Table 2. Combination Chemotherapy For Extensive-Stage Small Cell Lung Cancer continued...
Evidence (duration of treatment):
The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.[7,18,19]
No clear evidence is available from reported data from randomized trials that maintenance chemotherapy will improve survival duration.[20,21,22][Level of evidence: 1iiA] However, a meta-analysis of 14 published, randomized trials assessing the benefit of duration/maintenance therapy reported an odds ratio of 0.67 for both 1- and 2-year overall survival (OS) of 0.67 (95% CI, 0.56-0.79; P < .001 for 1-year OS and 0.53-0.86; P < .001 for 2-year OS). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[Level of evidence: 1iiA]
Evidence (dose intensification):
The role of dose intensification in patients with SCLC remains unclear.[24,25,26,27,28] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[24,25] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[26,27,28,29,30,31,32,33,34] These studies have yielded conflicting results.
Four studies have shown that a modest increase in dose intensity (25%-34%) was associated with a significant improvement in survival with no compromise in quality of life (QOL).[26,27,28,29][Level of evidence: 1iiA]
Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.[29,30,31,32][Level of evidence: 1iiA]
The European Organization for Research and Treatment of Cancer trial (EORTC-08923) reported a randomized comparison of standard-dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support. The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival.
A randomized, phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks, with twice weekly ICE with G-CSF and autologous blood support. Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[Level of evidence: 1iiA] Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection.
A randomized, phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05). However, given the small study size (only 70 patients), these results should be viewed with caution.