Stage IV NSCLC Treatment
Maintenance therapy following first-line chemotherapy
One treatment strategy that has been investigated extensively in NSCLC is maintenance therapy following initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:
- Continuing the initial combination chemotherapy regimen.
- Continuing only single-agent chemotherapy.
- Introducing a new agent as "maintenance."
Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.
- None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles.
- Two trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[37,38]
- No consistent improvement in quality of life was reported.[38,39,40]
- Chemotherapy-related toxicities were greater with prolonged chemotherapy.[39,40]
- For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy prior to disease progression.
- These data suggest that PFS, but not OS, may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events from additional cytotoxic chemotherapy and no consistent improvement in quality of life.
Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it should be administered for no more than six cycles.[37,38,39,40]
One randomized trial has reported favorable outcome with the addition of pemetrexed following standard first-line platinum-based combination chemotherapy.
- In the trial, 663 patients with stage IIIB or stage IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed or placebo until disease progression.
- Both the primary endpoint of PFS and the secondary endpoint of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR = 0.50; 95% CI, 0.42-0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR = 0.79; 95% CI, 0.65-0.95; P = .012).
- Benefit was not seen in patients with squamous histology.
- Higher than grade 3 toxicity and treatment discontinuations resulting from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.
- No pemetrexed-related deaths occurred.
- Relatively fewer patients in the pemetrexed group than in the placebo group received systemic postdiscontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).
Maintenance therapy with pemetrexed is well tolerated and offers improved PFS and OS compared with placebo in patients with advanced NSCLC. Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.