New Chemotherapeutic Regimens Tried Against Brain Cancer's

NEW YORK— Three researchers at the Chemotherapy Foundation Symposium XVII reported efforts to improve survival in the brain cancers glioblastoma multiforme and astrocytoma with new chemotherapeutic combinations.

Robert L. Fine, MD, director of the Experimental Therapeutics Program, Columbia University, is concentrating on a factor that may block chemotherapeutic agents from reaching their targets.

Since paclitaxel (Taxol) exhibits substantial activity against human glioblastoma cell lines in vitro but has proved only minimally effective clinically, Dr. Fine reasoned that the blood-brain barrier might be part of the problem. In laboratory studies, he found that tam-oxifen (Nolvadex) was able to bind and inhibit P-glycoprotein, a fundamental part of the blood-brain barrier.

Encouraged by rat studies combining tamoxifen and paclitaxel, Dr. Fine is conducting a clinical trial that has enrolled 12 patients with recurrent gliomas and 5 with metastatic brain tumors. In all cases, he said, surgery was deemed to be the next appropriate clinical step.

Patients were randomized to receive either paclitaxel alone at the standard dose of 175 mg/m² or paclitaxel at the same dose preceded by tamoxifen, 150 mg/m² twice daily for 6 days. Patients had surgery 3 to 18 hours after the paclitaxel infusion ended. Concentrations of paclitaxel in the resected tissue were determined.

Interim results, Dr. Fine reported, showed that the combination of tam-oxifen and paclitaxel dramatically increased deposition of the latter drug in and around gliomas. At the center of the tumor, the concentration doubled (mean, 2.02). At the interface of tumor and normal tissue, it tripled. In adjacent normal tissue, it increased by 1.88.

The increase in the adjacent tissue, Dr. Fine emphasized, may be particularly relevant, since most relapses in glioma occur within 1 to 2 cm of the original resection. Paclitaxel’s pharmacokinetics, he added, were not altered by the combination with tamoxifen.

Metastatic Tumors

“For metastatic tumors, unfortunately, we did not see much difference,” Dr. Fine said. “In fact, metastatic tumors, I think, are biologically different from gliomas in the sense that drugs penetrate better into metastatic tumors than they do into gliomas, at least in our studies.” One reason tamoxifen may not boost pacli-taxel concentration in metastatic tumors, he suggested, may be that these tumors do not have as much P-glycoprotein as gliomas.

In fact, Dr. Fine found that paclitaxel penetrated all areas of metastatic brain tumors equally well, suggesting there is no blood-brain barrier in metastatic disease. Thus, he believes that “the best way to treat metastatic brain tumors with chemotherapy is to use the agents that have been reported to be of clinical efficacy instead of using agents that may not be clinically useful in that tumor type but are able to penetrate the blood-brain barrier.”

Dr. Fine is also studying whether the combination of tamoxifen and paclitaxel can improve drug penetration into the cerebrospinal fluid (CSF). In rat studies, high-dose tamoxifen increased penetration of paclitaxel into the CSF by 40-fold. To date, he has tried the regimen in two breast cancer patients with carcinomatous meningitis, first giving paclitaxel alone and then the combination. With tamoxifen pretreatment, he reported, the levels of paclitaxel in the CSF quadrupled at 30 minutes.

Despite his results with the tamoxifen-paclitaxel combination, Dr. Fine remains cautious. “A single tumor cell can have multiple mechanisms of drug resistance,” he said, “and thus inhibiting P-glycoprotein is not going to cure cancer because other mechanisms of resistance are operative at the same time.”

Thalidomide Plus Carboplatin

Michael L. Gruber, MD, director of neuro-oncology and clinical associate professor of neurology, New York University Medical Center, is investigating whether suppressing tumor angiogenesis can improve chemotherapeutic effectiveness. He is combining thalidomide (Thalomid) with carboplatin (Paraplatin) in patients with recurrent glioblastoma multiforme or malignant astrocytoma.

The phase I trial to define the maximum tolerated dose of thalidomide enrolled 19 patients, 17 of whom had glioblastomas. The researchers dose-escalated beginning at 100 mg/m², and determined that the maximum tolerated dose was 300 mg/m². In this trial, patients were to receive six cycles of carboplatin if possible and to continue on thalidomide until disease recurrence.

Among the trial’s 10 evaluable patients, one had a complete response, Dr. Gruber reported, and is alive 84 weeks after initiation of the therapy. Two other patients had a partial response, and four had stable disease.

Of the 71 patients in the phase II trial, 40 previously had nitrosourea-based therapy, 11 had received other forms of chemotherapy, and 20 had only surgery and radiation.

Among the 53 patients evaluable for response, 2 had a partial response, 35 had stable disease, and 18 had disease progression. The median time to tumor progression was 22 weeks, and median survival was 39 weeks. “Interestingly, when we looked at survival, it had quite a nice tail,” Dr. Gruber said. “About 30% of patients were alive at 1 year.”

Plans for a phase III trial, he said, call for patients in one arm to be treated with thalidomide plus carboplatin and those in the other arm to receive carboplatin only. The aim of the study is to determine whether “thalidomide is indeed the active agent,” Dr. Gruber said.

In a current study in which thalidomide is the only agent being given to patients with recurrent brain metastases, 2 of the 13 patients enrolled have had a complete response.

Temozolomide

Temozolomide (Temodar), recently approved by the FDA for anaplastic astrocytoma, is being investigated for potential usefulness in glioblastomas as well, alone and in combination with other agents, said Victor A. Levin, MD, professor of neuro-oncology, M.D. Anderson Cancer Center.

In a randomized trial in glioblastoma multiforme, 46% of patients had a partial response or stable disease with temozolomide, compared with 33% of those given procarbazine (Matulane). Median progression-free survival at 6 months was 21% with temozolomide and 8% with procarbazine.

An oral agent, temozolomide crosses the blood-brain barrier and achieves good distribution in the CSF. Dr. Levin noted that toxicity is much more predictable than with the nitrosoureas. “With the nitrosoureas, you sometimes have to wait 6 to 8 to 10 weeks after the stem cell effects are over before you can re-treat,” he said. “Temozolomide can be given like a clock, almost every 4 weeks.”

In recurrent glioblastoma, Dr. Levin and his colleagues are evaluating the usefulness of a combination of temozolo-mide, at a dose of 150 mg/m2, and interferon-alfa (Intron A) given three times a week subcutaneously.

Preliminary results, he reported, show a 22% partial response or stable disease rate in glioblastoma, and a median time to failure of 14 weeks. In anaplastic tumors, the partial response and stable disease rate was 68%, and the median time to failure has not yet been reached. “If the combination is going to work, it will work best in the anaplastic astrocytoma patients,” Dr. Levin said.

Also underway is research combining temozolomide with carmustine (BiCNU) in patients with glioblastoma and astrocytoma.

In another study, patients with newly diagnosed glioblastoma are being randomized to receive either temozolomide alone or temozolomide with prinomastat (an investigational agent from Agouron).

In patients with recurrent brain tumors, temozolomide is being given in combination with cis-retinoic acid, which alone is one of the most active agents against glioblastoma multiforme, Dr. Levin said.

In yet another study, temozolomide is being combined with marimastat, an investigational matrix metalloproteinase inhibitor licensed to Schering Plough by its British developers. “In this limited phase II study,” Dr. Levin said, “we’re asking, Do we really have a killer therapy, something worth testing in a large randomized, meaningful phase II study? We’re not looking for a me-too therapy. We’re looking for something that will change the direction of treatment.”