Elsevier

European Journal of Cancer

Volume 100, September 2018, Pages 85-93
European Journal of Cancer

Original Research
Safety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia—A retrospective analysis

https://doi.org/10.1016/j.ejca.2018.06.001Get rights and content

Highlights

  • Twenty-nine patients with pancreatic carcinoma and cholestatic hyperbilirubinaemia treated with nab-paclitaxel/gemcitabine.

  • Nab-P/G doses were adapted on an individual basis considering pt history and organ function.

  • No unexpected toxicity of nab-P/G was observed in patients with cholestasis and hyperbilirubinaemia.

  • Nab-P/G seems to be an efficient and safe treatment in patients.

Abstract

Introduction

Treatment of patients with advanced pancreatic carcinoma (APC) and hyperbilirubinaemia is problematic because these patients were regularly excluded from clinical studies. Nanoparticle albumin–bound paclitaxel and gemcitabine (nab-P/G) is an evidence-based treatment for patients with APC. This retrospective study investigated the safety and efficacy of nab-P/G in patients with APC and cholestatic hyperbilirubinaemia.

Methods

We screened our prospective database for patients with APC treated with nab-P/G at total bilirubin levels of ≥1.2 mg/dl. Patients were assigned into three groups according to their bilirubin level (A: 1.2–3 mg/dl, B: >3–5 mg/dl, C: >5 mg/dl). Analyses with regard to safety and survival were performed.

Results

Twenty-nine of 168 patients screened between Dec 2013 and Dec 2015 fulfilled the inclusion criteria. Most patients (83%) were male; median age was 63 [41–79] years. Nab-P/G administrations in patients with an elevated bilirubin level (median, range) did not result in unexpected toxicities assessed by predefined (non-)haematological parameters. Median overall survival (mOS) for the whole group was 11.7 (95% confidence interval [CI]: 6.8–14.0) months; for A: 11.8 (95% CI: 6.5–16.5), B: 9.2 (95% CI: 1.1 – NA) months and C 11.8 (95% CI: 5.9–20.0] months (p = 0.843). Again, mOS from the first application of nab-P/G did not differ between the groups (p = 0.13).

Conclusion

Nab-P/G administrations in our pts with cholestatic hyperbilirubinaemia suffering from APC were feasible and safe with respect to individualised dose administrations. A multicenter phase 1 trial in pts with hyperbilirubinaemia is started (AIO-PAK-0117) to confirm these findings in a prospective setting.

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,

References (13)

  • M. Malvezzi et al.

    European cancer mortality predictions for the year 2016 with focus on leukaemias

    Ann Oncol

    (2016 Apr)
  • S.M. Singh et al.

    Surgical palliation for pancreatic cancer. The UCLA experience

    Ann Surg

    (1990)
  • D.K. Chang et al.

    Improving outcomes for operable pancreatic cancer: is access to safer surgery the problem?

    J Gastroenterol Hepatol

    (2008)
  • H.A. Burris et al.

    Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial

    J Clin Oncol

    (1997)
  • D.D. Von Hoff et al.

    Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine

    N Engl J Med

    (2013)
  • T. Conroy et al.

    FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer

    N Engl J Med

    (2011)
There are more references available in the full text version of this article.

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