Purpose Extraprostatic disease will be manifest in a third of men after radical prostatectomy. We present the long-term followup of a randomized clinical trial of radiotherapy to reduce the risk of ...subsequent metastatic disease and death. Materials and Methods A total of 431 men with pT3N0M0 prostate cancer were randomized to 60 to 64 Gy adjuvant radiotherapy or observation. The primary study end point was metastasis-free survival. Results Of 425 eligible men 211 were randomized to observation and 214 to adjuvant radiation. Of those men under observation 70 ultimately received radiotherapy. Metastasis-free survival was significantly greater with radiotherapy (93 of 214 events on the radiotherapy arm vs 114 of 211 events on observation; HR 0.71; 95% CI 0.54, 0.94; p = 0.016). Survival improved significantly with adjuvant radiation (88 deaths of 214 on the radiotherapy arm vs 110 deaths of 211 on observation; HR 0.72; 95% CI 0.55, 0.96; p = 0.023). Conclusions Adjuvant radiotherapy after radical prostatectomy for a man with pT3N0M0 prostate cancer significantly reduces the risk of metastasis and increases survival.
Studies of dietary ω-3 fatty acid intake and prostate cancer risk are inconsistent; however, recent large prospective studies have found increased risk of prostate cancer among men with high blood ...concentrations of long-chain ω-3 polyunsaturated fatty acids (LCω-3PUFA 20:5ω3; 22:5ω3; 22:6ω3. This case-cohort study examines associations between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial.
Case subjects were 834 men diagnosed with prostate cancer, of which 156 had high-grade cancer. The subcohort consisted of 1393 men selected randomly at baseline and from within strata frequency matched to case subjects on age and race. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between fatty acids and prostate cancer risk overall and by grade. All statistical tests were two-sided.
Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Associations were similar for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response.
This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.
Background: Prostate-specific antigen (PSA) testing is the primary method used to diagnose prostate cancer in the United States. Methods to integrate other risk factors associated with prostate ...cancer into individualized risk prediction are needed. We used prostate biopsy data from men who participated in the Prostate Cancer Prevention Trial (PCPT) to develop a predictive model of prostate cancer. Methods: We included 5519 men from the placebo group of the PCPT who underwent prostate biopsy, had at least one PSA measurement and a digital rectal examination (DRE) performed during the year before the biopsy, and had at least two PSA measurements performed during the 3 years before the prostate biopsy. Logistic regression was used to model the risk of prostate cancer and high-grade disease associated with age at biopsy, race, family history of prostate cancer, PSA level, PSA velocity, DRE result, and previous prostate biopsy. Risk equations were created from the estimated logistic regression models. All statistical tests were two-sided. Results: A total of 1211 (21.9%) men were diagnosed with prostate cancer by prostate biopsy. Variables that predicted prostate cancer included higher PSA level, positive family history of prostate cancer, and abnormal DRE result, whereas a previous negative prostate biopsy was associated with reduced risk. Neither age at biopsy nor PSA velocity contributed independent prognostic information. Higher PSA level, abnormal DRE result, older age at biopsy, and African American race were predictive for high-grade disease (Gleason score ≥7) whereas a previous negative prostate biopsy reduced this risk. Conclusions: This predictive model allows an individualized assessment of prostate cancer risk and risk of high-grade disease for men who undergo a prostate biopsy.
Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines ...may be associated with the development of obesity‐related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor sOB‐R and plasminogen activator inhibitor‐1 PAI‐1) with five obesity‐related cancers (colorectal, pancreatic, renal cell carcinoma RCC, ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary‐level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB‐R and PAI‐1 (P value for inclusion<5 × 10−8). Causal estimates were obtained using two‐sample MR methods. In the inverse‐variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 95% confidence interval = 0.84‐0.97; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB‐R and PAI‐1 were also similarly unrelated to risk of obesity‐related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB‐R and PAI‐1 concentrations on the development of five obesity‐related cancers.
What's new?
Chronic inflammation attributed to obesity may influence cancer development. However, little is known about the relationship between oncogenesis and changes in adipokine secretion stemming from immune cell infiltration in adipose tissue. Here, large‐scale Mendelian randomization analysis was used to assess possible causal associations of adipokine concentrations influenced by genetic variation and risk of five obesity‐related cancers, including renal cell carcinoma and colorectal, pancreatic, ovarian and endometrial cancer. In general, no association was detected between adipokines and the five malignancies, suggesting that adipokine levels have no causal influence on these cancers.
Summary Background The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in ...prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. Methods In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00134056. Findings 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5–9·9) in the atrasentan group and 9·1 months (8·4–10·2) in the placebo group (hazard ratio 1·02, 0·89–1·16; p=0·81). Median overall survival was 17·8 months (16·4–19·8) in the atrasentan group versus 17·6 months (16·4–20·1) in the placebo group (1·04, 0·90–1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Interpretation Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. Funded National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.
This randomized trial tested the idea that finasteride, which inhibits the production of androgens within the prostate, can prevent prostate cancer. The participants were to receive finasteride or a ...placebo daily for seven years. Prostate cancer was found in 18.4 percent of the men in the finasteride group and in 24.4 percent of those in the placebo group. Higher-grade cancers (Gleason score, 7, 8, 9, or 10) were more common in the finasteride group than in the placebo group. Sexual dysfunction was more common in the finasteride group, and urinary difficulties were more common in the placebo group.
A test of the idea that finasteride can prevent prostate cancer.
To date, the management of prostate cancer, the most common nondermatologic neoplasm in men in the United States, has focused on early diagnosis and treatment. Given that the development of prostate cancer is a long-term process involving multiple steps, however, prevention may be a more effective approach.
There is abundant evidence that androgens influence the development of prostate cancer.
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The development of finasteride, an inhibitor of steroid 5α-reductase, the enzyme that converts testosterone to the more potent androgen dihydrotestosterone, created an opportunity to test the possibility that lowering the androgen levels in the prostate would reduce the risk of . . .
Reports have suggested that metastatic site is an important predictor of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC), but these were based on a limited ...number of patients. We investigate the impact of site of metastases on OS of a substantial sample of men with mCRPC who received docetaxel chemotherapy in nine phase III trials.
Individual patient data from 8,820 men with mCRPC enrolled onto nine phase III trials were combined. Site of metastases was categorized as lymph node (LN) only, bone with or without LN (with no visceral metastases), any lung metastases (but no liver), and any liver metastases.
Most patients had bone with or without LN metastases (72.8%), followed by visceral disease (20.8%) and LN-only disease (6.4%). Men with liver metastases had the worst median OS (13.5 months). Although men with lung metastases had better median OS (19.4 months) compared with men with liver metastases, they had significantly worse median survival duration than men with nonvisceral bone metastases (21.3 months). Men with LN-only disease had a median OS of 31.6 months. The pooled hazard ratios for death in men with lung metastases compared with men with bone with or without LN metastases and in men with any liver metastases compared with men with lung metastases were 1.14 (95% CI, 1.04 to 1.25; P = .007) and 1.52 (95% CI, 1.35 to 1.73; P < .0001), respectively.
Specific sites of metastases in men with mCRPC are associated with differential OS, with successive increased lethality for lung and liver metastases compared with bone and nonvisceral involvement. These data may help in treatment decisions, the design of future clinical trials, and understanding the variation in biology of different sites of metastases in men with mCRPC.
We leveraged two trials to test the hypothesis of an inflammation-prostate cancer link prospectively in men without indication for biopsy.
Prostate Cancer Prevention Trial (PCPT) participants who had ...an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as "baseline." Five men with PSA > 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race.
Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (
= 41) and 68.2% of controls (
= 85) had at least one baseline biopsy core (∼5 evaluated per man) with inflammation. The odds of prostate cancer (
= 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum <4+3 disease (
= 31 cases; vs. 0%, >0-<1.8% OR = 1.70, 1.8-<5.0% OR = 2.39, ≥5% OR = 3.31,
= 0.047). In men previously in the finasteride arm, prevalence of inflammation did not differ between cases (76.5%;
= 51) and controls (75.0%;
= 108).
Benign tissue inflammation was positively associated with prostate cancer.
This first prospective study of men without biopsy indication supports the hypothesis that inflammation influences prostate cancer development.
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IMPORTANCE: Low-grade non–muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT). OBJECTIVE: To determine whether immediate post-TURBT ...intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non–muscle-invasive urothelial cancer compared with saline. DESIGN, SETTING, AND PARTICIPANTS: Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non–muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016. INTERVENTIONS: Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT. MAIN OUTCOMES AND MEASURES: The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause. RESULTS: Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90; P<.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non–muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35-0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower. CONCLUSIONS AND RELEVANCE: Among patients with suspected low-grade non–muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00445601
The use of finasteride to prevent prostate cancer reduced the risk of low-grade tumors by 43%, as compared with placebo. High-grade tumors were more common in the finasteride group, but long-term ...follow-up did not show a significant between-group difference in survival.
With the advent of prostate-specific antigen (PSA) testing in the late 1980s, the rate of diagnosis of prostate cancer rose dramatically. Currently, a man in the United States has a 16.5% lifetime risk of receiving a diagnosis of prostate cancer.
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The timing and magnitude of the 44% reduction in prostate-cancer mortality after the widespread adoption of PSA testing suggest that both screening and treatment improvements have contributed to this decline.
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Unfortunately, treatments for prostate cancer (radiation and surgery) are associated with a substantial risk of side effects, including sexual, urinary, and bowel complications, that can dramatically affect quality of life. . . .
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