Critical Reviews in Oncology/Hematology 115 (2017) 59–66
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Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc
Treatment options for metastatic colorectal cancer in patients with liver dysfunction due to malignancy L. Faugeras a,∗ , A. Dili b , A. Druez c , B. Krug d , C. Decoster e , L. D’Hondt a a
Oncology Department, CHU Dinant Godinne UCL Namur, Yvoir, Belgium Services of Surgery, Endocrinology, CHU Dinant Godinne UCL Namur, Yvoir, Belgium Services of Gastroenterology, CHU Dinant Godinne UCL Namur, Yvoir, Belgium d Division of Nuclear Medicine, CHU Dinant Godinne UCL Namur, Yvoir, Belgium e Pharmacy department, CHU Dinant Godinne UCL Namur, Yvoir, Belgium b c
Contents 1. 2. 3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Material and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.1. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.1.1. 5-fluorouracil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.1.2. Capecitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.1.3. Irinotecan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 3.1.4. Oxaliplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 3.1.5. Trifluridine/tipiracil (TAS 102) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 3.2. Targeted therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 3.2.1. Cetuximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 3.2.2. Panitumumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.2.3. Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.2.4. Aflibercept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.2.5. Regorafenib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.3. Supportive treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
a r t i c l e
i n f o
Article history: Received 12 December 2016 Received in revised form 28 February 2017 Accepted 27 March 2017 Keywords: Hepatic dysfunction Chemotherapy Hyperbilirubinaemia Monoclonal antibodies Targeted therapy
a b s t r a c t Background: The survival of colorectal cancer patients is frequently determined by the extent of metastatic invasion to the liver; in cases of major involvement, therapeutic strategies are limited because the liver is necessary for drug metabolism. Material and methods: We have reviewed articles about the pharmacokinetic profiles of each drug used in colorectal cancer patients with hepatic dysfunction to determine which of these treatments are most feasible. Results: Some drugs appear to be feasible options for patients with hepatic insufficiency. Agents such as 5-fluorouracil and oxaliplatin, as well as monoclonal antibodies such as bevacizumab, cetuximab, and panitumumab, can potentially be used in these cases. On the other hand, irinotecan and regorafenib cannot be recommended because of the risk of increased toxicity.
Abbreviations: 5-FU, 5-fluorouracil; CEA, carcinoembryonic antigen; CYP3A4, cytochrome 3A4; DPD, dihydropyrimidine dehydrogenase; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; IV, intravenous; LV, leucovorin; LV/5FU, leucovorin-base plus 5-fluorouracil; OS, overall survival; PD, progressive disease; PR, partial response; PFS, progression-free survival; SD, stable disease; UGT, uridine diphosphate glucuronosyltransferase; ULN, upper limit of normal; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; TAS 102, Trifluridine/tipiracil; T½, half-life time. ∗ Corresponding author at: Oncology Department, CHU Dinant Godinne UCL Namur, 1 rue gaston Therasse, 5530 Yvoir, Belgium. E-mail address:
[email protected] (L. Faugeras). http://dx.doi.org/10.1016/j.critrevonc.2017.03.029 1040-8428/© 2017 The Author(s). Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
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Conclusion: Treatment of patients with colorectal cancer and liver dysfunction represents a major challenge because the prognosis is usually very poor and alteration of liver function is normally an exclusion criterion in clinical trials. In this review, we present evidence regarding the use of each drug in patients with colorectal cancer and hepatic impairment. © 2017 The Author(s). Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Colorectal cancer is the second most commonly diagnosed cancer in the world. In 2012, 1.3 millon new cases of colorectal cancer were diagnosed worldwide, with 447,000 new cases in Europe alone (Van Cutsem et al., 2014; Ferlay et al., 2015). Colorectal cancer mortality has decreased by 39% in United States in the past two decades due to early detection of the disease as well as better access to colonoscopy and new treatments (Ait Ouakrim et al., 2015). In Europe, chemotherapy regimens for patients with colorectal cancer commonly include 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (Van Cutsem et al., 2016). New targeted therapies continue to be developed; the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have currently approved five targeted therapies: bevacizumab, aflibercept, cetuximab, panitumumab, and regorafenib. Approximately 50% of patients with colorectal cancer will develop liver metastases during their lifetime; 20% will be synchronous and 30% metachronous (Roderburg et al., 2011). Fortunately, there has been tremendous progress in the treatment of patients with colorectal cancer that has metastasized to the liver, including novel targeted therapies, SIR-Spheres, chemoembolization, and hepatic arterial infusion chemotherapy. Liver dysfunction due to malignancy is an uncommon cause of acute liver failure. The mechanism by which malignancy causes liver dysfunction is multifactorial and may include direct reduction of the volume of functional healthy liver or intrahepatic and extrahepatic biliary obstruction (Field et al., 2008). Furthermore, portal vein occlusion due to portal-vein thrombosis as a consequence of a hypercoagulable state or tumor thrombi may cause parenchymal infarction (Field et al., 2008; Khashab et al., 2007; Harrison et al., 1981). Humoral and immunological factors associated with cancer may also increase cholestasis and inflammatory damage in the liver (Field et al., 2008). Serological tests of liver function evaluate synthetic function by serum albumin levels and prothrombin time, cellular injury by asparate aminotransferase and alanine aminotransferase concentrations, and cholestasis by alkaline phosphatase, gammaglutamyltransferase, and direct-reacting bilirubin levels. The serum concentration of bilirubin is a specific measure of potentially serious liver damage and an important indicator of liver functional loss (Field et al., 2008). Prognosis is considered dismal if impaired liver function is secondary to metastasized colorectal cancer, with a median survival time of only a few weeks (Harrison et al., 1981). Management of such patients represents a serious challenge because there is little published guidance regarding the choice of therapy. It is further complicated by the increased risk of chemotherapy-related complications. Nevertheless, the literature contains a few examples of such therapies. In this review, we compare different chemotherapy and targeted therapy modalities that have been employed to treat patients with colorectal cancer and liver deficiency induced by metastasis and make recommendations based on our findings from the literature.
2. Material and methods We reviewed articles regarding the pharmacokinetic profile of each drug that has been used in patients with colorectal cancer and hepatic dysfunction to determine which drugs are the most feasible and safe. We subsequently performed an electronic search of the Medline database covering the period from 1996 to 2016 using the MeSH headings “colorectal cancer,” “liver dysfunction,” and the names of all of the drugs used to treat metastatic colorectal cancer namely “FOLFOX”, “5FU”, “FOLFIRI”, “Capecitabine”, “Regorafenib”, “TAS 102”, “Cetuximab”, “ Bevacizumab”, “Panitumumab”, “Aflibercept”. The search was limited to English-language publications and human subjects. We reviewed all pertinent titles and abstracts and further assessed papers that we judged appropriate for inclusion in this review. We discuss papers that describe use of the various drugs in patients with colorectal cancer and liver dysfunction. 3. Results 3.1. Chemotherapy Chemotherapy is the cornerstone of metastatic colorectal cancer treatment. 5-FU is the standard chemotherapeutic agent for palliative therapy. It has a proven impact on survival time in patients with colorectal cancer, with response rates ranging from 10% to 50% depending on the regimen used (Simmonds, 2000; De Gramont et al., 1988; Piedbois et al., 1998). The addition of oxaliplatin or irinotecan to 5-FU regimens results in a significant increase in positive response, prolonged time to tumor progression, and survival (Saltz et al., 2000; de Gramont et al., 2000). Although there are pharmacokinetic studies for monotherapy anticancer drugs, there is a lack of data regarding drug combinations. 3.1.1. 5-fluorouracil First-line systemic chemotherapy for metastatic colorectal cancer commonly includes 5-FU and leucovorin base (LV/5-FU). The main effect of the pyrimidine analogue 5-FU is irreversible inhibition of thymidylate synthase. Eighty percent of 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD) in the liver, where it is abundantly expressed. DPD is the rate-limiting enzyme in 5FU catabolism and converts 5-FU to dihydrofluorouracil (Longley et al., 2003; Fleming et al., 2003). There appears to be no correlation between bilirubin levels and 5-FU clearance. We did not find any pharmacokinetic data regarding administration of 5-FU bolus in patients with liver dysfunction. However, Fleming et al. investigated infusional administration of LV/5-FU in patients with liver dysfunction, including those with bilirubin levels >5 mg/dL (Fleming et al., 2003). It seems that it can be safely used without additional toxicity in patients with hyperbilirubinemia (Fleming et al., 2003). 3.1.2. Capecitabine Capecitabine is an oral prodrug that is metabolized to 5-FU. It is equivalent in effectiveness to 5-FU in patients with metastatic colorectal cancer (Eklund et al., 2005; Hwang et al., 2006; Petrelli et al., 2012; Loree et al., 2014; Ducreux et al., 2011; Cassidy et al., 2011a;
L. Faugeras et al. / Critical Reviews in Oncology/Hematology 115 (2017) 59–66
Cassidy et al., 2011b). Capecitabine is both extensively activated and broken down in the liver and thus extensively metabolized by the liver. However, a pharmacokinetic study revealed mildto-moderate hepatic dysfunction that had no clinically significant influence on the pharmacokinetic parameters of capecitabine and its metabolites. Based on these reports, capecitabine can be used without dose adjustment in patients with liver dysfunction (Eklund et al., 2005; Twelves et al., 1999). 3.1.3. Irinotecan Irinotecan is mainly activated in the liver and (to a lesser extent) in the kidneys. Both irinotecan and its active metabolite SN-38 are synthetic camptothecin-derived DNA topoisomerase I inhibitors. SN-38 is metabolized into SN-38 glucuronide by uridine diphosphate glucuronosyltransferase (UGT1A1), the same isoenzyme responsible for glucuronidation of bilirubin. There is wide intersubject variability in UGT1A1 activity due to UGT1A1 polymorphisms. Irinotecan can cause severe neutropenia and diarrhea in patients with deficient UGT1A1 activity, such as individuals with Gilbert syndrome (Wasserman et al., 1997). Several polymorphisms of UGT1A1 have been identified as predictors of irinotecan toxicity (Soria et al., 2017; Innocenti et al., 2004). Some polymorphisms, such as homozygous UGT1A1*28/*28 and UGT1A1*6, increase the risk of secondary side effects (Innocenti et al., 2014; Xu et al., 2013), while others, such as homozygous UGT1A1*1/*1 or heterozygous UGT1A1 *1/*28, are more favorable and associated with less toxicity (Schulz et al., 2009). Normal liver function is critical for the detoxification and excretion of irinotecan and SN-38 (Raymond et al., 2002; Venook et al., 2003). Raymond et al. demonstrated in a phase I study that irinotecan clearance decreases exponentially with increased bilirubin and alkaline phosphatase levels. The dosage of irinotecan monotherapy must be reduced in patients with bilirubin levels >1.5-fold the upper limit of normal (ULN). For bilirubin levels between 1.5and 3-fold the ULN, the dose of irinotecan should be reduced by 40%. Irinotecan is not recommended for patients in whom baseline bilirubin levels exceed the ULN by 3-fold (Raymond et al., 2002). Despite the findings described above, Yeh et al. reported results from one patient with rectosigmoid cancer and liver metastases who had hyperbilirubinemia (total bilirubin level of 5.94 mg/dL). This patient was successfully treated with FOLFIRI (folinic acid, 5-FU, and irinotecan) and bevacizumab after identification of polymorphism UGT1A1 6/6 or 6/7. The irinotecan dosage was adjusted based on this genotype and initiated at 120 mg/m2 (Yeh et al., 2014). Based on our findings in the literature, irinotecan in monotherapy or associated with FU must be restricted to patients with adequate or mildly altered liver function. 3.1.4. Oxaliplatin The current first-line option for systemic chemotherapy in patients with metastatic colorectal cancer is either FOLFOX (folinic acid, 5-FU and oxaliplatin) or capecitabine plus oxaliplatin (XELOX) (Cassidy et al., 2011a). The platinum derivative oxaliplatin (transdiaminocyclohexane) forms a platinum adduct on DNA to block transcription and replication. Oxaliplatin is cleared by the kidneys (Extra et al., 1998), and consequently its kinetics are not affected by liver dysfunction (Synold et al., 2007). However, hepatic impairment does influence other factors; for example, it decreases serum albumin levels which in turn increases concentrations of free oxaliplatin, leading to adverse effects related to the drug. The National Cancer Institute Organ Dysfunction Working Group conducted a phase I study on the pharmacokinetics of oxaliplatin in patients with solid tumors and hepatic dysfunction. Their preliminary results revaled that oxaliplatin is well tolerated and can be administered at doses of up to 130 mg/m2 every 21 days in patients with severe hepatic functional abnomalities (Doroshow
61
et al., 2003). Synold et al. also showed that reduced dosage of oxaliplatin in monotherapy was unnecessary in patients with liver dysfunction (Synold et al., 2007). Oxaliplatin is commonly used in combination with 5-FU, but we were unable to find any highquality data regarding the pharmacokinetics of FOLFOX or XELOX in patients with liver failure. However, a few case reports have described good tolerance (Table 1). Out of ten patients with liver dysfunction treated by FOLFOX, only one did not respond (Kasi et al., 2015). These data suggest a clinical benefit for patients with metastatic colorectal cancer and severe lever dysfunction who are treated with FOLFOX. 3.1.5. Trifluridine/tipiracil (TAS 102) As regorafenib, Trifluridine/tipiracil (TAS 102) is novel antitumoral agent for patients with metastatic colorectal cancer refractory to standard systemic therapy (Sueda et al., 2016). The result of the phase III RECOURSE trial shows a significant increase in the overall survival rate of 1.8 months compared to the placebo group (Mayer et al., 2015). TAS 102 is the combination of drugs associating an antineoplastic thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride. Trifluorothymidine is considered a thymidine analogue and belongs to the family of deoxynucleoside analogues(Zaniboni et al., 2016). The major elimination pathway of FTD is metabolism by thymidine phosphorylase(Lenz et al., 2015). The main side effects are asthenia, nausea, decreased appetite, diarrhea and neutropenia (Mayer et al., 2015; Longo-Munoz et al., 2017). Increase in aspartate aminotransferase, alanine aminotransferase and bilirubin levels with TAS-102 can also be seen (Masuishi et al., 2016). The hepatic selection criteria to initiate treatment with TAS 102 in the various studies was aspartate aminotransferase level (AST) and alanine aminotransferase level (ALT) less than 200 IU/L when patients with liver metastases and total bilirubin less than 1.5 mg/dL(Yoshino et al., 2016). Patients with moderate (bilirubin total greater than 1.5–3 times UNL and any AST) or severe (total bilirubin greater than 3 times UNL and any AST) hepatic impairment were not enrolled in the RECOURSE Study. There is therefore currently no information on the use of the TAS 102 in patients with liver dysfunction. However, a phase I open label study is under way to evaluate the Safety, Tolerability, and Pharmacokinetics of TAS102 in Patients With Advanced Solid Tumors and Varying Degrees of Hepatic Impairment (ClinicalTrials.gov NCT02301104) (Lenz et al., 2015). 3.2. Targeted therapy The development of targeted therapies that employ monoclonal antibodies has significantly improved the management of colorectal cancer (Lee and Oh, 2016). The FDA and EMA approved cetuximab in 2004; bevacizumab was approved by the FDA in 2004 and by the EMA in 2005. 3.2.1. Cetuximab Cetuximab is a recombinant, human–mouse chimeric monoclonal IgG1 antibody that specifically targets epidermal growth factor receptor (EGFR). EGFR activation of RAS genes contributes to the proliferation and survival of cancer cells and the production of angiogenic factors. Thus, by blocking EGFR, cetuximab inhibits expression of angiogenic factors by tumor cells and reduces tumor neovascularization and metastasis. Some metastatic colorectal cancers have RAS gene mutations that cause constitutive activation of RAS protein independent of EGFR signals, rendering cetuximab ineffective (Husson, 2013). The incidence of RAS mutations is approximately 35–45% metastatic colorectal cancer (Cunningham et al., 2004; Jonker et al., 2007). Cetuximab is approved for use in association with FOLFIRI (Van Cutsem et al., 2009) or FOL-
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Table 1 Published case reports of patients with severe liver dysfunction who were treated with FOLFOX for metastatic colorectal cancer. Age (y), sex
Baseline
After cycles
Fakih, 2004
Case 1: 63, M Case 2: 59, F Case 3: 37, F
3 3 2
Elsoueidi et al., 2014
Case 4: 67, M
Shimura et al., 2011 Terasawa et al., 2013
Roderburg et al., 2011
Kasi et al., 2015
ECOG performance status
Regimens
Bilirubin total (mg/dL)
CEA (ng/mL)
Response
FOLFOX cycles until disease progression
Survival (months)
Baseline
After cycles
Baseline
After cycles
2 cycles: 1 2 cycles: 2 2 cycles: 1
mFOLFOX4 mFOLFOX4 mFOLFOX4
3.5 5.9 4.2
2 cycles: 1.2 2 cycles: 2.1 2 cycles: 2.1
188 1.34 3685
2 cycles: 4.8 2 cycles: 895 2 cycles: 937
PR SD PR
14 8 >10
9 4 –
–
–
9.4
–
Case 5: 58, F Case 6: 54, M
– –
– –
Bolus 5-FU: 200 mg/m2 , IV 5-FU: 1200 mg/m2 , LV: 200 mg, oxaliplatin: 75 mg/m2 mFOLFOX6 FOLFOX6 at 20% lower dosage
12.2
2 cycles: 4
PR
21
–
3.9 15.6
2 cycles: 2.2 4 cycles: 2.3
102.1 –
2 cycles: 96 –
SD –
6 –
15 –
Case 7: 68, M
2
4 cycles: 0
mFOLFOX4
12.1
4 cycles: 2.9 4 cycles: 4
26
4 cycles: 12
PR
10
10
Case 8: 76, F
3
4 cycles: 1
mFOLFOX4
25.3
70
4 cycles: 32
PR
12
–
Case 9: 43, M Case 10: 64, M
1 1
1 cycles: 5 –
mFOLFOX7 mFOLFOX7
9.4 8.4
1 cycle: 18.4 3.9
271.9 0.7
2770 –
PD PR
1 10
1.5 18
5-FU: 5-fluorouracil; CEA: carcinoembryonic antigen; ECOG: Eastern Cooperative Oncology Group; IV: intravenous; LV: leucovorin; PD: progressive disease; PR: partial response; SD: stable disease.
L. Faugeras et al. / Critical Reviews in Oncology/Hematology 115 (2017) 59–66
Reference
L. Faugeras et al. / Critical Reviews in Oncology/Hematology 115 (2017) 59–66
FOX (Bokemeyer et al., 2011) in patients whose tumors are RAS wild-type. It can also be administered as monotherapy in patients who were treated previously with fluoropyrimidines, irinotecan, and oxaliplatin (Jonker et al., 2007). Like all antibodies, cetuximab is cleared from the body by means of nonspecific intracellular catabolism that involves the reticuloendothelial system and internalization of EGFR. This occurs independent of liver function (Krens et al., 2014a; Shitara et al., 2009). Thus, it is not necessary to adjust the dosage in patients with liver failure. The literature describes patients with liver dysfunction who were treated successfully with cetuximab as monotherapy. These patients had improved performance status and liver enzyme levels (Shitara et al., 2009; Sakisaka et al., 2014). 3.2.2. Panitumumab Panitumumab is a fully human IgG2 antibody directed against EGFR. It inhibits signal transduction and cell proliferation and induces apoptosis. Although it has the same therapeutic target as cetuximab, the two agents differ in several respects. For instance, panitumumab does not elicit hypersensitivity reactions as cetuximab does. Additionally, their mechanisms of action appear to be somewhat different, although how they differ is unclear (Saif et al., 2010). Power et al. and Saif et al. showed that panitumumab is efficacious after progression following treatment with cetuximab (Saif et al., 2010; Power et al., 2010). The clearance pathway of this agent is likely mediated by the reticuloendothelial system and internalization of EGFR. Thus, as with other antibody therapeutic agents, hepatic dysfunction has no effect on panitumumab pharmacokinetics (Giusti et al., 2008; Krens et al., 2014b). We found only one case report of a patient with liver dysfunction who was treated with panitumumab, even though this antibody is considered safe and efficient without requiring any adjustments in dosage (Krens et al., 2014b). 3.2.3. Bevacizumab Bevacizumab is a humanized monoclonal IgG antibody directed against vascular endothelial growth factor (VEGF). It decreases VEGF binding to its receptors, thereby neutralizing this ligand’s function and reducing neovascularization of tumors. Bevacizumab is eliminated through cellular internalization and further intracellular catabolism; the elimination pathway is thus independent of liver function. However, a clinical pharmacokinetic study by Lu et al. found a 19% faster clearance of bevacizumab in patients with low serum albumin levels (483 IU/L). Serum alkaline phosphatase and albumin variations are often observed in association with liver failure (Lu et al., 2008); moreover, the relationship between bevacizumab exposure and clinical outcomes in patients with liver failure has not been explored. In addition to the development of therapeutic antiEGFR antibodies, anti-VEGF antibodies such as bevacizumab have improved chemotherapeutic efficacy. In 2004, the phase III study AVF2107g demonstrated a survival benefit when bevacizumab is added to irinotecan, 5-FU, and LV; this regimen was approved by the FDA (Grothey et al., 2008; Hurwitz et al., 2004). Subsequently, three phase III studies (NO16966, E3200, and ML18147) confirmed that adding bevacizumab to chemotherapy regimens improves progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone (Giantonio et al., 2007; Saltz et al., 2008; Bennouna et al., 2013). The E3200 study showed that bevacizumab monotherapy or FOLFOX alone produce less favorable PFS and objective response rates than the combination of FOLFOX and bevacizumab (Giantonio et al., 2007). Hence, bevacizumab is beneficial when combined with chemotherapy, although it does not appear to offer superior benefits as a monotherapy. Bevacizumab in combination with LV/5-FU, FOLFOX, or FOLFIRI has not been stud-
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ied in patients with liver dysfunction. After reviewing the results of the BOND-2 trial (Saltz et al., 2007), Moosmann et al. administered a combined antibody treatment of cetuximab and bevacizumab to a patient with a serum bilirubin level of 12.8 mg/dL in 2007; serum bilirubin levels normalized after eight cycles (Moosmann et al., 2007). However, we cannot recommend this nonhepatotoxic regimen of EGFR-specific monoclonal antibody and bevacizumab because subsequent publications showed significantly reduced PFS and exacerbation of toxicity compared to treatment with a regimen of bevacizumab plus chemotherapy (Marshall, 2009).
3.2.4. Aflibercept In August 2012, the FDA approved Ziv-aflibercept (aflibercept) in combination with FOLFIRI to treat patients with metastatic colorectal cancer resistant to or progressing after treatment with an oxaliplatin-based regimen (Ziv-Aflibercept, 2012). Aflibercept is a novel anti-angiogenic agent that binds to VEGF and decreases neovascularization and vascular permeability, thereby inhibiting tumor growth. The VELOUR trial demonstrated significantly improved OS and PFS in patients treated with FOLFIRI plus aflibercept versus FOLFIRI plus placebo after progression with an oxaliplatin-containing regimen (Saif, 2014). We did not find any data on the use of aflibercept as monotherapy in patients with liver dysfunction. However, clearance of aflibercept is increased in patients with low serum albumin concentrations or high concentrations of serum alkaline phosphatase; hence, exposure to free aflibercept is decreased (Thai et al., 2013). Aflibercept is used in combination with FOLFIRI, but this combination is contraindicated in patients with liver dysfunction.
3.2.5. Regorafenib The novel anticancer agent regorafenib was introduced in 2012 following the results of the phase III CORRECT trial (Grothey et al., 2013), which demonstrated survival benefits for regorafenib compared to placebo in metastatic colorectal cancer that had progressed after all standard therapies were attempted. Regorafenib is a small-molecule multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases (e.g., VEGF receptor 2 [VEGFR2], VEGFR1, VEGFR3, fibroblast growth factor receptor 1, RAF, KIT, RET, and BRAF) (Waddell and Cunningham, 2013; Krishnamoorthy et al., 2015). It is metabolized mainly in the liver by CYP3A4 and UGT1A9 into two active metabolites: regorafenib N-oxide and N-desmethyl (Solimando and Waddell, 2013). No differences in mean exposure to regorafenib or its metabolites have been observed in patients with mild or moderate hepatic impairment; therefore, no dose adjustment is necessary for these patients (Wayne, 2012). However, regorafenib has not been studied in patients with severe hepatic dysfunction and cannot currently be recommended.
3.3. Supportive treatments Corticosteroids are frequently administered when massive hepatic metastatic invasion induces liver failure. Massive infiltration can cause an inflammatory reaction within the liver parenchyma. Corticosteroids may reduce this inflammation and allow some recovery of liver function. However, there are no data available on this topic. In view of the very poor prognosis of patients with massive hepatic metastatic invasion and liver failure, the low toxicity profile associated with short-term use of corticosteroids, and their analgesic effect, their administration has been widely adopted. A future retrospective study is expected to check the efficacy of corticosteroid therapy with respect to improved liver function.
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Table 2 List of therapies for patients with metastatic colorectal cancer and hepatic impairment. Pharmacokinetics
Metabolism
Excretion
Dosage adaptation
Comments
5-FU
T½ 6–15 min
Hepatic by DPD
Pulmonary and urinary
No
Capecitabine
T½ 45 min, capecitabine metabolite T½ 3–4 h T½ plasma elimination: 40 h, T½ terminal elimination: 250 h T½ 12–15 h; inrinotecan metabolite T½ 15–20 h
Hepatic metabolization to 5-FU
Urinary and biliary
No
Nonenzymatic
Urinary
No
Changed into active metabolite SN-38 then metabolized by UGT1A1 Reticuloendothelial system
Fecal and urinary
–
Bilirubin 3 × ULN No
Can be used without dosage adjustment with no increase in side effects Can be used without dosage adjustment with no increase in side effects Can be used without dosage adjustment with no increase in side effects Not recommended
Oxaliplatin
Irinotecan
Dosage adaptation No adaptation 75% Contraindication
Cetuximab
T½ 70–100 h
Panitimumab
T½ 4–11 days
Reticuloendothelial system
–
No
Bevacizumab
T½ 20 days
Reticuloendothelial system
–
No
Aflibercept
T½ 6 days
Reticuloendothelial system
–
No
Regorafenib
T½ 20–30 h; regorafenib metabolite T½ 100 h T½ for trifluridine: 2.1 h T½ for tpiracil: 2.4 h
Hepatic by CYP3A4 M2 and M5, also by UGT1A9 metabolism via thymidine phosphorylase to form an inactive metabolite
Fecal and urinary
Child-Pugh class A: no adaptation, Child-Pugh B: close monitoring, Child-Pugh C: contraindicated Dosage adaptation Bilirubin 3ULN
TAS 102
–
Can be used without dosage adjustment with no increase in side effects Can be used without dosage adjustment with no increase in side effects Can be used without dosage adjustment with no increase in side effects, but can’t be used as monotherapy Can be used without dosage adjustment with no increase in side effects, but can’t be used as monotherapy Not recommended
phase I open label study in progress
5-FU: 5-fluorouracil, T½: half-life time, DPD: dihydropyrimidine dehydrogenase, UGT1A: uridine diphosphate glucuronosyltransferase 1A, CYP3A4: cytochrome 3A4, ULN: upper limit of normal.
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Drugs
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4. Conclusion The pharmacokinetics of drugs used to treat metastatic colorectal cancer have not been fully investigated in patients with hepatic impairment, and the necessity of dosage adjustments in most cases remains undetermined. However, some drugs appear to be feasible options in patients with hepatic insufficiency, particularly chemotherapeutic agents such as 5-FU, capecitabine, and oxaliplatin. Antibody-based therapeutic agents such as bevacizumab, cetuximab, and panitumumab may also potentially be used in these patients. FOLFOX is a safe option in patients with metastatic colorectal cancer with severe liver dysfunction. Irinotecan, due to its metabolism, and regorafenib, due to the lack of safety data, cannot be recommended because of the risk of increased toxicity (Table 2). The choice of therapeutic agents remains a challenge in patients whose prognosis is very poor. Conflict of interests This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References Ait Ouakrim, D., Pizot, C., Boniol, M., Malvezzi, M., Boniol, M., Negri, E., et al., 2015. Trends in colorectal cancer mortality in Europe: retrospective analysis of the WHO mortality database. BMJ 351, h4970. Bennouna, J., Sastre, J., Arnold, D., Osterlund, P., Greil, R., Van Cutsem, E., et al., 2013. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 14, 29–37. Bokemeyer, C., Bondarenko, I., Hartmann, J.T., de Braud, F., Schuch, G., Zubel, A., et al., 2011. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann. Oncol. 22, 1535–1546. Cassidy, J., Clarke, S., Diaz-Rubio, E., Scheithauer, W., Figer, A., Wong, R., et al., 2011a. XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br. J. Cancer 105, 58–64. Cassidy, J., Saltz, L., Twelves, C., Van Cutsem, E., Hoff, P., Kang, Y., et al., 2011b. Efficacy of capecitabine versus 5-fluorouracil in colorectal and gastric cancers: a meta-analysis of individual data from 6171 patients. Ann. Oncol. 22, 2604–2609. Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., et al., 2004. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337–345. De Gramont, A., Krulik, M., Cady, J., Lagadec, B., Maisani, J.E., Loiseau, J.P., et al., 1988. High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer. Eur. J. Cancer Clin. Oncol. 24, 1499–1503. Doroshow, J.H., Synold, T.W., Gandara, D., Mani, S., Remick, S.C., Mulkerin, D., et al., 2003. Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: a preliminary report of the National Cancer Institute Organ Dysfunction Working Group. Semin. Oncol. 30, 14–19. Ducreux, M., Bennouna, J., Hebbar, M., Ychou, M., Lledo, G., Conroy, T., et al., 2011. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int. J. Cancer 128, 682–690. Eklund, J.W., Trifilio, S., Mulcahy, M.F., 2005. Chemotherapy dosing in the setting of liver dysfunction. Oncology (Williston Park) 19, 1057–1063, discussion 63-4 69. Elsoueidi, R., Craig, J., Mourad, H., Richa, E.M., 2014. Safety and efficacy of FOLFOX followed by cetuximab for metastatic colorectal cancer with severe liver dysfunction. J. Natl. Compr. Canc. Netw. 12, 155–160. Extra, J.M., Marty, M., Brienza, S., Misset, J.L., 1998. Pharmacokinetics and safety profile of oxaliplatin. Semin. Oncol. 25, 13–22. Fakih, M.G., 2004. 5-fluorouracil leucovorin and oxaliplatin (FOLFOX) in the treatment of metastatic colon cancer with severe liver dysfunction. Oncology 67, 222–224. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., et al., 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–86. Field, K.M., Dow, C., Michael, M., 2008. Part I: Liver function in oncology: biochemistry and beyond. Lancet Oncol. 9, 1092–1101. Fleming, G.F., Schilsky, R.L., Schumm, L.P., Meyerson, A., Hong, A.M., Vogelzang, N.J., et al., 2003. Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction. Ann. Oncol. 14, 1142–1147. Giantonio, B.J., Catalano, P.J., Meropol, N.J., O’Dwyer, P.J., Mitchell, E.P., Alberts, S.R., et al., 2007. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer:
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