Updated Recommendations for the Dosing of Anticancer Drugs in Kidney Dysfunction

The eviQ resource, established by the Cancer Institute NSW, has developed an International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD). This guideline, created in collaboration with an international, multidisciplinary working party, aims to be a decision-support tool for cancer clinicians treating patients with chronic kidney disease (CKD).

It is estimated that 15-20% of cancer patients have an eGFR of 30-59mL/min/1.73m². Accurate assessment of renal function is particularly important for these patients as minor differences in estimated renal function may significantly impact prescribed therapy. This could be in the form of dose adjustments or avoidance of first-line therapies.

Recommendations from the ADDIKD guideline include significant changes to clinical practice regarding the assessment of renal function and dosing recommendations for 59 anticancer drugs in kidney dysfunction.

Key changes:

Standardised categories for kidney dysfunction

The Kidney Disease Improving Global Outcomes (KDIGO) CKD categories are recommended to guide dose adjustments and monitor drug-related adverse events for anticancer drugs. These categories are shown in Table 1.

Table 1. KDIGO kidney function categories based on measured/estimated GFR

*KRT = kidney replacement therapy

While there are limited studies investigating the use of KDIGO CKD categories in the oncology setting, standardisation of kidney dysfunction classification is expected to reduce complexity and promote uniformity.

Method of assessing kidney function

The preferred method of estimating kidney function in cancer patients is the estimated glomerular filtration rate via the Chronic Kidney Dysfunction-Epidemiology Collaboration 2009 equation (eGFR_CKD-EPI). This equation provides a more accurate and precise estimate of the directly measured glomerular filtration rate (mGFR) compared to other estimation methods, such as the Cockcroft-Gault equation. However, directly mGFR may be required in some clinical situations.

Directly mGFR remains the most accurate method to evaluate renal function in cancer patients. Direct methods measure the clearance of exogenous filtration markers such as inulin or iohexol. These agents are freely filtered by the glomerulus but not reabsorbed or secreted by the tubules. While direct mGFR is more precise, its use is limited by cost, time, and access issues.

Dosing modifications

The eGFR_CKD-EPI is recommended to guide the dosing of anticancer drugs that are dosed according to renal function. Exceptions have been made for specific clinical situations and specific anticancer drugs where this method may be unreliable.

The eGFR_CKD-EPI equation is not suitable for use in pregnant women, patients younger than 18 years, and kidney replacement therapy. Alternative methods of assessing renal function should be used in these patients.

In addition, there are many clinical scenarios where eGFR_CKD-EPI may be considered unreliable, including:

• Extremes of body size or muscle mass;
• Amputees;
• Persons with paraplegia;
• Skeletal muscle conditions;
• Advanced liver disease;
• Untreated hypothyroidism;
• Ureteric obstruction;
• People taking creatine supplements or drugs that interfere with creatinine secretion or creatinine assay; and
• Dosing of certain anticancer drugs, including carboplatin, methotrexate (doses ≥ 500 mg/m²), and cisplatin.

Directly mGFR is preferred for initial dosing in the above scenarios.

Calculating carboplatin doses

Carboplatin is predominantly excreted via glomerular filtration. Most of the dose is excreted within the first six hours, with 65% eliminated in the urine within 24 hours of administration. As renal function declines, urinary elimination decreases, and the area under the curve (AUC) increases. There is a strong correlation between carboplatin AUC, kidney function, and the severity of thrombocytopenia and, to a lesser degree, leucopenia.

In the case of carboplatin, directly mGFR is the preferred option in most cases. Body surface area-adjusted eGFR_CKD-EPI is a suitable alternative to use in the Calvert formula, especially where the eGFR falls between 45 and 125 mL/min/1.73 m², treatment intent is non-curative, and the patient is neither an amputee, paraplegic nor has conditions of skeletal muscle or an extreme of body size or muscle mass.

A new carboplatin dose calculator is available on the eviQ website. This calculator employs the Calvert formula with a target AUC. There are currently three options for the input of kidney function: directly mGFR, BSA-adjusted eGFR_CKD-EPI, and creatinine clearance calculated via the Cockcroft-Gault equation. The option of using creatinine clearance is included to support practice during the transition but will be phased out in the future.

Implications

The ADDIKD guideline is intended to guide clinical decision-making for the use of anticancer drugs in CKD; it is not meant to be prescriptive.

It should also be stressed that the new guideline does not apply to:

• Dose adjustment in kidney dysfunction beyond the first cycle of treatment (dosing for subsequent cycles requires an assessment of the patient’s tolerance to the initial dosing regimen);
• Dosing in acute kidney injury or unstable kidney function;
• Dose adjustment for kidney dysfunction in stem cell mobilisation, bone marrow transplantation and cellular therapies;
• Specific dosing instructions in kidney failure (eGFR < 15 mL/min/1.73 m² with or without KRT);
• Dosing in patients < 18 years of age with kidney dysfunction; and
• Dosing in pregnant women with kidney dysfunction

Current status

The ADDIKD guideline is published and available on the eviQ website. However, eviQ protocols have not yet been updated to align with the recommendations of the ADDIKD. In 2023, eviQ will begin progressively updating protocols by cancer type. This process is expected to take between 12 and 18 months. A link to the full guideline has been added to each eviQ protocol to avoid confusion during this interim phase.

eviQ has added two new calculators to its website to support the adoption of the ADDIKD guideline recommendations. The first is the eGFR calculator with the option to adjust for BSA. The second is the carboplatin dose calculator.

More detailed information, along with online learning modules, are also available at eviQ.