Prognostic Significance of VEGF after Twenty-Year Follow-up in a Randomized Trial of Fenretinide in Non-Muscle-Invasive Bladder Cancer.

Non-muscle-invasive bladder cancer (NMIBC) may progress to muscle-invasive disease, but no effective preventive treatments are available. In addition, no reliable prognostic biomarkers have been identified. We assessed the long-term effect of the oral retinoid fenretinide and the prognostic value of circulating VEGF levels. We updated through the Tumor Registry the vital status of 99 patients with resected Ta/T1 bladder tumors who were recruited in a randomized trial of 2 years of fenretinide or no treatment in 1993-1994. Serum VEGF levels measured at baseline and 12 months were available in a subgroup of 62 patients. After a median of 20.5 years, 54 subjects died, 35 of any cancer and 14 of bladder cancer. Neither overall survival (OS), nor cancer survival (CS) or bladder cancer survival (BCS) was affected by fenretinide (log-rank P ≥ 0.2). DNA aneuploidy in bladder washing was associated with shorter OS (P = 0.02), CS (P = 0.05), and BCS (P = 0.09). Subjects with baseline VEGF levels in the top quintile (≥350 pg/mL) had a significantly shorter OS (P = 0.01), CS (P = 0.02), and BCS (P = 0.008). The trend across quintiles of VEGF was significant for BCS (P = 0.007). Multivariate analyses showed that, in addition to smoking status, VEGF level in the top quintile was an independent prognostic factor for OS (HR = 2.7; 95% CI, 1.1-6.5), CS (HR = 3.3; 95% CI, 1.1-9.4) and BCS (HR = 8.9; 95% CI,1.3-61). Fenretinide did not affect the long-term outcome of patients with NMIBC. High serum VEGF level was a significant predictor of overall and cancer death and may help to identify high-risk subjects who may benefit from a preventive therapy. Cancer Prev Res; 9(6); 437-44. ©2016 AACR.

[Intravesical chemotherapy]. / La chemioterapia endovescicale.

Bladder cancer care continues to represent a significant financial burden on the population and on the healthcare system. The incidence of bladder cancer has increased over the last two decades. Therapeutic advances have occurred in bladder cancer care, but at an increased cost to payers, providers, and patients. Intravesical treatment of non-muscle invasive tumors represents one of the main costs. For this reason therapeutic schedules need to be rationalized. In this perspective, we present some critical remarks on: the use of gemcitabine in clinical practice; the real impact of the perioperative chemotherapy, emphasizing the cost and effectiveness in high-risk patients, and finally the optimization of intravesical treatments. There is a need for the scientific community to focus on their resources and convey efforts not in the treatment of low-risk cancers (present in significant numbers in various studies), which the Anglo-Saxons call "nuisance tumor" since they can be treated easily and effectively at low cost, but definitely to engage in the study of the treatment of cancer at high risk of recurrence and progression, and it is on this field that the cost (economic, management, subjective) / benefit ratio must be assessed.

Are referral centers for non-muscle-invasive bladder cancer compliant to EAU guidelines? A report from the vesical antiblastic therapy Italian study.

INTRODUCTION: Adherence to international guidelines is viewed as a prerequisite for optimal medical care delivery. Previously reported surveys for non-muscle-invasive bladder cancer (NMIBC) employed mailed questionnaires to urologists or patients resulting in conflicting degrees of agreement with existing guidelines. In the current study, contemporary information on the management of NMIBC was generated from a sample of italian centers. PATIENTS AND METHODS: Eight Italian referral centers for the treatment of NMIBC were asked to collect information relative to all consecutive patients with a histology-proven NMIBC undergoing a transurethral resection from January 1 to March 31, 2009. The primary study objective was to verify the level of adherence of disease management with European guidelines. RESULTS: 344 patients resulted in being evaluable. 49.2% of high-risk patients underwent a repeat transurethral resection. Bacillus Calmette-Guérin was employed in 35% of cases, while chemotherapy was in 22%. An early single regimen was adopted in 136 patients and only in 1 out of 3 low-risk patients. High-risk NMIBC received bacillus Calmette-Guérin and chemotherapy as first-line therapy in 66 and 12.5% respectively. After 3 months, cystoscopy had been reported for 82.5% of patients with a recurrence rate of 13%. CONCLUSION: Adherence of Italian Institutions to EAU guidelines was optimal when reporting baseline variables. Significant degrees of discrepancy emerged in treatment choices.

Prognostic effect of DNA aneuploidy from bladder washings in superficial bladder cancer.

BACKGROUND: Superficial (papillary) bladder cancer is associated with progression and death from muscle-invasive bladder cancer, but no reliable predictors of the outcomes have been identified. METHODS: We analyzed the long-term prognostic effect of DNA flow cytometry in bladder washings from 93 subjects with previously resected T(a) and T(1) bladder tumors who participated in a chemoprevention trial of the synthetic retinoid fenretinide. Kaplan-Meier analysis and Cox regression were used to determine the prognostic effect of DNA aneuploidy on cancer progression and mortality in conjunction with conventional clinical factors after a median of 11.5 years (interquartile range, 9.5-11.7 years). RESULTS: Overall, 58 of 93 (62%) specimens were DNA aneuploid at baseline. Progression-free survival was significantly shorter in subjects with stage T(1) [hazard ratio (HR), 31.6; 95% confidence interval (95% CI), 2.6-386.1; P < 0.001] and in subjects with baseline DNA aneuploid washing (HR, 10.5; 95% CI, 1.1-126.1; P = 0.03). The risk of death was also greater for stage T(1) tumors (HR, 2.6; 95% CI, 1.04-6.7; P = 0.04). DNA aneuploidy was a significant prognostic factor also for overall survival (HR, 2.8; 95% CI, 1.0-9.0; P = 0.05). Fenretinide treatment had no significant effect on cancer progression and death. CONCLUSIONS: DNA aneuploidy in washings from endoscopically normal bladder is a significant predictor of progression and death in addition to tumor stage. This biomarker may help to identify and monitor a high-risk group who may benefit from a chemoprevention intervention.

Pre and postoperative quantitative detection of fragments of cytokeratins 8 and 18 (UBC IRMA) as markers of early recurrence of superficial bladder tumor.

OBJECTIVES: The Urinary Bladder Cancer (UBC) test is a marker that detects urinary fragments of cytokeratin 8 and 18. The aim of this study is to evaluate the usefulness of the pre and post operative UBC test to detect early recurrences of a bladder tumor in the first year after the transurethral resection of a bladder tumor. MATERIALS AND METHODS: A multicentric perspective study on 36 patients with superficial bladder cancer (pTa-pT1) treated with transurethral resection (TUR) was performed. Each patient underwent 4 specific urine collections: 1) preoperatively, 2) 3 days after TUR, 3) 7 days after TUR, 4) 30 days after TUR. UBC was analysed on urine with the IRMA method and the cut off value of 12 mg/L was used. Cystoscopy was performed after 3, 6, 9, and 12 months after TUR, with the aim of identifying all cancer recurrences in the first year postoperatively. Statistical analyses to identify differences between patients with or without early recurrence were performed in accordance with Fisher's exact test and Chi-square analysis. RESULTS: Of the 36 patients included in the study 15 showed early recurrence and 21 were recurrence free 1 year after surgery. UBC levels measured in recurrence free patients 30 days after TUR showed normal values, values decreasing as compared with preoperative levels or both circumstances, even if a statistically significant difference was not found between the two groups. CONCLUSIONS: In this study we reported an insignificant correlation between the postoperative modifications of UBC levels and the risk of tumor recurrence during the first year of follow-up. A larger study group with longer follow-ups will probably allow better evaluation of the real power of UBC tests in clinical practice.

Intravesical gemcitabine in superficial bladder cancer: a phase II safety, efficacy and pharmacokinetic study.

BACKGROUND: We investigated the safety, efficacy and pharmacokinetics of the intravesical administration of 2000 mg gemcitabine once a week in the four weeks before transurethral resection of superficial bladder cancer (TUR), and in the four successive weeks. MATERIALS AND METHODS: Nine patients with superficial transitional cell bladder carcinoma were studied. Two thousand mg of gemcitabine dissolved in 50 ml of distilled water were administered intravesically. The dwell time was 60 min. The pharmacokinetics of gemcitabine and its metabolite, 2',2'-difluorodeoxyuridine (dFdU), were studied in plasma and urine before and after TUR. Cystoscopy was repeated 30 days after completion of the TUR treatment and subsequently at time intervals of one or two months. RESULTS: No systemic toxicity was noted, and only three patients displayed modest signs of local toxicity. One patient had recurrence 1 month after TUR, three between 3 and 6 months, and another three after 8, 11 and 18 months, respectively; two were recurrence-free after 21 and 22 months, respectively. The peak plasma concentrations of gemcitabine never exceeded 1000 ng/ml before TUR and 350 ng/ml after TUR, and declined rapidly. The plasma levels of dFdU were higher than those of gemcitabine, increased until 60 min and then declined little. Between 52% and 100% of the gemcitabine dose was present in voided urine. CONCLUSION: Intravesical gemcitabine, at the dose of 2000 mg, is well tolerated, is associated with minimal systemic absorption and has a moderate efficacy in the treatment of superficial bladder cancer.