Novel Delivery of Topotecan Shows Promise for Extending Survival Time in Patients with Malignant Gliomas

Newswise — Malignant gliomas are generally fatal tumors that are highly resistant to treatment. Glioblastoma multiforme (GBM) is the most invasive type of glial tumor. These tumors tend to grow rapidly, spread to other tissue, and have a poor prognosis. One of the biggest challenges is that gliomas have roots or tentacles, making it impossible to completely remove them surgically. Thus a combination of radiation and chemotherapy is the usual course of treatment after surgery. Chemotherapy is not very effective because drugs are not able to penetrate the blood brain barrier, which prevents most drugs in the bloodstream from entering the brain. In general, current treatments have not yielded significant increases in survival rates, which is why research into novel therapies is so crucial.

Researchers at the Neurological Institute at Columbia University Medical Center investigated the use of Topotecan, a topoisomerase inhibitor in patients with malignant gliomas. The results of this study, Phase I Trial Of Topotecan By Convection Enhanced Delivery for Recurrent Malignant Gliomas, will be presented by Jeffrey N. Bruce, MD, FACS, 3:46 to 4:00 pm, Monday, May 4, 2009, during the 77th Annual Meeting of the American Association of Neurological Surgeons in San Diego. Co-authors are Casilda Balmaceda, MD, Peter Canoll, MD, PhD, Robert L. DeLaPaz, MD, Robert L. Fine, MD, Benjamin C. Kennedy, BA, Rose Lai, MD, Guy M. McKhann II, MD, Steven S. Rosenfeld, MD, PhD, Steve A. Sands, PhD, Michael B. Sisti, MD, Aaron Tannenbaum, BA, and Candix L. Yanes, RN.

"Topotecan is a chemotherapy drug that is capable of killing glioma cells, but it has not been useful for patients since it causes too many toxic side effects when it is delivered through the bloodstream. This study was primarily designed to determine the safety of this treatment and its effect on the patient's quality of life," stated Dr. Bruce.

To address this problem in patients with malignant gliomas, a novel drug delivery strategy known as convection enhanced delivery was utilized. This enables the drug to be pumped directly into the tumor via two catheters stereotactically placed into the tumor tissue. This special delivery system is designed to maximize the amount of drug that infiltrates the tumor and minimize the side effects that occur in other parts of the body.

Sixteen patients with radiographically localized recurrent malignant gliomas (10 GBM, 6 anaplastic glioma) were assigned to one of five dose groups using a dose escalation strategy (dose range=0.02-0.133 mg/ml.) until a maximum tolerated dose was established. Topotecan was delivered in a 40 ml. dose over 100 hours through two catheters stereotactically placed into tumoral/periturmoral tissue. Patients were assessed clinically, radiographically and with neuropsychological testing for toxicity and anti-tumor response. The following results were noted:

"¢There was no toxicity at infusion concentrations less than 0.1 mg/ml.

"¢At the highest dose concentration (0.133 mg/ml.), Grade 3 or 4 local toxicities were seen in two of four patients (one parietal lobe syndrome, one left upper extremity weakness).

"¢Median survival was 45 weeks (GBM = 59 weeks, anaplastic glioma = 45 weeks).

"¢Median time to progression was 20 weeks (GBM = 27 weeks, anaplastic glioma = 12 weeks).

"¢Overall 6-month survival was 77 percent.

"¢MRI scans showed tumor regression in many patients.

"Topotecan by convection enhanced delivery has significant anti-tumor effects at doses that are not harmful to normal brain tissue. These promising preliminary results indicate that this treatment provides a survival advantage that is favorable compared to other treatments that are often used for recurrent malignant gliomas. This study has established a benchmark of a maximum tolerated dose of Topotecan, which we look forward to further testing in a larger, multicenter Phase II patient trial," concluded Dr. Bruce.

Founded in 1931 as the Harvey Cushing Society, the American Association of Neurological Surgeons (AANS) is a scientific and educational association with more than 7,400 members worldwide. The AANS is dedicated to advancing the specialty of neurological surgery in order to provide the highest quality of neurosurgical care to the public. All active members of the AANS are certified by the American Board of Neurological Surgery, the Royal College of Physicians and Surgeons (Neurosurgery) of Canada or the Mexican Council of Neurological Surgery, AC. Neurological surgery is the medical specialty concerned with the prevention, diagnosis, treatment and rehabilitation of disorders that affect the entire nervous system, including the spinal column, spinal cord, brain and peripheral nerves.

Funding for this research was provided by the National Institutes of Health (NIH). The author reports no conflicts of interest.

Media Representatives: If you would like to cover the meeting or interview a neurosurgeon " either on-site or via telephone " please contact the AANS Communications Department at (847) 378-0517 or call the Annual Meeting Press Room beginning Monday, May 4 at (619) 525-6252.