Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis.
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.


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.
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
D
D
Raggi
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
R
R
Miceli
UAB Comprehensive Cancer Center, Birmingham.
G
G
Sonpavde
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
P
P
Giannatempo
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
L
L
Mariani
Mount Sinai School of Medicine, Tisch Cancer Institute, New York.
M D
MD
Galsky
Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA.
J
J
Bellmunt
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy andrea.necchi@istitutotumori.mi.it.
A
A
Necchi
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D006801:Humans; D016879:Salvage Therapy; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
chemotherapy; combination chemotherapy; salvage therapy; single-agent chemotherapy; urothelial carcinoma