Long-term oncological outcomes of patients with paratesticular sarcoma.

OBJECTIVES: To present long-term oncological outcomes of patients with paratesticular sarcoma treated by a multidisciplinary team. PATIENTS AND METHODS: Patients managed at the Princess Margaret Cancer Centre, between 1990 and 2012, were analysed. A sarcoma expert performed central pathology review. Kaplan-Meier graphs compared local recurrence (LR), metastasis, and overall survival (OS) of patients treated with hemiscrotectomy vs those who did not. Univariable Cox proportional hazards analysis was performed to delineate predictors of LR, metastasis, and OS. RESULTS: Overall, 51 patients with a median (interquartile range) follow-up of 132 (51.6-226.8) months were analysed. At presentation, 92.2% (47 patients) had localised disease. Only five patients (9.8%) had undergone initially planned hemiscrotectomy. Completion and salvage hemiscrotectomy was performed in 25 (54.3%) and seven (15.2%) patients, respectively. Recurrence and metastasis occurred in 12 (25.5%) and 10 patients (19.6%), respectively. At the last follow-up, 21.6% (11 patients) had died, with eight dying from their disease. Kaplan-Meyer graphs demonstrated that hemiscrotectomy improved LR (median not reached vs 62.4 months, log-rank P = 0.008) and OS (median not reached vs 168 months, log-rank P = 0.081). Univariable analysis found hemiscrotectomy to be associated with a lower LR rate (hazard ratio [HR] 0.21, P = 0.02), whilst positive margins at initial surgery were associated with increased LR (HR 4.81, P = 0.047). No metastasis predictors were found, but age (HR 1.04, 95% confidence interval [CI] 1.0-1.08; P = 0.02) and non-localised disease at presentation (HR5.17, 95% CI 1.33-20.06; P = 0.017) were associated with worse OS. CONCLUSION: Paratesticular sarcoma is a rare tumour, predominantly manifesting as localised disease. Most patients receive an initial suboptimal oncological surgery. Improved long-term outcomes are demonstrated following early hemiscrotectomy.

Immediate intravesical chemotherapy for low-grade bladder tumors in California: An underutilized practice and its impact on recurrence.

OBJECTIVES: To demonstrate patterns of uptake and impact on recurrence of intravesical chemotherapy (IC) immediately following transurethral resection of bladder tumor (TURBT) for low-grade non-muscle-invasive bladder cancer (NMIBC) at a population level. METHODS: Incident cases of low-grade (LG) Ta or T1 NMIBC from 2005 to 2012 were identified from the California Cancer Registry. We determined rates of IC utilization following TURBT. Multivariable logistic regression models were utilized to assess predictors of IC utilization. Multivariable Cox proportional hazards regression was used to assess the association of IC utilization with recurrence-free survival, bladder cancer-specific survival, and overall survival. RESULTS: Ten thousand thirty-one patients with LG NMIBC diagnosed in California between 2005 and 2012. The overall rate of IC utilization was 5.1%, and increased from 1.7% (2005-2006) to 9.6% (2011-2012). More recent year of diagnosis (Odds ratio 1.74, confidence interval 1.60-1.90 for 2-year increments) was associated with an increased likelihood of undergoing immediate postoperative IC. The cumulative incidence of recurrence at 24 months for patients who received IC was 25.2% compared to 30.2% among those who did not receive IC. Use of IC was significantly associated with improved recurrence-free survival (Hazards ratio 0.82, confidence interval 0.70-0.97). CONCLUSION: Utilization of IC for LG NMIBC remains dismally low, with less than 10% of patients receiving this standard of care. Low utilization is associated with increased rates of recurrence. We demonstrate a major shortcoming in quality of care with potential widespread impact on outcomes and cost of care.

Sociodemographic disparities in chemotherapy treatment and impact on survival among patients with metastatic bladder cancer.

OBJECTIVE: To evaluate how socioeconomic status and other demographic factors are associated with the receipt of chemotherapy and subsequent survival in patients diagnosed with metastatic bladder cancer. METHODS: Using data from the California Cancer Registry, we identified 3,667 patients diagnosed with metastatic urothelial carcinoma of the urinary bladder between 1988 and 2014. The characteristics of patients who did and did not receive chemotherapy as part of the first course of treatment were compared using chi-square tests. Logistic regression was used to identify predictors of chemotherapy treatment. Fine and Gray competing-risks regression and Cox proportional hazards regression were used to estimate bladder cancer-specific and all-cause mortality, respectively. RESULTS: Less than half (46.3%) of patients received chemotherapy. Patients from the lowest socioeconomic quintile were half as likely to have chemotherapy as those from highest quintile (odds ratio = 0.5, 95% CI: 0.4, 0.7). Unmarried patients were significantly less likely to receive treatment (odds ratio = 0.6, 95% CI: 0.5, 0.7). Not receiving chemotherapy was associated with greater mortality from bladder cancer (subdistribution hazard ratio = 1.4, 95% CI: 1.3, 1.5) and from all causes (hazard ratio = 2.0, 95% CI: 1.8, 2.1). CONCLUSIONS: We found clear disparities in chemotherapy treatment and survival with respect to socioeconomic and marital status. Future studies should explore the possible reasons why patients with low socioeconomic status and who are unmarried are less likely to have chemotherapy.

The Promise and Disappointment of Neoadjuvant Chemotherapy and Transurethral Resection for Muscle Invasive Bladder Cancer: Updated Results and Long-Term Followup.

INTRODUCTION: Radical cystectomy with neoadjuvant chemotherapy is the standard of care for patients with localized muscle invasive urothelial carcinoma of the bladder. One of the strongest predictors of survival in these patients is pathological response to initial treatment. Our objective was to determine whether we could stratify the need for radical cystectomy based on pathological response to neoadjuvant chemotherapy. METHODS: We present a cohort of patients with muscle invasive urothelial carcinoma of the bladder to whom surveillance and bladder preservation were offered if complete response was achieved following neoadjuvant chemotherapy. Descriptive statistics and survival analysis were performed to assess overall, cancer specific and metastasis-free survival. Patients were stratified based on pathological response to neoadjuvant chemotherapy. RESULTS: A total of 60 patients were included in the cohort, of whom 32 (55%) had absence of residual disease on post-neoadjuvant chemotherapy transurethral resection and 27 (45%) had persistent disease. Of patients undergoing surveillance 52% maintained the bladder without evidence of recurrence. By comparison, of those with recurrence only 20% preserved the bladder and were without evidence of disease. CONCLUSIONS: Long-term followup shows a subset of patients achieving good outcomes while preserving the bladder. However, we also observed an inability to reliably identify this subset of patients given current clinical and pathological markers. Until we are able to achieve that goal, the safest oncologic approach remains neoadjuvant chemotherapy followed by radical cystectomy.

Utility of Anterior Zone Biopsy in Men Enrolled in Active Surveillance for Prostate Cancer.

BACKGROUND: Anterior zone (AZ) disease is present in one-fifth of men with newly diagnosed prostate cancer and has been associated with poor pathologic features. However, anterior targeted biopsies are not a routine part of active surveillance (AS) protocols. Our purpose is to assess the utility of AZ sampling for prostate biopsy in patients undergoing surveillance for low-risk prostate cancer. METHODS: A prospective data collection of men enrolled in AS between 2006 and 2014 was performed. Patient and disease characteristics were collected, including number of positive cores and Gleason score on all diagnostic and surveillance biopsies. Progression was defined as incident Gleason > 6 in any core and/or receipt of definitive therapy including radical prostatectomy or radiotherapy. Rate of anterior disease and relationship to subsequent disease progression was assessed. RESULTS: A total of 85 men were included, of which 45% demonstrated progression. Median follow-up was 40 months. Among those undergoing AZ sampling at initial diagnosis, 37% presented with AZ disease. A total of 47% of men with AZ-only disease progressed, whereas 78% of men with AZ and peripheral zone disease progressed. This compares with a 39% rate of progression among men with only peripheral zone disease. Multivariable logistic regression identified increasing body mass index as a significant predictor of disease progression (odds ratio, 5.18; 95% confidence interval, 1.06-25.31; P = .04). CONCLUSIONS: Over one-third of men enrolled in AS for low-risk prostate cancer had AZ disease on diagnostic biopsy. Progression occurred in the majority of these men. AZ sampling should be considered in biopsy surveillance strategies.

Evolving patterns of care in the management of stage I non-seminomatous germ cell tumors: data from the California Cancer Registry.

PURPOSE: To assess the shifting population-level practice patterns across a 20-year time span in the management of stage I non-seminomatous germ cell tumors (NSGCT). METHODS: Using the California Cancer Registry, we reviewed all patients with stage I NSGCT between 1988 and 2010. We determined their primary treatment and their overall rates across the years. Other analyzed variables included patient age, T stage, socioeconomic status, race, and year of diagnosis. Predictors of treatment were assessed using logistic regression analysis. Predictors of overall and CSS were assessed using Cox proportional hazards models. RESULTS: Three thousand nine hundred and sixty-one patients with stage I NSGCT were identified. The most common treatment was surveillance (48 %), followed by RPLND (26 %) and chemotherapy (24 %). Rates of surveillance increased from 35 % in 1988 to 61 % in 2010; rates of RPLND decreased from 44 % in 1988 to 10 % in 2010. These were significant changes in treatment strategies (p < 0.01). Significant predictors of undergoing surveillance included diagnosis after 2006 (OR 1.52, CI 1.25-1.84) and age at diagnosis >60 years old (OR 1.63, CI 1.19-5.82). With a median follow-up of 96 months, 5-year overall survival rate was 95 %. CONCLUSIONS: Treatment patterns in the management of stage I NSGCT have shifted in the past two decades with an increased utilization of surveillance and concurrent decrease in use of RPLND. Surveillance is now the dominant strategy, potentially reflecting changes in perception of the oncologic safety and morbidity profile of such an approach.

A contemporary population-based study of testicular sex cord stromal tumours: Presentation, treatment patterns, and predictors of outcome.

INTRODUCTION: We aimed to characterize demographic distribution, patient outcomes, and prognostic features of testicular sex cord stromal tumours (SCST) using a large statewide database. METHODS: Adult male patients diagnosed with SCST between 1988 and 2010 were identified within the California Cancer Registry (CCR). Baseline demographic variables and disease characteristics were reported. Primary outcome measures were cancer-specific survival (CSS) and overall survival (OS). Bivariate and multivariate Cox proportional hazards models were employed to identify predictors of survival. RESULTS: A total of 67 patients with SCST were identified, of which 45 (67%) had Leydig cell and 19 (28%) had Sertoli cell tumours. Median age was 40 years and the majority of patients (84%) presented with localized disease. Following orchiectomy, nine patients (15%) underwent retroperitoneal lymph node dissection (RPLND), whereas 54 patients (80%) had no further treatment. With a median followup of 75 months, two-year OS and CSS was 91% and 95%, respectively, for those presenting with stage I disease. For those presenting with stage II disease, two-year OS and CSS was 30%. Predictors of worse OS included age >60 (hazard ratio [HR] 5.64; p<0.01) and metastatic disease (HR 8.56; p<0.01). Presentation with metastatic disease was the only variable associated with worse CSS (HR 13.36; p<0.01). Histology was not found to be a significant predictor of either CSS or OS. CONCLUSIONS: We present the largest reported series to date for this rare tumour and provide contemporary epidemiological and treatment data. The primary driver of prognosis in patients with SCST is disease stage, emphasizing the importance of early detection and intervention.

Effect of Neoadjuvant Chemotherapy on Renal Function following Radical Cystectomy: Is there a Meaningful Impact?

Objective: To evaluate the patterns of impact of neoadjuvant chemotherapy (NAC) on renal function across the initial year following treatment for muscle-invasive bladder cancer (MIBC) with radical cystectomy (RC). Methods: We reviewed the charts of 241 patients who underwent RC for urothelial carcinoma of the bladder between 2003-14 at our institution. Renal function was evaluated at multiple time points (pre-chemotherapy, pre-operatively, post-operatively, 6-12 months follow-up), and then classified by CKD staging. Univariable and multivariable logistic regression analyses were performed to determine relationship between NAC and change in CKD stage. Results: Of the 241 patients who underwent RC for urothelial carcinoma of the bladder, 66 (27%) received NAC and 175 (73%) did not. In multivariable analysis, NAC was significantly associated with a decrease of at least one CKD stage from baseline to post-op (p = 0.009), but not to the 6-12 months follow-up time point (p = 0.050). The loss of GFR in the NAC cohort occurs up-front with chemotherapy, but the peri-operative course is similar to those who underwent cystectomy alone. Of the 15 NAC patients (26.8%) who were Stage 3 CKD prior to chemotherapy, none progressed to a higher stage CKD. Conclusion: NAC is associated with an initial decline in GFR, which then remains stable through the first year following RC. Despite an initial insult, patients receiving NAC are not vulnerable to further deterioration. When appropriately selected, NAC does not appear to result in a clinically significant deterioration of renal function.

Decreased expression of let-7c is associated with non-response of muscle-invasive bladder cancer patients to neoadjuvant chemotherapy.

The identification and development of biomarkers which predict response of muscle invasive bladder cancer (MIBC) patients to neoadjuvant chemotherapy would likely increase usage of this treatment option and thereby improve patient survival rates. MiRNA array and qRT-PCR validation was used to identify miRNA which are associated with response to neoadjuvant chemotherapy. RNA was extracted from a total of 41 archival, fully annotated, MIBC patient diagnostic biopsies (20 chemo-responders and 21 non-responders (response is defined as > 5 year survival rate and being pT0 post-chemotherapy)). Microarray and qPCR identified let-7c as being differentially expressed in chemo-responder versus non-responder patients. Patients with higher let-7c expression levels had significantly higher odds of responding to chemotherapy (p = 0.023, OR 2.493, 95% CI 1.121, 5.546), and assessment of let-7c levels allowed for prediction of patient response (AUC 0.72, positive predictive value 59%). Decreased let-7c was associated with MIBC incidence (p < 0.001), and significantly correlated with other related miRNA including those that were not differentially expressed between responders and non-responders. The combined data indicate let-7c plays a role in mediating chemoresistance to neoadjuvant chemotherapy in MIBC patients, and is a modest, yet clinically meaningful, predictor of patient response.

A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is up-regulated in castration-resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up-regulation of the androgen receptor (AR) pathway. METHODS: Patients who were eligible for this study had to have progressive CRPC with serum testosterone levels <50 ng/dL. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment included oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, with a cycle defined as 4 weeks. The primary endpoint was the prostate-specific antigen (PSA) response (≥30% reduction) from baseline. A sample size of 23 patients would have power of 0.8 and an α error of .05 (1-sided) if the combination had a PSA response rate of 50% versus a historic rate of 25% with bicalutamide alone. RESULTS: Twenty-four patients were enrolled. The mean age was 71.1 years (range, 53.0-87.0 years), the mean PSA level at study entry was 43.4 ng/dL (range, 2.5-556.9 ng/dL), and the mean length of treatment was 8 cycles (range, 1.0-23.0 cycles). Of 24 patients, 18 had a PSA response (75%; 95% confidence interval [CI], 0.53-0.90), whereas 15 (62.5%; 95% CI, 0.41-0.81) had a PSA decrease ≥50%. The median overall survival was 28 months (95% CI, 14.1-42.7 months). Fourteen patients (54%; 95% CI, 0.37-0.78) developed grade 3 (13 patients) or grade 4 (1 patient with sepsis) adverse events that were attributable to treatment. CONCLUSIONS: The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus-related toxicity. Cancer 2016;122:1897-904. © 2016 American Cancer Society.

Perioperative Outcomes following Neoadjuvant Chemotherapy and Radical Cystectomy-Is There Room for Improvement?

INTRODUCTION: We identify the impact of neoadjuvant chemotherapy before open radical cystectomy on perioperative outcomes and identify actionable areas for improvement. METHODS: The impact of neoadjuvant chemotherapy on perioperative outcomes after radical cystectomy for muscle invasive bladder cancer from 2003 to 2014 was assessed using an institutional database. Individual outcomes (venous thromboembolism, surgical site infection, cardiac event) and a composite score using the Clavien-Dindo classification were identified. Univariable and multivariable logistic regression models were used to identify predictors of perioperative complication and 30-day readmission rates. RESULTS: A total of 241 patients were included in the study, of whom 175 underwent radical cystectomy alone (72.6%) and 66 were treated with neoadjuvant chemotherapy plus radical cystectomy (27.4%). The 30-day readmission rate for the neoadjuvant chemotherapy cohort was 30.5% compared to 17.2% for radical cystectomy alone. Multivariable logistic regression analysis identified neoadjuvant chemotherapy as an independent predictor of 30-day readmission (OR 3.47, p=0.01). Of the patients on neoadjuvant chemotherapy readmitted within 30 days 72.2% were readmitted with infections. All other outcomes were not significantly associated with neoadjuvant chemotherapy. CONCLUSIONS: While the administration of neoadjuvant chemotherapy did not significantly increase perioperative complications, patients receiving neoadjuvant chemotherapy had an increased rate of 30-day readmission, with infection being the most common etiology. This increased readmission rate has not been previously identified in this patient population to our knowledge and is an important focus for quality improvement.

Metastatic signet-ring cell carcinoma of the urinary bladder: A novel management approach to a rare tumour.

Primary signet-ring cell carcinoma (SRCC) of the urinary bladder, a variant of adenocarcinoma, is exceedingly rare and as a result no gold standard exists for its management. We report a case of primary SRCC of the bladder with recurrent metastases; we utilized an innovative diagnostic approach and the patient exhibited a treatment response to palliative FOLFOX-6 chemotherapy.

Partial nephrectomy for the treatment of renal cell carcinoma (RCC) and the risk of end-stage renal disease (ESRD).

OBJECTIVE: To assess whether radical nephrectomy (RN) compared with partial nephrectomy (PN) for the treatment of renal cell carcinoma (RCC) is associated with greater risk of end-stage renal disease (ESRD). PATIENTS AND METHODS: We performed a population-based, retrospective cohort study using linked administrative databases in the province of Ontario, Canada. We included individuals with pathologically confirmed RCC diagnosed between 1995 and 2010. Cox proportional hazards, propensity score, and competing risks models were used to assess the impact of treatment choice. The primary outcome was ESRD. Secondary outcomes included overall mortality, myocardial infarction, and new-onset chronic kidney disease (CKD). A modern cohort of patients (2003-2010) was analysed separately. RESULTS: We included 11,937 patients, of whom 2107 (18%) underwent PN. The median follow-up was 57 months. In the full cohort, type of surgery was not associated with the rate of ESRD, whereas PN was associated with a decreased likelihood of ESRD compared with RN in the modern cohort using a multivariable proportional hazards model [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.25-0.75) or propensity score modelling (HR 0.48, 95% CI 0.27-0.82). PN was also associated with a lower risk of new-onset CKD (HR 0.48, 95% CI 0.41-0.57). CONCLUSIONS: Although it is well-known that RN is associated with more CKD than PN, we provide the first direct evidence that PN is associated with less ESRD requiring renal replacement therapy than RN in a modern cohort of patients with RCC.

The role of EGFR family inhibitors in muscle invasive bladder cancer: a review of clinical data and molecular evidence.

PURPOSE: Conventional platinum based chemotherapy for advanced urothelial carcinoma is plagued by common resistance to this regimen. Several studies implicate the EGFR family of RTKs in urothelial carcinoma progression and chemoresistance. Many groups have investigated the effects of inhibitors of this family in patients with urothelial carcinoma. This review focuses on the underlying molecular pathways that lead to urothelial carcinoma resistance to EGFR family inhibitors. MATERIALS AND METHODS: We performed a PubMed® search for peer reviewed literature on bladder cancer development, EGFR family expression, clinical trials of EGFR family inhibitors and molecular bypass pathways. Research articles deemed to be relevant were examined and a summary of original data was created. Meta-analysis of expression profiles was also performed for each EGFR family member based on data sets accessible via Oncomine®. RESULTS: Many clinical trials using inhibitors of EGFR family RTKs have been done or are under way. Those that have concluded with results published to date do not show an added benefit over standard of care chemotherapy in an adjuvant or second line setting. However, a neoadjuvant study using erlotinib before radical cystectomy demonstrated promising results. CONCLUSIONS: Clinical and preclinical studies show that for reasons not currently clear prior treatment with chemotherapeutic agents rendered patients with urothelial carcinoma with muscle invasive bladder cancer resistant to EGFR family inhibitors as well. However, EGFR family inhibitors may be of use in patients with no prior chemotherapy in whom EGFR or ERBB2 is over expressed.

Ablative efficiency of 532-nm laser vaporization compared to transurethral resection of the prostate: results from a prospective three-dimensional ultrasound volumetry study.

PURPOSE: To assess and compare postoperative prostate volume changes following 532-nm laser vaporization (LV) and transurethral resection of the prostate (TURP). To investigate whether differences in volume reduction are associated with differences in clinical outcome. METHODS: In this prospective, non-randomized study, 184 consecutive patients undergoing 120 W LV (n = 98) or TURP (n = 86) were included. Transrectal three-dimensional ultrasound and planimetric volumetry of the prostate were performed preoperatively, after catheter removal, 6 weeks, 6 and 12 months. Additionally, clinical outcome parameters were recorded. Mann-Whitney U test and analysis of covariance were utilized for statistical analysis. RESULTS: Postoperatively, a significant prostate volume reduction was detectable in both groups. However, the relative volume reduction was lower following LV (18.4 vs. 34.7 %, p < 0.001). After 6 weeks, prostate volumes continued to decrease in both groups, yet differences between the groups were less pronounced. Nonetheless, the relative volume reduction remained significantly lower following LV (12 months 43.3 vs. 50.3 %, p < 0.001). All clinical outcome parameters improved significantly in both groups. However, the maximum flow rate (Q max) and prostate-specific antigen (PSA) reduction were significantly lower following LV. Subgroup analyses revealed significant differences only if the initial prostate volume was >40 ml. Re-operations were necessary in three patients following LV. CONCLUSIONS: The modest but significantly lower volume reduction following LV was associated with a lower PSA reduction, a lower Q max and more re-operations. Given the lack of long-term results after LV, our results are helpful for preoperative patient counseling. Patients with large prostates and no clear indication for the laser might not benefit from the procedure.

A population-based study of surgeon characteristics associated with the uptake of contemporary techniques in renal surgery.

INTRODUCTION: We have witnessed the slow uptake of many contemporary techniques in the surgical management of renal tumours. We sought to evaluate surgeon-level characteristics associated with the uptake of laparoscopy, partial nephrectomy (PN) and adrenal-sparing approaches in surgically managing these tumours. METHODS: Using the Ontario Cancer Registry, we identified surgeons treating renal cell carcinoma (RCC) in the province of Ontario, Canada between 2002 and 2004. We then classified individuals within this cohort as either high or low utilizers of laparoscopy, PN or adrenal-sparing approaches. Further variables analyzed included academic status, surgeon graduation year and surgical volume status. We then used univariable and multivariable logistic regression models to assess predictors of uptake. RESULTS: We evaluated a total of 108 surgeons for their uptake of both laparoscopy and adrenal-sparing approaches and 94 surgeons for their uptake of PN. We identified 32 surgeons (30%) as high users of laparoscopy. Predictors of uptake of laparoscopy included graduation year after 1990 (odds ratio [OR] 4.81, confidence interval [CI] 1.57-14.8) and high-surgeon volume (OR 4.33, CI 1.60-10.4). We identified 41 surgeons (44%) as high users of PN. The only predictor of uptake of PN was academic status (OR 5.83, CI 1.96-17.3). We identified 69 surgeons (65%) as high users of adrenal-sparing approaches, but did not identify any significant predictors for uptake in this group. DISCUSSION: We identify unique factors contributing to the uptake of distinct surgical techniques in the management of RCC. This information sheds lights on the underlying mechanisms and helps us understand how to further encourage the dissemination of these practices.