GnRH antagonist monotherapy versus a GnRH agonist plus bicalutamide for advanced hormone-sensitive prostate cancer; KYUCOG-1401.

OBJECTIVES: To compare the effectiveness and safety of gonadotropin-releasing hormone (GnRH) antagonist monotherapy to combined androgen blockade (CAB) with a GnRH agonist and bicalutamide in patients with advanced hormone-sensitive prostate cancer (HSPC). METHODS: The study was conducted as KYUCOG-1401 trial (UMIN000014243) and enrolled 200 patients who were randomly assigned to either group A (GnRH antagonist monotherapy followed by the addition of bicalutamide) or group B (CAB by a GnRH agonist and bicalutamide). The primary endpoint was PSA progression-free survival. The secondary endpoints were the time to CAB treatment failure, radiographic progression-free survival, overall survival, changes in serum parameters, including PSA, hormones, and bone and lipid metabolic markers, and adverse events. RESULTS: PSA progression-free survival was significantly longer in group B (hazard ratio [HR], 95% confidence interval [CI]; 1.40, 1.01-1.95, p = 0.041). The time to CAB treatment failure was slightly longer in group A (HR, 95% CI; 0.80, 0.59-1.08, p = 0.146). No significant differences were observed in radiographic progression-free survival or overall survival. The percentage of patients with serum testosterone that did not reach the castration level was higher at 60 weeks (p = 0.046) in group A. No significant differences were noted in the serum levels of bone metabolic or lipid markers between the two groups. An injection site reaction was more frequent in group A. CONCLUSIONS: The present results support the potential of CAB using a GnRH agonist and bicalutamide as a more effective treatment for advanced HSPC than GnRH antagonist monotherapy.

Bone-modifying agents are protective for symptomatic skeletal events in Radium-223 treatment.

INTRODUCTION: Radium-223 (Ra-223) dichloride therapy increases overall survival and delays time to the first symptomatic skeletal event (SSE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Bone-modifying agents (BMA) reduce SSE in patients with bone metastasis, but there is little information on their use with Ra-223. This study aimed to investigate the effect of BMA on SSE in patients with bone metastatic CRPC treated with Ra-223 in real-world practice. METHODS: We included 73 patients treated with Ra-223 from 10 institutions in Japan. Time to the first SSE was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. We used univariate analysis to ascertain the association between variables and SSE. RESULTS: During a median follow-up of 12.7 months (interquartile range, 7-21.7), 12 (16.4%) patients presented SSE. Age and BMA use were different between men with and without SSE. The 1-year SSE-free survival rate from Ra-223 treatment initiation was 82.4% (95% CI, 69.4%-90.2%). BMA use was associated with favorable SSE-free survival (hazard risk, 0.23; 95% confidence interval, 0.061-0.85; p = 0.027). Two (4.7%) and seven (23.3%) patients presented symptomatic pathological bone fracture in groups with and without BMA use, respectively (p = 0.017). CONCLUSION: This study stresses the importance of BMA use in patients with CRPC and bone metastases in Ra-223 treatment.

Effectiveness and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and bone metastases in real-world practice: A multi-institutional study.

OBJECTIVE: Radium-223 (Ra-223) dichloride is the bone-targeted radioligand therapy that prolongs overall survival (OS) in patients with bone-metastatic castration-resistant prostate cancer (CRPC). We aimed to evaluate the safety and effectiveness of this treatment in real-world practice. METHODS: We included Japanese men treated with Ra-223 for bone-metastatic CRPC from 10 institutions, retrospectively. Primary endpoint was OS. Secondary endpoint was maximum decline of alkaline phosphatase (ALP), lactate dehydrogenase, and prostate-specific antigen values, the rate of adverse events, and time to pathological fracture after Ra-223 treatment. Exploratory endpoint was the associations between clinical parameters and OS. RESULTS: In total, 73 men with bone metastatic CRPC treated with Ra-223 were enrolled. The median OS was 20.9 months. ALP levels decreased significantly from pre-treatment (p = 0.03). Anemia occurred in three (4.1%) patients. Grade ≥ 3 non-pathological fractures occurred in four (5.5%) men. Nine (12.3%) patients presented pathological fracture; 7/30 (23.3%) were in men without concomitant use of a bone-modifying agent (BMA) while 2/43 (4.7%) were in patients with concomitant BMA (p = 0.03). The median OS in patients with ≥3 cycles treatment (27.2 months, p < 0.001) or hemoglobin ≥12 g/dl (27.2 months, p = 0.001) or absence of bone pain (36.3 months, p = 0.004) was significantly longer compared to those who with ≤2 cycles or hemoglobin<12 g/dl or presence of bone paint, respectively. CONCLUSIONS: This study has shown the outcomes of Ra-223 treatment in real-world practice, where the number of treatment cycles, baseline anemia and bone pain may be useful to predict OS in Ra-223 treatment.

Optimal Timing of Switching from Platinum-based Chemotherapy to Pembrolizumab for Advanced Urothelial Carcinoma Based on Real-world Data: A Multi-institutional Retrospective Study.

BACKGROUND/AIM: The optimal timing of switching from platinum-based chemotherapy to pembrolizumab in patients with advanced urothelial carcinoma (UC) remains unclear. PATIENTS AND METHODS: Thirty-four patients who received pembrolizumab as second-line treatment after first-line platinum-based chemotherapy were retrospectively evaluated. RESULTS: According to overall survival (OS) from pembrolizumab, there was a significant difference between ≤4 and >4 prior chemotherapy cycles (7.0 and 25.5 months, p=0.034), but not between ≤6 and >6 cycles (11.3 and 6.6 months, p=0.658). According to the Cox proportional hazards regression model, the number of chemotherapy cycles was not correlated with better OS in pembrolizumab-treated patients. According to the OS from the first-line treatment, there was a significant difference between ≤4 and >4 prior chemotherapy cycles (17.3 and 37.1 months, p<0.001), but not between ≤6 and >6 cycles (18.6 and 27.3 months, p=0.276). CONCLUSION: The optimal timing of switching from platinum-base chemotherapy to pembrolizumab in advanced UC is around six cycles.

Ureterosciatic hernia successfully treated by ureteral stent placement.

A 76-year-old woman with history of cholecystectomy, hysterectomy, and vesicourethral suspension presented with acute lumbar backache and discomfort in the lower abdomen and severe nausea, with frequent vomiting, but without any associated fever. Physical examination revealed knocking tenderness at the left costal-vertebral angle. The patient's serum white blood cell count was 14,900/mm(3) and the results of other laboratory tests, including urinalysis, were normal. Non-enhanced computed tomography revealed left hydroureteronephrosis and obstruction of the distal left ureter with herniation into the sciatic foramen. A left ureteral stent was inserted with a double-J stent. The stent was removed after 2 months and thereafter the patient did not experience any recurrence.

Paclitaxel and carboplatin chemotherapy after platinum-based chemotherapy and pembrolizumab for metastatic urothelial carcinoma.

Pembrolizumab has been available for the treatment of radical resectable urothelial carcinoma (UC) when it is exacerbated after chemotherapy since December 2017 in Japan. However, the efficacy of chemotherapy for cases progressing after pembrolizumab is unclear. The present study compared the outcomes and toxicities in patients with metastatic UC after failure of platinum-based chemotherapy and pembrolizumab, who were selected to receive paclitaxel and carboplatin (TC) chemotherapy, with those in patients who received the best supportive care (BSC). A total of 36 patients received pembrolizumab for metastatic UC at four institutions between January 2018 and August 2019. Of the 21 patients who progressed after pembrolizumab, 7 received TC chemotherapy (TC group) and 14 selected BSC (BSC group). The median observation period was 4.1 months. The 7 aforementioned patients who received TC chemotherapy (4 male and 3 female; median age, 62 years; range, 57-79 years) were analyzed in the present study. The ECOG performance status was 0 in three patients, 1 in one patient, 2 in two patients and 3 in one patient. Two patients had upper urinary tract UC, two had bladder UC and three had both types of UC. Six patients had visceral metastasis. The number of chemotherapy regimens before pembrolizumab was one in four patients, two in two patients and three in one patient. The objective response rate was 28.6% (partial response, 2 patients; stable disease, 4 patients; progressive disease, 1 patient), the median progression-free survival time was 3.4 months and the median overall survival time was 10.9 months (vs. 2.7 months in BSC group; P=0.0156). Although grade ≥3 adverse events developed in five patients, there were no treatment-associated deaths. The present results suggested that TC chemotherapy may be a preferred option for patients who require aggressive treatment after the failure of platinum-based chemotherapy and pembrolizumab.

Clinical Outcomes of Mixed Response to Pembrolizumab in Advanced Urothelial Carcinoma After Platinum-based Chemotherapy.

BACKGROUND/AIM: Despite the presence of a mixed response (MR) in patients with urothelial carcinoma (UC) who receive immune checkpoint inhibitors, the clinical outcome of these patient has not been reported. We evaluated the clinical outcome of MR to pembrolizumab for advanced UC. PATIENTS AND METHODS: Advanced UC patients who received pembrolizumab after platinum-based chemotherapy failure with measurable disease in multiple organs were retrospectively analyzed. RESULTS: Among 31 patients, MR [including progressive disease (PD)+complete response (CR) or partial response (PR)] was confirmed in 4 (12.9%). The median overall survival (OS) of the CR+PR (including CR+SD±PR), stable disease (SD), PD (including PD±SD) and MR groups was 16.0, 5.1, 5.4 and 4.3 months, respectively. There was no significant difference in the OS between the MR and CR+PR response groups (log-rank test, p=0.069). CONCLUSION: A mixed response to pembrolizumab in advanced UC was not uncommon. Despite the non-significant difference in the OS between the mixed and CR+PR response groups, the OS of the MR group tended to be similar to that of the SD and PD response groups.

Organ-Specific Tumor Response to Pembrolizumab in Advanced Urothelial Carcinoma After Platinum-Based Chemotherapy.

BACKGROUND: To evaluate the organ-specific therapeutic effect of pembrolizumab after the failure of platinum-based chemotherapy for advanced urothelial carcinoma (UC). MATERIALS AND METHODS: Patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy and who had measurable disease were retrospectively analyzed. The objective response rate (ORR) and organ-specific response rate (OSRR) were evaluated according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: We analyzed 69 patients (male, n=51; median age, 71 years) with 226 metastases. The ORR was 23.2%. In total, 32, 31, 16, 14, 13 and 7 patients had measurable lung (OSSR 31.3%), lymph node (OSSR 29.0%), local recurrence (OSSR 12.5%), primary tumor organ (OSSR 7.1%), liver (OSSR 23.1%) and bone (OSSR 28.6%) disease, respectively. The median overall survival (OS) for pembrolizumab was 10.9 months (95% confidence interval, 5.9­13.7 months). Regarding organ-specific OS, a Log rank test significant differences in OS were confirmed between patients with and without primary tumor organ disease (p=0.046) and liver metastasis (p<0.001). CONCLUSION: Metastases and primary tumor organ disease showed different tumor responses to pembrolizumab. The most prominent tumor response was found in lung metastasis and the least response was found in primary organ sites. The mechanisms of these different responses were unclear and there does not appear to be a constant trend between tumor shrinkage and OS in tumor sites. Further studies are needed.

The Risk Factors of Febrile Urinary Tract Infection After Ureterorenoscopic Lithotripsy.

We aimed to evaluate the risk factors for febrile urinary tract infection (fUTI) following ureterorenoscopic lithotripsy (URSL) for upper urinary tract stones. We retrospectively reviewed the data of 109 patients with upper urinary tract stones who underwent URSL at our hospital from October 2016 to March 2019. We divided the patients into two groups: those who developed fUTI after URSL (fUTI group) and those who did not (non-fUTI group). The retrospectively collected data, including age, sex, body mass index (BMI), mobility, diabetes mellitus, operative duration, preoperative ureteral stent placement, number of stones, stone diameter, CT value of stone, stone location, preoperative UTI, preoperative urine culture, preoperative pyelonephritis, and stone-free status were compared between the two groups. Postoperative fUTI occurred in three of the 109 patients (2.8%). Comparing the two groups, a significant risk factor for developing fUTI after URSL was a low BMI. However, in our study, only three cases developed fUTI after URSL; thus, a multivariate analysis could not be performed. One of the three cases in which fUTI occurred was accompanied by anorexia nervosa and an extremely low BMI of 11 kg/m². In summary, even though we had only 3 fUTI patients and did not perform multivariate analysis, our data suggested a significant risk factor for developing fUTI was a low BMI. Increasing the sample size, and further study seem desirable.

Treating Japanese Patients With Pembrolizumab for Platinum-Refractory Advanced Urothelial Carcinoma in Real-World Clinical Practice.

BACKGROUND: Since December 2017, pembrolizumab has been approved in Japan as a second-line treatment for radical unresectable urothelial carcinoma (UC) that has become exacerbated after chemotherapy by the international randomized phase 3 trial, KEYNOTE-045. The aim of this study was to evaluate the oncological efficacy and safety of pembrolizumab after failure of platinum-based chemotherapy in Japanese patients with advanced UC in real-world clinical practice. METHODS: A total of 34 patients who received pembrolizumab after the failure of platinum-based chemotherapy for advanced urothelial carcinoma at four institutions between January 2018 and August 2019 were retrospectively evaluated. In all patients, UC was histopathologically diagnosed, and disease progression after platinum-based chemotherapy was radiologically confirmed. RESULTS: The median follow-up period was 7.7 months. The objective response rate, median progression-free survival, and median overall survival were 20.6%, 3.3 months, and 11.7 months, respectively. Regarding the toxicities associated with pembrolizumab, adverse events (AEs) of any grade occurred in 61.8%, and grade 3 AEs occurred in 23.5%; grade ≥ 4 AEs did not occur in any patients. Univariate analyses revealed that the Eastern Cooperative Oncology Group Performance Status, neutrophil/lymphocyte ratio, liver metastases, and time from previous chemotherapy were prognostic variables. Multivariate analyses revealed that liver metastases (positive: hazard ratio, 4.23; 95% confidence interval, 1.48 - 12.08; P < 0.01) and time from previous chemotherapy (≥ 3 months: hazard ratio, 5.06; 95% confidence interval, 1.43 - 17.91; P = 0.01) were independent prognostic factors. CONCLUSIONS: In this real-world clinical study, these findings concerning the efficacy and safety of pembrolizumab for advanced UC in Japanese patients were comparable to those of the open-label, international, phase 3 trial KEYNOTE-045. Liver metastases and time from previous chemotherapy were independent prognostic factors in the present study.