Prevention: fluids, diuretics and additives
There is wide variability in the quality of the studies examining various hydration protocols prior to cisplatin administration. Most well referenced studies support the use of normal saline. The use of hypertonic saline is not recommended and the use of dextrose/saline is not consistent with the suggestion that it is important to obtain high tonicity in the renal tubule before cisplatin administration.
Volume of hydration
Patients receiving high hydration volumes, or prolonged regimes, did not have significantly less nephrotoxicity than patients receiving lower hydration volumesr and the authors suggest that the minimum required fluid volume may be somewhat less than that used routinely by many groups. (see below under Administration time)
Timing of hydration
The timing of interventions appears important with salt loading BEFORE cisplatin administration being protective but not so when applied three hours after cisplatin.
There is no conclusive evidence that the volume of urine output prior to cisplatin administration impacts on nephrotoxicity. Consensus opinion varies from there being no need to measure urine output to ensuring urine output is at least be 3-4 L/dayrr, with the urine output volume requirement most consistently reported to be >100 mL/hrr. Therefore, measurement of urine output, the volume of urine output required before cisplatin administration and monitoring of urine flow post administration should be determined by on an individual basis as per institutional policy.
Despite the fact that many centres previously used prolonged hydration regimes (as recommended in the initial prescribing information); many centres now use short hydration regimes. Short hydration is also incorporated into most of the current clinical trials.rr A study published in 1983,r examined the nephrotoxicity of various doses of cisplatin administered by 24 hour infusion. There was a correlation between measured plasma platinum and nephrotoxicity and the 24 hr infusion allowed higher doses of cisplatin to be administered however prolonged infusion did not uniformly prevent nephrotoxicity. Subsequent studies have shown that prolonged administration of cisplatin did not improve toxicity or efficacy and administration over 72 hours was found to be inactive in a group of NSCLC patients. On the basis of safety and efficacy, cisplatin in 1 litre of normal saline over 1 hour is standard of care.
Routine use of magnesium is recommended before or following cisplatin administration.
Magnesium supplementation mitigates against hypomagnesaemia and possibly provides renal protection.rr Magnesium supplementation is thought to replace losses due to cisplatin and to other physiological factors. There is no evidence against the use of routine magnesium supplementation. As one of the better studies was performed using the BEP regimen which is low dose daily treatment for five days, there does not seem to be any rationale to restrict the use of magnesium supplementation to regimes containing higher dose cisplatin.
In terms of timing of administration, studies suggest that magnesium is most effectively given before or with cisplatin rather than following cisplatin administration or after hypomagnesaemia has developed.
The recommended dose of magnesium varies considerably depending on the study and historical local treatment practices. Many years of experience at one centre using a low dose of 10 mmol (2.74 g) per dose of cisplatin has not resulted in any symptomatic hypomagnesaemia.
Mannitol use is variable across sites and the evidence for its use is inconclusive. Some studies suggest that mannitol may aggravate nephrotoxicity and therefore it should not be used. These studies however had methodological limitations making it difficult to conclude that mannitol was responsible for the nephrotoxicity.
Many sites have used mannitol routinely for many years without renal toxicity and it has been included in most trial protocols since the mid 80s.
The routine use of frusemide to increase urine flow is not recommended.
Cisplatin dose modifications
In most cancers, cisplatin is the more active platinum, but practitioners often avoid prescribing cisplatin in patients who are deemed “unfit”. The definition of “unfit” is however arbitrary. Certainly patient age should not be used as the sole determinant of suitability for cisplatin since studies have shown that older patients can be treated with cisplatin without undue toxicity. However, it should be noted that renal function (Glomerular Filtration Rate) declines by 1 mL/min/1.73 m2 per year after age 30 to 40 years.
The current gold standard for assessing renal function involves the measurement of Glomerular Filtration Rate (GFR) based on plasma clearance of inulin. However, as using this method is complex it has largely been replaced by simpler measures, using plasma clearance of radio-labelled isotopes to approximate GFR.
The Cockcroft-Gault formula is widely recommended because it was used in the pharmacokinetic studies of many drugs; however cisplatin was not one of the drugs in these studies. In the cancer population, studies showed that using the Cockcroft-Gault formula underestimated renal function and resulted in treatment exclusion or underdosing.r Other methods of estimating GFR include the 4 variable Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas which are more accurate and better validated than the Cockcroft-Gault formula and are preferred methods for assessment of GFR, but have not been validated for determining eligibility for treatment with cisplatin.r Note, however, the MDRD and CKD-EPI formulas report per 1.73 m2 (BSA), and therefore, do not account for individual body mass and the eGFR may need to be adjusted for patients who have a body surface area significantly more or less than this. In Australia, the CKD-EPI formula is being adopted in most laboratories as per recommendations by the Australasian Creatinine Consensus Working Group.
The product information indicates that cisplatin is contraindicated in patients with any degree of renal impairment. This recommendation has likely arisen from observations of severe nephrotoxicity in patients treated without the benefit of current hydration protocols and anti-emetic regimens. The data of Cho et al support the possibility that cisplatin can be used in patients with reduced renal function although safe administration was predicted on measuring creatinine clearance (24 hr urine collection) prior to each cycle.r In this study, two episodes of transient dialysis were required in patients with low renal reserve who had received multiple cycles of cisplatin. Measuring creatinine clearance before each cycle, is not recommended by the National Kidney Disease Education Program.r In addition to collection errors, diurnal variation in GFR and day to day variation in creatinine excretion, also contribute to the errors with timed urine collection.r The National Kidney Disease Education Program also caution “Neither eGFR or eCrCL will be accurate in individuals with extremes of body size or muscle mass, including the frail, elderly, critically ill, or cancer patients who are likely to require medication”. If greater accuracy is required for an individual patient, a measured GFR using radio-labelled isotopes is recommended. Correlations can then be made in relation to the measured plasma creatinine.
Based on the extremely limited available evidence, the eviQ reference committee proposes the following dose modifications for dose calculations for cisplatin containing protocols on eviQ.
|eGFR (CKI-EPI or MDRD) or eCrCL (Cockcroft Gault)(mL/min)
||Refer to discussion above regarding limitations for each method
|greater than or equal to 70
||No dose modifications necessary
|50 to less than 70
||Reduce cisplatin by 25%
|30 to less than 50
||Reduce cisplatin by 50% or consider alternative*
|less than 30
||Cease cisplatin or consider alternative*
|*refer to paragraph below on substitution with carboplatin
High peak plasma concentration of cisplatin has been shown to increase the risk of cisplatin nephrotoxicity. Case reports describe occurrences of a raised serum creatinine after standard delivery of a single dose of cisplatin. Following recovery of renal function, subsequent split doses of cisplatin were administered without any deleterious effect on measured renal function.r
Substitution with carboplatin
Carboplatin is a less nephrotoxic analogue of cisplatin and has been substituted in many chemotherapy regimens for ovarian and non-small cell lung cancer. However the relative activity of cisplatin and carboplatin in different diseases needs to be considered before using carboplatin.