NASHVILLE, TennesseeThe failure of current chemotherapy to
make much of an impact on lung cancer mortality makes the need for more
effective chemotherapy obvious and data on active new agents was presented at
the Vanderbilt University Symposium by Alan Sandler, MD.
"Lung cancer accounts for more deaths than breast, colon,
and prostate cancer combined," Dr. Sandler noted. Among the approximately
135,000 patients diagnosed with non-small-cell lung cancer (NSCLC) annually,
about 30% to 40% have metastatic disease at presentation, and untreated
patients have a median survival of about 5 months. Cisplatin-based therapy
improves median survival by only about 2 months, and 1-year survival improves
from 10% without treatment to approximately 20%-25%, although it does relieve
symptoms and improve quality of life (QOL) in 66% to 78% of patients with stage
Widely Used Combinations
Most of the drugs reviewed, including paclitaxel (Taxol),
docetaxel (Taxotere), vinorelbine (Navelbine), and gemcitabine (Gemzar), are in
clinical trials of combination therapy (Figure 1). A number of combinations are
already being widely used in the clinic. "Cisplatin/paclitaxel,
cisplatin/gemcitabine, and cisplatin/vinorelbine are approved by the Food and
Drug Administration for advanced NSCLC due to a demonstrated increase in
survival," Dr. Sandler said. "Cisplatin/irinotecan has produced
comparable results in two Japanese trials."
Dr. Sandler, who is associate professor of medicine and medical
director of thoracic oncology at Vanderbilt University Medical Center in
Nashville, Tennessee, cited a phase II study by Fukuoka et al. That study
showed a 31.9% response rate to irinotecan at 100 mg/m2 weekly, with a median
survival of 42 weeks in 72 untreated patients with advanced NSCLC. Principal
toxicities were grade 3/4 leukopenia in 25% and grade 3/4 diarrhea in 21% of
Negoro et al reported similar results: responses were seen in
23 of 67 untreated patients (34%) with advanced NSCLC. "A comparison of
irinotecan/cisplatin, vinorelbine/cisplatin, and single-agent irinotecan in
NSCLC showed a response rate of 44% with irinotecan/cisplatin median survival
of 50 weeks, and 1-year overall survival of 46%," Dr. Sandler stated.
"Future directions in NSCLC include evaluating irinotecan
in other combinations including doublets (with taxanes or gemcitabine) and
triplets such as paclitaxel/carboplatin/irinotecan. Other future studies should
include combinations with noncytotoxics such as angiogenesis inhibitors,
tyrosine kinase inhibitors, or metalloprotease inhibitors," Dr. Sandler
said. "There should also be continued evaluation of irinotecan in locally
Small-Cell Lung Cancer
Small-cell lung cancer constitutes 15% to 25% of the 171,000
new lung cancer cases diagnosed each year in the United States. Irinotecan used
as a single agent in previously untreated extensive small-cell lung cancer
(SCLC) has produced response rates of 50%
(4/8) as first-line treatment and 14% to 47% as second-line treatment,
according to Dr. Sandler. Irinotecan combined with cisplatin produced complete
response rates of 29% to 30% (overall response rate > 80%) and median
survival of 13.0 to 14.3 months.
Irinotecan/cisplatin has been compared to etoposide/cisplatin
as first-line therapy in a Japanese phase III trial in extensive disease SCLC.
"Two-year survival as of March 2000 was 18.9% with irinotecan/cisplatin vs
6.5% with etoposide/cisplatin (P = .0021)," Dr. Sandler said.
Dr. Sandler will be one of the principle investigators in a
multicenter trial led by Vanderbilt University, University of Colorado, Indiana
University, and Fox Chase Cancer Center comparing cisplatin/etoposide to
cisplatin/irinotecan. This study will utilize a 3-week regimen of
cisplatin/irinotecan as hematologic toxicity often resulted in reduced or
missed doses of irinotecan on day 15 in the Japanese trial.
"Future directions for studies in SCLC will be to evaluate
irinotecan in doublet and triplet combinations and in combinations with
noncytotoxics including angiogenesis inhibitors, tyrosine kinase inhibitors,
and metalloprotease inhibitors," Dr. Sandler said. "Irinotecan should
also be evaluated in limited SCLC."