Effect of Adequate Local Radiation Dose on Oncological Outcomes in Localized Prostate Cancer Patients Treated With Low-dose-rate Brachytherapy.

BACKGROUND/AIM: We retrospectively investigated the effect of a biologically effective dose (BED) of Low-dose rate brachytherapy (LDR-BT) and its possible interaction with androgen deprivation therapy (ADT) during LDR-BT treatment for intermediate-risk prostate cancer (PCa). PATIENTS AND METHODS: A total of 693 patients with localized, intermediate-risk PCa, who underwent LDR-BT with or without supplemental external beam radiotherapy, were included in this study. We stratified patients into two groups according to BED (<180 Gy2, lower BED group; ≥180 Gy2, higher BED group) and evaluated the effect of ADT duration on the oncological outcomes of each group. RESULTS: In total, 431 patients received BED ≥180 Gy2. Significant differences in biochemical recurrence-free survival (BCRFS) and clinical progression-free survival (CPFS) were observed among the non-ADT, ADT ≤3 months, and ADT >3 months subgroups of the lower BED group (p=0.005 and 0.049, respectively). However, no significant differences in BCRFS or CPFS were detected in the higher BED group (p=0.63 and 0.76, respectively). Multivariate analysis of BCR and CP in the lower BED group revealed a significant decreasing trend in the BCRFS (p for trend=0.001) and CPFS rates (p for trend=0.015) as ADT duration increased, which was associated with favorable outcomes. However, no significant trend was observed in the BCRFS or CPFS rate in the higher BED group. CONCLUSION: An adequate local radiation dose provides favorable oncological outcomes and could potentially reduce the need for long-term ADT.

Docetaxel versus abiraterone for metastatic hormone-sensitive prostate cancer with focus on efficacy of sequential therapy.

PURPOSE: We aimed to assess the oncologic efficacy of combining docetaxel (DOC) versus abiraterone (ABI) with androgen deprivation therapy (ADT) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC), with a focus on the efficacy of sequential therapy, in a real-world clinical practice setting. METHODS: The records of 336 patients who harbored de novo high-risk mHSPC, based on the LATITUDE criteria, and had received ADT with either DOC (n = 109) or ABI (n = 227) were retrospectively analyzed. Overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), including time to castration-resistant prostate cancer (CRPC), time to 2nd-line progression (PFS2), and 2nd- and 3rd-line PFS, were compared. We used one-to-two propensity score matching to minimize the confounders. The differential efficacy of 2nd-line therapy based on agents in each arm was evaluated using the unmatched cohort as an additional interest. RESULTS: After propensity score matching, 86 patients treated with DOC + ADT and 172 with ABI + ADT were available for analyses. The 3-year OS and CSS for DOC versus ABI were 76.2% versus 75.1% (p = 0.8) and 78.2% versus 78.6% (p = 1), respectively. There was no difference in the median PFS2 (49 vs. 43 months, p = 0.39), while the median time to CRPC in patients treated with ABI was significantly longer compared to those treated with DOC (42 vs. 22 months; p = 0.006). The median 2nd-line PFS (14 vs. 4 months, p < 0.001) and 3rd-line PFS (4 vs. 2 months, p = 0.012) were significantly better in the DOC group than in the ABI group. Among the unmatched cohort, after ABI for mHSPC, the median 2nd-line PFS did not differ between the patients treated with DOC and those treated with enzalutamide as 2nd-line therapy (both 3 months, p = 0.8). CONCLUSIONS: ADT with DOC or ABI has comparable oncologic outcomes in terms of OS, CSS, and PFS2 in patients with de novo high-risk mHSPC. Compared to DOC, ABI resulted in longer time to CRPC but worse 2nd and 3rd-line PFS. Further studies are needed to clarify the optimal sequence of therapy in the upfront intensive treatment era.

Pagetoid spread of urothelial carcinoma controlled without resection.

Introduction: Extramammary Paget's disease is an eczematous skin condition that affects the vulva and perineum. Extramammary Paget's disease secondary to urothelial carcinoma is a rare condition that is typically treated with invasive surgical resection of the lesion. Case presentation: An 80-year-old woman with a 7-year history of urothelial carcinoma presented with erythema of the labia majora. Immunostaining of skin biopsy specimens suggested extramammary Paget's disease secondary to urothelial carcinoma. The patient did not consent to resection of the lesion. Nine cycles of first-line platinum-based chemotherapy for metastatic urothelial carcinoma were administered. As tumor cells remained after systemic chemotherapy, pembrolizumab will be administered to the patient for treating residual extramammary Paget's disease. Conclusion: Platinum-based chemotherapy can control extramammary Paget's disease secondary to urothelial carcinoma.

Combination of docetaxel versus nonsteroidal antiandrogen with androgen deprivation therapy for high-volume metastatic hormone-sensitive prostate cancer: a propensity score-matched analysis.

PURPOSE: The aim of this study was to investigate the oncologic efficacy of combining docetaxel with androgen deprivation therapy (ADT) versus nonsteroidal antiandrogen (NSAA) with ADT in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC) with focus on the effect of sequential therapy in a real-world clinical practice setting. METHODS: The records of 382 patients who harbored high-volume mHSPC, based on the CHAARTED criteria, and had received ADT with either docetaxel (n = 92) or NSAA (bicalutamide) (n = 290) were retrospectively analyzed. The cohorts were matched by one-to-one propensity scores based on patient demographics. Overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), including time to castration-resistant prostate cancer (CRPC), and time to second-line progression (PFS2) were compared. 2nd-line PFS defined as the time from CRPC diagnosis to progression after second-line therapy was also compared. RESULTS: After matching, a total of 170 patients were retained: 85 patients treated with docetaxel + ADT and 85 patients treated with NSAA + ADT. The median OS and CSS for docetaxel + ADT versus NSAA + ADT were not reached (NR) vs. 49 months (p = 0.02) and NR vs. 55 months (p = 0.02), respectively. Median time to CRPC and PFS2 in patients treated with docetaxel + ADT was significantly longer compared to those treated with NSAA (22 vs. 12 months; p = 0.003 and, NR vs. 28 months; p < 0.001, respectively). There was no significant difference in 2nd-line PFS between the two groups. CONCLUSIONS: Our analysis suggested that ADT with docetaxel significantly prolonged OS and CSS owing to a better time to CRPC and PFS2 in comparison to NSAA + ADT in high-volume mHSPC.

Does castration status affect docetaxel-related adverse events? :Identification of risk factors for docetaxel-related adverse events in metastatic prostate cancer.

BACKGROUND: Docetaxel-related adverse events (AEs) such as neutropenia and febrile neutropenia (FN) can be life-threatening. A previous in vivo study raised the hypothesis that the castration status affects the rate of hematologic AEs. We aimed to investigate the impact of castration status on the incidence of docetaxel-related AE in metastatic prostate cancer (mPCa) patients. METHODS: We retrospectively analyzed the records of 265 mPCa patients treated with docetaxel, comprising 92 patients with metastatic hormone-sensitive prostate cancer (mHSPC) and 173 patients with metastatic castration-resistant prostate cancer (mCRPC) between January 2015 and December 2021. Common terminology Criteria for Adverse Events (CTCAE) was applied to evaluate AEs. We analyzed the differential incidences between mHSPC and mCRPC, and risk factors of hematologic and nonhematologic AEs using a logistic regression model. RESULTS: The rate of patients who received primary prophylaxis against neutropenia was higher in those with the mHSPC compared with those with the mCRPC (7.5% vs. 33%, p < 0.001). Among the patients without primary prophylaxis, incidence rates of severe neutropenia (CTCAE ≥ Grade3) and FN were 89% and 16% in patients with mCRPC compared to 81% and 18% in those with mHSPC. Logistic regression analysis revealed that age ≥ 75 years and failure to provide primary prophylaxis were independent risk factors of severe neutropenia (odds ratio [OR]: 2.39, 95% confidential interval [CI]: 1.10-5.18 and OR: 15.8, 95% CI: 7.23-34.6, respectively). Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≧ 1 was an independent risk factor of FN (OR: 2.26, 95% CI: 1.13-4.54). Castration status (mHSPC vs. mCRPC) was not associated with the risks of severe neutropenia and FN. CONCLUSIONS: Castration status did not affect the risk of severe neutropenia or FN in mPCa patients treated with docetaxel regardless of the disease state. Failure to provide primary prophylaxis and advanced patient age are independent risk factors of severe neutropenia; while patients with poor PS are more likely to develop FN. These findings may help guide the clinical decision-making for proper candidate selection of docetaxel treatment.

Clinical benefit of continuing pembrolizumab treatment beyond progression in patients with metastatic urothelial carcinoma.

BACKGROUND: There has been no clinical evidence to justify continued pembrolizumab therapy beyond progression in patients with metastatic urothelial carcinoma (UC). MATERIALS AND METHODS: We conducted a multicenter retrospective study evaluating the clinical efficacy of continued use of pembrolizumab beyond progression in patients with metastatic UC. Data from 51 patients with metastatic UC, who developed progression during second-line pembrolizumab therapy, were analyzed. Progression was defined based on the Immunotherapy Response Evaluation Criteria in Solid Tumors. The outcome was overall survival (OS). The association between continued treatment, OS, and the risk of all-cause mortality was tested using log-rank test, conventional and time-dependent Cox regression models. RESULTS: No significant difference in patient characteristics was noted between patients continuing pembrolizumab beyond progression (N = 21) and those discontinuing pembrolizumab (N = 30). Median OS was significantly longer in the continuation group (17.8 vs. 8.8 months; P = 0.038). A multivariable conventional Cox regression model identified continued pembrolizumab administration as a significant independent prognostic factor of all-cause mortality (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.05-0.90, P = 0.036), irrespective of the time from treatment initiation to progression and concurrent clinical progression. Further, longer duration of pembrolizumab treatment beyond progression was independently associated with a reduced risk of all-cause mortality in a multivariable time-dependent Cox regression model, when used as a time-dependent variable (HR: 0.07, 95% CI: 0.01-0.45, P = 0.006). CONCLUSIONS: Continued pembrolizumab administration beyond progression might be beneficial in patients with metastatic UC who were clinically stable.

Abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer.

BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.

Clear identification of the rare solitary external iliac lymph node metastasis of testicular cancer by using indocyanine green fluorescence guidance.

INTRODUCTION: There are few reports on indocyanine green fluorescence-guided surgery in testis-related diseases. CASE PRESENTATION: A 38-year-old man underwent orchiectomy for left testicular cancer. Pathological diagnosis was pT1 seminoma. Seven years after the surgery, solitary left external iliac lymph node metastasis was suspected. We decided to perform laparoscopic lymph node dissection combined with indocyanine green fluorescence injection. During the operation, we injected indocyanine green fluorescence into his left inner inguinal ring and found that the lymph node was directly drained from the injection point. The pathological diagnosis of the indocyanine green fluorescence-positive left external iliac lymph node was testicular cancer metastasis. CONCLUSION: We experienced a case of solitary left external iliac lymph node recurrence in testicular cancer. Using indocyanine green fluorescence injection, we could visualize the lymphatic drainage route, which helped us identify the lymph node as the primary landing site of metastasis.

Impact of Dose-Effect in Smoking on the Effectiveness of Pembrolizumab in Patients with Metastatic Urothelial Carcinoma.

BACKGROUND: Subgroup analysis of KEYNOTE-045 suggested that cigarette smoking had a positive impact on the effectiveness of pembrolizumab in patients with advanced urothelial carcinoma (UC), whereas studies on other cancers treated with immune checkpoint inhibitors reported inconsistent results. OBJECTIVES: This study aimed to examine the association between smoking-related factors and the effectiveness of pembrolizumab in patients with metastatic UC. PATIENTS AND METHODS: This multicenter retrospective study was conducted using data from 95 patients with metastatic UC treated with pembrolizumab. The primary outcomes were progression and all-cause mortality. Time-to-event outcomes were compared with smoking history and lifetime smoking exposure at treatment initiation. Survival curves were compared using the log-rank test, with hazard ratios (HRs) estimated from Cox regression models. Cubic spline regression analysis was used to depict event hazards. RESULTS: We identified 32 (34.7%) patients with heavy smoking exposure (≥ 25 pack-years). Moreover, 19 (20.0%), 36 (37.9%), and 40 (42.1%) patients were current, former, and never smokers, respectively. Multivariable models showed that heavy smoking exposure was significantly associated with lower risk of progression (HR 0.58; 95% confidence interval (CI) 0.35-0.97; P = 0.047) and all-cause mortality (HR 0.30; 95% CI 0.11-0.82; P = 0.019). Cubic spline regression analyses revealed a dose-effect relationship. No significant association was observed between smoking history alone and effectiveness of pembrolizumab. CONCLUSIONS: Lifetime smoking exposure plays a significant role in the effectiveness of pembrolizumab in patients with metastatic UC.

Comparison of the Immunotherapy Response Evaluation Criteria in Solid Tumours (iRECIST) with RECIST for capturing treatment response of patients with metastatic urothelial carcinoma treated with pembrolizumab.

OBJECTIVE: To evaluate the clinical usefulness of Immunotherapy Response Evaluation Criteria in Solid Tumours (iRECIST) in patients with metastatic urothelial carcinoma (UC) treated with pembrolizumab. The iRECIST is designed to accurately capture the tumour response treated with immunotherapy. PATIENTS AND METHODS: We conducted a multicentre retrospective study evaluating the clinical utility of iRECIST in 91 patients with metastatic UC treated with second-line pembrolizumab. The objective response (OR) and time to progression (TTP) in accordance with both iRECIST and RECIST version 1.1 were compared with overall survival (OS) and risk of all-cause mortality, and analysed using log-rank and multivariable Cox regression models, respectively. Predictive performance of the criteria was studied using Harrell's concordance index (c-index). The clinical usefulness of each criterion was compared using decision curve analysis. RESULTS: Of 57 patients with progressive disease per RECIST, a considerable number of patients were reclassified to immune stable disease (six, 10.5%), immune partial response (two, 3.5%), and immune complete response (two, 3.5%) per iRECIST. Multivariable Cox regression models showed that both OR (hazard ratio [HR] 0.10, 95% confidence interval [CI] 0.03-0.35; P = 0.001) and TTP (HR 0.59, 95% CI 0.46-0.77; P < 0.001) per iRECIST were significantly associated with all-cause mortality. Furthermore, iRECIST had a significant, increased predictability of OS compared with RECIST (OR, c-index: 0.70, increase: 0.04, P = 0.046; TTP, c-index: 0.88, increase: 0.07, P = 0.039). On decision curve analysis, iRECIST presented better net benefit gains than did RECIST. CONCLUSIONS: Compared with RECIST, iRECIST could more accurately predict OS of patients with metastatic UC treated with pembrolizumab. The iRECIST has the potential to be a new standard for tumour response evaluation of these patients.

No survival benefit found after extended treatment with docetaxel for patients with castration-resistant prostate cancer.

BACKGROUND: Docetaxel (DOC) has been widely accepted as a therapeutic option for castration-resistant prostate cancer (CRPC). Evidence-based clinical guidelines have stipulated its use up to 10 cycles in most health care systems. There has been a paucity of information regarding potential benefits of its use over 10 cycles. The purpose of this study is to re-examine the rationale for the clinical guidelines concerning cycles of DOC in CRPC. METHODS: Between July 2007 and July 2016, a total of 122 CRPC patients received at least five cycles of DOC at Jikei University and its affiliate hospitals. Doses of DOC (75 mg/m 2 ) were administered every 3 to 4 weeks. Clinical outcomes between patients receiving extended cycles of DOC (≥11 cycles, extended [ex]-DOC group) were compared to those receiving fewer (≤10 cycles, short-DOC group). A subgroup of patients who had discontinued DOC owing to adverse events, but whose disease did not progress, were also considered for comparison (adverse events [AE] group). Overall survival from the induction of DOC was the primary outcome measure. Univariate and multivariate analyses were conducted to analyze variables associated with overall survival. RESULTS: The ex- and short-DOC groups included 80 and 42 patients, respectively. Most baseline demographics did not differ between groups. However, in the short-DOC group more patients had received abiraterone acetate and/or enzalutamide before chemotherapy, age at DOC induction was younger, and lactate dehydrogenase at DOC induction was higher. Overall survival was significantly longer in the ex-DOC group compared to the short-DOC group (median, 53 and 27 months, respectively; P = .04). A subgroup of 22 patients in AE group was compared to compensate for potential bias. Overall survival from the induction of DOC was comparable between AE group and ex-DOC groups (median, 53 vs 53 months, respectively; P = 0.87). Univariate and multivariate analyses did not show any advantage of extended use of DOC on patient survival. CONCLUSIONS: The results of this study failed to show the survival benefit of extended use of DOC over 10 cycles in CRPC patients in the era of innovative drugs such as abiraterone acetate, enzalutamide, and cabazitaxel. Further prospective studies are required to confirm our findings.