Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm's influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival.
Three chronomodulation schedules (5:00-13:00, 13:00-21:00, and 21:00-5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI).
Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00-13:00, 15 at 13:00-21:00, and 13 at 21:00-5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2-107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1-2), MSKCC score (0-2 vs. ≥ 3), IMDC risk score (0-2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule.
IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.
Cytokine. 2020 Jan 20 [Epub ahead of print]
Giovanni Lo Re, Davide A Santeufemia, Francesco Lo Re, Roberto Bortolus, Paolo Doretto, Wally Marus, Lorenzo Buttazzi, Oliviero Lenardon, Alessandra Falda, Rita Piazza, Sandro Sulfaro
Medical Oncology and Immune-Related Tumors, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Gallini 2, 33081 Aviano, PN, Italy. Electronic address: ., Oncology Unit, Alghero Hospital, ASSL Sassari, Via Don Minzoni 137, I-07041 Alghero, SS, Italy. Electronic address: ., Pharmacology and Clinical Toxicology, University of Milan, Via Vanvitelli 32, I-20129 Milan, MI, Italy. Electronic address: ., Radiotherapy Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Gallini 2, I-33081 Aviano, PN, Italy. Electronic address: ., Clinical Pathology, AAS5 Pordenonese, Via Montereale 24, I-33170 Pordenone, Italy. Electronic address: ., Pathology, AAS5 Pordenonese, Via Montereale 24, I-33170 Pordenone, Italy. Electronic address: ., Urology Unit, AAS5 Pordenonese, Via Montereale 24, I-33170 Pordenone, Italy. Electronic address: ., Urology Unit, AAS5 Pordenonese, Via Montereale 24, I-33170 Pordenone, Italy. Electronic address: ., Clinical Pathology, AAS5 Pordenonese, Via Montereale 24, I-33170 Pordenone, Italy. Electronic address: ., Cardiology Unit, AAS5 Pordenonese, Via Montereale 24, I-33170 Pordenone, Italy. Electronic address: ., Pathology, AAS5 Pordenonese, Via Montereale 24, I-33170 Pordenone, Italy. Electronic address: .