Open Access Review

Article DOI: 10.7759/cureus.2798

Dosage Adjustments for Chemotherapy and

Targeted Therapies in Colorectal and
Pancreatic Cancer Patients with Hepatic
Impairment
Sidra Khalid 1 , Aariez Khalid 2 , Bernadette A. Clark 3 , Abdo Haddad 4 , Timothy Pp. Spiro 4 ,
Hamed Daw 4

1. Internal Medicine Residency, Fairview Hospital, Cleveland Clinic, USA 2. Bachelor of Science
(biomedical Science), University of Guelph, Binbrook, CAN 3. Oncology, Cleveland Clinic Fairview
Hospital, Cleveland, USA 4. Department of Hematology and Oncology, Fairview Hospital, Cleveland
Clinic, USA, Cleveland, USA

 Corresponding author: Sidra Khalid, [email protected]

Disclosures can be found in Additional Information at the end of the article

Abstract
There are many novel chemotherapeutic options and targeted therapies available for the
treatment of colorectal and pancreatic cancer. Patients with these cancers often have hepatic
impairment either from the metastasis to the liver or from the chemotherapy or targeted
therapies used to treat the disease. It is important to describe the effects of these agents in
patients with hepatic impairment. This article will review the dosage recommendations for the
chemotherapy regimens and targeted therapies in colorectal and pancreatic cancer patients in
the setting of hepatic impairment.

Categories: Internal Medicine, Gastroenterology, Oncology

Keywords: hepatic impairment, colon cancer, rectal cancer, pancreatic cancer, chemotherapy, targeted
therapy

Introduction And Background

Hepatic impairment in colorectal and pancreatic cancer often occurs in the setting of liver
metastasis and/or because of the use of chemotherapy and targeted therapies. When clinicians
are faced with managing metastatic colorectal and pancreatic cancer in patients with hepatic
impairment, there is a need to adjust the doses of chemotherapy and targeted therapy to avoid
toxicity. In this article, we will review chemotherapy and targeted therapies used for colorectal
Received 06/01/2018 and pancreatic cancer along with their mechanisms of action. We will advise as to whether dose
Review began 06/02/2018 adjustments are required and, if necessary, we will provide recommendations based on the
Review ended 06/10/2018 degree of hepatic impairment.
Published 06/13/2018

© Copyright 2018
Khalid et al. This is an open access Review
article distributed under the terms of
the Creative Commons Attribution
Medications without recommendations for dose adjustments
License CC-BY 3.0., which permits
There are many options available for treating colorectal and pancreatic cancer patients with
unrestricted use, distribution, and
hepatic impairment. Some of the medications do not require dose adjustments. Many
reproduction in any medium,
provided the original author and medications are not metabolized in the liver and the pharmacokinetics and pharmacodynamics
source are credited. are not expected to be affected by impaired liver function. Other medications were not studied
in patients with hepatic impairment in clinical trials and therefore recommendations for

How to cite this article

Khalid S, Khalid A, Clark B A, et al. (June 13, 2018) Dosage Adjustments for Chemotherapy and Targeted
Therapies in Colorectal and Pancreatic Cancer Patients with Hepatic Impairment. Cureus 10(6): e2798.
DOI 10.7759/cureus.2798
 adjustments are not made (Table 1).

US Food and Drug Administration (US FDA)

Medication Drug Class
approved indications

-Metastatic colorectal cancer, in combination with 5-

-Vascular endothelial growth factor fluorouracil for first or second line treatment -
Bevacizumab
(VEGF) antibody Metastatic colorectal cancer in combination with
fluoropyrimidine-based chemotherapy

-EGFR expressing metastatic colorectal cancer after

failure of irinotecan and oxaliplatin-based
-Epidermal growth factor receptor chemotherapy -in combination with irinotecan in
Cetuximab
(EGFR) antagonist EGFR expressing metastatic colorectal cancer in
patients who are refractory to irinotecan-based
chemotherapy

-Single-agent treatment for metastatic colorectal

cancer with disease progression on or following
Panitumumab -EGFR antagonist
fluoropyrimidine, oxaliplatin, and irinotecan
chemotherapy regimens

-Used in combination with 5-fluorouracil/leucovorin

-Platinum-based chemotherapeutic in adjuvant treatment of stage III colon cancer with
Oxaliplatin
agent complete resection of the primary tumor; treatment
of advanced colorectal cancer

-Used in patients with metastatic colorectal cancer

Trifluridine-tipiracil
who have had a prior treatment with fluoropyrimidine,
*do not use in -Nucleoside inhibitor and thymidine
oxaliplatin, irinotecan-based chemotherapy; anti-
moderate or severe phosphorylate inhibitor
VEGF therapy; or if RAS wild-type, an anti-EGFR
hepatic impairment
therapy

Ramucirumab *no -Used in combination with FOLFIRI (irinotecan, folinic

-Monoclonal antibody that binds to
data available for acid, 5-fluorouracil) in metastatic colorectal cancer
vascular endothelin growth factor
severe hepatic with progression on or after prior therapy with
receptor (VEGFR) 2 -Antiangiogenic
impairment bevacizumab, oxaliplatin, and fluoropyrimidine

Nivolumab *not
studied in moderate -Mismatch repair deficient (dMMR) and microsatellite
to severe hepatic -Anti-program cell death protein instability high (MSI-H) metastatic colorectal cancer
impairment *monitor (PD) 1 human monoclonal antibody that has progressed following treatment with
for immune-mediated fluoropyrimidine, oxaliplatin, and irinotecan
hepatitis

-Recombinant fusion protein that

Ziv-Afibercept *no consists of VEGF-binding portions -Used in combination with 5-fluorouracil, leucovorin,
data available for from the extracellular domains of irinotecan, in metastatic colorectal cancer that is
severe hepatic human VEGFR 1 and 2 fused to Fc resistant to or has progressed following an oxaliplatin
impairment portion of human IgG1 chemotherapy regimen
immunoglobulin

2018 Khalid et al. Cureus 10(6): e2798. DOI 10.7759/cureus.2798 2 of 9

 TABLE 1: Medications that do not require dose adjustment for hepatic impairment.

Medications that require dose adjustments due to hepatic

impairment
The chemotherapeutic agents and targeted therapies that require dosage adjustment are mostly
metabolized in the liver. When hepatic impairment leads to difficulty in metabolizing the
medications and their metabolites, there is an increased risk of toxicity. In order to prevent
toxicity, these medications require dose adjustments in the setting of hepatic impairment.

5-fluorouracil

5-fluorouracil is a pyrimidine analogue that is Food and Drug Administration (FDA) approved
for colorectal and pancreatic cancer [1]. It inhibits thymidylate synthase which leads to the
decreased synthesis of thymidine, a nucleotide used for DNA and RNA synthesis. 5-fluorouracil
can cause transient hepatotoxicity through direct intrinsic injury of the hepatocytes. It is
metabolized by the liver through the microsomal enzyme system. Production of a toxic
intermediate causes the liver injury. 5-fluorouracil administration can lead to a mild elevation
of serum aminotransferases. At higher doses delivered by continuous infusion, there can be a
rapid development of hepatic coma with hyperammonemia. Patients can develop
encephalopathy within 72 hours of receiving 5-fluorouracil. In these cases, 5-fluorouracil
should be held and an ammonia lowering therapy should be initiated. Although, there is no
recommended dose that can be safely administered after developing hepatic coma and
hyperammonemia, patients who develop this complication may be able to tolerate 5-
fluorouracil at lower doses when the toxic complications resolve [2].

In a phase 1 study by Fleming et al., 64 patients with organ dysfunction were administered 5-
fluorouracil and leucovorin as a 24-hour continuous infusion. They were divided into three
cohorts: cohort 1 – creatinine >1.5 mg/dL, normal bilirubin; cohort 2 – bilirubin >1.5 mg/dL,
normal creatinine; cohort 3 – bilirubin ≥5.0 mg/dL, normal creatinine. After comparing the
results for the three cohorts, it was concluded that patients with elevated bilirubin levels could
be safely treated with weekly doses of 5-fluorouracil at 2600 mg/m2 with leucovorin 500
mg/m2 as a continuous 24-hour infusion [3]. It is recommended liver function tests be drawn at
baseline. In moderate to severe hepatic impairment, 5-fluorouracil doses need to be reduced. If
bilirubin is <2 times the upper limit of normal (ULN) and aspartate transaminase (AST)/alanine
transaminase (ALT) 3-5 times ULN reduce the dose to 75%. If bilirubin is 2-4 times ULN or
AST/ALT are 5-10 times ULN reduce the dose to 50-75%. If bilirubin is >4 times ULN or AST/ALT
are >10 times ULN, 5-fluorouracil should not be administered [4].

Capecitabine

Capecitabine is a prodrug of 5-fluorouracil. It undergoes hydrolysis in the liver and tissues to

become fluorouracil. It is approved as a first-line agent for metastatic colorectal cancer and for
stage III colorectal cancer patients who have undergone resection of their primary tumor. Its
mechanism of causing hepatotoxicity is due to its conversion into fluorouracil and has been
described in this review previously [5]. Mild to moderate hepatic impairment from liver
metastasis does increase the AUC (area under the curve) of capecitabine and Cmax (maximum
serum concentration) by 60%. However, the active drug (fluorouracil) is not affected. Serum
aminotransferase elevations above five times the upper limit occur rarely in <1% patients.
Bilirubin elevation mostly indirect hyperbilirubinemia can also be seen, and are usually self-

2018 Khalid et al. Cureus 10(6): e2798. DOI 10.7759/cureus.2798 3 of 9

 limited and mild [5]. Twelves et al. demonstrated that hepatic metastasis had no clinically
significant effect on the pharmacokinetic properties of capecitabine or its metabolites.
Capecitabine dose adjustment is not required in mild to moderate hepatic impairment [6]. In
the study trial, capecitabine was compared to 5-fluorouracil as adjuvant treatment for stage III
colon cancer. In the capecitabine alone group, hyperbilirubinemia was reported in 50/995
patients (all grades) and 20/995 patients developed grade 3 or 4 [7]. When grade 3 or 4
elevations in bilirubin occur, it is recommended that capecitabine be discontinued until
bilirubin levels decrease to less than three times the ULN, and then reduce the dose as described
in the labeling [8].

Regorafenib

Regorafenib is an oral multi-kinase inhibitor. It inhibits VEGFR 2 and 3, Ret, Kit, platelet-
derived growth factor receptor (PDGFR) and Raf kinases, which prevents angiogenesis and
tumor cell proliferation [9]. It is approved for use in unresectable gastrointestinal stromal
tumors (GIST), which have progressed on imatinib and sunitinib. It is also approved for
metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin, and
irinotecan-containing chemotherapy regimens, anti-vascular endothelial growth factor (VEGF)
therapy and if KRAS wild-type, anti-epidermal growth factor receptor (EGFR) therapy
[10]. Grothey et al. in a phase 3 trial for metastatic colorectal cancer compared regorafenib to
placebo. Side effects included elevated bilirubin, AST and ALT levels in 2% vs 1% of patients,
respectively. Severe drug-induced liver injury was seen only in the regorafenib group, and it can
be life-threatening [11]. In a phase 3 trial by Demetri et al. for advanced GIST, regorafenib was
compared to placebo. One death due to hepatic failure was described [12]. Regorafenib carries
an FDA black box warning for hepatotoxicity. It is recommended the dose be reduced from 160
mg to 120 mg for grade 3 AST/ALT elevations. Regorafenib should be discontinued if AST/ALT
are >20 times ULN, AST/ALT >3 times ULN and a bilirubin >2 times ULN, any reoccurrence of
AST/ALT >5 times ULN with a bilirubin > 2 times ULN; reoccurrence of AST/ALT >5 times ULN
on a dose of 120 mg, or a grade 4 adverse reaction [13].

Irinotecan

Irinotecan is a topoisomerase I inhibitor. It binds to the topoisomerase DNA cleavage complex

and leads to single-strand breaks of DNA, resulting in cell death. It is approved as first-line
therapy in combination with 5-fluorouracil and leucovorin in patients with metastatic
carcinoma of the colon or rectum, and for patients with metastatic colon or rectal carcinoma
that has recurred or progressed following 5-fluorouracil-based therapy [14]. The
pharmacokinetics of irinotecan in hepatic impairment were studied by Raymon et al. Patients
were divided into four groups: group 1 – bilirubin within normal range; group 2 – bilirubin 1 to
1.5 times ULN; group 3 – bilirubin 1.51 to 3 times ULN; group 4 – bilirubin >3.1 times ULN. In
groups 1 and 2 the starting dose was 350 mg/m2. In groups 3 and 4, the starting doses were 175
and 100 mg/m2 respectively. The results showed that the recommended dose in hepatic
impairment with a bilirubin level ≤ 1.5 times ULN is 350 mg/m2 and 1.51 to 3.0 times ULN is 200
mg/m2 [15]. The dosage recommendations for irinotecan are to reduce the initial dose by one
dose level, from 125 to 100 mg/m2 weekly, and from 350 to 300 mg/m 2 every three weeks when
increased bilirubin levels are present. When irinotecan is combined with 5-fluorouracil and
leucovorin with a bilirubin level <2 mg/dL, it is recommended to initiate treatment with a one
level dose reduction [16].

Everolimus

Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor [17]. It is FDA approved

2018 Khalid et al. Cureus 10(6): e2798. DOI 10.7759/cureus.2798 4 of 9

 for pancreatic neuroendocrine tumors that are unresectable, locally advanced, or metastatic
[18]. It is extensively metabolized by the cytochrome P450 system and p-glycoprotein, and liver
injury can occur due to everolimus, or its toxic intermediate [19]. In a phase 3 trial, everolimus
was compared with placebo in patients with advanced neuroendocrine pancreatic tumors. Less
than 1% of the patients had increased AST and ALT levels in the everolimus group [17].
Peveling-Oberhag et al. studied the pharmacokinetics of everolimus in patients with hepatic
impairment. They concluded that the dose of everolimus should be decreased to 7.5 mg in mild
and 5 mg in moderate hepatic impairment. For patients with severe hepatic impairment,
everolimus is not recommended, but a dose of 2.5 mg can be administered if the benefit
outweighs the risk [20].

Gemcitabine

Gemcitabine is approved as a first-line treatment for locally advanced (unresectable stage II or

stage III) or metastatic (stage IV) adenocarcinoma of the pancreas [21]. It is a pyrimidine
analogue related to cytarabine. It is metabolized to form the nucleotide gemcitabine
diphosphate (dFdCDP) and triphosphate (dFdCTP), which are then incorporated into DNA, and
block DNA synthesis resulting in cell death [22]. Venook et al. conducted a phase I
pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction. They
divided patients into three groups; group 1 – AST levels ≤2 times normal and bilirubin levels
<1.6 mg/dL; group 2 – bilirubin level of 1.6 to 7 mg/dL; and group 3 – creatinine level of 1.6 to 5
mg/dL. They assessed 40 patients for toxicity. The results showed that there was a transient
elevation of transaminases, which was not dose-limiting. However, patients with elevated
bilirubin levels had further deterioration in liver function. They recommended a dose reduction
of gemcitabine in patients with elevated bilirubin levels [23]. Likewise, a retrospective study at
the Medical University of South Carolina reviewed the charts of seven patients with elevated
bilirubin levels >4 mg/dL who were given gemcitabine at a dose of 1000 mg/m2. One patient
developed thrombocytopenia requiring that gemcitabine be discontinued. They concluded that
no dose reduction is required for patients with liver dysfunction, unless the bilirubin is elevated
[24]. Based on these trials, patients who have a total bilirubin level >1.6 mg/dL, should have
a starting dose of 800 mg/m2, and if tolerated, the dose can be escalated [22].

Paclitaxel Albumin-Stabilized Nanoparticle

Paclitaxel albumin-stabilized nanoparticle (nab-paclitaxel) is approved by the FDA for

metastatic pancreatic cancer in combination with gemcitabine. It inhibits cellular mitosis by
binding to microtubulin and disrupting the cytoskeleton of the cancer cells. Its mechanism of
hepatic injury is also probably due to its effect on the microtubule function of hepatocytes [25].
A phase 3 clinical trial in 861 patients with advanced pancreatic cancer was performed. Patients
were divided into a nab-paclitaxel and gemcitabine group (431) and a gemcitabine alone group
(430), all had adequate hepatic function, and bilirubin levels at or below ULN. Serious
hepatotoxicity was not reported [26]. Studies in patients with moderate to severe hepatic
impairment have not been conducted.

Sunitinib Malate

Sunitinib malate is FDA approved for progressive well-differentiated pancreatic neuroendocrine

tumors that are unresectable, locally advanced and metastatic [27]. It is a tyrosine kinase
inhibitor that blocks the activity of VEGFR2, PDGFR b, and c-kit, thereby preventing
angiogenesis and cellular proliferation [28]. It is metabolized by the CYP 3A4 pathway and can
cause liver injury through a toxic metabolite [29]. It carries an FDA black box warning of
hepatotoxicity. It is recommended liver function tests be drawn prior to starting treatment,
during each cycle of treatment and as clinically indicated [30]. Bello et al. conducted an open-

2018 Khalid et al. Cureus 10(6): e2798. DOI 10.7759/cureus.2798 5 of 9

 label study for patients with normal, mild or moderate hepatic impairment who were given
sunitinib 50 mg daily. They looked at the pharmacokinetics of sunitinib and its metabolite and
saw no difference in the systemic exposure between patients with normal liver function and
those with mild or moderate hepatic impairment [31].

Erlotinib

Erlotinib is an EGFR tyrosine kinase inhibitor. It is FDA approved in combination with

gemcitabine for locally advanced, unresectable, or metastatic pancreatic cancer [32]. It causes
direct liver injury as it is metabolized by the cytochrome P450 system in the liver [33]. In a
phase 3 trial, erlotinib plus gemcitabine was compared with gemcitabine alone in 569 patients
with advanced pancreatic cancer. Grade 4 hepatotoxicity including elevated bilirubin, AST, ALT
levels occurred in <1% of patients in the erlotinib and gemcitabine group [34]. It is
recommended to discontinue treatment with erlotinib in patients with a serum bilirubin >2
times ULN, and/or serum transaminases >3 times ULN; or the bilirubin level is three times ULN
or transaminases are five times ULN [35] (Table 2).

Hepatic Dosage
Medication Drug Class FDA approved indications
Impairment Adjustment

Bilirubin <2 x ULN

Reduce dose to
AST/ALT 3-5 x
75%
ULN

5- -Pyrimidine -Colorectal adenocarcinoma -Pancreatic Bilirubin 2-4 x ULN

Reduce dose to
fluorouracil analogue adenocarcinoma AST/ALT 5-10 x
50-75%
ULN

Bilirubin 3-4 x ULN

Discontinue
AST/ALT

Mild to moderate None

-Adjuvant colon cancer (Duke’s C) -First
-Prodrug of 5-
Capecitabine line treatment for metastatic colorectal
fluorouracil Discontinue until
cancer Severe
bilirubin <3 x ULN

Grade 3 AST/ALT Reduce dose to

-Multi-kinase -Unresectable GIST, which has elevation 120 mg

inhibitor - progressed on imatinib and sunitinib - -AST/ALT >20 x

inhibits VEGFR Metastatic colorectal cancer previously ULN -AST/ALT >3
Regorafenib 2 and 3, Ret, treated with fluoropyrimidine, oxaliplatin, x ULN with
Kit, PDGFR irinotecan chemotherapy, anti-VEGF
bilirubin >2 x ULN Discontinue
and Raf therapy and if KRAS wild-type, anti- -AST/ALT >5 x
kinases EGFR therapy ULN on 120 mg -
Grade 4

Not studied in
Bilirubin >2 x ULN
clinical trials
-First-line with 5-fluorouracil and
Reduce initial
leucovorin in metastatic colorectal
- dose by one dose
carcinoma -Metastatic colorectal
Irinotecan Topoisomerase level -from 125 to
carcinoma that has recurred or

2018 Khalid et al. Cureus 10(6): e2798. DOI 10.7759/cureus.2798 6 of 9

 I inhibitor progressed following 5-fluorouracil Bilirubin ≤2 x ULN 100 mg/m 2 weekly
therapy -from 350 to 300
mg/m2 every three
weeks

Mild Reduce to 7.5 mg

-Pancreatic neuroendocrine tumors
-mTOR Moderate Reduce to 5 mg
Everolimus (unresectable, locally advanced, or
inhibitor
metastatic) 2.5 mg if benefit
Severe
outweighs risk

-First line for locally advanced

-Pyrimidine (unresectable stage II or stage III) or Bilirubin >1.6 Starting dose of
Gemcitabine
analogue metastatic (stage IV) adenocarcinoma of mg/dL 800 mg/m 2
the pancreas

Administer at 125
Paclitaxel Normal to mild
albumin- -Mitotic -Metastatic pancreatic cancer in mg/m2
stabilized inhibitor combination with gemcitabine
Moderate to Not studied in
nanoparticle
severe clinical trials

-Tyrosine Mild to moderate None

-Progressive well-differentiated
kinase inhibitor
Sunitinib pancreatic neuroendocrine tumors
-inhibits Not studied in
malate (unresectable, locally advanced, Severe
VEGFR2, clinical trials
metastatic)
PDGFR b, c-kit

Bilirubin > 2 x ,
AST/ALT > 3 x in a
patient with
-Combination with gemcitabine for
baseline hepatic
Erlotinib -EGFR inhibitor locally advanced, unresectable, or Hold/discontinue
impairment Or
metastatic pancreatic cancer
Bilirubin > 3 x
ULN, AST/ALT 5 x
ULN

TABLE 2: Medications that require dose adjustments for hepatic impairment.

FDA: Food and Drug Administration; ULN: Upper limit of normal; AST: Aspartate transaminase; ALT: Alanine transaminase;
VEGFR: Vascular endothelin growth factor receptor; GIST: Gastrointestinal stromal tumor; PDGFR: Platelet-derived growth factor
receptor; EGFR: Epidermal growth factor receptor.

Conclusions
Dosage adjustment of medication is sometimes necessary in colorectal and pancreatic cancer
patients with hepatic impairment in order to prevent serious adverse events. This review article
discusses the chemotherapeutic agents and targeted therapies available for the treatment of
colorectal and pancreatic cancer patients. It highlights the classes of these agents as well as the
dosage adjustments required, when necessary, for hepatic impairment. Along with the dose
adjustment at therapy initiation, it is recommended that hepatic function tests be done with

2018 Khalid et al. Cureus 10(6): e2798. DOI 10.7759/cureus.2798 7 of 9

 each treatment cycle, and as clinically indicated. Further dose adjustments may be required in
the setting of worsening liver function. For colorectal and pancreatic cancer patients with
hepatic impairment, clinicians need to review the available therapeutic options, adjust their
doses, in order to treat these patients effectively.

Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors
declare the following: Payment/services info: All authors have declared that no financial
support was received from any organization for the submitted work. Financial relationships:
All authors have declared that they have no financial relationships at present or within the
previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or
activities that could appear to have influenced the submitted work.

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2018 Khalid et al. Cureus 10(6): e2798. DOI 10.7759/cureus.2798 9 of 9