TOKYOA 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
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 microtubulesbut 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
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. Thats 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
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
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.