john Posted April 28, 2004 Share Posted April 28, 2004 Not sure how old this is but here it is Introduction The 1990s saw the introduction of many new chemotherapy agents for the treatment of small-cell lung cancer (SCLC), including irinotecan, topotecan, paclitaxel, docetaxel, gemcitabine, and vinorelbine. As single agents, these new drugs showed activity levels ranging from 8% to 50% in first-line treatment, while, as second-line agents, these same drugs had activity levels of 11% to 47%. How best to combine these agents with prior chemotherapy has been the subject of several clinical investigations. The Eastern Cooperative Oncology Group trial 7593 showed no survival advantage when patients were randomized to topotecan vs observation following 4 cycles of etoposide and cisplatin (EP) chemotherapy. Paclitaxel was combined with EP (PET) in a Southwest Oncology Group trial of 90 patients. The response rate of 56%, median survival time of 11 months, and 1-year survival of 43% are not much different than historic treatment outcomes using EP. An Intergroup trial comparing PET with an internal EP control has recently closed and will likely be presented at the next meeting of the American Society of Clinical Oncology (ASCO). It is uncertain whether these trial results will echo those negative results reported recently by Mavroudis and associates using an identical regimen compared with an identical control. All but 1 of several studies combining irinotecan with platinum and/or etoposide-based regimens have failed to show meaningful survival differences.[4-6] The 1 positive study did show a 21.7% 2-year survival for patients treated with irinotecan and cisplatin, although grades 3 and 4 hematologic toxicity was quite significant. This phase 3 study comparing irinotecan/cisplatin vs EP showed an overall response rate of 89% vs 67% in favor of the irinotecan arm, with slightly but significantly longer progression-free and median survival times. The scheduled day-15 dose of irinotecan was not administered to 50% of patients secondary to hematologic toxicity, although more grade 3 and 4 hematologic toxicity was found in the EP arm. As expected, diarrhea was more common in the irinotecan arm (16% vs 0%). A phase 3 National Cancer Institute-sponsored trial is currently evaluating this same regimen (with only day-1 and day-8 doses) vs standard EP. If this trial confirms the results of the aforementioned Japanese trials, irinotecan/cisplatin may replace EP as the standard of therapy for extensive-stage SCLC. Nevertheless, the clinical community seems to be placing its future hopes not in further endless study of cytotoxic chemotherapy combinations, but in new agents with well-defined molecular targets. New Targeted Therapies for SCLC Dr. Michael Perry focused briefly on new cytotoxic agents still in the early stages of clinical investigation. These include a new-generation platinum, ZD0473, that has been designed to overcome platinum resistance. A modest response has been seen in phase 2 testing among chemosensitive patients. New taxanes are also being developed. One appears to have a wider clinical activity spectrum, another is highly soluble in aqueous solution, and another comes in the form of an oral drug. Epothilones, a new class of tubulin-polymerizing agents designed to overcome multidrug resistance, are currently in phase 2 testing. Pemetrexed disodium (LY231514), a novel multitargeted antifolate, is being combined with cisplatin in phase 1 studies, as is tirapazamine, a bioreductive agent active in hypoxic cells. STI171 has recently been shown to inhibit kit kinase, which is found in 70% of all SCLC cells, but, so far, there is no suggestion of response in 17 patients who have been treated with this tyrosine kinase inhibitor. Trastuzumab, another targeted tyrosine kinase inhibitor directed at the erbB-2 receptor, may have activity in SCLC, as recent reports have identified overexpression of this receptor in more than 10% of SCLC cases.[9,10] Marimistat, an oral matrix metalloproteinase inhibitor, has shown little activity and significant musculoskeletal toxicity, as presented by Dr. Frances Shepherd at this year's ASCO meeting. G3139, a bcl-2 antisense oligonucleotide that has shown in vivo activity against bcl-2 overexpression, involved in circumvention of apoptosis and expressed in many cases of SCLC, has shown 17% disease stabilization with good tolerance. Vaccine studies have also been launched. Quote Link to comment Share on other sites More sharing options...
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