Treatment of Prostate Cancer in Obese Patients
Treatment of Prostate Cancer in Obese Patients
Obesity is a complex, chronic disease that has reached epidemic proportions in the United States. Obesity is now linked with numerous health conditions, including many oncologic diagnoses. Its association with prostate cancer, the most prevalent cancer in men, has also been investigated, with studies suggesting a direct relationship between increasing obesity and prostate cancer mortality. Outcomes data for specific interventions in obese patients with prostate cancer have only recently begun to emerge. Surgery, while feasible even in the very obese, may result in less than optimal cancer control rates. Brachytherapy data are emerging, and are promising. No outcomes data are available for the use of external-beam radiation in obese patients. Long-term data for external-beam radiation, as well as for surgery and brachytherapy, are required to determine the most appropriate treatment for obese patients with prostate cancer. These data, coupled with a more thorough understanding of the biochemical relationship between obesity and prostate cancer, will be necessary to make optimal management decisions for obese patients with prostate cancer in the future.
Obesity has increased to epidemic proportions in the United States. The percentage of obese adults has swelled from 13.3% of the adult population in the early 1960s to 31.1% in 1999 through 2002. The potential causes for this increase have been debated, as obesity is a complex, multifaceted, chronic disease mediated by genetics, the psychosocial environment, and physiologic variables. The causes notwithstanding, the detrimental health effects of this demographic shift are becoming clear.
Obesity is a known risk factor for numerous health conditions, including cataracts, coronary heart disease, diabetes, erectile dysfunction, gastro-esophageal reflux disease (GERD), hypercholesterolemia, hypertension, osteoarthritis, and respiratory compromise, among others. Moreover, while some analyses suggest that there is no such association, many studies have linked obesity status with numerous oncologic diagnoses such as uterine, breast, gallbladder, and colon cancer.[4,5] In addition, several studies have investigated the relationship between obesity and prostate cancer with respect to epidemiology and outcome, often with seemingly conflicting results.
Body Mass Index
In such studies, the most frequently utilized method of assessing obesity is the calculation of body mass index (BMI), in which a person's weight in kilograms is divided by the person's height in square meters. A BMI < 25 kg/m2 is considered normal, 25 to 29.9 kg/m2 is considered overweight, while BMI ≥ 30 kg/m2 is considered obese. This latter group is further divided into grade 1 (30-34.9 kg/m2), grade 2 (35-39.9 kg/m2), and grade 3 (≥ 40 kg/m2).
In the Health Professionals Follow-up Study, which is a prospective cohort study of over 51,000 US male health professionals started in 1986, the risk of developing prostate cancer was found to be decreased in men with a BMI ≥ 30 kg/m2 for men younger than 60 years of age or with a family history of prostate cancer. Among men with no family history of prostate cancer, BMI was not statistically associated with prostate cancer development. Some other epidemiologic studies have supported this inverse relationship of obesity and the development of prostate cancer,[8,9] while some have not.
The association between obesity and the risk of developing prostate cancer may be equivocal; studies are fairly consistent, however, in showing a relationship between increasing BMI levels and prostate cancer mortality. An American Cancer Society (ACS) study of over 400,000 US adults showed that the mortality risk associated with prostate cancer increased with higher BMI levels. Patients with grade 1 obesity had a 20% increase in mortality relative to men with a normal BMI between 18.5 and 24.9 kg/m2. Furthermore, men with grade 2 obesity had a 34% increase in mortality relative to men with a normal BMI. An earlier study by the ACS that followed over 450,000 men also suggested an increase in prostate cancer mortality with higher BMI levels. Surgical series have generally demonstrated higher tumor grades and more advanced disease in obese patients, with higher biochemical failure rates even when surgical margins are clear.
Explaining the Relationship
Several hypotheses have been proposed to explain the complex association between obesity and aggressive prostate cancer. Perhaps the most prevalent explanation, given that prostate cancer is a hormonally dependent malignancy, is that obesity affects the hormonal milieu, which in turn affects the biologic progression of prostate cancer. Decreased serum androgen levels have been shown to occur with obesity[14,15]; prostate cancer that proliferates in low-testosterone environments may be inherently partially androgen-independent, and therefore, a more aggressive form of the disease.[16,17] Other hormones, including estradiol, insulin, leptin, and adiponectin, may also exacerbate prostate cancer in obese patients.
Obese patients have increased levels of estradiol, which, in combination with testosterone, may enhance tumorigenesis relative to testosterone alone.[18,19] Obesity is also related to insulin resistance and elevated levels of insulin and insulin-like growth factor (IGF), the latter of which imparts a stimulatory, proliferative effect on cells. Moreover, elevated IGF-1 levels have been shown to specifically increase the risk of prostate cancer, and have been correlated with advanced-stage disease.[21,22] Leptin, a polypeptide hormone produced by adipocytes, has been demonstrated to promote angiogenesis, as well as the growth of androgen-independent cell lines in-vitro. Leptin serum levels are directly associated with the degree of obesity and have been correlated with larger, higher-grade, and more advanced tumors.[23,24] Adiponectin, another adipocyte-produced polypeptide hormone, has been shown to inhibit angiogenesis, and is indirectly related to obesity. Lower adiponectin levels have been associated with higher-grade and more advanced cancer.[25,26]
In addition to these hormonal alterations, difficulties with prostate cancer detection may partly explain the more aggressive nature of prostate cancer at presentation in obese patients. Obesity may result in lower serum prostate-specific antigen (PSA) levels, resulting in delayed biopsies and, consequently, more advanced disease at diagnosis.[14,15] Alternatively, simply having an elevated BMI may impede cancer detection with prostate biopsy. Presti and colleagues reported that overweight and obese men had a lower cancer detection rate by biopsy compared to men with a normal BMI, even when controlling for PSA levels.