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Dosing carboplatin in patients assigned to hemodialysis
Carboplatin is a platinum-analog alkylating agent that plays a role in treating several types of malignancies, often being preferred to its relative cisplatin due to its favorable toxicity profile and ease of delivery. The major dose-limiting toxicity of carboplatin is myelosuppression, especially thrombocytopenia. The major route of elimination of carboplatin is through the kidneys, and subsequently it requires a downward dose adjustment for patients with impaired renal function to prevent severe hematologic toxicity.
Renal function is inherently adjusted for in the Calvert equation, in which the suggested carboplatin dose in milligrams is dependent on the desired area under the concentration time curve and glomerular filtration rate: dose (mg) = (GFR + 25) × AUC.
Carboplatin is usually administered to previously treated patients at AUC of four minutes mg/mL to six minutes mg/mL and chemotherapy-naive patients at AUC of six minutes mg/mL to eight minutes mg/mL. The goal of using AUC dosing is to increase efficacy and minimize toxicity.
A question still often raised is: How does one appropriately dose carboplatin in patients with end-stage renal disease who are administered hemodialysis? Although more information on the pharmacokinetics of carboplatin in hemodialysis has become available in the past 10 years, there is still a lack of consensus on a recommended dose of carboplatin in these patients.
Insight into carboplatin pharmacokinetics
Exogenously administered platinum exists in both protein-bound and nonprotein-bound forms in the body, and it is the nonprotein-bound form that is active and able to be excreted by the kidneys. Unlike cisplatin, which is highly protein-bound, the majority of the carboplatin dose remains in the unbound form in the plasma, facilitating its removal by hemodialysis. However, it is not clear how much carboplatin is removed by each hemodialysis session. One source stated only 15% to 20% of carboplatin is removed by hemodialysis. Suzuki et al reported that the concentration of carboplatin in the venous line was decreased to approximately 10% of that in the arterial line during hemodialysis. Another report by Chatelut et al reported a 20% decrease in the AUC with hemodialysis performed 24 hours after the dose.
In patients with normal renal function, the greatest excretion of carboplatin occurs within the first eight hours after administration, with 60% to 90% of the dose excreted unchanged in the urine within 24 hours. Consequently, the timing of hemodialysis after carboplatin administration becomes an important consideration in reaching the desired AUC for adequate treatment and limiting systemic exposure to prevent severe adverse effects.
Carboplatin dose, timing of hemodialysis
To determine the dose of carboplatin for patients undergoing hemodialysis, many clinicians have continued to use the Calvert equation with the assumption that the GFR is equal to zero or some small rate between 10 mL/hour to 20 mL/hour. Watanabe et al evaluated the pharmacokinetics and pharmacodynamics of carboplatin in a patient assigned to hemodialysis being treated for stage III ovarian cancer with carboplatin/paclitaxel. The GFR was assumed to be zero, and 125 mg of carboplatin was administered to produce a target AUC of five minutes mg/mL. Hemodialysis was started 1.5 hours after the end of carboplatin administration in the first cycle and continued for four hours. The measured AUC of free platinum was 2.21 minutes mg/mL, which was much lower than expected.
For the second cycle, the same dose of carboplatin was administered on a nondialysis day, and hemodialysis was started 16 hours after completion of carboplatin. The AUC of free platinum was increased to 4.43 minutes mg/mL. The remaining cycles were completed the same way and treatment was well tolerated. In addition, tumors showed complete response by CT scan and the patient remained disease-free at eight months.
Chao et al also reported of a woman with stage IV ovarian cancer and chronic renal failure assigned to hemodialysis who was treated with carboplatin/paclitaxel combination chemotherapy. In this case, the GFR was also assumed to be zero with a target AUC of five minutes mg/mL, and thus the carboplatin dose was 125 mg. However, unlike the previous case report, the patient experienced severe pancytopenia with the first cycle, requiring transfusion and a rest from treatment. Her subsequent carboplatin doses were reduced to 80 mg, which were tolerated without recurrence of severe bone marrow suppression. The timing of hemodialysis with respect to the dose was not mentioned in this study. These two case reports demonstrated two very different responses to the same dose of carboplatin, arrived at using the Calvert equation and assuming a GFR of zero. This demonstrates that toxicity can still occur despite low carboplatin doses.
Successful use of higher doses of carboplatin (200 mg/m2 to 300 mg/m2) with hemodialysis initiated within one hour has been reported without occurrence of life-threatening adverse effects. These larger carboplatin doses that are based on body surface area are seen in regimens for treatment of certain types of cancer, such as small cell lung cancer. However, there have also been reports of severe myelosuppression with these higher doses in patients administered hemodialysis.
Inuoe et al reported grade-3/4 hematologic toxicity in two patients being treated with carboplatin 300 mg/m2 (with etoposide) for advanced SCLC. Hemodialysis was initiated one hour after the dose in both patients. Subsequent doses of carboplatin were reduced to 240 mg/m2. In another case report by Niikura et al, severe or prolonged thrombocytopenia occurred in two patients who were assigned 200 mg/m2 of carboplatin for gynecological malignancies. Hemodialysis was started two hours after the dose in both patients. Subsequent doses were reduced to 100 mg/m2. For patients administered hemodialysis who are assigned to carboplatin, Bristol-Myers Squibb recommends initial doses of carboplatin, not to exceed 150 mg/m2, with hemodialysis to begin within 24 hours to 48 hours of treatment.
Not only is the evidence conflicting for the appropriate dose of carboplatin in hemodialysis, but there are also conflicting reports on the timing of hemodialysis with respect to carboplatin administration. Results of studies have demonstrated that the AUC can be increased by increasing the time between carboplatin administration and the start of hemodialysis.
Several recent case reports have evaluated the pharmacokinetics of carboplatin in patients assigned to hemodialysis with their respective doses, time to onset of hemodialysis and measured AUC. It is difficult to compare and contrast these reports due to differences in dosing methods. Interestingly, these case reports have only indicated starting hemodialysis one hour to two hours after the dose and 16 hours to 24 hours after the dose but at no other time point in between. From these case reports and their respective pharmacokinetic studies, there is a trend of higher doses requiring shorter time to onset of hemodialysis and lower doses requiring a delay in hemodialysis to reach the desired AUC. The kinetics of carboplatin in the blood of a hemodialysis patient also depend on individual differences such as age and general condition, which contribute to the difficulty of determining the optimal time to start hemodialysis for all patients.
Upon review of the literature, it is difficult to recommend a single dose adjustment for carboplatin to apply to all patients assigned to hemodialysis. In general, patients administered hemodialysis who are assigned to higher doses of carboplatin (200 mg/m2 to 300 mg/m2) should receive hemodialysis within one hour to two hours of the dose to prevent hematologic toxicity. For patients administered carboplatin doses estimated using the Calvert equation, assuming a GFR of zero, consider timing the dose approximately 16 hours before the next hemodialysis session to ensure the desired AUC is attained. It is important to monitor patients for hematologic toxicity and keep in mind that the AUC can be increased or decreased by adjusting the time between carboplatin administration and the start of hemodialysis.
Jocelyn Mohs, PharmD, is a PGY-2 Oncology Pharmacy Resident, University of Minnesota Medical Center, Fairview, Minneapolis.
For more information:
- Chao TJ. Taiwan J Obstet Gynecol. 2007;46:460-462.
- Chatelut E. Nephron. 1994;66:157-161.
- Inoue A. Ann Oncol. 2004;15:51-54.
- Niikura H. Anticancer Drugs. 2003;14:735-738.
- Suzuki S. Nephrol Dial Transplant. 1997;12:137-140.
- Watanabe M. Gynecol Oncol. 2002;84:335-338.
