Rising Weight Increases Risk of Prostate Cancer Death

BETHESDA, Md., Jan. 10 -- For men who have prostate cancer, extra poundage may increase the risk of dying from an aggressive form of it, according to investigators here.

In a prospective study of almost 300,000 men, of whom nearly 10,000 developed prostate cancer, a rising body mass index (BMI) and significant adult weight gain -- 44 to 88 pounds from age 18 to the study's baseline -- were paralleled by a risk of death, found Margaret Wright, Ph.D., of the National Cancer Institute, and colleagues.

However, neither being overweight nor obese was associated with developing the malignancy in the first place, they reported online in advance of the Feb. 15 issue of Cancer.

"BMI and adult weight gain each were linked with higher prostate cancer mortality, strongly suggesting that adiposity is related adversely to prostate cancer progression leading to death," they wrote.

Compared with normal-weight men, overly obese men (BMI ?35 kg/m²) had twice the risk of dying of prostate cancer, while men who had gained significant amounts of weight since the age of 18 also had an increased risk of a fatal outcome.

After adjusting for confounding factors, men who gained 20 kg to 40 kg or more between age 18 and the study baseline had increasing relative risks of prostate cancer mortality, ranging from 1.74 to 2.98 (P for trend .009).

Although the relationship between adiposity and prostate cancer rates have been studied extensively, the results remain inconclusive, said Dr, Wright and colleagues. Hormonal changes, they wrote, may be involved in both incidence and mortality.

The findings came from a prospective study of BMI and adult weight change in relation to prostate cancer incidence and mortality in 287,760 men, ages 50 years to 71 at enrollment (1995-1996). The men were recruited from the NIH-AARP Diet and Health Study.

At baseline, participants completed questionnaires regarding height, weight, and cancer screening practices, including digital rectal examinations and prostate-specific antigen (PSA) tests.

In all, 9,986 incident prostate cancers were identified during five years of follow-up, with 173 prostate cancer deaths during six years of follow-up. Of these, 8,541 men had localized disease, and 1,445 men had extraprostatic disease. The mean patient age was 62.1, and the average BMI at baseline was 27.3 kg/m².

In multivariate models, a higher baseline BMI was associated with significantly reduced total prostate cancer incidence, the researchers found. This, they explained, was largely because of the correlation with localized tumors (for men in the highest BMI category [?40 kg/m²] versus men in the lowest BMI category [< 25 kg/ m²]: RR, 0.67; 95% CI, 0.50-0.89; P=0.0006).

Conversely, a significant elevation in prostate cancer mortality was seen at higher BMI levels with a twofold greater risk for severely obese men (BMI ?35 kg/m²). Results were as follows:

• (BMI < 25 kg/m²: RR, 1.0 [referent group];
• BMI 25-29.9 kg/ m²: RR, 1.25; 95% CI, 0.87-1.80;
• BMI 30-34.9 kg/ m²: RR, 1.46; CI, 0.92-2.33;
• BMI ?35 kg/ m²: RR, 2.12; CI, 1.08-4.15; P=0.02).

Adult weight gain from age 18 years to baseline was also positively associated with fatal prostate cancer (P=0.009), with a strong dose-response trend (RR 1.06 to 2.98 with increasing weight gain), but not with incident disease, the investigators reported. The association between mortality and increased weight gain did not vary by age, family history of prostate cancer, race, or screening history, the researchers said.

In this study, obesity was related inversely to localized prostate cancer and possibly to extraprostatic tumors. However, the researchers noted that they were unable to explain the divergent associations of obesity with extraprostatic (possibly inverse) and fatal prostate cancer (positive), because both are considered to reflect aggressive disease.

Several biologic mechanisms have been proposed to explain the relation between adiposity and the risk of prostate cancer, they said. The predominant hypotheses concern hormonal and metabolic alterations sustained in obese men. Some of these changes may lower prostate cancer risk (decreased circulating levels of testosterone), whereas others could increase risk (enhanced levels of insulin).

It is possible, the investigators said, that in normal prostatic growth, high testosterone levels stimulate proliferation in the organ. Thus, depressed testosterone concentrations in obese men may explain an inverse association between BMI and indolent prostate cancer. However, low testosterone may increase the risk of developing poorly differentiated and hormone-insensitive prostate tumors.

The observation of a positive association between obesity and risk of fatal prostate cancer, they said, "suggests that in this group of particularly aggressive cancers, the adverse effects of excess body fat outweigh hormonal perturbations that potentially may decrease the risk of prostate cancer in obese men."

An important potential explanation of the inverse relationship of obesity and prostate cancer incidence, they pointed out, is detection bias.

"Our study was initiated after the widespread introduction of PSA testing in the United States," they wrote. "We observed that the proportion of men who reported PSA and/or digital rectal examination testing prior to baseline declined across increasing BMI levels, suggesting lower prostate cancer detection rates because of less frequent screening among obese men compared with lean men."

"Furthermore, studies have shown that prostate cancer is more difficult to detect in obese men because of a combination of lower serum PSA levels, fewer abnormal digital rectal examination findings, and larger prostate sizes than lean individuals."

Limitations of the study, the researchers said, include the short period of follow-up, the possibility of undiagnosed prostate cancer at baseline because of slow tumor growth rates, and the lack of information on Gleason scores, an important clinical variable that predicts survival.

Also, they said, that although BMI is a widely used indicator of obesity, it is an indirect measure of total adiposity and is limited by its inability to differentiate between body fat and lean body mass. Analyses of body fat distribution, including waist-to-hip ratio or waist circumference, may provide additional insight into the role of obesity in prostate carcinogenesis.

Furthermore, the investigators said, studies of adiposity in childhood and adolescence would contribute to our understanding of the relevant period in life during which adiposity affects the risk for prostate cancer.

In summary, Dr. Wright's team wrote that although the current results indicated that BMI is associated inversely with incident prostate cancer, this finding may be attributed in part to detection bias.

In contrast, BMI and adult weight gain each were linked with higher prostate cancer mortality, strongly suggesting that adiposity is related adversely to prostate cancer progression leading to death.

"Public health efforts should continue to address the health consequences of the growing prevalence of obesity in Western countries and worldwide," they concluded.