When should I discontinue Cisplatin (Cis-diamminedichloroplatinum) due to impaired renal function, as indicated by decreased creatinine clearance?

From the Guidelines

Cisplatin should be discontinued or dose-adjusted when your creatinine clearance falls below 60 mL/min, with a dose reduction of 25-50% recommended for creatinine clearance between 30-60 mL/min, and avoided entirely when creatinine clearance drops below 30 mL/min. According to the study by 1, cautionary notes for prescribing cisplatin in people with chronic kidney disease (CKD) include reducing the dose when GFR < 60 ml/min/1.73 m2 and avoiding it when GFR < 30 ml/min/1.73 m2.

Key Considerations

• Regular monitoring of kidney function before each treatment cycle is essential, as cisplatin is highly nephrotoxic 1.
• The drug causes direct tubular damage and can lead to permanent kidney injury with cumulative doses.
• To minimize kidney damage while on cisplatin, ensure adequate hydration with IV fluids before and after treatment, maintain good urine output, and avoid other nephrotoxic medications when possible.
• Alternative platinum agents like carboplatin (which is less nephrotoxic) may be considered if kidney function deteriorates but platinum-based therapy remains necessary for the condition.

Recent Guidelines and Studies

• A recent study published in 2023 1 discusses the management of cisplatin-ineligible patients with resected, high-risk, locally advanced squamous cell carcinoma of the head and neck, highlighting the importance of considering renal function, hearing loss, and age when determining cisplatin eligibility.
• The study also notes that cisplatin-related toxicity is dose-dependent, and retrospective analyses suggest that up to half of patients who start cisplatin do not complete the full planned dose.
• However, the most recent and highest-quality study 1 provides clear guidance on dose reduction and avoidance of cisplatin based on creatinine clearance, which should be prioritized in clinical decision-making.

From the FDA Drug Label

Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m 2. It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of cisplatin can be given.

Discontinuation of cisplatin due to creatinine clearance should be considered when renal function does not return to normal before another dose of cisplatin can be given.

• Key points to consider:
  • Renal toxicity is a major dose-limiting toxicity of cisplatin
  • Renal function must return to normal before another dose of cisplatin can be given
  • Elderly patients may be more susceptible to nephrotoxicity 2

From the Research

Discontinuation of Cisplatin based on Creatinine Clearance

• Cisplatin is contraindicated in patients with a creatinine clearance < 60 mL/min, according to two German summary of product characteristics (SmPC) 3.
• A study found that 37 cisplatin prescriptions were made for patients with a creatinine clearance < 60 mL/min, which is 2.0% of all cisplatin prescriptions 3.
• Another study found that cisplatin discontinuation rate was 27.7%, of which 8.1% was due to renal toxicity 4.
• The decision to discontinue cisplatin based on creatinine clearance should be made on a case-by-case basis, taking into account the patient's overall health and the potential benefits and risks of continuing treatment.

Factors Influencing Nephrotoxicity

• Factors that may increase the risk of nephrotoxicity in patients receiving cisplatin include cirrhosis, hypertension, alcohol intake, and a total number of cycles < 4 4.
• Concomitant administration of NSAIDs may also increase the risk of permanent renal toxicity 4.
• Patients with these risk factors may require more frequent post-cycle check-up visits and hydration treatment should be guaranteed as soon as a reduction of creatinine clearance is detected 4.

Hydration and Diuresis

• Hydration in conjunction with appropriate diuresis can decrease the incidence of nephrotoxicity in patients receiving cisplatin 5.
• The administration of magnesium and mannitol may assist in maintaining renal function and reducing nephrotoxicity in adults receiving cisplatin 5.
• High-volume hydration (> 3 L intravenous isotonic saline) and forced diuresis (mannitol and/or furosemide) have been generally used to lower the risk of cisplatin-induced nephrotoxicity 6.