Effect of a variant histology on the oncological outcomes of Japanese patients with upper tract urothelial carcinomas after radical nephroureterectomy: a multicenter retrospective study.

Background: An earlier systematic review and meta-analysis found that patients with a certain histological variant of upper tract urothelial carcinoma (UTUC) exhibited more advanced disease and poorer survival than those with pure UTUC. A difference in the clinicopathological UTUC characteristics of Caucasian and Japanese patients has been reported, but few studies have investigated the clinical impact of the variant histology in Japanese UTUC patients. Methods: We retrospectively enrolled 824 Japanese patients with pTa-4N0-1M0 UTUCs who underwent radical nephroureterectomy without neoadjuvant chemotherapy. Subsequently, we explored the effects of the variant histology on disease aggressiveness and the oncological outcomes. We used Cox's proportional hazards models to identify significant predictors of oncological outcomes, specifically intravesical recurrence-free survival (IVRFS), recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: Of the 824 UTUC patients, 32 (3.9%) exhibited a variant histology that correlated significantly with a higher pathological T stage and lymphovascular invasion (LVI). Univariate analysis revealed that the variant histology was an independent risk factor for suboptimal RFS, CSS, and OS. However, significance was lost on multivariate analyses. Conclusions: The variant histology does not add to the prognostic information imparted by the pathological findings after radical nephroureterectomy, particularly in Japanese UTUC patients.

Prognostic factors for overall survival in clinical node-positive patients with upper tract urothelial carcinoma.

BACKGROUND: There is sparse evidence regarding optimal management and prognosticators for oncologic outcomes in patients with clinical node-positive (cN+) upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively analyzed the data from 105 UTUC patients with cN1-2M0 between June 2010 and June 2022 at multiple institutions affiliated with our university. At the time of diagnosis, all patients received standard-of-care treatment including radical nephroureterectomy (RNU), chemotherapy, and/or palliative care. We employed a Cox regression model to analyze the prognostic importance of various factors on overall survival (OS). RESULTS: Of 105 patients, 54 (51%) underwent RNU, while 51 (49%) did not. RNU was likely to be selected in patients with younger and higher G8 score, resulting in better median OS in patients who underwent RNU than in those who did not (42 months vs. 15 months, p < 0.001). Multivariable analysis among the entire cohort revealed that low G8 score (≤14) (hazard ratio [HR]: 2.07, 95% confidence interval [CI]: 1.08-3.99), elevated pretreatment C-reactive protein (CRP) (HR: 3.35, 95%CI: 1.63-6.90), and failure to perform RNU (HR: 2.16, 95%CI: 1.06-4.42) were independent prognostic factors for worse OS. In the subgroup analyses of cohorts who did not undergo RNU, elevated pretreatment CRP was the only independent prognostic factor for worse OS in cN+ UTUC patients. CONCLUSIONS: RNU seems to be a reasonable treatment option in cN+ UTUC patients where applicable. Elevated pretreatment CRP appears to be a reliable prognosticator of worse OS and may be helpful in optimizing candidate selection for intensified treatment in this setting.

Prognostic significance of subclassifying pathological T3 upper tract urothelial carcinoma: Results from a multicenter cohort study.

OBJECTIVE: The population with pathological T3 (pT3) upper tract urothelial carcinoma (UTUC) is heterogeneous, thereby making prognostication challenging. We assessed the clinical ramifications of subclassifying pT3 UTUC after nephroureterectomy. METHODS: We conducted a retrospective analysis including 308 patients who underwent nephroureterectomy for pT3N0-1M0 UTUC. pT3 was subclassified into pT3a and pT3b based on invasion of the peripelvic and/or periureteral fat. Cox's proportional hazard models were utilized to determine the significant prognosticators of oncological outcomes, encompassing intravesical recurrence-free survival, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival. RESULTS: Multivariate analysis elucidated that pT3b status, pathological N1 status, and lymphovascular invasion status were independent risk factors for an unfavorable RFS and CSS. Although the RFS and CSS of patients with pT3b UTUC were superior to those in patients with pT4 UTUC, no significant disparities were detected between patients with pT3a and pT2. CONCLUSION: Our findings demonstrate that pT3 UTUC with peripelvic/periureteral fat invasion is independently associated with metastasis and cancer-specific death after nephroureterectomy. These findings provide patients and physicians with invaluable insight into the risk for disease progression in pT3 UTUC patients.

Real-world outcomes of adjuvant immunotherapy candidates with upper tract urothelial carcinoma: results of a multicenter cohort study.

BACKGROUND: Recent clinical trials have reported improved disease-free survival rates of patients with stage pT3-4/ypT2-4 or pN + upper tract urothelial carcinoma (UTUC) on adjuvant nivolumab therapy. However, the appropriateness of the patient selection criteria used in clinical practice remains uncertain. METHODS: We retrospectively analyzed 895 patients who underwent nephroureterectomy to treat UTUC. The patients were divided into two groups: grade pT3-4 and/or pN + without neoadjuvant chemotherapy (NAC) or grade ypT2-4 and/or ypN + on NAC (adjuvant immunotherapy candidates) and others (not candidates for adjuvant immunotherapy). Kaplan-Meier curves were drawn to assess the oncological outcomes, including recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Cox proportional hazards models were used to identify significant prognostic factors for oncological outcomes. RESULTS: The Kaplan-Meier curves revealed notably inferior RFS, CSS, and OS of patients who were candidates for adjuvant immunotherapy. Multivariate analysis revealed that pathological T and N grade and lymphovascular invasion (LVI) status were independent risk factors for poor RFS, CSS, and OS. CONCLUSION: In total, 44.8% of patients were candidates for adjuvant immunotherapy. In addition to pathological T and N status, LVI was a significant predictor of survival, and may thus play a pivotal role in the selection of patients eligible for adjuvant immunotherapy.

Comparison of neoadjuvant and adjuvant chemotherapy for upper tract urothelial carcinoma in real-world practice: a multicenter retrospective study.

BACKGROUND: Multiple studies have demonstrated the effectiveness of neoadjuvant chemotherapy and adjuvant chemotherapy in patients with upper tract urothelial carcinoma compared with surgery alone. However, no clinical trial has established the superiority of neoadjuvant chemotherapy or adjuvant chemotherapy in terms of perioperative outcomes. METHODS: We conducted a retrospective analysis encompassing 164 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy and received perioperative chemotherapy. Of these patients, 65 (39.6%) and 99 (60.4%) received neoadjuvant chemotherapy and adjuvant chemotherapy, respectively. Recurrence-free survival and cancer-specific survival were computed using the Kaplan-Meier method. Additionally, we conducted Cox regression analyses to evaluate the risk factors for recurrence-free survival and cancer-specific survival. RESULTS: Pathological downstaging was seen in 37% of the neoadjuvant chemotherapy group. However, no pathological complete response was observed in this cohort. The Kaplan-Meier curves demonstrated significantly lower recurrence-free survival and cancer-specific survival in patients who received adjuvant chemotherapy. Multivariate Cox regression analysis revealed patients treated with adjuvant chemotherapy exhibited a marked association with inferior recurrence-free survival and cancer-specific survival. CONCLUSION: Our study has suggested that neoadjuvant chemotherapy would be more effective in high-risk upper tract urothelial carcinoma patients compared with adjuvant chemotherapy.

En Bloc Resection Versus Conventional TURBT for T1HG Bladder Cancer: A Propensity Score-Matched Analysis.

BACKGROUND: We aimed to assess the clinical, oncological, and pathological impact of en bloc resection of bladder tumors (ERBT) compared with conventional transurethral resection of bladder tumors (cTURBT) for pT1 high-grade (HG) bladder cancer. PATIENTS AND METHODS: We retrospectively analyzed the record of 326 patients (cTURBT: n = 216, ERBT: n = 110) diagnosed with pT1 HG bladder cancer at multiple institutions. The cohorts were matched by one-to-one propensity scores based on patient and tumor demographics. Recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and perioperative and pathologic outcomes were compared. The prognosticators of RFS and PFS were analyzed using the Cox proportional hazard model. RESULTS: After matching, 202 patients (cTURBT: n = 101, ERBT: n = 101) were retained. There were no differences in perioperative outcomes between the two procedures. The 3-year RFS, PFS, and CSS were not different between the two procedures (p = 0.7, 1, and 0.7, respectively). Among patients who underwent repeat transurethral resection (reTUR), the rate of any residue on reTUR was significantly lower in the ERBT group (cTURBT: 36% versus ERBT: 15%, p = 0.029). Adequate sampling of muscularis propria (83% versus 93%, p = 0.029) and diagnostic rates of pT1a/b substaging (90% versus 100%, p < 0.001) were significantly better in ERBT specimen compared with cTURBT specimen. On multivariable analyses, pT1a/b substaging was a prognosticator of disease progression. CONCLUSIONS: In patients with pT1HG bladder cancer, ERBT had similar perioperative and mid-term oncologic outcomes compared with cTURBT. However, ERBT improves the quality of resection and specimen, yielding less residue on reTUR and yielding superior histopathologic information such as substaging.

Comparison of Quality of Life and Injection Site Reactions After Switching from Degarelix 80 mg to 480 mg in Advanced Prostate Cancer: A Prospective Trial.

BACKGROUND/AIM: Degarelix has been widely used for prostate cancer; however, injection site reactions (ISRs) can be a clinical issue. We assessed differences in ISR intensity and patient quality of life (QOL) between degarelix 80 mg and 480 mg, a three-month formulation launched in 2020 in Japan. PATIENTS AND METHODS: We prospectively analyzed 25 patients with advanced prostate cancer. ISR intensity and patient QOL were evaluated before and after switching from degarelix 80 mg to 480 mg. A visual analogue scale (VAS) and faces rating scale (FRS) were applied to assess the ISRs. We applied a rating format from the M. D. Anderson Symptom Inventory (MDASI) to assess patient QOL. RESULTS: For degarelix 80 mg and a first dose of 480 mg, the incidence rate of ISRs was 84% and 92%, respectively (p=0.083). ISR pain on the third day after injection scored by VAS was 2.7±2.8 and 5.2±2.7, respectively (p<0.001). Other ISR findings such as redness, induration, swelling, warmth, and itching were significantly worse for degarelix 480 mg than for 80 mg. In the category of patient QOL, interference with activities of daily living such as general activity was significantly worse after degarelix 480 mg (p=0.003). However, 80% of patients were able to continue degarelix 480 mg during the nine months of follow-up. CONCLUSION: Degarelix 480 mg seems to exacerbate pain and other ISR findings, and to reduce patient QOL, compared with degarelix 80 mg. Optimal management of ISRs is essential to maintain patient QOL when using degarelix 480 mg.

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.

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.

Clinical Significance of Horizontal and Vertical Margin of En Bloc Resection for Nonmuscle Invasive Bladder Cancer.

PURPOSE: The primary advantage of en bloc resection of bladder tumors is to provide better diagnostic accuracy. However, the clinical significance of horizontal and vertical margin has not been demonstrated. We evaluated the clinical importance of surgical margins in patients who underwent en bloc resection of bladder tumors. MATERIALS AND METHODS: We retrospectively analyzed the records of 140 consecutive patients who underwent en bloc resection of bladder tumors for nonmuscle invasive bladder cancer. We analyzed perioperative and oncological outcome, and compared patient demographics and recurrence-free survival for horizontal findings. The relationship between surgical margin and second transurethral resection outcome in pT1 bladder cancer was also analyzed. RESULTS: Mean tumor diameter was 17.2±9.8 mm. Pathological stages were 93 cases in pTa and 47 cases in pT1. Diagnostic rates for the horizontal and vertical margins were 63% and 99%, respectively. The rates of sessile, carcinoma in situ, high grade, and pT1 tumors were significantly higher in the horizontal margin positive group (41) than in the negative group (47). There was no significant difference in 2-year recurrence-free survival based on horizontal margin findings (negative: 72.4%, positive: 75.4%, p=0.87). A second transurethral resection was performed in 31 of the 47 pT1 patients; pT1 residue was seen only in vertical margin positive cases, and 5 pTa/pTis residues at the transurethral resection scar were seen in 15 horizontal margin positive patients. CONCLUSIONS: Horizontal margin positive findings were not associated with recurrence-free survival, but careful assessment is warranted regarding residue at the original site. A second transurethral resection should be considered in patients with horizontal and vertical margin positive pT1 bladder cancer.

Values of alkaline phosphatase at the diagnosis of castration resistance and response to primary androgen deprivation therapy as predictors of subsequent metastasis in non-metastatic castration-resistant prostate cancer.

PURPOSE: Among various therapeutic options available for metastatic castration-resistant prostate cancer (mCRPC), only apalutamide and enzalutamide have shown evidences of improved metastasis-free survival (MFS) for non-metastatic castration-resistant prostate cancer (nmCRPC). However, there is a paucity of evidence to indicate who may be targeted for aggressive therapy among patients with nmCRPC. The objectives of this retrospective study were to explore predictors of metastasis in patients with nmCRPC and to identify a subpopulation of patients with nmCRPC who may benefit from aggressive therapy. METHODS: A total of 115 patients with CRPC who had no metastasis detected at the time of diagnosis of CRPC were included in this retrospective study. All patients were treated at Jikei University and its affiliated hospitals. The primary outcome measure was MFS from the time of diagnosis of CRPC. Predictors of MFS were also explored with a multivariate Cox hazard model. RESULTS: The median observation period after diagnosis of CRPC was 30 months (range 2-143 months). Kaplan-Meier analysis revealed a median MFS of 76. Multivariate analysis demonstrated that low alkaline phosphatase (ALP) values at diagnosis of CRPC and favorable response to primary androgen deprivation therapy (ADT) were significant predictors of longer MFS (P = 0.011, and 0.031, respectively). CONCLUSIONS: Results of this study suggest that high ALP values at diagnosis of CRPC and poor response to primary ADT may predict the propensity of metastasis in patients with nmCRPC. Further prospective studies will be required enrolling more patients to confirm our findings.

Earlier use of androgen receptor-axis-targeted drugs may improve overall survival in patients with non-metastatic castration-resistant prostate cancer.

BACKGROUND: To evaluate the role of androgen receptor-axis-targeted drugs (ARAT) in non-metastatic castration-resistant prostate cancer (nmCRPC) versus mCRPC. METHODS: Chemotherapy-naive patients (n = 114) with CRPC who had no metastasis at the time of diagnosis were included in this retrospective study. All patients were treated with ARAT at Jikei University and its affiliated hospitals from July 2014 to March 2017. The patients were stratified into nmCRPC (n = 81) and mCRPC (n = 33) groups according to their metastatic status at ARAT induction. The primary outcome measure was difference in overall survival (OS) between groups from the time of CRPC diagnosis. The patients were compared for progression-free survival (PFS) and prostate-specific antigen (PSA) response. The predictors of OS were explored by a multivariate Cox model. RESULTS: The baseline demographics did not differ significantly between the groups. The median observation period from the diagnosis of CRPC was 24.5 months (range: 3-135) and 20 months (range: 1-66) in nmCRPC and mCRPC groups, respectively. The nmCRPC group demonstrated better OS from the time of diagnosis of CRPC in Kaplan-Meier analysis than mCRPC group (86 months vs 40 months; P = 0.004), with similar results obtained for PFS (P = 0.048) and PSA response (P = 0.0014). Multivariate analysis demonstrated non-metastatic status, low PSA, and long PSA doubling time (PSADT) at ARAT induction as the significant predictors of longer OS (P = 0.044, 0.0001, and 0.026, respectively). CONCLUSIONS: Early use of ARAT may improve OS, PFS, and PSA response in CRPC. Larger, prospective studies will be required to confirm our findings.

[SALVAGE CRYOABLATION TARGETING RECURRENT LESIONS AFTER DEFINITIVE RADIOTHERAPY FOR PROSTATE CANCER: IMPACT OF POST CRYOABLATION CHANGE IN URINARY AND SEXUAL FUNCTION].

(Purpose) To describe our initial experience in salvage cryoablation targeting recurrent lesions after definitive irradiation for prostate cancer. (Methods) Eligible patients for this treatment were those who developed biochemical failure after definitive radiotherapy for localized prostate cancer, but without distant metastasis, and with solid lesions identifiable on multiparametric magnetic resonance imaging (mpMRI). Histological proof of recurrence with mapping biopsy covering corresponding sites was obtained. Two to four cryoprobes were inserted transperineally into the prostate under general anesthesia with extensive lithotomy position. The rapid expansion of argon gas cryogen through a small opening within the cryoprobe cools itself to make an ice ball and the quick exchange to helium gas induces an active thawing phase. Entire procedure is monitored and guided with the use of transrectal ultrasonography. Postoperative follow-up included patient interview, digital rectal examination, prostate specific antigen (PSA) testing and quality of life (QOL) monitoring using IPSS and IIEF-5 at 1, 3, 6 and 12 months postoperatively. Changes of mpMRI findings with time, particularly at one month, were used to judge immediate treatment impact. (Results) Five patients underwent salvage cryoablation between October 2015 and September 2016. No grade 3/4 complications such as rectal fistula or urethral stenosis were experienced. Mean and maximal percent decline of PSA from baseline levels at 1, 3, 6 and 12 months following cryoablation were 72.2 and 94.7%, 79.4% and 93.9%, 78.2% and 92.1%, 79.6% and 90.9%, respectively. Posttreatment IPSS showed temporary worsening with average changes in score of 1.8, 1.5, 1.6, and 1.0 times over baseline levels, respectively. IPSS score returned to the baseline in one at six months and two at 12 months. Two of 5 patients were sexually active prior to therapy and thus evaluable. Both showed significant decline in IIEF score by 95% at 12 months. No patients showed any signs of recurrence. mpMRI at one month following cryoablation confirmed complete disappearance of visible lesions in all cases. (Conclusions) Salvage cryoablation for recurrent lesions of prostate cancer after definitive radiotherapy is feasible with minimal morbidity. Both oncological outcome and adverse events should be monitored carefully with longer follow up.