AANS 2009: Novel Delivery for Topotecan Shows Promise for Gliomas

Allison Gandey

June 05, 2009

June 5, 2009 (San Diego, California) — Topotecan (Hycamtin, GlaxoSmithKline) by convection-enhanced delivery appears to offer antitumor activity while circumventing systemic toxicity, report researchers. Presenting phase 1 results at the recent American Association of Neurological Surgeons 77th Annual Meeting, investigators demonstrated a survival advantage.

The work won the National Brain Tumor Society Mahaley Award given for the best clinical study in neuro-oncology.

Presenter Jeffrey Bruce, MD, from Columbia University Medical Center, in New York City, pointed out that gliomas are among the most malignant tumors and carry a poor prognosis. They tend to be resistant to conventional treatment with radiation and chemotherapy and typically recur within 2 cm of origin after resection.

In this prospective dose-escalation study, investigators evaluated the toxicity of topotecan by convection-enhanced delivery. They also evaluated the radiographic response, the effect on quality of life, and the potential for antitumor activity using nontoxic drug doses.

Convection-Enhanced Delivery

Edward Oldfield, MD, from the University of Virginia Health System in Charlottesville, congratulated the researchers. "This is a very nice piece of work, and I'm delighted to see that award," said Dr. Oldfield, who received similar honors in the past and served as a discussant at the meeting. It was Dr. Oldfield's research team that first developed convection-enhanced drug delivery.

Convection-enhanced delivery is a strategy in which drugs are slowly infused directly into tumors and surrounding brain through the interstitial space. When administered intravenously, the researchers point out, many antitumor drugs are highly toxic.

Topotecan is such an example. It a topoisomerase inhibitor and is considered an ideal antiglioma drug for local delivery. It is cytotoxic to glioma cells that express high levels of topoisomerase but nontoxic to normal brain where topoisomerase expression is low.

In this nonrandomized trial, investigators studied 16 patients. They assigned participants to 1 of 5 groups using a dose-escalation strategy until a maximal tolerated dose was established.

The researchers report there was no toxicity at infusion concentrations of less than 0.1 mg/mL. At the highest dose concentration (0.133 mg/mL), they observed grade 3 or 4 local toxicities, including a parietal lobe syndrome and a left upper-extremity weakness.

Small Sample

"Outcome data are difficult to interpret in such a limited series of patients," Dr. Bruce said. "However, the median progression-free survival of 20 weeks, the median overall survival of 59 weeks, and the 6-month survival of 75% compare favorably to historical control groups with refractory recurrent malignant gliomas."

Asked by Medscape Neurology to comment on the study, Alex Valadka, MD, from the University of Texas Medical School at Houston, said: "This just may be the way to go. This appears to be an effective method to deliver therapy to tumors, and while it does not offer a definitive cure, it may buy time."

Given the benefits of convection-enhanced delivery over systemic delivery methods, investigators anticipate that many drugs are likely to be effective, since much higher concentrations in the tumor and surrounding brain can be achieved. "The ideal characteristics for use with convection-enhanced delivery include drugs that are cytotoxic to tumor, nontoxic to surrounding brain tissue, and less likely to cross the blood–brain barrier, since it is already on the therapeutic side of the vasculature," said Dr. Bruce.

Drawbacks of treatment are its requirement for a surgical procedure to implant catheters and the risk for infection. The research team has established a maximum tolerated dose of topotecan for use in a planned multicenter phase 2 trial.

This study was funded by the National Institutes of Health. The researchers have disclosed no relevant financial relationships.

American Association of Neurological Surgeons 77th Annual Meeting: Abstract 607. Presented May 4, 2009.


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