Stephen J. Freedland

Risk of Prostate Cancer–Specific Mortality Following Biochemical Recurrence After Radical Prostatectomy

ContextThe natural history of biochemical recurrence after radical prostatectomyncan be long but variable. Better risk assessment models are needed to identifynmen who are at high risk for prostate cancer death early and who may benefitnfrom aggressive salvage treatment and to identify men who are at low risknfor prostate cancer death and can be safely observed.ObjectivesTo define risk factors for prostate cancer death following radical prostatectomynand to develop tables to risk stratify for prostate cancer–specificnsurvival.Design, Setting, and PatientsRetrospective cohort study of 379 men who had undergone radical prostatectomynat an urban tertiary care hospital between 1982 and 2000 and who had a biochemicalnrecurrence and after biochemical failure had at least 2 prostate-specificnantigen (PSA) values at least 3 months apart in order to calculate PSA doublingntime (PSADT). The mean (SD) follow-up after surgery was 10.3 (4.7) years andnmedian follow-up was 10 years (range, 1-20 years).Main Outcome MeasureProstate cancer–specific mortality.ResultsMedian survival had not been reached after 16 years of follow-up afternbiochemical recurrence. Prostate-specific doubling time (<3.0 vs 3.0-8.9nvs 9.0-14.9 vs ≥15.0 months), pathological Gleason score (≤7 vs 8-10),nand time from surgery to biochemical recurrence (≤3 vs >3 years) were allnsignificant risk factors for time to prostate-specific mortality. Using thesen3 variables, tables were constructed to estimate the risk of prostate cancer–specificnsurvival at year 15 after biochemical recurrence.ConclusionClinical parameters (PSADT, pathological Gleason score, and time fromnsurgery to biochemical recurrence) can help risk stratify patients for prostatencancer–specific mortality following biochemical recurrence after radicalnprostatectomy. These preliminary findings may serve as useful guides to patientsnand their physicians to identify patients at high risk for prostate cancer–specificnmortality following biochemical recurrence after radical prostatectomy tonenroll them in early aggressive treatment trials. In addition, these preliminarynfindings highlight that survival in low-risk patients can be quite prolonged.

Impact of Obesity on Biochemical Control After Radical Prostatectomy for Clinically Localized Prostate Cancer: A Report by the Shared Equal Access Regional Cancer Hospital Database Study Group

PURPOSEnGiven the limited information regarding the impact of obesity on treatment outcomes for prostate cancer, we sought to examine the relationship between body mass index (BMI) and cancer control after radical prostatectomy (RP).nnnPATIENTS AND METHODSnWe compared clinicopathologic and biochemical outcome information across BMI groups from 1,106 men treated with RP between 1988 and 2002. Multivariate analysis was used to determine if BMI significantly predicted adverse pathology or biochemical recurrence.nnnRESULTSnObesity was related to year of surgery (P <.001) and race (P <.001), with black men having the highest obesity rates. Obese patients had higher biopsy and pathologic grade tumors (P <.001). On multivariate analysis, BMI > or = 35 kg/m(2) was associated with a trend for higher rates of positive surgical margins (P =.008). Overweight patients (BMI, 25 to 30 kg/m(2)) had a significantly decreased risk of seminal vesicle invasion (P =.039). After controlling for all preoperative clinical variables including year of surgery, BMI > or = 35 kg/m(2) significantly predicted biochemical failure after RP (P =.002). After controlling for surgical margin status, BMI > or = 35 kg/m(2) remained a significant predictor of biochemical failure (P =.012). There was a trend for BMI > or = 35 kg/m(2) to be associated with higher failure rates than BMI between 30 and 35 kg/m(2) (P =.053).nnnCONCLUSIONnThe percentage of obese men undergoing RP in our data set doubled in the last 10 years. Obesity was associated with higher-grade tumors, a trend toward increased risk of positive surgical margins, and higher biochemical failure rates among men treated with RP. A BMI > or = 35 kg/m(2) was associated with a higher risk of failure than a BMI between 30 and 35 kg/m(2).

Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy

OBJECTIVESnTo determine the ideal cutpoint for defining prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Although various cutpoints have been used, a recent study suggested that 0.4 ng/mL may be the most appropriate.nnnMETHODSnA retrospective survey of 358 men undergoing RP at the West Los Angeles Veterans Affairs Medical Center between 1991 and 2001 was undertaken. The 3-year and 5-year risk of PSA recurrence was estimated by Kaplan-Meier analyses using various cutpoints of postoperative PSA to define recurrence: greater than 0.1, greater than 0.2, greater than 0.3, greater than 0.4, and greater than 0.5 ng/mL. The 1 and 3-year risk of PSA progression after a detectable PSA level (PSA rising to a higher cutpoint) was evaluated for each definition of PSA recurrence using Kaplan-Meier analyses. Multivariate analysis using a Cox proportional hazards model was used to determine the clinical variables that were significant independent predictors of PSA recurrence at each cutpoint.nnnRESULTSnFor patients with a detectable postoperative PSA value from 0.11 to 0.2 ng/mL, the 1 and 3-year risk of PSA progression was 64% (95% confidence interval [CI] 46% to 82%) and 93% (95% CI 74% to 99%), respectively. For patients with a PSA value from 0.21 to 0.3 ng/mL, the 1 and 3-year risk of PSA progression was 86% (95% CI 69% to 97%) and 100% (95% CI 87% to 100%), respectively. The use of higher PSA cutpoints to define recurrence resulted in a lower 5-year risk of PSA recurrence. The 5-year risk of PSA recurrence using a greater than 0.1 ng/mL cutpoint resulted in a 43% (95% CI 36% to 50%) risk of recurrence compared with only 23% (95% CI 18% to 30%) for a greater than 0.5 ng/mL cutpoint. In multivariate analysis, PSA and biopsy Gleason score were significant independent predictors of biochemical recurrence, regardless of the definition of PSA recurrence used (P <or=0.002).nnnCONCLUSIONSnPSA and biopsy Gleason score were significant predictors of biochemical failure, regardless of the definition of failure used. However, the definition of PSA recurrence dramatically affected the perceived success of therapy. Patients with a postoperative PSA value greater than 0.2 ng/mL are at very high risk of developing an additional rise in PSA. On the basis of this finding, a PSA value greater than 0.2 ng/mL is an appropriate cutpoint to define PSA recurrence after RP.

Prostate Size and Risk of High-Grade, Advanced Prostate Cancer and Biochemical Progression After Radical Prostatectomy: A Search Database Study

PURPOSEnProstate growth and differentiation are under androgenic control, and prior studies suggested that tumors that develop in hypogonadal men are more aggressive. We examined whether prostate weight was associated with tumor grade, advanced disease, or risk of biochemical progression after radical prostatectomy (RP).nnnPATIENTS AND METHODSnWe evaluated the association of prostate weight with pathologic tumor grade, positive surgical margins, extracapsular disease, and seminal vesicle invasion using logistic regression and with biochemical progression using Cox proportional hazards regression among 1,602 men treated with RP between 1988 and 2003 at five equal-access medical centers, which composed the Shared Equal Access Regional Cancer Hospital (SEARCH) Database.nnnRESULTSnIn outcome prediction models including multiple predictor variables, it was found that the predictor variable of prostate weight was significantly inversely associated with the outcomes of high-grade disease, positive surgical margins, extracapsular extension (all P < or = .004), and biochemical progression (comparing prostate weight < 20 v > or = 100 g: relative risk = 8.43; 95% CI, 2.9 to 24.0; P < .001). Similar associations were seen between preoperative transrectal ultrasound-measured prostate volume and high-grade disease, positive surgical margins, extracapsular extension (all P < or = .005), seminal vesicle invasion (P = .07), and biochemical progression (P = .06).nnnCONCLUSIONnMen with smaller prostates had more high-grade cancers and more advanced disease and were at greater risk of progression after RP. These results suggest that prostate size may be an important prognostic variable that should be evaluated for use pre- and postoperatively to predict biochemical progression.

Obesity, Serum Prostate Specific Antigen and Prostate Size: Implications for Prostate Cancer Detection

PURPOSEnObesity has been associated with lower serum testosterone, theoretically resulting in decreased PSA production. Obesity has also been associated with prostatic enlargement, making the detection of existent cancer more difficult. Together these findings would result in an apparent protective effect of obesity on prostate cancer risk due to technical detection issues unrelated to cancer biology. We examined the association between BMI, and PSA and prostate weight in a cohort of men undergoing RP.nnnMATERIALS AND METHODSnWe evaluated the association of BMI with prostate weight and PSA using linear regression, adjusting for patient age at RP, year of RP, race, and pathological stage and grade in 1,414 men treated with RP between 1988 and 2004 at the 5 equal access medical centers that comprise the Shared Equal Access Regional Cancer Hospital Database.nnnRESULTSnOn multivariate analysis increasing BMI was associated with increasing prostate weight but only in men younger than 63 years and not in men 63 years or older (p-trend <0.001 and 0.44, respectively). In men younger than 63 years mean multivariate adjusted prostate weight +/- SE in those with a BMI of less than 25 vs 30 to 34.9 kg/m was 33.8 +/- 1.4 vs 41.4 +/- 1.6 gm. There was no significant association between BMI and preoperative PSA (p-trend = 0.70).nnnCONCLUSIONSnIn a cohort of men undergoing RP obesity was associated with larger prostate size but only in younger men. There was no association between BMI and PSA. Assuming equal PSA, the degree of prostatic enlargement observed in younger obese men in this study would be expected to result in a modest decrease in the odds of detecting prostate cancer in a contemporary series of PSA screened men due to the decreased sensitivity of cancer detection related to larger prostate size. Obesity may appear protective for prostate cancer in younger men due to technical issues unrelated to cancer biology.

PERCENT PROSTATE NEEDLE BIOPSY TISSUE WITH CANCER IS MORE PREDICTIVE OF BIOCHEMICAL FAILURE OR ADVERSE PATHOLOGY AFTER RADICAL PROSTATECTOMY THAN PROSTATE SPECIFIC ANTIGEN OR GLEASON SCORE

PURPOSEnBiopsy Gleason score, serum prostate specific antigen (PSA) levels, and clinical stage are known to be independent predictors of adverse pathological features and biochemical failure after radical prostatectomy. We determine whether various prostate needle biopsy parameters were predictive of either adverse pathological findings or disease recurrence after radical prostatectomy.nnnMATERIALS AND METHODSnA single pathologist reviewed the prostate needle biopsy specimens of 190 men who underwent radical prostatectomy between 1991 and 2000. Biopsy specimens were examined for Gleason score, perineural invasion, number and percent of cores with cancer, and percent of total biopsy tissue with cancer and Gleason grade 4 or 5 cancer. Multivariate analysis was used to determine the prostate needle biopsy parameters and preoperative clinical variables, including serum PSA, clinical stage, patient age and race, that were most significant for predicting positive surgical margins, nonorgan confined disease, seminal vesicle invasion and biochemical failure after radical prostatectomy.nnnRESULTSnOf the prostate needle biopsy parameters examined percent of tissue with cancer was the strongest predictor of biochemical recurrence in the multivariate analysis (p <0.001). Percent of tissue with cancer was a stronger predictor of biochemical recurrence than either PSA (p = 0.048) or biopsy Gleason score (p = 0.053). It was also a strong independent predictor of seminal vesicle invasion (p = 0.015) and nonorgan confined disease (p = 0.024). Perineural invasion, percent and number of cores with cancer, and percent of tissue with Gleason grade 4 or 5 were not independent predictors of either adverse pathology or biochemical failure.nnnCONCLUSIONSnOf all the preoperative variables examined, including the standard clinical variables of serum PSA, Gleason score and clinical stage, percent of biopsy tissue with cancer was the strongest predictor of biochemical recurrence, seminal vesicle invasion and nonorgan confined disease. Consideration should be given to reporting percent of total biopsy tissue with cancer in all prostate biopsy results.

COLLECTING DUCT RENAL CELL CARCINOMA: CLINICAL STUDY OF A RARE TUMOR

PURPOSEnCollecting duct carcinoma is a rare type of renal cell carcinoma that affects younger patients, and is associated with aggressive regional and distant spread. The clinical and pathological features of 6 patients with collecting duct carcinoma treated at a single institution are described.nnnMATERIALS AND METHODSnThere were 6 patients with collecting duct carcinoma included in the University of California School of Medicine, Los Angeles, Kidney Cancer Database. Demographic, clinical, pathological and survival data were gathered.nnnRESULTSnAverage patient age plus or minus standard deviation was 56 +/- 11 years, and 5 of 6 had TNM stage IV disease. The average survival of these patients was 11.5 months (range 7 to 17). There was 1 patient who had TNM stage I disease and survived without evidence of disease at 5 years. Transient response to chemotherapy was seen in 1 patient.nnnCONCLUSIONSnCollecting duct carcinoma is associated with poor prognosis. For the majority of patients surgical treatment will not result in a cure. Previously recommended chemotherapy and/or immunotherapy appears to have a limited role in treatment of this disease, and early detection may be the best method for prolonging patient survival.

Time trends in biochemical recurrence after radical prostatectomy: results of the SEARCH database

OBJECTIVESnTo determine whether in the prostate-specific antigen (PSA) era stage and/or grade migration of patients treated with radical prostatectomy (RP) has occurred. We also examined whether the biochemical recurrence rates after RP have changed with time.nnnMETHODSnA total of 1654 patients from the Shared Equal Access Regional Cancer Hospital (SEARCH) database were analyzed for time trends in age, preoperative PSA level, clinical stage, biopsy Gleason score, prostatectomy Gleason grade, pathologic stage, margin status, and recurrence rates after RP. Results were stratified into three 4-year blocks of time between 1988 and 2002 for analysis.nnnRESULTSnThe preoperative PSA level, patient age, tumor stage, rate of capsular penetration, and lymph node involvement decreased with time. Both biopsy and pathologic Gleason grade steadily increased with time. The positive margin rate and incidence of seminal vesicle involvement remained stable. On multivariate analysis, only serum PSA level (P <0.001) and biopsy Gleason score (P <0.001) were significant independent predictors of the time to recurrence after RP. The year of surgery was not a significant independent predictor of biochemical recurrence after RP in multivariate analysis.nnnCONCLUSIONSnDespite lower stage and lower PSA levels with time, we found no improvement in PSA recurrence rates over time. This may reflect lead-time bias in detecting PSA recurrence by the use of more sensitive PSA assays in recent years.

Race as an outcome predictor after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

OBJECTIVESnWhether race is an independent predictor of prostate-specific antigen (PSA) recurrence after RP is controversial. To compare racial differences in clinical and pathologic features and biochemical recurrence in men undergoing radical prostatectomy (RP), we used a newly established multicenter database of patients from four equal-access healthcare centers in California, the Shared Equal Access Regional Cancer Hospital (SEARCH) database.nnnMETHODSnA retrospective survey of 1547 patients treated with RP at four different equal-access medical centers in California between 1988 and 2001 was undertaken. Race was categorized as white (n = 1014), black (n = 338), or nonwhite-nonblack (n = 195). Patients were analyzed for racial differences in preoperative variables (age at surgery, clinical stage, PSA, and biopsy Gleason score) and surgical variables (pathologic stage, surgical Gleason score, incidence of seminal vesicle invasion, positive surgical margins, capsular penetration, and pelvic lymph node involvement). Patients were followed up for PSA recurrence. Multivariate analysis was used to determine whether race was an independent predictor of biochemical failure.nnnRESULTSnSignificant differences were found among the races in the preoperative factors of clinical stage, age, serum PSA, and biopsy Gleason score, although the absolute differences were small. No differences were found among the races in the pathologic features of the RP specimens, including Gleason score, pathologic stage, and incidence of positive surgical margins, capsular penetration, seminal vesicle invasion, or lymph node involvement. In both univariate and multivariate analyses, only serum PSA (P <0.001) and biopsy Gleason score (P <0.001) were significant independent predictors of time to biochemical recurrence.nnnCONCLUSIONSnIn a large multicenter cohort of patients from four equal-access medical care facilities in California, although racial differences were found in clinical stage, age, biopsy Gleason score, and serum PSA level at diagnosis, we found race was not an independent predictor of biochemical recurrence after RP. Race should not be used in models or nomograms predicting PSA failure after RP. The current study represents the largest series of black patients and the first large series of nonwhite-nonblack patients treated with RP reported to date. The Shared Equal Access Regional Cancer Hospital database is a valuable resource for studying patients treated with RP.

Are findings from studies of obesity and prostate cancer really in conflict

Recent studies on the association between obesity and prostate cancer appear to be in conflict. A recent prospective cohort study reported that the incidence of prostate cancer was lower among obese men under the age of 60xa0years and among those men with a family history of prostate cancer. Similarly, a case–control study found obesity was inversely associated with prostate cancer risk in men aged 40–64xa0years. However, several prospective cohort studies found that obese men are more likely to die from prostate cancer than non-obese men. Finally, two recent studies found that among men with prostate cancer, obese men were more likely to have a biochemical progression after surgery. We postulate that by closely examining the comparison groups used in these studies, these findings may, in fact, be in agreement. Specifically, this paradox within the literature may result from the possibility that obesity influences the development of aggressive (i.e., higher stage, higher grade, recurrence, death) and non-aggressive disease differently. We suggest that obesity may reduce the risk of non-aggressive disease but simultaneously increase the risk of aggressive disease. Finally, additional methodological issues are discussed that investigators need to be aware of to be able to draw inferences across studies of obesity and prostate cancer outcomes.