Trimodality Therapy With Iodine-125 Brachytherapy, External Beam Radiation Therapy, and Short- or Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer: Results of a Multicenter, Randomized Phase 3 Trial (TRIP/TRIGU0907).

PURPOSE: This phase 3 randomized investigation was designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiation therapy (EBRT) for localized high-risk prostate cancer. METHODS AND MATERIALS: This study was conducted at 37 hospitals on men aged 40 to 79 years, with stage T2c-3a, prostate-specific antigen >20 ng/mL, or Gleason score >7, who received 6 months of ADT combined with iodine-125 brachytherapy followed by EBRT. After stratification, patients were randomly assigned to either no further treatment (short arm) or 24 months of adjuvant ADT (long arm). According to the Phoenix definition of failure, the primary endpoint was the cumulative incidence of biochemical progression. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific mortality, overall survival, and grade 3+ adverse events. An intention-to-treat analysis was conducted using survival estimates determined using competing risk analyses. RESULTS: Of 332 patients, 165 and 167 were randomly assigned to the short and long arms, respectively. The median follow-up period was 9.2 years. The cumulative incidence of biochemical progression at 7 years was 9.0% (95% CI, 5.5-14.5) and 8.0% (4.7-13.5) in the short and long arms, respectively (P = .65). The outcomes of secondary endpoints did not differ significantly between the arms. Incidence rates of endocrine- and radiation-related grade 3+ adverse events for the short versus long arms were 0.6 versus 1.8% (P = .62) and 1.2 versus 0.6% (P = .62), respectively. CONCLUSIONS: Both treatment arms showed similar efficacy among selected populations with high-risk features. The toxicity of the trimodal therapy was acceptable. The present investigation, designed as a superiority trial, failed to demonstrate that 30-month ADT yielded better biochemical control than 6-month ADT when combined with brachytherapy and EBRT. Therefore, a noninferiority study is warranted to obtain further evidence supporting these preliminary results.

Secondary bladder cancer during long-term follow-up after iodine-125 permanent seed implantation for localized prostate cancer.

INTRODUCTION: Brachytherapy for prostate cancer treatment may induce secondary bladder cancer during long-term follow-ups. This study reviews the risk and tumor characteristics of secondary bladder cancer after brachytherapy. METHODS: This single-institution retrospective study included 1162 patients treated with low-dose-rate permanent seed implantation brachytherapy with iodine-125, with or without external beam radiation therapy, for localized prostate cancer. We calculated and compared the rates of secondary bladder cancer among patients treated with brachytherapy and radical prostatectomy (n = 218) before and after a propensity score-matching analysis. Possible risk factors for secondary bladder cancer, such as patient age and external beam radiation therapy administration, were analyzed. RESULTS: Of 1162 patients with a median follow-up period of 11.4 (range: 0.7-15.5) years, 26 presented with urothelial carcinomas and 1 with adenocarcinoma at a median of 8.9 (range: 2.9-14.0) years after brachytherapy, although the incidence rates of secondary bladder cancer after brachytherapy were not significantly different from those after radical prostatectomy. No significant risk factors for secondary bladder cancer were identified. The initial symptoms of secondary bladder cancer were gross hematuria (74%) and microscopic hematuria with positive urine cytology (15%). Among 26 cases of secondary urothelial carcinoma, 54% were high-grade and 46% were invasive. After brachytherapy, invasive urothelial carcinoma occurred later than noninvasive urothelial carcinoma (p = 0.01). CONCLUSIONS: Considering the aggressive malignancy of secondary bladder cancer, cystoscopy and urine cytology should be performed for further investigation of the causes of gross or microscopic hematuria and rule out secondary bladder cancer in cases followed longer than 3 years after brachytherapy.

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial.

BACKGROUND: Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. RESULTS: In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11-0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. CONCLUSIONS: Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

Comparison of prostate verification with implanted gold markers in tissue surrounding the prostate and pelvic bony anatomy for external beam radiation therapy following low-dose-rate brachytherapy: a prospective clinical trial.

We aimed to investigate whether gold marker implantation in the tissue surrounding the prostate could accurately monitor setup errors during external beam radiation therapy (EBRT) following low-dose-rate (LDR) brachytherapy. Thirty-eight patients had confirmed intermediate- or high-risk prostate cancer and received EBRT following LDR brachytherapy. In >175 computed tomography imaging sessions, the average values of the weekly setup error during EBRT to the prostate centroid at the time of gold marker matching in the surrounding tissue of the prostate and pelvic bone matching were measured and then compared using the Wilcoxon signed-rank test. Gold marker matching in the surrounding tissue of the prostate estimated setup errors better than those estimated by bone matching (3D displacement = 2.7 ± 2.0 vs 3.8 ± 2.6 mm, P < 0.01). Overall, the standard deviation of systematic (Σ) and random (σ) setup error was lower with gold marker matching than with bone matching (3D displacement = 1.8 and 1.1 mm vs 2.1 and 1.6 mm, respectively). With gold marker matching, the setup error of the position of the prostate centroid was smaller, and the optimal setup margin was lower than that with bone matching (2Σ + 0.7σ and 2.5Σ + 0.7σ of 3D displacement = 4.3 and 5.2 mm vs 5.3 and 6.4 mm, respectively). This high-precision radiotherapy approach placing gold markers in the surrounding tissue of the prostate can allow more accurate setup during EBRT following LDR brachytherapy.

Sub-classification of patients with intermediate-risk metastatic renal cell carcinoma treated with targeted therapy.

BACKGROUND: International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. METHODS: We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. RESULTS: Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. CONCLUSIONS: We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.

Impact of inflammatory marker levels one month after the first-line targeted therapy initiation on progression-free survival prediction in patients with metastatic clear cell renal cell carcinoma.

OBJECTIVES: Progression-free survival of first-line targeted therapy greatly influences the survival of patients with metastatic renal cell carcinoma. We evaluated whether post-treatment inflammatory markers and lactate dehydrogenase levels had impacts on progression-free survival prediction in addition to those of conventional predictors. METHODS: Two hundred and fifteen patients whose tumors were clear cell type and in whom first-line targeted therapies could be continued for >1 month were evaluated. Pretreatment clinical factors, pathological factors and laboratory data 1 month after targeted therapy initiation-including inflammatory markers (neutrophil count, neutrophil-to-lymphocyte ratio and C-reactive protein) and lactate dehydrogenase-were reviewed. To identify progression-free survival predictors, multivariate analyses were done. RESULTS: The 1-year progression-free survival rate was 47%. Female gender, Karnofsky performance status <80%, time from diagnosis to systemic treatment <12 months, pretreatment C-reactive protein >3.0 mg/dl and post-treatment neutrophil-to-lymphocyte ratio >3.0 were independent predictors for progression-free survival. In contrast, neither C-reactive protein increase nor neutrophil-to-lymphocyte ratio increase after targeted therapy initiation were independent predictors. Pretreatment lactate dehydrogenase, post-treatment lactate dehydrogenase and lactate dehydrogenase decline were not independent predictors. When all patients were stratified by these independent factors into three groups (0 risk vs. 1 or 2 risks vs. 3 or more risks), there were significant differences in progression-free survival rates between the groups (P < 0.0001). Furthermore, there were also significant differences in overall survival rates between the groups (P < 0.0001). CONCLUSIONS: Integration of post-treatment neutrophil-to-lymphocyte ratio value with pretreatment factors may lead to the establishment of effective predictive model for disease progression in patients with metastatic clear cell renal cell carcinoma who received first-line targeted therapies.

Plan reproducibility of intraoperatively custom-built linked seeds compared to loose seeds for prostate brachytherapy.

PURPOSE: Few studies have compared the implant quality of linked and loose seeds for prostate brachytherapy. This study aimed to evaluate and compare plan reproducibility of intraoperatively built custom linked seeds and loose seeds for prostate brachytherapy. MATERIAL AND METHODS: Between December 2010 and March 2014, 76 localized prostate cancer patients received Iodine-125 brachytherapy with external beam radiotherapy. Linked and loose seeds were implanted in 39 and 37 patients, respectively. The primary endpoint was the mean (± standard deviation) of the absolute change in the minimum dose received by 90% of the prostate volume between intraoperative and post-operative planning (ΔD90) to confirm plan reproducibility. Comparisons between the groups were evaluated using 2-sample t tests. RESULTS: The ΔD90 values were 6.95 ± 11.6% and -0.41 ± 8.5% for the loose and linked seed groups, respectively (p < 0.01). The linked seed group showed decreased post-operative D90 (118.8% vs. 127.2%), V150 (51.7% vs. 66.7%), and RV100 (0.44 ml vs. 0.61 ml) compared to the loose seed group (p < 0.01), whereas lung migration tended to be reduced (0% vs. 8%). CONCLUSIONS: The plan reproducibility of the linked seed group was better than that of the loose seed group. Moreover, the linked seed group showed less migration and lower rectal dose.

Prostate-specific antigen nadir within 12 months as an early surrogate marker of biochemical failure and distant metastasis after low-dose-rate brachytherapy or external beam radiotherapy for localized prostate cancer.

Prostate-specific antigen nadir (nPSA) after radiotherapy for localized prostate cancer has been investigated as a predictor. However, nPSA usually requires several years, limiting its clinical utility. We investigated the significance of nPSA within 12 months (nPSA12) after low-dose-rate prostate brachytherapy (LDR-PB) or external beam radiotherapy (EBRT) on treatment outcomes. Between 2006 and 2014, 663 patients with prostate cancer were treated with LDR-PB or EBRT at two institutions. Four hundred and seventy-four men received LDR-PB and 189 men received EBRT, without androgen deprivation therapy. The Kaplan-Meier method was used for biochemical failure (BF)-free survival (BFFS) and distant metastasis (DM)-free survival (DMFS) analyses, and multivariable Cox regression analysis was performed. The median follow-up was 61.3 months. The median nPSA12 in the LDR-PB and EBRT cohorts was 0.7 and 1.0 ng/mL, respectively. The 7-year BFFS and DMFS rates in LDR-PB patients with nPSA12 ≤ 0.7 ng/mL were 99.1% and 99.5%, respectively; when nPSA12 was >0.7 ng/mL, they were 90.2% and 94.8%, respectively. In EBRT patients with nPSA12 ≤ 1.0 ng/mL, BFFS and DMFS rates were 85.4% and 98.5%, respectively; when nPSA12 was >1.0 ng/mL, they were 67.1% and 87.2%, respectively. nPSA12 was an independent predictor of BF and DM in both cohorts (LDR-PB, P = 0.004 and 0.020, respectively; EBRT, P = 0.005 and 0.041, respectively). The nPSA12 after LDR-PB or EBRT is significantly associated with treatment outcomes of prostate cancer. Higher nPSA12 may identify patients at high risk of relapse who might benefit from salvage treatment.

Significance of a frozen section analysis of the ureteral margin in bladder cancer patients treated with radical cystectomy and neoadjuvant chemotherapy.

Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.

Quantitative analysis of genitourinary toxicity after iodine-125 brachytherapy for localized prostate cancer: Followup of the International Prostate Symptom Score and Overactive Bladder Symptom Score.

PURPOSE: To analyze genitourinary toxicity by followup of the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS) after prostate brachytherapy. METHODS AND MATERIALS: Six hundred eighty patients were treated with iodine-125 brachytherapy for localized prostate cancer. IPSS, OABSS, and two categories of IPSS questions (storage symptom score [IPSS-S] and voiding symptom score [IPSS-V]) were evaluated. RESULTS: The median followup was 54 months (range, 24-108). All scales showed rapid increases followed by gradual decreases. The median times to IPSS peak and resolution were 1 and 6 months, respectively. The resolution rates of IPSS, IPSS-S, IPSS-V, and OABSS at the last followup were 84.2%, 86.3%, 89.5%, and 83.0%, respectively. The difference between IPSS baseline and peak was greater for larger preimplant prostate volumes (≥25 mL, p = 0.004). The time to resolution was longer for higher biologic effective dose (BED) (≥210 Gy, p = 0.019 [IPSS]), in those with larger prostate volumes (≥25 mL, p = 0.025 [OABSS]), in younger patients (younger than 70 years, p = 0.043 [IPSS-S]), and in those with androgen deprivation therapy (ADT) use (p = 0.049 [IPSS-V]). Urge incontinence, included in the OABSS, was observed more commonly in older patients (75 years and older, p = 0.018), with ADT use (p < 0.001), and for higher BED (≥210 Gy, p = 0.006). CONCLUSIONS: The IPSS and OABSS showed similar patterns of change. Urinary symptoms improved more rapidly in those with high baseline IPSS levels. The OABSS was useful for following urinary symptoms after prostate brachytherapy. Age, ADT use, preimplant prostate volume, and BED were significantly associated with urinary outcomes.

Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy: A proposal of the modified-IMDC risk model.

PURPOSE: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model has been designed for prognostification in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy. One factor is neutrophil count; however, increasing evidence has suggested the superiority of neutrophil-to-lymphocyte ratio (NLR) for predicting outcome. In this study, we evaluate the prognostic effect of NLR levels on patients with mRCC treated with targeted therapy, and then we compare the predictive accuracy of the IMDC risk model and its modified one by using NLR, instead of neutrophil count. PATIENTS AND METHOD: A total of 277 patients are included for the analysis. All patients underwent targeted therapies and associated outcome are assessed using multivariate analysis. RESULTS: Pretreatment NLR levels are elevated in 30.3% and 23.1% of patients in the first-line and subsequent second-line setting, respectively. Kaplan-Meier curves reveal that elevated pretreatment NLR is significantly associated with poor overall survival (OS) since first-line (P<0.001) and second-line targeted therapy administration (P<0.001). Also, multivariate analyses show that elevated pretreatment NLR is an independent predictor for poor OS since first-line and second-line targeted therapy administration. The addition of NLR to the IMDC risk model, instead of neutrophil count, significantly improves the predictive accuracy for OS, and estimated gain is 1.7% and 6.2% in first-line and second-line targeted therapy, respectively. CONCLUSION: Changes in NLR levels could be predictive for prognosis in patients with mRCC treated with first-line and second-line targeted therapy. The addition of NLR significantly improves the predictive accuracy of the IMDC risk model in the first-line and subsequent second-line setting.

Effect of reclassification of the IMDC model in patients with metastatic renal cell carcinoma treated with targeted therapy in the first-line and second-line settings.

PURPOSE: To investigate the prognostic effect of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model reclassification after targeted therapy administration in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHOD: A total of 245 mRCC patients treated with targeted therapy are included. The IMDC model reclassification is performed at 1 month after treatment induction of both first-line and second-line targeted therapy. RESULTS: Of the 245 patients, 74 (30.2%) are divided into different risk groups by the IMDC model reclassification after first-line targeted therapy, and patients newly classified with intermediate risk tend to have better overall survival than those remaining in the primary poor-risk group (P = 0.018). Of the 119 patients treated with subsequent second-line targeted therapy, 25 (21.0%) are divided into different risk groups by the IMDC model reclassification after second-line targeted therapy, and patients newly classified with poor risk tend to have increased all-cause mortality compared with those remaining in the primary intermediate-risk group (P = 0.007), whereas patients newly classified with intermediate risk tend to have better overall survival than those remaining in the primary poor-risk group (P = 0.034). CONCLUSION: Approximately a quarter of the mRCC patients are classified into different risk groups of the IMDC model following targeted therapy administration in the first-line and second-line settings. There is a significant difference in overall survival of subgroups after the IMDC model reclassifications.

Impact of Second-Line Targeted Therapy Dose Intensity on Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Relative dose intensity (RDI) is a simple index for evaluation of the amount of drug administered per unit time. We retrospectively investigated the prognostic impact of RDI for patients with metastatic renal cell carcinoma (mRCC) treated with second-line targeted therapy. METHODS: We enrolled 168 patients with mRCC. We assessed RDI at 4 weeks after second-line targeted therapy induction. RESULTS: The median follow-up after second-line targeted therapy was 18.1 months. The median time-to-treatment-failure (TTF) and overall survival (OS) were 4.9 and 25.4 months, respectively. In the Kaplan-Meier analysis, the median OS of patients with second-line RDI < 0.7 was significantly shorter than those with RDI ≥ 0.7 (12.1 vs. 31.3 months; P = .030). In the subgroup analysis, second-line RDI was definitely prognostic in the poor-risk group of the International Metastatic Renal Cell Carcinoma Database Consortium criteria, showing second-line RDI was an independent predictor for both TTF (hazard ratio [HR], 3.6; 95% confidence interval [CI], 1.6-8.0; P = .002) and OS (HR, 3.1; 95% CI, 1.1-8.4; P = .026). Also, assessing the type of second-line regimen, the multivariate analysis showed that second-line RDI was an independent prognostic indicator of TTF (HR, 1.7; 95% CI, 1.0-2.9; P = .040) and OS (HR, 2.7; 95% CI, 1.3-5.7; P = .009) in patients treated with everolimus. In this group, the median TTF and OS of patients with RDI < 0.7 were 2.4 and 11.1 months, and those with RDI ≥ 0.7 were 5.3 and 25.9 months, respectively. CONCLUSION: The results suggest that second-line RDI may be a prognostic predictor for patients with mRCC treated with second-line targeted therapy, particularly in both the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and everolimus-treated group.

Multi-institutional retrospective analysis of learning curves on dosimetry and operation time before and after introduction of intraoperatively built custom-linked seeds in prostate brachytherapy.

This multi-institutional retrospective analysis examined learning curves for dosimetric parameters and operation time after introduction of intraoperatively built custom-linked (IBCL) seeds. Data from consecutive patients treated with seed implantation before and after introduction of IBCL seeds (loose seed, n = 428; IBCL seed, n = 426) were collected from 13 centers. Dose-volume histogram parameters, operation times, and seed migration rates were compared before and after introduction of IBCL seeds. At the 1-month CT analysis, no significant differences were seen in dose to 90% of prostate volume between before and after IBCL seed introduction. No learning curve for dosimetry was seen. Prostate and rectal volume receiving at least 150% of prescription dose (V150 and RV150) were higher in the loose-seed group than in the IBCL-seed group. Operation time was extended by up to 10 min when IBCL seeds were used, although there was a short learning curve of about five patients. The percentage of patients with seed migration in the IBCL-seed group was one-tenth that in the loose-seed group. Our study revealed no dosimetric demerits, no learning curve for dosimetry, and a slightly extended operation time for IBCL seeds. A significant reduction in the rate of seed migration was identified in the IBCL-seed group.

External Validation of the MSKCC and IMDC Risk Models in Patients Treated with Targeted Therapy as a First-line and Subsequent Second-line Treatment: A Japanese Multi-institutional Study.

BACKGROUND: Two risk models, the Memorial Sloan Kettering Cancer Center (MSKCC) model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, have been studied in metastatic renal cell carcinoma (mRCC) treated with targeted therapy. OBJECTIVE: To validate externally the predictive accuracies of the MSKCC and IMDC models for prognosis in mRCC patients treated with first-line and subsequent second-line targeted therapy. DESIGN, SETTING, AND PARTICIPANTS: A total of 311 patients were assessed retrospectively. INTERVENTION: All patients underwent targeted therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival outcomes were assessed using Kaplan-Meier analysis. The predictive ability was evaluated using the c-index. RESULTS AND LIMITATIONS: Regarding to the first-line targeted therapy, the 3-yr overall survival (OS) rates of the MSKCC (p<0.001) and IMDC models (p<0.001) were 76.2% and 77.3%, respectively, in the favorable-risk group; 46.7% and 47.9%, respectively, in the intermediate-risk group; and 13.4% and 15.6%, respectively, in the poor-risk group. The c-indexes were 0.68 for the MSKCC model and 0.69 for the IMDC model in a first-line setting. Regarding the second-line targeted therapy, the 1-yr OS rates of the MSKCC (p<0.001) and IMDC models (p<0.001) were 80.9% and 90.5%, respectively, in the favorable-risk group; 71.4% and 70.6%, respectively, in the intermediate-risk group; and 31.7% and 24.6%, respectively, in the poor-risk group. The c-indexes were 0.66 for the MSKCC model and 0.65 for the IMDC model in the second-line setting. The study is limited by its retrospective nature. CONCLUSIONS: The results may assist physicians in providing more appropriate patient counseling and imply the need for a future prognostic tool in mRCC treated with targeted therapy. PATIENT SUMMARY: Both risk models were useful for the risk stratification in metastatic renal cell carcinoma (mRCC) patients treated with first-line and second-line targeted therapy; however, it might be necessary to further update or optimize the models for our Japanese cohort of mRCC patients.

Comparison of genitourinary and gastrointestinal toxicity among four radiotherapy modalities for prostate cancer: Conventional radiotherapy, intensity-modulated radiotherapy, and permanent iodine-125 implantation with or without external beam radiotherapy.

PURPOSE: To compare late genitourinary (GU) and gastrointestinal (GI) toxicity following different prostate cancer treatment modalities. MATERIALS AND METHODS: This study included 1084 consecutive prostate cancer patients treated with conventional radiotherapy, intensity-modulated radiotherapy (IMRT), permanent iodine-125 implantation (PI) alone, and PI combined with external beam radiotherapy (PI+EBRT). The effects of treatment- and patient-related factors on late grade ⩾ 2 (G2+) GU/GI toxicity risk were assessed. RESULTS: The median follow-up was 43 months (range, 12-97 months). Compared to the PI+EBRT, there was significantly less G2+ GU toxicity in the conventional radiotherapy (hazard ratio [HR] = 0.39; 95% CI, 0.20-0.77) and the IMRT (HR=0.45, 95% CI, 0.27-0.73). Compared to the PI+EBRT, there was significantly more G2+ GI toxicity in the IMRT (HR = 2.38; 95% CI, 1.16-4.87). In PI-related groups, prostate equivalent dose in 2 Gy fractions was a significant predictor of G2+ GU toxicity (p = 0.001), and the rectal volume receiving more than 100% of the prescribed dose was a significant predictor of G2+ GI toxicity (p = 0.001). CONCLUSION: The differences in the late G2+ GU/GI risk cannot be explained by the differences in treatment modalities themselves, but by the total radiation dose to the GU/GI tract, which had a causal role in the development of late G2+ GU/GI toxicity across all treatment modality groups.

Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high risk patients with upper tract urothelial carcinoma: a Japanese multi-institution experience.

PURPOSE: Current guidelines do not yet provide any recommendations for adjuvant chemotherapy in patients with upper tract urothelial carcinoma managed with radical nephroureterectomy. We evaluated whether an adjuvant chemotherapeutic regimen would affect the clinical outcome in patients with high risk upper tract urothelial carcinoma. MATERIALS AND METHODS: We identified 873 patients who had undergone radical nephrouretectomy for localized upper tract urothelial carcinoma at 14 Japanese institutions between 1993 and 2011. We assessed whether the type of regimen, such as methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and cisplatin, in an adjuvant setting, could affect the subsequent clinical outcome of patients with upper tract urothelial carcinoma. RESULTS: On multivariate analysis pathological T stage, tumor grade, lymphovascular invasion and lymph node involvement were prognostic factors for recurrence-free survival and cancer specific survival. We defined 229 patients with 3 or more of these factors as the high risk group. In an analysis according to adjuvant regimen, Kaplan-Meier curves showed that the 1 and 2-year recurrence-free survival rates in the methotrexate, vinblastine, doxorubicin and cisplatin treated group were 71.4% and 47.9%, which were significantly higher than in the gemcitabine and cisplatin treated group (48.2% and not reached, p=0.022) or those not treated with adjuvant chemotherapy (53.4% and 39.6%, p=0.039). Similar results were observed in terms of cancer specific survival. CONCLUSIONS: Our study showed that pT3-4, tumor grade 3, positive lymphovascular invasion and lymph node involvement were independent risk factors for disease mortality in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. In the high risk group methotrexate, vinblastine, doxorubicin and cisplatin adjuvant chemotherapy contributed to improve subsequent mortality compared to gemcitabine and cisplatin or no adjuvant chemotherapy.

A multi-institutional validation of the prognostic value of the neutrophil-to-lymphocyte ratio for upper tract urothelial carcinoma treated with radical nephroureterectomy.

BACKGROUND: To externally validate the prognostic impact of preoperative neutrophil-lymphocyte ratio (pre-NLR) in patients with upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU). METHODS: A total of 665 patients from 12 institutions were included. The median follow-up was 28 months. Associations between pre-NLR level and outcome were assessed using multivariate analysis. A pre-NLR level of >3.0 was defined as elevated. RESULTS: Pre-NLR levels were elevated in 184 patients (27.7 %), and pre-NLR elevation was significantly associated with worse pathological features such as tumor grade 3, advanced pT stage, positive lymphovascular invasion (LVI), and lymph node involvement in RNU specimens. The 5-year recurrence-free and cancer-specific survival rates were 57.0 % (p < 0.001) and 60.2 % (p < 0.001), respectively, in patients with elevated pre-NLR, and 69.2 and 77.3 %, respectively, in their counterparts. Multivariate analysis showed that elevated pre-NLR was an independent risk factor for predicting subsequent disease recurrence (p = 0.037; hazard ratio (HR) 1.38) and cancer-specific mortality (p = 0.036;, HR 1.47), although the addition of pre-NLR slightly improved the accuracies of the base model for predicting both disease recurrence and cancer-specific mortality to 79.8 % (p = 0.041) and 83.0 % (p = 0.039), respectively (gain in predictive accuracy: 0.2 and 0.1 %, respectively). CONCLUSION: This multi-institutional study revealed that elevated pre-NLR was significantly associated with worse pathological features such as tumor grade 3, advanced pT stage, positive LVI, and lymph node involvement in RNU specimens, and elevated pre-NLR was an independent risk factor of disease recurrence and cancer-specific mortality in UTUC patients treated with RNU.

Independent predictors for bladder outcomes after treatment of intravesical recurrence following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma.

BACKGROUND: Few studies have described the clinical courses and outcomes in the bladder after treatment of intravesical recurrence after radical nephroureterectomy (RNU) in patients with primary upper tract urothelial carcinoma (UTUC). We investigated the indicators for predicting subsequent bladder outcomes after treatment of intravesical recurrence after RNU. METHODS: A total of 241 patients with primary UTUC (pTa-4N0M0) who experienced intravesical recurrence after RNU were included. Of these patients, 101 (41.9 %) underwent Bacillus Calmette-Guérin treatments, whereas 49 (20.3 %) underwent intravesical chemotherapy. The median follow-up period after initial transurethral resection of the bladder tumor was 33 months. Relationships with bladder outcomes were analyzed by using multivariable analysis. RESULTS: Ninety-six patients experienced intravesical recurrence, and bladder progression was observed in 13. Cumulative incidence rates of intravesical recurrence at 1 and 5 years after treatment of the first intravesical recurrence were 31.0 and 48.4 %, whereas those of bladder progression at 1 and 5 years thereafter were 2.4 and 8.0 %. Multivariate analysis showed that the number of recurrent tumors and pT1 tumors at the time of the first intravesical relapse were independent risk factors for subsequent intravesical recurrence. With respect to bladder progression, multivariate analysis showed that pT1 tumors, the appearance of concomitant carcinoma-in situ at the time of the first intravesical relapse, and the absence of the Bacillus Calmette-Guérin treatment were independent risk factors. CONCLUSIONS: This retrospective study presents a detailed picture of further bladder outcomes after intravesical recurrence after RNU in primary UTUC patients. The results may assist physicians to develop a more rational protocol in bladder surveillance.

Combined brachytherapy and external beam radiotherapy without adjuvant androgen deprivation therapy for high-risk prostate cancer.

BACKGROUND: To report the outcomes of patients treated with combined iodine-125 (I-125) brachytherapy and external beam radiotherapy (EBRT) for high-risk prostate cancer. METHODS: Between 2003 and 2009, I-125 permanent prostate brachytherapy plus EBRT was performed for 206 patients with high-risk prostate cancer. High-risk patients had prostate-specific antigen ≥ 20 ng/mL, and/or Gleason score ≥ 8, and/or Stage ≥ T3. One hundred and one patients (49.0%) received neoadjuvant androgen deprivation therapy (ADT) but none were given adjuvant ADT. Biochemical failure-free survival (BFFS) was determined using the Phoenix definition. RESULTS: The 5-year actuarial BFFS rate was 84.8%. The 5-year cause-specific survival and overall survival rates were 98.7% and 97.6%, respectively. There were 8 deaths (3.9%), of which 2 were due to prostate cancer. On multivariate analysis, positive biopsy core rates and the number of high-risk factors were independent predictors of BFFS. The 5-year BFFS rates for patients in the positive biopsy core rate <50% and ≥ 50% groups were 89.3% and 78.2%, respectively (p = 0.03). The 5-year BFFS rate for patients with the any single high-risk factor was 86.1%, compared with 73.6% for those with any 2 or all 3 high-risk factors (p = 0.03). Neoadjuvant ADT did not impact the 5-year BFFS. CONCLUSIONS: At a median follow-up of 60 months, high-risk prostate cancer patients undergoing combined I-125 brachytherapy and EBRT without adjuvant ADT have a high probability of achieving 5-year BFFS.