Projecting prostate cancer mortality in the PCPT and REDUCE chemoprevention trials

BACKGROUND.

Two recent chemoprevention trials demonstrated significant reductions in overall prostate cancer incidence. However, a possible increase in high‐grade disease has raised concerns that the harms of the drugs, including mortality because of high‐grade disease, may outweigh the benefits. The authors attempted to estimate the effect of these drugs on prostate cancer mortality to be able to better evaluate the cost‐benefit tradeoff.

METHODS.

The authors analyzed prostate cancer incidence in the Prostate Cancer Prevention Trial (PCPT) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which evaluated finasteride and the related compound dutasteride, respectively (both vs placebo). They used 13‐year prostate cancer survival data from the Prostate, Lung, Colorectal and Ovarian (PLCO) trial to project prostate cancer mortality from incidence patterns; survival rates were applied to incident cancers according to prognostic strata, which were defined by Gleason score, prostate‐specific antigen level, and clinical stage. For PCPT, the analysis was performed using both original trial results and previously published adjusted analyses that attempted to account for artifacts related to the drugs' effect on prostate volume.

RESULTS.

For the PCPT trial, the estimated relative risk (RR) for prostate cancer mortality was 1.02 (95% confidence interval [95% CI], 0.85‐1.23) using the original trial results and 0.87 (95% CI, 0.72‐1.06) and 0.91 (95% CI, 0.76‐1.09) based on the adjusted PCPT analyses. For the REDUCE trial, the RR for prostate cancer mortality was 0.93 (95% CI, 0.80‐1.08).

CONCLUSIONS.

Projecting a mortality outcome of the PCPT and REDUCE trials as an approach to weighing benefits versus harms suggests at most a small increase in prostate cancer mortality in the treatment arms, and possibly a modest decrease. Cancer 2013. © 2012 American Cancer Society.     

Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50

BACKGROUND:

We previously reported that a single prostate‐specific antigen (PSA) measured at ages 44‐50 was highly predictive of subsequent prostate cancer diagnosis in an unscreened population. Here we report an additional 7 years of follow‐up. This provides replication using an independent data set and allows estimates of the association between early PSA and subsequent advanced cancer (clinical stage ≥T3 or metastases at diagnosis).

METHODS:

Blood was collected from 21,277 men in a Swedish city (74% participation rate) during 1974‐1986 at ages 33‐50. Through 2006, prostate cancer was diagnosed in 1408 participants; we measured PSA in archived plasma for 1312 of these cases (93%) and for 3728 controls.

RESULTS:

At a median follow‐up of 23 years, baseline PSA was strongly associated with subsequent prostate cancer (area under the curve, 0.72; 95% CI, 0.70‐0.74; for advanced cancer, 0.75; 95% CI, 0.72‐0.78). Associations between PSA and prostate cancer were virtually identical for the initial and replication data sets, with 81% of advanced cases (95% CI, 77%‐86%) found in men with PSA above the median (0.63 ng/mL at ages 44‐50).

CONCLUSIONS:

A single PSA at or before age 50 predicts advanced prostate cancer diagnosed up to 30 years later. Use of early PSA to stratify risk would allow a large group of low‐risk men to be screened less often but increase frequency of testing on a more limited number of high‐risk men. This is likely to improve the ratio of benefit to harm for screening. Cancer 2011. © 2010 American Cancer Society.     

Ten-year outcomes of high-dose, intensity-modulated radiotherapy for localized prostate cancer

BACKGROUND.

The authors investigated long‐term tumor control and toxicity outcomes after high‐dose, intensity‐modulated radiation therapy (IMRT) in patients who had clinically localized prostate cancer.

METHODS.

Between April 1996 and January 1998, 170 patients received 81 gray (Gy) using a 5‐field IMRT technique. Patients were classified according to the National Comprehensive Cancer Network‐defined risk groups. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events Version 3.0. Freedom from biochemical relapse, distant metastases, and cause‐specific survival outcomes were calculated. The median follow‐up was 99 months.

RESULTS.

The 10‐year actuarial prostate‐specific antigen relapse‐free survival rates were 81% for the low‐risk group, 78% for the intermediate‐risk group, and 62% for the high‐risk group; the 10‐year distant metastases–free rates were 100%, 94%, and 90%, respectively; and the 10‐year cause‐specific mortality rates were 0%, 3%, and 14%, respectively. The 10‐year likelihood of developing grade 2 and 3 late genitourinary toxicity was 11% and 5%, respectively; and the 10‐year likelihood of developing grade 2 and 3 late gastrointestinal toxicity was 2% and 1%, respectively. No grade 4 toxicities were observed.

CONCLUSIONS.

To the authors' knowledge, this report represents the longest followed cohort of patients who received high‐dose radiation levels of 81 Gy using IMRT for localized prostate cancer. The findings indicated that high‐dose IMRT is well tolerated and is associated with excellent long‐term tumor‐control outcomes in patients with localized prostate cancer Cancer 2011. © 2010 American Cancer Society.     

Plasma insulin‐like growth factor 1 is positively associated with low‐grade prostate cancer in the Health Professionals Follow‐up Study 1993–2004

The insulin‐like growth factor (IGF) axis plays a role in growth and progression of prostate cancer. High circulating IGF‐1 levels have been associated with an increased risk of prostate cancer. Results for IGF binding protein 3 (IGFBP‐3) are inconclusive. Some studies have indicated that the positive association with IGF‐1 is observed only for low‐grade prostate cancer (Gleason sum < 7). We previously reported in the Health Professionals Follow‐up Study (HPFS) a direct positive association between ELISA‐measured plasma IGF‐1 and IGFBP‐3 and risk of prostate cancer (462 cases diagnosed after providing a blood specimen (between 1993 and 1995), but before February 1998). With additional follow‐up through January 31st 2004, and 1,331 case–control pairs in total, we were now able to investigate low‐grade (Gleason sum < 7, n = 635) and high‐grade (Gleason sum ≥ 7, n = 515) prostate cancer separately. Matched odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. ORs of total prostate cancer comparing top to bottom quartiles were 1.41 (95% CI 1.12–1.78, p‐trend = 0.001) for IGF‐1 and 1.58 (95% CI 1.24–2.01, p‐trend = 0.003) for IGFBP‐3. IGF‐1 was more strongly associated with low‐grade (OR = 1.61 top versus bottom quartile, 95% CI 1.16–2.25, p‐trend = 0.01), than with high‐grade (OR = 1.29, 95% CI 0.89–1.88, p‐trend = 0.12) prostate cancer (p‐heterogeneity = 0.08). We hypothesize that these findings reflect that high‐grade prostate cancers are more autonomous, and, thus, less sensitive to the action of IGF‐1 than low‐grade cancers.     

Ixabepilone,mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

BACKGROUND:

Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second‐line chemotherapy in patients with docetaxel‐refractory castration‐resistant prostate cancer. Clinical noncross‐ resistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose‐limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination.

METHODS:

Patients with metastatic progressive castration‐resistant prostate cancer during or after 3 or more cycles of taxane‐based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m² and mitoxantrone 12 mg/m² administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity.

RESULTS:

Results are reported for the 56 evaluable patients. Twenty‐five (45%; 95% confidence interval [CI], 31%‐59%) experienced confirmed ≥50% prostate‐specific antigen (PSA) declines, 33 (59%; 95% CI, 45%‐72%) experienced confirmed ≥30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%‐39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5‐5.6), and median progression‐free survival was also 4.4 months (95% CI, 3.0‐6.0). Median overall survival was 12.5 months (95% CI, 10.2‐15.9). Thirty‐two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment‐related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively.

CONCLUSIONS:

These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration‐resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;. © 2010 American Cancer Society.     

Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer

BACKGROUND:

The long‐term survival of patients with high‐risk prostate cancer was compared after radical prostatectomy (RRP) and after external beam radiation therapy (EBRT) with or without adjuvant androgen‐deprivation therapy (ADT).

METHODS:

In total, 1238 patients underwent RRP, and 609 patients received with EBRT (344 received EBRT plus ADT, and 265 received EBRT alone) between 1988 and 2004 who had a pretreatment prostate‐specific antigen (PSA) level ≥ 20 ng/mL, a biopsy Gleason score between 8 and 10, or clinical tumor classification ≥ T3. The median follow‐up was 10.2 years, 6.0 years, and 7.2 years after RRP, EBRT plus ADT, and EBRT alone, respectively. The impact of treatment modality on systemic progression, cancer‐specific survival, and overall survival was evaluated using multivariate Cox proportional hazard regression analysis and a competing risk‐regression model.

RESULTS:

The 10‐year cancer‐specific survival rate was 92%, 92%, and 88% after RRP, EBRT plus ADT, and EBRT alone, respectively (P = .06). After adjustment for case mix, no significant differences in the risks of systemic progression (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.51‐1.18; P = .23) or prostate cancer death (HR, 1.14; 95% CI, 0.68‐1.91; P = .61) were observed between patients who received EBRT plus ADT and patients who underwent RRP. The risk of all‐cause mortality, however, was greater after EBRT plus ADT than after RRP (HR, 1.60; 95% CI, 1.25‐2.05; P = .0002).

CONCLUSIONS:

RRP alone and EBRT plus ADT provided similar long‐term cancer control for patients with high‐risk prostate cancer. The authors concluded that continued investigation into the differing impact of treatments on quality‐of‐life and noncancer mortality will be necessary to determine the optimal management approach for these patients. Cancer 2011. © 2011 American Cancer Society.     

Comorbidity,body mass index,and age and the risk of nonprostate‐cancer‐specific mortality after a postradiation prostate‐specific antigen recurrence

BACKGROUND:

Some men with a postradiation therapy (RT) prostate‐specific antigen (PSA) recurrence will die of noncancer causes before developing metastases. Therefore, our ability to determine who would benefit from salvage hormonotherapy (HT) would be enhanced if an individual's risk of nonprostate‐cancer‐specific mortality were known.

METHODS:

Among 206 men with unfavorable‐risk localized prostate cancer initially randomized to RT+/?HT, 87 men who experienced PSA recurrence were studied. Fine and Gray's competing risks regression was used to assess whether body mass index (BMI) and the Adult Comorbidity Evaluation‐27 comorbidity level at randomization were associated with the risk of nonprostate‐cancer‐specific mortality after PSA recurrence, adjusting for age at recurrence.

RESULTS:

After a median postrecurrence follow‐up of 4.4 years, moderate/severe comorbidity (adjusted hazard ratio [HR] = 3.15; P = .02), BMI ≥ median (27.4 kg/m²; adjusted HR=2.98; p=.04), and increasing age at recurrence (adjusted HR = 1.17; P = .03) were significantly associated with an increased risk of nonprostate‐cancer‐specific mortality. Five‐year cumulative incidence estimates of nonprostate‐cancer‐specific mortality were as follows: 0% (95% confidence interval [CI] [0,0]) for low‐risk patients (mild/no comorbidity and age<median [76.2 years] and BMI<median), 18.8% (5.8‐31.8) for intermediate‐risk patients (mild/no comorbidity and either age≥median or BMI≥median); and 37.9% (95% CI, 6.8‐68.9) for high‐risk patients (moderate/severe comorbidity; P = .03 overall).

CONCLUSIONS:

After a post‐RT PSA recurrence, men with moderate/severe comorbidity and those who are obese or older face a substantial risk of nonprostate‐cancer‐specific mortality, and they could be considered for surveillance protocols with a plan to initiate salvage HT if the PSA rises rapidly (eg, PSA doubling time <6 months) or the patient develops clinically or radiographically evident disease. Cancer 2010. © 2009 American Cancer Society.     

Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer

BACKGROUND.

It has been demonstrated that Agent Orange exposure increases the risk of developing several soft tissue malignancies. Federally funded studies, now nearly a decade old, indicated that there was only a weak association between exposure and the subsequent development of prostate cancer. Because Vietnam War veterans are now entering their 60s, the authors reexamined this association by measuring the relative risk of prostate cancer among a cohort of men who were stratified as either exposed or unexposed to Agent Orange between the years 1962 and 1971 and who were followed during the interval between 1998 and 2006.

METHODS.

All Vietnam War era veterans who receive their care in the Northern California Veteran Affairs Health System were stratified as either exposed (n = 6214) or unexposed (n = 6930) to Agent Orange. Strata‐specific incidence rates of prostate cancer (International Classification of Diseases, 9th Revision code 185.0) were calculated. Differences in patient and disease characteristics (age, race, smoking history, family history, body mass index, finasteride exposure, prebiopsy prostate‐specific antigen (PSA) level, clinical and pathologic stage, and Gleason score) were assessed with chi‐square tests, t tests, a Cox proportional hazards model, and multivariate logistic regression.

RESULTS.

Twice as many exposed men were identified with prostate cancer (239 vs 124 unexposed men, respectively; odds ratio [OR], 2.19; 95% confidence interval [95% CI], 1.75‐2.75). This increased risk also was observed in a Cox proportional hazards model from the time of exposure to diagnosis (hazards ratio [HR], 2.87; 95% CI, 2.31‐3.57). The mean time from exposure to diagnosis was 407 months. Agent Orange‐exposed men were diagnosed at a younger age (59.7 years; 95% CI, 58.9‐60.5 years) compared with unexposed men (62.2 years; 95% CI, 60.8‐63.6 years), had a 2‐fold increase in the proportion of Gleason scores 8 through 10 (21.8%; 95% CI, 16.5%‐27%) compared with unexposed men (10.5%; 95% CI, 5%‐15.9%), and were more likely to have metastatic disease at presentation than men who were not exposed (13.4%; 95% CI, 9%‐17.7%) than unexposed men (4%; 95% CI, 0.5%‐7.5%). In univariate analysis, distribution by race, smoking history, body mass index, finasteride exposure, clinical stage, and mean prebiopsy PSA were not statistically different. In a multivariate logistic regression model, Agent Orange was the most important predictor not only of developing prostate cancer but also of high‐grade and metastatic disease on presentation.

CONCLUSIONS.

Individuals who were exposed to Agent Orange had an increased incidence of prostate cancer; developed the disease at a younger age, and had a more aggressive variant than their unexposed counterparts. Consideration should be made to classify this group of individuals as ‘high risk,’ just like men of African‐American heritage and men with a family history of prostate cancer. Cancer 2008. © 2008 American Cancer Society.     

Alcohol consumption and PSA‐detected prostate cancer risk—A case‐control nested in the ProtecT study

Alcohol is an established carcinogen but not an established risk factor for prostate cancer, despite some recent prospective studies suggesting increased risk among heavy drinkers. The aim of this study was to investigate the role of alcohol on prostate‐specific antigen (PSA) levels and prostate cancer risk. Two thousand four hundred PSA detected prostate cancer cases and 12,700 controls matched on age and general practice were identified through a case‐control study nested in the PSA‐testing phase of a large UK‐based randomized controlled trial for prostate cancer treatment (ProtecT). Linear and multinomial logistic regression models were used to estimate ratios of geometric means (RGMs) of PSA and relative risk ratios (RRRs) of prostate cancer by stage and grade, with 95% confidence intervals (CIs), associated with weekly alcohol intake and drinking patterns. We found evidence of lower PSA (RGM 0.98, 95% CI: 0.98–0.99) and decreased risk of low Gleason‐grade (RRR 0.96; 95%CI 0.93–0.99) but increased risk of high‐grade prostate cancer (RRR 1.04; 95%CI 0.99–1.08; p_difference=0.004) per 10 units/week increase in alcohol consumption, not explained by current BMI, blood pressure, comorbidities, or reverse causation. This is the first large population‐based study to find evidence of lower PSA levels for increasing alcohol consumption, with potential public health implications for the detection of prostate cancer. Our results also support a modestly higher risk of high‐grade disease for heavy drinkers, but require independent replication to establish the nature of the association of alcohol with low‐grade disease, preferably in cohorts with a heterogeneous case‐mix.     

Hypofractionated stereotactic body radiotherapy in low-risk prostate adenocarcinoma: preliminary results of a multi-institutional phase 1 feasibility trial

BACKGROUND:

Recent reports using extreme hypofractionated regimens in the treatment of low‐risk prostate adenocarcinoma have been encouraging. Here, the authors report on their own multi‐institutional experience with extreme hypofractionated stereotactic radiotherapy for early stage disease.

METHODS:

In total, at 4 centers, 45 patients with National Comprehensive Cancer Network‐defined, low‐risk prostate adenocarcinoma were enrolled in a phase 1, multi‐institutional trial of hypofractionated radiosurgery with a proprietary radiosurgical device (CyberKnife). Thirty‐four patients received 7.5 grays (Gy) delivered in 5 fractions, 9 patients received 7.25 Gy delivered in 5 fractions, and 2 patients received other regimens. The variables evaluated were biochemical progression‐free survival (bPFS), prostate‐specific antigen (PSA) bounce, and toxicities. Health‐related quality of life was evaluated using the Sexual Health Inventory for Men (SHIM), American Urological Association (AUA), and Expanded Prostate Cancer Index Composite (EPIC) questionnaires.

RESULTS:

The median follow‐up for surviving patients was 44.5 months (range, 0‐62 months). The bPFS rate at 3 years was 97.7%. The median PSA declined from 4.9 ng/mL at diagnosis to 0.2 ng/mL at last follow‐up, and the median percentage PSA decline at 12 months was 80%. Nine patients experienced at least 1 PSA bounce ≥0.4 ng/mL, and 4 patients experienced 2 PSA bounces. The median time to first PSA bounce was 11.6 months (range, 7.2‐18.2 months), and the mean percentage PSA bounce was 1.07 ng/mL. There was 1 episode of late grade 3 urinary obstruction, and there were 2 episodes of late grade 3 proctitis. There was a significant late decline in SHIM and EPIC sexual scores and a small, late decline in the EPIC Bowel domain score.

CONCLUSIONS:

In a select population, extreme hypofractionation with stereotactic radiosurgery was safe and effective for the treatment of low‐risk prostate adenocarcinoma. Cancer 2012. © 2011 American Cancer Society.     

Long-term outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostate-specific antigen level > or =50 ng/mL

BACKGROUND.

The authors evaluated the long‐term outcomes of men with prostate cancer and very high (≥50 ng/mL) preoperative serum prostate‐specific antigen (PSA) values that were treated with radical prostatectomy.

METHODS.

This study included 236 men with preoperative serum PSA values ≥50ng/mL who underwent radical retropubic prostatectomy between 1987 and 2004. For comparison, the study cohort was divided into 2 groups: patients with PSA levels between 50 and 99 ng/mL and patients with PSA levels ≥100 ng/mL. Biochemical recurrence was defined as a single postoperative serum PSA value of 0.4 ng/mL or greater. Systemic disease progression was defined as the development of a local recurrence or systemic metastases, and any death resulting from prostate cancer or its treatment was defined as a cancer‐specific mortality.

RESULTS.

Biochemical recurrence‐free survival rates in the groups of patients with a PSA level 50 to 99 ng/mL and ≥100 ng/mL were 43% and 36% at 10 years, respectively. Systemic progression‐free survival rates in the PSA 50 to 99 ng/mL and PSA ≥100 ng/mL groups were 83% and 74% at 10 years, respectively. Estimated overall cancer‐specific survival was 87% at 10 years.

CONCLUSIONS.

Patients with prostate cancer and a serum PSA level ≥50 ng/mL have very high‐risk prostate cancer that carries a high likelihood of being pathologically advanced. Although the probability of realizing long‐term survival in these high‐risk patients is less than in patients with more favorable disease, 10‐year survival outcomes remain excellent and argue for aggressive management of these cases. Cancer 2008. © 2008 American Cancer Society.     

Prostate cancer‐specific mortality and the extent of therapy in healthy elderly men with high‐risk prostate cancer

BACKGROUND:

The risk of prostate cancer‐specific mortality (PCSM) in healthy elderly men may depend on extent of treatment. The authors of this report compared the use of brachytherapy alone with combined brachytherapy, external‐beam radiation to the prostate and seminal vesicles, and androgen‐suppression therapy (CMT) in this population.

METHODS:

The study cohort comprised 764 men aged ≥65 years with high‐risk prostate cancer (T3 or T4N0M0, prostate‐specific antigen >20 ng/mL, and/or Gleason score 8‐10) who received either brachytherapy alone (n = 206) or CMT (n = 558) at the Chicago Prostate Cancer Center or at a 21st Century Oncology facility. Men either had no history of myocardial infarction (MI) or had a history of MI treated with a stent or surgical intervention. Fine and Gray regression analysis was used to identify the factors associated with PCSM.

RESULTS:

The median patient age was 73 years (interquartile range, 70‐77 years). After a median follow‐up of 4.9 years, 25 men died of prostate cancer. After adjusting for age and prostate cancer prognostic factors, the risk of PCSM was significantly less (adjusted hazard ratio, 0.29; 95% confidence interval, 0.12‐0.68; P = .004) for men who received CMT than for men who received brachytherapy alone. Other factors that were associated significantly with an increased risk of PCSM included a Gleason score of 8 to 10 (P = .017).

CONCLUSIONS:

Elderly men who had high‐risk prostate cancer without cardiovascular disease or with surgically corrected cardiovascular disease had a lower risk of PCSM when they received CMT than when they received brachytherapy alone. These results support aggressive locoregional treatment in healthy elderly men with high‐risk prostate cancer. Cancer 2010. © 2010 American Cancer Society.     

Age‐specific physical activity and prostate cancer risk among white men and black men

BACKGROUND:

The relation of physical activity across the lifespan to risk of prostate cancer has not been thoroughly investigated, particularly among black men. The authors investigated physical activity, including activity during different age periods and of various intensities, in relation to prostate cancer incidence among white men and black men.

METHODS:

In total, 160,006 white men and 3671 black men ages 51 years to 72 years who were enrolled in the National Institutes of Health‐AARP Diet and Health Study reported their time spent per week engaging in physical activity during ages 15 to 18 years, 19 years to 29 years, 35 years to 39 years, and during the past 10 years. Cox regression models were used to examine physical activity, categorized by intensity (moderate or vigorous, light, and total), in relation to prostate cancer risk.

RESULTS:

During 7 years of follow‐up, 9624 white men and 371 black men developed prostate cancer. Among white men, physical activity had no association with prostate cancer regardless of age period or activity intensity. Among black men, engaging in ≥4 hours of moderate/vigorous intensity physical activity versus infrequent activity during ages 19 years to 29 years was related to a 35% lower risk of prostate cancer (relative risk, 0.65; 95% confidence interval [95% CI], 0.43‐0.99 [P_trend = .01]). Frequent moderate/vigorous physical activity at ages 35 years to 39 years also potentially was related to reduced prostate cancer risk (relative risk, 0.59; 95% CI, 0.36‐0.96 [P_trend = .15]).

CONCLUSIONS:

Regular physical activity may reduce prostate cancer risk among black men, and activity during young adulthood may yield the greatest benefit. This novel finding needs confirmation in additional studies. Cancer 2009. Published 2009 by the American Cancer Society.     

A population-based nested case-control study in taiwan: use of 5α-reductase inhibitors did not decrease prostate cancer risk in patients with benign prostate hyperplasia

Background.

5α-Reductase inhibitors (5ARIs) are commonly used to treat benign prostate hyperplasia (BPH) by blocking the conversion of testosterone into the more potent dihydrotestosterone. This study explored a possible association between the use of the 5ARIs finasteride and dutasteride and the subsequent risk of prostate cancer or other cancers.

Methods.

We analyzed data from the Taiwanese National Health Insurance system. In a BPH cohort, we identified 1,489 patients with cancer and included them in our study group. For the control group, 3 patients without cancer were frequency matched with each BPH case for age, BPH diagnosis year, index year, and month. Information regarding past 5ARI use was obtained from the Taiwanese National Health Insurance Research Database (NHIRD). Multivariate logistic regression analysis was conducted, and odds ratio (OR) and 95% confidence interval (CI) were estimated.

Results.

Finasteride use marginally increased the incidence of prostate and overall cancer at a level of statistical significance (prostate cancer: OR = 1.90; 95% CI: 1.00–3.59; overall cancer: OR = 1.51; 95% CI: 1.00–2.28). Dutasteride use significantly increased kidney cancer risk (OR = 9.68, 95% CI: 1.17–80.0). Dosage analysis showed that lower doses of finasteride were associated with higher overall and prostate cancer risks. The major limitation is the lack of important data in the NHIRD, such as prostate cancer histologic grades, smoking habits, alcohol consumption, body mass index, socioeconomic status, and family history of cancer.

Conclusions.

This population-based nested case-control study suggested that finasteride use may increase prostate and overall cancer risks for patients with BPH. The effects were more prominent for patients using lower doses of finasteride.     

Preoperative hypogonadism is not an independent predictor of high-risk disease in patients undergoing radical prostatectomy

BACKGROUND:

A study was undertaken to assess the association between either preoperative serum total testosterone (TT) or hypogonadism (defined as TT <3 ng/mL) with high‐risk prostate cancer (PCa) (defined as patients with pathological extracapsular extension [ECE], seminal vesicle invasion [SVI], or Gleason grades ≥4 + 3 [high‐grade PCa]) at radical prostatectomy (RP).

METHODS:

A cohort of 673 consecutive Caucasian‐European patients who underwent RP at a single institute was used. None of the patients had taken any hormonal neoadjuvant treatment or other hormonal preparations during the previous 12 months. Serum TT was measured the day before surgery (8‐10 AM ) in all cases. Logistic regression models tested the associations among predictors (eg, prostate‐specific antigen, clinical stage, biopsy Gleason sum, body mass index, and TT) and ECE, SVI, and high‐grade PCa.

RESULTS:

Median TT was 4.5 ng/mL (mean, 4.5; range, 0.02‐13.6). Hypogonadism was found in 144 (21.4%) patients, and severe hypogonadism (defined as TT <1 ng/mL) was observed in 37 (5.5%) men. Extracapsular extension, SVI, and high‐grade PCa were found in 96 (14.6%), 88 (13.1%), and 153 (22.7%) patients, respectively. Patients with high‐risk PCa had median TT comparable to those with low‐risk disease. At multivariate analysis, TT did not achieve independent predictor status for ECE, SVI, and high‐grade PCa. Only circulating TT <1 ng/mL was an independent predictor of SVI (odds ratio, 3.11; P = .006).

CONCLUSIONS:

In contrast with previous reports, preoperative circulating TT levels were not associated with high‐risk PCa. Likewise, hypogonadism did not achieve independent predictor status for high‐risk PCa. Cancer 2011;. © 2011 American Cancer Society.     

Overtreatment of men with low-risk prostate cancer and significant comorbidity

BACKGROUND:

Men with low‐risk prostate cancer and significant comorbidity are susceptible to overtreatment. The authors sought to compare the impact of comorbidity and age on treatment choice in men with low‐risk disease.

METHODS:

The authors sampled 509 men with low‐risk prostate cancer diagnosed at the Greater Los Angeles and Long Beach Veterans Affairs Medical Centers between 1997 and 2004. Rates of aggressive treatment (radical prostatectomy, radiation therapy, brachytherapy) were determined among men of different ages and with different Charlson comorbidity scores. Multivariate modeling was used to determine the influence of both variables in predicting nonaggressive treatment, and Cox proportional hazards analysis was used to compare the risk of other‐cause mortality among groups according to Charlson score and age.

RESULTS:

Men with Charlson scores ≥3 were treated aggressively in 54% of cases (30 of 56 men), while men aged >75 years at diagnosis were treated aggressively in 16% of cases (7 of 44 men). In multivariate analysis, age >75 years was a much stronger predictor of nonaggressive treatment (relative risk, 12.0; 95% confidence interval [CI], 5.4‐28.3) than a Charlson score ≥3 (relative risk, 2.0; 95% CI, 1.3‐2.9). In survival analysis, men with Charlson scores ≥3 had an 8‐fold increased risk (hazard ratio, 8.4; 95% CI, 4.2‐16.6) and 70% probability of other‐cause mortality at 10 years, whereas age >75 years was associated with a 5‐fold increased risk (hazard ratio, 4.9; 95%CI, 1.7‐13.8) and a 24% probability of other‐cause mortality.

CONCLUSIONS:

Men with significant comorbidity often were overtreated for low‐risk prostate cancer. Like advanced age, significant comorbidity should be a strong relative contraindication to aggressive treatment in men with low‐risk disease. Cancer 2011. © 2010 American Cancer Society.     

Impact of socioeconomic status on prostate cancer diagnosis,treatment, and prognosis

BACKGROUND:

The objective of the current study was to evaluate the impact of socioeconomic disparities on prostate cancer presentation, treatment, and prognosis in Geneva, Switzerland, in which healthcare costs, medical coverage, and life expectancy are considered to be among the highest in the world.

METHODS:

This population‐based study included all patients diagnosed with invasive prostate cancer among the resident population between 1995 and 2005. Patients were divided into 3 socioeconomic groups according to their last known occupation. Compared were patient and tumor characteristics and treatment patterns between socioeconomic groups. Cox multivariate regression analysis was used to assess and explain socioeconomic inequalities in prostate cancer‐specific mortality.

RESULTS:

Compared with patients of high socioeconomic class, those of low socioeconomic class were more often foreigners, were found less frequently to have screen‐detected cancer, were found to have a more advanced stage of disease at diagnosis, and less often had information regarding disease characteristics and staging. These patients underwent prostatectomy less frequently and were more often managed with watchful waiting. The risk of dying as a result of prostate cancer (hazards ratio [HR]) in patients of a low versus high socioeconomic status was increased 2‐fold (95% confidence interval [95% CI], 1.5‐2.6). After adjustment for patient and tumor characteristics and treatment, the mortality risk was no longer found to be significantly increased (HR, 1.2; 95% CI, 0.8‐1.6).

CONCLUSIONS:

In the current study, patients of low socioeconomic class were found to be at increased risk of dying as a result of their prostate cancer. This increased mortality is largely attributable to delayed diagnosis, poor diagnostic workup, and less invasive treatments in these individuals. Cancer 2009. © 2009 American Cancer Society.     

Circulating estradiol, but not testosterone, is a significant predictor of high-grade prostate cancer in patients undergoing radical prostatectomy

BACKGROUND:

The objective of this study was to assess the association between preoperative circulating levels of 17β‐estradiol (E₂) and high‐grade prostate cancer (HGPCa) (Gleason grade ≥4 + 3) at the time patients underwent radical retropubic prostatectomy (RRP).

METHODS:

Serum total testosterone (tT), sex hormone‐binding globulin (SHBG), and E₂ levels were measured the day before surgery (8‐10 AM ) in a cohort of 655 consecutive Caucasian‐ European patients who underwent RRP at a single institution. Logistic regression models were used to test the association between predictors (including age, body mass index, prostate‐specific antigen [PSA], clinical tumor classification, biopsy Gleason sum, tT, SHBG, and E₂) and HGPCa. Serum E₂ was included in the model as both a continuous variable and a categorized variable (according to the most informative cutoff: 50 pg/mL).

RESULTS:

Pathologic HGPCa was identified in 156 patients (23.8%). Patients with HGPCa had significantly higher PSA, clinical tumor classification, and biopsy Gleason sum than those without HGPCa (all P < .001). No other significant differences were observed between groups. At univariate analysis, continuously coded E₂ was not associated significantly with HGPCa (odds ratio [OR], 1.009; P = .25), whereas patients with E₂ levels ≥50 pg/mL had a 3.24‐fold increased risk of HGPCa (P < .001). At multivariate analysis, E₂ was associated significantly with HGPCa both as a continuous predictor (OR, 1.02; P = .04) and as a categorical predictor (OR, 3.94; P < .001) after accounting for other variables. Conversely, tT and SHBG levels were not associated significantly with HGPCa.

CONCLUSIONS:

E₂ was associated significantly with pathologic HGPCa, whereas SHBG and tT failed to demonstrate any association with HGPCa in patients who underwent RRP. Cancer 2011;. © 2011 American Cancer Society.     

Phase 2 study of neoadjuvant docetaxel plus bevacizumab in patients with high-risk localized prostate cancer : A Prostate Cancer Clinical Trials Consortium trial

BACKGROUND:

Treatment of high‐risk localized prostate cancer remains inadequate. The authors performed a phase 2 multicenter trial of neoadjuvant docetaxel plus bevacizumab before radical prostatectomy.

METHODS:

Eligibility included any of the following: prostate‐specific antigen (PSA) >20 ng/mL or PSA velocity >2 ng/mL/y, cT3 disease, any biopsy Gleason score 8 to 10, and Gleason score 7 with T3 disease by endorectal magnetic resonance imaging (MRI) at 1.5 T. Also, those with ≥50% biopsy cores involved and either Gleason score 7, PSA >10, or cT2 disease were eligible. Patients were treated with docetaxel 70 mg/m² every 3 weeks for 6 cycles and bevacizumab 15 mg/m² every 3 weeks for 5 cycles. The primary endpoint was partial response by endorectal MRI.

RESULTS:

Forty‐one patients were treated. Median age was 55 years (range, 40‐66 years). Baseline characteristics included: median PSA, 10.1 ng/mL; cT2, 49%, cT3, 32%; and Gleason score 8 to 10, 73%. Thirty‐eight of 41 (93%) patients completed all 6 cycles. Grade ≥3 adverse events were rare, although 3 of 41 (7%) experienced febrile neutropenia. Twelve patients (29%; 95% confidence interval [CI], 16%‐45%) achieved a >50% reduction in tumor volume, and 9 patients (22%; 95% CI, 11%‐38%) achieved a >50% post‐treatment decline in PSA. Thirty‐seven of the 41 patients underwent radical prostatectomy; there were no complete pathologic responses.

CONCLUSIONS:

Neoadjuvant docetaxel and bevacizumab is safe, and results in reductions in both tumor volume and serum PSA, in men with high‐risk localized prostate cancer. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in general, requires further elucidation through ongoing and planned trials. Cancer 2012. © 2012 American Cancer Society.     

Population‐based 10‐year oncologic outcomes after low‐dose‐rate brachytherapy for low‐risk and intermediate‐risk prostate cancer

BACKGROUND.

The objective of this study was to report the rates of disease‐free survival (DFS), cause‐specific survival (CSS), and overall survival after low‐dose‐rate (LDR) prostate brachytherapy (PB).

METHODS.

Data from 1006 consecutive patients with prostate cancer who received LDR‐PB and underwent implantation on or before October 23, 2003 were extracted from a prospective database on November 11, 2011. The selected patients had low‐risk (58%) or intermediate‐risk (42%) disease according to National Comprehensive Cancer Network criteria. The Phoenix threshold was used to define biochemical relapse. Sixty‐five percent of patients received 3 months of neoadjuvant androgen‐deprivation therapy (ADT) and 3 months of concomitant ADT. Univariate and multivariate analyses are reported in relation to patient, tumor, and treatment variables.

RESULTS.

The median follow‐up was 7.5 years. By using Fine and Gray competing risks analysis, the 5‐year and 10‐year actuarial DFS rates were 96.7% (95% confidence interval, 95.2%‐97.7%) and 94.1% (95% confidence interval, 92%‐95.6%), respectively. When applied to the whole cohort, none of the usual prognostic variables, including dose metrics, were correlated with DFS. However, in both univariate and multivariate models, increasing dose was the only covariate that correlated with improved DFS for the subset of men (N = 348) who did not receive ADT (P = .043). The actuarial 10‐year CSS rate was 99.1% (95% confidence interval, 97.3%‐99.7%). The overall survival rate was 93.8% at 5 years (95% confidence interval, 92%‐95.1%) and 83.5% at 10 years (95% confidence interval, 79.8%‐86.6%). Only age at implantation (P = .0001) was correlated with overall survival in multivariate analysis.

CONCLUSIONS.

In a consecutive cohort of 1006 men with National Comprehensive Cancer Network low‐risk and intermediate‐risk prostate cancer, the actuarial rate of recurrent disease after LDR‐PB was approximately 3% at 5 years and 6% at 10 years. Cancer 2013. © 2012 American Cancer Society.