Activity of high-dose toremifene plus cisplatin in platinum-treated nonsmall-cell lung cancer: a phase II California Cancer Consortium Trial

Purpose: Although cisplatin is an important agent in non-small-cell lung ca ncer (NSCLC), de novo resistance is common and acquired resistance emerges rapidly during therapy. Proposed mediators of platinum resistance include t he protein kinase C (PKC) signal transduction pathway and associated c-FOS overexpression. While estrogen administration has been reported to upregula te PKC and c-FOS expression, the triphenylethylenes tamoxifen and toremifen e potentiate platinum cytotoxicity by inhibition of PKC. Downregulation of c-FOS expression has been reported to result from PKC inhibition. In view o f these findings, we hypothesized that toremifene would reverse platinum re sistance and that this interaction would be influenced by tumor estrogen re ceptor (ER) status. Materials and methods: A phase II trial of high-dose to remifene (600 mg orally daily on days 1-7) plus cisplatin (50 mg/m(2) intra venously 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 t olerated with minimal hematologic and non-hematologic toxicity. Common toxi city 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% Cl 6-37). Median overall survival was 8.1 months (95% Cl 5.4-17). To assess PKC, ER, and c-Fos expression by immunohistochemistry, 12 informa tive pretreatment patient tumor specimens were obtained. Four patient tumor specimens were positive for one or both PKC isoforms (alpha and epsilon) w hile c-Fos was overexpressed in three. None of the responding patient tumor s exhibited c-FOS or PKC-E overexpression. ER expression was found to be in frequent (8%), contrasting with previous reports in this tumor type. Conclu sion: While this phase 11 study indicates that high-dose toremifene plus ci splatin is feasible. active, and well tolerated in NSCLC patients previousl y treated with platinum compounds, the mechanism of action remains unclear. Further study of this regimen is warranted.