Manuel S. Eisenberg

The SPARC Score: A Multifactorial Outcome Prediction Model for Patients Undergoing Radical Cystectomy for Bladder Cancer

PURPOSE While multiple independent clinicopathological variables are associated with the outcome of radical cystectomy for bladder cancer, limited prediction tools exist to facilitate individualized risk assessment. We developed the SPARC (Survival Prediction After Radical Cystectomy) score, a prediction model for bladder cancer specific survival after radical cystectomy. MATERIALS AND METHODS We evaluated 2,403 patients who underwent radical cystectomy without neoadjuvant therapy at our institution between 1980 and 2008 with pathological re-review of all specimens. Of these patients 1,776 with nonmetastatic urothelial carcinoma were identified for analysis. A multivariate model was developed using stepwise selection to determine variables associated with cancer specific survival. We created a scoring system based on the β coefficients of this model. RESULTS Median followup after radical cystectomy in patients alive at last followup was 10.5 years (IQR 7.3, 15.3), during which time 610 had died of bladder cancer. In addition to pathological tumor stage, nodal status, multifocality and lymphovascular invasion, the patient specific factors of Charlson comorbidity index, Eastern Cooperative Oncology Group (ECOG) performance status, current smoking, preoperative hydronephrosis and receipt of adjuvant chemotherapy were significantly associated with the risk of bladder cancer death. We used cumulative scores of these variables to stratify patients into risk groups with 95%, 80%, 60%, 38% and 23% 5-year cancer specific survival from the lowest to the highest risk group, respectively (p<0.0001). The concordance index of this model was 0.75. CONCLUSIONS We present a model to individualize the estimation of cancer specific survival after radical cystectomy. Pending external validation, these data may be used for patient counseling, specifically in regard to recommendations for adjuvant therapy and surveillance frequency, as well as for clinical trial development.

Effect of metformin on prostate cancer outcomes after radical prostatectomy

OBJECTIVE Recent studies have shown a relative risk reduction in the incidence of prostate cancer in patients taking metformin. However, there are conflicting findings on the effect of metformin on established cases of prostate cancer. In this study we evaluated the effect of metformin on survival and pathologic outcomes in established prostate cancer. MATERIALS AND METHODS We retrospectively identified 12,052 patients who underwent radical prostatectomy between 1997 and 2010 at Mayo Clinic. Among these, 885 (7.3%) were diabetics, including 323 taking and 562 not taking metformin. Kaplan-Meier method was utilized to calculate rates of biochemical recurrence (BCR), systemic progression (SP), and all-cause mortality (ACM). Cox models were used to estimate the metformin hazard ratio (HR) adjusted for clinical and pathologic variables. RESULTS AND CONCLUSIONS Median follow-up was 5.1 years. In univariate analysis, metformin HR (95% confidence intervals) was not significant for BCR (1.13 [0.84, 1.52]; P = 0.40), SP (1.37 [0.69, 2.72]; P = 0.37), and ACM (1.32 [0.84, 2.05]; P = 0.23). After adjusting for covariates of interest, the HRs for metformin among diabetics remained nonsignificant for BCR (0.91 [0.67, 1.24]; P = 0.55), SP (0.83 [0.39, 1.74]; P = 0.62); and ACM (1.16 [0.73, 1.86]; P = 0.53). No significant difference was seen between metformin users and nonusers in the final pathologic Gleason score (P = 0.33), stage (P = 0.1), rate of positive surgical margins (P = 0.29), or tumor volume (P = 0.76). Metformin use was not associated with a risk reduction in BCR, SP, or ACM. Besides presenting survival data, our results describing metformins effect on final pathology are unique.

Risk Stratification of Patients with Extraprostatic Extension and Negative Lymph Nodes at Radical Prostatectomy: Identifying Optimal Candidates for Adjuvant Therapy

PURPOSE Randomized trials demonstrate a benefit to adjuvant radiation therapy after radical prostatectomy in patients with pathologically locally advanced tumors. However, limited data exist on natural history, specifically in men with extraprostatic extension, and wide variability in outcomes has been reported. We evaluated long-term outcomes in patients with pT3aN0 disease and determined predictors of recurrence in these men. MATERIALS AND METHODS We evaluated 20,744 patients who underwent radical prostatectomy at our clinic between 1987 and 2011. Of these men 1,073 with pT3aN0 disease were identified who did not receive neoadjuvant or adjuvant therapy. Biochemical recurrence-free survival was estimated using the Kaplan-Meier method. Multivariate stepwise selection was used to develop a prognostic model for biochemical recurrence. RESULTS Median followup after radical prostatectomy was 10.9 years, during which 449 patients experienced biochemical recurrence. On stepwise selection preoperative prostate specific antigen (HR 1.3, p=0.0003), clinical tumor stage (HR 1.2, p=0.001), pathological Gleason score (HR 1.9, p<0.0001), surgical margin status (HR 1.6, p<0.0001) and detectable first postoperative prostate specific antigen (HR 2.2, p<0.0001) were significantly associated with biochemical recurrence. Cumulative weighted scores of these variables were used to stratify patients into quintiles according to biochemical recurrence risk. The 15-year biochemical recurrence-free survival rate in the lowest to the highest risk group was 70%, 56%, 44%, 34% and 25%, respectively (p<0.0001). The c-index for this model was 0.69. CONCLUSIONS We present a model to individualize the estimation of biochemical recurrence in men with pT3aN0 disease at radical prostatectomy. These data may be used for patient counseling, specifically in regard to risk stratification when discussing secondary therapy.

Long-term results of radical cystectomy and role of adjuvant chemotherapy for small cell carcinoma of the bladder.

To review our experience with radical cystectomy for small cell carcinoma of the bladder, to compare outcomes with a cohort of patients with urothelial carcinoma, and to determine the effect of adjuvant chemotherapy and pathology re‐review in this setting.

Comparative impact of continent and incontinent urinary diversion on long-term renal function after radical cystectomy in patients with preoperative chronic kidney disease 2 and chronic kidney disease 3a

To evaluate the differences in estimated glomerular filtration rate decline by urinary diversion type (incontinent diversion vs continent diversion) and preoperative estimated glomerular filtration rate among patients undergoing radical cystectomy and urinary diversion.

Association of Microvascular and Capillary-Lymphatic Invasion with Outcome in Patients with Renal Cell Carcinoma

PURPOSE We evaluated the association of microvascular and capillary-lymphatic invasion with patient outcome after nephrectomy for renal cell carcinoma. MATERIALS AND METHODS We identified 1,433 patients surgically treated for sporadic, unilateral renal cell carcinoma between 2001 and 2008. All specimens were reviewed by a single uropathologist for microvascular and capillary-lymphatic invasion. Associations with time to metastasis and death from renal cell carcinoma were evaluated using Cox proportional hazards models, controlling for established clinicopathological prognostic variables. RESULTS Microvascular invasion and capillary-lymphatic invasion were identified in 119 (11%) and 17 (2%) of the 1,103 patients with clear cell, 5 (2%) and 1 (less than 1%) of the 219 with papillary, and 1 (1%) and 0 of the 86 with chromophobe renal cell carcinoma, respectively. Median followup in survivors was 6.4 years (range 0 to 11). In clear cell renal cell carcinoma cases microvascular invasion was univariately associated with an increased risk of metastasis and cancer specific death (HR 3.5 and 3.0, respectively, each p <0.001). However, on multivariate analysis these associations were no longer statistically significant (HR 1.2, p = 0.4 and HR 1.3, p = 0.1, respectively). Capillary-lymphatic invasion remained significantly associated with an increased risk of metastasis and death on univariate analysis (HR 15.9 and 11.6) and on multivariate analysis (HR 3.2 and HR 3.1, respectively, each p <0.001). CONCLUSIONS Microvascular invasion is associated with an increased risk of metastasis and cancer death in patients with clear cell renal cell carcinoma, although this did not remain significant after controlling for established prognostic variables. Capillary-lymphatic invasion appears to be independently associated with metastasis and cancer death even after controlling for known prognostic risk factors. However, given its rarity, this feature may prove to be of limited clinical significance.

Racial disparity in renal cell carcinoma patient survival according to demographic and clinical characteristics

Disparities in health care are well documented; however, their prevalence in the field of urology continues to be defined. Studies of prostate cancer have indicated differential treatments and outcomes in minority groups, and disparities in the treatment of renal masses continue to emerge. Chow et al recently examined survival outcomes for renal cell carcinoma using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, demonstrating that although black patients present more frequently with localized disease and at a younger age, they have worse survival even when stratifying by sex, age, tumor stage, tumor size, histologic subtype, and type of surgical treatment. Furthermore, this gap appears to be widening over time, with the largest disparity noted in the most recent era. Chow et al conclude that although white patients with renal cell carcinoma have a survival advantage over black patients in nearly all categories evaluated, the underlying mechanisms have not been described. We applaud their efforts to bring this important observation to the forefront of medical thought, especially as we undergo a tumultuous overhaul of the medical system aimed in part at reducing differential health outcomes. Their article provides an important foundation for further examination into disparities, as well as demonstrates the need to take a deeper look beyond the characteristics of black and white race and gender. Indeed, recent examinations into urologic oncology procedures indicate that income=socioeconomic status, insurance type, and access to care may play just as an important role as race. Furthermore, as the genomics era flourishes, we are gaining insights that indicate that differences in race may have less to do with the genomic and molecular underpinnings of disease than once thought, with genetic variations demonstrating a higher prevalence within racial and ethnic groups than between groups. Taken together, these findings indicate that race itself may not be the underlying cause of differential outcomes, but instead may be a marker of environmental, situational, and other nonbiologic factors, as well as a continued differential in interpersonal interactions. As the field moves forward in the important examination of health care disparities, a more complex examination of interacting factors, as initiated by Chow et al, will be needed to identify those areas in which future interventions can have the most impact to improve the health of all patients.

Re: Phillip J. Gray, Stacey A. Fedewa, William U. Shipley, et al. Use of Potentially Curative Therapies for Muscle-invasive Bladder Cancer in the United States: Results from the National Cancer Data Base. Eur Urol 2013;63:823–9

We applaud the work by Gray et al. in defining contemporary treatment patterns for muscle-invasive bladder cancer, going beyond just surgery and evaluating disparities in receipt of standard-of-care therapies [1]. Their work highlights the inferior care received by the disadvantaged groups in the United States, including the elderly, blacks, and the uninsured. In particular, Gray et al. demonstrate that these vulnerable patient populations have a greater risk of not receiving aggressive therapy for an aggressive malignancy: bladder cancer [1]. This study, along with others, continues the description of disparities in cancerspecific survival in disadvantaged groups spanning the urologic malignancies, as well as other cancers [2–4]. This work is instrumental in an understanding of the multiple influences on the health outcomes of our patients and the magnitude of worse outcomes among disadvantaged groups, including elderly patients. However, an important question remains: What do we do next? While some of the disparities in the United States may be addressed by the implementation of the Affordable Care Act—specifically, access to care by the uninsured—disparities in other groups are likely to persist. Disparities in access to high-quality oncologic care among minorities, uninsured patients, and underinsured patients have been well documented. Yet research dedicated to examining the causal factors that explain these disparities in health outcomes and proposing interventions or policies to ameliorate them have been lacking. The National Institutes of Health in recent years has recognized the limited and delayed application of basic science work to the community and has implemented programs aimed at fostering the ‘‘bench-to-bedside’’ transition. With this paradigm in mind, increased effort is needed to translate the health disparities research at numerous academic centers into actual implementation within the community, in essence, going from database to ‘‘Main Street.’’ One such method is the initiation of community-based participatory research, as described recently by Wilson et al. in an effort funded by the National Institute on Minority Health and Health Disparities [5]. In that example, knowledge of the differential racial outcomes in prostate cancer mortality was the basis of a project that gathered university researchers, community leaders, and community members to design and implement an educational tool aimed directly at increasing the informed decision making regarding prostate cancer screening in the African American community of Tampa Bay, Florida. In doing so, the researchers went beyond simply acknowledging that disparities exist and recruited and engaged a specific atrisk community. By engaging the community itself in the design and implementation process, an intervention was created that was specifically designed by and for the target population. With time, such community-engaged research may prove to be the optimal tool needed to address the continued disparities recognized by Gray et al. [1].