PARP Inhibitors in the Treatment of Prostate Cancer: From Scientific Rationale to Clinical Development.

Prostate cancer (PC) treatment has reached a milestone with the introduction of poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors (PARPi) induce breaks in single-stranded and/or double-stranded DNA, resulting in synthetic lethality in cancer cells lacking functional homologous recombination genes. Around 20% to 25% of patients with metastatic castration-resistant prostate cancer harbor mutations in DNA damage repair genes, either somatic or germline. The success of PARPi in these patients has prompted studies exploring its potential in tumors classified as "BRCAness," which refers to tumors without germline BRCA1 or BRCA2 mutations. Additionally, there is a proposed connection between androgen receptor signaling and synthetic lethality of PARPi. The inclusion of genetic mutation tests in the treatment algorithm for PC is a significant step towards precision and personalized medicine, marking a first in the field. The objectives of this review encompass understanding the mechanism of action of PARPi in both monotherapy and combination therapy, exploring patient selection criteria, discussing pivotal studies that led to its approval, and offering future prospects. However, numerous unanswered questions remain, including the identification of the patient population that could benefit most from PARPi, determining whether to use PARPi as monotherapy or in combination, and finding the optimal timing of PARPi administration in advanced or localized disease. To address these questions, several ongoing clinical trials are being conducted.

Approaches to Clinical Complete Response after Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer: Possibilities and Limitations.

In the surgical oncology field, the change from a past radical surgery to an organ preserving surgery is a big trend. In muscle-invasive bladder cancer treatment, neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for muscle-invasive bladder cancer (MIBC) patients eligible for cisplatin. There is a growing interest in bladder preserving strategies after NAC because good oncologic outcome has been reported for pathologic complete response (pCR) patients after NAC, and many studies have continued to discuss whether bladder preservation treatment is possible for these patients. However, in actual clinical practice, decision-making should be determined according to clinical staging and there is a gap that cannot be ignored between clinical complete response (cCR) and pCR. Currently, there is a lack in a uniform approach to post-NAC restaging of MIBC and a standardized cCR definition. In this review, we clarify the gap between cCR and pCR at the current situation and focus on emerging strategies in bladder preservation in selected patients with MIBC who achieve cCR following NAC.

Emerging agents for the treatment of metastatic urothelial cancer.

Over the past few decades, platinum-based combination chemotherapy (PBCC) has been the preferred initial therapy for metastatic urothelial cancer (mUC). However, despite a response rate of approximately 50%, a small proportion of patients with distant metastases may be cured by cisplatin-based combination chemotherapy (CBCC). In addition, up to 50% of patients are not eligible for CBCC due to age or comorbidities. Furthermore, adverse effects from PBCC are a major concern. The emergence of check-point inhibitors (CPIs), particularly those with antibodies directed against programmed cell death 1 protein (PD-1) or its ligand (PD-L1), advanced the treatment of mUC. Avelumab switch-maintenance therapy is recommended in patients with locally advanced or mUC who did not progress on initial PBCC. With the recent advances in tumor molecular biology and the discovery of actionable therapeutic targets, the clinical application of targeted therapy is now being explored for mUC. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown positive outcomes in patients with advanced UC with FGFR alterations. Another recent technological development is antibody-drug conjugates (ADCs), which are complex molecules composed of an antibody linked to a biologically active cytotoxic drug (payload) that targets and kills tumor cells while sparing healthy cells. Enfortumab vedotin, a monoclonal antibody targeting nectin-4 conjugated to monomethyl auristatin E, has demonstrated clinically significant efficacy in patients who do not respond to both cytotoxic chemotherapy and CPIs. In this review, we describe switch-maintenance therapies using CPI, various targeted agents, and ADCs that have been investigated for mUC treatment.

Lower Urinary Tract Symptoms in Prostate Cancer Patients Treated With Radiation Therapy: Past and Present.

The incidence of prostate cancer (PCa) is increasing concomitantly with population aging. Accordingly, interest in radiation therapy (RT) and the frequency of RT are also increasing. The types of RT can be broadly divided into external beam RT (EBRT), brachytherapy (BT), and combination therapy (EBRT+BT). Lower urinary tract symptoms (LUTS) after RT for the treatment of PCa are common; however, there are few reviews on the relationship between RT and LUTS. Herein, we review the causes and incidence of LUTS, as well as the evaluation and treatment options. Because of the reported risks of RT, patients undergoing RT should be counseled regarding the challenges of treatment and informed that they may have higher failure rates than nonirradiated patients. Moreover, thorough evaluation and treatment strategies are needed to support treatment recommendations. With a review of the existing literature, this narrative article provides an overview to aid urologists in treating patients presenting with complications associated with RT for the treatment of PCa. Further research is required to provide evidence of the effectiveness and feasibility of the management approach to the care of patients with LUTS after RT for the treatment of PCa.

Impact of Benign Prostatic Hyperplasia and/or Prostatitis on the Risk of Prostate Cancer in Korean Patients.

PURPOSE: We evaluated the impact of benign prostatic hyperplasia (BPH) and prostatitis on the risk of prostate cancer (PCa) in patients using nationally representative data of the Korean population from the National Health Insurance Service. MATERIALS AND METHODS: A total of 5,580,495 Korean men, aged >20 years, who had undergone health screening in 2009 were followed-up for 9 years until 2017. Multivariate adjusted Cox regression analysis was conducted to determine the hazard ratio (HR) and 95% confidence interval (CI) for the association between BPH and/or prostatitis and PCa. The HR for PCa according to the presence of BPH and/or prostatitis was stratified by a combination of BPH and prostatitis in multivariable-adjusted models. RESULTS: The HR for PCa significantly increased in patients with BPH and prostatitis than in patients without BPH and prostatitis (adjusted HR, 1.626; 95% CI, 1.567-1.688 and adjusted HR, 1.557; 95% CI, 1.500-1.618, respectively). In particular, for the combination of BPH and prostatitis, the adjusted HR was 1.856 (95% CI, 1.743-1.976), which was the highest when a diagnosis of both BPH and prostatitis was made. CONCLUSIONS: BPH and/or prostatitis are associated with an increased incidence for PCa in Korean patients, which is likely associated with similar effects to prostate-specific antigen (PSA) screening, so care must be taken in the interpretation. However, if follow-up survival studies demonstrate differences between the two groups (BPH and prostatitis vs. general), it could be one of the evidence for the introduction of PSA screening in Korea.

Docetaxel-resistant prostate cancer cells become sensitive to gemcitabine due to the upregulation of ABCB1.

BACKGROUND: Docetaxel is the preferred chemotherapeutic agent for hormone-refractory prostate cancer (PC) patients. However, patients eventually develop docetaxel resistance, and no effective treatment options are available for them. OBJECTIVE: We aimed to establish docetaxel resistance in castration-resistant prostate cancer (CRPC) cell lines (DU145/TXR, PC-3/TXR, and CWR22/TXR) and characterized transcriptional changes upon acquiring resistance to the docetaxel. METHODS: Human PC cells (DU145, PC-3, CWR22) and all docetaxel-resistant cells were maintained in Roswell Park Memorial Institute Medium (RPMI) 1640 media supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. ABCB1 was detected by using both parental and docetaxel-resistant CRPCs prepared for flow cytometry. For the evaluation of tumor-suppressive effects under each chemotherapeutic agent, subcutaneous xenografts of DU145 or DU145/TXR were implanted at the mouse flank. RESULTS: The P-glycoprotein-encoding gene ABCB1 was distinctively upregulated in the resistant cells, and its overexpression played an essential role in docetaxel resistance in CRPC. When tested for the cytotoxicity of gemcitabine, another option for chemotherapy, the docetaxel-resistant cells were shown to become sensitive to the drug, implying additional phenotypic transformation in the docetaxel-resistant cells. Studies using xenograft animal models demonstrated that the growth of tumors composed of both docetaxel-sensitive and docetaxel-resistant cells was deterred most profoundly when docetaxel and gemcitabine were administered together. CONCLUSION: This study suggests that when a drug develops therapeutic resistance, sensitivity tests could be another option, ultimately providing insight into a novel alternative clinical strategy.

Correlation Analyses of Computed Tomography and Magnetic Resonance Imaging for Calculation of Prostate Volume in Colorectal Cancer Patients with Voiding Problems Who Cannot Have Transrectal Ultrasonography.

OBJECTIVE: To evaluate the value of computed tomography (CT) and magnetic resonance imaging (MRI) in determining total prostate volume (TPV) for patients with colorectal cancer, as an alternative to transrectal ultrasonography (TRUS) of the prostate when TRUS is not an option. METHODS: We retrospectively evaluated the medical records of 122 male cancer patients who were referred to our urology department between 2014 and 2016 for voiding problems. They underwent colorectal surgery within 3 months; we estimated the correlations of the TPV measurements made using CT, MRI, and TRUS. A total of 122 TRUS, 88 MRI, and 34 CT images were reviewed repeatedly, twice by 2 independent urologists within 1 month after the initial evaluation. The correlations were statistically evaluated using a Bland-Altman plot and Spearman and Pearson correlation analyses. RESULTS: Overall median age was 70.5 years and the median TPV, as measured using TRUS, CT, and MRI, was 33.2, 43.4, and 30.1 mL, respectively. There was a good correlation in TPV measured with CT (coefficient >0.7) and MRI (>0.8). There was not a good correlation between TRUS and preoperative and postoperative CT/MRI; preoperative CT/MRI had a higher correlation (>0.7) than postoperative CT/MRI (>0.8). When stratified by prostate volume, preoperative CT (>0.58-0.59) correlated better for <30 mL and preoperative MRI (0.70-0.75) correlated better for ≥30 mL. CONCLUSIONS: The study showed that preoperative MRI had the best correlation with TRUS, especially in prostates ≥30 mL despite overestimations in CT and MRI measurements compared with TRUS.

Use of docetaxel plus androgen deprivation therapy for metastatic hormone-sensitive prostate cancer in Korean patients: A retrospective study.

Purpose: We aimed to evaluate the efficacy and safety of the use of docetaxel plus androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC) in Korean patients. Materials and Methods: This study was conducted retrospectively. In total, 61 Korean patients with mHSPC who used docetaxel plus ADT were identified from medical records. Patients received docetaxel plus ADT at a dose of 75 mg/m2 every 3 weeks for 6 cycles. We evaluated prostate-specific antigen (PSA) response, PSA progression, progression to castration-resistant prostate cancer (CRPC), clinical progression, and adverse events. Results: Most of the patients had high volume disease (98.3%) and 83.6% had a Gleason score of 8 or higher. The median PSA level at the start of ADT was 131.4 ng/mL. The percentage of patients whose PSA levels decreased to less than 0.2 ng/mL at 3, 6, and 12 months were 28.3%, 41.0%, and 45.0%, respectively. During a median of 12.0 months after treatment, PSA progression occurred in 13.3% of patients. Clinical progression and progression to CRPC were observed in 15.1% and 14.8%, respectively. Neutropenia grade ≥3 and febrile neutropenia occurred in 63.5% and 11.5%, respectively. Conclusions: Comparing our findings with those of the prior chemohormonal therapy versus androgen ablation randomized trial for extensive disease in prostate cancer (CHAARTED) study, in Korean patients, the use of docetaxel plus ADT for mHSPC showed similar results for early oncologic outcomes including PSA response and time to clinical progression. However, we observed a higher rate of adverse events, which should be considered seriously.

Single-Center Analysis of Human Papillomavirus Infection and P16INK4A Expression among Korean Patients with Penile Cancer.

PURPOSE: This study aimed to evaluate the statuses of P16INK4A expression and human papillomavirus (HPV) infection among patients with penile cancer at a single Korean institution. PATIENTS AND METHODS: Fourteen patients with penile cancer at our center were retrospectively identified and their clinicopathological data were analyzed. The patients' HPV and P16INK4A expression status (a known tumor suppressor protein) were tested using genotyping with a DNA chip assay and immunohistochemical staining, respectively. The results regarding HPV status were compared to those from another Asian study. RESULTS: The mean age at diagnosis was 60 years (range: 34-86 years). The median tumor size was 3.0 cm (range: 0.6-4.7 cm). Ten tumors were located on the penile glans. Five patients tested positive for HPV DNA (5/14, 36%) and all cases involved HPV type 16 (5/5, 100%). Positive expression of P16INK4A was observed in 6 cases (6/14, 43%). Among the HPV positive cases, 80% of cases (4/5) were also positive for P16INK4A. The prevalence of HPV infection in our study (36%) was higher than in a previous Asian study (23%). CONCLUSIONS: This is the first study to evaluate the prevalence of HPV infection and P16INK4A expression among patients with penile cancer at a single Korean institution. The prevalence of HPV (36%) was slightly higher than the results from a previous Asian study. Additional multi-center studies are needed to better understand penile cancer in Korea and to identify biomarkers that can determine high-risk cases and predict their prognosis.

The neutrophil-to-lymphocyte ratio makes the Heng risk model improve better the prediction of overall survival in metastatic renal cell cancer patients.

OBJECTIVE: The aim of this study was to predict the discriminating prognostic power of the neutrophil-to-lymphocyte ratio for overall survival in patients with metastatic renal cell carcinoma and to make a new model using the neutrophil-to-lymphocyte ratio. METHODS: From 2007 to 2014, 190 patients with metastatic renal cell carcinoma treated with either systemic immunotherapy or/and vascular endothelial growth factor-targeted therapy were enroled. A multivariable proportional hazard model was developed to investigate the effects of the neutrophil-to-lymphocyte ratio as predictive prognostic factors for overall survival. This new model was incorporated into the current Heng risk model to validate a modified prognostic classification for overall survival. RESULTS: In multivariable analysis, a high neutrophil-to-lymphocyte ratio [hazard ratio (HR) = 1.65] was a significant independent predictor of shorter overall survival (P = 0.005). Additional neutrophil-to-lymphocyte ratio markers improved the discriminating power of the Heng risk classification, as compared to the existing classification model (C-statistic: 0.7198 vs. 0.6943, P = 0.008). The reclassification of patient prognostic categories using the new model showed a total overall net improvement of 61.4% (P < 0.001). CONCLUSION: The neutrophil-to-lymphocyte ratio was a significant prognostic factor of overall survival in metastatic renal cell carcinoma patients treated with systemic therapy. Adding the neutrophil-to-lymphocyte ratio to the Heng model significantly improved the discriminatory power of risk prediction in metastatic renal cell carcinoma.

Risk of second primary Cancer among bladder Cancer patients: a population-based cohort study in Korea.

BACKGROUND: For the expanding population of bladder cancer survivors in Korea, the development of subsequent cancers is a significant concern. Here, we provide the second primary cancer incidence rates and types in Korean patients with bladder cancer. METHODS: Using population-based data from the Korea Central Cancer Registry from 1993 to 2013, we studied the standardized incidence ratios among 48,875 individuals with an initial diagnosis of bladder cancer. Standardized incidence ratios for second primary cancers were evaluated according to age at diagnosis, latency, diagnostic year, and treatment. RESULTS: Over the same period, the overall risk of a second primary cancer was reduced by 6% in patients with bladder cancer compared with the development of a new malignancy in the general population (standardized incidence ratio = 0.94; 95% CI, 0.91-0.97, p < 0.05). For specific cancers, the standardized incidence ratios for stomach, colon, liver, and non-Hodgkin lymphoma were significantly lower in patients with bladder cancer. However, the risk of prostate and kidney cancer in patients with bladder cancer were significantly increased. The risk of lung squamous cell carcinoma and lung adenocarcinoma as second primary cancers was significantly elevated in patients with bladder cancer. CONCLUSION: Korean patients with bladder cancer have a 6% lower risk of developing a second primary cancer. However, they have a higher risk of developing subsequent prostate and kidney cancers, lung squamous cell carcinoma, and lung adenocarcinoma, suggesting the need for continual intensive cancer surveillance among bladder cancer survivors.

Factors that Predict Neutropenia in Korean Patients with Advanced Urothelial Cancer after Cisplatin- Based Systemic Chemotherapy.

PURPOSE: The aim of this study was to identify factors that can be used to predict severe neutropenia (grade 3 or higher) in patients with advanced urothelial cancer after cisplatin-based systemic chemotherapy. MATERIALS AND METHODS: The study examined 79 Korean patients with advanced urothelial cancer who were treated with several cycles of cisplatin-based systemic chemotherapy from May 2006 to May 2015. Risk factors for neutropenia (grade 3 or higher) and for the occurrence of neutropenia (grade 3 or higher) during the first cycle of chemotherapy were examined. RESULT: Thirty-six out of the 79 patients (45.6%) developed neutropenia at grade 3 or higher during the first cycle of cisplatin-based systemic chemotherapy: 18 (22.7%) of these experienced grade 3 neutropenia and 18 (22.7%) experienced grade 4. Multivariate analysis identified pretreatment neutrophil counts (P = .001) as the only significant factor predictive for severe neutropenia. CONCLUSION: The pretreatment neutrophil count was found to be the factor that poses a significant and independent risk in development of severe neutropenia induced by applying cisplatin-based systemic chemotherapy to patients with advanced urothelial cancer.

Clear cell papillary renal cell carcinoma: A case report and review of the literature.

Clear cell papillary renal cell carcinoma (ccpRCC) was recently established as a distinct type of epithelial neoplasm by the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia. Here, we report a case of partial nephrectomy for a ccpRCC detected during the routine follow-up of a previously treated liposarcoma in a 70-year-old male patient. The patient was referred to the urology department for a right-sided renal mass (size: 2 cm) detected during routine annual imaging follow-up for a malignant right inguinal fibrous histocytoma and liposarcoma that had been diagnosed 6 and 4 years earlier, respectively, and treated with surgery and adjuvant radiation therapy. Following partial nephrectomy, the renal mass was pathologically diagnosed as ccpRCC, and immunohistochemistry revealed carbonic anhydrase 9 (CA9) expression. No recurrences or metastases were detected on follow-up imaging for 6 months. This is the first report of partial nephrectomy for incidentally discovered CA9-positive ccpRCC.

Second Primary Cancer Risk among Kidney Cancer Patients in Korea: A Population-Based Cohort Study.

PURPOSE: Secondary primary cancers (SPCs) commonly arise in patients with renal cell carcinoma (RCC). We designed the present study to estimate the SPC incidence in Korean patients with RCC. MATERIALS AND METHODS: The study cohort was population-based and consisted of 40,347 individuals from the Korean Central Cancer Registry who were diagnosed with primary renal cancer between 1993 and 2013. Standardized incidence ratios (SIRs) for SPCs were estimated for different ages at diagnosis, latencies, diagnostic periods, and treatments. RESULTS: For patients with primary RCC, the risk of developing a SPC was higher than the risk of developing cancer in the general population (SIR, 1.13; 95% confidence interval, 1.08 to 1.18). Most cancer types showed higher incidences in patients with RCC than in the general population. However, the relative incidence of gastric cancer as an SPC varied by age. Gastric cancer incidence was elevated in young patients (< 30 years) with RCC, but reduced in older (≥ 30) patients with RCC. Patients with advanced RCC died prematurely, regardless of SPC development. In contrast, those with early-stage RCC survived for longer periods, although SPC development affected their post-RCC survival. After SPC development, women had better survival than men. CONCLUSION: In Korean patients with primary RCC, the incidence of SPC was 13% higher than the incidence of cancer in the general population. These findings may play important roles in the conduct of follow-up evaluations and education for patients with RCC.

Hand-Holding during Cystoscopy Decreases Patient Anxiety, Pain, and Dissatisfaction: A Pilot Randomized Controlled Trial.

OBJECTIVE: Often a sick or an anxious person can experience pain or anxiety relief if another person holds his or her hand. In this study, we conducted investigations to determine whether hand-holding during cystoscopy decreases patient anxiety, pain, and dissatisfaction while at the same time increasing patient comfort and tolerance during the procedure. PATIENTS AND METHODS: Eighty-six male patients who underwent flexible cystoscopy between November 2015 and March 2017 were randomized as follows: hand-holding (group I, n = 43) or non-hand-holding (group II, n = 43) during the procedure. Before flexible cystoscopy, lidocaine gel was instilled in the urethra. Patients' anxiety levels were quantified using the State-Trait Anxiety Inventory. A visual analog scale (0-10) was used for self-assessment of satisfaction, discomfort, and willingness to undergo repeat cystoscopy. RESULTS: Demographic characteristics, mean age, procedure duration, procedure indications, and preprocedural analyses did not differ significantly between the 2 groups. In group I, the postprocedural mean anxiety level, pain score, heart rate, and systolic blood pressure were significantly lower compared with those in group II (p = 0.009, p = 0.003, p = 0.022, and p = 0.014, respectively). In group I, postprocedural mean satisfaction score were higher, and patients were more likely to undergo a repeat cystoscopy, compared with those in group II (p = 0.001 and p = 0.004, respectively). CONCLUSIONS: Hand-holding during cystoscopy significantly reduced patients' feelings of anxiety, pain, discomfort, and dissatisfaction. Hand-holding served as a simple, inexpensive, and effective adjunct to sedation during cystoscopy.

Lifestyle Risk Prediction Model for Prostate Cancer in a Korean Population.

PURPOSE: The use of prostate-specific antigen as a biomarker for prostate cancer (PC) has been controversial and is, therefore, not used by many countries in their national health screening programs. The biological characteristics of PC in East Asians including Koreans and Japanese are different from those in the Western populations. Potential lifestyle risk factors for PC were evaluated with the aim of developing a risk prediction model. MATERIALS AND METHODS: A total of 1,179,172 Korean men who were cancer free from 1996 to 1997, had taken a physical examination, and completed a lifestyle questionnaire, were enrolled in our study to predict their risk for PC for the next eight years, using the Cox proportional hazards model. The model's performance was evaluated using the C-statistic and Hosmer‒Lemeshow type chi-square statistics. RESULTS: The risk prediction model studied age, height, body mass index, glucose levels, family history of cancer, the frequency of meat consumption, alcohol consumption, smoking status, and physical activity, which were all significant risk factors in a univariate analysis. The model performed very well (C statistic, 0.887; 95% confidence interval, 0.879 to 0.895) and estimated an elevated PC risk in patients who did not consume alcohol or smoke, compared to heavy alcohol consumers (hazard ratio [HR], 0.78) and current smokers (HR, 0.73) (p < 0.001). CONCLUSION: This model can be used for identifying Korean and other East Asian men who are at a high risk for developing PC, as well as for cancer screening and developing preventive health strategies.