""""""""DISCONTINUED The foci of our research efforts in the treatment of lung cancer have been clinical trials for patients with lung cancer based on our in vitro experiments and retrospective analyses of patients with small cell lung cancer. In vitro studies published this year showed paclitaxel had 1000-fold more cytotoxic activity against non-small cell lung cancer cell lines when exposed to paclitaxel for 4 days rather than 3 hours. A phase I trial using 4 days of paclitaxel with a bolus dose of cisplatin showed the recommended phase II dose was 120 mg/m2 of paclitaxel and 80 mg per meter square of cisplatin. The recommended phase II dose is now being used in a phase II trial for patients with stage IV and IIIb (with pleural effusion) NSCLC and in a neoadjuvant trial combined with 6000 cGy of chest radiation for patients with stage IIIa and IIIb. Three different studies have evaluated both long-term survivors of small cell lung cancer and patients with extensive stage disease. A cooperative North American working group from 10 institutions identified 611 patients surviving two or more years after treatment for small cell lung cancer who developed 87 second cancers, a 3.5-fold increased relative risk. This was principally caused by an 11-fold increase in the risk of lung cancer. This risk increased with the passage of time; 3 fold from 2 to 10 years after the start of treatment. The cumulative risk of non-small cell lung cancer at 12 years for these patients was 30%. Chest irradiation and continued cigarette smoking contributed to the increased risk. We have evaluted the outcome of patients with small cell lung cancer treated at our institution over the last 20 years. The patients treated on the most recent etoposide cisplatin plus concurrent chest radiation trial live modestly longer than patients treated on the older cyclophosphamide-based combined modality trials (chemotherapy plus chest radiotherapy; 21 versus 14 months). In contrast, the survival of patients treated for extensive stage small cell lung cancer over the past 20 years has not changed significantly. Our observation of the patients with extensive stage small cell lung cancer treated at our institution prompted a review of the Cancer Therapy and Evaluation Program sponsored trials for patients with extensive stage small cell lung cancer. This was done to develop additional aids for selecting regimens with an increased likelihood of improved outcome for patients with small cell lung cancer. We identified 22 randomized phase III trials for patients with extensive stage small cell lung cancer performed in North America from 1972-1993. Eighteen of the 22 (82%) trials showed no difference in survival between the control and experimental arms. Only 4 of these 22 trials showed a difference in survival. Nine phase I or phase II trials preceded the experimental arms used in the phase III trials. A statistical model was developed which used the number of patients, number of deaths, and their median survival to generate a predicted power which is the usual statistical power averaged with regard to the size of the treatment difference to be expected on the basis of the phase II trial and previous experience with regimen. The median predicted power from the phase II trials was 0.39 with a range of 0.076 to 0.73. Five of the 6 phase II trials which led to the experimental arm in randomized trials which did not give longer survivals than control treatments in phase III trials had a power of 0.5 showed a difference in survival between the experimental and control arms. The results of these retrospective analyses suggest that a power of >0.5 may be a reasonable value to achieve in a phase II trial before taking it to a phase III study. These data suggest that a statistical model which utilizes the results of the past 20 years of treatment for patients with extensive stage small cell lung cancer can help predict which phase II regimens should be advanced into phase III randomized trials.""""""""
