Eleven phase II studies (n=712) evaluated single-agent chemotherapy regimens.
One RCT (n=204) compared second-line chemotherapy with BSC.
Three RCTs (n=821) compared single-agent chemotherapy regimens with other single-agent regimens.
Twelve phase II studies (n=359) evaluated two-drug platinum-based regimens.
Twenty phase II (n=733) studies evaluated two-drug non-platinum- containing regimens.
Five RCTs (n=585) evaluated combinations of two drugs.
Ten phase II studies (n=387) evaluated weekly schedules of single agents , 3 phase II and phase III RCTs (n=561) evaluated weekly schedules of single agents, and 3 phase II studies (n=109) evaluated weekly schedules of combinations of two agents.
Eight phase II studies (n=328) evaluated novel chemotherapy agents.
Does chemotherapy improve survival?
The only RCT (204 patients who had previously received platinum-based chemotherapy) that compared chemotherapy plus BSC with BSC alone reported that docetaxel every 3 weeks significantly improved median time to progression (10.6 weeks versus 6.7 weeks, p=0.001), median survival (7.0 months versus 4.6 months, p=0.04) and 1-year survival (37% versus 12%, p=0.03) compared with BSC alone. With 75 mg/m2 docetaxel, there were no toxic deaths and there was a low rate of febrile neutropenia (1.8%), but grade 3 to 4 neutropenia was common (67.3%). Patient-rated pain was lower with docetaxel on the Lung Cancer Symptom scale but there were no significant differences in various QoL domains assessed using the EORT QLQ-C30 (no supporting data were presented).
Is one single-agent chemotherapy superior to another?
Three RCTs compared docetaxel with vinorelbine or ifosfamide, paclitaxel and pemetrexed. One RCT reported significantly improved 1-year survival with docetaxel compared with vinorelbine or ifosfamide (32% versus 19%, p=0.02). One RCT reported similar 1-year survival for docetaxel and pemetrexed (29.7% for both), but reported increased grade 3 and 4 neutropenia (40.2% versus 5.3%, p<0.001) and febrile neutropenia (12.7% versus 1.9%, p<0.001), leading to increased hospital admissions (13.4% versus 1.5%, p<0.001). The third RCT was underpowered and reported poor 1-year survival rates for both docetaxel and paclitaxel (6% for both).
Is a combination of two or more drugs superior to single-agent chemotherapy?
Five RCTs compared docetaxel with combination chemotherapy regimens containing docetaxel plus gemcitabine or irinotecan or vinorelbine. Studies reported no convincing improvement in survival with combination regimens: median survival was 6.5 versus 6.4 months for docetaxel plus irinotecan (p=0.4); 6.2 versus 7.3 months for docetaxel plus irinotecan (p=0.6); 9.0 versus 7.0 months for docetaxel plus gemcitabine (p=0.5); and 6 versus 6 months for docetaxel plus either gemcitabine or vinorelbine. Two RCTs were halted prematurely due to increased toxicity in the combination drug treatment group: one of the RCTs reported significantly higher interstitial lung toxicity with the combination treatment (21% versus 2%) and a 5% rate of toxic deaths; the second RCT reported that 70% of patients receiving docetaxel plus vinorelbine developed neutropenic fever. Another study reported significantly higher rates of grade 3 to 4 thrombocytopenia (17% versus 6%, p=0.04) and increased grade 3 to 4 diarrhoea (12% versus 3%, p=0.05) with docetaxel plus irinotecan compared with docetaxel alone.
Is a weekly chemotherapy schedule better than a 3- to 4-weekly schedule?
Relevant studies compared weekly and 3- to 4-weekly regimens containing docetaxel or paclitaxel either alone or in combination with gemcitabine, vinorelbine, or irinotecan. The overall response rate varied widely for single-agent regimens (0% to 37.5%) and two-drug combination regimens (9.5% to 53%). The differences between studies made it impossible to draw firm conclusions.
Three RCTs compared weekly docetaxel with 3-weekly docetaxel. The studies reported median survival times of 5.5 versus 5.8 months, 6.7 versus 5.8 months, and more than 8 months versus 5.8 months (p=0.08 for the latter). One study reported improved safety and improved QoL for the weekly schedule (no supporting data were presented), while another reported fewer grade 3 to 4 haematological toxicities with the weekly schedule.
How many cycles of second-line chemotherapy should NSCLC patients receive?
The mean number of cycles reported in studies ranged from two to four. Reasons for discontinuation of treatment were not consistently reported.
Were any new second-line treatments identified?
The results reported in studies of an alkylating agent (1 study), platinum compound (1 study), taxanes (1 study) and/or II topo-isomerase inhibitors (1 study), ifosfamide derivatives (2 studies), vinca-alkaloid derivative (1 study) and capecitabine plus irinotecan (1 study) were similar or worse than results reported for studies of standard single-agent regimens. The results for studies of cyclooxygenase-2-enzyme inhibitors and epidermal growth factor receptor tyrosine kinase inhibitors were also discussed.