Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Multimodal treatment for high-risk locally-advanced prostate cancer following radical prostatectomy and extended lymphadenectomy.

BACKGROUND: The aim of this study was to prospectively evaluate the safety and oncologic outcomes of multimodal treatment in high risk-locally advanced prostate cancer patients (PCa). METHODS: High-risk-locally advanced prostate cancer patients without distant metastases before radical prostatectomy (RP) were included. Adjuvant high-dose intensity-modulated radiation therapy (IMRT) with concurrent docetaxel and long-term androgen-deprivation therapy (ADT) were started after 3-6 months from RP. ADT was maintained for two years. Acute and late toxicity were evaluated with the Common Terminology Criteria for Adverse Events (v. 3.0). Biochemical and clinical recurrence-free survival were explored by using the Kaplan-Meier method. RESULTS: Overall 42 patients were included. Acute genitourinary toxicity was observed with Grade I, II, and III in four (9.5%), two (4.8%), and one (2.3%) patients, respectively. Acute gastrointestinal toxicity was reported to be of Grade I and II in 12 (29.3%) and three (7.2%) patients, respectively. In these patients, concomitant genito-urinary and gastrointestinal toxicity occurred in three (7.2%) cases. A residual GU Grade I toxicity was present only in one patient. Toxicity due to CHT was found in four (9.5%) patients. Complete continence after RP and IMRT was achieved in 32 patients (76.2%). After a median follow-up of 3.4 years, BCR and clinical recurrence were observed in 16.7% and 9.5% of patients, respectively. A 5-year biochemical and clinical recurrence-free survival rate were 70.7% and 84.0%, respectively. Five-year overall survival was 93.6%. None of the patients died for prostate cancer during follow-up. CONCLUSIONS: This novel multimodal treatment paradigm for high-risk locally advanced prostate cancer has an acceptable level of toxicity and good oncological outcomes observed after a long follow-up.

Color Doppler appearance of penile cavernosal-spongiosal communications in patients with severe Peyronie's disease.

Our objective was to investigate the prevalence and Doppler characteristics of penile cavernosal-spongiosal communications (CSC) in patients with severe Peyronie's disease. These vessels are either anastomoses connecting the cavernosal arteries with the urethral arterial network or afferent vessels to the corpus spongiosum. Twenty patients with severe Peyronie's disease underwent penile color Doppler US after intracavernous injection of prostaglandin E(1). Study inclusion criteria were penile curvature or shortening which made intercourse difficult or impossible. The quality of erectile response was subjectively scored. The spectral characteristics of CSC were evaluated in comparison with waveform changes in cavernosal artery. There were 4 patients with normal erectile response, 10 with discrepancy in rigidity of the penile base and tip, 4 with veno-occlusive dysfunction and 2 with arteriogenic dysfunction. The CSC just proximal to the plaques had peak systolic velocity (PSV) significantly higher and resistance index (RI) significantly lower than the other CSC. The PSV in CSC near the plaques of patients with base-tip discrepancy and with veno-occlusive dysfunction were significantly higher than in the other patients. In patients with severe Peyronie's disease CSC near the plaques remain patent with low-resistance flow supporting the hypothesis that blood leakage can occur through these vessels.

High-flow priapism: treatment and long-term follow-up.

OBJECTIVES: To determine the long-term follow-up of treatment of high-flow priapism, we reviewed the case records of 10 patients who were examined by the Urologic Clinic in Trieste from 1995 to 1998. High-flow or arterial priapism is a fairly rare dysfunction, generally resulting from penile or perineal trauma. In some cases, the etiology remains unknown. METHODS: Trauma was reported in 6 of 10 cases. No etiologic causes were evident in the other patients. Nine patients underwent selective embolization during arteriography, and in 1 patient, corporotomy and ligature of the cavernous artery were performed. Color Doppler ultrasonography was repeated 1 day, 1 month, and 6 months after the operation. The determination of erectile function at a mean follow-up of 41 months (range 17 to 64) was performed using the International Index of Erectile Function. RESULTS: Postoperatively, color Doppler ultrasonography revealed the absence of recurrence in 6 patients. Fistula recurrence was detected in 4 of 9 patients treated with selective embolization (44%). In three of these patients, a second embolization procedure was conclusive. In 1 case (11%), three consecutive embolizations were not conclusive and surgical ligature of the dorsal artery and collateral at the emergence of the penile root, out of the corpus cavernosum, was required. Sexual function was completely preserved in 80% of patients. CONCLUSIONS: Pudendal angiography with superselective embolization is the treatment of choice. It is well tolerated and ensures a high preservation of premorbid erectile function.