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In Reply:

University Hospital Zürich, Division of Oncology, Zürich, Switzerland

Chevreau et al confirm our findings of severe ototoxicity using a high-dose carboplatin–containing regimen (mean target, carboplatin area under the curve [AUC] of 24 [mg/mL] x minute per cycle).^1,2 They perform a daily drug monitoring of carboplatin ultrafiltrable plasma concentrations and adjust the daily carboplatin dose according to the observed carboplatin clearance of the previous day in order to obtain minimal deviations from the target AUC.³ Chevreau et al recommend drug monitoring carboplatin on day 1 of each cycle, but even with their more intensive daily drug monitoring and consecutive dose adjustments, they still observe major ototoxicity in all of their assessable patients. The optimal method for dosing of carboplatin in the high-dose setting is still not defined. Different methods of estimating the glomerular filtration rate (GFR) have been compared and remarkably different results have been obtained. In his reply, Motzer^1,2 reported that he currently uses the Jelliffe formula to estimate GFR in patients treated with the high-dose paclitaxel, ifosfamide, carboplatin, and etoposide (TICE) regimen. We used the Cockcroft-Gault formula to estimate the GFR in our previously reported nine patients with carboplatin-induced ototoxicity.¹ This formula is widely used in Europe to estimate GFR. The main difference between the Cockcroft-Gault and the Jelliffe formula is that the Cockcroft-Gault formula is based on the patient’s body weight, whereas the Jelliffe formula is based on the patient’s body-surface area. This can lead to significantly different carboplatin doses as can be seen in Figure 1.

View larger version (24K): [in this window] [in a new window]   Fig 1. Upward shift of the creatinine clearance (CrCl) with increasing body-weight when using the Cockroft-Gault formula (blue curves) compared with the Jelliffe formula (red curves) to estimate the creatinine clearance. The curves are superimposable at a body weight of 60 kg (solid lines), start to shift at 70 kg and 80 kg (dotted lines), and differ notably at 90 kg (solid lines). Example above was calculated for a 40-year-old man, height: 180 cm. BSA, body-surface area.

In patients with prior therapy of 6 cycles of cisplatin-containing combination therapy, Motzer et al escalated the carboplatin dose to AUC of 32 (mg/mL) x minute. They reported that most of the time the measured AUC did not reach the target AUC with the greatest discrepancy for the high target levels. Our nine patients all received 4 prior cycles of cisplatin-containing chemotherapy, and in all of them the target AUC was 24 (mg/mL) x minute per cycle. AUC of carboplatin was not measured. We were not able to correlate measured AUC to the incidence of severe ototoxicty.

The optimal dose of carboplatin in this setting, as well as the critical dose level resulting in ototoxicity, are unknown. The clinical value of monitoring carboplatin plasma concentrations should be further investigated to minimize ototoxicity.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Dubs A, Jacky E, Stahel R, et al: Ototoxicity in patients with dose-intensive therapy for cisplatin-resistant germ cell tumors. J Clin Oncol 22 : 1158 , 2004 (letter; reply: J Clin Oncol 22:1158-1159, 2004)[Free Full Text]

2. Motzer RJ, Mazumdar M, Sheinfeld J, et al: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18 : 1173 -1180, 2000[Abstract/Free Full Text]

3. Chatelut E, Pivot X, Otto J, et al: A limited sampling strategy for determining carboplatin AUC and monitoring drug dosage. Eur J Cancer 36 : 264 -269, 2000

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Related Correspondence

• Ototoxicity of High-Dose Carboplatin
  Christine Chevreau, Fabienne Thomas, Corinne Couteau, Florence Dalenc, Loic Mourey, and Etienne Chatelut
  JCO 2005 23: 3649-3650 [Full Text]

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