Platinum analogue combination chemotherapy: Cisplatin and carboplatin - A phase I trial with pharmacokinetic assessment of the effect of cisplatin administration on carboplatin excretion

D. L. Trump, J. L. Grem, K. D. Tutsch, J. K.V. Willson, K. J. Simon, D. Alberti, B. Storer, D. C. Tormey

Research output: Contribution to journalArticle

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Abstract

Cisplatin (NSC 119875) and carboplatin (NSC 241240) are platinum (II) analogues with very different spectra of toxicity. Cisplatin dose is limited by nausea and vomiting, renal dysfunction, and dose-related peripheral neuropathy, whereas carboplatin is myelosuppressive. There are also clinical and laboratory data that suggest that these drugs may not be completely cross-resistant. Therefore, the following phase I trial of combination therapy with cisplatin and carboplatin was undertaken. Since carboplatin toxicity is enhanced in the presence of renal impairment, carboplatin excretion was also evaluated in selected patients at the maximum tolerated dose. Thirty-three patients received 50 mg/m2 cisplatin and doses of carboplatin between 160 mg/m2 and 400 mg/m2. Sequential 20-minute infusions of carboplatin and then cisplatin were able to be administered at the standard doses of carboplatin (320 and 400 mg/m2) with thrombocytopenia to the degree expected if carboplatin alone had been given. However, 280 mg/m2 carboplatin followed by 25 mg/m2 cisplatin/d x 3 caused unexpectedly severe thrombocytopenia in seven of eight patients (median platelet nadir 45,000/μL; range, 12 to 321,000/μL; nadir was < 90,000 in seven of eight patients). In three patients treated with 280 mg/m2 carboplatin plus 25 mg/m2/d x 3 cisplatin, pharmacokinetics of carboplatin were compared during consecutive monthly cycles without and with cisplatin. Modestly increased areas under the curve (AUC) for carboplatin (15% and 35%) with cisplatin were seen in the two patients who experienced more pronounced platelet suppression with combination therapy. No other limiting or unusual toxicity was seen with this combination. Responses, primarily in 'platinum responsive' tumors, were seen. The combination of cisplatin plus carboplatin is feasible and merits further study.

Original languageEnglish (US)
Pages (from-to)1281-1289
Number of pages9
JournalJournal of Clinical Oncology
Volume5
Issue number8
DOIs
StatePublished - Jan 1 1987
Externally publishedYes

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Carboplatin
Combination Drug Therapy
Platinum
Cisplatin
Pharmacokinetics
Thrombocytopenia
Blood Platelets
Kidney
Maximum Tolerated Dose
Peripheral Nervous System Diseases
Nausea
Area Under Curve
Vomiting

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Platinum analogue combination chemotherapy : Cisplatin and carboplatin - A phase I trial with pharmacokinetic assessment of the effect of cisplatin administration on carboplatin excretion. / Trump, D. L.; Grem, J. L.; Tutsch, K. D.; Willson, J. K.V.; Simon, K. J.; Alberti, D.; Storer, B.; Tormey, D. C.

In: Journal of Clinical Oncology, Vol. 5, No. 8, 01.01.1987, p. 1281-1289.

Research output: Contribution to journalArticle

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abstract = "Cisplatin (NSC 119875) and carboplatin (NSC 241240) are platinum (II) analogues with very different spectra of toxicity. Cisplatin dose is limited by nausea and vomiting, renal dysfunction, and dose-related peripheral neuropathy, whereas carboplatin is myelosuppressive. There are also clinical and laboratory data that suggest that these drugs may not be completely cross-resistant. Therefore, the following phase I trial of combination therapy with cisplatin and carboplatin was undertaken. Since carboplatin toxicity is enhanced in the presence of renal impairment, carboplatin excretion was also evaluated in selected patients at the maximum tolerated dose. Thirty-three patients received 50 mg/m2 cisplatin and doses of carboplatin between 160 mg/m2 and 400 mg/m2. Sequential 20-minute infusions of carboplatin and then cisplatin were able to be administered at the standard doses of carboplatin (320 and 400 mg/m2) with thrombocytopenia to the degree expected if carboplatin alone had been given. However, 280 mg/m2 carboplatin followed by 25 mg/m2 cisplatin/d x 3 caused unexpectedly severe thrombocytopenia in seven of eight patients (median platelet nadir 45,000/μL; range, 12 to 321,000/μL; nadir was < 90,000 in seven of eight patients). In three patients treated with 280 mg/m2 carboplatin plus 25 mg/m2/d x 3 cisplatin, pharmacokinetics of carboplatin were compared during consecutive monthly cycles without and with cisplatin. Modestly increased areas under the curve (AUC) for carboplatin (15{\%} and 35{\%}) with cisplatin were seen in the two patients who experienced more pronounced platelet suppression with combination therapy. No other limiting or unusual toxicity was seen with this combination. Responses, primarily in 'platinum responsive' tumors, were seen. The combination of cisplatin plus carboplatin is feasible and merits further study.",
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