Eunsik Lee

Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial

PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: Final overall survival results and safety update

BACKGROUND In this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported. METHODS Treatment-naive or cytokine-pretreated mRCC patients (n=435) stratified and randomised (2:1) to pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover. FINDINGS The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR]=0.91; 95% confidence interval [CI], 0.71-1.16; one-sided P=.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR=0.504; 95% CI, 0.315-0.762; two-sided P=.002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR=0.43; 95% CI, 0.215-1.388; two-sided P=.172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events. INTERPRETATION Although no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.

Prognostic Significance of The Nadir Prostate Specific Antigen Level After Hormone Therapy for Prostate Cancer

PURPOSE We determine whether the nadir prostate specific antigen (PSA) level after hormone therapy can be used to predict the progression to hormone refractory prostate cancer. MATERIALS AND METHODS We reviewed the progressive status and survival of 177 patients with stage C or D prostate cancer who had received hormone therapy at our institution. The overall survival rate, incidence of progression to hormone refractory prostate cancer and interval until progression were analyzed with reference to the nadir PSA level. Multiple regression analysis was used to analyze the predictive factors for progression to hormone refractory prostate cancer, and the relative efficacy of the nadir PSA level in predicting progression was evaluated by receiver operating characteristics analysis. RESULTS Median followup was 39 months (range 3 to 89) and 85.4% of patients (151) responded to treatment, of whom 77.5% (117) had progression to hormone refractory prostate cancer. Median time until nadir PSA levels were reached after hormone therapy was 8.1 months and median time until hormone refractory prostate cancer was 24.0 months. Nadir PSA levels were less than 0.2 ng./ml. in 31% of respondents, 0.2 to 1.0 ng./ml. in 23%, 1.1 to 10 ng./ml. in 42% and greater than 10 ng./ml. in 5%. These groups had similar clinicopathological characteristics. Nadir PSA levels correlated significantly with pretreatment PSA levels, Gleason scores and progression to hormone refractory prostate cancer (p = 0.01, p <0.01 and p <0.001, respectively), and inversely correlated with the interval to the establishment of hormone refractory prostate cancer (r = -0.465, p <0.05). By univariate analysis bone metastasis, nadir PSA, PSA at 6 months after treatment and pretreatment PSA were significantly associated with progression to hormone refractory prostate cancer. Only the nadir PSA was calculated to be an independent factor by multivariate analysis. Receiver operating characteristics analysis indicated that nadir PSA predicted progression to hormone refractory prostate cancer after 2 years with an accuracy of 86.2%. With the lower limit of the nadir PSA level set to 1.1 ng./ml., sensitivity was 80.3% and specificity was 83.8%, and these levels were deemed the most appropriate. Furthermore, nadir PSA after hormone therapy was an independent prognosticator for survival, as were initial levels of hemoglobin and alkaline phosphatase. CONCLUSIONS The nadir PSA level after hormone therapy may be the most accurate factor predicting the progression to hormone refractory prostate cancer and is an independent prognostic factor for survival. Furthermore, a lower limit for the nadir PSA level of 1.1 ng./ml. gives optimal sensitivity and specificity.

Prevalence of lower urinary tract symptoms in Korean men in a community-based study

Objective: The prevalence of lower urinary tract symptoms was determined in Korean men aged 50 and over. Methods: A community-based, epidemiologic study was performed in Yonchon County, Korea. The Korean version of the International Prostate Symptom Score (I-PSS) was used to assess the severity of urinary symptoms in a representative sample of 514 men. Results: Nocturia and weak stream were the most prevalent symptoms and urgency was the least. Overall, 23.2% of the men were moderately to severely symptomatic: 17.7% in the age group of 50–59 years, 23.3% in that of 60–69 years and 35.3% in that of 70 years and over. The proportion of severely symptomatic men approximately doubled with each decade of age. The ‘quality of life’ score showed a high correlation with the I-PSS. Our estimation indicated that in 1995 approximately 800,000 Korean men had moderate to severe lower urinary tract symptoms that were likely to be associated with benign prostatic hyperplasia. Conclusions: The prevalence of moderate to severe lower urinary tract symptoms in Korean men is substantially similar to that in Caucasians.

The application of an antiangiogenic gene (thrombospondin-1) in the treatment of human prostate cancer xenografts

Angiogenesis is a critical event for solid tumor growth and metastasis. Within a given microenvironment, the angiogenic response is determined in part by the balance between angiogenesis inducers and inhibitors. The aim of this study was to establish a thrombospondin-1 (TSP-1) (an antiangiogenic gene) expression vector, and to determine the feasibility for use of TSP-1 in prostate cancer gene therapy. The results of this study showed that pCR-TSP-1, the cloned TSP-1 expression plasmid vector, expressed the TSP-1 gene efficiently in DU145, a human prostate cancer cell line. pCR-TSP-1 did not exert any significant growth inhibitory activity on the tested cell line in vitro. However, TSP-1 overexpression inhibited the growth of DU-145 xenografts in Balb/c nude mice when directly transfected with pCR-TSP-1 in combination with a liposomal agent (DOSPER). Histological analysis showed that there were extensive areas of necrosis in the TSP-1 overexpressing tumors, whereas no necrotic foci were observed in the control tumors. Furthermore, the microvessel density was lower in the TSP-1 overexpressing tumors compared to the control tumors. These results suggest that TSP-1 may be a potentially useful gene for prostate cancer gene therapy. Cancer Gene Therapy (2000) 7, 1537–1542.

Accuracy of bladder volume determinations by ultrasonography: are they accurate over entire bladder volume range?

OBJECTIVES To investigate the accuracy of a portable three-dimensional hand-held BladderScan (BS) and two-dimensional conventional ultrasonography (CUS) in the estimation of bladder volumes. METHODS The bladder volume of 65 subjects was measured during filling cystometry using two ultrasound modalities. Serial measurements were performed when the infused volume reached 100, 200, 300, and 400 mL; the investigator measured the volumes three times each with BS and CUS. Each corresponding true volume was calculated by interpolation using zero volume and the final catheterized volume at the end of cystometry. The accuracy of the two ultrasound methods was compared using raw scaled values of the volumes and the percentage of differences of volume. RESULTS Bladder volumes determined by CUS and BS were underestimated by 21.8% and 3.3% (mean values), respectively. The percentage of differences of volume of BS was not statistically significant (P >0.05), but that of CUS was statistically significant (P <0.00001). No significant percentage of differences of volume change according to the volume status was observed by either ultrasound measurement method (P >0.05). Linear regression analysis between the true volumes and the raw scaled volumes showed that the slope of the BS was closer to 1.0 than that of the CUS, and the difference was statistically significant (P <0.001). The effects of diagnosis, age, sex, and body mass index were not significant in determining the bladder volume by either method (P >0.05). CONCLUSIONS Our results demonstrated that a three-dimensional hand-held scanner measures the bladder volume in a reproducible and accurate manner for a wide range of bladder volumes and is superior to two-dimensional stationary ultrasonography.

Augmentation of cisplatin sensitivity in cisplatin-resistant human bladder cancer cells by modulating glutathione concentrations and glutathione-related enzyme activities

To investigate the roles of glutathione and glutathione‐S‐transferase (GST) in cisplatin‐resistance mechanisms in human bladder cancer, by using glutathione‐depleting or GST‐blocking agents.

Effect of subclinical prostatic inflammation on serum psa levels in men with clinically undetectable prostate cancer

OBJECTIVES To examine whether subclinical prostatic inflammation might influence serum prostate-specific antigen (PSA) levels in men with clinically undetectable prostate cancer. METHODS A total of 461 patients who underwent prostate biopsy at our hospital were studied between January 1996 and December 1999. Of these patients, a total of 125 patients without detectable prostate cancer or a history or symptoms of prostatitis, with serum PSA levels of less than 20.0 ng/mL and other specified exclusion criteria, were included in the study. Inflammation observed at biopsy was scored for inflammation extent and inflammatory aggressiveness, and the effects of these morphologic aspects of inflammation on serum PSA levels were examined. RESULTS The extent of inflammation tended to increase as the prostate volume increased (P = 0.006). Patients with a PSA greater than 2.5 ng/mL had a greater extent and aggressiveness of inflammation than those with PSA levels of 2.5 ng/mL or less (P = 0.004 and P = 0.050, respectively). However, no statistically significant differences were found in terms of the extent of inflammation or inflammatory aggressiveness between patients with PSA levels greater than 4.0 ng/mL and those with PSA levels of 4.0 ng/mL or less. Furthermore, the extent of inflammation did not account for PSA levels greater than 2.5 or 4.0 ng/mL by multivariate analysis. CONCLUSIONS Our results indicate that subclinical prostatic inflammation is not the etiology of a serum PSA greater than 4.0 ng/mL in men without clinically detectable prostate cancer.

Prognostic Factors for Chronic Kidney Disease After Curative Surgery in Patients With Small Renal Tumors

OBJECTIVES To investigate the incidence and predictive factors associated with newly developed chronic kidney disease (CKD) after curative surgery in patients with small renal tumors. METHODS From 1998 to 2005, we retrospectively investigated 225 patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN) for renal tumors, of size <or= 4 cm, with normal contralateral kidney. The glomerular filtration rate (GFR) was calculated using the four-variable modification of diet in renal disease formula. CKD was defined as GFR of < 60 mL/min per 1.73 m(2). Demographic and clinicopathologic parameters were evaluated using Cox proportional hazards model to determine the variables independently associated with the development of postoperative CKD. RESULTS A total of 129 (57.3%) and 96 (42.7%) patients were included in the RN and PN groups. A total of 97 patients (43.1%) developed CKD; 86 (66.7%) underwent an RN and 11 (11.5%) underwent a PN. The 2-year probability of absence of CKD with an RN and a PN was 58.3% and 95.7%, respectively (P <.001). Among 20 patients with diabetes, 12 (60.0%) developed CKD: 10 patients underwent an RN and 2, a PN. The 2-year probability of absence of CKD with and without diabetes was 46.5% and 76.4%, respectively (P = .006). The multivariate analysis showed that age (P = .001), type of operation (P <.001), preoperative GFR (P = .001), and diabetes (P = .042) were associated with the development of CKD. CONCLUSIONS The results of this study show that nephron-sparing surgery for small renal mass should be attempted to prevent CKD in all eligible patients, especially those with diabetes.

Expression of Ki-67 and COX-2 in Patients With Upper Urinary Tract Urothelial Carcinoma

OBJECTIVES To investigate the prognostic value of Ki-67, cyclooxygenase-2 (COX-2), E-cadherin, and retinoblastoma protein (pRB) in patients with urothelial carcinoma of the upper urinary tract. METHODS From January 1998 to December 2005, the specimens from 107 patients with urothelial carcinoma of the upper urinary tract who had undergone nephroureterectomy were analyzed. The expression of Ki-67, COX-2, E-cadherin, and pRB was examined by immunochemistry on tissue microarray sections. The correlation of the immunoreactivity with the pathologic parameters and progression-free and cancer-specific survival were examined. RESULTS Ki-67 and COX-2 were overexpressed in 26 (24%) and 38 patients (36%), respectively. The loss of E-cadherin expression was observed in 66 patients (62%). Altered pRB expression was found in 37 patients (34%). Overexpression of Ki-67 (P = .041 and P = .006, respectively) and COX-2 (P = .002 and P = .001, respectively) was associated with the pathologic stage and grade. Multivariate analysis showed that Ki-67 overexpression (P = .002), T stage (P = .009), and lymph node metastases (P = .009) were independent predictors of progression-free survival. In addition, Ki-67 overexpression (P = .007) and pathologic T stage (P = .003) were independent predictors of cancer-specific survival. No association was found between the pathologic findings and prognosis and the other markers (E-cadherin and pRB). CONCLUSIONS Our results suggest that Ki-67 overexpression is an independent predictor of the progression of urothelial carcinoma of the upper urinary tract. Patients with Ki-67 overexpression should be followed up more closely. In addition, they might be candidates for future prospective therapy trials.