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Cisplatin preceded by concurrent cytarabine and hydroxyurea: a pilot study based on an in vitro model
K S Albain1, L J Swinnen, L C Erickson
1Section of Hematology and Oncology, Loyola University Stritch School of Medicine, Maywood, IL 60153.
Cancer Chemotherapy and Pharmacology
|January 1, 1990
Summary
This study investigated a combination of hydroxyurea (HU), cytarabine (Ara-C), and cisplatin (cis-Pt) for refractory solid tumors. The regimen showed promising response rates and modulated cisplatin resistance, despite manageable toxicities like thrombocytopenia and azotemia.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Cytotoxic synergy between cytarabine (Ara-C) and hydroxyurea (HU) was previously observed in vitro for DNA repair inhibition in cisplatin (cis-Pt)-treated colon cancer cells.
- This study aimed to translate these in vitro findings into a clinical setting for patients with refractory solid tumors.
Purpose of the Study:
- To determine the toxicity profile of a novel three-drug combination regimen (HU, Ara-C, cis-Pt) in patients with refractory solid tumors.
- To evaluate the efficacy and response rates of this combination therapy.
- To explore the potential of the HU/Ara-C combination in overcoming cisplatin resistance.
Main Methods:
- A pilot study involving two patient cohorts (previously treated and treatment-naïve) with refractory solid tumors.
- Monthly cycles of oral hydroxyurea (HU), followed by oral cytarabine (Ara-C) and intravenous cisplatin (cis-Pt).
- Dose escalation and toxicity assessment, including monitoring for thrombocytopenia, azotemia, uric acid, and lactate dehydrogenase (LDH).
Main Results:
- The combination regimen was associated with expected toxicities such as nausea, vomiting, and fatigue, with significant but transient thrombocytopenia and dose-limiting azotemia observed.
- Partial responses were observed in 9 of 32 patients with measurable disease, and improvement was noted in 5 of 8 patients with evaluable disease.
- Responses occurred across various tumor types, including non-small-cell lung cancer, breast carcinoma, glioblastoma, ovarian carcinoma, small-cell lung cancer, and mesothelioma, with notable activity in patients pre-treated with cisplatin.
Conclusions:
- The combination of hydroxyurea, cytarabine, and cisplatin demonstrates encouraging anti-tumor activity in patients with refractory solid tumors.
- The regimen appears to modulate cisplatin resistance, suggesting a potential role in overcoming treatment failure.
- Further investigation with modified dosing to manage toxicities is warranted and has been initiated in a subsequent study.