INTENSIVE LIFESTYLE CHANGES MAY AFFECT THE PROGRESSION OF PROSTATE CANCER

Purpose: Men with prostate cancer are often advised to make changes in diet and lifestyle, although the impact of these changes has not been well documented. Therefore, we evaluated the effects of comprehensive lifestyle changes on prostate specific antigen (PSA), treatment trends and serum stimulated LNCaP cell growth in men with early, biopsy proven prostate cancer after 1 year. 

Materials and Methods: Patient recruitment was limited to men who had chosen not to undergo any conventional treatment, which provided an unusual opportunity to have a nonintervention randomized control group to avoid the confounding effects of interventions such as radiation, surgery or androgen deprivation therapy. A total of 93 volunteers with serum PSA 4 to 10 ng/ml and cancer Gleason scores less than 7 were randomly assigned to an experimental group that was asked to make comprehensive lifestyle changes or to a usual care control group.

Results: None of the experimental group patients but 6 control patients underwent conventional treatment due to an increase in PSA and/or progression of disease on magnetic resonance imaging. PSA decreased 4% in the experimental group but increased 6% in the control group (p  0.016). The growth of LNCaP prostate cancer cells (American Type Culture Collection, Manassas, Virginia) was inhibited almost 8 times more by serum from the experimental than from the control group (70% vs 9%, p 0.001). Changes in serum PSA and also in LNCaP cell growth were significantly associated with the degree of change in diet and lifestyle.

Conclusions: Intensive lifestyle changes may affect the progression of early, low grade prostate cancer in men. Further studies and longer term followup are warranted. Although this decision was made for reasons unrelated to this study, the choice to perform watchful waiting was clinically reasonable in these men. This subgroup of patients provided an unusual opportunity to have a nonintervention randomized control group to avoid the confounding effects of interventions such as radiation, surgery or androgen deprivation therapy. MATERIALS AND METHODS Patients in this study had biopsy documented prostate cancer with Gleason less than 7, serum PSA 4 to 10 ng/ml, and stages T1 and T2 disease. They had elected not to undergo conventional treatment. Patients were excluded if they had active prostatitis, had already made comprehensive lifestyle changes, had other life threatening comorbidities or major psychiatric disturbances, or were abusing alcohol, nicotine or other drugs. The University of California-San Francisco Committee on Human Research institutional review board approved this study and all patients provided proper consent. A randomized consent design was chosen to decrease the likelihood that control group patients might make diet and lifestyle changes comparable to those of the experimental group that could dilute between group differences and increase the likelihood of a type 2 error by decreasing the amount of information about the lifestyle intervention available to the control group. 

8 Of the 181 patients who were eligible for the study 93 enrolled, including 44 in the experimental group and 49 in the control group. Reasons for refusal to participate were unwillingness to make or not make comprehensive lifestyle changes and/or refusal to undergo periodic testing. An additional 15 patients with Gleason scores of 7 or greater were excluded because it is a unique prognostic category with biologically distinct and more aggressive neoplasms. Three experimental group patients withdrew soon after beginning the intervention because they said it was too difficult to follow and they refused further testing. No other patients were lost to followup. 

Experimental group patients were prescribed an intensive lifestyle program that included a vegan diet supplemented with soy (1 daily serving of tofu plus 58 gm of a fortified soy protein powdered beverage), fish oil (3 gm daily), vitamin E (400 IU daily), selenium (200 mcg daily) and vitamin C (2 gm daily), moderate aerobic exercise (walking 30 minutes 6 days weekly), stress management techniques (gentle yoga based stretching, breathing, meditation, imagery and progressive relaxation for a total of 60 minutes daily) and participation in a 1-hour support group once weekly to enhance adherence to the intervention. 
The diet was predominantly fruits, vegetables, whole grains (complex carbohydrates), legumes and soy products, low in simple carbohydrates and with approximately 10% of calories from fat. The diet is intensive but palatable and practical. In earlier studies most patients were able to adhere to this diet for at least 5 years.

A registered dietitian was available for nutrition education and counseling. A nurse case manager contacted patients by telephone once weekly for the first 3 months and once monthly thereafter. Control group patients were asked to follow the advice of their physicians regarding lifestyle changes. All therapeutic decisions, including whether to undergo conventional treatment during the study course, were deferred to the personal physician of each patient. Serum PSA was measured twice at baseline and at 1 year. 

Patients were counseled to avoid activities that might affect PSA for 3 days prior to testing, including sexual activity, exercise and digital rectal examination. Serum PSA was measured at Memorial Sloan-Kettering Cancer Center prospectively by a heterogeneous sandwich magnetic separation assay with the Immuno 1™ System. Testosterone was measured by a competitive immunoassay with an Immulite® automated analyzer. 

LNCaP cells were grown in 75 cm2 flasks in RPMI-1640 medium without phenol red, as previously described in detail.12 Cells were collected using 0.25% Trypsin-ethylenediaminetetraacetic acid (Sigma Chemical Co., St. Louis, Missouri) and then experiments were performed in duplicate (5 103 cells per well in 96-well plates). After 24 hours fresh medium composed of 10% fetal bovine serum (FBS) or 10% human serum was replaced and the cells were incubated (37C, 5% CO2) for 48 hours. FBS served as a control for each assay and results are expressed as percent FBS. Cell growth was assessed by MTS Assay (Promega, Madison, Wisconsin). For apoptosis cells were plated at a density of 1 104 cells per well in 96-well culture plates and incubated as described for the growth assay. After 48 hours apoptosis was detected by Cell Death Detection ELISAPLUS (Roche Applied Science, Indianapolis, Indiana). CRP determinations were done in duplicate by ultrasensitive enzyme-linked immunosorbent assay with 1.6 ng/ml sensitivity, and with intra-assay and interassay coefficients of variation of 3.9% and 5.1%, respectively. 

Dietary intake assessing the percent of calories from fat and mg cholesterol was measured with a semiquantitative food frequency questionnaire. Nutrient assessment was calculated elsewhere using United States Department of Agriculture food composition tables and other sources. The frequency and duration of exercise and of stress management techniques were assessed by self-reporting questionnaires. Attendance at group support sessions was recorded. The level of adherence to the recommended lifestyle change was based on a formula validated in previous studies.

A total score of 1 indicated 100% adherence to the program and 0 indicated no adherence. Eligible patients were randomly assigned to the control or the intervention group. Assessment of outcome measures were done while blinded to group assignment. Baseline equivalence of the 2 groups were analyzed using the independent sample t test in the case of continuous variables and the chi-square test of association in the case of categorical variables. 

Between group differences in baseline to 12-month changes in clinical and behavioral outcomes were compared using ANCOVA with baseline values as covariates. Although control patients were not asked to make changes in diet and lifestyle, some did so in varying degrees, that is 18% to 137% (experimental group 58% to 316%). As a secondary analysis, we correlated the degree of lifestyle change with changes in serum PSA, LNCaP cell growth, LNCaP apoptosis, serum testosterone and CRP across the 2 groups regardless of group assignment with baseline values as a covariate. Natural log transformation achieved normality (ln-CRP). 

All reported significance levels are 2-sided and p 0.05 was considered the required value for concluding tAt baseline there were no significant differences between the groups in demographic or clinical measures (table 1). Subject age, PSA and Gleason scores in those who were randomized into the study but refused to participate were not significantly different from values in those who participated. After 1 year adherence to the intervention was 95% in the experimental group and 45% in the control group. There were no adverse events attributable to the lifestyle intervention. Diet, exercise, stress management techniques and group support improved significantly more in the experimental group than in the control group (table 2). 
Six control group patients withdrew before 12 months and underwent conventional treatment, including radical prostatectomy in 3, and androgen deprivation, external beam radiation and brachytherapy in 1 each. Four of these patients underwent conventional treatment due to an increase in PSA during the study and 2 underwent it due to progression of prostate cancer, as assessed by magnetic resonance imaging compared with earlier studies. 

In contrast, no experimental group patients underwent conventional treatment during the study. Changes in serum PSA and LNCaP cell growth from baseline to 12 months were significantly different between the groups, showing more favorable changes in the experimental group. 
Specifically serum PSA decreased an average of 0.25 ng/ml or 4% of the baseline average in the experimental group but it showed an average increase of 0.38 ng/ml or 6% of the baseline average in the control group (F  5.6, p  0.016, fig. 1). Serum from experimental group patients inhibited LNCaP cell growth by 70%, whereas serum from control group patients inhibited growth by only 9% (p 0.001, fig. 2). CRP decreased more in the experimental group (p  0.07). There were no significant differences between the groups in serum testosterone or in apoptosis (table 3). Pearson correlations between changes in serum PSA, LNCaP, apoptosis, testosterone and CRP, and following recommended lifestyle changes in the entire sample indicated that the extent to which participants made changes in diet and lifestyle was significantly related to decreases in PSA (r  0.23, p  0.035, fig. 3) and to LNCaP cell growth (r 0.37, p 0.001, fig. 4).

Key words: prostate, prostatic neoplasms, prostate-specific antigen, life style, nutrition Increasing evidence from epidemiological and laboratory studies suggests that diet and lifestyle may have a role in the development of prostate cancer.1–5 The intake of total and specific vegetables, tomato products (lycopene), vitamin E, selenium, vitamin C and soy products has been inversely associated with prostate cancer risk. In addition, epidemiological evidence and migrant studies indicate that the incidence of clinically significant prostate cancer is much lower in parts of the world where people eat a predominantly low fat, plant based diet.6 There is considerable interest in the role of diet and lifestyle changes as complementary therapy in those with prostate cancer, especially because no consensus exists regarding the relative benefits and risks of conventional treatments in many patients. Many men are making changes in diet and lifestyle in the hope of preventing or slowing the progression of prostate cancer without the benefit of data from randomized, controlled trials to help guide these decisions. We examined if comprehensive changes in diet and lifestyle may affect the progression of prostate cancer, as measured by serial prostate specific antigen (PSA), treatment trends and serum stimulated LNCaP cell growth, in men with early, biopsy proven prostate cancer. To assess possible mechanisms mediating the relationship between changes in lifestyle and these measures we also evaluated changes in testosterone and C-reactive protein (CRP). Patient recruitment was limited to men who had chosen not to undergo any conventional treatment and who had low risk prostate cancer, as defined by baseline serum PSA and Gleason score. Submitted for publication September 9, 2004. Study received University of California-San Francisco Committee on Human Research institutional review board approval. Supported by Department of Defense Uniformed Services University Grant MDA905–99 –1– 0003 via the Henry M. Jackson Foundation Grant 600 – 06971000 –236, The Prostate Cancer Foundation, National Institutes of Health 5P50CA089520 – 02 University of California-San Francisco Prostate Cancer Specialized Program of Research Excellence, Bucksbaum Family Foundation, Ellison Foundation, Fisher Foundation, Gallin Foundation, Highmark, Inc., Koch Foundation, Resnick Foundation, Safeway Foundation, Wachner Foundation, Walton Family Foundation and Wynn Foundation. Foundation, Walton Family Foundation and Wynn Foundation. No supporting agencies were involved in the design or conduct of the study, in the collection, analysis or interpretation of the data, or in the preparation, review or approval of the manuscript. *

Correspondence: Preventive Medicine Research Institute, University of California-San Francisco, 900 Bridgeway, Sausalito, California 94965 (e-mail: d.ornish@pmri.org). † Financial interest and/or other relationship with Random House and Harper-Collins. ‡ Financial interest and/or other relationship with TAP Pharmaceutical Products, AstraZeneca, Pfizer and National Institutes of Health. 0022-5347/05/1743-1065/0 Vol. 174, 1065–1070, September 2005 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION DOI: 10.1097/01.ju.0000169487.49018.73 1065
DEAN ORNISH, GERDI WEIDNER, WILLIAM R. FAIR, RUTH MARLIN, ELAINE B. PETTENGILL, CAREN J. RAISIN, STACEY DUNN-EMKE, LILA CRUTCHFIELD, F. NICHOLAS JACOBS, R. JAMES BARNARD, WILLIAM J. ARONSON, PATRICIA MCCORMAC, DAMIEN J. MCKNIGHT, JORDAN D. FEIN, ANN M. DNISTRIAN, JEANMAIRE WEINSTEIN, TUNG H. NGO, NANCY R. MENDELL AND PETER R. CARROLL‡ From the Departments of Urology (PRC) and Medicine (DO) and Preventive Medicine Research Institute (DO, RM, EBP, CJR, SDE, LC, PM, DJM, JDF, JW, GW), University of California-San Francisco, San Francisco and Departments of Physiological Science (RJB, THN) and Urology (WJA), University of California-Los Angeles, Los Angeles, California, Department of Urologic Oncology, Memorial SloanKettering Cancer Center (WRF and AMD), New York and Department of Statistics, State University of New York at Stony Brook (NRM), Stony Brook, New York, and Windber Research Institute (FNJ), Johnstown, Pennsylvania ABSTRACT