NASHVILLE--Adding gemcitabine (Gemzar) to the widely used combination
of paclitaxel (Taxol) and carboplatin (Paraplatin) may increase the
response rate in advanced non-small-cell lung cancer (NSCLC),
compared with the two-drug combination, a phase I/II study has shown.
The three drugs led to a trend toward a higher overall response rate
and increased median and 1-year survival. The incidence of
myelotoxicity increased, but was manageable without the use of growth
factors in most cases, John D. Hainsworth, MD, director of clinical
research, Sarah Cannon-Minnie Pearl Cancer Center, Nashville,
reported at an ASCO poster session.
The rationale for the study came from evidence that the
paclitaxel-carboplatin combination leads to 1-year survival of about
40% and moderate myelosuppression in NSCLC. Gemcitabine also is
active in NSCLC and has a different mechanism of action.
"Traditionally in cancer therapy, when you can use combinations
of drugs that have different mechanisms of action and use the drugs
at a reasonable dose, that sometimes translates into a more effective
therapy," Dr. Hainsworth said.
The trial involved 77 patients with stage IIIb or IV NSCLC. The
patients had no history of chemotherapy and were not eligible for
other combined therapies.
Treatment consisted of paclitaxel at 200 mg/m² on day 1,
carboplatin infused to an AUC of 5 on day 1, and gemcitabine at 1,000
mg/m² on days 1 and 8. The regimen was repeated every 21 days
for 4 to 10 cycles. For comparison, Dr. Hainsworth and his colleagues
used data from a previous trial in which they treated 155 NSCLC
patients with paclitaxel and carboplatin.
Of the 71 evaluable patients, the three-drug regimen led to a
complete response in 2 patients and a partial response in 32
patients, resulting in an overall response rate of 48%. An additional
25 patients (35%) had disease stabilization.
In contrast, the two-drug combination in the earlier study achieved
responses in 37% of patients, and an additional 33% had disease stabilization.
Median survival was 9.5 months with the three drugs vs 8 months in
the earlier trial of paclitaxel/carboplatin. One-year survival
improved to 45% with the addition of gemcitabine, compared with 40%
in the two-drug study.
"Even after adding gemcitabine, we found we could use a full
dose of paclitaxel and a slightly lower dose of carboplatin,"
Dr. Hainsworth said. "In this trial, we used a gemcitabine dose
that is reasonably close to a full dose, so we felt that we were
getting the drugs into the patients in the way that we wanted."
Compared with the two-drug regimen, the incidence of myelosuppression
increased when gemcitabine was added. Grade 3-4 leukopenia occurred
in 24% of the courses administered vs 12% with the two-drug regimen;
thrombocytopenia occurred in 17% vs 4%, and anemia in 12% vs 4%.
Nonhematologic toxicity did not differ markedly between the two- and
"The results suggest that the addition of the third drug
increases the effectiveness," Dr. Hainsworth said.
"Its not a big improvement, and it could have occurred by
chance. The improvement really doesnt mean much without a
randomized trial, but at least we can say that all the survival
figures were moving in the right direction. We definitely feel the
regimen warrants further evaluation."
The study was conducted in 15 community-based oncology practices,
which suggests the results are comparable to those that can be
obtained with the combination in the oncology community at large, he
added. A randomized clinical trial has already begun and will include
the paclitaxel/carboplatin/gemcitabine combination as one of four
regimens evaluated in patients with advanced NSCLC.