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Prostate Cancer

Prostate Cancer

Overview

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer mortality in American men. Despite the fact that this cancer will be diagnosed in an estimated 233,000 American men in 2014 and will lead to the death of approximately 29,480 men, there is no universally agreed-upon strategic plan for its detection, diagnosis, and management. The estimated number of cases increased from the previous year. However, the death rate per 100,000 people declined 3.7% per year from 2004 to 2008, and the denominator (the older population) grew, so the overall rate of death is lower.

Epidemiology

Age

The risk of developing prostate cancer begins to increase at age 50 years in white men who have no family history of the disease and at age 40 years in black men and those who have a first-degree relative (father, brother) with prostate cancer. Risk increases with age, but unlike other cancers, prostate cancer has no "peak" age or modal distribution. There has been a downward "age migration" in the prostate-specific antigen (PSA) era such that the median age at diagnosis is now approximately 60 years.

Race

The highest incidence of prostate cancer in the world is found in American black men, who have approximately a 9.8% lifetime risk of developing this cancer. This rate is slightly higher than the 8% lifetime risk for American white men. Black men have an incidence of prostate cancer that is 1.6 times that of white men.

The Japanese and mainland Chinese populations have the lowest rates of prostate cancer. Interestingly, although Japanese immigrants to the United States have a higher incidence of prostate cancer than Japanese people living in Japan, their rate is still about half that of American whites.

Socioeconomic status appears to be unrelated to the risk of prostate cancer, and the explanation for racial variability is unknown. However, an interplay of diet, hormonal factors, and genetics likely accounts for the variability.

Geography

The incidence of prostate cancer is highest in Scandinavian countries (22 cases per 100,000 population) and lowest in Asia (5 per 100,000). Risk may be inversely related to ultraviolet light exposure, as the incidence increases the farther one lives from the equator. However, studies show extremely high rates of prostate cancer in populations of African heritage, such as Jamaicans.

Etiology and Risk Factors

Family History

Men who have a first-degree relative with prostate cancer have approximately a twofold increased risk of developing prostate cancer during their lifetime. An individual who has two first-degree relatives with prostate cancer has a ninefold increase in lifetime risk.

True hereditary prostate cancer occurs in a small number of men and tends to develop at an early age (< 55 years old).

Dietary Fat

Although early studies suggested a link between dietary fat and prostate cancer risk, more recent studies have failed to confirm these observations. Thus, the relationship between dietary fat and prostate cancer risk remains unclear. Using animal models, one study pointed to high levels of simple carbohydrates being a culprit in promoting prostate cancer growth.

Studies indicate that progression of prostate cancer, which is likely to be more clinically relevant, has different risk factors from those associated with its initiation/incidence and that some of these risk factors are likely modifiable. Findings from the Health Professionals Follow-up study have, however, demonstrated different dietary risk factors for the incidence compared with progression of prostate cancer. For example, African-American race, a positive family history, low consumption of tomato products, and high consumption of alpha-linolenic acid have been associated with higher risks of incident prostate cancer. However, height, body mass index (BMI), low physical activity, smoking, low consumption of tomato sauce, high calcium and alpha-linolenic acid intake, African-American race, and positive family history have all been associated with more advanced cancer.

In addition, findings suggest that cruciferous or brassica family vegetables may reduce the risk of advanced prostate cancer. This family includes broccoli, cauliflower, cole slaw, and sauerkraut. Interestingly, the intake of brussels sprouts, spinach, and mustard greens did not appear to be protective, and the consumption of fruit was not associated with the incidence or progression of prostate cancer.

Vasectomy

Several large epidemiologic studies suggest that vasectomy may increase the relative risk of prostate cancer by as much as 1.85. However, these same studies do not report an increased risk of dying from prostate cancer associated with vasectomy but do indicate a statistically increased risk of dying from lung cancer. These findings argue against an association between vasectomy and prostate cancer. Currently, this association is unproved and does not constitute grounds for fundamental changes in the use of vasectomy.

Sexual Activity/Sexually Transmitted Disease

A large prospective study of more than 29,000 men demonstrated an association between high ejaculatory frequency (more than 21 ejaculations/month) and a decreased risk of prostate cancer, with a lifetime relative risk of 0.67. However, there may be several confounding factors associated with high sexual activity, such as differences in prostate cancer screening or lifestyle. There was no associated increased risk for men in the lowest ejaculatory frequency category.

Inflammation may underlie the findings associated with a relatively higher risk of prostate cancer in men seen in sexually transmitted disease (STD) clinics, but it may also be related to screening bias. Several cohort studies and one meta-analysis have demonstrated a protective role for the daily intake of aspirin and the risk of prostate cancer. In addition, the lipid-lowering and anti-inflammatory statin compounds have been associated with a reduction in the risk of high-grade tumors. These findings require prospective validation in randomized trials.

Recent data related to a possible viral etiology of prostate cancer (ie, the XMRV virus) have now been formally withdrawn; they were likely due to a contamination artifact and are unlikely to be causally related to prostate cancer.

Prevention

Active research into the chemoprevention of prostate cancer is ongoing. Two prospective randomized trials have demonstrated a 20% to 25% reduction in the risk of prostate cancer among men randomized to receive either finasteride or dutasteride (Avodart) daily vs men on the placebo arm. Finasteride or dutasteride chemopreventive agents have not been universally accepted, however, because of concerns over the relative merits of prevention of low-grade disease, with little effect on high-grade tumors. In addition, concerns over side effects such as impotence, as well as reductions in PSA levels with these therapies that may make cancer detection more challenging, have limited the generalized use of these drugs and thus an individualized risk/benefit discussion about use of these agents as preventive measures is recommended. Finally, randomized trials using selenium and vitamin E have failed to demonstrate a benefit of these agents to reduce prostate cancer risk. Ongoing studies will examine vitamin D and omega-3 fatty acid supplementation as preventive strategies in cancer, including prostate cancer. Andriole and colleagues reported on a long-term prostate cancer prevention study with dutasteride (a dual 5-alpha reductase inhibitor) in men with an elevated PSA level and a negative initial biopsy. They demonstrated a 22.8% relative risk reduction overall in prostate cancer incidence (5.1% absolute risk), although the for-cause rate of biopsies (ie, not protocol-specified) was not different between the two arms. There was an apparent greater reduction in this trial of low-grade (Gleason score < 7) tumors, and no major effect in preventing higher-grade tumors, with a higher percentage of Gleason score 8-10 tumors detected in the dutasteride arm in years 3 and 4. Dutasteride is known to reduce PSA levels by more than twofold, and its use in prevention should take into account consideration of risk and uncertainty around the benefits, appropriate surveillance strategies for patients while they are being treated with a dihydrotestosterone inhibitor, and side effects including erectile/sexual dysfunction. The US Food and Drug Administration (FDA) has ruled that dutasteride is not approvable for prostate cancer chemoprevention. In a follow-up report of the SELECT trial (Selenium and Vitamin E Cancer Prevention Trial), there was an increased risk of prostate cancer for men randomized to treatment with vitamin E. Compared with the placebo (referent) group, in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR] = 1.17; 99% confidence interval [CI], 1.004–1.36, P = .008), as did 575 in the selenium group (HR = 1.09; 99% CI, 0.93–1.27; P = .18) and 555 in the selenium plus vitamin E group (HR = 1.05; 99% CI, 0.89–1.22; P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1,000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. Patients should be informed about supplementation with vitamin E and the increased risk of prostate cancer.

Smoking

Studies of smoking in relation to prostate cancer mortality or recurrence in prostate cancer patients are limited, with few prostate cancer–specific outcomes. A large prospective observational study of 5,366 men diagnosed with prostate cancer between 1986 and 2006 in the Health Professionals Follow-Up Study was published in 2011 by Kenfield et al in JAMA. There were 1,630 deaths, 524 (32%) due to prostate cancer and 416 (26%) due to cardiovascular disease, and 878 biochemical recurrences. Absolute crude rates for prostate cancer–specific death for never vs current smokers were 9.6 vs 15.3 per 1,000 person-years; for all-cause mortality, the corresponding rates were 27.3 and 53 per 1,000 person-years. Smoking at the time of prostate cancer diagnosis is associated with increased overall and cardiovascular disease mortality and prostate cancer–specific mortality and recurrence. Men who have quit for at least 10 years have prostate cancer–specific mortality risks similar to those who have never smoked.

Sidebar: In the Prostate Cancer Prevention Trial (PCPT), finasteride significantly reduced the risk of prostate cancer but was associated with an increased risk of high-grade disease. Now with up to 18 years of follow-up, prostate cancer was diagnosed in 989 of 9,423 (10.5%) in the finasteride group and 1,412 of 9,457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% confidence interval [CI], 0.65–0.76; P < .001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1–1.37; P = .05). Of the men who died, 2,538 were in the finasteride group and 2,496 were in the placebo group, for 15-year survival rates of 78% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride group was 1.02 (95% CI, 0.97–1.08; P = .46). Ten-year survival rates were 83% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73% and 73.6%, respectively, for those with high-grade prostate cancer. There was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer. These data suggest that finasteride is safe and effective for prostate cancer chemoprevention although the drug remains not approved by the US Food and Drug Administration for this indication (Thompson IM Jr., et al: N Engl J Med 369:603–610, 2013).

Signs and Symptoms

Early-Stage Disease

Men with organ-confined prostate cancer often are completely asymptomatic, given the predominant posterior peripheral zone location of prostate adenocarcinomas. Men with a large component of benign prostatic hyperplasia often present with bladder outlet obstruction unrelated to prostate cancer.

Locally Advanced Disease

Bladder outlet obstruction is the most common sign of locally advanced prostate cancer. A few men with locally advanced disease present with hematuria, urinary tract infections, and irritative voiding symptoms secondary to bladder outlet obstruction.

Advanced Disease

Rarely, men with bulky lymph node metastasis may present with bilateral lower-extremity edema. Men with bony metastasis often present with bone pain and, uncommonly, with lower-extremity weakness or paralysis from spinal cord compression.

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