Philipp Gild

Effect of obesity on bladder cancer and renal cell carcinoma incidence and survival

Purpose of review The prevalence of obesity has risen dramatically in the general population and among cancer survivors in the last three decades. In this review, we highlight the impact of obesity on carcinogenesis and survival with a focus on bladder cancer and renal cell carcinoma (RCC). Recent findings Obesity presents an established risk factor for an up to 1.8-fold relative risk of RCC. Data with regard to bladder cancer are less abundant but support this association as well. Possible biological mechanisms involved are the insulin/insulin-like growth factor pathway, sex steroids, adipokines and chronic inflammation as well as treatment disparities within normal weight versus obese patients. With regard to survival, no conclusion can be drawn in either tumor entity at this time because of contradictory findings. These can in part be attributed to methodological limitations, while at the same time data exist to support the notion that obese patients exhibit less aggressive tumors. Summary Obesity drives cancer risk in RCC and potentially bladder cancer. Evidence regarding survival has been contradictory and therefore no clear-cut recommendation can be made regarding weight management in cancer survivors despite to maintain a healthy lifestyle. However, given the future cancer burden that obesity will constitute, physicians should encourage weight loss and help prevent weight gain in the general population.

Survival benefit of local versus no local treatment for metastatic prostate cancer-Impact of baseline PSA and metastatic substages

To test whether local treatment (LT), namely radical prostatectomy (RP) or brachytherapy (BT) still confers a survival benefit versus no local treatment (NLT), when adjusted for baseline PSA (bPSA). To further examine whether the effect of LT might be modulated according to bPSA and M1 substages.

Peri-operative allogeneic blood transfusion does not adversely affect oncological outcomes after radical cystectomy for urinary bladder cancer: a propensity score-weighted European multicentre study

To evaluate the effect of peri‐operative blood transfusion (PBT) on recurrence‐free survival, overall survival, cancer‐specific mortality and other‐cause mortality in patients undergoing radical cystectomy (RC), using a contemporary European multicentre cohort.

Impact of the Ki-67 labeling index and p53 expression status on disease-free survival in pT1 urothelial carcinoma of the bladder

Background The identification of protein biomarkers to guide treatment decisions regarding adjuvant therapies for high-risk non-muscle-invasive bladder cancer (NMIBC) has been of increasing interest. Evidence of the impact of tumor suppressor gene product p53 and cell proliferation marker Ki-67 on oncologic outcomes in bladder cancer patients at highest risk of recurrence and progression is partially contradictory. We sought to mirror contemporary expression patterns of p53 and Ki-67 in a select cohort of patients with pT1 bladder cancer. Methods Patients from four Northern German institutions with a primary diagnosis of pT1 bladder cancer between 2009 and 2016 and complete data regarding p53 or Ki-67 expression status were included for final analyses. Baseline patient characteristics (age, gender, age-adjusted Charlson comorbidity index) and tumor characteristics [diagnostic sequence, tumor focality, concomitant carcinoma in situ, 1973 World Health Organization (WHO) grading, lymphovascular invasion, adjuvant instillation therapy] were abstracted by retrospective chart review. Immunohistochemistry for detection of p53 and Ki-67 expression was performed according to standardized protocols. Microscopic analyses were performed by central pathologic review. First, we compared patients with positive vs. negative p53 expression and Ki-67 labeling index [>40% vs. ≤40%; cutoffs based on best discriminative ability in univariable Cox regression analysis with disease-free survival (DFS) as endpoint] with regard to baseline and tumor characteristics. Second, we evaluated the effect of biomarker positivity on DFS by plotting univariable Kaplan-Meier curves and performing uni- and multivariable Cox regression analyses. Results Of 102 patients with complete information on p53 status, 44 (43.1%) were p53 positive, and they more often harbored concomitant carcinoma in situ (50.0% vs. 27.6%; P=0.032) and 1973 WHO grade 3 (97.7% vs. 69.0%; P=0.001) compared to their p53 negative counterparts. Of 79 patients with complete information on Ki-67 expression status, 30 (38.0%) had a labeling index >40%. Mean Ki-67 labeling index was higher in WHO grade 3 vs. grade 2 tumors (45.8 vs. 29.7; P=0.004). At a median follow-up of 51.0 months, 31/91 patients with complete follow-up information (34.1%) suffered from disease recurrence or progression. In univariable Kaplan-Meier analyses, no difference regarding DFS was found in p53 positive vs. negative (P=0.8) or Ki-67 labeling index >40% vs. ≤40% (P=0.078) patients. In multivariable analyses, Ki-67 labeling index >40% remained an independent predictor of DFS [hazard ratio (HR), 2.66; 95% confidence interval (CI), 1.02–6.95; P=0.046], after adjusting for p53 expression and lymphovascular invasion. However, p53 status was not associated with our endpoint (P=0.8). Conclusions While we found an association of a Ki-67 labeling index >40% and shorter DFS in pT1 bladder cancer patients, this did not hold true for p53 positivity. Future research is needed to identify additional microscopic and molecular risk factors and biomarker panels to improve risk stratification and guide adjuvant therapies in those patients.

Characterizing trends in treatment modalities for localized muscle-invasive bladder cancer in the pre-immunotherapy era

IntroductionMuscle-invasive bladder cancer (MIBC) is an aggressive disease for which treatment strategies are continuously evolving. We characterized trends in treatment modalities for MIBC from 2004 to 2013 (the “pre-immunotherapy era”) and identified predictors of receiving the current standard of care treatment: neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC).MethodsWe used the National Cancer Database to identify individuals diagnosed with clinically localized MIBC from 2004 to 2013. We calculated the yearly prevalence of NAC followed by RC, RC as first treatment, trimodal therapy, chemotherapy and/or radiation alone, and no treatment. We then identified factors associated with receiving NAC prior to RC.ResultsThere was a notable increase in the use of NAC followed by RC over the study period, from 3.68% in 2004 to 14.83% in 2013 (P < 0.001). Factors associated with decreased odds of receiving this regimen included being older, Black, uninsured, less educated, and more burdened by comorbidities. Rates of trimodal therapy and chemotherapy and/or radiation alone remained relatively constant (approximately 5 and 17%, respectively). There was a consistent decline in the proportion of patients who did not receive any treatment, down to 34.20% in 2013.ConclusionTrends in localized MIBC treatment have evolved substantially since the early 2000s, and certain patient characteristics are associated with lower odds of receiving the current standard of care. This serves as a foundation from which to judge the impact of the upcoming immunotherapy era on the treatment landscape for this disease.

Liver Disease in Men Undergoing Androgen Deprivation Therapy for Prostate Cancer

Purpose: Androgen deprivation therapy is associated with the development of diabetes and metabolic syndrome. To our knowledge its effect on the development of nonalcoholic fatty liver disease, a condition which frequently co‐occurs with metabolic syndrome and other subsequent liver conditions such as liver cirrhosis, hepatic necrosis or any liver disease, has not been investigated. Materials and Methods: We identified 82,938 men 66 years old or older who were diagnosed with localized prostate cancer in the SEER (Surveillance, Epidemiology and End Results)‐Medicare database from 1992 to 2009. Men with preexisting nonalcoholic fatty liver disease, liver disease, diabetes or metabolic syndrome were excluded from study. Propensity score adjusted, competing risk regression models were created to compare the risk of nonalcoholic fatty liver disease in men who were vs were not treated with androgen deprivation. We also explored the influence of cumulative exposure to androgen deprivation therapy, calculated as monthly equivalent doses of gonadotropin‐releasing hormone agonists/antagonists (fewer than 7, 7 to 11 or more than 11 doses). Results: Overall 37.5% of men underwent androgen deprivation therapy. They were more likely to be diagnosed with nonalcoholic fatty liver disease (HR 1.54, 95% CI 1.40–1.68), liver cirrhosis (HR 1.35, 95% CI 1.12–1.60), liver necrosis (HR 1.41, 95% CI 1.15–1.72) and any liver disease (HR 1.47, 95% CI 1.35–1.60). A dose‐response relationship was observed between the number of androgen deprivation therapy doses, and nonalcoholic fatty liver disease and any liver disease. Conclusions: Androgen deprivation therapy in men with prostate cancer is associated with the diagnosis of nonalcoholic fatty liver disease. The usual limitations of an observational study design apply, including possible inaccuracy in defining outcomes in a population based registry.

Testing the external validity of the EORTC randomized trial 30904 comparing overall survival after radical nephrectomy vs nephron-sparing surgery in contemporary North American patients with renal cell cancer

EORTC 30904 reported that for solitary renal mass <=5cm, radical nephrectomy (RN) is associated with higher overall survival compared with nephron sparing surgery (NSS). This trial remains the only available level one evidence on this subject. To test external validity of the trial, patients who met clinical and pathological inclusion criteria of EORTC 30904 within the National Cancer Database (NCDB) were identified. We found that median age (60years in NCDB vs. 62years in trial) and median clinical tumour size (30mm in both) were similar between the cohorts. These two variables are most important determinants of mortality and stage of cancer, respectively, implying that the trial was able to recruit patients virtually representative of those seen in “real-world” practice. Moreover, in NCDB, more patients had clear-cell histology (81.9% vs. 62.9% in trial) and high-grade disease (21.1% vs. 11.2% in trial), implying more aggressive tumors compared to the trial. Arguably, these patients are better served with RN which has a higher probability of completely eradicating the tumor, making the results of the trial even more relevant to practice. Our results indicate that EORTC 30904 cohort was not significantly different from the NCDB cohort in a manner that could influence reported trial outcomes. This article is protected by copyright. All rights reserved.

Impact of adequate pelvic lymph node dissection on overall survival after radical cystectomy: A stratified analysis by clinical stage and receipt of neoadjuvant chemotherapy

PURPOSE An adequate pelvic lymph node dissection (LND) during radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) has been shown to provide a survival benefit. We designed a study to assess the effect of adequate LND on overall survival (OS) according to cT stage and receipt of neoadjuvant chemotherapy (NAC). MATERIAL AND METHODS We identified 16,505 patients with localized BCa who received RC in the National Cancer Database (2004-2012). Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier and Cox regression analyses were used to compare OS between patients who received adequate LND (defined as ≥10 nodes removed) and those who did not, stratified by cT stage and receipt of NAC. RESULTS Overall 8,673 (52.55%) patients underwent adequate LND at RC for localized BCa. Median time to last follow-up was 55.49 months (IQR, 34.73-75.96 months). IPTW-adjusted Kaplan-Meier curves showed that median OS was improved in patients who received adequate LND (60.06 vs. 46.88 months). In patients who did not receive NAC, adequate LND was associated with an OS benefit for cT1/a/cis, cT2, and cT3/4 disease (P ≤ 0.008). Among patients who received NAC, adequate LND was not associated with any OS difference regardless of cT stage. CONCLUSION Our data suggest that patients who did not receive NAC benefit from an adequate LND. However, the receipt of an adequate LND was not associated with an OS benefit in patients pretreated with NAC. Our study indicates that the receipt of NAC may eradicate micrometastatic disease, and thus limit the benefit of an adequate LND.

The effect of AB0 and Rhesus blood grouping systems on oncological outcome in patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma

OBJECTIVES To investigate the effect of AB0 and Rhesus factor expression blood group systems on outcomes of upper tract urothelial carcinoma patients treated with radical nephroureterectomy. PATIENTS AND METHODS We analyzed data from 271 patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy at 3 German academic institutions. Cox and logistic regression models assessed the association of AB0 blood group antigen and Rhesus factor expression with tumor biologic features and outcomes, respectively. RESULTS In total, 119 patients (43.9%) had blood group antigen A0, 42 patients (15.4%) antigen B0, 15 patients (5.5%) antigen AB, and 95 patients (35.0%) the antigen 00. A total of 231 patients (85.2%) were Rhesus factor positive. The AB0 blood group antigen expression was associated with a higher tumor grade (P = 0.049) and sessile tumor architecture (P = 0.019). Both, AB0 blood group system and Rhesus factor expression, were associated with worse performance status (P = 0.024, and P = 0.003, respectively). In contrast, Rhesus factor expression status was not associated with any clinicopathologic characteristics. Neither the AB0 blood group antigens nor the Rhesus factor was associated with survival. CONCLUSION AB0 blood group antigens and Rhesus factor expression are not associated with survival. The association of the AB0 blood group antigens with adverse pathological features warrants further validation.

MP91-04 ADVERSE EFFECTS OF TESTOSTERONE REPLACEMENT THERAPY FOR MEN, A MATCHED COHORT STUDY

INTRODUCTION AND OBJECTIVES: To evaluate role of lowintensity shock wave therapy (LI-SWT) in penile rehabilitation (PR) post nerve sparing radical cysto-prostatectomy (NS-RCP). METHODS: Eighty seven sexually active men with muscle invasive bladder cancer were enrolled in this prospective study. After bilateral NS-RCP with orthotopic diversion (W-Pouch) by a single expert surgeon between January 2015 & October 2016, patients were randomized into 3 groups (29 patients/group). SWL Group received 12 sessions of penile LI-SWT (2/week for 3 weeks, then 3 weeks free of treatment, then 2/week for another 3 weeks). Phosphodiesterase type-5 inhibitors (PDE5i) Group received oral PDE5i of 50 mg /day for 6 months. Control Group was followed up only without any therapy. Patients were assessed before surgery and at 1 (FU1), 3 (FU2), 6 (FU3) and 9-month (FU4) post operatively. Effectiveness was assessed by IIEF-15 questionnaire and erection hardness score (EHS). RESULTS: Mean age was 54.1 5.9 years with mean followup period 15.9 4.2 months. There were no statistically significant differences regarding preoperative patients demographic data & tumor criteria. At FU1; All patients have insufficient erection for vaginal penetration. EHS < 2; with decrease of preoperative IIEF-EF mean score from 28 to 6.6. In SWL group; At FU2; 17/29 patients regained potency which is maintained in 15 only at FU3&4. However; 6 of remaining 12 patients regained & maintained potency at FU3&4. Statistical evaluation showed significant increase in IIEF-EF score from 6.6 at FU1 to 23 at FU2, 24 at FU3 and 24.5 at FU4 ( P <0.001). In PDE5i group; At FU2; 16/29 patients regained & maintained potency at FU3&4. However; 7 of remaining 13 patients regained & maintained potency at FU3&4. Statistical evaluation showed significant increase in IIEF-EF score from 6.6 at FU1 to 22.8 at FU2, 24 at FU3 and 24.7 at FU4 (P <0.001). In Control group; At FU2; 12/29 patients regained & maintained potency at FU3&4. However; 6 of remaining 17 patients regained & maintained potency at FU3&4. Statistical evaluation showed no significant difference in potency recovery rates at FU2 & FU3,4 among the groups ( P 1⁄4 0.14 & P 1⁄4 0.24 respectively). Potency recovery rates at FU2 were 58.6% vs 55.2% vs 41.4% in SWL, PDE5i and Control group, respectively. While potency recovery rates at FU3,4 were 72.4% vs 79.3% vs 62.1% in SWL, PDE5i and Control group, respectively. CONCLUSIONS: LI-SWT is safe and as effective as oral PDE5i in PR post NS-RCP. A large-scale study is required to determine the value of this treatment modality in ED post NS-RCP.