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Classification of hepatic dysfunction for chemotherapy dose modifications

The lack of standardised parameters to define the severity of organ impairment is a major problem, and thus, why there is no consensus on the definition of the severity of liver dysfunction.

Functional parameters such as the serum bilirubin level, serum albumin level and prothrombin time are the key “LFT” parameters to be considered when considering dosing of chemotherapeutic drugs that are cleared by the liver. However, results must be interpreted in light of the overall clinical context rather than in isolation. The medical history, clinical examination and, when there exists any clinical suspicion of intrinsic liver disease, liver imaging are important. Dose reduction would seem reasonable in patients with impaired hepatic function, as reflected by Child-Pugh class B or C or a correspondingly elevated MELD score. Importantly, drug metabolism may be impaired in patients with liver disease even when these functional parameters are normal, especially when clearance is dependent on the cytochrome P450 rather than glucuronidation route and, for those drugs whose clearance is limited by hepatic blood flow, when the latter is compromised.

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Different parameters are currently utilised to describe the severity of hepatic dysfunction, and are included below:

A. Model for end-stage liver disease (MELD) score (not appropriate for patients under the age of 12)rr

This may be a more accurate method but is less accessible to most clinicians because it involves calculating the score. The MELD score uses serum creatinine, serum bilirubin and INR (international normalized ratio), but the actual calculation is complex and requires log scale. For ease of use, several online calculators are readily available for calculating the MELD score, such as the Lille Model. However, it is worth noting that this model was developed for predicting survival in patients with cirrhosis and not for dosing.

B. Child-Pugh scorerrr

Child-Pugh score (for adults)
Para​meter Score
1 point 2 points 3 points
Ascites none mild (medically controlled moderate or severe (poorly controlled)
Bilirubin less than 35 micromol/L
(less than 2 mg/dL)		 35 to 50 micromol/L
(2 to 3 mg/dL)		 greater than 50 micromol/L
(greater than 3 mg/dL)
Albumin greater than 35 g/L 28 to 35 g/L less than 28 g/L
INR less than 1.7 1.7 to 2.3  greater than 2.3
Encephalopathy none Grade 1 to 2 (medically controlled) Grade 3 to 4 (poorly controlled)

Interpretation of Child-Pugh score

The sum of the five scores from the above table is used to assign a Child-Pugh grade of A, B or C. This grade is used to gauge mortality using the following table:

Grade Score Description 1 year survival 2 year survival
A 5 to 6 Indicates a well functioning liver 100 % 85 %
B 7 to 9 Indicates significant functional compromise 80 % 60 %
C 10 to 15 Indicates a decompensation of the liver 45 % 35 %

Depending on hepatic clearance and the therapeutic index of the drug, dose adjustments or drug avoidance may be required in grades B or C chronic liver disease. The Child-Pugh score should be reassessed when clinically indicated, as the patient's clinical condition may improve or deteriorate.

C. NCI-organ dysfunction working group (ODWG)

The National Cancer Institute-sponsored Organ Dysfunction Working Group is leading an effort to formally assess promising or recently approved agents in patients with organ dysfunction and to develop dosing guidelines for these agents.r They have used different criteria which utilise two objective and readily measurable laboratory parameters, specifically: total serum bilirubin and aspartate aminotransferase (AST).

A small study has shown that there is some correlation between the Child-Pugh and NCI-ODWG criteria.r

Group A B C D E
Liver function Normal Mild Moderate Severe Liver transplant
Total bilirubin < ULN B1: < ULN
B2: > 1 to 1.5 x ULN		 > 1.5 to 3 x ULN > 3 x ULN Any
SGOT/AST < ULN B1: > ULN
B2: Any		 Any Any Any
Note:
  • Patients with Gilbert's syndrome often have elevated total and unconjugated serum bilirubin which is usually less than 50 micromol/L. Chemotherapy dose does not need to be modified except for irinotecan (dose reduction).
  • INR may be prolonged in patients without liver disease due to administration of coumarin anticoagulants (warfarin) or occasionally due to administration of antibiotics.

The recommendations made in eviQ regarding dose modification are intended as a guide and are generally conservative, placing a greater weight on safety compared to efficacy. It should be noted however, that dose modifications which are intended to improve the safety profile of a drug may compromise the efficacy of the regimen. Dose escalations may be considered if no side effects are experienced following the administration of a dose reduced regimen. The exception to this rule applies if a dose reduction was made because of haematological toxicity or dose limiting cumulative toxicity.

eviQ dose modification guidelines

The following guidelines for dose modifications have been developed by classifying drugs according to their hepatic clearance with recommendations from individual product information, micromedex and references listed below.r

Group 1: Drugs with high hepatic clearance and narrow therapeutic ratio

Hepatic dysfunction  
Minimal Reduce [drug] by 25 %
Mild Reduce [drug] by 50 %
Moderate/severe Omit [drug]

Group 2: Drugs with high hepatic clearance

Hepatic dysfunction  
Mild Reduce [drug] by 25 %
Moderate Reduce [drug] by 50 %
Severe Omit [drug]

Group 3: Drugs with moderate hepatic clearance

Hepatic dysfunction  
Mild No dose modifications necessary
Moderate Reduce [drug] by 25 %
Severe Reduce [drug] by 50 %

Group 4: Drugs with minimal hepatic clearance

Hepatic dysfunction  
Mild No dose modifications necessary
Moderate No dose modifications necessary
Severe Reduce [drug] by 25 %

eviQ classification of drugs according to hepatic clearance and therapeutic index

Note: This is not a complete list of drugs used in cancer treatments and we are working on the remaining ones. These guidelines have been developed for use with medical oncology protocols. Dose modification guidelines for haematology protocols may differ. Please refer to individual haematology protocols for more information.

Group 1 Group 2 Group 3 Group 4
  • Docetaxel
  • Irinotecan
  • Dacarbazine
  • Doxorubicin
  • Epirubicin
  • Etoposide
  • Paclitaxel
  • Vincristine
  • Vinorelbine
  • Vinblastine
  • Capecitabine
  • Gemcitabine*
  • Fluorouracil
  • Mitozantrone
  • Methotrexate
*No data available for recommendations in severe hepatic impairment r
Drugs which do not require dose modifications for hepatic impairment
Bleomycin Mitomycin
Carboplatin Oxaliplatin
Cisplatin Pemetrexed
Cyclophosphamide Raltitrexed
Ifosfamide Temozolomide
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Version 2

Date Summary of changes

31/05/2017

Transferred to new eviQ website.
Previous website ID: 58

While every effort has been made to ensure the accuracy of the content at the time of publication, the Cancer Institute NSW does not accept any liability, with respect to loss, damage, injury or expense arising from any such errors or omission in the contents of this work. Any reference to specific pharmaceuticals and/or medical products as examples does not imply endorsement of any of these products. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/3248

27 Feb 2021