Combination chemotherapy

Two meta-analyses evaluated the role of platinum combinations versus nonplatinum combinations.

Two meta-analyses evaluated the role of platinum combinations versus nonplatinum combinations.

A Cochrane analysis did not identify a difference in 6-, 12-, or 24-month survival.[9]

Two meta-analyses evaluated the role of platinum combinations versus nonplatinum combinations.

A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those receiving a nonplatinum agent.[6][Level of evidence A1]

The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide.[10] The median survival was 11.8 months in the cisplatin arm and 12.5 months in the carboplatin arm.[10][Level of evidence A1] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED.

Irinotecan. Five trials and two meta-analyses have evaluated the combination of etoposide and cisplatin versus irinotecan and cisplatin. Only one of the trials showed the superiority of the irinotecan-and-cisplatin combination.[11][Level of evidence A1] Subsequent trials and the meta-analyses support that the regimens provide equivalent clinical benefit with differing toxicity profiles.[12-17][Level of evidence A1] Irinotecan-and-cisplatin regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than etoposide-and-cisplatin regimens. Treatment-related deaths were comparable between the two groups.

Topotecan. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not superior to etoposide and cisplatin.[18] The 1-year survival rate was 31% (95% CI, 27%–36%) and was deemed to be noninferior, as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[18][Level of evidence A1]

Paclitaxel. No consistent survival benefit has resulted from the addition of paclitaxel to etoposide and cisplatin.[19,20]

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.[10,21,22]

Reported data from randomized trials show no clear evidence that maintenance chemotherapy improves survival duration.[23-25][Level of evidence A1] 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 OS (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.[26][Level of evidence A1]

The role of dose intensification in patients with SCLC remains unclear.[27-31] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[27,28] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[29-37] These studies have yielded conflicting results.

The role of dose intensification in patients with SCLC remains unclear.[27-31] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[27,28] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[29-37] 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).[29-32][Level of evidence A1]

The role of dose intensification in patients with SCLC remains unclear.[27-31] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[27,28] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[29-37] These studies have yielded conflicting results.

Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.[32-35][Level of evidence A1]

The role of dose intensification in patients with SCLC remains unclear.[27-31] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[27,28] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[29-37] These studies have yielded conflicting results.

The European Organisation 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.[35] 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.

The role of dose intensification in patients with SCLC remains unclear.[27-31] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[27,28] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[29-37] These studies have yielded conflicting results.

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.[36] 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.[36][Level of evidence A1] Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection.

The role of dose intensification in patients with SCLC remains unclear.[27-31] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[27,28] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[29-37] These studies have yielded conflicting results.

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).[37] However, given the small study size (only 70 patients), these results should be viewed with caution.