Chemotherapy for Non-Small-Cell Lung Cancer: Are We Making Progress?
Abstract & Commentary
Synopsis: A prospective, randomized study was conducted to compare 3 experimental chemotherapy regimens with a reference regimen of cisplatin and paclitaxel for patients with advanced non-small cell lung cancer. A total of 1207 patients (1155 eligible) were randomly assigned to receive cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. The overall response rate for all eligible patients was 19%, with a median survival of 7.9 months (95% confidence interval, 7.3-8.5 months). While differences in toxicity profiles were demonstrated, none of the 4 regimens offered a significant advantage over the others for overall survival.
Source: Schiller JH, et al. N Engl J Med. 2002;346(2):92-98.Non-small-cell lung cancer is a common disease and a leading cause of death from cancer.1 The prognosis for patients with untreated metastatic non-small-cell lung cancer is extremely poor, with median survival of approximately 5 months and 1-year survival rates around 10%.1 The results of chemotherapy for the treatment of patients with metastatic non-small-cell lung cancer have been disappointing. While several studies have demonstrated a small survival improvement with chemotherapy for patients with advanced non-small-cell lung cancer, the magnitude of benefit has been small.2,3 Chemotherapy has been shown to improve symptoms and improve quality of life when compared with "best supportive care."4 Thus, numerous chemotherapy regimens have been developed for patients with advanced non-small- cell lung cancer. Uncontrolled Phase II studies have suggested high response rates as well as prolonged survival with several of these regimens. Thus, a randomized, clinical study was needed to compare overall survival of non-small-cell lung cancer patients following treatment with a reference chemotherapy regimen (cisplatin and paclitaxel) or with newer regimens including cisplatin and gemcitabine, cisplatin and docetaxel, and carboplatin and paclitaxel.
The study by Schiller and associates was a prospective, randomized study of 1207 patients with advanced non-small-cell lung cancer. Eligible patients had non-small-cell lung cancer that was Stage IIIB (with malignant pleural or pericardial effusion), stage IV, or recurrent disease, and received 1 of 4 treatments. The cisplatin and paclitaxel regimen consisted of 135 mg of paclitaxel/m2 of body surface area administered over a 24-hour period on day 1, followed by 75 mg of cisplatin/m2 on day 2. The cycle was repeated every 3 weeks. The cisplatin and gemcitabine regimen consisted of gemcitabine at a dose of 1000 mg/m2 administered on days 1, 8, and 15; and cisplatin at a dose of 100 mg/m2 administered on day 1 of a 4-week cycle. The cisplatin and docetaxel regimen consisted of docetaxel at a dose of 75 mg/m2 and cisplatin at a dose of 75 mg/m2 on day 1 of a 3-week cycle. The carboplatin and paclitaxel regimen consisted of paclitaxel at a dose of 225 mg/m2 over a 3-hour period followed by carboplatin at a dose calculated to produce an area under the concentration-time curve of 6.0 mg/mL/min on day 1 of a 3-week cycle. Stratification variables include performance status, weight loss in the previous 6 months, stage IIIB vs. IV or recurrent disease, and presence or absence of brain metastases. Patient characteristics including age, sex, performance status, brain metastases, weight loss, race, and disease stage were well balanced among treatment groups. There were a similar number of ineligible patients in each of the treatment groups. The overall outcome for all eligible 1155 patients was a response rate of 19%, median survival of 7.9 months, 33% 1-year survival, 11% 2-year survival, and a median time to progression of 3.6 months.
These results were not significantly different from the results for all 1207 randomized patients. There was no significant difference in overall survival between any of the 3 experimental treatment groups and the reference group receiving cisplatin and paclitaxel. Median survival for patients receiving cisplatin and paclitaxel was 7.8 months (range, 7.0-8.9 months). Median survival following treatment with cisplatin and gemcitabine was 8.1 months (range, 7.2-9.4 months); cisplatin and docetaxel was 7.4 months (range, 6.6-8.8 months); and carboplatin and paclitaxel was 8.1 months (range, 7.0-9.5 months). Similar results were seen in all groups with the percent of patients alive at 1 and 2 years, and results with cisplatin and paclitaxel achieved a 1-year survival of 31% (CI, 26-36) and a 2-year survival of 10% (CI, %). There was a statistically significant increase in median time to progression with the cisplatin and gemcitabine group. However, this time to progression was 4.2 months (range, 3.7-4.8 months), and this was marginally improved from the 3.4-month median time to progression in the cisplatin and paclitaxel group (range, 2.8-3.9 months). However, no difference in overall survival was seen between these groups. Differences in toxicities were seen following treatment with the different regimens. Cisplatin and gemcitabine appeared to be more toxic than cisplatin and paclitaxel. There were more Grade 3 and Grade 4 renal toxic effects, more anemia and thrombocytopenia, but less febrile neutropenia with cisplatin and gemcitabine than with cisplatin and paclitaxel. The regimen of carboplatin and paclitaxel had significantly fewer overall grade 4 and 5 toxic events when compared with cisplatin and paclitaxel. Schiller et al concluded that no advantage in survival is achieved with any of the 4 commonly used regimens. The regimen of carboplatin and paclitaxel was selected as a reference regimen for future studies on the basis of a lower rate of toxic effects.
Comment by Mark R. Albertini, MD
Several studies have demonstrated limited benefits for chemotherapy for the treatment of patients with advanced non-small-cell lung cancer. These benefits include a modest improvement in overall survival as well as some improvement in overall quality of life. Several chemotherapy regimens are being used based on initial results suggesting potential benefit for several of these regimens. Thus, comprehensive phase III investigation was warranted to determine potential superiority of any of the newer chemotherapy regimens and to establish a reference regimen for subsequent clinical investigation. The study by Schiller et al provides comprehensive data on 1207 patients randomly assigned to receive 1 of 4 chemotherapy regimens for advanced non-small-cell lung cancer. They provide a comprehensive assessment of toxicity as well as clinical activity of each of these regimens. The toxicity with each of these regimens was particularly problematic in patients with a poor performance status. This toxicity resulted in a caution about the routine use of platinum-based chemotherapy for poor performance status patients. Schiller et al demonstrate no significant survival advantage for any of the 3 experimental regimens when compared with the reference regimen of cisplatin and paclitaxel. They identified less toxicity of carboplatin and paclitaxel when compared with the reference regimen of cisplatin and paclitaxel. Thus, carboplatin and paclitaxel was selected as a reference regimen for subsequent investigation. This selection was based on some improved toxicity profile, although improvement in survival was not achieved.
This phase III study clearly identifies the need for additional treatment approaches for patients with advanced non-small-cell lung cancer. The results achieved in this large number of prospectively randomized patients who were treated according to 1 of 4 regimens provide a valuable reference for subsequent studies. The limitations of current chemotherapy interventions are certainly highlighted by this report. Current chemotherapy regimens achieve only marginal benefit for patients with metastatic non-small-cell lung cancer. New approaches are required. Alternate treatments such as biologic response modifiers or interventions based on defined biologic targets may offer additional treatment opportunity.5 Given the limited benefits with current chemotherapy approaches, participation in carefully designed clinical studies is required to make progress against this devastating disease.
References
1. Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36. [published erratum appears in CA Cancer J Clin. 2001;51:144].
2. Rapp E, et al. J Clin Oncol. 1988;6:633-641.
3. Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:899-909.
4. Cullen M, et al. J Clin Oncol. 1999;17:3188-3194.
5. Carney DN. N Engl J Med. 2002;346(2):126-128.
Dr. Albertini is Associate Professor, Department of Medicine, University of Wisconsin Medical School, Madison, WI.
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