Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer

A systematic review and meta-analysis

Daniele Raggi, R. Miceli, G. Sonpavde, P. Giannatempo, L. Mariani, M. D. Galsky, J. Bellmunt, Andrea Necchi

Research output: Contribution to journalArticle

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Abstract

Background: The efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC. Patients and methods: Literature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3-4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status =1 and hepatic metastases. Results: Forty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1-17.9] versus 31.9% [95% CI 27.3-36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P <0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284).When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P <0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3-4 toxicity were seen between the two groups. Conclusions: Despite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations.

Original languageEnglish
Pages (from-to)49-61
Number of pages13
JournalAnnals of Oncology
Volume27
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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Salvage Therapy
Meta-Analysis
Drug Therapy
Neoplasms
Disease-Free Survival
Survival
Carcinoma
Confidence Intervals
Taxoids
Combination Drug Therapy
Platinum
Odds Ratio
Neoplasm Metastasis
Safety

Keywords

  • Chemotherapy
  • Combination chemotherapy
  • Salvage therapy
  • Single-agent chemotherapy
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer : A systematic review and meta-analysis. / Raggi, Daniele; Miceli, R.; Sonpavde, G.; Giannatempo, P.; Mariani, L.; Galsky, M. D.; Bellmunt, J.; Necchi, Andrea.

In: Annals of Oncology, Vol. 27, No. 1, 01.01.2016, p. 49-61.

Research output: Contribution to journalArticle

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abstract = "Background: The efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC. Patients and methods: Literature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3-4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status =1 and hepatic metastases. Results: Forty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2{\%} [95{\%} confidence interval (CI) 11.1-17.9] versus 31.9{\%} [95{\%} CI 27.3-36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P <0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284).When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P <0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3-4 toxicity were seen between the two groups. Conclusions: Despite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations.",
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T1 - Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer

T2 - A systematic review and meta-analysis

AU - Raggi, Daniele

AU - Miceli, R.

AU - Sonpavde, G.

AU - Giannatempo, P.

AU - Mariani, L.

AU - Galsky, M. D.

AU - Bellmunt, J.

AU - Necchi, Andrea

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N2 - Background: The efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC. Patients and methods: Literature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3-4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status =1 and hepatic metastases. Results: Forty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1-17.9] versus 31.9% [95% CI 27.3-36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P <0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284).When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P <0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3-4 toxicity were seen between the two groups. Conclusions: Despite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations.

AB - Background: The efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC. Patients and methods: Literature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3-4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status =1 and hepatic metastases. Results: Forty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1-17.9] versus 31.9% [95% CI 27.3-36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P <0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284).When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P <0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3-4 toxicity were seen between the two groups. Conclusions: Despite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations.

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