Division of Hematology-Oncology,
University of California Davis Cancer Center, Sacramento
95817, USA.
PURPOSE: Although cisplatin is an
important agent in non-small-cell lung cancer (NSCLC),
de novo resistance is common and acquired resistance
emerges rapidly during therapy. Proposed mediators
of platinum resistance include the protein kinase
C (PKC) signal transduction pathway and associated
c-FOS overexpression. While estrogen administration
has been reported to upregulate PKC and c-FOS _expression,
the triphenylethylenes tamoxifen and toremifene potentiate
platinum cytotoxicity by inhibition of PKC. Downregulation
of c-FOS _expression has been reported to result from
PKC inhibition. In view of these findings, we hypothesized
that toremifene would reverse platinum resistance
and that this interaction would be influenced by tumor
estrogen receptor (ER) status. MATERIALS AND METHODS:
A phase II trial of high-dose toremifene (600 mg orally
daily on days 1-7) plus cisplatin (50 mg/m2 intravenously
on days 4 and 11) every 28 days in NSCLC patients
was conducted. A group of 30 patients with metastatic
NSCLC who had been previously treated with platinum-based
therapy were enrolled. RESULTS: All of the 30 patients
were assessable for toxicity and 28 for tumor response.
Therapy was well tolerated with minimal hematologic
and non-hematologic toxicity. Common toxicity criteria
grade 3 hematologic toxicity was seen in only three
patients. Five patients achieved a partial response
for an overall response rate of 18% (95% CI 6-37).
Median overall survival was 8.1 months (95% CI 5.4-17).
To assess PKC, ER, and c-Fos _expression by immunohistochemistry,
12 informative pretreatment patient tumor specimens
were obtained. Four patient tumor specimens were positive
for one or both PKC isoforms (alpha and epsilon) while
c-Fos was overexpressed in three. None of the responding
patient tumors exhibited c-FOS or PKC-epsilon overexpression.
ER _expression was found to be infrequent (8%), contrasting
with previous reports in this tumor type. CONCLUSION:
While this phase II study indicates that high-dose
toremifene plus cisplatin is feasible, active, and
well tolerated in NSCLC patients previously treated
with platinum compounds, the mechanism of action remains
unclear. Further study of this regimen is warranted.
