Treatment Therapies
Chemotherapy
Second-line Therapy
A consequence of the improved 1-year survival rates for first-line, cisplatin-based chemotherapy is an increased need for the second-line treatment of those patients in whom NSCLC has subsequently progressed. The failure of first-line therapy, suggests clonal development with particular resistance to the agent of choice (i.e. platinum-based combinations). In pre-treated patients, second-line single-agent treatment with vindesine, etoposide, epirubicin or cisplatin has produced response rates of between 0% and 10%.20
Docetaxel has emerged as the most promising of the third-generation chemotherapies with the literature citing initial phase II response rates of between 15% and 20% in pre-treated NSCLC.20,36 These initial results have been explored further in multicentre, phase III studies.2,3 In the study by Fossella et al.,2 patients with locally advanced or metastatic NSCLC who had been treated previously with one or more platinum-based regimens, were randomised to docetaxel 100mg/m2 every 3 weeks, or docetaxel 75mg/m2 every 3 weeks, or an established second-line therapy (vinorelbine or ifosfamide at the discretion of the investigator). The RRs were 7.9% in the 100mg/m2 docetaxel arm, 12.2% in the 75mg/m2 docetaxel arm and 2.0% in the vinorelbine or ifosfamide arm. There was a significant 1-year survival benefit for the lower dose docetaxel arm (32%) when compared with the higher dose arm (21%), and the vinorelbine or ifosfamide arm. In the study by Shepherd et al.,3 patients with NSCLC who had been treated previously with platinum compounds, were randomised to docetaxel or best supportive care (patients were specifically excluded if they had previously received a taxane).
The initial docetaxel dose of 100mg/m2 was reduced to 75mg/m2 as a result of an unacceptable toxic death rate. The RR for the 75mg/m2 was low at 7.1%, but median survival was 7.5 months compared with 4.6 months on best supportive care. The 1-year survival rate was 37% for patients receiving docetaxel 75mg/m2 and 12% for those who received best supportive care.3 This study also found that patients receiving docetaxel suffered less worsening of their PS indicators and required less use of concomitant medications relating to the management of their disease symptoms.
Of the remaining third-generation agents, gemcitabine has been shown to be active in the second-line setting against refractory, platinum-treated NSCLC. Initial studies reported response rates of 20% with 1-year survival rates approaching 50% and median survival periods of approximately 7.2 months.7 A more recent study reported overall RRs of 35%, a 1-year survival rate of 16%, a median survival period of 5.1 months, and maintenance or improvement in QoL indicators for approximately 50% of patients.7 The phase II study by Hoang et al.5 reported no responses, 1-year survival rates of 25.4% and a median survival of 6.4 months, and concluded that gemcitabine monotherapy has limited activity in this setting. Clearly, the use of single-agent gemcitabine for the second-line treatment of NSCLC remains investigational.
A phase II study of the latest generation, novel antifolate (pemetrexed) has reported RRs of 4.5% in patients pre-treated with platinum and 14.1% in those pre-treated with non-platinum therapies. The median survival period was 5.7 months and the survival rate at 6 months was estimated to be 48%.6 The results of a phase III study were published recently, comparing the efficacy and toxicity of pemetrexed and docetaxel in 571 patients with advanced NSCLC, who had previously received chemotherapy. Overall RRs were 9.1% and 8.8% for pemetrexed and docetaxel, respectively, with median progression free survival 2.9 months for both treatments, and median survival time 8.3 vs 7.9 months. The 1-year survival rate was 29.7% for both treatments, while patients were less likely to suffer side effects with pemetrexed than with docetaxel.8 While this study shows comparable anti-tumour activity in this setting, it did not significantly extend survival compared with docetaxel.
The non-inferiority of pemetrexed to docetaxel could not be demonstrated. This is despite the fact that the majority (88.6%) of pemetrexed patients had a good performance status (0–1).
Lastly, vinorelbine and irinotecan have also been shown to have activity in the second-line setting for NSCLC, but as is the case with other single-agent approaches, neither was considered to be superior to docetaxel in terms of response rate or survival.9
The use of combination therapy in the second-line setting for NSCLC after failure with platinum-based regimens, has not been extensively studied and remains exploratory.9,10
1. Novello S, Le Chevalier T. Chemotherapy for non-small-cell lung cancer. Part 2: Advanced disease. Oncology 2003;17: 457–71.
2. Fossella FV, DeVore R, Kerr R, et al. Randomised phase III trial of docetaxel versus vinorelbine or ifosfomide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: the TAX 320 Non-Small-Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–62.
3. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomised trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18: 2095–103.
4. Gillenwater HH, Tynan M, Natoli S, Schell MJ, Socinski MA. Second-line gemcitabine in refractory stage IV non-small-cell lung cancer: a phase II trial. Clin Lung Cancer 2000;2:133–8.
5. Hoang T, Kim K, Jaslowski A, et al. Phase II study of second-line gemcitabine in sensitive or refractory small-cell lung cancer. Lung Cancer 2003;42:97–102.
6. Smit EF, Mattson K, von Pawel J, et al. ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: a phase II study. Ann Oncol 2003;14:455–60.
7. Crino L, Mosconi AM, Scagliotti G, et al. Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 1999;17: 2081–5.
8. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–97.
9. Shepherd FA. Second-line chemotherapy for non-small-cell lung cancer. Expert Rev Anticancer Ther 2003;3:435–42.
10. Bunn PA Jr. Chemotherapy for advanced non-small-cell lung cancer: who, what, when, why. J Clin Oncol 2002; 20(Suppl.18):23s–33s.
