Philippe E. Spiess

Lymph Node Density Is Superior to TNM Nodal Status in Predicting Disease-Specific Survival After Radical Cystectomy for Bladder Cancer: Analysis of Pooled Data From MDACC and MSKCC

PURPOSE To compare the utility of lymph node density (LND) with TNM nodal status in predicting disease-specific survival (DSS) after radical cystectomy. PATIENTS AND METHODS We identified 248 patients with nodal metastasis after radical cystectomy (without neoadjuvant chemotherapy): 162 patients from Memorial Sloan-Kettering Cancer Center (MSKCC) and 86 patients from M.D. Anderson Cancer Center (MDACC). We assessed the effect of several variables on DSS. RESULTS After a median follow-up duration of 24 months, 134 patients died of their disease. The median DSS was 36 months, and the 1-year, 2-year, and 5-year DSS rates were 83.7%, 57.4%, and 36.6%, respectively. The median LND was 20%. The 5-year DSS rate was 54.6% for patients with LND < or = 20% v 15.3% for patients with LND higher than 20% (P < .01). Pathologic nodal (pN) status in patients was 78 for pN1 (32%), 127 for pN2 (51%), and 43 for pN3 (17%). On univariate analysis, pN status and LND were significant predictors of DSS (P < .01). However, when pN status and LND were considered jointly in a multivariate model, only LND higher than 20% predicted decreased DSS (hazard ratio [HR], 2.75; P < .01). In addition, while nonorgan-confined (ie, > pT2) primary tumor (HR, 2.40; P < .01) and adjuvant chemotherapy (HR, 0.47; P < .01) were predictors of DSS, LND remained a predictor of DSS even after accounting for adjuvant chemotherapy. CONCLUSION LND is superior to TNM nodal status in predicting DSS for patients with lymph node-positive disease after radical cystectomy, even in the context of adjuvant chemotherapy.

Locally Recurrent Prostate Cancer After Initial Radiation Therapy: A Comparison of Salvage Radical Prostatectomy Versus Cryotherapy

PURPOSE We compared the treatment outcomes of salvage radical prostatectomy and salvage cryotherapy for patients with locally recurrent prostate cancer after initial radiation therapy. MATERIALS AND METHODS We retrospectively reviewed the medical records of patients who underwent salvage radical prostatectomy at the Mayo Clinic between 1990 and 1999, and those who underwent salvage cryotherapy at M. D. Anderson Cancer Center between 1992 and 1995. Eligibility criteria were prostate specific antigen less than 10 ng/ml, post-radiation therapy biopsy showing Gleason score 8 or less and prior radiation therapy alone without pre-salvage or post-salvage hormonal therapy. We assessed the rates of biochemical disease-free survival, disease specific survival and overall survival in each group. Biochemical failure was assessed using the 2 definitions of 1) prostate specific antigen greater than 0.4 ng/ml and 2) 2 increases above the nadir prostate specific antigen. RESULTS Mean followup was 7.8 years for the salvage radical prostatectomy group and 5.5 years for the salvage cryotherapy group. Compared to salvage cryotherapy, salvage radical prostatectomy resulted in superior biochemical disease-free survival by both definitions of biochemical failure (prostate specific antigen greater than 0.4 ng/ml, salvage cryotherapy 21% vs salvage radical prostatectomy 61% at 5 years, p <0.001; 2 increases above nadir with salvage cryotherapy 42% vs salvage radical prostatectomy 66% at 5 years, p = 0.002) and in superior overall survival (at 5 years salvage cryotherapy 85% vs salvage radical prostatectomy 95%, p = 0.001). There was no significant difference in disease specific survival (at 5 years salvage cryotherapy 96% vs salvage radical prostatectomy 98%, p = 0.283). After adjusting for post-radiation therapy biopsy Gleason sum and pre-salvage treatment serum prostate specific antigen on multivariate analysis salvage radical prostatectomy remained superior to salvage cryotherapy for the end points of any increase in prostate specific antigen greater than 0.4 ng/ml (HR 0.24, p <0.0001), 2 increases in prostate specific antigen (HR 0.47, p = 0.02) and overall survival (HR 0.21, p = 0.01). CONCLUSIONS Young, healthy patients with recurrent prostate cancer after radiation therapy should consider salvage radical prostatectomy as it offers superior biochemical disease-free survival and may potentially offer the best chance of cure.

Treatment Outcomes of Small Cell Carcinoma of the Prostate A Single-Center Study

The current study was conducted to determine the clinical characteristics and prognostic features associated with prostatic small cell carcinoma (SCC).

Pretreatment Semen Parameters in Men With Cancer

PURPOSE Whether the presence or specific type of cancer significantly affects semen quality is controversial. We evaluated the semen parameters and associated malignancies of men with cancer who cryopreserved sperm at our institution before undergoing therapy. MATERIALS AND METHODS We reviewed the database from our cryopreservation laboratory during a 5-year period. Office charts of 409 of 1,409 patients were available for review. Age at banking, semen volume, sperm density, percent motile sperm and type of cancer were recorded. Semen parameters were compared to values for fertile and subfertile men established by the National Cooperative Reproductive Medicine Network as well as from a large local pre-vasectomy cohort to consider geographic variations. RESULTS A total of 717 semen samples from 409 men included 45% with testicular cancer, 10% with Hodgkins lymphoma, 7% with nonHodgkins lymphoma, 6% with sarcoma, 6% with prostate cancer, 5% with leukemia, 3% with gastrointestinal cancer and 2% with central nervous system tumors. Of these men 16% had unspecified or other rare malignancies. Mean patient age was 29.9 years (range 11.9 to 87.7), mean semen volume was 2.8 ml (range 0.1 to 15.0), mean sperm density was 47.4 x 10(6)/ml (range 0.1 to 320) and mean sperm motility was 50.0% (range 1% to 90%). For men with testicular cancer sperm density and motility were in the intermediate range. Parameters for men with all other malignancies were in the fertile range for density and intermediate range for motility. CONCLUSIONS Men with most types of cancer have pretreatment semen parameters in the fertile range for density and in the intermediate range for motility. However, men with testicular cancer statistically have lower semen quality compared to those with other malignancies. These findings further highlight the importance of pretreatment fertility preservation in this patient population before undergoing gonadotoxic treatments.

Multicenter Assessment of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

BACKGROUND The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting. OBJECTIVE We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013. INTERVENTION NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages. RESULTS AND LIMITATIONS Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6). CONCLUSIONS Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined. PATIENT SUMMARY There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.

Prostate cancer progression in the presence of undetectable or low serum prostate-specific antigen level.

The serum prostate‐specific antigen (PSA) level after definitive treatment for prostate cancer (PC) is a powerful predictor of outcome. Occasionally, PC progression can occur despite low or undetectable PSA levels. The authors report on the clinical and pathologic characteristics of patients who experienced PC progression with undetectable or low PSA levels.

Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison

PURPOSE Men receiving androgen-deprivation therapy (ADT) for prostate cancer may be at risk for cognitive impairment; however, evidence is mixed in the existing literature. Our study examined the impact of ADT on impaired cognitive performance and explored potential demographic and genetic predictors of impaired performance. PATIENTS AND METHODS Patients with prostate cancer were assessed before or within 21 days of starting ADT (n = 58) and 6 and 12 months later. Age- and education-matched patients with prostate cancer treated with prostatectomy only (n = 84) and men without prostate cancer (n = 88) were assessed at similar intervals. Participants provided baseline blood samples for genotyping. Mean-level cognitive performance was compared using mixed models; cognitive impairment was compared using generalized estimating equations. RESULTS ADT recipients demonstrated higher rates of impaired cognitive performance over time relative to all controls (P = .01). Groups did not differ at baseline (P > .05); however, ADT recipients were more likely to demonstrate impaired performance within 6 and 12 months (P for both comparisons < .05). Baseline age, cognitive reserve, depressive symptoms, fatigue, and hot flash interference did not moderate the impact of ADT on impaired cognitive performance (P for all comparisons ≥ .09). In exploratory genetic analyses, GNB3 single-nucleotide polymorphism rs1047776 was associated with increased rates of impaired performance over time in the ADT group (P < .001). CONCLUSION Men treated with ADT were more likely to demonstrate impaired cognitive performance within 6 months after starting ADT relative to matched controls and to continue to do so within 12 months after starting ADT. If confirmed, findings may have implications for patient education regarding the risks and benefits of ADT.

Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer : Implications for therapy

Purpose: It has previously been reported that the patient response to gefitinib depends on the presence of mutations within the kinase domain of epidermal growth factor receptor (EGFR) or the expression of its truncated form, EGFR variant III (EGFRvIII). The focus of this study was to determine if these alterations are present within the tyrosine kinase and ligand-binding domain of EGFR in urothelial carcinoma. Experimental Design: The kinase domain found within exons 18 to 21 of the EGFR from 11 bladder cancer cell lines and 75 patient tumors were subjected to automated sequencing. EGFRvIII expression was determined by immunohistochemistry using a urothelial carcinoma tissue microarray, and its expression was subsequently verified by reverse transcription PCR, real-time PCR, and Western blot analysis, using an EGFRvIII-transfected glioblastoma cell line and glioblastoma tumors as positive controls. Results: Our analysis failed to detect mutations within the tyrosine kinase domain of EGFR in the 11 cell lines and 75 patients tested. The initial analysis of EGFRvIII expression by immunohistochemistry revealed that at least 50% of the patient tumors expressed EGFRvIII in a urothelial carcinoma tissue microarray. Conflicting reports exist, however, regarding the extent of EGFRvIII expression in tissues owing to the specificity of the antibodies and the methodologies used. Therefore, we sought to validate this observation by reverse transcription PCR, real-time PCR, and Western blot analysis. In these assays, none of the samples were positive for EGFRvIII except for control transfectants and glioblastomas. Conclusions: When our results are taken together, we conclude that alterations within the tyrosine kinase domain and expression of EGFRvIII are rare events in bladder cancer. The present study has clinical implications in selecting tyrosine kinase inhibitors for the therapy of urothelial carcinoma.

Quantitation of Aurora Kinase A Gene Copy Number in Urine Sediments and Bladder Cancer Detection

BACKGROUND Chromosome missegregation and the resulting aneuploidy is a common change in neoplasia. The Aurora kinase A (AURKA) gene, which encodes a key regulator of mitosis, is frequently amplified and/or overexpressed in cancer cells, and the level of AURKA amplification is associated with the level of aneuploidy. We examined whether AURKA gene amplification is a biomarker for the detection of bladder cancer. METHODS The effect of ectopic expression of Aurora kinase A (AURKA) using an adenoviral vector in simian virus 40-immortalized urothelial cells (SV-HUC) on centrosome multiplication and chromosome copy number was measured in vitro by immunofluorescence and fluorescence in situ hybridization (FISH), respectively. The FISH test was also used to examine AURKA gene copy number in exfoliated cells in voided urine samples from 23 patients with bladder cancer and 7 healthy control subjects (training set), generating a model for bladder cancer detection that was subsequently validated in an independent set of voided urine samples from 100 bladder cancer patients and 148 control subjects (92 healthy individuals and 56 patients with benign urologic disorders). An AURKA gene score (the proportion of cells with three or more AURKA signals) was used to produce receiver operating characteristic (ROC) curves and to calculate the specificity and sensitivity of the AURKA FISH test. Differences between mean AURKA scores in different pathogenetic groups of bladder cancer stratified according to histological grade and stage were tested by unpaired Mann-Whitney t tests or one-way Wilcoxon tests. All statistical tests were two-sided. RESULTS Forced overexpression of AURKA in urothelial cells induced amplification of centrosomes, chromosome missegregation, and aneuploidy, and natural overexpression was detectable in in situ lesions from patients with bladder cancer. The FISH test for the AURKA gene copy number performed on the validation set yielded a specificity of 96.6% (95% confidence interval [CI] = 92.3% to 98.5%) and sensitivity of 87% (95% CI = 79.0% to 92.2%) and an area under the ROC curve of 0.939 (95% CI = 0.906 to 0.971; P < .001). CONCLUSION Overexpression of AURKA can cause aneuploidy in urothelial cells, and the AURKA gene copy number is a promising biomarker for detection of bladder cancer.

Salvage Cryoablation for Locally Recurrent Prostate Cancer Following Primary Radiotherapy

CONTEXT The purpose of this paper is to review current salvage cryoablation (SCA) outcomes in patients with locally recurrent prostate cancer (PCa) following primary radiation therapy. OBJECTIVE The objectives of this review are (1) to analyze the eligibility criteria for careful patient selection for these salvage modalities and (2) to evaluate the oncologic results and reported complication rates for these respective modalities. EVIDENCE ACQUISITION A Medline/PubMed literature search was performed of peer-reviewed scientific articles published from 1991 to 2012 regarding salvage therapy for radiorecurrent PCa. The following search terms and various permutations were used: radiorecurrent prostate cancer, local salvage treatment, salvage radical prostatectomy, salvage cryoablation, salvage brachytherapy, and salvage high-intensity focused ultrasound. Only articles written in English were included. EVIDENCE SYNTHESIS SCA is a feasible and efficacious treatment modality, especially using third-generation technology, whereby the biochemical disease-free survival is estimated to be between 50% and 70% at 5-yr follow-up in properly selected patients. Severe complications such as rectourethral fistulas are significantly less common over the last decade than was reported in the past. Because there are no prospective, randomized studies and the definitions of PSA failure vary among many studies, comparisons between these different salvage modalities are limited in terms of cancer-specific outcomes. Nevertheless, in recent years, tertiary care referral centers for prostate cryotherapy have reported their treatment outcomes using rigorous treatment end points and morbidity grading systems, dramatically improving the quality of reported clinical data. Consequently, favorable predictors of treatment outcomes have been identified. CONCLUSIONS The inability to effectively salvage patients with locally recurrent PCa following radiation therapy has in large part resulted from the lack of sufficiently sensitive and specific diagnostic tools to detect local recurrences at an early, potentially curable stage. Consequently, a more stringent definition of biochemical failure, improved imaging techniques, and accurate PCa mapping imaging technology is greatly needed within our diagnostic armamentarium. Additional research and randomized clinical trials are required to determine which salvage modality is superior in terms of oncologic efficacy and reduced morbidity.