taxane and Carcinoma--Small-Cell

For more than 2 decades, combination chemotherapy has been the standard treatment for patients with small-cell lung cancer. Despite high initial response rates in both extensive- and limited-stage disease, long-term survival rates are only 10% to 20%. Camptothecins and taxanes are newer classes of agents that have shown significant activity against small-cell lung cancer. Their incorporation into chemotherapy regimens for small-cell lung cancer is being actively studied. In one randomized multicenter study, patients with advanced small-cell lung cancer treated with irinotecan (CPT-11, Camptosar) and cisplatin had a better survival time than patients receiving standard therapy. The combination of taxanes and irinotecan holds promise as an active regimen that may be tolerated better than cisplatin and irinotecan.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Small Cell; Docetaxel; Humans; Irinotecan; Lung Neoplasms; Paclitaxel; Randomized Controlled Trials as Topic; Taxoids

Over the last 20 years, progress in the therapy of small cell lung cancer has been painfully slow. Despite dramatic initial responses to chemotherapy, most patients relapse quickly with an overall 5-year survival of about 5%. Recent trials however offer some hope at changing this picture. Combining standard regimens with newer agents has doubled median survival in some cases. The use of novel targeted agents holds the promise of significantly increasing the survival in this disease, with manageable toxicity. This review outlines current treatment strategies, summarizes recent clinical trials and offers a view of what the next 5 years may hold for the treatment of small cell lung cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged-Ring Compounds; Carcinoma, Small Cell; Clinical Trials as Topic; Humans; Lung Neoplasms; Palliative Care; Phosphoinositide-3 Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Sirolimus; Taxoids; Topoisomerase I Inhibitors

Cisplatin (Platinol)-based chemotherapy has been the standard systemic therapy for both non-small-cell and small-cell lung cancer for the past 2 decades, though the efficacy and benefit remain modest. Recently, several novel agents have been introduced that have single-agent activity comparable to cisplatin and offer the possibility of improved therapy for lung cancer. Camptothecin and taxane derivatives are associated with both different mechanisms of action and nonhematologic toxicities, and have demonstrated additive or synergistic activity when used in combination in preclinical studies. We review pertinent clinical studies of these agents in lung cancer and present our experience in combining irinotecan (Camptosar, CPT-11) with taxanes on a weekly schedule in dose-finding and efficacy studies. When chemotherapy is delivered for 4 consecutive weeks followed by a 2-week rest, hematologic toxicity is dose limiting and most prominent during weeks 3 and 4. Dose intensification is feasible if the schedule is modified so the chemotherapy is given on days 1 and 8, with cycles repeated every 3 weeks. The most common nonhematologic toxicities remain asthenia, neuropathy, and diarrhea. Future studies will explore and better define the role of these drug combinations in the treatment of lung cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Prognosis; Survival Rate; Taxoids

Cancer management in the older patient is a growing concern, particularly with the increasing geriatric population and the high incidence of cancer among these individuals. Incidence of lung cancer in particular is known to rise with age. This article reviews prognosis, treatment options, and decision-making issues for both clinician and patient with respect to both non-small-cell and small-cell lung cancer in this population. Research findings dealing with response rates, survival rates, and symptom control in this age group are reviewed for radiotherapy, surgery, and for various chemotherapy agents, including gemcitabine, the taxanes, vinorelbine, and the topoisomerase 1 inhibitors. Quality- of-life issues are also addressed.

Topics: Age Factors; Aged; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Combined Modality Therapy; Decision Making; Deoxycytidine; Gemcitabine; Geriatrics; Humans; Lung Neoplasms; Prognosis; Quality of Life; Survival Analysis; Taxoids; Vinblastine; Vinorelbine

Treatment for small cell lung cancer has not improved substantially in the past 15 years. Some advances are being made in supportive care and by use of more intense concurrent thoracic radiotherapy. New agents such as the taxanes and the topoisomerase I inhibitors hold promise and are currently in phase III evaluation. The question whether dose intensity can improve the outcome of patients with small cell lung cancer has been raised for many years. Improving supportive care enhances our ability to test this question more thoroughly. This paper reviews the historical and current experience using high-dose therapy with hematopoietic stem cell support for the treatment of small lung cancer. Future directions are identified.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Carcinoma, Small Cell; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Lung Neoplasms; Radiotherapy Dosage; Taxoids; Topoisomerase I Inhibitors; Treatment Outcome

Using a selection process designed to reflect clinically relevant conditions, a panel of taxane-selected variants were developed to study further the mechanisms of resistance in lung cancer. Unlike continuous or pulse exposure to high concentrations of chemotherapeutic drugs which yield high resistance and often cross resistance, most variants developed here displayed low level resistance to the selecting drug with slight cross-resistance. Pulsing with taxol resulted in more highly resistant clones (up to 51.4-fold). Analysis of taxol and taxotere in the four major lung cancer cell types showed the taxanes to be more effective against NSCLC (with the exception of SKMES-taxane selected variants) than against the SCLC. Comparison of taxol and taxotere shows that taxol induces higher levels of resistance than taxotere. Further, in taxotere-selected cell lines, the cells are more resistant to taxol than taxotere, suggesting that taxotere may be a superior taxane from a clinical view. Taxol treatment resulted in increased cross-resistance to 5-FU in all classes of lung cancer except DMS-53. The high levels of Pgp in the DMS-53 and selected variant suggests this mechanism is not related to Pgp expression. Analysis of the Pgp and MRP-1 status by combination inhibitory assays and Western blotting showed no consistent relationship between expression of the membrane pumps Pgp or MRP-1 and resistance. However, where high level resistance was seen, the parent cell line expressed Pgp or MRP-1 and was accompanied by increased levels in the variants. Overall we found that the clinically relevant models used here are useful for investigating mechanisms of taxane resistance.

Topics: Adenocarcinoma; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bridged-Ring Compounds; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Survival; Docetaxel; Drug Combinations; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Taxoids

Patients with cancer may present with one or more circulatory markers of haemostatic activation which may be associated with tumor growth and cancer cell dissemination. In our clinical practice we observed haemostatic abnormalities with or without thrombotic episodes in cancer patients. The aim of the present study was to detect the D-dimer plasma levels in advanced-stage lung cancer patients before, during and after chemotherapy, and to determine whether there is a correlation with response rate, disease recurrence and survival, in order to estimate the possible predictive value of D-dimer plasma levels. Forty-seven/52 patients were evaluable and analysed; 38 patients had non-small-cell lung cancer (NSCLC) and 9 small-cell lung cancer (SCLC) and all were at an advanced stage or inoperable. Two (4.3%) achieved complete response (CR), 17 (36.2%) partial response (PR), and 16 (34%) had progressive disease (PD). We found that 14/19 (73.7%) patients with CR or PR showed a reduction in D-dimer plasma values and 11/16 (68.8%) with PD showed increased values; also, in patients with recurrent disease (12/13, 92.3%), D-dimer plasma levels were increased. All of the above values were statistically significant. D-Dimer plasma levels decrease or increase after response and progressive disease, respectively, and can act as a predictive factor of the evolution of the disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged-Ring Compounds; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Deoxycytidine; Disease Progression; Docetaxel; Female; Fibrin Fibrinogen Degradation Products; Gemcitabine; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Patient Compliance; Predictive Value of Tests; Prospective Studies; Survival Analysis; Taxoids; Treatment Outcome; Vinblastine