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Review Article

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Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine

Vogel A.a · Kullmann F.b · Kunzmann V.c · Al-Batran S.-E.d · Oettle H.e · Plentz R.f · Siveke J.g · Springfeld C.h · Riess H.i

Author affiliations

aKlinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Germany; bMedizinische Klinik I, Klinikum Weiden, Weiden i.d. OPf., Germany; cMedizinische Klinik und Poliklinik II, Schwerpunkt Medizinische Onkologie, Universitätsklinikum Würzburg, Germany; dKrankenhaus Nordwest, University Cancer Center Frankfurt/M., Germany; eOnkologische Schwerpunktpraxis, Friedrichshafen, Germany; f University Clinics Tübingen, Germany; gMedizinische Klinik II, Klinikum rechts der Isar, Technical University Munich, Germany; hNational Center for Tumor Diseases, Heidelberg University Hospital, Germany; iMedizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Charité, Universitätsmedizin Berlin, Germany

Corresponding Author

Prof. Dr. med. Hanno Riess

Charité - Universitätsmedizin Berlin

Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie

Charitéplatz 1, 10117 Berlin, Germany

hanno.riess@charite.de

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Oncol Res Treat 2015;38:596-603

Abstract

In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years, new treatment options such as the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in patients with good performance status. Unfortunately, patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients, have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical treatment of this patient group is limited. In a meeting of German medical oncology experts, the available clinical evidence and own clinical experience regarding the management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present publication summarises the discussion outcomes with regard to appropriate management of these patients, including consensus-based recommendations for nab-paclitaxel/gemcitabine treatment, according to the best available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the experts provide advice for an initial dose reduction of chemotherapy with nab-paclitaxel/gemcitabine based on the total bilirubin level in patients with biliary obstruction or extensive liver metastasis.

© 2015 S. Karger GmbH, Freiburg


Introduction

Treatment of Advanced Pancreatic Cancer

Pancreatic carcinoma ranks among the top 5 mortal cancers for both sexes in Europe, despite a relatively low average incidence of 6.8/100,000 [1]. Pancreatic cancer is rare in adults < 40 years of age, with a median age at diagnosis of 71 years [2]. As symptoms usually only appear once the disease has progressed, approximately 85-90% of patients have unresectable disease at diagnosis [3] and thus a low overall 5-year survival rate of less than 5% [4]. Tumour resection remains the only curative treatment but is only suitable for the minority of patients with early disease [5]. Even after complete resection followed by adjuvant chemotherapy, around 80% of the patients will die within 5 years [6].

The available treatment options for patients with advanced, initially unresectable, relapsed or metastasised pancreatic cancer are still far from satisfactory. The introduction of combination chemotherapies within the last 4 years, such as the multidrug combination of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) [7] and the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine [8], has nevertheless offered a clinically relevant survival benefit over gemcitabine monotherapy, the former treatment standard for more than 15 years. In a phase III study with selected patients from specialised centres, FOLFIRINOX chemotherapy led to a substantial benefit in overall survival compared to gemcitabine monotherapy (11.1 vs. 6.8 months; hazard ratio (HR) for death = 0.57 (95% confidence interval (CI): 0.45-0.73); p < 0.001), although it was also associated with a marked potential for toxicities and was limited to patients ≤ 75 years of age [7,9]. In an international large-scale phase III study, the combination of nab-paclitaxel plus gemcitabine was associated with a clinically relevant prolongation of overall survival compared to gemcitabine alone (8.7 vs. 6.6 months; HR for death = 0.72 (95% CI: 0.62-0.83); p < 0.001) [8]. Although treatment with nab-paclitaxel plus gemcitabine involved adverse reactions including haematological cytopenias and peripheral neuropathy, the tolerability profile was considered as manageable [8,9]. The recently updated US National Comprehensive Cancer Network (NCCN) guideline recommends FOLFIRINOX and nab-paclitaxel plus gemcitabine as the preferred treatment options for patients with good performance status and metastatic disease and as possible options for the treatment of locally advanced, unresectable pancreatic cancers [10]. Thus, at present, FOLFIRINOX or nab-paclitaxel plus gemcitabine are considered the standard treatment for patients with good performance status who do not have severe comorbidities [2]. Although a head-to-head comparison of both treatment regimens is not available, chemotherapy with nab-paclitaxel plus gemcitabine seems to be less toxic than FOLFIRINOX treatment [9] and is not restricted to patients ≤ 75 years of age [8]. Consequently, we herein focus on recommendations for treatment with nab-paclitaxel plus gemcitabine since it may be used for a broader patient population compared to FOLFIRINOX.

Hyperbilirubinaemia in Patients with Pancreatic Cancer

Around 60-70% of pancreatic cancers are located in the pancreatic head [2], leading to hyperbilirubinaemia caused by obstruction of the central bile duct in 70-80% of these patients [5]. Biliary obstruction and the resulting hyperbilirubinaemia usually complicate the management of patients by increasing the risk of cholangitis and causing frequent hospitalisations [11]; hyperbilirubinaemia has been associated with shorter overall survival in patients with pancreatic cancer [12,13]. Biliary decompression in patients with obstructive hyperbilirubinaemia is commonly performed using endoscopic stent placement [10], which not only reduces morbidity [14] but also facilitates treatment with chemotherapy by allowing total bilirubin levels to drop to ≤ 1.5-2 times the upper limit of normal (≤ 1.5-2 × ULN). Other possible causes of hyperbilirubinaemia in patients with pancreatic cancer are obstruction of the peripheral intrahepatic bile ducts due to tumour metastases, without major impairment of other aspects of liver function, or massive infiltration of the liver by tumour metastases resulting in non-cirrhotic liver failure.

Unmet Need for Medical Treatment of Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia

Many phase I, II and III studies have excluded patients with abnormal serum liver biochemical tests, including elevated bilirubin, thus probably falsely excluding a considerable patient population from potentially beneficial therapies [15]. Therefore, our knowledge on the most appropriate starting doses of chemotherapy in these individuals is limited [15]. Likewise, pivotal clinical trials with nab-paclitaxel plus gemcitabine have only included patients with bilirubin levels within the normal range [8,16]. With the exception of single case reports [17], there is currently no evidence from clinical studies to support nab-paclitaxel plus gemcitabine treatment in patients with pancreatic cancer and elevated bilirubin. Thus, according to the current recommendation in the European summary of product characteristics, treatment with nab-paclitaxel is not recommended in pancreatic cancer patients with moderate to severe hepatic impairment (total bilirubin > 1.5 × ULN and aspartate aminotransferase ≤ 10 × ULN) since there are insufficient data to permit dosage recommendations [18]. Despite its long-standing use in clinical practice, similar restrictions exist for the recommendation of gemcitabine: Due to insufficient information from clinical studies to allow for clear dose recommendations for this patient population, gemcitabine should be administered with caution in patients with hepatic insufficiency [19]. An ongoing phase I study with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer who have cholestatic hyperbilirubinaemia secondary to bile duct obstruction [20] will hopefully shed more light on the impact of hyperbilirubinaemia on the efficacy and safety of nab-paclitaxel plus gemcitabine. In this publication, experienced experts will give some guidance for the management of patients with advanced pancreatic cancer and hyperbilirubinaemia, especially regarding chemotherapy with nab-paclitaxel plus gemcitabine.

Materials and Methods

Data were retrieved from the published literature indexed in MEDLINE/PubMed. The information was accessed until March 2015. For consensus development, a task force of clinical experts and practicing oncologists in the field of medical oncology with long-standing expertise in the management of patients with pancreatic cancer was established. The task force members discussed the available clinical evidence, reported their clinical practice and agreed on a consensus statement based on a face-to-face meeting in January 2015. A core group of experts summarised the current state of the art of management of patients with pancreatic cancer and hyperbilirubinaemia and verbalised the German perspective on the treatment of this patient population with nab-paclitaxel plus gemcitabine.

Results

Determining the Underlying Cause of Hyperbilirubinaemia in Patients with Pancreatic Cancer

Bilirubin, a breakdown product of haemoproteins, is taken up from plasma into liver hepatocytes where it is conjugated to glucuronic acid; the conjugated form is excreted into bile [21]. The upper limit of the reference range of total bilirubin amounts to 1.2 mg/dl (21 μmol/l) [22] and jaundice can be detected when the plasma concentration is 2-3-fold elevated [23]. The reasons for an elevated serum bilirubin concentration can be grouped into 3 main categories: (1) prehepatic dysfunction, e.g. haemolysis, resulting in unconjugated hyperbilirubinaemia, (2) intrahepatic dysfunction, e.g. intrahepatic biliary obstruction or liver damage caused by hepatotoxic drugs, leading to predominantly conjugated hyperbilirubinaemia, and (3) posthepatic biliary obstruction resulting in predominantly conjugated hyperbilirubinaemia [21,24]. As outlined, in the majority of patients with pancreatic cancer, hyperbilirubinaemia is caused by obstruction of the common bile duct due to a tumour in the pancreas head [5]. In patients with extensive liver metastasis, bilirubin might be elevated due to intrahepatic biliary obstruction and/or metastasis-related liver insufficiency. Some patients might suffer from hyperbilirubinaemia caused by pre-existing hepatic dysfunction, e.g. liver cirrhosis [21,25]. The prerequisite for the appropriate management of affected patients is to clearly determine the underlying cause of hyperbilirubinaemia. Therefore, a combination of laboratory parameters should be analysed since patterns of abnormalities are more meaningful than elevations or reductions of individual parameters [21] (table 1). Since the laboratory test results in most cases do not exactly identify the aetiology of predominant conjugated hyperbilirubinaemia, imaging techniques including sonography, computed tomography (CT) and magnetic resonance imaging (MRI) are essential to precisely determine the specific problem [24]. In order to direct therapy and to predict the survival of patients with chronic liver disease, scoring systems have been developed [26]. The long-established Child-(Turcotte-)Pugh score divides patients into classes A-C, based on the extent of clinical ascites, encephalopathy and laboratory parameters including albumin, the international normalised ratio (INR) and bilirubin [27,28]. The model for end-stage liver disease (MELD) score is based on a mathematical equation incorporating the bilirubin concentration, the INR and the serum creatinine level [29]. Recently, the albumin-bilirubin (ALBI) grade was developed. This is a mathematical equation incorporating only the serum bilirubin and albumin levels and thus eliminating the need for subjective variables such as ascites and encephalopathy [30].

Table 1

Selection of laboratory tests in patients with hyperbilirubinaemia

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Biliary Decompression in Patients with Pancreatic Cancer and Obstructive Hyperbilirubinaemia Intended for Chemotherapy

The rationale for biliary decompression in patients with unresectable pancreatic cancer and obstructive cholestasis is the normalisation of the bilirubin levels to allow palliative chemotherapy, and the prevention of other adverse outcomes such as cholangitis and frequent hospitalisations [11]. According to the current German, European and American treatment guidelines, stent placement via endoscopic retrograde cholangiopancreatography (ERCP) is the preferred method for biliary decompression in these patients [5,10,31]. In case ERCP is not possible, percutaneous transhepatic biliary drainage (PTCD) is recommended [5,10,31]. Endoscopic ultrasound-guided transoesophageal or transduodenal biliary drainage represents a treatment alternative in selected patients not suitable for conventional ERCP and PTCD [32,33].

Basically, 3 types of stents can be used: plastic stents, uncovered self-expandable metallic stents and covered self-expandable metallic stents [11]. The choice of stent depends on several aspects such as the anatomical situation, the experience of the endoscopist, the expected survival time and cost-effectiveness (table 2). Based on the longer patency time compared to plastic stents, self-expanding metal stents (either covered or uncovered) may be the preferred option for patients with a life expectancy of > 3 months, according to the treatment guidelines [5,31].

Table 2

Pros and cons of available stents (modified from [11, 34])

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While there is no discussion regarding prophylactic perioperative administration of antibiotics in conjunction with hepatobiliary surgery [31], antibiotic coverage during stent implantation is still a matter of debate. Although severe complications with ERCP procedures are rare, infectious complications remain prevalent [39]. Although no randomised study has been conducted to test the benefit of peri-interventional infection prophylaxis, antibiotic prophylaxis should be considered since biliary drainage leads to bacterial contamination of the bile ducts in almost 100% of cases [40].

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Impact of Hyperbilirubinaemia on the Efficacy and Tolerability of Chemotherapy with nab-Paclitaxel plus Gemcitabine

Hepatic dysfunction in patients with pancreatic cancer may affect the pharmacokinetic properties of drugs in different ways. A reduced metabolic capacity of the liver, especially with respect to cytochrome P450 (CYP450) isoenzymes, may change their hepatic clearance [21]. Depending on the metabolic profile, this could either result in impaired bioactivation of a prodrug or in impaired drug inactivation [21]. Obstruction of the common bile duct may interfere with the clearance of drugs excreted via bile [41]. Portal-vein thrombosis caused by a hypercoagulable state or by portal-vein infiltration may compromise vascular supply to healthy liver parenchyma and thereby impair drug metabolisation [21]. Consequently, interference with the drug kinetics in patients with hepatic dysfunction may result in reduced effectiveness or increased toxicity of the chemotherapy [21]. Compounds metabolised via CYP450 isoenzymes and secreted via bile are especially affected.

nab-Paclitaxel

Originally, the paclitaxel formulation was based on the solvent Cremophor EL (polyoxyethylated castor oil + dehydrated ethanol) to increase the solubility and bioavailability of paclitaxel. A major drawback of chemotherapy with this formulation is the occurrence of adverse effects including hypersensitivity reactions and neurotoxicity, which are caused by the solvent [42,43]. Encapsulation of paclitaxel into albumin nanoparticles (nab-paclitaxel) allowed for solvent-free administration of the lipophilic compound, thus avoiding the toxicity associated with the solvent [42]. Pharmacokinetic studies with solvent-based paclitaxel revealed that the compound is metabolised via hydroxylation by CYP450 isoenzymes to the main metabolite 6-α-hydroxypaclitaxel (CYP2C8) and to 3'-p-hydroxypaclitaxel (CYP3A4), as well as 6-α,3'- p-dihydroxypaclitaxel (CYP2C8 and CYP3A4). Around 70% of the administered dose is eliminated via biliary excretion [18,44,45]. The hydroxy metabolites of paclitaxel are less cytotoxic than the parent compound [44].

Few small studies on the influence of hepatic dysfunction and hyperbilirubinaemia on the pharmacokinetic properties and the toxicity of solvent-based paclitaxel have been performed. Consistent with its mentioned metabolic profile, population-based pharmacokinetic-pharmacodynamic analyses involving patients with solid tumours and varying degrees of hepatic impairment revealed a negative impact of hyperbilirubinaemia on the clearance of paclitaxel: An increase of 0.6 mg/dl (10 μmol) in total bilirubin was associated with a 12-19% decrease of the elimination capacity of paclitaxel [46,47,48]. These findings are in agreement with clinical data showing that paclitaxel treatment of patients with hepatic impairment and hyperbilirubinaemia was associated with a higher incidence of haematological and non-haematological toxic effects [49,50], especially in patients with more advanced hepatic impairment [48]. A pharmacokinetic-pharmacodynamic model, derived from one of the mentioned studies in 35 patients with solid tumours receiving paclitaxel monotherapy, predicted the following recommendation for the initial paclitaxel dose based on the total bilirubin level: ≤ 1.25 × ULN: 175 mg/m2 (100% dose), 1.26-2.0 × ULN: 115 mg/m2 (66%), 2.1-3.5 × ULN: 100 mg/m2 (57%) and 3.6-10 × ULN: 70 mg/m2 (40%) [48]. The validity of the recommendation for an initial paclitaxel dose of 40% was confirmed in a pharmacokinetic study in 9 patients with severe hepatic dysfunction caused by liver metastases and a bilirubin level of 3-11 × ULN: Treatment with 70 mg/m2 paclitaxel was safe and led to adequate plasma concentrations [51].

However, interpretation of the results derived from these studies using solvent-based paclitaxel is difficult due to the small sample size and the large heterogeneity of included patients, especially regarding the kind of hepatic dysfunction - the underlying aetiology of hyperbilirubinaemia has not been reported. In addition, data obtained with solvent-based paclitaxel are not directly applicable to solvent-free nab-paclitaxel because of the different distribution and elimination kinetics of the 2 formulations: nab-paclitaxel exhibits a faster distribution and a 9-fold larger distribution volume, as well as a slower elimination compared to solvent-based paclitaxel [52]. The more rapid tissue distribution of paclitaxel when administered as nab-paclitaxel results in a shorter duration of high systemic drug concentrations, which likely contributes to its reduced haematotoxicity in comparison to solvent-based paclitaxel [52]. Furthermore, administration of nab-paclitaxel led to 33% higher intratumoral drug accumulation in animal studies [53].

In accordance with the results for solvent-based paclitaxel [46,47,48], a pilot study in 15 patients with solid tumours and hyperbilirubinaemia showed that nab-paclitaxel clearance was significantly inversely correlated with the total bilirubin levels [54]. The study supports the same dose modification scheme in patients with hepatic dysfunction as recommended for solvent-based paclitaxel [54]. However, its main limitations are that a control group of patients with normal hepatic function was lacking and - as is the case for the studies with solvent-based paclitaxel - that the population was mixed with respect to the underlying aetiology of hyperbilirubinaemia [54]. Recently, a meta-analysis of 8 clinical studies of nab-paclitaxel was conducted: In 150 patients with different solid tumours, mostly melanoma (29%) and breast cancer (16%), 13.3% of the patients had hyperbilirubinaemia [52]. In patients with total bilirubin of > 1 to ≤ 1.5 × ULN, the elimination rate of nab-paclitaxel was not significantly reduced [52]. Total bilirubin concentrations > 1.5 to ≤ 3 × ULN or > 3 to ≤ 5 × ULN led to a 22% or 26% decrease in the maximum elimination rate of paclitaxel and to an approximately 20% increase in the mean paclitaxel area under the curve (AUC) [52]. Thus, in contrast to the results of the pilot study [54], changes in total bilirubin had only limited effect on paclitaxel elimination [52]. According to the results of the meta-analysis, a 20% reduction of the nab-paclitaxel dose may be considered a safe starting level for patients with total bilirubin of > 1.5 to ≤ 5 × ULN to avoid a potential increase in systemic drug exposure [52]. Regarding treatment of metastatic breast cancer, this recommendation has been approved by the European authorities and was added to the summary of product characteristics of nab-paclitaxel [18]. Nevertheless, similar to the pilot study, the validity of this study for the treatment of pancreatic cancer patients is limited due to the small sample size. Furthermore, patients with pancreatic cancer and mechanic obstruction of the bile duct were not included in the analysis [52].

Gemcitabine

Paclitaxel and gemcitabine do not share a common metabolic pathway, making pharmacokinetic interactions unlikely. Gemcitabine (difluorodeoxycytidine) is a nucleoside analogue prodrug requiring intracellular activation by phosphorylation to di- and triphosphates [19]. The compound is rapidly inactivated by cytidine deaminase to its main metabolite difluorodeoxyuridine and 99% of the administered dose is eliminated via renal excretion [19]. Treatment with gemcitabine leads to mild, mostly asymptomatic and transient increases in transaminases in about two-thirds of the patients, and in serum bilirubin in a small proportion of patients [55]. However, rare cases of mostly fatal liver failure in association with gemcitabine therapy have been previously observed - presumably caused by a metabolic idiosyncratic reaction to the compound [56,57]. Consequently, careful monitoring of hepatic parameters during therapy with gemcitabine is recommended [21].

To study the impact of hepatic dysfunction on gemcitabine-induced toxicity, a prospective dose escalation study of the standard 30-min infusion was performed in 40 patients with hepatic impairment and total bilirubin levels of 1.7-5.7 mg/dl, of whom 17 patients had metastatic gastrointestinal cancer [58]. Patients with hyperbilirubinaemia at baseline were prone to develop substantial but mostly transient increases in the concentrations of bilirubin and liver transaminases [58]. Thus, a reduction of the gemcitabine starting dose to 800 mg/m2 (= 80% of the standard dose) was recommended [58]. A small phase II study in 43 patients with advanced unresectable hepatobiliary carcinomas revealed a high frequency (30%) of grade 3/4 thrombocytopenias in the 18 patients with hepatocellular carcinoma and liver cirrhosis (Child A: n = 5, Child B: n = 13) of this group [59]. In contrast, a smaller study involving 9 patients with pancreatic (n = 5) or biliary tract cancer (n = 4) and hepatic impairment showed that the full dose of gemcitabine can be safely used in patients with elevated total bilirubin and transaminases when administered via the slower 10-mg/m2/min infusion [60]. Another recent study in 12 patients with advanced pancreatic (n = 7) or biliary tract cancer (n = 5) and extra- or intrahepatic cholestasis, receiving gemcitabine plus capecitabine chemotherapy, revealed a further interesting aspect: A total bilirubin level of ≥ 2 × ULN was associated with an impaired intracellular activation of gemcitabine to gemcitabine triphosphates, suggesting limited anti-tumour activity [61]. A larger study to confirm this finding is warranted.

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Treatment Advice for Chemotherapy with nab-Paclitaxel plus Gemcitabine in Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia

Based on the underlying cause of hyperbilirubinaemia, patients with pancreatic cancer and elevated total bilirubin can be grouped into individuals with (1) biliary obstruction (mostly caused by a tumour in the pancreas head), (2) extensive liver metastasis and (3) pre-existing chronic liver disease. The percentages of patients in the 3 groups receiving first-line chemotherapy were estimated by the panel to be approximately 70%, 20% and 10%, respectively. According to the current guidelines, the prerequisite for initiation of chemotherapy is as much biliary decompression as possible [10]. The expert panel recommends starting treatment as soon as the bilirubin concentration is sufficiently decreased or further decreasing, since the time between first diagnosis and treatment start may be of prognostic relevance [62]. Due to the increased risk of infections after stent insertion [39] and the risk of leucopenia associated with chemotherapy [8], risks and benefits of an early treatment start, as well as favouring a standard or a reduced starting dose of chemotherapy, have to be weighed against each other. In this context, antibiotic prophylaxis has to be considered. As disease remission is the primary treatment goal, the expert panel prefers to use the combination treatment with nab-paclitaxel plus gemcitabine at a reduced starting dose over gemcitabine monotherapy in patients with hyperbilirubinaemia. The experts' recommendation for starting doses of nab-paclitaxel and gemcitabine in patients with biliary obstruction or extensive liver metastasis based on the total bilirubin level and other parameters is summarised in table 3. Patients with pre-existing chronic liver disease, e.g. liver fibrosis or cirrhosis, are a very heterogeneous patient population with respect to remaining liver function. Therefore, the experts do not provide a general treatment recommendation in this patient group; each individual case should be carefully evaluated. According to the German S3 treatment guideline for pancreatic cancer, treatment with adjuvant chemotherapy is unrestricted in patients with Child A liver cirrhosis but not recommended in patients with Child B and C liver cirrhosis [31].

Table 3

Panel recommendation for initial doses of nab-paclitaxel and gemcitabine in patients with advanced pancreatic cancer based on the underlying cause of hyperbilirubinaemia

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Conclusions

Many patients with advanced pancreatic cancer suffer from hyperbilirubinaemia [5], and these constitute a substantial population that has been excluded from most clinical studies [15]. Consequently, treatment of these individuals is complicated as the knowledge of appropriate starting doses of chemotherapy is limited to single case reports or small clinical studies in largely heterogeneous patient populations with regard to the tumour type and underlying aetiology of hyperbilirubinaemia [15]. The recommendations provided by the German expert panel are based on the best available evidence from clinical studies and their long-standing clinical experience in the management of patients with pancreatic cancer. Most importantly, since hyperbilirubinaemia can be a symptom of different types of hepatic dysfunction, its underlying aetiology should be clearly determined before initiation of chemotherapy. Furthermore, the metabolisation routes of the cytotoxic agents must be considered. Due to the possible impact of hepatic impairment on the pharmacokinetic route of nab-paclitaxel and gemcitabine that was shown in small clinical studies, these compounds should be used with caution in patients with hyperbilirubinaemia, and careful monitoring of patients and liver parameters during chemotherapy is warranted. It should be kept in mind that data derived from studies with solvent-based paclitaxel cannot be directly transferred to nab-paclitaxel due to large differences in the pharmacokinetic properties of these 2 formulations. In general, the experts provide advice on reduced starting doses of nab-paclitaxel and gemcitabine based on the total bilirubin level when initiating chemotherapy in patients with biliary obstruction or with extensive liver metastasis (summarised in table 3). Due to large heterogeneity regarding the remaining liver function of patients with pre-existing chronic liver disease, no general treatment recommendation for this patient group can be made.

In summary, effective treatment options including nab-paclitaxel plus gemcitabine should also be made available for patients with advanced pancreatic cancer and primary disease-associated conditions such as hyperbilirubinaemia - provided that the appropriate precautions are considered.

Acknowledgements

The authors thank Jutta Walstab, Physicians World Europe GmbH, Mannheim, Germany for providing medical writing assistance in the preparation of this manuscript, supported by Celgene GmbH, Munich, Germany. The authors directed and are fully responsible for all content and editorial decisions for this manuscript.

Disclosure Statement

A.V.: Honoraria for lectures and consultancy and travel grants from Celgene and Roche; F.K.: honoraria for lectures and consultancy and travel grants from Celgene, Lilly, Roche, Sanofi and Merck; V.K.: honoraria for lectures and consultancy from Celgene, Roche and Merck; H.R.: honoraria for lectures and consultancy and travel grants from Amgen, Bayer, Celgene, Merck, Roche and Sanofi-Aventis.


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  24. Levitt DG, Levitt MD: Quantitative assessment of the multiple processes responsible for bilirubin homeostasis in health and disease. Clin Exp Gastroenterol 2014;7:307-328.
  25. Reichel C, Grünhage F: [Differential diagnosis of jaundice]. MMW Fortschr Med 2006;148:37-40; quiz 41-32.
    External Resources
  26. Angermayr B, Cejna M, Karnel F, Gschwantler M, Koenig F, Pidlich J, Mendel H, Pichler L, Wichlas M, Kreil A, Schmid M, Ferlitsch A, Lipinski E, Brunner H, Lammer J, Ferenci P, Gangl A, Peck-Radosavljevic M: Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt. Gut 2003;52:879-885.
  27. Child C, Turcotte J: Surgery and portal hypertension; in Child C (ed): Liver and Portal Hypertension. Philadelphia, WB Saunders, 1964, pp 50-64.
    External Resources
  28. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R: Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-649.
  29. Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, Kremers W, Lake J, Howard T, Merion RM, Wolfe RA, Krom R, United Network for Organ Sharing Liver Disease Severity Score Committee: Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91-96.
  30. Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O'Beirne J, Fox R, Skowronska A, Palmer D, Yeo W, Mo F, Lai P, Inarrairaegui M, Chan SL, Sangro B, Miksad R, Tada T, Kumada T, Toyoda H: Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach - the ALBI grade. J Clin Oncol 2015;33:550-558.
  31. Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft DK, AWMF): S3-Leitlinie Exokrines Pankreaskarzinom, Langversion 1.0. http://leitlinienprogramm-onkologie.de/Leitlinien.7.0.html, 2013.
  32. Will U, Meyer F: [Endoscopic ultrasonography (EUS)-guided transluminal cholangiodrainage (EUCD) - a novel option of interventional endoscopy in the interdisciplinary management of obstructive jaundice]. Zentralbl Chir 2012;137:20-31.
  33. Kim YS, Gupta K, Mallery S, Li R, Kinney T, Freeman ML: Endoscopic ultrasound rendezvous for bile duct access using a transduodenal approach: cumulative experience at a single center. A case series. Endoscopy 2010;42:496-502.
  34. Bhalala M, Rude K, Wang A, Sauer B, White GE, Kahaleh M, Shami VM: Analysis of complications after EUS-FNA in patients with obstructive jaundice and drained with plastic biliary stents or self-expandable metal stent (SEMS): Do complications differ between the type of stent? J Interv Gastroenterol 2013;3:128-132.
  35. Arguedas MR, Heudebert GH, Stinnett AA, Wilcox CM: Biliary stents in malignant obstructive jaundice due to pancreatic carcinoma: a cost-effectiveness analysis. Am J Gastroenterol 2002;97:898-904.
  36. Prat F, Chapat O, Ducot B, Ponchon T, Pelletier G, Fritsch J, Choury AD, Buffet C: A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct. Gastrointest Endosc 1998;47:1-7.
  37. Kaassis M, Boyer J, Dumas R, Ponchon T, Coumaros D, Delcenserie R, Canard JM, Fritsch J, Rey JF, Burtin P: Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc 2003;57:178-182.
  38. Davids PH, Groen AK, Rauws EA, Tytgat GN, Huibregtse K: Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet 1992;340:1488-1492.
  39. Schwarz RE: Technical considerations to maintain a low frequency of postoperative biliary stent-associated infections. J Hepatobiliary Pancreat Surg 2002;9:93-97.
  40. Herzog T, Belyaev O, Muller CA, Mittelkotter U, Seelig MH, Weyhe D, Felderbauer P, Schlottmann R, Schrader H, Schmidt WE, Uhl W: Bacteribilia after preoperative bile duct stenting: a prospective study. J Clin Gastroenterol 2009;43:457-462.
  41. Eklund JW, Trifilio S, Mulcahy MF: Chemotherapy dosing in the setting of liver dysfunction. Oncology (Williston Park) 2005;19:1057-1063; discussion 1063-1054, 1069.
    External Resources
  42. Viudez A, Ramirez N, Hernandez-Garcia I, Carvalho FL, Vera R, Hidalgo M: nab-Paclitaxel: a flattering facelift. Crit Rev Oncol Hematol 2014;92:166-180.
  43. Li Y, Chen N, Palmisano M, Zhou S: Pharmacologic sensitivity of paclitaxel to its delivery vehicles drives distinct clinical outcomes of paclitaxel formulations. Mol Pharm 2015;12:1308-1317.
  44. Sparreboom A, Huizing MT, Boesen JJ, Nooijen WJ, van Tellingen O, Beijnen JH: Isolation, purification, and biological activity of mono- and dihydroxylated paclitaxel metabolites from human feces. Cancer Chemother Pharmacol 1995;36:299-304.
  45. Walle T, Walle UK, Kumar GN, Bhalla KN: Taxol metabolism and disposition in cancer patients. Drug Metab Dispos 1995;23:506-512.
    External Resources
  46. Henningsson A, Sparreboom A, Sandstrom M, Freijs A, Larsson R, Bergh J, Nygren P, Karlsson MO: Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients. Eur J Cancer 2003;39:1105-1114.
  47. Joerger M, Huitema AD, van den Bongard DH, Schellens JH, Beijnen JH: Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of paclitaxel in patients with solid tumors. Clin Cancer Res 2006;12:2150-2157.
  48. Joerger M, Huitema AD, Huizing MT, Willemse PH, de Graeff A, Rosing H, Schellens JH, Beijnen JH, Vermorken JB: Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study. Br J Clin Pharmacol 2007;64:622-633.
  49. Venook AP, Egorin MJ, Rosner GL, Brown TD, Jahan TM, Batist G, Hohl R, Budman D, Ratain MJ, Kearns CM, Schilsky RL: Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264. J Clin Oncol 1998;16:1811-1819.
    External Resources
  50. Wilson WH, Berg SL, Bryant G, Wittes RE, Bates S, Fojo A, Steinberg SM, Goldspiel BR, Herdt J, O'Shaughnessy J, et al.: Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion. J Clin Oncol 1994;12:1621-1629.
    External Resources
  51. Briasoulis E, Karavasilis V, Tzamakou E, Piperidou C, Soulti K, Pavlidis N: Feasibility study and pharmacokinetics of low-dose paclitaxel in cancer patients with severe hepatic dysfunction. Anticancer Drugs 2006;17:1219-1222.
  52. Chen N, Li Y, Ye Y, Palmisano M, Chopra R, Zhou S: Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: disposition kinetics and pharmacology distinct from solvent-based paclitaxel. J Clin Pharmacol 2014;54:1097-1107.
  53. Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P: Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophor-free, albumin-bound paclitaxel, ABI-007, compared with Cremophor-based paclitaxel. Clin Cancer Res 2006;12:1317-1324.
  54. Biakhov MY, Kononova GV, Iglesias J, Desai N, Bhar P, Schmid AN, Loibl S: nab-Paclitaxel in patients with advanced solid tumors and hepatic dysfunction: a pilot study. Expert Opin Drug Saf 2010;9:515-523.
  55. Aapro MS, Martin C, Hatty S: Gemcitabine - a safety review. Anticancer Drugs 1998;9:191-201.
  56. Saif MW, Shahrokni A, Cornfeld D: Gemcitabine-induced liver fibrosis in a patient with pancreatic cancer. JOP 2007;8:460-467.
    External Resources
  57. Stellman A, Loke MM, Mann S: Acute liver failure secondary to gemcitabine. BMJ Case Rep 2010;2010:bcr1220081371.
  58. Venook AP, Egorin MJ, Rosner GL, Hollis D, Mani S, Hawkins M, Byrd J, Hohl R, Budman D, Meropol NJ, Ratain MJ: Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol 2000;18:2780-2787.
    External Resources
  59. Kubicka S, Rudolph KL, Tietze MK, Lorenz M, Manns M: Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology 2001;48:783-789.
    External Resources
  60. Felici A, Di Segni S, Milella M, Colantonio S, Sperduti I, Nuvoli B, Contestabile M, Sacconi A, Zaratti M, Citro G, Cognetti F: Pharmacokinetics of gemcitabine at fixed-dose rate infusion in patients with normal and impaired hepatic function. Clin Pharmacokinet 2009;48:131-141.
  61. Joerger M, Huitema AD, Koeberle D, Rosing H, Beijnen JH, Hitz F, Cerny T, Schellens JH, Gillessen S: Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction. Cancer Chemother Pharmacol 2014;73:113-124.
  62. Glant JA, Waters JA, House MG, Zyromski NJ, Nakeeb A, Pitt HA, Lillemoe KD, Schmidt CM: Does the interval from imaging to operation affect the rate of unanticipated metastasis encountered during operation for pancreatic adenocarcinoma? Surgery 2011;150:607-616.

Author Contacts

Prof. Dr. med. Hanno Riess

Charité - Universitätsmedizin Berlin

Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie

Charitéplatz 1, 10117 Berlin, Germany

hanno.riess@charite.de


Article / Publication Details

First-Page Preview
Abstract of Review Article

Received: August 18, 2015
Accepted: September 28, 2015
Published online: October 20, 2015
Issue release date: November 2015

Number of Print Pages: 8
Number of Figures: 0
Number of Tables: 3

ISSN: 2296-5270 (Print)
eISSN: 2296-5262 (Online)

For additional information: https://www.karger.com/ORT


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  24. Levitt DG, Levitt MD: Quantitative assessment of the multiple processes responsible for bilirubin homeostasis in health and disease. Clin Exp Gastroenterol 2014;7:307-328.
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    External Resources
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  29. Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, Kremers W, Lake J, Howard T, Merion RM, Wolfe RA, Krom R, United Network for Organ Sharing Liver Disease Severity Score Committee: Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91-96.
  30. Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O'Beirne J, Fox R, Skowronska A, Palmer D, Yeo W, Mo F, Lai P, Inarrairaegui M, Chan SL, Sangro B, Miksad R, Tada T, Kumada T, Toyoda H: Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach - the ALBI grade. J Clin Oncol 2015;33:550-558.
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  32. Will U, Meyer F: [Endoscopic ultrasonography (EUS)-guided transluminal cholangiodrainage (EUCD) - a novel option of interventional endoscopy in the interdisciplinary management of obstructive jaundice]. Zentralbl Chir 2012;137:20-31.
  33. Kim YS, Gupta K, Mallery S, Li R, Kinney T, Freeman ML: Endoscopic ultrasound rendezvous for bile duct access using a transduodenal approach: cumulative experience at a single center. A case series. Endoscopy 2010;42:496-502.
  34. Bhalala M, Rude K, Wang A, Sauer B, White GE, Kahaleh M, Shami VM: Analysis of complications after EUS-FNA in patients with obstructive jaundice and drained with plastic biliary stents or self-expandable metal stent (SEMS): Do complications differ between the type of stent? J Interv Gastroenterol 2013;3:128-132.
  35. Arguedas MR, Heudebert GH, Stinnett AA, Wilcox CM: Biliary stents in malignant obstructive jaundice due to pancreatic carcinoma: a cost-effectiveness analysis. Am J Gastroenterol 2002;97:898-904.
  36. Prat F, Chapat O, Ducot B, Ponchon T, Pelletier G, Fritsch J, Choury AD, Buffet C: A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct. Gastrointest Endosc 1998;47:1-7.
  37. Kaassis M, Boyer J, Dumas R, Ponchon T, Coumaros D, Delcenserie R, Canard JM, Fritsch J, Rey JF, Burtin P: Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc 2003;57:178-182.
  38. Davids PH, Groen AK, Rauws EA, Tytgat GN, Huibregtse K: Randomised trial of self-expanding metal stents versus polyethylene stents for distal malignant biliary obstruction. Lancet 1992;340:1488-1492.
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  41. Eklund JW, Trifilio S, Mulcahy MF: Chemotherapy dosing in the setting of liver dysfunction. Oncology (Williston Park) 2005;19:1057-1063; discussion 1063-1054, 1069.
    External Resources
  42. Viudez A, Ramirez N, Hernandez-Garcia I, Carvalho FL, Vera R, Hidalgo M: nab-Paclitaxel: a flattering facelift. Crit Rev Oncol Hematol 2014;92:166-180.
  43. Li Y, Chen N, Palmisano M, Zhou S: Pharmacologic sensitivity of paclitaxel to its delivery vehicles drives distinct clinical outcomes of paclitaxel formulations. Mol Pharm 2015;12:1308-1317.
  44. Sparreboom A, Huizing MT, Boesen JJ, Nooijen WJ, van Tellingen O, Beijnen JH: Isolation, purification, and biological activity of mono- and dihydroxylated paclitaxel metabolites from human feces. Cancer Chemother Pharmacol 1995;36:299-304.
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    External Resources
  46. Henningsson A, Sparreboom A, Sandstrom M, Freijs A, Larsson R, Bergh J, Nygren P, Karlsson MO: Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients. Eur J Cancer 2003;39:1105-1114.
  47. Joerger M, Huitema AD, van den Bongard DH, Schellens JH, Beijnen JH: Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of paclitaxel in patients with solid tumors. Clin Cancer Res 2006;12:2150-2157.
  48. Joerger M, Huitema AD, Huizing MT, Willemse PH, de Graeff A, Rosing H, Schellens JH, Beijnen JH, Vermorken JB: Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study. Br J Clin Pharmacol 2007;64:622-633.
  49. Venook AP, Egorin MJ, Rosner GL, Brown TD, Jahan TM, Batist G, Hohl R, Budman D, Ratain MJ, Kearns CM, Schilsky RL: Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264. J Clin Oncol 1998;16:1811-1819.
    External Resources
  50. Wilson WH, Berg SL, Bryant G, Wittes RE, Bates S, Fojo A, Steinberg SM, Goldspiel BR, Herdt J, O'Shaughnessy J, et al.: Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion. J Clin Oncol 1994;12:1621-1629.
    External Resources
  51. Briasoulis E, Karavasilis V, Tzamakou E, Piperidou C, Soulti K, Pavlidis N: Feasibility study and pharmacokinetics of low-dose paclitaxel in cancer patients with severe hepatic dysfunction. Anticancer Drugs 2006;17:1219-1222.
  52. Chen N, Li Y, Ye Y, Palmisano M, Chopra R, Zhou S: Pharmacokinetics and pharmacodynamics of nab-paclitaxel in patients with solid tumors: disposition kinetics and pharmacology distinct from solvent-based paclitaxel. J Clin Pharmacol 2014;54:1097-1107.
  53. Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P: Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophor-free, albumin-bound paclitaxel, ABI-007, compared with Cremophor-based paclitaxel. Clin Cancer Res 2006;12:1317-1324.
  54. Biakhov MY, Kononova GV, Iglesias J, Desai N, Bhar P, Schmid AN, Loibl S: nab-Paclitaxel in patients with advanced solid tumors and hepatic dysfunction: a pilot study. Expert Opin Drug Saf 2010;9:515-523.
  55. Aapro MS, Martin C, Hatty S: Gemcitabine - a safety review. Anticancer Drugs 1998;9:191-201.
  56. Saif MW, Shahrokni A, Cornfeld D: Gemcitabine-induced liver fibrosis in a patient with pancreatic cancer. JOP 2007;8:460-467.
    External Resources
  57. Stellman A, Loke MM, Mann S: Acute liver failure secondary to gemcitabine. BMJ Case Rep 2010;2010:bcr1220081371.
  58. Venook AP, Egorin MJ, Rosner GL, Hollis D, Mani S, Hawkins M, Byrd J, Hohl R, Budman D, Meropol NJ, Ratain MJ: Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol 2000;18:2780-2787.
    External Resources
  59. Kubicka S, Rudolph KL, Tietze MK, Lorenz M, Manns M: Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology 2001;48:783-789.
    External Resources
  60. Felici A, Di Segni S, Milella M, Colantonio S, Sperduti I, Nuvoli B, Contestabile M, Sacconi A, Zaratti M, Citro G, Cognetti F: Pharmacokinetics of gemcitabine at fixed-dose rate infusion in patients with normal and impaired hepatic function. Clin Pharmacokinet 2009;48:131-141.
  61. Joerger M, Huitema AD, Koeberle D, Rosing H, Beijnen JH, Hitz F, Cerny T, Schellens JH, Gillessen S: Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction. Cancer Chemother Pharmacol 2014;73:113-124.
  62. Glant JA, Waters JA, House MG, Zyromski NJ, Nakeeb A, Pitt HA, Lillemoe KD, Schmidt CM: Does the interval from imaging to operation affect the rate of unanticipated metastasis encountered during operation for pancreatic adenocarcinoma? Surgery 2011;150:607-616.
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