Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer

BACKGROUND:

The natural history of castration‐resistant nonmetastatic prostate cancer is poorly defined.

METHODS:

The authors used data from 331 subjects in the placebo group of a randomized controlled trial to evaluate the relations of disease and host characteristics with time to first bone metastases in men with prostate cancer, rising prostate‐specific antigen (PSA) despite androgen deprivation therapy, and no radiographic evidence of metastases. Relations between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were age, body mass index, prior prostatectomy, prior orchiectomy, Gleason score, performance status, PSA, urinary N‐telopeptide, bone alkaline phosphatase, albumin, lactate dehydrogenase, and hemoglobin.

RESULTS:

At 2 years, 46% of subjects had developed bone metastases, and 20% had died. Median bone metastasis‐free survival was 25 months. In multivariate analyses, baseline PSA ≥13.1 ng/mL was associated with shorter overall survival (relative risk [RR], 2.34; 95% confidence interval [CI], 1.71–3.21; P < .0001), time to first bone metastasis (RR, 1.98; 95% CI, 1.43‐2.74; P < .0001), and bone metastasis‐free survival (RR, 1.98; 95% CI, 1.45–2.70; P < .0001). PSA velocity was significantly associated with overall and bone metastasis‐free survival. Other covariates were not consistently associated with clinical outcomes.

CONCLUSIONS:

In men with progressive castration‐resistant prostate cancer and no detectable metastases, baseline PSA was significantly associated with time to first bone metastasis, bone metastasis‐free survival, and overall survival. Other disease and host characteristics, including body mass index and bone turnover markers, were not consistently associated with clinical outcomes. Cancer 2011. © 2010 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.     

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.     

Impact of postoperative prostate‐specific antigen disease recurrence and the use of salvage therapy on the risk of death

BACKGROUND:

This report evaluated whether biochemical recurrence (BCR) as a time‐dependent covariate (t) after radical prostatectomy (RP) for prostate cancer was associated with the risk of death and whether salvage therapy with radiotherapy (RT) and/or hormonal therapy (HT) can lessen this risk

METHODS:

This was a retrospective cohort study of 3071 men who underwent RP at Duke University between 1988 and 2008 and had complete follow‐up data. A Cox regression multivariable analysis was used to determine whether BCR (t) was associated with the risk of death in men after adjusting for age, prostatectomy findings, and the use of salvage RT and/or HT.

RESULTS:

After a median follow‐up of 7.4 years, 546 (17.8%) men experienced BCR and 454 (14.8%) died. The median follow‐up after prostate‐specific antigen (PSA) failure was 11.2 years (interquartile range, 5.8‐16.0 years). BCR (t) was associated with an increased risk of death (adjusted hazards ratio [AHR], 1.03; 95% confidence interval [95% CI], 1.004‐1.06 [P = .025]). In men who experienced BCR, a PSA doubling time <6 months was associated with an increased risk of death (AHR, 1.55; 95% CI, 1.15‐2.1 [P = .004]); whereas a decrease in the risk of death was observed in men who received RT (AHR, 0.58; 95% CI, 0.40‐0.58 [P = .002]) or HT (AHR, 0.56; 95% CI, 0.37‐0.84 [P = .005]) after BCR.

CONCLUSIONS:

The occurrence of BCR was found to increase the risk of death in men undergoing RP for prostate cancer, and this risk appeared to increase as the time to BCR shortened. However, the addition of RT and/or HT in men with BCR significantly lowered this risk. Cancer 2010. © 2010 American Cancer Society.     

Interval to biochemical failure as a biomarker for cause-specific and overall survival after dose-escalated external beam radiation therapy for prostate cancer

BACKGROUND:

After external beam radiation therapy (EBRT) for prostate cancer, a short interval to biochemical failure of <18 months has been proposed as a surrogate for cause‐specific survival. Because EBRT dose influences biochemical failure, the authors investigated the interval to biochemical failure in a cohort of patients treated with dose‐escalated EBRT.

METHODS:

From 1998 to 2008, 710 patients were treated with EBRT (≥75 grays) ± androgen deprivation therapy (ADT) at the University of Michigan. Biochemical failure was defined using the Phoenix consensus definition (nadir + 2 ng/mL). A short interval to biochemical failure was defined as <18 months after completing radiotherapy and/or ADT. The associations between biochemical failure, the interval to biochemical failure, and clinical factors with cause‐specific survival (CSS) and overall survival (OS) were evaluated.

RESULTS:

There were 149 biochemical failures (21%), and short interval to biochemical failure accounted for 14% and 40% of biochemical failures in those with intermediate‐risk or high‐risk disease, respectively. Biochemical failure impacted CSS (P < .0001) but not OS (P = .36). However, a short interval to biochemical failure predicted decreased CSS (P < .0001; hazard ratio [HR], 5.6; 95% confidence interval [CI], 2.4‐13.0) and OS (P < .0001; HR, 4.8; 95% CI, 2.3‐10.3) when compared with a long interval to biochemical failure. The 8‐year OS was 78% without biochemical failure, compared with 87% with a long interval to biochemical failure (P = .1; HR, 0.7; 95% CI, 0.4‐1.1) and 38% with a short interval to biochemical failure (P < .0001; HR, 3.7; 95% CI, 2.3‐5.9). On multivariate analysis, a short interval to biochemical failure increased the risk of prostate cancer death (P < .0001; HR, 18.1; 95% CI, 8.4‐39) and all cause mortality (P = .0027; HR, 1.5; 95% CI, 1.2‐2.1), whereas a long interval to biochemical failure did not.

CONCLUSIONS:

The relation between the interval to biochemical failure, CSS, and OS was independently validated in patients treated with dose‐escalated EBRT. Further evaluation of the interval to biochemical failure as a surrogate endpoint is warranted. Cancer 2012. © 2011 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.     

Biochemical recurrence after radical prostatectomy for prevalent versus incident cases of prostate cancer : implications for management

BACKGROUND.

Among screened populations, it is unknown whether men with prostate cancer (PC) diagnosed at the initial screening (prevalent cases) have a different outcome than men who are diagnosed at subsequent screenings (incident cases) after adjusting for known prognostic factors.

METHODS.

The current study cohort was comprised of 1923 men from a prospective PC screening study who underwent radical prostatectomy (RP) between September 19, 1989 and May 22, 2002. Cox regression multivariate analysis was used to determine whether having prevalent PC versus incident PC was associated with the time to prostate‐specific antigen (PSA) failure after RP after adjusting for PSA level, Gleason score, clinical tumor (T) classification, and year of RP.

RESULTS.

Men with prevalent PC had higher PSA levels (P < .001) and more advanced clinical T classification (P < .001) than men with incident PC. After a median follow‐up of 6.1 years, factors that were associated with a significantly shorter time to PSA failure after RP were prevalent PC (adjusted hazard ratio [AHR], 1.8; 95% confidence interval [95% CI], 1.3‐2.6; P = .0005), baseline PSA (AHR, 1.07; 95%CI, 1.04‐1.09; P < .001), Gleason 7 disease (AHR, 2.5; 95% CI, 1.9‐3.3; P < .001), Gleason 8 to 10 disease (AHR, 2.3; 95%CI, 1.5‐3.5; P < .001), and the year of RP (AHR, 0.92; 95%CI, 0.86‐0.97; P = .003). Men with prevalent PC also had worse outcomes after adjusting for their more advanced pathologic features.

CONCLUSIONS.

After adjusting for known prognostic factors, men with prevalent PC had a poorer outcome after RP than men with incident PC. The authors believe that this finding should be taken into consideration when weighing the risk of recurrence and treatment options for men who are diagnosed with PC on their initial screening. Cancer 2008. © 2008 American Cancer Society.     

Statin medication use and the risk of biochemical recurrence after radical prostatectomy

BACKGROUND:

Although controversial, evidence suggests statins may reduce the risk of advanced prostate cancer (PC), and recently statin use was associated with prostate‐specific antigen (PSA) reductions among men without PC. The authors sought to examine the association between statin use and PSA recurrence after radical prostatectomy (RP).

METHODS:

The authors examined 1319 men treated with RP from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Time to PSA recurrence was compared between users and nonusers of statin at surgery using Cox proportional hazards models adjusted for multiple clinical and pathological features.

RESULTS:

In total, 236 (18%) men were taking statins at RP. Median follow‐up was 24 months for statin users and 38 for nonusers. Statin users were older (P < .001) and underwent RP more recently (P < .001). Statin users were diagnosed at lower clinical stages (P = .009) and with lower PSA levels (P = .04). However, statin users tended to have higher biopsy Gleason scores (P = .002). After adjusting for multiple clinical and pathological factors, statin use was associated with a 30% lower risk of PSA recurrence (hazard ratio “HR”, 0.70; 95% confidence interval “CI”, 0.50‐0.97; P = .03), which was dose dependent (relative to no statin use; dose equivalent<simvastatin 20 mg: HR, 1.08; 95% CI, 0.66‐1.73; P = .78; dose equivalent = simvastatin 20 mg: HR, 0.57; 95% CI, 0.32‐1.00; P = .05; dose equivalent>simvastatin 20 mg: HR, 0.50; 95% CI, 0.27‐0.93; P = .03).

CONCLUSIONS:

In this cohort of men undergoing RP, statin use was associated with a dose‐dependent reduction in the risk of biochemical recurrence. If confirmed in other studies, these findings suggest statins may slow PC progression after RP. Cancer 2010. © 2010 American Cancer Society.     

Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate cancer?

BACKGROUND:

To quantify the magnitude of benefit of the addition of hormone treatment (HT) to exclusive radiotherapy for locally advanced prostate cancer, a literature‐based meta‐analysis was conducted.

METHODS:

Event‐based relative risks (RR) with 95% confidence intervals (CIs) were derived through a random‐effect model. Differences in primary (biochemical failure and clinical progression‐free survival) and secondary outcomes (cancer‐specific survival, overall survival [OS], recurrence patterns, and toxicity) were explored. Absolute differences and numbers of patients needed to treat (NNT) were calculated. A heterogeneity test, a metaregression analysis with clinical predictors of outcome, and a correlation analysis for surrogate endpoints were also performed.

RESULTS:

Seven trials (4387 patients) were gathered. Hormone suppression significantly decreased both biochemical failure (RR, 0.76; 95% CI, 0.70‐0.82; P < .0001) and clinical progression‐free survival (RR, 0.81; 95% CI 0.71‐0.93; P = .002), with absolute differences of 10% and 7.7%, respectively, which translates into 10 and 13 NNT. cancer‐specific survival (RR, 0.76; 95% CI, 0.69‐0.83; P < .0001) and OS (RR, 0.86; 95% CI, 0.80‐0.93; P < .0001) were also significantly improved by the addition of HT, without significant heterogeneity, with absolute differences of 5.5% and 4.9%, respectively, which translates into 18 and 20 NNT. Local and distant relapse were significantly decreased by HT, by 36% and 28%, respectively, and no significant differences in toxicity were found. Primary and secondary efficacy outcomes were significantly correlated.

CONCLUSIONS:

Hormone suppression plus radiotherapy significantly decreases recurrence and mortality of patients with localized prostate cancer, without affecting toxicity. Cancer 2009. © 2009 American Cancer Society.     

Dose‐escalated radiation therapy for intermediate‐risk prostate cancer

BACKGROUND:

Randomized trials supported the use of androgen deprivation therapy (ADT) with radiation therapy (RT) for intermediate‐risk prostate cancer. However, the value of concurrent ADT was less certain with dose‐escalated RT. Better methods of stratifying patients in this risk group may help select patients who are most likely to benefit.

METHODS:

A total of 238 men with intermediate‐risk (prostate specific antigen [PSA] 10‐20, Gleason 7, or stage T2b‐c) adenocarcinoma of the prostate were treated with external beam RT between 1989 and 2006. Patients had Gleason≤6 (39%) or 7 (61%) tumors; median PSA was 10.5 ng/mL. A median of 37.5% of biopsy cores were positive from a median of 9 biopsy cores sampled. The median RT dose was 74 Gy to the prostate. A total of 112 patients (47%) received neoadjuvant and concurrent ADT (median, 4 months). Median follow‐up period was 49 months.

RESULTS:

The freedom from biochemical failure (FFBF, nadir + 2 definition) was 93% at 3 years, 86% at 4 years, and 80% at 5 years. On univariate analysis, the only factor associated with FFBF was percentage of positive cores (PPC, P = .0340). The prognostic value of PPC≥50 was not evident in patients receiving ADT (FFBF at 4 years 90% vs 91%, P = .3015). For patients not receiving ADT, the impact of PPC≥50 (FFBF at 4 years 76% vs 93%, P = .0844) was more pronounced. On multivariate analysis, PPC (P = .0388) was significantly associated with FFBF, whereas Gleason sum, ADT, RT dose, PSA, and T‐stage were not.

CONCLUSIONS:

After dose‐escalated external beam RT, intermediate‐risk prostate cancer patients with PPC≥50 had the highest risk for biochemical failure and may be most likely to derive a benefit from ADT. Cancer 2009. © 2009 American Cancer Society.     

C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial

BACKGROUND.

Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen‐independent prostate cancer (AIPC) who are initiating docetaxel‐based chemotherapy.

METHODS.

Baseline plasma samples were stored (?80°C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo‐controlled trial comparing weekly docetaxel plus high‐dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate‐specific antigen (PSA) decline.

RESULTS.

C‐reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20–1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (≤8 mg/L) or abnormal (>8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52–5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60–0.92 [P = .007]).

CONCLUSIONS.

Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel‐based therapy. Cancer 2008. © 2008 American Cancer Society.     

Combination external beam radiation and brachytherapy boost with androgen deprivation for treatment of intermediate-risk prostate cancer: long-term results of CALGB 99809

BACKGROUND:

Combined transperineal prostate brachytherapy and external beam radiation therapy (EBRT) is widely used for treatment of prostate cancer. Long‐term efficacy and toxicity results of a multicenter phase 2 trial assessing combination of EBRT and transperineal prostate brachytherapy boost with androgen deprivation therapy (ADT) for intermediate‐risk prostate cancer are presented.

METHODS:

Intermediate‐risk patients per Memorial Sloan‐Kettering Cancer Center/National Comprehensive Cancer Network criteria received 6 months of ADT, and 45 grays (Gy) EBRT to the prostate and seminal vesicles, followed by transperineal prostate brachytherapy with I¹²⁵ (100 Gy) or Pd¹⁰³ (90 Gy). Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2 and Radiation Therapy Oncology Group late radiation morbidity scoring systems. Disease‐free survival (DFS) was defined as time from enrollment to progression (biochemical, local, distant, or prostate cancer death). In addition to the protocol definition of biochemical failure (3 consecutive prostate‐specific antigen rises >1.0 ng/mL after 18 months from treatment start), the 1997 American Society for Therapeutic Radiology and Oncology (ASTRO) consensus and Phoenix definitions were also assessed in defining DFS. The Kaplan‐Meier method was used to estimate DFS and overall survival.

RESULTS:

Sixty‐one of 63 enrolled patients were eligible. Median follow‐up was 73 months. Late grade 2 and 3 toxicity, excluding sexual dysfunction, occurred in 20% and 3% of patients. Six‐year DFS applying the protocol definition, 1997 ASTRO consensus, and Phoenix definitions was 87.1%, 75.1%, and 84.9%. Six deaths occurred; only 1 was attributed to prostate cancer. Six‐year overall survival was 96.1%.

CONCLUSIONS:

In a cooperative setting, combination of EBRT and transperineal prostate brachytherapy boost plus ADT resulted in excellent DFS with acceptable late toxicity for patients with intermediate‐risk prostate cancer. Cancer 2011;. © 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.     

Mortality in men with localized prostate cancer treated with brachytherapy with or without neoadjuvant hormone therapy

BACKGROUND:

Discrepancies exist regarding the impact of neoadjuvant hormone therapy (NHT) on the risk of all‐cause mortality (ACM) in men who receive brachytherapy for localized prostate cancer. Therefore, the objective of the current study was to examine the effect of NHT on the risk of ACM in men with prostate cancer who receive with brachytherapy.

METHODS:

The study cohort included 2474 men with localized prostate cancer who either received NHT (N = 1083) or did not receive NHT (N = 1391) and brachytherapy without supplemental external beam radiation between 1991 and 2005 at centers within the 21st Century Oncology Consortium. All men had at least 2 years of follow‐up. Low‐risk, intermediate‐risk, and high‐risk disease was present in 65%, 23%, and 12% of men, respectively. A Cox regression multivariate analysis was used to evaluate the risk of ACM in men who received NHT compared with all others adjusting for age, prostate‐specific antigen level, Gleason score, and tumor classification.

RESULTS:

After a median follow‐up of 4.8 years (interquartile range, 3.3‐7.5 years) and adjusting for known prostate cancer prognostic factors and age, treatment with NHT was associated significantly with an increased risk of ACM (adjusted hazard ratio, 1.24; 95% confidence interval, 1.01‐1.53; P = .04) in men aged ≥73 years. In men who were younger than the median age of 73 years, hormone therapy use was not significant (P = .34).

CONCLUSIONS:

Compared with men who were younger than the median age of 73 years, men aged ≥73 years with localized prostate cancer who received brachytherapy and NHT had an increased risk of ACM compared with men who did not receive NHT. Cancer 2010. © 2010 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.     

The use of anticoagulants improves biochemical control of localized prostate cancer treated with radiotherapy

BACKGROUND:

Substantial experimental evidence suggests that anticoagulants (ACs) may inhibit cancer growth and metastasis, although the limited data from clinical trials have been inconsistent. The potential antineoplastic effect of ACs was investigated in patients who received radiotherapy for localized prostate cancer.

METHODS:

The study cohort consisted of 662 patients with adenocarcinoma of the prostate who received radiotherapy (RT) with curative intent. Among those 622 men, 243 (37%) were receiving ACs (warfarin, clopidogrel, and/or aspirin). All patients received external‐beam RT, permanent seed implantation, or a combination of both. Prostate‐specific antigen (PSA) values were monitored for biochemical control of disease.

RESULTS:

At a median follow‐up of 49 months, the biochemical control rate at 4‐years was significantly better in patients who received ACs at 91% compared with 78% in patients who did not receive ACs (P = .0002). The distant metastasis rate at 4 years also was reduced in the AC group compared with the non‐AC group (1% vs 5%; P = .0248). In subgroup analysis, the improvement in biochemical control was significant only for patients with high‐risk disease. Along with Gleason score, T classification, and initial PSA, the use of AC therapy was associated independently with improved biochemical control in multivariate analysis.

CONCLUSIONS:

AC therapy was associated with an improvement in biochemical control in patients with prostate cancer who received RT with curative intent. The effect was most prominent in patients who had high‐risk disease. Cancer 2010. © 2010 American Cancer Society.     

Why are pretreatment prostate‐specific antigen levels and biochemical recurrence poor predictors of prostate cancer survival?

BACKGROUND:

The value of pretreatment (initial) prostate‐specific antigen (iPSA) and biochemical recurrence (BR) as prognostic factors for survival remains unclear. The authors sought to determine why using randomized trial data with 7‐year minimum follow‐up.

METHODS:

In the Trans‐Tasman Radiation Oncology Group 96.01 trial, 802 men with T2b, T2c, T3, or T4 N0 prostate cancer (PC) were randomized to radiotherapy alone or with 3 or 6 months neoadjuvant androgen deprivation between 1996 and 2000. Cox modeling was used to identify outcome predictors at follow‐up landmark points.

RESULTS:

Higher iPSA was found to be a potent predictor of BR–free survival (P < .01) but was not prognostic for prostate cancer–specific survival (PCSS) from randomization. Patients experiencing BR had unfavorable initial prognostic factors compared with patients who did not. After BR, these factors were not prognostic for PC death in models adjusted for time to BR (TTBR). In these models, TTBR predicted PCSS more satisfactorily than the occurrence of BR itself. Survival probability 5 years after BR exceeded 90% for men with TTBR ≥4 years; however, it dropped to 44% ± 6% for men with TTBR <1 year. After BR, rapid PSA doubling time (DT), low iPSA, and short TTBR were identified as the most important predictors of inferior PCSS.

CONCLUSIONS:

When BR occurs, prognostic factors for survival change. Low iPSA, short TTBR, and rapid PSA DT take over at this point, providing reasons why iPSA and occurrence of BR alone predict PCSS unsatisfactorily. Cancer 2009. © 2009 American Cancer Society.     

Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426)

BACKGROUND.

Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi‐institutional prospective trial.

METHODS.

Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone‐releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate‐specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration.

RESULTS.

A total of 210 eligible and evaluable patients had a median follow‐up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of ≥50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression‐free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12‐month or greater progression‐free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA‐only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response.

CONCLUSIONS.

These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (≥1 year) in approximately 19% of patients. Cancer 2008. © 2008 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.     

A validated prognostic index predicting response to dexamethasone and diethylstilbestrol in castrate‐resistant prostate cancer

BACKGROUND:

The objective of this study was to identify subgroups of patients with castrate‐resistant prostate cancer (CRPC) who had a prolonged response to combined dexamethasone and diethylstilbestrol (DS) therapy by constructing a prognostic index.

METHODS:

Multivariate and cutoff point analyses with bootstrapping were performed 1 month after commencing DS therapy, and data were validated using an independent external dataset.

RESULTS:

The median overall survival for 145 patients was 18.3 months (95% confidence interval [CI], 15.4‐23.3 months). Only 2 factors were significant on multivariate analysis: a prostate‐specific antigen (PSA) level below the median at the start of DS therapy and a decline >50% in the PSA level after 1 month on DS therapy. Subsequent cutoff point analyses revealed that a PSA level <88 ng/mL at the start of DS therapy and a reduction >53.1% in PSA after the first month of treatment were the most significant factors. These 2 factors were used to construct a prognostic index, which was validated successfully by the external dataset (median overall survival, 18.3 months [95% CI, 16.4‐28.0 months]; concordance, 72% [95% CI, 68%‐76%]). The prognostic index identified 3 prognostic groups: The 2‐year overall survival rate for these 3 groups was 68% (95% CI, 57%‐98%) for the good prognostic group, 40% (95% CI, 31%‐52%) for the intermediate prognostic group, and 12% (95% CI, 5%‐25%) for the poor prognostic group.

CONCLUSIONS:

The easy‐to‐use prognostic index that the authors developed was able to identify a subgroup of patients with CRPC who had prolonged survival only 1 month after starting DS therapy. Cancer 2010. © 2010 American Cancer Society.