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Nonplatinum Regimen Appears Active in Advanced NSCLC

Nonplatinum Regimen Appears Active in Advanced NSCLC

TOKYO—A regimen of paclitaxel (Taxol) and vinorelbine (Navelbine) in non-small-cell lung cancer (NSCLC) appears to yield results similar to those with platinum-based regimens, according to phase I/II studies presented at the 9th World Conference on Lung Cancer.

Use of nonplatinum doublets to treat NSCLC “is something we might not have heard that much about even several years ago,” said Steven Grunberg, MD, of the University of Vermont, Burlington. Today, he noted, with the drugs that have shown significant activity against lung cancer, there are 25 potential nonplati-num doublets.

A rationale for combining paclitaxel and vinorelbine, Dr. Grunberg explained, is that both affect microtubules—but differently. “Paclitaxel inhibits depolymerization and vinorelbine inhibits polymerization, therefore allowing a combined effect and hopefully a synergistic effect on microtubule structure,” he said. Both also affect apoptosis, he noted.

Six doses were tested. Vinorelbine was infused on days 1, 2, and 3 of a 21-day cycle and paclitaxel on day 1 after vinorelbine was given.

The schedule rationale was based in part on earlier studies at the University of Chicago and on local circumstances. “Our institution, the University of Vermont, is in a rural area where travel to the hospital can be limited both by distance and by weather,” Dr. Grunberg said. “We felt that three consecutive days every 3 weeks would be an easier schedule for our patients than attempting to come to the hospital on a weekly basis.”

Because significant myelosuppression was expected with the regimen, all patients were to receive G-CSF (Neupogen) “until the absolute granulocyte counts were past 5,000,” Dr. Grunberg said.

Dose-limiting toxicity was defined as grade 3 nonhematologic toxicity or grade 4 hematologic toxicity lasting more than 3 days. “The maximum tolerated dose,” he said, “was determined to be one step below the dose level at which at least two of the first four patients experienced dose-limiting toxicity.”

In all, 30 patients with stage IV NSCLC and 5 with stage IIIB disease not amenable to radiotherapy were enrolled. “Patients were allowed to have had prior neoadjuvant chemotherapy if neither paclitaxel nor vinorelbine had previously been administered,” he said.

The first dose level tested was 160 mg/m² paclitaxel and 24 mg/m² vinorel-bine daily. The dosages were selected because they were thought to be modest to moderate and should be tolerable. “However, two of our first three patients did experience dose-limiting toxicity with these doses,” he said. Both patients had asthenia marked by fatigue and myalgia so severe that they had to be hospitalized.

The investigators then dropped to a dosage of 135 mg/m² paclitaxel and 10 mg/m² vinorelbine daily. They incrementally escalated to 150 mg/m² paclitaxel and 19 mg/m² vinorelbine daily; the first two patients at this dose had severe asthenia and also developed severe stomatitis and upper esophagitis.

The maximum tolerated dose, carried into the phase II study, was determined to be 150 mg/m² paclitaxel and 16 mg/m² vinorelbine daily. Of the 22 patients who received the selected treatment dose or the dose on the level just below (150 mg/m² paclitaxel; 13 mg/m² vinorelbine daily), 7 (32%) had a partial response, and 5 had a minor response. “That’s 56% with a clinical benefit,” Dr. Grunberg said.

Partial responses were those in which a reduction in tumor area of 50% or more was confirmed by two determinations a month apart. Minor responses were those in which a 50% reduction of tumor was noted on one occasion or when a 25% to 50% reduction could be confirmed a month later.

Duration of the partial responses ranged from 2 to 16 months (median, 6 months). The median estimated survival is “just over 1 year,” Dr. Grunberg said.

The number of treatment cycles per patient ranged from 1 to 10 with a median of 4. Three patients suffered severe peripheral neuropathy. “Peripheral neuropathy is a cumulative toxicity of a paclitaxel-vinorelbine regimen,” Dr. Grunberg said. “All of the patients who received 8 or more cycles did indeed develop notable peripheral neuropathy.” Grade 1 and 2 peripheral neuropathies were seen with less extensive treatment.

The dose-limiting toxicity of the combination is nonhematologic, he stressed, with the acute limitation being asthenia and chronic peripheral neuropathy.

“We did not see a synergistic effect on microtubules in our correlative study,” Dr. Grunberg said, “but we did see a synergistic effect in the induction of apoptosis.” The synergism, he added, “is reflected in the fact that we were able to achieve these results with doses much lower than one would have expected to have used with these drugs.”

 
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