BACKGROUND: Studies suggest that retinoic acid (RA) can augment the antitumor effects of interferon-based therapy in patients with advanced renal cell carcinoma (RC); however, this benefit has not been achieved convincingly using oral formulations of 13-cis RA and all-trans RA. Liposome-encapsulated all-trans RA (ATRA-IV) has improved pharmacokinetics with increased and prolonged ATRA serum levels compared with oral retinoids. METHODS: Cohorts of 3-6 patients with progressive metastatic RC received a dose of 3 MU interferon alpha2b per day subcutaneously, which was escalated weekly to 5 MU and then to 10 MU, plus ATRA-IV beginning at a dose of 90 mg/m(2) intravenously three times per week (Monday, Wednesday, and Friday), with a planned escalation to a maximum of 140 mg/m(2). RESULTS: Two of the initial five patients experienced Grade 3 leukopenia while receiving 3 MU interferon and 90 mg/m(2) ATRA-IV. Therefore, the trial was amended to begin ATRA-IV at a dose of 15 mg/m(2) three times per week with a planned escalation by 15 mg/m(2) per cohort plus interferon-alpha at a dose of 3 MU subcutaneously 5 days per week (Monday through Friday), which was escalated weekly to 5 MU and then to 10 MU. Twelve patients were treated on the revised schedule. Toxicity was mild and included Grade 2 anemia (n = 7 patients), leukopenia (n = 2 patients), nausea (n = 2 patients), fatigue (n = 2 patients), fever (n = 2 patients), hepatic toxicity (n = 1 patient), edema (n = 1 patient), neurocortical toxicity (n = 1 patient), headache (n = 1 patient), and infection (n = 1 patient). One patient developed hyperthyroidism, and one patient required admission for bacteremia from a line infection. Dose limiting toxicity was Grade 3 hepatic toxicity, which was observed at a dose of 30 mg/m(2) ATRA-IV in 2 of 6 patients. Only 2 of 12 patients agreed to a dose escalation up to 10 MU interferon-alpha. Of 12 patients who were evaluable for response, 2 patients (17%) had a partial response in bone and lung, including 1 partial response of > 91 weeks' duration, at a dose of 15 mg/m(2) ATRA-IV three times per week and 5 MU interferon-alpha. Five additional patients experienced stable disease, two of whom had disease progression in bone only. CONCLUSIONS: The acceptable toxicity profile and preliminary efficacy results suggest that this regimen warrants further evaluation. ATRA-IV (15 mg/m(2) TIW) and interferon-alpha (3 MU Monday through Friday escalated weekly to 5 MU and to 7 MU) are recommended for further study in patients with advanced RC. Copyright 2002 American Cancer Society.
BACKGROUND: Studies suggest that retinoic acid (RA) can augment the antitumor effects of interferon-based therapy in patients with advanced renal cell carcinoma (RC); however, this benefit has not been achieved convincingly using oral formulations of 13-cis RA and all-transRA. Liposome-encapsulated all-transRA (ATRA-IV) has improved pharmacokinetics with increased and prolonged ATRA serum levels compared with oral retinoids. METHODS: Cohorts of 3-6 patients with progressive metastatic RC received a dose of 3 MU interferon alpha2b per day subcutaneously, which was escalated weekly to 5 MU and then to 10 MU, plus ATRA-IV beginning at a dose of 90 mg/m(2) intravenously three times per week (Monday, Wednesday, and Friday), with a planned escalation to a maximum of 140 mg/m(2). RESULTS: Two of the initial five patients experienced Grade 3 leukopenia while receiving 3 MU interferon and 90 mg/m(2) ATRA-IV. Therefore, the trial was amended to begin ATRA-IV at a dose of 15 mg/m(2) three times per week with a planned escalation by 15 mg/m(2) per cohort plus interferon-alpha at a dose of 3 MU subcutaneously 5 days per week (Monday through Friday), which was escalated weekly to 5 MU and then to 10 MU. Twelve patients were treated on the revised schedule. Toxicity was mild and included Grade 2 anemia (n = 7 patients), leukopenia (n = 2 patients), nausea (n = 2 patients), fatigue (n = 2 patients), fever (n = 2 patients), hepatic toxicity (n = 1 patient), edema (n = 1 patient), neurocortical toxicity (n = 1 patient), headache (n = 1 patient), and infection (n = 1 patient). One patient developed hyperthyroidism, and one patient required admission for bacteremia from a line infection. Dose limiting toxicity was Grade 3 hepatic toxicity, which was observed at a dose of 30 mg/m(2) ATRA-IV in 2 of 6 patients. Only 2 of 12 patients agreed to a dose escalation up to 10 MU interferon-alpha. Of 12 patients who were evaluable for response, 2 patients (17%) had a partial response in bone and lung, including 1 partial response of > 91 weeks' duration, at a dose of 15 mg/m(2) ATRA-IV three times per week and 5 MU interferon-alpha. Five additional patients experienced stable disease, two of whom had disease progression in bone only. CONCLUSIONS: The acceptable toxicity profile and preliminary efficacy results suggest that this regimen warrants further evaluation. ATRA-IV (15 mg/m(2) TIW) and interferon-alpha (3 MU Monday through Friday escalated weekly to 5 MU and to 7 MU) are recommended for further study in patients with advanced RC. Copyright 2002 American Cancer Society.
Authors: Daniel Heudobler; Michael Rechenmacher; Florian Lüke; Martin Vogelhuber; Sebastian Klobuch; Simone Thomas; Tobias Pukrop; Christina Hackl; Wolfgang Herr; Lina Ghibelli; Christopher Gerner; Albrecht Reichle Journal: Front Pharmacol Date: 2018-11-28 Impact factor: 5.810