J.H. Hong

Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma

BACKGROUNDnRetrospective and molecular biologic data suggest that sunitinib may be effective in patients with non-clear cell renal cell carcinoma (nccRCC).nnnPATIENTS AND METHODSnEligibility criteria included advanced nccRCC except for collecting duct carcinoma and sarcomatoid carcinoma without identifiable renal cell carcinoma subtypes. Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest. The primary end point was overall response rate (RR).nnnRESULTSnThirty-one eligible patients were enrolled. Twenty-four patients (77%) had prior nephrectomy. By Memorial Sloan-Kettering Cancer Center criteria, 8 patients (26%) had poor risk and 14 (45%) had intermediate risk. Twenty-two patients had papillary renal cell carcinoma (RCC), and three had chromophobe RCC. Eleven patients had partial response with a RR of 36% (95% confidence interval (CI) 19% to 52%) and an additional 17 patients (55%) had stable disease. Median duration of response was 12.7 months (95% CI 6.3-19.1 months), and median progression-free survival was 6.4 months (95% CI 4.2-8.6 months). At a median follow-up duration of 18.7 months (95% CI 13.7-23.7 months), 13 patients (42%) had died, resulting in an estimated median survival of 25.6 months (95% CI 8.4-42.9 months). Toxicity profiles were commensurate with prior reports.nnnCONCLUSIONSnSunitinib has promising activity in patients with nccRCC (NCT01219751).BACKGROUNDnRetrospective and molecular biologic data suggest that sunitinib may be effective in patients with non-clear cell renal cell carcinoma (nccRCC).nnnPATIENTS AND METHODSnEligibility criteria included advanced nccRCC except for collecting duct carcinoma and sarcomatoid carcinoma without identifiable renal cell carcinoma subtypes. Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest. The primary end point was overall response rate (RR).nnnRESULTSnThirty-one eligible patients were enrolled. Twenty-four patients (77%) had prior nephrectomy. By Memorial Sloan-Kettering Cancer Center criteria, 8 patients (26%) had poor risk and 14 (45%) had intermediate risk. Twenty-two patients had papillary renal cell carcinoma (RCC), and three had chromophobe RCC. Eleven patients had partial response with a RR of 36% (95% confidence interval (CI) 19% to 52%) and an additional 17 patients (55%) had stable disease. Median duration of response was 12.7 months (95% CI 6.3-19.1 months), and median progression-free survival was 6.4 months (95% CI 4.2-8.6 months). At a median follow-up duration of 18.7 months (95% CI 13.7-23.7 months), 13 patients (42%) had died, resulting in an estimated median survival of 25.6 months (95% CI 8.4-42.9 months). Toxicity profiles were commensurate with prior reports.nnnCONCLUSIONSnSunitinib has promising activity in patients with nccRCC (NCT01219751).

RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial

BACKGROUNDnThe standard sunitinib schedule, 4 weeks on, followed by 2 weeks off (4/2 schedule), is associated with troublesome toxicities, and maintenance of adequate sunitinib dosing and drug levels, which are essential for achieving an optimal treatment outcome, is challenging. The objective of this study was to investigate the efficacy and safety of an alternative sunitinib dosing schedule of 2 weeks on and 1 week off (2/1 schedule) compared with the standard sunitinib schedule of 4 weeks on and 2 weeks off (4/2 schedule).nnnPATIENTS AND METHODSnIn this multicenter, randomized, open-label, phase II trial, treatment-naïve patients with clear-cell type metastatic renal cell carcinoma (mRCC) were randomly assigned to 4/2 or 2/1 schedules after stratification by Memorial Sloan Kettering Cancer Center risk group and the presence or absence of measurable lesions. The primary end point was the 6-month failure-free survival (FFS) rate, determined by intention-to-treat analysis.nnnRESULTSnFrom November 2007 to February 2014, 76 patients were accrued, and 74 were eligible. FFS rates at 6 months were 44% with the 4/2 schedule (N = 36) and 63% with the 2/1 schedule (N = 38). Neutropenia (all grades, 61% versus 37%; grade 3-4, 28% versus 11%) and fatigue (all grades, 83% versus 58%) were more frequently observed with schedule 4/2. There was a strong tendency toward a lower incidence of stomatitis, hand-foot syndrome, and rash with schedule 2/1. Objective response rates (ORRs) were 47% in schedule 2/1 and 36% in schedule 4/2. With a median follow-up of 30.0 months, the median time to progression (TTP) was 12.1 months in schedule 2/1 and 10.1 months in schedule 4/2.nnnCONCLUSIONnSunitinib administered with a 2/1 schedule is associated with less toxicity and higher FFS at 6 months than a 4/2 schedule, without compromising the efficacy in terms of ORR and TTP (NCT00570882).

Changes in the Upper Urinary Tract After Radical Cystectomy and Urinary Diversion: A Comparison of Antirefluxing and Refluxing Orthotopic Bladder Substitutes and the Ileal Conduit

PURPOSEnWe evaluated and compared the effects of different types of urinary diversion on functional and radiographic changes in the upper urinary tract.nnnMATERIALS AND METHODSnWe analyzed data on 275 patients who underwent radical cystectomy and urinary diversion for bladder cancer and were observed at least 12 months. Of the patients 197 received an orthotopic bladder substitute, including antirefluxing ureteral anastomoses in 111 (group 1) and refluxing ureteral anastomoses in 86 (group 2). Ileal conduits were created in 78 patients (group 3). Serial serum Cr, radiographic changes in the upper urinary tract after diversion and the number of episodes of APN were compared by diversion method. Mean followup was 52 months (range 12 to 174 months) with no difference among the groups.nnnRESULTSnCompared with group 3 patients in groups 1 and 2 demonstrated a significantly higher incidence of moderate to severe hydronephrosis (p = 0.001) but the incidence was similar between groups 1 and 2 (6.3%, 8.3% and 1.4% of the renal units in groups 1 to 3, respectively). Stabilized postoperative Cr did not differ among the groups. CRF, defined as Cr 3.0 mg/dl or greater, occurred in 2.7% of the patients in group 1 and in 3.5% of those in group 2 but in none in group 3. APN was noted in 3.3%, 4.4% and 0.4% of patients in groups 1 to 3, respectively (p = 0.012).nnnCONCLUSIONSnAn ileal conduit with a lower rate of diversion related hydronephrosis, CRF and morbidity associated with APN was superior to orthotopic bladder substitutes. Between the refluxing and antirefluxing types of orthotopic bladder substitutes no significant difference in functional or radiographic changes was noted.

Prognostic factors of metastatic renal cell carcinoma with extensive sarcomatoid component

PurposeTo evaluate clinical characteristics including the response to targeted therapy, the benefits of cytoreductive nephrectomy, or the prognostic factors in advanced renal cell carcinoma (RCC) with extensive sarcomatoid component (ESC), a rare but fatal disease.MethodsData from 37 consecutive patients with metastatic or recurrent RCC with ESC (≥25xa0% on resected kidney or exclusive sarcomatoid histology on needle biopsy) were analyzed.ResultsOf the 37 patients, 27 patients (73xa0%) had synchronous metastatic disease. The median percentage of sarcomatoid component (PSC) was 50xa0% (range 25–93xa0%). Twenty (74xa0%) of the 27 synchronous metastatic patients underwent cytoreductive nephrectomy. Of the nine patients undergoing cytokine therapy, none showed objective responses. Two (15xa0%) of the 13 patients undergoing targeted agent therapy had partial responses, and five patients (38xa0%) achieved stable disease. The median overall survival for all patients was 5.9xa0months [95xa0% confidence interval (CI) 1.0–10.9]. In multivariate analysis, age (>58xa0years), ECOG performance status (>1), PSC (>50xa0%), and time from first diagnosis to advanced disease (<6xa0months) remained independent prognostic factors. Neither the type of systemic therapy nor cytoreductive nephrectomy had an effect on survival.ConclusionsPatients with RCC with ESC have a dismal clinical course, and the majority of patients have rapid disease progression, especially in response to immunotherapy. Four clinical factors can be used to model survival outcomes for advanced RCC with ESC and may be helpful in selecting patients for aggressive treatment.

Gemcitabine-oxaliplatin plus prednisolone is active in patients with castration-resistant prostate cancer for whom docetaxel-based chemotherapy failed.

Background:There has been no previous study on the activity of gemcitabine in combination with oxaliplatin (GemOx) for castration-resistant prostate cancer (CRPC).Methods:The GemOx was preclinically tested for cytotoxic activity in human prostate cancer cell lines. Clinically, patients with CRPC who failed prior docetaxel were treated with gemcitabine 1000u2009mgu2009m−2 and oxaliplatin 100u2009mgu2009m−2 intravenously every 2 weeks and prednisolone 5u2009mg orally twice daily. The primary end point was the prostate-specific antigen (PSA) response rate.Results:The GemOx displayed synergistic effects based on Chou and Talalay analysis. In the phase II study, 33 patients were accrued. The median dose of docetaxel exposure was 518u2009mgu2009m−2. A total of 270 cycles were administered with a median of eight cycles per patient. A PSA response rate was 55% (95% CI, 38–72) and radiologic response rate was 82% (9 out of 11). With a median follow-up duration of 20.5 months, the median time to PSA progression was 5.8 months (95% CI, 4.4–7.2) and the median overall survival was 17.6 months (95% CI, 12.6–22.6). The most frequently observed grade 3 or 4 toxicities were neutropenia (13%) and thrombocytopenia (13%).Conclusions:The GemOx is active and tolerable in patients with metastatic CRPC after docetaxel failure (NCT 01487720).

Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: the PECULIAR study (KCSG 10-17).

Background:Pemetrexed has shown a favourable response rate of about 30% with minimal toxicity when used as a single agent for treatment of advanced urothelial carcinoma. This phase II study evaluated the efficacy and safety of pemetrexed plus cisplatin in advanced urothelial carcinoma.Methods:This multicentre, single-arm, open-label, phase II clinical trial enrolled patients who had advanced urothelial carcinoma, ECOG PS 0–2, and measurable disease. Pemetrexed 500u2009mgu2009m−2 with cisplatin 70u2009mgu2009m−2 on day 1 were administered every 3 weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.Results:A total of 42 patients were enrolled (median age, 66 years; ECOG 0–1, 100%; visceral metastasis, 54.8%; recurrent disease, 57.1%). Twenty-seven partial responses for an ORR of 64.3% (95% CI, 49.2%–77.0%) were documented. Seven patients had stable disease. Median PFS and OS were 6.9 (95% CI, 6.2–7.6) and 14.4 (95% CI, 10.4–18.4) months, respectively. Grade 3 or 4 neutropenia was observed in 28.6% of patients. No patients experienced febrile neutropenia.Conclusion:The combination of pemetrexed and cisplatin is active, and well tolerated in patients with advanced urothelial cancer as a first-line treatment.

Transforming growth factor-β downregulates interleukin-2-induced phosphorylation of signal transducer and activator of transcription 5 in human renal cell carcinoma

PurposeWe investigated signal transducer and activator of transcription-5 (STAT5) activation status in renal cell carcinoma (RCC) and the role of transforming growth factor-β (TGF-β) in the process.MethodsTwenty normal and RCC tissues were obtained from radical nephrectomy specimens for the assessment of expressions of phosphorylated STAT5 (p-STAT5) and TGF-β1 (Western blot) and for localization and assessment of their relationship (immunohistochemical and immunofluorescence stains). By using four RCC cell lines and four primary cultured cells, the effect of TGF-β1 and/or interleukin-2 (IL-2) on the expressions of p-STAT5 were analyzed.ResultsIn RCC samples, expression of p-STAT5 was significantly reduced while expression of TGF-β was enhanced compared with normal kidney tissues (Pxa0<xa00.001 and Pxa0=xa00.003, respectively). P-STAT5 was observed almost exclusively in the nuclei of normal kidney tissues while TGF-β was identified in the cytoplasm of cells of both tissues reflecting the Western results. In both RCC cell lines and cells from primary cultures, treatment with TGF-β or antibody did not significantly alter STAT5 activation. However, TGF-β significantly suppressed IL-2-induced STAT5 activation, whereas anti-TGF-β antibodies enhanced IL-2-induced STAT5 further.ConclusionsSTAT5 activation is suppressed in RCC compared with normal renal parenchyma. It may be attributed to the RCC-derived TGF-β which also interferes with IL-2-induced STAT5 pathway activation.

S&T-60 THE INFLUENCE OF LENGTH, GRADE, AND LOCATION OF POSITIVE SURGICAL MARGIN (PSM) ON BIOCHEMICAL RECURRENCE IN ORGAN CONFINED PROSTATE CANCER

history. Without doctor’s explanation the CRR was decreased in patients with urologic medical history. CONCLUSIONS: The RR of FVC was increased by doctor’s explanation in patients aged <50 years, without private insurance, with high school graduate or higher and without past medical history. To explain personally the necessity and the completion method of a FVC by doctor was a help to record accurately the FVC in patients aged <50 years and with urologic medical history.

Comparison of Trends in Suicide Methods and Rates Among Older Adults in South Korea and United States

Lethality of the chosen method during a suicide attempt is a strong risk factor for completion of suicide. We examined whether annual changes in the pattern of suicide methods is related to annual changes in suicide rates among older adults in South Korea and the United States. We analyzed annual the World Health Organization data on rates and methods of suicide from 2000 to 2011 in South Korea, and from 2000 to 2010 in the United States. We found that. for both Korean male and female older adults, there was a significant positive correlation between suicide rate and the rate of hanging, and a significant negative correlation between suicide rate and the rate of poisoning. Among older adults in the U.S., annual changes in the suicide rate and the pattern of suicide methods were less conspicuous, and no correlation was found between them. The results of the present study suggest that the increasing use of lethal suicide methods has contributed to the rise in suicide rates among older adults in South Korea. Targeted efforts to reduce the social acceptability and accessibility of lethal suicide methods might lead to lower suicide rate among older adults in South Korea.

PROGNOSTIC SIGNIFICANCE OF ABSENCE OF PROPER MUSCLE IN THE RESECTED SPECIMEN OF PRIMARY T1G3 BLADDER CANCER

Purpose: According to the presence of proper muscle in the resected specimens from primary T1G3 bladder tumors, we compared the prognosis and investigated factors that were predictive of disease progression during the follow-up and upstaging after radical cystectomy. Materials and Methods: We reviewed the records of 157 patients who were diagnosed with primary T1G3 bladder cancer for the assessment and comparison of disease recurrence, disease progression and patient survival. There were 101 and 56 patients with and without proper muscle in the their transurethral resection (TUR) specimens (T1G3 and T1xG3, respectively); 30 and 20 of these patients, respectively, had undergone immediate cystectomy. Results: Among the patients who were followed up after transurethral surgery, there were no differences in the survival between the two groups. For the patients treated by immediate cystectomy, the 5-year cancer-specific survival was 100% for the T1G3 patients at a mean follow-up of 54.5 months while it was 76.6% for the T1xG3 patients at a mean follow-up of 46.0 months (p=0.042). With the absence of radiologic findings suggestive of invasive bladder cancer, 55.6% of the T1xG3 patients were upstaged after radical cystectomy, whereas only 12.0% of the T1G3 patients were upstaged (p=0.002). Between the followed-up group and the cystectomy groups, more patients in the cystectomy group had non-papillary shaped bladder tumor (75.0% vs. 38.9%, respectively, p=0.010). Similarly, the T1xG3 patients who progressed during follow-up or who were upstaged after radical cystectomy had more non-papillary shaped tumor than the patients who were without progression or upstaging (80.1% vs. 38.5%, respectively, p=0.006). Conclusions: For primary T1G3 bladder cancer, non-papillary shaped tumor without proper muscle in the resected specimen is a risk factor for the progression during follow-up or upstaging after radical cystectomy that should warrant consideration for repeated resection or early cystectomy. (Korean J Urol 2006;47:137-142)