Original ResearchSafety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia—A retrospective analysis
Introduction
Pancreatic adenocarcinoma ranks as the fourth deadliest cancer in men and women within Europe [1]. Owing to the late onset of symptoms, 85–90% of patients with pancreatic cancer are diagnosed with locally advanced or metastatic stage when curatively intended resection is no longer an option [2]. Prognosis of these patients is bleak with a 5-year overall survival (OS) rate of less than 5% [3].
For patients with inoperable advanced pancreatic carcinoma (APC), gemcitabine monotherapy had been the standard first-line treatment with palliative intention for almost two decades [4]. Only in the last few years, new regimens were introduced which significantly improved the clinical outcomes compared with gemcitabine alone. The combination of nanoparticle albumin–bound paclitaxel and gemcitabine (nab-P/G) [5] and the regimen FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) [6] are currently considered as the standard treatment options for patients with a good performance status [7]. Because patients with elevated bilirubin levels were excluded from the phase 3 clinical studies for FOLFIRINOX and nab-P/G, both regimens are not recommended for patients with total bilirubin (TB) levels >1.5 upper limit of normal (ULN) [6], [8].
However, hyperbilirubinaemia is common in patients suffering from APC and is mainly due to obstructions of the bile duct system by the primary tumour, lymph nodes or hepatic metastases. The majority of pancreatic cancers (60–70%) arise in the pancreatic head in proximity to the common bile duct [7]. Furthermore, local lymph nodes and the liver are the most frequent sites of metastatic spread. Thus, jaundice is one of the most frequent symptoms at diagnosis, affecting more than 50% of patients [9].
Hence, those patients constitute a considerable patient population whose need for effective medical treatment is currently unmet, and information about the feasibility of newer treatment regimens is scarce [10].
While gemcitabine is mainly eliminated via the kidneys [11], the main elimination pathway of paclitaxel is hydroxylation by CYP450 enzymes in the liver followed by excretion via the bile [8]. However, a recent meta-analysis of pharmacokinetic data from patients with various solid tumours showed that TB levels had only limited effect on paclitaxel elimination if administered in the nab-paclitaxel formulation [12]. Because of low numbers, pts with APC could not be analysed in this setting. These results however suggest that nab-P/G might also be a feasible treatment option for patients with APC and hyperbilirubinaemia. Currently, only single case reports exist for this constellation, [13] and more data are needed to determine under which circumstances this therapeutic option can be offered to these patients.
Herein we present the results of an investigation evaluating the feasibility, safety and treatment effect of nab-P/G in patients with cholestatic hyperbilirubinaemia.
Section snippets
Patients/material and methods
We screened our prospective database containing data from patients treated at our cancer centre according to the following criteria: histologically proven locally advanced or metastatic pancreatic carcinoma and total hyperbilirubinaemia at treatment initiation with nab-P/G; total hyperbilirubinaemia caused by primary cancer or metastatic extrahepatic or intrahepatic malignant bile duct obstruction (e.g. no haemolysis, hepatitis, hereditary liver function diseases); optimised biliary tract flow
Patients
A total of 168 patients with APC were treated with nab-P/G between Dec 2013 and Dec 2015.Thirty-six pts had elevated bilirubin levels at the initiation of nab-P/G treatment; of those, 29 patients with a sufficient data set were included in the analysis. Biliary stenting was, however, not feasible in approximately half of the patients. In some cases, stenting was prohibited because of anatomical changes owing to previous operations; in others, sufficient drainage by the biliary stent was not
Discussion
Hyperbilirubinaemia is common in patients with APC, mainly due to biliary main tract obstruction and/or more rarely due to extensive liver metastases. However, treatment of these patients is complicated because the pivotal phase 3 studies excluded patients with elevated bilirubin levels, and therefore, only limited data on safety or efficacy of the available chemotherapy regimen exist [10], [13]. In this investigation, we evaluate the feasibility of nab-P/G-treatment in 29 patients with APC
Conclusions
Our investigation indicates that nab-P/G could be a feasible and safe treatment option for patients with hyperbilirubinaemia, with respect to an individual basis under the supervision of an experienced oncologist.
Conflict of interest statement
U.P. is a consultor or advisor to Celgene, Shire, Amgen and Halozyme and is a part of speakers’ bureau for Celgene, Bayer Pharma, Shire, and Servier. R.-Z. is an employee of Celgene GmbH, Munich. M.S. is a consultor or advisor to Baxalta and received research funding from LEO Pharma and travel and accommodation expenses from Amgen, Bayer Pharma, Servier, Novo Nordisk. H.R. received honoraria from Aspen Pharmacare, is a consultor or advisor to Boehringer Ingelheim, Celgene, Bayer Pharma,
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Contributed equally.