Wade J. Sexton

Pathologic Variables and Recurrence Rates As Related to Obesity and Race in Men With Prostate Cancer Undergoing Radical Prostatectomy

PURPOSE To determine if obesity is associated with higher prostate specific antigen recurrence rates after radical prostatectomy (RP), and to explore racial differences in body mass index (BMI) as a potential explanation for the disparity in outcome between black and white men. PATIENTS AND METHODS A retrospective, multi-institutional pooled analysis of 3,162 men undergoing RP was conducted at nine US military medical centers between 1987 and 2002. Patients were initially categorized as obese (BMI > or = 30 kg/m(2)), overweight (BMI 25 to 30 kg/m(2)), or normal (BMI < or = 25 kg/m(2)). For analysis, normal and overweight groups were combined (BMI < 30 kg/m(2)) and compared with the obese group (BMI > or = 30 kg/m(2)) with regard to biochemical recurrence (prostate-specific antigen > or = 0.2 ng/mL) after RP. RESULTS Of 3,162 patients, 600 (19.0%) were obese and 2,562 (81%) were not obese. BMI was an independent predictor of higher Gleason grade cancer (P <.001) and was associated with a higher risk of biochemical recurrence (P =.027). Blacks had higher BMI (P <.001) and higher recurrence rates (P =.003) than whites. Both BMI (P =.028) and black race (P =.002) predicted higher prostate specific antigen recurrence rates. In multivariate analysis of race, BMI, and pathologic factors, black race (P =.021) remained a significant independent predictor of recurrence. CONCLUSION Obesity is associated with higher grade cancer and higher recurrence rates after RP. Black men have higher recurrence rates and greater BMI than white men. These findings support the hypothesis that obesity is associated with progression of latent to clinically significant prostate cancer (PC) and suggest that BMI may account, in part, for the racial variability in PC risk.

Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy

PURPOSE Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach. MATERIALS AND METHODS Of 5,382 men in the database who underwent primary radical prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1,352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome. RESULTS Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05). CONCLUSIONS The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue.

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial

BACKGROUND Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.

Alvimopan Accelerates Gastrointestinal Recovery After Radical Cystectomy: A Multicenter Randomized Placebo-Controlled Trial

BACKGROUND Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). OBJECTIVE To assess the efficacy of alvimopan to accelerate GI recovery after RC. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. INTERVENTION Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. RESULTS AND LIMITATIONS Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. CONCLUSIONS Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. PATIENT SUMMARY This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT00708201.

Temporarily Deferred Therapy (watchful waiting) for Men Younger Than 70 Years and With Low-Risk Localized Prostate Cancer in the Prostate-Specific Antigen Era

Purpose: Watchful waiting (WW) is an acceptable strategy for managing prostate cancer (PC) in older men. Prostate-specific antigen (PSA) testing has resulted in a stage migration, with diagnoses made in younger men. An analysis of the Department of Defense Center for Prostate Disease Research Database was undertaken to document younger men with low- or intermediate-grade PC who initially chose WW. Patients and Methods: We identified men choosing WW who were diagnosed between January 1991 and January 2002, were 70 years or younger, had a Gleason score ≤ 6 with no Gleason pattern 4, had no more than three positive cores on biopsy, and whose clinical stage was ≤ T2 and PSA level was ≤ 20. We analyzed their likelihood of remaining on WW, the factors associated with secondary treatment, and the influence of comorbidities. Results: Three hundred thirteen men were identified. Median follow-up time was 3.8 years. Median age was65.4 years (range, 41 to 70 years). Ninety-eight patients remained on WW; 215 proceeded...

Bladder cancer: a review of non-muscle invasive disease.

BACKGROUND Bladder cancer is one of the most common cancers affecting men and women and thus has a profound impact on health care. The majority of patients (75%) with newly diagnosed urothelial tumors have non-muscle invasive disease confined to the bladder mucosa or the lamina propria. METHODS The authors review the literature as well as recently published clinical guidelines regarding the bladder cancer risk and causative factors, diagnostic and pathologic evaluation, prognostic variables, and management strategies for patients with non-muscle invasive bladder cancer. RESULTS Recurrence and progression remain problematic for many patients and are dependent on multiple clinical and pathological features, the most important of which are tumor stage, grade, multifocality, size, recurrence patterns, and the association with carcinoma in situ. Accurate assessment of clinical stage and tumor grade is critical in determining management and surveillance strategies. Intravesical therapies positively influence tumor recurrence rates. Disease progression rates may be impacted in high-risk patients who receive both induction bacille Calmette-Guérin (BCG) and a maintenance BCG regimen. Cystectomy still plays a pivotal role in patients with high-risk tumors and in patients who fail more conservative attempts to eradicate non-muscle invasive disease. CONCLUSIONS Non-muscle invasive bladder cancers represent a broad group of tumors with varying biologic potential. Successful treatment depends on the careful integration of diagnostic and surveillance tests, macroablation through transurethral resection, accurate assessment of clinical stage, and the timely and appropriate delivery of intravesical chemotherapeutic and immunomodulatory agents.

Important surgical considerations in the management of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumour thrombus.

Whats known on the subject? and What does the study add?

Alvimopan, a peripherally acting μ-opioid receptor antagonist, is associated with reduced costs after radical cystectomy: economic analysis of a phase 4 randomized, controlled trial.

PURPOSE We evaluated the effect of alvimopan treatment vs placebo on health care utilization and costs related to gastrointestinal recovery in patients treated with radical cystectomy in a randomized, phase 4 clinical trial. MATERIALS AND METHODS Resource utilization data were prospectively collected and evaluated by cost consequence analysis. Hospital costs were estimated from 2012 Medicare reimbursement rates and medication wholesale acquisition costs. Differences in base case mean costs between the study cohorts for total postoperative ileus related costs (hospital days, study drug, nasogastric tubes, postoperative ileus related concomitant medication and postoperative ileus related readmissions) and total combined costs (postoperative ileus related, laboratory, electrocardiograms, nonpostoperative ileus related concomitant medication and nonpostoperative ileus related readmission) were evaluated by probabilistic sensitivity analysis using a bootstrap approach. RESULTS Mean hospital stay was 2.63 days shorter for alvimopan than placebo (mean±SD 8.44±3.05 vs 11.07±8.23 days, p=0.005). Use of medications or interventions likely intended to diagnose or manage postoperative ileus was lower for alvimopan than for placebo, eg total parenteral nutrition 10% vs 25% (p=0.001). Postoperative ileus related health care costs were

Interobserver reliability of the RENAL nephrometry scoring system.

2,340 lower for alvimopan and mean total combined costs were decreased by

Lack of BK virus DNA sequences in most transitional‐cell carcinomas of the bladder

2,640 per patient for alvimopan vs placebo. Analysis using a 10,000-iteration bootstrap approach showed that the mean difference in postoperative ileus related costs (p=0.04) but not total combined costs (p=0.068) was significantly lower for alvimopan than for placebo. CONCLUSIONS In patients treated with radical cystectomy alvimopan decreased hospitalization cost by reducing the health care services associated with postoperative ileus and decreasing the hospital stay.