Delayed radical prostatectomy for intermediate-risk prostate cancer is associated with biochemical recurrence: possible implications for active surveillance from the SEARCH database.

INTRODUCTION: Active surveillance (AS) is increasingly accepted as appropriate management for low-risk prostate cancer (PC) patients. It is unknown whether delaying radical prostatectomy (RP) is associated with increased risk of biochemical recurrence (BCR) for men with intermediate-risk PC. METHODS: We performed a retrospective analysis of 1,561 low and intermediate-risk men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database treated with RP between 1988 and 2011. Patients were stratified by interval between diagnosis and RP (≤ 3, 3-6, 6-9, or >9 months) and by risk using the D'Amico classification. Cox proportional hazard models were used to analyze BCR. Logistic regression was used to analyze positive surgical margins (PSM), extracapsular extension (ECE), and pathologic upgrading. RESULTS: Overall, 813 (52%) men were low-risk, and 748 (48%) intermediate-risk. Median follow-up among men without recurrence was 52.9 months, during which 437 men (38.9%) recurred. For low-risk men, RP delays were unrelated to BCR, ECE, PSM, or upgrading (all P > 0.05). For intermediate-risk men, however, delays >9 months were significantly related to BCR (HR: 2.10, P = 0.01) and PSM (OR: 4.08, P < 0.01). Delays >9 months were associated with BCR in subsets of intermediate-risk men with biopsy Gleason score ≤ 3 + 4 (HR: 2.51, P < 0.01), PSA ≤ 6 (HR: 2.82, P = 0.06), and low tumor volume (HR: 2.59, P = 0.06). CONCLUSIONS: For low-risk men, delayed RP did not significantly affect outcome. For men with intermediate-risk disease, delays >9 months predicted greater BCR and PSM risk. If confirmed in future studies, this suggests delayed RP for intermediate-risk PC may compromise outcomes.

Differing perceptions of quality of life in patients with prostate cancer and their doctors.

PURPOSE: As the number of prostate cancer survivors increases, urologists must recognize their quality of life impairment. In the past physician ratings of patient symptoms did not correlate with patient self-assessments. We determined if urologists have improved their reporting of patient health related quality of life. We also investigated if urologists assessed health related quality of life more accurately in the short or long term. MATERIALS AND METHODS: We identified 1,366 men from CaPSURE™, a national, prospective cohort, who had undergone prostatectomy, brachytherapy or external beam radiation therapy. At each visit urologists assessed fatigue, pain, and sexual, urinary and bowel dysfunction. Participants independently completed the SF-36™ and the UCLA-PCI. We contrasted the frequency of impairment reported by physicians and participants in select health related quality of life domains in the short (less than 1 year) and long (greater than 2 years) term. We also compared physician-patient concordance between the periods 1995 to 2000 and 2001 to 2007. RESULTS: In short-term and long-term followup, and for the 1995 to 2000 and 2001 to 2007 cohorts, physician and participant assessments differed in all analyzed domains. Urologists noted impairment in urinary and sexual function more often than fatigue or pain. Disagreement between physician and participant ratings did not vary dramatically from short-term to long-term followup, or from the earlier to the later cohort. CONCLUSIONS: In men treated for localized prostate cancer physician ratings of symptoms do not correlate well with patient self-assessments of health related quality of life. Physician reporting did not improve over time. It is increasingly important to recognize and address impairments in quality of life from prostate cancer and its treatment.

Diabetes predicts metastasis after radical prostatectomy in obese men: results from the SEARCH database.

OBJECTIVE: To examine the association between diabetes and metastasis risk after radical prostatectomy (RP) and to determine if race or obesity modifies this relationship. PATIENTS AND METHODS: Patients comprised 2058 US veterans with prostate cancer (PCa) enrolled in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database and treated with RP between 1988 and 2010. The association of diabetes with metastasis risk or secondary treatment rates was examined using Cox proportional hazards, adjusting for preoperative and, separately, clinical and postoperative findings. The effect modification by race (black vs white) and obesity (body mass index [BMI] ≥30 vs <30 kg/m(2) ) was tested via interaction terms. RESULTS: Men with diabetes had higher BMIs and were more likely to be non-white (all P ≤ 0.001). On multivariable analysis, diabetes was not associated with metastasis risk (P ≥ 0.45), but, among men with diabetes, longer diabetes duration was associated with higher metastasis risk (P ≤ 0.035). When stratified by obesity, diabetes was linked with higher metastasis risk in obese but not in non-obese men (P-interaction ≤ 0.037), but there was no significant interaction with race (P-interaction ≥ 0.56). Diabetes also predicted more aggressive secondary treatment among obese men but less aggressive treatment among non-obese men (hazard ratio 1.39 vs 0.63, P-interaction = 0.006). Where applicable, results were similar for both pre- and postoperative models. CONCLUSIONS: Diabetes was not associated with metastasis risk overall. Stratification by obesity yielded significant differences, with diabetes linked to a fourfold higher metastasis risk in obese men, despite predicting more aggressive secondary treatment. Longer diabetes duration was also associated with increased metastasis risk.

High serum folate is associated with reduced biochemical recurrence after radical prostatectomy: results from the SEARCH Database.

INTRODUCTION: To analyze the association between serum levels of folate and risk of biochemical recurrence after radical prostatectomy among men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. MATERIALS AND METHODS: Retrospective analysis of 135 subjects from the SEARCH database treated between 1991-2009 with available preoperative serum folate levels. Patients' characteristics at the time of the surgery were analyzed with ranksum and linear regression. Uni- and multivariable analyses of folate levels (log-transformed) and time to biochemical recurrence were performed with Cox proportional hazards. RESULTS: The median preoperative folate level was 11.6 ng/mL (reference = 1.5-20.0 ng/mL). Folate levels were significantly lower among African-American men than Caucasians (P = 0.003). In univariable analysis, higher folate levels were associated with more recent year of surgery (P < 0.001) and lower preoperative PSA (P = 0.003). In univariable analysis, there was a trend towards lower risk of biochemical recurrence among men with high folate levels (HR = 0.61, 95 %CI = 0.37-1.03, P = 0.064). After adjustments for patients characteristics' and pre- and post-operative clinical and pathological findings, higher serum levels of folate were independently associated with lower risk for biochemical recurrence (HR = 0.42, 95 %CI = 0.20-0.89, P = 0.023). CONCLUSION: In a cohort of men undergoing radical prostatectomy at several VAs across the country, higher serum folate levels were associated with lower PSA and lower risk for biochemical failure. While the source of the folate in the serum in this study is unknown (i.e. diet vs. supplement), these findings, if confirmed, suggest a potential role of folic acid supplementation or increased consumption of folate rich foods to reduce the risk of recurrence.

Effect of race and socioeconomic status on surgical margins and biochemical outcomes in an equal-access health care setting: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

BACKGROUND: The impact of race and socioeconomic status (SES) in prostate cancer (CaP) outcomes has been well-studied, but controversy remains. The associations of race/SES with intermediate CaP outcomes, including positive surgical margin (PSM) and biochemical recurrence (BCR), were explored in an equal-access setting. METHODS: Data were retrospectively collected from 2502 men in the Shared Equal Access Regional Cancer Hospitals (SEARCH) database who underwent radical prostatectomy from 1989 to 2010. SES (income, education, employment, and poverty) was estimated from linkage of home ZIP code to census data. Logistic regression with adjustment for pre- and postoperative covariates estimated risk for associations between race/SES and pathologic outcomes. Cox proportional hazards models estimated risk for associations between race/SES and time to BCR. RESULTS: Black men were more likely to have lower SES than white men (P < .001). On multivariate analysis, race was not associated with PSM, but higher SES was associated with less PSM and fewer Gleason sum ≥ 7 pathologic tumors when SES was assessed by education, employment, or poverty (P trend ≤ .051) and income, employment, or poverty (P trend ≤ 0.059), respectively. Crude Cox models showed black men had higher BCR risk (hazards ratio = 1.20, 95% confidence interval = 1.05-1.38, P = .009) that persisted after adjustment for covariates including SES (hazards ratio ≥ 1.18, P ≤ .040). Higher SES measured by income and poverty were associated with less BCR, but only for black men (P trend ≤ .048). CONCLUSIONS: Even in an equal-access setting, higher SES predicted lower PSM risk, and race persisted in predicting BCR despite adjustment for SES. Low SES black patients may be at greatest risk for postprostatectomy BCR.

Prostate size does not predict high grade cancer.

PURPOSE: Several radical prostatectomy series have linked small prostates with high grade cancer based on the hypothesis that a small prostate results from a low androgen milieu that selects for less hormone dependent, more aggressive tumors. We previously reported that this association resulted from ascertainment bias from the performance characteristics of prostate specific antigen rather than from tumor biology in our radical prostatectomy cohort. In this study we analyzed this association in a more generalized population of men who underwent prostate needle biopsy. MATERIALS AND METHODS: The prostate needle biopsy database at our institution was queried for all initial biopsies. Included patient characteristics were age, race, family history of prostate cancer, prostate specific antigen, abnormal digital rectal examination and prostate volume in ml on transrectal ultrasound. Multivariate logistic regression was used to determine the influence of prostate volume on the odds of high grade cancer. RESULTS: The study population included 1,295 patients during 2000 to 2010, of whom 582 (44.9%) had prostate cancer and 398 (30.7%) had high grade cancer. When all patients were pooled, the OR for high grade cancer was 0.85 (95% CI 0.78-0.92) for each 10 ml increase in prostate volume. When patients were divided by clinical T stage, the corresponding ORs for those with T1c disease was 0.83 (95% CI 0.74-0.93) and for those with T2 or greater disease it was 0.99 (0.98-1.00). CONCLUSIONS: The association between small prostates and high grade cancer exists only in men with clinical T1c (normal digital rectal examination) prostate cancer. It likely resulted from ascertainment bias due to the performance characteristics of prostate specific antigen rather than tumor biology.

Plasmacytoid carcinoma of the bladder: a urothelial carcinoma variant with a predilection for intraperitoneal spread.

PURPOSE: Bladder plasmacytoid carcinoma is an invasive urothelial carcinoma subtype that is emphasized for its morphological overlap with plasma cells and metastatic carcinoma. Our experience suggests frequent intraperitoneal spread that is not typical of conventional urothelial carcinoma. MATERIALS AND METHODS: We identified cases of plasmacytoid urothelial carcinoma diagnosed on radical cystectomy. Patient age, gender, American Joint Committee on Cancer (7th edition) stage, metastatic spread/recurrence sites and clinical disease status at last followup were recorded. RESULTS: A total of 10 male and 5 female patients 42 to 81 years old were identified. One tumor was pT2, 11 pT3 and 3 pT4. Six of 15 patients (40%) presented with lymph node metastasis and 5 (33%) had intraperitoneal metastasis at cystectomy. These initial sites of metastatic spread included the prerectal space, ovary and vagina, ovary and fallopian tube, bowel serosa, and omentum and bowel serosa in 1 case each. Three patients had subsequent metastasis involving the prerectal space, pleural fluid and small bowel serosa, and bowel serosa in 1 each. Eight patients had followup information available, including 3 who died of disease, 3 with disease and 2 with no evidence of disease. CONCLUSIONS: Of the patients 33% with the plasmacytoid variant of urothelial carcinoma presented with intraperitoneal disease spread and 20% had subsequent metastasis involving serosal surfaces. The possibility of noncontiguous intraperitoneal spread involving serosal surfaces should be recognized to ensure proper intraoperative staging and clinical followup for patients with plasmacytoid carcinoma.

Are repeat prostate biopsies safe? A cohort analysis from the SEARCH database.

PURPOSE: Patients question whether multiple biopsy sessions cause worse prostate cancer outcomes. Therefore, we investigated whether there is an association between the number of prior biopsy sessions and biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: Men in the SEARCH (Shared Equal Access Regional Cancer Hospital) database who underwent radical prostatectomy between 1988 and 2010 after a known number of prior biopsies were included in the analysis. Number of biopsy sessions (range 1 to 8) was examined as a continuous and categorical (1, 2 and 3 to 8) variable. Biochemical recurrence was defined as a prostate specific antigen greater than 0.2 ng/ml, 2 values at 0.2 ng/ml or secondary treatment for an increased prostate specific antigen. The association between number of prior biopsy sessions and biochemical recurrence was analyzed using the Cox proportional hazards model. Kaplan-Meier estimates of freedom from biochemical recurrence were compared among the groups. RESULTS: Of the 2,739 men in the SEARCH database who met the inclusion criteria 2,251 (82%) had only 1 biopsy, 365(13%) had 2 biopsies and 123 (5%) had 3 or more biopsies. More biopsy sessions were associated with higher prostate specific antigen (p<0.001), greater prostate weight (p<0.001), lower biopsy Gleason sum (p=0.01) and more organ confined (pT2) disease (p=0.017). The Cox proportional hazards model demonstrated no association between number of biopsy sessions as a continuous or categorical variable and biochemical recurrence. Kaplan-Meier estimates of freedom from biochemical recurrence were similar across biopsy groups (log rank p=0.211). CONCLUSIONS: Multiple biopsy sessions are not associated with an increased risk of biochemical recurrence in men undergoing radical prostatectomy. Multiple biopsy sessions appear to select for a low risk cohort.

Quantitative tissue analyses of prostate cancer foci in an unselected cystoprostatectomy series.

UNLABELLED: What's known on the subject? and What does the study add? Much of our understanding of the pathological basis of prostate cancer comes from our analysis of radical prostatectomy specimens. Prostate cancer diagnosed by transrectal ultrasonography-guided biopsy is more likely to be posterior and basal in orientation rather than anterior or apical. Quantitative tissue analyses have not been undertaken both with details and in an unselected population, e.g. prostate specimens from autopsy cystoprostatectomy series from bladder cancer. Quantitative tissue analysis of incidentally detected prostate cancer such as largest cancer surface area, volume, site of origin, multifocality and laterality could be of paramount importance when trying to understand the findings of screen-detected programmes and focal therapy. Cancers were found in 30% of prostates. In the 96 prostates, 215 cancer foci were identified (mean 2.24). Prostate cancer was multifocal in 60% and bilateral in 80% of cases. The site of origin was in the peripheral and transition zone (TZ) in 75% and 25%, respectively. Overall, 90% of cancer foci were clinically insignificant with volume of <0.5 mL and no grades 4-5. In all, 75% of the cancer foci were in the peripheral zone, the remainder were within the TZ. One third of cancer foci were anteriorly located beyond the area sampled by posterior biopsies. One fifth of cancer foci were ≤ 6 mm of the apex. OBJECTIVE: • To describe multifocality, volume and location of prostate cancers incidentally found in cystoprostatectomy specimens. Quantitative tissue analysis of prostate cancer in a population free of the evaluation bias associated with prostate-specific antigen level and biopsy is important as some men are likely to be offered tissue-preserving therapeutic strategies in the future. PATIENTS AND METHODS: • Cystoprostatectomy specimens for bladder cancer from 345 consecutive patients without clinically manifest prostate cancer were included. • Cancers were found in 104/345 (30%) of prostates. Cases with largest cancer >2 mL (eight patients) were excluded from morphometric study. Quantitative tissue analysis of 3-mm step-sectioned glands included largest cancer surface area, volume, site of origin, multifocality and laterality. RESULTS: • In the 96 prostates, 215 cancer foci were identified (mean 2.24). Prostate cancer was multifocal in 58% and bilateral in 79% of cases. • Of the 215 cancers, 90% were <0.5 mL and 79% <0.2 mL. Overall, 88% of cancer foci were clinically insignificant with a volume of <0.5 mL and no grades 4-5. • In all, 75% of the cancer foci were in the peripheral zone, the remainder were within the transition zone. • One third of cancer foci were anteriorly located beyond the area sampled by posterior biopsies. One fifth of cancer foci were ≤ 6 mm of the apex. • Limitations include the fact that cystoprostatectomy cancer foci are at an earlier stage than screened-detected cancers. CONCLUSION: • This detailed morphometric analysis of prostate cancer foci in a population that is free from the selection bias associated with screening can help inform our diagnostic and treatment strategies.

Obesity is associated with castration-resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: results from the SEARCH database.

UNLABELLED: Study Type - Prognosis (cohort series). Level of Evidence 2a. What's known on the subject? and What does the study add? The incidence and prevalence of obesity in the USA and Europe is increasing. Higher body mass index is associated with a lower risk of overall prostate cancer diagnosis but also with an increased risk of high grade prostate cancer. Obese men undergoing primary therapy with radical prostatectomy or external beam radiation are more likely to experience a biochemical recurrence after treatment compared with normal weight men. Finally, obesity is associated with increased prostate-cancer-specific mortality. We hypothesized that obese men on androgen deprivation therapy may be at increased risk for prostate cancer progression. Previous studies have shown that obese men have lower levels of testosterone compared with normal weight men. Additionally, one previous study found that obese men have higher levels of testosterone on androgen deprivation therapy. Men with higher levels of testosterone on androgen deprivation therapy are at increased risk of prostate cancer progression. We found that men with higher body mass index were at increased risk of progression to castration-resistant prostate cancer, development of metastases and prostate-cancer-specific mortality. When we adjusted for various clinicopathological characteristics, obese men were at increased risk of progression to castration-resistant prostate cancer and development of metastases. The results of our study help generate hypotheses for further study regarding the mechanisms between obesity and aggressive prostate cancer. OBJECTIVE: • To investigate whether obesity predicts poor outcomes in men starting androgen deprivation therapy (ADT) before metastasis, since previous studies found worse outcomes after surgery and radiation for obese men. METHODS: • A retrospective review was carried out of 287 men in the SEARCH database treated with radical prostatectomy between 1988 and 2009. • Body mass index (BMI) was categorized to <25, 25-29.9 and ≥ 30 kg/m2. • Proportional hazards models were used to test the association between BMI and time to castration-resistant prostate cancer (PC), metastases and PC-specific mortality adjusting for demographic and clinicopathological data. RESULTS: • During a median 73-month follow-up after radical prostatectomy, 403 men (14%) received early ADT. • Among 287 men with complete data, median BMI was 28.3 kg/m2. • Median follow-up from the start of ADT was 52 months during which 44 men developed castration-resistant PC, 34 developed metastases and 24 died from PC. • In multivariate analysis, higher BMI was associated with a trend for greater risk of progression to castration-resistant PC (P= 0.063), a more than threefold increased risk of developing metastases (P= 0.027) and a trend toward worse PC-specific mortality (P= 0.119). • Prognostic biomarkers did not differ between BMI groups. CONCLUSIONS: • Among men treated with early ADT, our results suggest that obese men may have increased risk of PC progression. • These data support the general hypothesis that obesity is associated with aggressive PC, although validation of these findings and further study of the mechanisms linking obesity and poor PC outcomes are required.