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Abstract
Introduction. The combination of EDP (etoposide, doxorubicin, cisplatin) chemotherapy with mitotane represents the standard first-line therapy for adrenocortical carcinoma (ACC). Achieving therapeutic serum concentrations of mitotane has been associated with improved progression-free survival (PFS) and overall survival (OS) in several studies. However, mitotane dosing in most prior research has followed institution-specific protocols, underscoring the need for a validated and standardized dosing regimen.
Materials and Methods. A single-center, prospective, phase II study was conducted using a Simon's two-stage design. Eligible patients had locally advanced or metastatic ACC, ECOG performance status 0-1, and were naïve to mitotane. The primary endpoint was the rate of achieving therapeutic mitotane concentrations (14–20 μg/mL). The study aimed to increase this rate from a historical 50 to 70 % (β = 0.2; α = 0.05). Secondary endpoints included objective response rate (ORR), disease control (DC) ≥ 6 months, PFS, OS, and safety. Mitotane was initiated at 2 g/day, with dose escalation by 0.5 g every 3-5 days to a maximum of 4 g/day, followed by titration based on serum drug levels. All patients concurrently received standard platinum-based chemotherapy (EDP or EP/EC).
Results. Forty-seven patients were enrolled (27 male, 57.4 %). All received platinum-based chemotherapy, 45 (95.8 %) with EDP, 2 with EP/EC. After a median follow-up of 12.4 months, therapeutic mitotane concentration was achieved in 72.3 % of patients (n = 34), with a median time to achievement of 4.3 months (95 % CI 3.3–5.3). The ORR was 29.7 %, and DC ≥ 6 months was 63.8 %. Median PFS was 8.4 months (95 % CI 4.2–12.6), and median OS was 24.6 months (95 % CI 9.9–44.6). The safety profile was consistent with prior reports.
Conclusion. The investigated mitotane dosing regimen facilitates rapid and safe attainment of therapeutic drug levels in the majority of patients and can be recommended for routine clinical practice.
Introduction. The combination of EDP (etoposide, doxorubicin, cisplatin) chemotherapy with mitotane represents the standard first-line therapy for adrenocortical carcinoma (ACC). Achieving therapeutic serum concentrations of mitotane has been associated with improved progression-free survival (PFS) and overall survival (OS) in several studies. However, mitotane dosing in most prior research has followed institution-specific protocols, underscoring the need for a validated and standardized dosing regimen.
Materials and Methods. A single-center, prospective, phase II study was conducted using a Simon's two-stage design. Eligible patients had locally advanced or metastatic ACC, ECOG performance status 0-1, and were naïve to mitotane. The primary endpoint was the rate of achieving therapeutic mitotane concentrations (14–20 μg/mL). The study aimed to increase this rate from a historical 50 to 70 % (β = 0.2; α = 0.05). Secondary endpoints included objective response rate (ORR), disease control (DC) ≥ 6 months, PFS, OS, and safety. Mitotane was initiated at 2 g/day, with dose escalation by 0.5 g every 3-5 days to a maximum of 4 g/day, followed by titration based on serum drug levels. All patients concurrently received standard platinum-based chemotherapy (EDP or EP/EC).
Results. Forty-seven patients were enrolled (27 male, 57.4 %). All received platinum-based chemotherapy, 45 (95.8 %) with EDP, 2 with EP/EC. After a median follow-up of 12.4 months, therapeutic mitotane concentration was achieved in 72.3 % of patients (n = 34), with a median time to achievement of 4.3 months (95 % CI 3.3–5.3). The ORR was 29.7 %, and DC ≥ 6 months was 63.8 %. Median PFS was 8.4 months (95 % CI 4.2–12.6), and median OS was 24.6 months (95 % CI 9.9–44.6). The safety profile was consistent with prior reports.
Conclusion. The investigated mitotane dosing regimen facilitates rapid and safe attainment of therapeutic drug levels in the majority of patients and can be recommended for routine clinical practice.
References
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