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Originally published as JCO Early Release 10.1200/JCO.2004.11.973 on December 22 2003 © 2004 American Society of Clinical Oncology.
The "Skinny" on Obesity and Prostate Cancer PrognosisDepartment of Medicine and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY Of the 8.9 million cancer survivors in the United States, approximately 20% are prostate cancer survivors [1]. These men may live for years beyond their cancer diagnosis and must deal with the chronic and late effects of their initial treatment as well as the constant fear of recurrence. We, as clinicians, are expert in the conventional modalities of oncologic treatment, but are often at a loss when attempting to advise these survivors on how they can improve their prognosis in other ways. Yet patients and their families are often concerned and interested in such issues as diet and exercise, and how they may influence disease outcomes. Although most studies have focused on the role of lifestyle factors in the incidence of cancer, recent reports suggest that these same risk factors can also influence prognosis and survival after diagnosis. There is evidence that dietary intake and obesity influence survival from breast cancer [2,3] and that continued cigarette smoking during treatment reduces survival in small-cell lung cancer patients [4], but there has not been clear evidence that any modifiable lifestyle factors can affect cancer-related outcomes in prostate cancer survivors. Recent international trends show that prostate cancer incidence is increasing in low-incidence countries, such as China and Japan [5], at the same time that these countries are adopting Westernized lifestyles associated with higher rates of obesity [6]. These observations suggest that obesity may be a risk factor for prostate cancer. Establishing this association could have enormous implications for prostate cancer management, given that obesity is a modifiable factor. Obesity is a manifestation of energy imbalance, reflecting excessive caloric intake relative to physical activity. Studies evaluating the relationship of obesity with prostate cancer seek to demonstrate the influence of energy imbalance on prostate carcinogenesis. Several observational studies have addressed this issue, and they have produced inconsistent results. Although some large cohort studies have found a positive relationship between body mass index (BMI) and prostate cancer incidence [7,8], others have found no association [9,10]. In fact, a subset analysis of the Health Professionals Follow-Up Study found that obesity was protective for men who had a family history of prostate cancer or were under 60 years of age [9].
Although these studies have failed to consistently show that obesity is a risk factor for prostate cancer incidence, other studies have more conclusively shown that obesity is associated with prostate cancer mortality. Calle et al [11] recently reported that, among the cohort of participants in the Cancer Prevention Study II, men with BMI The biologic basis of these findings may be that obesity is not as involved in the initiation of prostate cancer as it is in its progression. The mechanism of this effect may be related both to the direct effect of dietary factors on prostate cancer cell growth and progression and to the disruption of the hormonal axis. Obesity is associated with lower testosterone levels [15], which have been associated with higher grade [16] and more advanced pathologic stage [17] in men with prostate cancer. Obesity is also associated with higher insulin and free insulin-like growth factor 1 levels [18], both of which are mitogenic. These obesity-induced hormonal changes may mediate the progression of subclinical tumors to more aggressive disease.
In this issue of the Journal of Clinical Oncology, Amling et al [19] and Freedland et al [20] report findings that lend further support to this thesis that obesity is a risk factor for aggressive prostate cancer. Both studies are retrospective, multi-institutional analyses that examined the relationship between BMI and the risk of prostate-specific antigen (PSA) recurrence among large, multiethnic samples of men who had undergone radical prostatectomy for localized prostate cancer. The study by Amling et al [19] included 3,162 men (20% of whom were black) who were treated at nine military medical centers in the United States. The patients were stratified based on BMI into an obese group (BMI
The study by Freedland et al [20] involved 1,106 patients (26% of whom were black) who underwent radical prostatectomy for localized prostate cancer at one of five centers. They also stratified patients into groups on the basis of BMI. Higher BMI was related to black race, younger age at diagnosis, higher Gleason score, and also year of surgery, with a higher proportion of obese patients treated in later years (which may reflect changes in the prevalence of obesity in the general population or a relaxation of the criteria used to determine which patients are deemed operable). After adjusting for year of surgery, BMI was still significantly related to higher Gleason score. The median follow-up was 33 months, and PSA recurrence-free survival was significantly related to BMI, especially in the group with BMI Similar themes are present in both studies: obesity is related to black race, younger age at diagnosis, and higher-grade tumors. Other studies, using large databases, have also found that black race is associated with younger age at diagnosis, higher PSA, worse stage, and higher-grade tumors in men undergoing radical prostatectomy or radiation therapy for localized prostate cancer [21–25], although black race is significantly associated with biochemical relapse in only some of these studies [25,26]. These studies did not assess BMI, and it is possible that higher BMI among black patients may have accounted, in part, for the observed differences in PSA recurrence-free survival. The studies by Amling et al and Freedland et al address this issue by examining obesity as a potential independent predictor of outcome after radical prostatectomy. In the study by Amling et al [19], race—but not BMI—remained a significant predictor of outcome in multivariate analysis, whereas the converse was true in the study by Freedland et al [20]. Additional studies that include BMI or other measures of obesity as potential predictors could help to clarify the relative importance of, and relationship between, obesity and race in prostate cancer outcomes. Both Amling et al and Freedland et al suggest that the higher grade and PSA recurrence rates seen among obese patients may be due to more aggressive tumor biology—perhaps related to obesity-induced alterations in sex hormone, insulin-like growth factor 1, or leptin levels. The resulting hormonal environment may promote the progression of a lower-grade tumor to a more malignant phenotype. This seems plausible, and longitudinal studies that measure these hormones in obese and nonobese prostate cancer patients and then correlate them to prostate cancer outcomes may corroborate this hypothesis. Another potential explanation for the higher grade and PSA relapse rates in obese men may be that obese men come to diagnosis at a later stage in their disease. Other comorbid illnesses associated with obesity, such as diabetes, cardiovascular disease, and benign prostatic hypertrophy, may mask prostate cancer-related symptoms. Obese men may also be less health-conscious on average and may avoid screening. As a result, diagnosis may be delayed in obese men. Indeed, the study by Amling et al [19] found that obese men had higher PSA levels (which might indicate a higher tumor burden), and higher BMI was associated with more advanced clinical stage, which might be related to delayed diagnosis. Finally, another reason why obese men may have higher PSA recurrence rates may be due to technical difficulties in performing an optimal prostate resection and lymph node dissection during surgery. Indeed, both studies [19,20] found that higher BMI was related to positive surgical margins, although the association in the study by Freedland et al did not reach statistical significance. Although the analysis by Freedland et al [20] adjusted for the presence of positive margins, it is possible that this remains an important factor in the poorer outcomes among obese patients. Additional studies that find higher recurrence rates among obese men treated with radiation therapy for localized prostate cancer would suggest that the poorer outcomes in obese men were not related to treatment modality but were due to biologic differences in tumor behavior between obese and nonobese patients. Such studies of patients treated with radiation therapy, however, should take into consideration the fact that patients who receive radiation differ from those who undergo surgery. Surgeons may not operate on obese patients because they are deemed to be of high operative risk because of obesity-related comorbidities or because the chances of a technically successful resection (as measured by negative margins) are judged to be poor. These patients may more often be referred for radiation therapy, and as a result the population treated with radiation may be more obese and have other poor prognostic factors. To determine the independent effect of obesity on prostate cancer outcomes in these patients, adjustment for these other factors must be made. These two studies [19,20] should be commended for presenting a provocative thesis relating obesity to prostate cancer aggressiveness and outcome. In light of the increasing worldwide incidence of obesity, the identification of obesity as a risk factor for aggressive prostate cancer is important because it may be one of the few modifiable risk factors for prostate cancer. Many questions, however, still remain concerning this association. For example, does the age of onset or duration of obesity influence prostate cancer incidence and prognosis? What is the effect of rapid weight gain in later life on prostate health? One hypothesis is that obesity before adulthood may actually be protective against prostate cancer by increasing estrogen levels, but that this protective effect is lost if weight gain occurs in later life because other negative exposures have become predominant [27]. The studies also raise some interesting issues pertaining to the management of prostate cancer in survivors. In obese men with prostate cancer, does weight reduction have an impact on the course of the disease? Perhaps weight reduction after treatment for localized prostate cancer would result in improved recurrence-free survival. Perhaps weight reduction in men with relapsed disease would help to slow clinical progression. In contrast, perhaps the die is cast early in life, and either pre- or postoperative rapid weight loss will not affect outcome. Indeed, although a low-fat, high-fiber diet failed to reduce prostate cancer incidence among men in the Polyp Prevention Trial [28], other diet and exercise studies in prostate cancer patients are already underway to help answer some of these questions about prostate cancer prognosis [29,30]. As the number of men who are survivors of prostate cancer steadily increases, we should be searching for lifestyle—as well as medical—interventions that may be effective in preventing recurrence and progression, while also promoting good overall health. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Daniel P. Petrylak, GPC Biotech, Cell Genesis. Served as an officer or member of the Board of a company: Alfred I. Neugut, Executive Health Exams. Received more than $2,000 a year from a company for either of the last 2 years: Daniel P. Petrylak, Lilly, Aventis. REFERENCES
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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30 kg/m2 had a 20% to 34% increased risk of prostate cancer death compared with men with BMI 18.5 to 24.9 kg/m2. Furthermore, other studies have found that in men who underwent radical prostatectomy for localized prostate cancer, a higher BMI was associated with higher-grade tumors [
25 kg/m2), the latter two of which were combined for analysis. The obese group was associated with younger age, black race, higher PSA, higher pathologic Gleason score, and positive surgical margins. In the Kaplan-Meier analysis of PSA recurrence-free survival, obesity and black race were both predictive of poorer outcome. Using a multivariable Cox proportional hazards model, they found that race—but not BMI—remained a significant predictor of recurrence-free survival. Therefore, although BMI was associated with adverse pathological variables, it did not have an independent effect on recurrence-free survival. 
