D Raggi1, R Miceli1, G Sonpavde2, P Giannatempo1, L Mariani1, M D Galsky3, J Bellmunt4, A Necchi5. 1. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 2. UAB Comprehensive Cancer Center, Birmingham. 3. Mount Sinai School of Medicine, Tisch Cancer Institute, New York. 4. Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA. 5. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy andrea.necchi@istitutotumori.mi.it.
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.
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.
Authors: Mark Warren; Michael Kolinsky; Christina M Canil; Piotr Czaykowski; Srikala S Sridhar; Peter C Black; Christopher M Booth; Wassim Kassouf; Libni Eapen; Som D Mukherjee; Normand Blais; Bernhard J Eigl; Eric Winquist; Naveen S Basappa; Scott A North Journal: Can Urol Assoc J Date: 2019-04-26 Impact factor: 1.862
Authors: Joaquim Bellmunt; Ronald de Wit; David J Vaughn; Yves Fradet; Jae-Lyun Lee; Lawrence Fong; Nicholas J Vogelzang; Miguel A Climent; Daniel P Petrylak; Toni K Choueiri; Andrea Necchi; Winald Gerritsen; Howard Gurney; David I Quinn; Stéphane Culine; Cora N Sternberg; Yabing Mai; Christian H Poehlein; Rodolfo F Perini; Dean F Bajorin Journal: N Engl J Med Date: 2017-02-17 Impact factor: 91.245
Authors: Andrea Necchi; Salvatore Lo Vullo; Luigi Mariani; Daniele Raggi; Patrizia Giannatempo; Giuseppina Calareso; Elena Togliardi; Flavio Crippa; Nicola Di Genova; Federica Perrone; Maurizio Colecchia; Biagio Paolini; Giuseppe Pelosi; Nicola Nicolai; Giuseppe Procopio; Roberto Salvioni; Filippo G De Braud Journal: Invest New Drugs Date: 2016-02-12 Impact factor: 3.850
Authors: Thomas Powles; Andrea Necchi; Galit Rosen; Subramanian Hariharan; Andrea B Apolo Journal: Clin Genitourin Cancer Date: 2017-12-06 Impact factor: 2.872
Authors: Daniel P Petrylak; Ronald de Wit; Kim N Chi; Alexandra Drakaki; Cora N Sternberg; Hiroyuki Nishiyama; Daniel Castellano; Syed A Hussain; Aude Fléchon; Aristotelis Bamias; Evan Y Yu; Michiel S van der Heijden; Nobuaki Matsubara; Boris Alekseev; Andrea Necchi; Lajos Géczi; Yen-Chuan Ou; Hasan Senol Coskun; Wen-Pin Su; Jens Bedke; Georgios Gakis; Ivor J Percent; Jae-Lyun Lee; Marcello Tucci; Andrey Semenov; Fredrik Laestadius; Avivit Peer; Giampaolo Tortora; Sufia Safina; Xavier Garcia Del Muro; Alejo Rodriguez-Vida; Irfan Cicin; Hakan Harputluoglu; Scott T Tagawa; Ulka Vaishampayan; Jeanny B Aragon-Ching; Oday Hamid; Astra M Liepa; Sameera Wijayawardana; Francesca Russo; Richard A Walgren; Annamaria H Zimmermann; Rebecca R Hozak; Katherine M Bell-McGuinn; Thomas Powles Journal: Lancet Oncol Date: 2019-11-18 Impact factor: 41.316