Lay Summary: Treating with new chemo drugs after first attempt at chemo fails in non-small cell lung cancer is supported by credible evidence.
Two randomized clinical trials have been reported that addressed the issue of second-line treatment in patients with advanced NSCLC that progresses after they have received first-line platinum-based chemotherapy. Both trials used docetaxel because this agent had shown significant activity in this patient population in single-arm phase II trials. The eligibility requirements for both trials were also very similar, resulting in similar groups of patients being entered into each trial. Patients could have received more than one previous chemotherapy regimen, but 65 to 77% of the patients entered into these studies had received only one regimen. In the trial of Shepherd et al,65 previous treatment with a taxane was also an exclusion criteria. The majority of patients had a good PS (ECOG level 0 to 1 in 75 to 83% of patients), had stage IV NSCLC (80 to 90%), and were men (72 to 82%).
The first trial compared two doses of docetaxel (100 mg/m2 and 75 mg/m2 every 3 weeks) to BSC in patients who were taxane-naïve but had previously been treated with a platinum-based regimen. The original design was a two-arm trial comparing docetaxel, 100 mg/m2, to BSC. The trial was halted when a 6% death rate was noted in 49 patients secondary to febrile neutropenia. Also, a median of only two cycles of therapy was delivered. The dose of docetaxel was subsequently reduced to 75 mg/m2. At this dose, the median number of cycles delivered was four, and no febrile neutropenic deaths occurred. In an analysis of all patients, both the median survival times (chemotherapy arm, 7.0 months; BSC arm, 4.6 months) and the 1-year survival rates (chemotherapy arm, 29%; BSC arm, 19%) were significantly better for patients receiving second-line docetaxel vs those receiving BSC (p = 0.047 [log rank test]). The median survival time and the 1-year survival rate for the patients treated with docetaxel, 75 mg/m2, were 7.5 months and 37%, respectively (p = 0.003 compared to BSC). The overall response rate was 7.1%, with 42.7% of patients having disease stabilization on treatment. Clinical benefit was shown in a QOL study68 in which all QOL parameters favored the docetaxel-treated patients. Specifically, a significant reduction in pain and fatigue scale scores among the docetaxel-treated patients and a reduction in the need for narcotics, nonmorphine analgesic agents, and radiotherapy were documented in this group of patients.
The second trial randomized 373 patients who had previously received platinum-containing chemotherapy to one of the three following arms: docetaxel, 100 mg/m2; docetaxel, 75 mg/m2; or a control regimen of either vinorelbine or ifosfamide (V/I). The overall response rates were 6.7 to 10.8% among patients in the two docetaxel arms vs 0.8% among patients in the V/I arm (p < 0.05). The time to progression and the progression-free survival at 26 weeks also significantly favored patients in the two docetaxel arms. Although the median survival time was not significantly different between the groups, the 1-year survival rate was significantly greater with docetaxel, 75 mg/m2, (32%) compared to V/I (19%; p = 0.025). The 1-year survival rate for patients receiving docetaxel at 100 mg/m2 was 21%.
Several of the other new agents have been studied in the second-line setting, including paclitaxel, gemcitabine, irinotecan, and vinorelbine. In general, these trials have included small numbers of patients with variable results. Response rates have ranged from 0 to 20% and median survival rates (when reported) of 4 to 8 months. No randomized trials including these other agents exist with the exception of vinorelbine, as noted above.
A recent review recommended that patients with a good PS who are experiencing disease progression after receiving platinum-based chemotherapy should be offered second-line chemotherapy. Level of evidence, good; benefit, moderate; grade of recommendation, B.
H. Cho, Y.-B. Song, I.-S. Choi, E.-H. Cho, J.-W. Choi, Y. M. Ahn, Y. H. Roh, S.-H. Nam, and B.-S. Kim
A Phase II Study of Single-Agent Gemcitabine as a Second-Line Treatment in Advanced Non-Small Cell Lung Cancer
Jpn. J. Clin. Oncol., January 1, 2006; 36(1): 50 – 54.
M. A. Socinski, D. E. Morris, G. A. Masters, and R. Lilenbaum
Chemotherapeutic Management of Stage IV Non-small Cell Lung Cancer
Chest, January 1, 2003; 123(1_suppl): 226S – 243S.
Paris D. Makrantonakis, Eleni Galani, Peter G. Harper, Non-Small Cell Lung Cancer in the Elderly The Oncologist, Vol. 9, No. 5, 556-560, September 2004;