Sequential Combination Chemotherapy in Patients with Advanced Nonsmall Cell Lung Carcinoma
Abstract & Commentary
Synopsis: Doublet chemotherapy has been associated with median survivals of 8-10 months and 1-year survivals of 30-35% in good performance status patients with advanced nonsmall cell lung cancer (NSCLC). Toxicity has often limited the duration of treatment and the exploration of more aggressive 3-drug regimens due to overlapping toxicities and the frequent presence of multiple comorbid conditions in this patient population. This report explores the use of a sequential chemotherapy regimen that uses a combination of carboplatin and gemcitabine for 3 cycles followed by 3 cycles of paclitaxel. After 6 cycles of treatment, patients were followed without active therapy until disease progression at which time selection of further treatment was at the discretion of the investigator. Even though 27% of patients had a performance status of 2, the regimen was generally well tolerated. There were 2 CRs and 8 PRs in 37 patients with stage IIIB (pleural effusions) (19%) and IV (81%) lung cancer (response rate 27%). Median, 1-year and 2-year survivals for all patients were 9.5 months, 36%, and 11%, respectively. This regimen is currently being compared to standard regimens in a cooperative group trial and represents a possible alternative for patients with poorer performance status.
Source: Edelman M, et al. Cancer. 2001;92:146-152.
Recent advances in chemotherapy have extended the median survival of patients with advanced lung cancer from 4-6 months to 8-10 months with 1-year survivals of 30-35%. These studies are, however, heavily influenced by patient selection. Recognizing that chemotherapy is often poorly tolerated in patients with significant comorbid conditions, entry onto clinical trials has typically been restricted to patients who are fully ambulatory (performance status [PS] 0 or 1). In addition, some trials have included patients with stage III disease without pleural effusions, a group that is known to respond better to chemotherapy. Edelman and associates treated 37 patients with NSCLC, 81% of whom had stage IV disease and the remainder with Stage IIIB with pleural effusions with a planned sequential chemotherapy regimen. Patients initially received carboplatin AUC 5.5 day 1 and gemcitabine 1000 mg/m2 days 1 and 8 every 21 days for 3 cycles followed by paclitaxel 225 mg/m2 every 21 days for 3 cycles.
In general, therapy was well tolerated. Eighteen patients received all 6 cycles of treatment. Thrombocytopenia was common on day 15 of the carboplatin/gemcitabine regimen but recovery typically occurred by day 21. Grade 4 neutropenia occurred in 21% of patients and in 9% of the cycles; however, febrile neutropenia occurred in only 1% of the cycles and only 3 patients received colony stimulating factors in subsequent cycles. One patient died with complete heart block, possibly related to paclitaxel. Dose reductions or delays, all due to myelosuppression, were required in 17% of the gemcitabine/carboplatin cycles and in 5% of the paclitaxel cycles. Toxicity in patients with PS of 2 was similar to that of the overall study population.
All 37 patients had completed therapy at the time of the report and were evaluable for survival with a median follow-up of 23.5 months. The median survival of the entire population was 9.5 months with 1- and 2-year survivals of 36% and 11%. The median survivals for patients with a PS of 0-1, PS of 2 and those with IIIB disease were 11.2, 6.4, and 15.6 months, respectively.
Comment by Michael J. Hawkins, MD
While controlled clinical trials understandably restrict eligibility to patients with good performance status, most patients with advanced NSCLC have numerous comorbid illnesses that often prevent aggressive chemotherapeutic approaches. Although a significant number of patients with a PS of 2 were entered and most patients had stage IV disease, the reported regimen produced response rates and survivals similar to those reported in other studies of NSCLC. However, the regimen appeared to be well tolerated and toxicity was primarily limited to myelosuppression; neurotoxicity, often dose limiting following repeated cycles of a platinum/taxane combinations, was not a major problem in this study. This regimen can be considered as a reasonable alternative for patients with poor performance status who wish to be treated for their lung cancer and who are not eligible for a clinical trial.
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