Digestive and Liver Disease 46 (2014) 452–459
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Oncology
Polychemotherapy or gemcitabine in advanced pancreatic cancer: A meta-analysis Fausto Petrelli ∗ , Andrea Coinu, Karen Borgonovo, Mary Cabiddu, Mara Ghilardi, Sandro Barni Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
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Article history: Received 24 October 2013 Accepted 1 January 2014 Available online 22 February 2014 Keywords: First line Gemcitabine Meta-analysis Overall survival Pancreatic cancer Polychemotherapy
a b s t r a c t Background: Gemcitabine monotherapy is the cornerstone of treatment for advanced pancreatic cancer. To date, no clear survival benefit has been found when combination chemotherapy has been compared with gemcitabine alone, except in a few studies. This meta-analysis compared the efficacy of polychemotherapy with gemcitabine alone in advanced pancreatic cancer. Methods: Randomised trials comparing combination chemotherapy with gemcitabine alone were identified through electronic searches of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Overall survival, reported as the hazard ratio at the 95% confidence interval, was the primary outcome measure. Results: 29 trials (19 phase III and 10 small randomised trials) that included 8421 patients were identified. Overall, polychemotherapy significantly improved overall survival (hazard ratio = 0.87; 95% CI, 0.81–0.93; P < 0.0001), progression-free survival (hazard ratio = 0.77; 95% CI, 0.70–0.84; P < 0.00001), and response rate (risk ratio = 1.71; 95% CI, 1.42–2.07; P < 0.00001) compared with gemcitabine alone. Conclusions: Compared with gemcitabine monotherapy, combinations of two or more drugs (particularly those with novel agents or associated with >20% response rates and triplets) improved outcomes and response rate in advanced pancreatic cancer, and they could be considered a new standard of care in advanced settings. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Pancreatic cancer (PC) in its advanced stages is a lethal disease, with median survival limited to a few months. Prolonging survival and improving disease symptoms and quality of life in addition to offering a clinical benefit are the main endpoints of palliative chemotherapy treatment. Gemcitabine was approved for metastatic PC because, compared with single-agent 5-fluorouracil (5FU), it modestly improved overall survival (OS) and offered a clinical benefit [1]. Conversely, polychemotherapy in the form of gemcitabine combinations did not yield a strong benefit. The addition of another agent to gemcitabine alone did not result in better survival except in patients with good performance status (PS) [2,3]. Since the Burris trial, single-agent gemcitabine chemotherapy has been the cornerstone of treatment for metastatic PC. In fact, no other active single agent has been consistently associated with
∗ Corresponding author at: Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Tel.: +39 0363424420; fax: +39 0363424380. E-mail address: [email protected] (F. Petrelli).
objective RRs of more than 10% or median OS duration of longer than a few months. The reason for the relative inefficacy of cytotoxic chemotherapy with regard to PC is unclear. Even targeted agents, apart from the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib, do not confer any additional benefit. These effects are probably associated with the various pathways involved in metastatic disease [4–7]. Recently, the combination of 5FU, irinotecan, and oxaliplatin, named FOLFIRINOX, produced a significantly better OS compared with gemcitabine alone in a phase III randomised trial [8]. In the ACCORD 11 trial, a total of 342 patients with chemotherapynaïve, metastatic PC, a PS of 0 or 1, and a serum bilirubin of 20% vs
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Oncology
Polychemotherapy or gemcitabine in advanced pancreatic cancer: A meta-analysis Fausto Petrelli ∗ , Andrea Coinu, Karen Borgonovo, Mary Cabiddu, Mara Ghilardi, Sandro Barni Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
a r t i c l e
i n f o
Article history: Received 24 October 2013 Accepted 1 January 2014 Available online 22 February 2014 Keywords: First line Gemcitabine Meta-analysis Overall survival Pancreatic cancer Polychemotherapy
a b s t r a c t Background: Gemcitabine monotherapy is the cornerstone of treatment for advanced pancreatic cancer. To date, no clear survival benefit has been found when combination chemotherapy has been compared with gemcitabine alone, except in a few studies. This meta-analysis compared the efficacy of polychemotherapy with gemcitabine alone in advanced pancreatic cancer. Methods: Randomised trials comparing combination chemotherapy with gemcitabine alone were identified through electronic searches of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Overall survival, reported as the hazard ratio at the 95% confidence interval, was the primary outcome measure. Results: 29 trials (19 phase III and 10 small randomised trials) that included 8421 patients were identified. Overall, polychemotherapy significantly improved overall survival (hazard ratio = 0.87; 95% CI, 0.81–0.93; P < 0.0001), progression-free survival (hazard ratio = 0.77; 95% CI, 0.70–0.84; P < 0.00001), and response rate (risk ratio = 1.71; 95% CI, 1.42–2.07; P < 0.00001) compared with gemcitabine alone. Conclusions: Compared with gemcitabine monotherapy, combinations of two or more drugs (particularly those with novel agents or associated with >20% response rates and triplets) improved outcomes and response rate in advanced pancreatic cancer, and they could be considered a new standard of care in advanced settings. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Pancreatic cancer (PC) in its advanced stages is a lethal disease, with median survival limited to a few months. Prolonging survival and improving disease symptoms and quality of life in addition to offering a clinical benefit are the main endpoints of palliative chemotherapy treatment. Gemcitabine was approved for metastatic PC because, compared with single-agent 5-fluorouracil (5FU), it modestly improved overall survival (OS) and offered a clinical benefit [1]. Conversely, polychemotherapy in the form of gemcitabine combinations did not yield a strong benefit. The addition of another agent to gemcitabine alone did not result in better survival except in patients with good performance status (PS) [2,3]. Since the Burris trial, single-agent gemcitabine chemotherapy has been the cornerstone of treatment for metastatic PC. In fact, no other active single agent has been consistently associated with
∗ Corresponding author at: Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy. Tel.: +39 0363424420; fax: +39 0363424380. E-mail address: [email protected] (F. Petrelli).
objective RRs of more than 10% or median OS duration of longer than a few months. The reason for the relative inefficacy of cytotoxic chemotherapy with regard to PC is unclear. Even targeted agents, apart from the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib, do not confer any additional benefit. These effects are probably associated with the various pathways involved in metastatic disease [4–7]. Recently, the combination of 5FU, irinotecan, and oxaliplatin, named FOLFIRINOX, produced a significantly better OS compared with gemcitabine alone in a phase III randomised trial [8]. In the ACCORD 11 trial, a total of 342 patients with chemotherapynaïve, metastatic PC, a PS of 0 or 1, and a serum bilirubin of 20% vs
