Paul Perrotte

Multi-Institutional Validation of a New Renal Cancer–Specific Survival Nomogram

PURPOSE We tested the hypothesis that the prediction of renal cancer-specific survival can be improved if traditional predictor variables are used within a prognostic nomogram. PATIENTS AND METHODS Two cohorts of patients treated with either radical or partial nephrectomy for renal cortical tumors were used: one (n = 2,530) for nomogram development and for internal validation (200 bootstrap resamples), and a second (n = 1,422) for external validation. Cox proportional hazards regression analyses modeled the 2002 TNM stages, tumor size, Fuhrman grade, histologic subtype, local symptoms, age, and sex. The accuracy of the nomogram was compared with an established staging scheme. RESULTS Cancer-specific mortality was observed in 598 (23.6%) patients, whereas 200 (7.9%) died as a result of other causes. Follow-up ranged from 0.1 to 286 months (median, 38.8 months). External validation of the nomogram at 1, 2, 5, and 10 years after nephrectomy revealed predictive accuracy of 87.8%, 89.2%, 86.7%, and 88.8%, respectively. Conversely, the alternative staging scheme predicting at 2 and 5 years was less accurate, as evidenced by 86.1% (P = .006) and 83.9% (P = .02) estimates. CONCLUSION The new nomogram is more contemporary, provides predictions that reach further in time and, compared with its alternative, which predicts at 2 and 5 years, generates 3.1% and 2.8% more accurate predictions, respectively.

Radical versus partial nephrectomy: effect on overall and noncancer mortality.

Relative to radical nephrectomy (RN), partial nephrectomy (PN) performed for renal cell carcinoma (RCC) may protect from non‐cancer‐related deaths. The authors tested this hypothesis in a cohort of PN and RN patients.

A Nomogram Predicting 10-Year Life Expectancy in Candidates for Radical Prostatectomy or Radiotherapy for Prostate Cancer

PURPOSE Candidates for definitive therapy for localized prostate cancer (PCa) should have life expectancy (LE) in excess of 10 years. However, LE estimation is difficult. To circumvent this problem, we developed a nomogram predicting 10-year LE for patients treated with either radical prostatectomy (RP) or external-beam radiation therapy (EBRT) and compared it with an existing tool. PATIENTS AND METHODS Between 1989 and 2000, 9,131 men were treated with either RP (n = 5,955) or EBRT (n = 3,176), without any secondary therapy and all deaths were considered unrelated to PCa. Age and Charlson comorbidity index (CCI) predicted 10-year LE in Cox regression models. We used 200 bootstrap resamples to internally validate the nomogram. RESULTS Median age was 66 years, median CCI was 1, median follow-up was 5.9 years and median actuarial survival was 13.8 years. Advanced age (P < .001), elevated CCI score (P < .001) and treatment type (EBRT v RP, P < .001) were independent predictors of poor 10 year LE. The nomogram predicting 10 year LE after either RP or EBRT was 84.3% accurate in split sample validation and was 2.9% (P = .007) more accurate than the existing tool. A cutoff of 70% or less was 84% accurate in identifying men who did not survive beyond 10 years. CONCLUSION Our nomogram can accurately identify those individuals who do not have sufficient LE to warrant definitive PCa treatment and can help optimizing therapy decision-making.

Age-Adjusted Incidence, Mortality, and Survival Rates of Stage-Specific Renal Cell Carcinoma in North America: A Trend Analysis

BACKGROUND The rising incidence of renal cell carcinoma (RCC) has been largely attributed to the increasing use of imaging procedures. OBJECTIVE Our aim was to examine stage-specific incidence, mortality, and survival trends of RCC in North America. DESIGN, SETTING, AND PARTICIPANTS We computed age-adjusted incidence, survival, and mortality rates using the Surveillance Epidemiology and End Results database. Between 1988 and 2006, 43,807 patients with histologically confirmed RCC were included. MEASUREMENTS We calculated incidence, mortality, and 5-yr survival rates by year. Reported findings were stratified according to disease stage. RESULTS AND LIMITATIONS Age-adjusted incidence rate of RCC rose from 7.6 per 100,000 person-years in 1988 to 11.7 in 2006 (estimated annual percentage change [EAPC]: +2.39%; p<0.001). Stage-specific age-adjusted incidence rates increased for localized stage: 3.8 in 1988 to 8.2 in 2006 (EAPC: +4.29%; p<0.001) and decreased during the same period for distant stage: 2.1 to 1.6 (EAPC: -0.57%; p=0.01). Stage-specific survival rates improved over time for localized stage but remained stable for regional and distant stages. Mortality rates varied significantly over the study period among localized stage, 1.3 in 1988 to 2.4 in 2006 (EAPC: +3.16%; p<0.001), and distant stage, 1.8 in 1988 to 1.6 in 2006 (EAPC: -0.53%; p=0.045). Better detailed staging information represents a main limitation of the study. CONCLUSIONS The incidence rates of localized RCC increased rapidly, whereas those of distant RCC declined. Mortality rates significantly increased for localized stage and decreased for distant stage. Innovation in diagnosis and management of RCC remains necessary.

Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma.

We examined the expression levels of a number of metastasis-related genes to determine the relationship of these levels to the development of metastasis in renal cell carcinoma. Gene expression was examined in 46 formalin-fixed, paraffin-embedded, archival specimens of primary organ-confined, clear-cell, renal cell carcinoma from patients who had undergone radical nephrectomy. Twenty samples were from patients who did not have metastasis after a median of 48 months; 26 were from patients with either synchronous or metachronous metastases. Microvessel density was assessed by anti-CD-34 immunohistochemical analysis. The expression levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), matrix metalloproteinases (MMP)-2 and -9, and E-cadherin were examined at the periphery of the tumor by a colorimetric in situ mRNA. The expression levels of bFGF, VEGF, IL-8, MMP-2, and MMP-9 were significantly higher in primary renal tumors from patients with either synchronous or metachronous metastases than those who were disease-free at a median of 48 months of follow-up. Multivariate analysis of disease-free survival showed that the ratio of MMP-9 to E-cadherin (P = 0.012) and the expression level of bFGF expression (P = 0.045), were independent predictors for the development of metastases. The expression levels of bFGF, VEGF, and IL-8 did not correlate with microvessel density, which in itself was not a significant predictor of progression (P = 0.21). In summary, expression levels of genes that regulate metastasis angiogenesis can predict the metastatic potential in individual patients with organ-confined clear-cell renal carcinoma.

Distribution of metastatic sites in renal cell carcinoma: a population-based analysis

BACKGROUND We assessed the distribution of site-specific metastases in patients with renal cell carcinoma (RCC) according to age. Moreover, we evaluated recommendations proposed by guidelines and focused specifically on bone and brain metastases. PATIENTS AND METHODS Patients with metastatic RCC (mRCC) were abstracted from the Nationwide Inpatient Sample (1998-2007). Age was stratified into four groups: <55, 55-64, 65-74 and ≥ 75 years. Cochran-Armitage trend test and multivariable logistic regression analysis tested the relationship between age and the rate of multiple metastatic sites. Finally, we examined the rates of brain or bone metastases according to the presence of other metastatic sites. RESULTS In 11,157 mRCC patients, the rate of multiple metastatic sites decreased with increasing age (P < 0.001). This phenomenon was confirmed in patients with lung, bone, liver and brain metastases (all P ≤ 0.01). The rate of bone metastases was 10% in patients with exclusive abdominal metastases and 49% in patients with abdominal, thoracic and brain metastases. The rate of brain metastases was 2% in patients with exclusive abdominal metastases and 16% in patients with thoracic and bone metastases. CONCLUSIONS The proportion of patients with multiple metastatic sites is higher in young patients. The rates of bone (10%-49%) and brain (2%-16%) metastases are nonnegligible in mRCC patients.

Validation of a Nomogram for Prediction of Side Specific Extracapsular Extension at Radical Prostatectomy

PURPOSE We have previously have reported a tree structured regression model for predicting SS-ECE. Others recently reported a logistic regression based SS-ECE nomogram. We developed a nomogram and compared the performance and discriminant properties of the tree regression and the nomogram in a contemporary cohort of European patients treated with radical retropubic prostatectomy. MATERIALS AND METHODS The cohort consisted of 1,118 patients with pretreatment prostate specific antigen 0.1 to 73.2 ng/ml (median 6.6). Each of the 2,236 prostate lobes was considered separately. Clinical stage, pretreatment PSA, biopsy Gleason sum, percent positive cores and percent cancer in the biopsy specimen were used as predictors in a logistic regression model predicting SS-ECE. Regression coefficients were then used to generate an SS-ECE nomogram. Performance characteristics and discriminant properties of the previously published tree regression were also tested in the same cohort. For internal validation and to decrease overfit bias 200 bootstrap re-samples were applied to accuracy estimates for each method. RESULTS ECE was present in 303 of 1,118 radical retropubic prostatectomy specimens (27%) and in 385 lobes (17%). In logistic regression models all variables were statistically significant multivariate predictors of SS-ECE except the percent of positive biopsy cores (p = 0.7). Bootstrap corrected predictive accuracy of the SS-ECE nomogram was 0.840 vs 0.700 for the tree regression model. CONCLUSIONS Logistic regression based nomogram predictions of SS-ECE are highly accurate and represent a valuable aid for assessing the risk of ECE prior to surgery.

C-reactive protein is an informative predictor of renal cell carcinoma-specific mortality: a European study of 313 patients.

C‐reactive protein (CRP) represents a promising prognostic variable in patients with sporadic renal cell carcinoma (RCC). It was hypothesized that CRP can improve the prognostic ability of standard RCC‐specific mortality (RCC‐SM) predictors in patients treated with nephrectomy for all stages of RCC.

A Competing-Risks Analysis of Survival After Alternative Treatment Modalities for Prostate Cancer Patients: 1988–2006

BACKGROUND The efficacy of prostate cancer (PCa) treatment modalities is a subject of continuous debate. OBJECTIVE We tested the hypothesis that significant differences in survival rates may exist among PCa patients treated with radical prostatectomy (RP), radiation therapy (RT), and observation. DESIGN, SETTING, AND PARTICIPANTS We focused on 404,604 patients with clinically localized PCa within 17 Surveillance, Epidemiology and End Results registries. MEASUREMENTS Competing-risks survival analyses were used to estimate cancer-specific mortality (CSM) and other-cause mortality (OCM) rates. Patients were stratified according to treatment type, age group, and PCa risk group (high risk: T2c and/or Gleason score 8-10; low to intermediate risk: all others). RESULTS AND LIMITATIONS The 10-yr CSM and OCM rates were 6.1% and 29.2%, respectively. In RP, RT, and observation patients, CSM rates were 3.6%, 6.5%, and 10.8% (p<0.001), respectively; OCM rates were 17.1%, 32.4%, and 48.9% (p<0.001), respectively. In low- to intermediate-risk patients, the lowest CSM (1.3-3.7%) and OCM (6.9-31.6%) rates within all age categories except octogenarians (8.9% and 62.8%, respectively) were recorded in RP. In high-risk patients, the lowest CSM (5.8-7.2%) and OCM (8.7-16.1%) rates in patients aged ≤69 yr were also recorded in RP. RT was equally favorable to RP in the 70-79 age category and appeared ideal in all octogenarian patients. CONCLUSIONS Our results showed that RP provides the most favorable survival rates in most patients. The exception is octogenarian men, in whom RT provides the best results. Finally, the least-favorable outcomes were recorded after observation. However, these findings must be interpreted within the context of the limitations of observational data.

Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: A phase I study of p53 gene therapy

PURPOSE We investigated the feasibility, safety, and biologic activity of adenovirus-mediated p53 gene transfer in patients with locally advanced bladder cancer. PATIENTS AND METHODS Patients with measurable, locally advanced transitional-cell carcinoma of the bladder who were not candidates for cystectomy were eligible. On a 28-day cycle, intravesical instillations of INGN 201 (Ad5CMV-p53) were administered on days 1 and 4 at three dose levels (10(10) particles to 10(12) particles) or on either 4 or 8 consecutive days at a single dose level (10(12) particles). RESULTS Thirteen patients received a total of 22 courses without dose-limiting toxicity. Specific transgene expression was detected by reverse transcriptase polymerase chain reaction in bladder biopsy tissue from two of seven assessable patients. There were no changes in p53, p21waf1/cip1, or bax protein levels in bladder epithelium evident from immunohistochemical analysis of 11 assessable patients. Outpatient administration of multiple courses was feasible and well tolerated. A patient with advanced superficial bladder cancer showed evidence of tumor response. CONCLUSION Intravesical instillation of Ad5CMV-p53 is safe, feasible, and biologically active when administered in multiple doses to patients with bladder cancer. Observations from this study indicate that this treatment has an antitumor effect in superficial transitional-cell carcinoma. Improvements in the efficiency of gene transfer and the levels of gene expression are required to develop more effective gene therapy for bladder cancer.