The Impact of Adding Taxanes to Gemcitabine and Platinum Chemotherapy for the First-Line Therapy of Advanced or Metastatic Urothelial Cancer: A Systematic Review and Meta-analysis.
BACKGROUND
Gemcitabine/platinum chemotherapy is the most widely used first-line regimen for metastatic urothelial carcinoma, and the potential improvement of adding taxanes needs to be clarified.


OBJECTIVE
To study the survival impact of taxane plus gemcitabine/platinum compared with gemcitabine/platinum alone as upfront therapy.


METHODS
Literature was searched for studies including gemcitabine/platinum ± taxanes (paclitaxel or docetaxel only). We pooled trial level data including the median, proportions, and confidence intervals on response-rate, progression-free survival, overall survival (OS), and side effects. Univariable and multivariable regression models evaluated the prognostic role of addition of taxanes after adjusting for platinum type, performance status 2, and the presence of visceral metastases. Data were weighted by the logarithm of the trial sample size.


RESULTS
Thirty-five arms of trials including 2,365 patients were selected (seven with taxanes [n=617], and 28 arms without taxanes [n=1,748]). Median OS was univariably significantly different (p=0.019) between trials with and without taxanes. Across trials, the median 'median OS' amongst trials containing taxanes was 15.5 mo, compared with 12.5 mo in trials which did not. Multivariably, visceral disease and performance status were significantly associated with OS, and the addition of taxanes trended toward significantly better OS (p=0.056) and increase in grade ≥ 3 neurotoxicity (p=0.051), regardless of specific platinum agent used.


CONCLUSIONS
In this meta-analysis, adding taxanes to gemcitabine and platinum showed a trend for improved OS and higher grade ≥ 3 neurotoxicity. Improvements in patient selection and the evaluation of a more potent and tolerable tubulin inhibitor in combination with gemcitabine/platinum in a well-powered trial are the critical next steps.


RESULTS
In this report, a trend for improved overall survival and worse neurotoxicity was observed for adding a taxane to first-line gemcitabine/platinum chemotherapy for metastatic urothelial carcinoma. More effective taxanes should be investigated further in urothelial carcinoma in combination with gemcitabine/platinum.
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Patrizia
P
Giannatempo
McMaster University, Hamilton, Ontario, Canada.
Gregory R
GR
Pond
UAB Comprehensive Cancer Center, Birmingham, AL, USA.
Guru
G
Sonpavde
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Daniele
D
Raggi
UAB Comprehensive Cancer Center, Birmingham, AL, USA.
Gurudatta
G
Naik
Mount Sinai School of Medicine, Tisch Cancer Institute, New York, USA.
Matthew D
MD
Galsky
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Joaquim
J
Bellmunt
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: andrea.necchi@istitutotumori.mi.it.
Andrea
A
Necchi
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D015999:Multivariate Analysis; D017671:Platinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D019459:Urothelium / Q000187:drug effects* / Q000473:pathology; D000093542:Gemcitabine
D017671:Platinum Compounds; D043823:Taxoids; D003841:Deoxycytidine; D000093542:Gemcitabine
First-line therapy; Meta-analysis; Systemic therapy; Taxanes; Urothelial carcinoma