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Ototoxicity of High-Dose Carboplatin

Institut Claudius-Regaud, Toulouse, France

To the Editor:

In the March 15, 2004, issue of the Journal of Clinical Oncology, Dubs et al¹ reported on neuro-otic toxicity linked to high-dose paclitaxel, ifosfamide, carboplatin (area under the curve [AUC] 24 mg/mL x minute per cycle), and etoposide (known as the TICE regimen) plus peripheral-blood stem-cell rescue. This treatment was initially proposed by Motzer et al,² who administered the treatment in a phase I/II trial in cisplatin-resistant germ cell tumors. Dubs et al confirmed Motzer et al’s favorable results in a group of nine patients (complete remission rate, 56%) but all of the patients eventually developed a clinically manifested hearing impairment. In reply, Motzer³ indicated that they had treated approximately 90 patients with the TICE regimen, and that they had observed some neuro-otic toxicity, but to a lesser degree than the number of patients reported by Dubs et al. Motzer concluded that the discrepancy might be due to the method they used for carboplatin dosing. Dubs et al did not report the method they used for estimating glomerular filtration rate (GFR) in their patients, which would impact carboplatin dose and AUC, and toxicity. Initially, Motzer et al² used the Calvert formula [dose (mg) = target AUC x (GFR + 25)], with GFR estimated by technetium-99m diethyl triamine penta-acetic acid (^99MTc-DTPA) plasma clearance. This method was associated with a poor correlation between target AUC (ie, 24 mg/mL x min) and observed AUC (range, 12 to 48 mg/mL x min). Motzer lately uses the Jellife formula to estimate GFR.⁴

From June 1997 to April 2004, we treated five poor prognosis patients in accordance with the Motzer regimen, but using daily (ie, day 1, 2, and 3) drug monitoring of carboplatin ultrafiltrable plasma concentrations and individual dosing in order to target the overall AUC. The first dose (day 1 of cycle 1) was calculated according to the Chatelut formula, and drug monitoring of carboplatin was performed using a limited sampling strategy (blood samples were taken at the end of infusion, and at 1 hour and 4 hours after the end of infusion) and a Bayesian pharmacokinetic approach based on NONMEM (NON linear Mixed Effect Model program, GloboMax, Hanover, MD) analysis⁵ in order to adjust the daily carboplatin dose in accordance with the observed carboplatin clearance (CL) of the previous day. In this way, was possible to determine the patients’ overall observed AUC and to regulate them within a narrow interval around the target value of 24 mg/mL x min (Table 1). For all patients, the daily dose had to be decreased from day 1 to day 2 of cycle 1, showing that Chatelut formula overestimated carboplatin CL for this group of patients (mean overestimation, +39%; range, +19% to +62%). The pharmacokinetic intrapatient variability was limited (mean coefficient of variation for carboplatin CL within cycle, 9%; range, 2% to 26%), indicating that drug monitoring at day 1 only would have been associated with doses similar to those actually administered based on daily monitoring. We retrospectively calculated the AUC that would have been observed in these patients by using Jelliffe formula to predict individual GFR; the rates would range from 15 to 41 mg/mL x min. Our experience confirms the favorable results in this group of patients (two of five patients are in durable complete remission; 48 and 4 months). Beside the expected hematologic toxicity, the ototoxicity was a considerable adverse effect with one grade 2 patient and three grade 3 patients among the 4 patients assessable for toxicity. None of these patients presented a clinical hearing impairment before the high-dose regimen. In conclusion, the Motzer regimen represents a valuable treatment for this subgroup of patients. However, the toxicity corresponding to an actual AUC of 24 was major. Lastly, drug monitoring performed at least on day 1 of each cycle is necessary to control individual carboplatin exposure since no method of prediction of carboplatin CL appears good enough for these patients.

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)[Free Full Text]

2. Motzer RJ, Mazumdar M, Sheifeld 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. Motzer RJ: Ototoxicity in patients with dose-intensive therapy for cisplatin-resistant germ cell tumors. J Clin Oncol 22 : 1158 -1159, 2004

4. Mazumdar M, Smith A, Tong WP, et al: Calvert's formula for dosing carboplatin: Overview and concerns of applicability in high-dose setting. J Natl Cancer Inst 92 : 1434 -1436, 2000[Free Full Text]

5. 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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• In Reply:
  Adrian Dubs and Christian Taverna
  JCO 2005 23: 3650-3651 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chevreau, C. Articles by Chatelut, E. Search for Related Content PubMed PubMed Citation Articles by Chevreau, C. Articles by Chatelut, E. Related Articles Related Reply Social Bookmarking                            What's this?