Prostate Cancer Aggressiveness Linked to Periprostatic Fat

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Periprostatic fat measured by computed tomography (CT) can predict tumor aggressiveness in patients with prostate cancer (PCa), according to a study.

In addition, the study revealed no link between body mass index (BMI) and PCa aggressiveness as defined by “high-risk” disease, a finding that contrasts with studies conducted in the United States, though obesity was linked with more advanced stage and Gleason sum 8 or higher.

Investigators in the Netherlands led by Joep G.H. van Roermund, MD, of University Medical Center Utrecht, studied 932 prostate cancer patients men treated with external beam radiotherapy or brachytherapy. All patients had CT scans that allowed researchers to measure periprostatic fat and subcutaneous fat. “A CT scan is an excellent technique to distinguish and quantify subcutaneous and visceral fat,” according to the investigators' online report in BJU International.

Each 1% increment in periprostatic fat density (PFD) was associated with a 6% increased likelihood of high-risk disease. With this in mind, the researchers observed, one should expect that the patients with the highest PFD are at the greatest risk of biochemical recurrence, though biochemical recurrence was not assessed in this study. The researchers found no association between subcutaneous fat thickness and prostate cancer aggressiveness.

The investigators divided patients into three risk categories. Low-risk patients were those with a PSA level below 10 ng/mL, a Gleason score below 7 and clinical stage T1c-T2a. Intermediate-risk patients were those with a PSA level of 10-20 ng/mL and a Gleason score of 7, and clinical stage T2b-T2c. High-risk patients were those with a PSA level greater than 20 ng/mL a Gleason score of 8 or higher or T3 clinical stage, or two or more intermediate-risk factors

Regarding the discrepancy between their study and previous American studies, Dr. van Roermund's group noted that North America has a different population composition than Europe. Moreover, compared with Europe, North American has a much higher prevalence and greater severity of obesity. The researchers pointed out that 9% to 14% of Europe's population is obese, whereas in the United States, the prevalence of obesity is as high as 30%.

Furthermore, noting that the American studies used BMI as a marker for general obesity, the investigators observed that visceral fat is the most metabolically active. The researchers cited a cohort study of 129,502 European men (the European Prospective Investigation into Cancer and Nutrition) showing that waist circumference and waist-to-hip ratio were positively associated with the risk of advanced disease among men with a lower BMI, but not among men with a higher BMI. These data suggest than an increased risk of advanced prostate cancer is more strongly associated with abdominal adiposity than with BMI, especially in a population that is less obese, the authors noted.

Stephen J. Freedland, MD, who was not involved in the new study but has conducted extensive research on the association between adiposity and prostate cancer, called the study “intriguing” and noted that it provides evidence of a potential biological link between adiposity and PCa aggressiveness. Still, the findings are clearly in need of validation, he said.

Dr. Freedland pointed out that it is difficult to assess PCa aggressiveness based on known features at the time of treatment. “This is subject to significant bias,” said Dr. Freedland, associate professor of surgery (urology) and pathology at the Duke Prostate Center at Duke University Medical Center in Durham, N.C. “Perhaps obese men with the worst disease weren't even offered local therapy. Thus, you can only see the subset of men who underwent treatment.”

Dr. Freedland said he generally defines aggressive disease as progression, something that occurs over time. Clinicians can adjust for known factors and evaluate whether a risk factor, such as obesity, predicts a poor outcome. “I do feel progression much better reflects biology than clinical features in a selected group,” he said.

In addition, the number of obese men in the new study was modest (11%-17%) compared with American studies, limiting the study's power to detect a link between BMI and PCa aggressiveness.

Still, the study showed that obese men were 2.6 times more likely to have T3 disease and 2.5 times more likely to have Gleason 8 disease or higher, which are significant risk factors for progression, Dr. Freedland observed. Various studies have shown that obese men have lower PSA levels (e.g., Bañez et al. JAMA. 2007;298:2275-2280). “Thus, it does not surprise me that obese men were not [shown to be] at greater risk of ‘high-risk' disease, when the definition of high-risk includes PSA,” he said.

In addition, Dr. Freedland observed that a number of studies have shown that high BMI predicts a worse outcome independent of PSA, stage, and grade.

“I would not say there was no association between BMI and aggressiveness in this study, but rather this study supports many others [showing] that obese men have worse disease as indicated by higher risk of T3 and Gleason 8 or higher,” Dr. Freedland added.
He pointed out that the amount of periprostatic fat ranged from 26 to 36 cm2, with each square centimeter increment in periprostatic fat raising the risk of high-risk disease by 4%. Even going from the lowest to the highest periprostatic fat amount (a 10 cm2 change) would have only a minimal impact on risk, he stated.

Lastly, as the data from the new study were not correlated with clinical outcomes (such as progression), it is unknown what information periprostatic fat could provide that PSA, clinical stage, and grade could not. The new study offers a “very interesting and potentially important observation and certainly deserves more study. However, the clinical utility, at least at this stage, is unclear at best.”

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