Significant Responses to Delivering Paclitaxel Directly to Brain Tumor

TEL HASHOMER, Israel—Israeli investigators report that a new technique delivering waves of paclitaxel (Taxol) directly into recurrent brain tumors has produced significant responses in patients with recurrent glioblastoma (ASCO abstract 316).

Five of 12 patients treated in a phase I study had a complete response, according to M. Raphael Pfeffer, MD, director of radiation oncology at Chaim Sheba Medical Center in Tel Hashomer, Israel. One patient had already survived 52 weeks, and another was 36 weeks out from the experimental treatment. The Israeli team, led by Zvi Ram, MD, is planning a large multicenter trial with investigators in Europe and the United States, Dr. Pfeffer said, and several international studies will test the technique with other drugs.

The new drug delivery method, called convection-enhanced delivery (CED), is used in conjunction with diffusion-weighted magnetic resonance imaging (MRI), as described at last year’s annual meeting of the American Society of Clinical Oncology.  CED pumps the drug through a catheter that has been inserted directly into the tumor. Delivery is in small pulses, rather than a continuous flow, and the researchers are able to monitor response inside the tumor in real-time by the diffusion-weighted MRI, which is sensitive to the speed of water molecules.

"Just like a wave propagates across a pond, the drug will propagate across the tumor, and therefore it gets well distributed in the tumor," Dr. Pfeffer said.

Although paclitaxel has been shown to be effective against glioblastoma in vitro, the drug does not cross the blood brain barrier. Previous attempts to deliver the drug directly into a tumor were unsuccessful, according to Dr. Pfeffer, because the drug pooled around the catheter. By delivering the drug in small pulses at a rate is of 5 µL/min, CED "makes a wave of fluid that oozes throughout the tumor," Dr. Pfeffer told ONI.

Dose Dropped 50%

The first three patients started treatment at a dose of 7 mg of paclitaxel per day for 5 days. Two developed peri-tumoral edema, somnolence, and chemical meningitis that lasted 4 to 5 days. The researchers dropped the dose by 50% to 3.5 mg of paclitaxel per day for up to 5 days (a total dose of 17.5 mg), and found the subsequent patients responded as well but without these side effects.

Two patients were reported to have slow wound healing. "The only serious toxicity was where the tumor was abutting the ventricles," Dr. Pfeffer said. "Then the drug oozed into the ventricles, and the patient suffered from ventriculitis and neurological symptoms. Otherwise the treatment was very well tolerated."

The only patient who did not respond had a cystic tumor. In two of three patients from whom tissue specimens were obtained, the researchers found no viable tumor. Minimal residual tumor was seen at the remote edges of the third resected tumor.

The diffusion-weighted MRIs have shown CED-delivered paclitaxel to distribute itself evenly throughout the tumor. "We saw that the drug specifically goes into tumor rather than healthy brain tissue," said Dr. Pfeffer. "We don’t really know why."