinical animal studies, but dramatically reduces or eliminates tumor burden in the brain and spine and leads to longer survival for children with malignant fourth ventricular tumors.