Anticancer Dose Adjustment For Patients With Renal and Hepatic Dysfunction: From Scientific Evidence To Clinical Application
Anticancer Dose Adjustment For Patients With Renal and Hepatic Dysfunction: From Scientific Evidence To Clinical Application
Pharmaceutica
Article
Anticancer Dose Adjustment for Patients with Renal
and Hepatic Dysfunction: From Scientific Evidence to
Clinical Application
Tomi Hendrayana 1,2, *, André Wilmer 1 , Verena Kurth 1 , Ingo GH Schmidt-Wolf 3 and
Ulrich Jaehde 1
1 Institute of Pharmacy, Clinical Pharmacy, University of Bonn, D-53121 Bonn, Germany;
[email protected] (A.W.); [email protected] (V.K.); [email protected] (U.J.)
2 School of Pharmacy, Institut Teknologi Bandung (ITB), Bandung 40132, Indonesia
3 Med. Klinik III und Poliklinik, Center for Integrated Oncology (CIO), University of Bonn,
D-53127 Bonn, Germany; [email protected]
* Correspondence: [email protected]
Abstract: Most anticancer agents exhibit a narrow therapeutic index, i.e., a small change in plasma
concentrations can lead to a less efficacious treatment or an unacceptable degree of toxicity. This study
aimed at providing health professionals with a feasible and time-saving tool to adapt the dose of
anticancer agents for patients with renal or hepatic dysfunction. A guideline for anticancer agents
was developed based on a literature search. An algorithm was generated to enhance the efficiency
of the dose adaptation process. Finally, the dosing guideline was converted into an easy-to-use
ExcelTM tool. The concept was applied to a total of 105 adult patients at the Centre for Integrated
Oncology, Bonn, Germany. In total, 392 recommendations for dose adaptation were made and
320 (81.6%) recommendations were responded to by the oncologists. 98.4% of the recommendations
were accepted. The algorithm simplifies the decision and screening process for high-risk patients.
Moreover, it provides the possibility to quickly decide which laboratory tests are required and
whether a dose adjustment for a particular anticancer drug is needed. The ExcelTM tool provides
a recommended individual dose for patients with renal or hepatic dysfunction. The effectiveness
of this strategy to reduce toxicity should be investigated in further studies before being adopted for
routine use.
1. Introduction
Anticancer agents are characterized by a narrow therapeutic index and large inter-individual
pharmacokinetic variability. Therefore a small change in plasma concentration due to organ function
impairment may lead to an unacceptable degree of toxicity, interfering with therapeutic outcomes and
impeding the success of an anticancer therapy [1,2]. Hence, individually adjusted dosing considering
personal conditions and the needs of the patient appears to be crucial for patient safety.
The main determining factors for plasma concentrations of drugs in general and anticancer agents
in particular are kidney and liver function, since these organs are responsible for drug metabolism and
excretion. Renal and hepatic functions decrease as people become older, leading to the fact that the number
of patients with renal or hepatic dysfunction increases with the age. Current studies show that more than
60% of all incidents of cancer and 70% of all cancer-related deaths occur in patients with more than 65 years
of age [3]. Keeping in mind that the aging of the population and the process of demographic change in
Western countries, the number of elderly cancer patients with insufficient renal or hepatic function will
increase within the next decade, bearing a high risk of overdosing and toxicity. Current studies focusing on
renal insufficiency in cancer patients show an incidence of 33% for patients with decreased renal function,
defined as a glomerular filtration rate (GFR) below 80 mL/min, regardless of age [4].
Clinical practice often copes with these challenges to a very low extent. This may be due to a lack
of information about the need for dose adjustment in hepatic or renal dysfunction for a large amount of
anticancer compounds. It may also be due to the inconsistency of the literature dealing with this issue,
since the approval and marketing of new anticancer drugs frequently proceeds with rather limited
information on pharmacokinetics alterations in renal or hepatic impairment [5]. Different sources show
high variability in dose recommendations, interfering with adequate dose adjustment [6].
Some researchers, hospitals, and institutions have created guidelines for dose adjustment in organ
dysfunction by using a literature search, such as the dosing guidelines for selected anticancer agents in
patients with renal or hepatic dysfunction by Lam et al. [7] or the recommendations for dose adjustment
for renal and hepatic impairment by the Derby-Burton Cancer Network [8]. Other possibilities
for obtaining information about dose adjustment are drug label dosing recommendations or
empiric experience.
To overcome the aforementioned problems of adequate dosing in tumor patients with organ
dysfunction, a practice-based approach is needed. It has to imply a relief of work for the physician
in charge and include evidence-based data and recommendations for specific dose adjustment.
Furthermore, the approach has to be compatible with a daily routine.
In this study, we developed a practicable framework for individual dose adjustment for cancer
patients undergoing chemotherapy and experiencing renal or hepatic dysfunction for the Centre of
Integrated Oncology (CIO) at the University of Bonn. Based on patient observation and a search of
the literature, we designed a feasible approach including an anticancer dose adjustment algorithm
and a convenient excel tool, facilitating daily work in the hospital. As distinguished from many other
studies covering either renal or hepatic dysfunction, our results include data and recommendations
for both organ impairments.
Our aim was to provide clinical oncologists and pharmacists with a feasible and timesaving
possibility to adapt the dosing of anticancer agents to the individual requirements of patients with
renal or hepatic dysfunction in order to maximize the therapeutic outcomes and minimize the toxic
effects due to overdosing.
3. Results
get close monitoring or a dose adaptation. The algorithm provides the possibility to decide quickly
which lab parameter is necessary for a decision about dose adaptation and whether or to what extent
a dose adjustment for a specific anticancer agent is necessary or not.
Table 1. Dosing guidelines of selected anticancer agents for patients with renal and/or
hepatic dysfunction.
Dose Adjustment in
No. Agent Ref.
Renal Dysfunction Hepatic Dysfunction
Moderate (transaminase 2.5–10 × ULN
1. Bendamustine • Renal impairment: CrCl < 40 mL/min, omit and T.Bil 1.5–3 × ULN) or severe [12]
(T.Bil > 3 × ULN), omit
• CrCl 45–60 mL/min, 80% of full dose Dosage adjustment maybe necessary;
5. Carmustine • CrCl 30–45 mL/min, 75% of full dose [20,21]
no specific recommendations found
• CrCl < 30 mL/min, 70% of full dose
7. Cladribine • CrCl 10–50 mL/min, 75% of full dose No specific recommendations found [8,23]
• CrCl < 10 mL/min, 50% of full dose
• CrCl 30–60 mL/min, 75% of full dose No specific recommendations found. Patient
• CrCl 10–30 mL/min, 50% of full dose with liver dysfunction receiving dacarbazine
10. Dacarbazine [7]
• CrCl < 10 mL/min, omit should be carefully monitored and adjust the
dose based on clinical judgment.
Table 1. Cont.
Dose Adjustment in
No. Agent Ref.
Renal Dysfunction Hepatic Dysfunction
18. Fludarabine • CrCl 30–70 mL/min, 50% of full dose No adjustment is required [8,30]
• CrCl < 30 mL/min, omit
19. Fluorouracil No adjustment is required • T.Bil > 5.0 mg/dL, omit [7,31]
• Initial dose:
• CrCl of 40 to 59 mL/min, doses > 600 mg are - severe hepatic impairment, initial
not recommended dose: 75% of full dose.
• CrCl 20 to 39 mL/min, 50% of full dose. • Hepatic toxicity during treatment:
24. Imatinib Dose can be increased up to max. 400 mg [34]
- transaminases > 5 × ULN or
• CrCl < 20 mL/min, use with caution T.Bil > 3 × ULN; omit.
(2 patients with severe renal impairment,
doses of 100 mg/day were tolerated) Restart at reduced doses (reduce from 400 mg
to 300 mg, from 600 mg to 400 mg, or from
800 mg to 600 mg) when transaminases
< 2.5 × ULN and T.Bil < 1.5 × ULN.
Sci. Pharm. 2017, 85, 8 6 of 16
Table 1. Cont.
Dose Adjustment in
No. Agent Ref.
Renal Dysfunction Hepatic Dysfunction
Irinotecan
• Increased AST: no need dose adjustment
(3 weekly, usual
26. No adjustment anticipated to be required • T.Bil > 1.5–3 × ULN, dose = 200 mg/m2 [27,35,36]
dose 350 mg/m2
every 3 weeks) • T.Bil > 3 × ULN, omit
• CrCl 30–60 mL/min, 75% of full dose • T.Bil 1.5–3.0 mg/dL, 50% of full dose
34. Mitomycin C • CrCl 10–30 mL/min, 50% of full dose • T.Bil > 3.0 mg/dL or transaminase [7]
• CrCl < 10 mL/min, omit > 3 × ULN, 25% of full dose
35. Mitoxantrone No adjustment is required • T.Bil 1.5-3.0 mg/dL, 50% of full dose [7,42]
• T.Bil > 3.0 mg/dL, 25% of full dose
36. Oxaliplatin CrCl < 30 mL/min, omit No adjustment is required [9,15,27,43]
Table 1. Cont.
Dose Adjustment in
No. Agent Ref.
Renal Dysfunction Hepatic Dysfunction
39. Pemetrexed • CrCl < 45 mL/min, omit No specific recommendations found [21,46]
45. Vinorelbine No adjustment is required • T.Bil 2.1–3 × ULN: 50% of dose [7,27,50,51]
• T.Bil > 3 × ULN: 25% of dose
Ref., references; CrCl, creatinine clearance; AST, aspartate aminotransferase; ALT, alanine aminotransferase;
ULN, upper limit normal; T.Bil, total bilirubin; GFR, glomerular filtration rate; AUC, area under the curve; ESRD, end
stage renal disease; ALP, alkaline phosphatase.
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Figure 2.
Figure 2. Algorithm
Algorithm of of dose
dose adjustment
adjustment of of anticancer
anticancer agents
agents for a patient
for a patient with
with hepatic
hepatic dysfunction.
dysfunction.
TDM, therapeutic drug monitoring; SCr, serum creatinine; T.Bil, total bilirubin;
TDM, therapeutic drug monitoring; SCr, serum creatinine; T.Bil, total bilirubin; AST, aspartate AST, aspartate
aminotransferase; ALT, alanine aminotransferase; ULN, upper limit normal;
aminotransferase; ALT, alanine aminotransferase; ULN, upper limit normal; * use full dose if * use full dose if not
not
contraindicated; (1) 1) contraindicated if T.Bil > 3 (2) ULN; 2) contraindicated if T.Bil
contraindicated; contraindicated if T.Bil > 3 ULN; contraindicated if T.Bil > 5 ULN; contraindicated(3) > 5 ULN; 3)
contraindicated
if T.Bil > 7 ULN; ifforT.Bil
(4) > 7 ULN;
Paclitaxel,
4) for and
24-h infusion Paclitaxel, 24-h
first course infusioncontraindicated
of therapy, and first course of> 7.5
if T.Bil therapy,
ULN;
contraindicated
(5) contraindicatedifif T.Bil
AST >>6 7.5
ULN;ULN; 5) contraindicated if AST > 6 ULN; 6) contraindicated if
(6) contraindicated if transaminase > 10 ULN.
transaminase > 10 ULN.
3.3. Excel Tool
For practical-use purposes, an easy-to-use Excel tool was developed in a final step based on the
dose adaptation guidelines, as shown in Figure 3. Depending on the queried anticancer agent, the user
is asked to insert all data crucial for a dose adjustment calculation for the particular drug. Inquired data
may be specific patient characteristics (e.g., age, weight, height and gender), laboratory data (e.g., SCr,
ALT, AST, ALP, T.Bil., GFR), and anticancer therapy information (e.g., standard daily dose, unit of
dose, target AUC (area under the curve), if hepatic toxicity occurred during treatment, if dialysis is
required). Based on the entered data, a precise individual dose recommendation is provided instantly
Sci. Pharm. 2017, 85, 8 10 of 16
in milligrams per day. Specific error messages give feedback if not all the required cells are filled in
Sci. Pharm. 2017, x, x FOR PEER REVIEW 10 of 15
correctly or some information is missing.
Figure 3. Easy-to-use
Figure 3. Easy-to-use Excel
Excel tool.
tool.
The tool was validated by three independent clinical pharmacists from the Institute of Pharmacy,
University of Bonn. A total of 46 fictitious cases were used for validation; that is at least one case
covering each anticancer agent. The validation was successful, given that the calculated results from
the Excel tool conformed to the guideline recommendations for each case. No problems emerged,
and all reviewers rated the tool as feasible and easy to use.
For each prescription, a recommendation was given based on the dose adaptation guideline,
if all necessary demographic and lab data (SCr, T.Bil., AST, body weight, and height) were available.
A total of 392 recommendations were made and 320 recommendations (81.6%) were responded to
by the physicians. Of the recommendations responded to, a proportion of 98.4% was accepted by
the physicians. Only five recommendations were rejected, and the reason for rejection was that the
CrCl had only slightly decreased below the guideline limit. In this case, the physician, based on his
experience, was of the opinion that the patient could tolerate the full dose.
4. Discussion
To our knowledge, this is the first time an algorithm that has the potential to facilitate the
dose adaptation process in clinical routine has been developed. Unlike other approaches, it covers
both renal and hepatic impairment and permits individual dose adaptation recommendations for
cancer patients with organ dysfunction in a feasible and timesaving manner. Potential toxicity due to
accumulation effects can be prevented in these patients, and, therefore, the tolerability and safety of
anticancer treatment can be improved. The development of the easy-to-use Excel tool takes account of the
advancing process of implementing electronic devices and software into daily medical care in hospitals.
Sci. Pharm. 2017, 85, 8 12 of 16
It is applicable for integration into prescription and dispensing software addressing oncologists and
clinical pharmacists. The easy-to-handle entry mask and the software-based calculation save time and
prevent entry and calculation errors potentially occurring during the demanding every day care process.
Nevertheless, like other tools, our tool has some limitations. The calculation and determination
of renal and hepatic function is based on clinical lab data. For our algorithm, we relied on the SCr
concentration for the calculation of renal function by CrCl using the equation of Cockcroft and Gault.
Like other studies, we found that relying only on SCr concentration without using prediction equations
to determine the patients with renal impairment would cause a great underestimation of the number
of affected patients [52]. Calculating CrCl with prediction equations is not at all an exact measure
of the GFR but only an estimate. SCr concentrations show a certain variability among individuals
due to a great dependency on dietary intake, total muscle mass, medication interfering with renal
creatinine handling, age, obesity, cachexia, and diseases [53,54]. Given that an exact measurement of
GFR using inulin or isotopic substances may be costly and complex and in general is not used in clinical
practice and since there are several studies that validated the prediction equations in different patient
populations, our approach to estimating CrCl via the Cockcroft-Gault equation is in accordance with
daily clinical practice [53,55,56]. Defining a CrCl of 60 mL/min as the threshold for renal dysfunction
is in accordance with the National Cancer Institute (NCI) organ dysfunction protocol templates, and
dose modification is crucial below this value for safety and efficacy reasons [57].
To determine liver function, we considered the clinical parameters total bilirubin, AST, and ALT.
Measuring these parameters is a typical way of assessing liver function in studies and clinical practice,
allowing an estimation of liver condition, integrity, and general metabolic function. Especially elevated
serum bilirubin concentrations can specifically indicate liver damage and functional loss [58]. What is
not possible by an assessment of these parameters is the prediction of the metabolising enzyme
capacity of specific drugs [54]. To overcome this problem, enzyme expression or activity tests could
be taken into consideration, which have been developed for several enzymes [59]. In addition to the
aforementioned clinical parameters, there are other criteria for the description of liver function based
on lab data and symptoms. Among these are the Child-Pugh score and the National Cancer Institute
Organ Dysfunction Working Group (NCI-ODWG) criteria. To assure consistent dose adaptation
recommendations in hepatic impairment, standard criteria for liver function measurement should be
defined [60,61].
The recommendations for dose adaptation emerging from our algorithm are based solely
on the aforementioned clinical parameters. They are appropriate only to determinate renal and
hepatic function. Every other condition and circumstance justifying dose adaptation, except for
organ dysfunction, is not covered by this algorithm. This applies particularly to the occurrence of
toxicity during chemotherapy. In this case, the dose has to be reduced with respect to patient safety,
regardless of the recommendations given by the dose adaptation guideline. Being aware of this issue,
we considered it in the first decision point of the algorithm, which asks for the occurrence of toxicity.
To avoid toxicity and assure the therapeutic effect of anticancer agents, therapeutic drug
monitoring (TDM) is probably the best alternative [54,62]. This could also be combined with
pharmacokinetic-pharmacodynamic (PK/PD) modelling for a dosing guideline based on toxicity
predictions [59]. However, due to the complexity of TDM and PK/PD models, in case of
toxicity, the dose typically is decreased according to the physician’s discretion in clinical practice.
Further research projects should focus on dose adaptation in cancer patients in the case of occurrence
of toxicity.
The risk of under-dosing due to toxicity-associated dose reduction cannot be prevented by
our guideline entirely, but, by preventing overdosing due to organ impairment at the beginning of
chemotherapy, the risk of toxicity will be decreased. Hence, decreasing the risk of toxicity will also
decrease the risk of under-dosing due to toxicity-associated dose reduction. Therefore, under-dosing
could be prevented by adapting the dose to the organ function at the beginning of chemotherapy.
Sci. Pharm. 2017, 85, 8 13 of 16
In case of a toxicity occurrence during therapy, the physician has to consider a dose reduction,
regardless of the algorithm.
Our research pointed out an approach to transfer scientific evidence to clinical routine and enhance
safety in anticancer drug therapy. The question of whether toxicity can be prevented, or at least reduced,
by adopting the tool in clinical practice can only be answered in a randomized controlled trial (RCT)
including an adequate number of cancer patients with organ dysfunction. The guideline was pretested
and applied in a sample of 105 patients in one hospital, but the sample size was too small to generate
significant results of efficacy. The developed algorithm and the Excel tool have not been yet assessed
in practice. Their feasibility and usability have to be demonstrated by routinely implementing them in
a clinical practice setting on oncologic wards by physicians and clinical pharmacists.
5. Conclusions
A dose adaptation guideline for anticancer agents in patients with organ dysfunction was
developed, followed by a dosing algorithm and an easy-to-use Excel tool. The algorithm simplifies the
decision and screening process for high-risk patients. Moreover, it provides the possibility of quickly
deciding which lab parameters are required and whether a dose adjustment for a particular anticancer
agent is needed. The Excel tool provides a recommended individual dose. The effectiveness of our
method to reduce toxicity should be assessed in a randomized controlled trial.
Acknowledgments: T.H. acknowledges The Directorate General of Higher Education, Department of National
Education of The Republic of Indonesia for financial support. Furthermore, we want to thank the physicians and
nurses at the CIO of University of Bonn.
Author Contributions: T.H. designed the study, developed the methodology, collected the data, performed
the analysis, and wrote the manuscript. A.W. wrote the manuscript. V.K. designed the easy-to-use Excel tool.
I.S.-W. designed the study and developed the methodology. U.J. designed the study, developed the methodology,
and wrote the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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