STUDIES OF NUTRITIONAL SUPPORT FOR PROSTATE CANCER PREVENTION AND THERAPY
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University
By
Elizabeth C. Miller, M.S., R.D.
*****
The Ohio State University 2005
Dissertation Committee: Approved by Steven K. Clinton, M.D., Ph.D., Adviser
Anne M. Smith, Ph.D., R.D. ______
Janet Buckworth, Ph.D. Adviser
Diane Habash, Ph.D., R.D. The Ohio State University Nutrition Graduate Program (OSUN)
ABSTRACT
Prostate cancer is a major cause of morbidity and mortality in the United States.
Epidemiologic, in vitro, and animal studies support the hypothesis that dietary patterns and nutritional compounds can influence prostate carcinogenesis. Prostate cancer generally has a protracted time course with decades between the development of premalignant lesions, prostate cancer diagnosis and progression to metastatic disease.
Thus, many opportunities exist for nutritional interventions to alter the course of disease.
Dietary components which have been hypothesized to influence prostate cancer include individual nutrients such as vitamin E, vitamin D, selenium, and calcium, and whole foods including tomatoes / tomato products and soy foods.
This thesis involves three studies that target men during: 1) primary prostate cancer prevention, 2) treatment for localized disease and 3) treatment for advanced disease. The first study quantifies the use of nutritional supplements and alternative medications in a subgroup of men participating in a large, nationwide chemoprevention trial of Finasteride (a 5-α-reductase inhibitor) to prevent prostate cancer. We found that a majority of men were consuming supplements which are hypothesized to influence prostate cancer risk and therefore, may impact the results of prevention studies. Our second study precisely defined nutritional supplement use among men undergoing
ii radiation therapy for primary treatment of newly diagnosed localized prostate cancer.
There are very few reports of nutritional supplement use among men actively undergoing treatment for prostate cancer, and how dietary supplements may influence radiation therapy is currently an area of controversy. We found a majority of men were consuming supplements and many of the commonly consumed supplements, specifically antioxidants, have been hypothesized to influence the efficacy or toxicity of radiation therapy. Our third study is a phase I/II intervention trial. We evaluated adherence, safety, and biological effects of a food-based approach incorporating a diet rich in tomatoes / tomato products and soy foods in men with advanced prostate cancer. Our findings suggest that men with advanced disease are very motivated and adherent to diet changes. A diet rich in tomatoes and soy foods was tolerable and does not result in significant toxicity. Additionally, we observed that a diet rich in tomatoes and soy protein reduced serum PSA in 30 to 40% of men and may prolong the interval before more aggressive cancer therapy is needed.
These studies indicate that men at risk of prostate cancer or undergoing primary treatment consume many supplements that may influence risk and response to therapy.
This data provides information that will help investigators define future intervention trials. Among the dietary components worthy of study for prostate cancer prevention and as an adjunct for therapy, tomatoes and soy are a reasonable combination for intervention studies.
iii
Dedicated to Etta Miller
iv
ACKNOWLEDGMENTS
This has been a long journey and there are many people I wish to sincerely thank for their invaluable guidance and support. First, my family, specifically my dad, for always encouraging me to read and my mom for secretly believing that I actually was capable of driving a stick shift.
I have been very fortunate to have a great committee who invested a lot of time and effort into this project. My adviser and mentor, Steven Clinton, who has generously allowed me to work as a research dietitian while pursuing this degree. I am indebted to
Dr. Clinton for the many challenging and rewarding academic and occupational opportunities he has given me over the last six years. Anne Smith has been an important part of my academic maturation for many years now, first as my adviser for my master’s degree, and now as a member of my doctoral committee. I am grateful for her advice, direction and scientific insights. Janet Buckworth continues to teach me about exercise psychology and physiology and her expertise has been a wonderful complement to my research interests. I hope to continue this relationship with future collaborations. Diane
Habash has contributed her expertise in human clinical trials not only to this thesis, but to my everyday work. In addition to helping me with the conceptual framework of this
v thesis, she is a great editor and found all of my undotted i’s and uncrossed t’s (and there were a lot!).
I am grateful for my classmates, co-workers, and friends with whom I have shared both the high roads and the lower roads. Triumphs, frustrations and Nutrition 793 were better experiences thanks to classmates Tracy Smith and Maureen Geraghty. I am grateful to everyone in the lab including Valerie DeGroff, Pete Carlton, Shihua Wang,
Anna Powlosky, Kim Carter, Dahlys Hoot, BJ Hauswirth, Kelly Slavens, Lisa Rader,
Paul Monk, John Reed, and Michelle VanLoon. A special thank you to Valerie who has edited every presentation, poster and manuscript associated with this thesis and never balks when I send her something that needs to be reviewed within the hour. Also thanks to Steve Schwartz and Nuray Unlu. Nuray very patiently walked me through the HPLC process and analyzed biological samples for this study. Thanks also to Amy Ferketich for helping with the statistical analysis and for pushing me to keep running throughout this stressful summer. Finally, my friends who continue to invite me to social events, despite the fact that I have not returned any calls in months. Gina, for always giving me good advice, and Andrew who reminds me there is no “I” in Ph.D.
vi VITA
November 12, 1968…………………… Born – Columbus, Ohio
1991…………………………………… B.S. Dietetics, Bowling Green State University
1998…………………………………… M.S. Human Nutrition, The Ohio State University
1993-1999……………………………… Clinical Dietitan, The Ohio State University Medical Center
1999-present……………………………. Research Dietitian, The Ohio State University Laboratory of Nutrition and Chemoprevention
PUBLICATIONS
Research Publications
1. Clinton S .K., E.C. Miller, and E.L. Giovannucci. 2005. Nutrition in the etiology and prevention of cancer. In: Cancer Medicine, 7th Edition, ed J.F. Holland, E. Frei, R.C. Bast Jr., D.W. Kufe, R.E. Pollock, R.R. Wichselbaum. Ontario, Canada: B.C. Decker.
2. Ang, E.C.L., E.C. Miller, S.K. Clinton. 2004. The Role of Lycopene in Carcinogenesis. In: Carotenoids in Health and Diesease, ed. N.I. Krinsky, S.T. Mayne, H. Sies, NY, New York: Marcel Dekker, Inc.
3. Pohar K.S., M.C. Gong, R. Bahnson, E.C. Miller, S.K. Clinton. 2003. Tomatoes, lycopene and prostate cancer: a clinician’s guide for counseling those at risk for prostate cancer. World J Urol. 21(1):9-14.
4. Miller, E.C. 2002. Feasibility and efficacy of low intensity diet and exercise counseling for overweight men with active prostate cancer (abstract). J Nutr. 132(11): 3542S-3543S.
vii 5. Clinton S .K., E.C. Miller, and E.L. Giovannucci. 2002. Nutrition in the Etiology and Prevention of Cancer. In Cancer Medicine, 6th Edition, ed J.F. Holland, E. Frei, R.C. Bast. Ontario, Canada: B.C. Decker.
6. Miller E.C., C.W. Hadley, S.J. Schwartz, J.W. Erdman, Jr. T.W-M. Boileau, and S.K. Clinton. 2002. Lycopene, tomato products and prostate cancer prevention. Have we established causality? Pure Appl Chem. 74(8): 1435-1441.
7. Hadley, C.W., E.C. Miller, S.J. Schwartz, S.K. Clinton. 2002. Tomatoes, lycopene, and prostate cancer: progress and promise. Exp Biol Med. 227(10): 869-880.
8. Schwartz, S.J., C.W. Hadley, E.C. Miller, and S.K. Clinton. 2002. Chemistry, Bioavailability and Health Benefits of Lycopene and Other Carotenoids. In: Tomato Products. Functionalities of Pigments in Food. Lisbon, Portugal; June 11-14: pgs. 61-69.
9. Miller, E.C., E.L. Giovannucci, J.W. Erdman Jr., R. Bahnson, S.J. Schwartz, and S.K. Clinton. 2002. Tomato products, lycopene and prostate cancer risk. Urol Clin N Am. 29(1):83-93.
10. Miller, E.C. 2001. Nutrient supplements and alternative medications for prostate cancer survivorship (abstract). J Nutr. 131(11S):3131S-3132S.
11. Miller, E.C., Z. Liao, Y. Guo, S.M. Shah, and S.K. Clinton. 2001. Chemoprevention: progress and opportunity. Adv Exp Med Biol. 492:263-274.
12. Clinton S .K., E.C. Miller, and E.L. Giovannucci. 2000. Nutrition in the etiology and prevention of cancer. In: Cancer Medicine, 5th Edition, ed J.F. Holland, E. Frei, R.C. Bast Jr., D.W. Kufe, R.E. Pollock, R.R. Wichselbaum. Ontario, Canada: B.C. Decker.
13. Miller, E.C., and P. Fahey. 2000. Sports nutrition for the competitive athlete. Family Practice Recertification. 22(1); 53-74.
14. Miller, E.C., and C. Maropis. 1998. Nutrition and diet-related problems. In: Prim Care. ed Fahey P., Gabel L., and Brown R. 25(1):193-210.
15. Fahey, P., and E.C. Miller. 1997. Management of the overweight patient. Family Practice Recertification. 19(8):45-80.
FIELD OF STUDY
Major Field: The Ohio State University Nutrition Graduate Program (OSUN)
viii TABLE OF CONTENTS Page
Abstract…………………………………………………………………… iii
Dedication………………………………………………………………… iv
Acknowledgments………………………………………………………… v
Vita………………………………………………………………………… vi
List of Tables………………………………………………………………. x
List of Figures……………………………………………………………… xii
Chapters:
1. Introduction……...... 1 1.1 Hypothesis…………………………………………………. 3 1.2 Objectives and specific aims …………………………...... 4
2. Review of the Literature…………………………………………………6 2.1 Introduction……………………………………………….... 6 2.2 Prostate carcinogenesis…………………………………...... 9 2.3 Prostate cancer prevention studies………………………... 11 2.4 Development of chemoprevention / dietary interventions for prostate cancer…………………………………………. 16 2.5 Nutritional support of therapy for localized disease………. 31 2.6 Nutrition and advanced prostate cancer…………………… 38 2.7 Summary…………………………………………………… 46
3. Consumption of Nutritional Supplements, Alternative Medications, and Prescription Medications in Men Participating in the Prostate Cancer Prevention Trial (PCPT)……………………………………… 47 3.1 Abstract………………………………………………….. 47 3.2 Introduction……………………………………………… 49 3.3 Materials and methods…………………………………... 51 3.4 Results…………………………………………………… 54 3.5 Discussion………………………………………………. 61
ix 4. Use of Nutritional Supplements and CAM (Complementary and Alternative Medicine) by Prostate Cancer Patients Undergoing Radiotherapy…………………………………………………………. 71 4.1 Abstract………………………………………………….. 71 4.2 Background……………………………………………… 73 4.3 Materials and methods…………………………………... 77 4.4 Results…………………………………………………… 79 4.5 Discussion……………………………………………….. 87
5. Diet Intervention with Lycopene-Rich Foods or Soy Protein in Men With Recurring, Asymptomatic Prostate Cancer…………………….. 89 5.1 Abstract…………………………………………………. 89 5.2 Background……………………………………………… 91 5.3 Subjects and methods…………………………………… 97 5.4 Statistical analysis………………………………………. 108 5.5 Results…………………………………………………… 110 5.6 Discussion……………………………………………….. 130
6. Conclusion……………………………………………………………. 136
List of References…………………………………………………….. 138
Appendix A: Institutional Review Board biomedical summary sheets and consent form…………………………………………………. 159
Appendix B: Personal and demographic information form and Institutional Review Board biomedical summary sheets and consent form………………………………………………………. 164
Appendix C: Institutional Review Board biomedical summary sheets and consent form………………………………………………….. 171
Appendix D: Participant education materials……………………………… 179
x LIST OF TABLES
Table Page
2.1 Selected results from the interim results of the PCPT…………….. 14
2.2 Relationship between selected dietary components and prostate cancer……………………………………………..… 17
3.1 The number of dietary supplement products consumed and demographic characteristics of 86 participants in the PCPT …….. 56
3.2 Intake of selected nutrients from all supplemental sources for 86 men participating in the PCPT at The Ohio State University…….. 59
4.1 Categories of nutritional supplements and examples of representative products……………………………………………. 80
4.2 Descriptive and anthropometric data of men with prostate cancer undergoing radiation therapy…………………………….. 81
4.4 Quantification of select nutrient intake summed from all dietary supplements among men undergoing radiation treatment for localized prostate cancer…………………………………………. 86
5.1 Nutrient analysis of soy protein powder…………………………. 104
5.2 Baseline characteristics of men enrolled in study………………… 111
5.3 Mean lycopene and soy protein intake……………………………. 112
5.4 Plasma carotenoid values…………………………………………. 115
5.5 Urinary isoflavone levels…………………………………………. 120
5.6 Group A diet analysis data………………………………………… 122
5.7 Group B diet analysis data……………………………………….. 123
xi 5.8 Testosterone, IGF-1 and lipid values………………………………. 125
5.9 Change in PSA and PSA doubling time…………………………… 126
5.10 PSA rate of rise stratified by PSA doubling time at enrollment….. 127
xii LIST OF FIGURES
Figure Page
2.1 The biologic and clinical continuum of prostate cancer………….. 8
2.2 The influence of finasteride on testosterone metabolism……….. 13
2.3 Incidence of prostate cancer in US and Asian countries………….. 19
2.4 Chemical structures of common isoflavones and metabolites…….. 20
2.5 Carotenoid structures and lycopene isomers……………………… 23
2.6 Consumption of selected foods and relative risk of prostate cancer among the Health Professional’s Follow-up Cohort………. 25
2.7 Mathematical equation for PSA Doubling Time (PSADT)……….. 41
3.1 Frequency of nutritional supplement use among 86 men enrolled in the PCPT at The Ohio State University………………. 57
3.2 Percent of men participating in the PCPT at The Ohio State University consuming dietary supplements or specific prescription drugs potentially related to prostate cancer risk…………………… 58
4.1 Frequency of nutritional supplement use among men with prostate cancer undergoing radiation therapy…………………….. 82
4.2 Frequency of nutritional supplement use among 48 men undergoing radiation therapy for localized prostate cancer………. 83
4.3 Frequency of herbal supplement use among men with prostate cancer undergoing radiation therapy………………………………. 85
5.1 Study design……………………………………………………….. 99
5.2 Study participant daily lycopene log sheet……………………...... 102
5.3 Study participant daily log for soy protein consumption………….. 105
xiii
5.4 Mean servings per week from various tomato products………….. 114
5.5 PSA slope week 0…………………………………………………. 128
5.6 PSA slope week 8………………………………………………….. 129
xiv CHAPTER 1
INTRODUCTION
Prostate cancer is a significant cause of morbidity and mortality in the U.S. An estimated 230,000 new cases of prostate cancer are diagnosed each year and over 30,000 men die from prostate cancer annually (3). Prostate cancer is the most common visceral malignancy in men representing one-third of all male cancers and it is the second most common cause of cancer death in males (3). The early 1990’s saw a dramatic increase in the diagnosis of prostate cancer largely due to the development and widespread clinical use of prostate specific antigen (PSA) screening. However, even though screening techniques have advanced and many new treatments for prostate cancer have been developed, the mortality rate from prostate cancer has been relatively unchanged since the 1950’s (3).
The economic costs and societal burden of this disease are enormous. In the U.S., total costs to screen, stage and treat early-stage prostate cancer have been estimated to be between 1.72 and 4.75 billion dollars (4). For men who develop advanced disease, the financial burden increases with each year of treatment. In the final year of life, men who eventually die from prostate cancer are estimated to incur costs approaching
1 $25,000 dollars (5). Importantly, men who are diagnosed with prostate cancer not only suffer from risk of death from their disease, but survivors suffer physiological and psychological decimation of quality of life as a result of treatment-related side effects (6,
7).
Because prostate cancer is a major public health burden, interventions that may reduce the risk of prostate cancer development, improve prostate cancer treatment or enhance prostate cancer survivorship are important. This manuscript will first review the natural history of prostate cancer, and then describe three original research projects. The first project is an evaluation of nutritional supplement use among the Prostate Cancer
Prevention Trial (PCPT) cohort. The second study is an evaluation of nutritional supplement use among men undergoing radiation therapy for localized prostate cancer.
Finally, the third study will describe an intervention with tomatoes and soy in a cohort of men with asymptomatic, recurrent prostate cancer. Collectively, these studies will help to describe the nutrition-related characteristics of men at different stages of prostate cancer, and they will provide important preliminary data for future studies.
2
HYPOTHESES
1. Men enrolled in the Prostate Cancer Prevention Trial (PCPT) frequently
consume nutritional supplements and alternative medications that may alter
prostate cancer risk.
2. Men who are undergoing radiation therapy for primary treatment of localized
prostate cancer are consuming nutritional supplements that may impact the
effectiveness of treatment.
3. Men with asymptomatic, recurrent prostate cancer characterized by a rising
PSA will adhere to a diet rich in tomatoes / tomato products in combination with a
soy protein supplement for eight weeks. These interventions will modulate in
vivo lycopene and isoflavone profiles and will not adversely impact biomarkers
associated with toxicity. Additionally the interventions will impact biomarkers
associated with prostate cancer progression.
3
OBJECTIVES AND SPECIFIC AIMS
1. To quantify the use of nutritional supplements and complementary and alternative
medicines (CAM) in men enrolled in a large cancer prevention trial at an
academic medical center.
a. Establish a detailed data-base that can be used to quantify the nutrient and
component intake from a wide variety of supplements / products.
b. Quantify the consumption of nutrients, supplements and prescription
medications that may be related to prostate cancer risk.
2. To quantify the use of nutritional supplements and CAM among men undergoing
curative radiation therapy for recently diagnosed and clinically localized prostate
cancer.
a. Establish a detailed data-base that can be used to quantify the nutrient and
component intake from a wide variety of supplements / products.
b. Quantify the consumption of nutrients, supplements and prescription
medications that may be related to prostate cancer risk.
3. To determine the feasibility of implementing a dietary intervention with tomato
products and soy for men with recurrent, asymptomatic prostate cancer.
a. Determine adherence to a diet rich in tomatoes and tomato products to
provide 25 mg of lycopene each day for either 4 or 8 weeks.
4 b. Determine adherence to a soy protein supplement providing 40 grams of
soy protein and 80 mg of isoflavones each day for either 4 or 8 weeks.
c. Monitor the toxicity of the intervention using standard criteria.
d. Examine the changes in blood carotenoids and soy isoflavones in men
consuming a diet rich in tomato products and a soy protein supplement.
e. Monitor the safety of consuming tomato and soy products together for
four weeks.
f. Explore the relationships between consumption of dietary tomato products
or soy protein and biomarkers associated with prostate cancer including
IGF-1, testosterone, PSA, and PSA doubling time.
5
CHAPTER 2
REVIEW OF THE LITERATURE
2.1. Introduction
The purpose of this literature review is to briefly describe the natural history of prostate cancer and to identify specific time points along the prostate cancer continuum where novel interactions with diet and nutritional interventions can provide important opportunities for scientific investigation. Prostate cancer is unique because the course of the disease is often very protracted, even after diagnosis (figure 2.1). This is not the case for most other cancers. Diseases such as lung and pancreatic cancers are often so advanced at diagnosis that life-expectancy is short and studies of dietary influences on prevention, response to therapy and survivorship are very difficult. The extended time course for prostate cancer offers several important opportunities for diet and nutrition research. The studies described in this thesis were designed to include specific phases of the prostate cancer continuum including the influence of diet and nutrients for primary prevention of prostate cancer, early treatment after cancer diagnosis, and interventions during advanced disease. We first evaluate the consumption of dietary
6 and nutritional supplements during the prevention phase of prostate carcinogenesis. The second project addresses the use of dietary supplements during the immediate post- diagnostic phase while undergoing curative radiation therapy. The final component is an intervention study for men with advanced, metastatic prostate cancer.
7
Prostate Cancer Prostate Cancer Dissertation Biological Events Clinical Course Projects
Birth
Premalignant Lesion Study 1
Puberty Consumption of Prostatic Intraepithelial Nutritional Supplements, Neoplasia (PIN) Alternative and Prescription Medications Adult by in Men in the PCPT
Localized Disease Prostate Cancer Diagnosis Study 2
Use of Nutritional Micrometastatic Therapy for Localized Supplements and CAM by Disease Disease Prostate Cancer Patients Undergoing Radiotherapy
Hormone Sensitive Rising PSA / Detection Disease of Metastatic Disease Study 3
Hormone Therapy / Combined Dietary PSA Decline Intervention with Tomato- Based Foods and Soy in Androgen Receptor Rising PSA / Hormone Men with Signaling Defect Resistance Recurrent Asymptomatic Prostate Cancer
Chemotherapy Sensitivity
Multiple Drug Chemotherapy Resistance Resistance
Death Death
Figure 2.1 The biologic and clinical continuum of prostate cancer
8 2.2. Prostate Carcinogenesis
Prostate cancer is a heterogeneous disease with significant variability in its course among men. However, some fundamental principles have clearly emerged. The pathogenesis of prostate cancer progression from normal epithelial tissue to a premalignant lesion to the time of cancer diagnosis takes many years, and in most men probably decades (figure 2.1). Autopsy studies have provided valuable clues to the time course and pathogenesis of early disease. Sakr, et al., evaluated prostate tissue from 152 deceased males ages 10 to 49 at autopsy with no known history of prostate cancer and found prostatic intraepithelial neoplasia (PIN) to be present in 9%, 20% and 44% of men in the third, fourth, and fifth decades of life, respectively (8). Small foci of histologic cancer were noted in 27% and 34% of men in their fourth and fifth decades, respectively
(8). This important finding indicates that premalignant lesions and small localized cancers are present in early adult years and accumulate with time (9).
It has been well documented that a variety of prostatic lesions are present in a large proportion of men, however many will not go on to develop clinically significant
(aggressive or lethal) prostate cancer (10, 11). Recently, there has been an increased interest in the relationship between chronic prostatic inflammation and prostate cancer.
Proliferative inflammatory atrophy, or PIA, are lesions in the prostate characterized by atrophy of the epithelium and by an increased proliferative index. These lesions are common in older men and have been hypothesized to be a precursor of prostate cancer
(10-12). Chronic prostate infections (prostatitis), genetics and dietary components have
9 all been hypothesized to be important in the development of PIA. Studies have reported that men with a history of sexually transmitted infections and men that have symptomatic prostatitis have a higher risk of prostate cancer (13-15). Interestingly, a few studies suggest that men consuming anti-inflammatory medications have a reduced risk of prostate cancer (12, 16). Although there are some provocative data, more clinical and epidemiological studies need to be conducted to further investigate the role of PIA in prostate carcinogenesis.
The fact that prostatic lesions, including PIN and PIA, are present in a large number of men is a key concept to fully understand the potential of prostate cancer chemoprevention. These types of lesions characterize latent prostate cancer is common, and the transition of a latent cancer to a lethal cancer is an important opportunity for chemoprevention efforts. This transition toward clinically significant cancer may take years or decades and only occurs in a small proportion of men with premalignant lesions.
Environmental factors, including diet may be important risk factors that influence the progression of latent prostatic lesions to clinically significant prostate cancer.
Migrant studies offer important insights about the role of environmental variables in the development of prostate cancer. Japan, China and other Asian countries have at least a 10 to 20-fold lower incidence of prostate cancer (17, 18). Yet, when men from these low-risk countries migrate to a higher-risk country such as the U.S., their risk of prostate cancer gradually increases with each generation and eventually equals that of the new host country (19-21). Because the genetic profile has not changed over this short
10 period of time, we can reason that other factors such as diet, physical activity, and other lifestyle exposures (such as exposure to tobacco or sunlight) may be contributing to this phenomenon.
2.3. Prostate Cancer Prevention Studies
Chemoprevention is defined as the use of agents to inhibit, delay, or reverse the carcinogenesis process. Primary prevention focuses upon an initial cancer while prevention of a cancer recurrence is secondary chemoprevention (22). Chemoprevention uses chemical agents to prevent cancer and is distinct from obtaining nutrients or phytochemicals as part of an overall dietary pattern. Chemoprevention research must investigate compounds that have minimal long-term health risks and are well-tolerated by large groups of people (23, 24). Potential chemoprevention agents for prostate cancer include purified agents such as drugs, vaccines, hormones, vitamins, minerals and phytochemicals. Administration of purified dietary compounds (for example, vitamin E) has been a major focus of prostate cancer chemoprevention research. More complex agents such as functional foods, food extracts, herbs and botanicals are also potential agents for study (23).
Prostate Cancer Prevention Trial (PCPT)
To date, there have been two large, prospective prostate cancer chemoprevention studies. Starting in 1994, the Prostate Cancer Prevention Trial (PCPT) randomized over
18,000 men to receive either finasteride (Proscar) or a placebo for seven years.
11 Finasteride is a drug that blocks the enzyme 5-α-reductase which converts dihydrotestosterone to the active metabolite testosterone (figure 2.2). In 2003, an interim analysis of the data revealed a relative prostate cancer risk reduction of 24.8% in the finasteride arm (95% CI = 18.6-30.6, p < 0.001)(table 2.1) (25). Although there were some important differences in side effects (significantly more sexual side effects and fewer urinary symptoms in the group taking finasteride) many men, especially men at high risk for prostate cancer, might find the potential risk for side effects is acceptable if finasteride confers a significant reduction in cancer risk (25). Interestingly, detailed data on nutritional supplement use was not methodically collected in the PCPT. The men did complete a brief questionnaire at enrollment which included health behaviors, however the data collected on nutritional supplements was very limited. With this limited data,
Neuhauser et al., reported that 60% of men in the PCPT regularly consumed nutritional supplements with the most common supplement being a multivitamin (44% of cohort)(26). However, information on dose of supplements was only requested for multivitamins, antioxidant blend supplements and five single supplements (vitamins E, C, beta-carotene, calcium, and zinc). For other compounds (vitamins A and D, selenium, iron, niacin, garlic pills and fish oil), data on frequency of use was collected, but not dose
(26). This information may prove to be important to collect in large chemoprevention studies where single nutrients or complex mixtures may impact cancer outcome.
12
DNA
Androgen Androgen Receptor + DHT Receptor
Testosterone Dihydrotestosterone (DHT) 5-alpha-reductase
finasteride
Figure 2.1 The influence of finasteride on testosterone metabolism
13
Finasteride Placebo n = 9423 n = 9457 no. (%) no. (%)
Prostate Cancer*† 803 (18%) 1147 (24%)
Medical Events and Side Effects**
Erectile dysfunction 6349 (67) 5816 (62)
Loss of libido 6163 (65) 5635 (60)
Gynecomastica 426 (5) 261 (3)
Benign prostatic hyperplasia 488 (5) 826 (9)
Urinary incontinence 1214 (13) 1474 (16)
Urinary retention 398 (4) 597 (6)
Prostatitis 418 (4) 576 (6)
Urinary tract infection 90 (1) 126 (1)
* Finasteride group had a 25 % prostate cancer risk reduction (95%CI = 19 – 31%), p < 0.001 † the number of men who developed cancer in the Finasteride group = 4368, Placebo = 4692 ** p < 0.001 for all comparisons, except for urinary incontinence
Table 2.1 Selected results from the interim results of the Prostate Cancer Prevention Trial (PCPT)
14 Selenium and Vitamin E Cancer Trial (SELECT)
The second prospective prostate cancer chemoprevention trial is currently underway. The study is evaluating the influence of two nutrients, vitamin E and selenium, on risk of prostate cancer. The Selenium and Vitamin E Cancer Trial, or
SELECT, began enrolling men in 2001 (27). The design of SELECT is a 2 x 2 factorial where men will consume two pills per day providing a combination of either 400 IU vitamin E, 200 µg selenium or a placebo (27). The design of SELECT was derived from laboratory studies and two other chemoprevention studies where a reduction in prostate cancer incidence was found upon secondary analysis. The Alpha-Tocopherol, Beta-
Carotene (ATBC) study followed 29,133 Finish smokers at high risk for lung cancer for 5 to 8 years (median = 6.1 years) (28). During an interim analysis, the men consuming 20 mg of beta carotene were found to have a statistically significant increased risk of lung cancer and the study was halted. However, secondary analyses revealed that men consuming 50 mg alpha tocopherol had a 32% (95%CI = -47% to -12%, p = 0.002) reduction in the incidence of prostate cancer (11.7% prostate cancer incidence in alpha- tocopherol arm v. 17.8% prostate cancer incidence in placebo arm) and a 41% reduction in prostate cancer mortality (95% CI = -65% to -1%, p value not reported) (29). These results stimulated many researchers to consider the role of vitamin E for a chemoprevention study of prostate cancer.
Several lines of evidence support a role for selenium in prostate cancer chemoprevention. In 1996 the results of a chemoprevention study using selenium supplements for recurrent skin cancer prevention were published by Clark, et al. (30).
15 This study randomized 1312 men and women with a history of basal or squamous cell carcinoma to consume either 200 µg selenium or a placebo and subjects were followed for 6.4 years (30). The results did not find an association between selenium and skin cancer recurrence, but a significant reduction in prostate cancer risk was noted for the men in the selenium arm (RR = 0.37, 95%CI = 0.18-0.71, p = 0.002) (30, 31). A second important study evaluated men enrolled in The Health Professional’s Follow-Up Study
(HPFS). The HPFS is a prospective cohort of over 50,000 male health professionals
(dentists, veterinarians, optometrists, pharmacists, etc.) who were aged 40 to 75 when the study started in 1986. In this cohort, prediagnostic toenail selenium levels (a measure of long-term selenium intake) was associated with a reduced risk of advanced prostate cancer (OR = 0.35 for comparison of the highest quintile to the lowest quintile, 95% CI =
0.16-0.78, p for trend = 0.03)(32). These studies, in addition to laboratory(33, 34), animal and a few smaller human studies (35) have provided supportive preliminary data, however many questions remain. SELECT has completed accrual and results are expected in 2013 (27).
2.4. Development of chemoprevention/ dietary interventions for prostate cancer
In addition to selenium and vitamin E, other diet-related components hypothesized to influence the risk of prostate cancer include: soy isoflavones, lycopene, calcium and vitamin D. The strength of the relationship between these compounds and prostate cancer is summarized in table 2.2.
16
Convincing Convincing Probable Possible Not enough data to assess
Finasteride X
Soy isoflavones X
Tomatoes / tomato products X
Lycopene X
Vitamin E X
Selenium X
Calcium (increases risk) X
Vitamin D X
Green Tea X
Omega-3 Fatty Acids X
Curcumin X
Flaxseed / Flax Oil X
Table 2.2 Relationship between selected dietary components and prostate cancer
17 Soy Protein and Soy Isoflavones
Differences in diet, specifically the consumption of soy foods, have been hypothesized to play a role in the large variation in prostate cancer incidence between the
U.S. and Asian countries. In the U.S., 104 men out of every 100,000 men are diagnosed with prostate cancer (36). The incidence rate in Asian countries is dramatically lower with a range of 3 to 16 diagnoses per 100,000 men (figure 2.3) (1). Soy products are widely consumed in Eastern Asian countries where prostate cancer is rare (37). Japanese adults consume an average of 1 to 1.5 servings of soy foods per day (37). In contrast, only about 27% of Americans consume soy foods on a weekly basis (37). This major dietary difference has resulted in considerable scientific interest in soy and its’ active components. Soy foods contain many interesting compounds including lignans, saponins and phytosterols. However, the components which have received the most attention are the isoflavones, in particular, genistein and daidzein (figure 2.4). Genistein and daidzein are flavonoid compounds which are naturally found only in soy foods.
Isoflavones are also manufactured and sold as nutritional supplements. Cell culture studies have suggested several potential mechanisms for soy compounds including: inducing cell-cycle arrest (38), inhibition of signal transduction pathways (39, 40) inhibition of growth factors (41, 42) and possibly through antioxidant mechanisms (43).
18
100.00
80.00
60.00
40.00
20.00 Incidence Rate Prostate of Cancer per 100,000 Men
0.00 US Phillipines Singapore Japan China, China, Hong Kong Singapore
Figure 2.3 Incidence of prostate cancer in US and Asian countries (1)
19
20
Figure 2.4 Chemical structures of common isoflavones and metabolites
20 Animal studies investigating soy beans and their purified compounds have been reported since the mid-1970’s (44, 45). More recently, Zhou et al., evaluated the ability of four different treatments of soy protein isolate and soy phytochemical concentrate to inhibit the growth of prostate cancer in 48 mice inoculated with a human prostate cancer cell line. The mice were sacrificed after three weeks and there was a reduction in tumor volume ranging from 11% in the group fed only soy protein to 40% in the group fed soy protein with 1.0% phytochemical concentrate compared with the casein-fed control mice
(46). In general, the majority of animal studies support a protective effect of soy in prostate carcinogenesis (46-50).
In human studies, two prospective epidemiologic studies and several case-control studies have found an association between consumption of soy foods and prostate cancer incidence(19, 51-55). In a study of 7,999 Japanese men living in Hawaii, tofu consumption was associated with a reduced incidence of prostate cancer (51), however when this cohort was followed for an additional 9 years with an additional 130 cases of prostate cancer, no association between tofu and cancer incidence was noted (56).
Jacobson et al., evaluated the diet of 12,395 Seventh Day Adventists and found that men who reported consuming more than one serving of soy milk per day had a 70% reduction in prostate cancer risk compared with men who consumed less than one serving of soy milk per day (RR = 0.3, 95%CI = 0.1-1.0, p for trend = 0.03)(52).
Food disappearance data has also been used in international studies to evaluate potential associations between soy and prostate cancer. In 1998, Hebert et al, analyzed
21 data from 59 countries and found soy foods to have a significantly protective effect for prostate cancer mortality. Although very few countries consumed significant amounts of soy, the authors reported the effect of soy per calorie was four times more protective than any other food (54, 57). As the manufacturing and popularity of soy foods grows in the
United States, opportunities for prospective investigations evaluating long-term exposure to soy foods and prostate cancer risk will be more realistic.
Tomatoes, Tomato products and Lycopene
Tomatoes, tomato products and their chemical constituents, including lycopene, have been actively investigated in prostate cancer prevention research over the last 10 years. Lycopene is a natural red pigment synthesized by plants and is found predominantly in tomatoes and tomato products. Unlike other members of the carotenoid family, such as beta carotene, lycopene lacks a β-ionone ring and therefore does not have provitamin A activity (figure 2.5). One of the first studies to uncover an association between tomatoes, lycopene and prostate cancer was a prospective human study using the
HPFS cohort. The HPFS used a 131-item food frequency questionnaire to examine the
22
Figure 2.5 Carotenoid structures and lycopene isomers
23 dietary habits of over 47,000 men. After six years, there were 773 cases of prostate cancer (non stage-A1) diagnosed during the follow-up period (1986-1992). The only fruit or vegetables found to be associated with a reduced risk of prostate cancer were: raw tomatoes, tomato sauce, pizza and strawberries (figure 2.6) (2). Giovannucci et al., estimated lycopene intake in the HPFS cohort using the USDA Carotenoid Database.
The estimated dietary intake of β-carotene, α-carotene, lutein and β-cryptoxanthin were not related to prostate cancer risk. However, dietary intake of lycopene (80% of which was derived from tomatoes and tomato products) was inversely related to risk when the highest quartile (> 6.4 mg lycopene / day) was compared with the lowest quartile (<2.3 mg lycopene / day, RR = 0.79, 95% CI = 0.64 – 0.99, p for trend = 0.04) (2). This landmark study stimulated cell culture and animal studies, as well as human metabolic studies to evaluate issues related to lycopene mechanisms, stability, bioavailability, and tissue accumulation that have been recently reviewed (58-60).
Although many studies focusing on lycopene and prostate cancer have published provocative results, tomatoes and tomato products contain hundreds of potentially bioactive compounds which also may be important. An important animal study was published in 2003 by Boileau et al. (59). This study treated 194 male rats with N-methyl-
N-nitrosourea and testosterone to induce prostate cancer. At six weeks of age, the rats were randomized to three groups and fed either: a standard AIN diet with whole tomato powder (13 mg lycopene /kg), a standard AIN diet with purified
24
raw tomatoes*
tomato sauce†
pizzaψ
strawberries£
0.5 0.6 0.7 0.8 0.9 1
* 0 servings v. 2-4 servings / week, RR = 0.74 (95%CI = 0.58 – 0.93) p for trend = 0.03 † 0 servings v. 2-4 servings / week, RR = 0.66 (95%CI = 0.49-0.90) p for trend = 0.001 ψ 0 servings v. 2-4 servings / week, RR = 0.85 (95% CI = 0.45 – 1.58) p for trend = 0.05 £ 0 servings v. 1 serving / week, RR 0.80 (95% CI = 0.57 – 1.10) p for trend = 0.005.
Note: strawberries do not contain lycopene FFQ data gathered from a 131-item questionnaire used in the HPFS cohort
Figure 2.6 Consumption of selected foods and relative risk of prostate cancer among the Health Professional’s Follow-up Study Cohort (HPFS) (2)
25 lycopene (161 mg lycopene /kg) or a standard AIN control diet. Rats fed the tomato powder diet had a statistically significant longer survival time than rats fed the control diet or the lycopene beadlet diet (HR = 0.74, 95% CI = 0.59-0.93, p = 0.009). The percentages of rats dying from prostate cancer were 80% (95% CI = 68% to 98%) in the control group, 72% (95% CI = 60 – 83%) in the lycopene beadlet group, and 62% (95%
CI = 48 to 75%) in the tomato powder group (59). This important study suggests that other compounds in tomatoes and tomato products may have anticarcinogenic properties, in addition to or synergistically with lycopene and that both lycopene and tomato foods may be active in prostate cancer prevention (59, 61).
Although there are still many unanswered questions regarding the relationship between tomatoes, tomato products and prostate cancer, recent scientific interest in lycopene has compelled manufacturers of nutritional supplements to start producing and marketing lycopene supplements for prostate cancer prevention. In addition to purified lycopene supplements, major multivitamin companies began adding lycopene to their products in 2003 (62). Although the amount of lycopene added to most multivitamin products is trivial, its presence increases the public’s awareness of diet components and cancer prevention and may increase interest in dietary supplement use. Several studies suggest that men ages 65 and older have the highest regular use of nutritional supplements of any male age group, and because prostate cancer risk increases with age, many men are likely to consider nutritional supplements for the purpose of reducing prostate cancer risk (62).
26 Calcium
Several recent human cohort studies have suggested an increased risk of prostate cancer with high intake of calcium (63-67). Most studies suggest that high amounts (>
600 mg) of calcium from dairy products confers approximately a 30% increase in prostate cancer risk, specifically for metastatic disease (65-67) however, calcium from dietary supplements has also been reported in some studies (67) but not all (63) to increase risk independent of calcium consumption from food sources (67).
Vitamin D
It has been proposed that dietary calcium increases cancer risk by suppressing concentrations of the active form of vitamin D, 1,25 (OH)2D3. This form of vitamin D has been demonstrated in cell culture to inhibit cellular proliferation and induce apoptosis
(68-71). Rodent studies using prostate cancer xenografts also support an antiproliferative mechanism of vitamin D (72, 73). Human studies evaluating serum levels of vitamin D metabolites have produced more equivocal results with some studies suggesting a protective effect of vitamin D (74, 75) and others finding no relationship (63, 65, 76). In addition to dietary sources, a major contributor of vitamin D is endogenous synthesis generated from exposure to sunlight. Although several studies have reported a lower risk of prostate cancer among men who receive more sunlight exposure (77, 78) a major problem in studies of vitamin D and prostate cancer is that most studies do not control for sunlight exposure or sunscreen use. While the relationship between vitamin D and prostate cancer is intriguing, well-controlled studies need to be completed before determining the role of vitamin D in prostate carcinogenesis.
27 Other potential directions
Green Tea: Green tea is frequently consumed in geographical regions where prostate cancer risk is low. Animal, human and cell-culture studies have investigated the role of green tea, either as a beverage or a capsular extract, on biomarkers of prostate cancer. Laboratory and rodent studies suggest that epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, can induce apoptosis, inhibit cell-growth and modulate the IGF-1/ IGFBP-3 signaling pathway (79, 80). However, the only published human, prospective clinical trial of green tea in hormone refractory prostate cancer suggested no clinical activity of green tea, and a significant number of mild to moderate side-effects
(primarily gastrointestinal distress) (81). Green tea appears to have several potential mechanisms, and may be more effective for hormone sensitive prostate cancer. More research is needed to define a role of green tea in prostate carcinogenesis.
Omega-3 Fatty Acids: Fish is rich in omega-3 fatty acids which include: alpha- linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Epidemiologic studies investigating dietary fish intake and prostate cancer have largely been equivocal (82, 83). A few cell culture and animal studies have found EPA and
DHA to inhibit androgen-receptor mediated cell growth in hormone prostate cancer sensitive cells, however there have been too few studies published to draw meaningful conclusions (84). Further complicating this issue is the theory that the ratio of omega-3 fatty acids to omega-6 fatty acids may be more important than absolute omega-3 fatty acid consumption (85, 86).
Curcumin: Curcumin is a compound responsible for the yellow color of tumeric, a spice commonly used in India. Cell culture and rodent studies suggest curcumin may
28 have a wide variety of effects on prostate cancer including induction of apoptosis and increasing the sensitivity of cancer cells to chemotherapy and radiation therapy (87-89).
However, very few laboratory studies, and no human studies investigating curcumin and prostate cancer have been reported. Much more research on curcumin and prostate cancer needs to be conducted.
Flaxseed: Flaxseeds (also called linseeds) contain a compound called lignan, which is structurally similar to estrogen, and omega-3 fatty acids. Only three studies
(two human and one rodent study) have been published investigating flaxseed and prostate cancer (90-92). The rodent study found that mice consuming a diet with 5% flaxseed added had significantly smaller prostate tumors and significantly less aggressive tumors than mice that consumed a standard AIN diet (91). In both of the human studies the diet of men scheduled to undergo a prostatectomy was supplemented and results suggested that flaxseed was associated with favorable changes in prostate cancer associated biomarkers (90, 92). However, in each study the addition of flaxseed to the diet was one of several dietary changes prior to surgery so caution must be employed when interpreting these results. These studies demonstrate some potential for flaxseed in prostate cancer prevention and more studies need to be undertaken.
Determining causality for dietary components and prostate cancer
The hypothesis that foods contain compounds that may modify prostate carcinogenesis is firmly established. However, scientists, regulatory agencies, marketers of products, and those defining public health policies have differing opinions regarding the strength of the data when applied to criteria for inference and causality. Causality can
29 be defined as a specific occurrence or outcome that is consistently preceded by a known set of circumstances or conditions (93, 94). To determine causality, we must be able to make conclusions about the occurrence of an event and have scientific knowledge regarding the reasons for the occurrence. In nutritional sciences, causality has been determined for many nutrient-deficiency diseases. The criteria have evolved over years of observation and include the following:
• Consistency: Replication of the findings across different studies.
• Strength of association: The magnitude of the relative incidence or mortality
ratios.
• Biological gradient: A dose-response relationship is observed.
• Temporality: The cause must precede the effect.
• Specificity: One cause and one effect.
• Biological plausibility, mechanisms and coherence: The extent to which the
association supports or contradicts what is generally known about the biology
of the disease.
• Experimental evidence: Data from a randomized clinical trial.
These criteria need to be considered in evaluating the relationships between nutrition and prostate cancer for both primary prevention and after a cancer diagnosis.
30 2.5. Nutritional support during therapy for localized disease
Common treatment modalities for localized prostate cancer
For men diagnosed with prostate cancer, the majority are diagnosed at an early stage where the cancer appears to be confined to the prostate gland, which is called localized disease. The standard treatment options for localized prostate cancer are surgery (radical prostatectomy), radiation therapy (either external beam radiotherapy or brachytherapy), hormone therapy or watchful waiting. A radical prostatectomy involves complete surgical removal of the prostate gland and the seminal vesicles. Today there are several different surgical techniques for prostatectomy surgery including: open, robotic, nerve-sparing and laparoscopic prostatectomy. The ten-year cure rate after a prostatectomy has been reported to be over 80%, however many men experience significant side effects as a result of surgical trauma (95-97). The most common side effects of surgery are erectile dysfunction (approximately 15 to 40% of men) and urinary incontinence (less than 10%) although the prevalence of these side effects has improved with advanced surgical techniques and nerve-sparing procedures and are less common among younger men (< 70 years) who undergo surgery (98, 99).
Radiation therapy (either external beam radiation therapy or brachytherapy) is now established and a frequently chosen option for men with localized prostate cancer.
Men who choose external beam radiation therapy (EBRT) will receive radiation therapy each day for 4 to 6 weeks. Although the goal of EBRT is to deliver focused radiation to the prostate, normal tissues are often also affected and the major complications with
31 EBRT include damage to the normal bladder and rectal tissue and erectile dysfunction
(100). Brachytherapy involves the insertion of radioactive seeds directly into the prostate allowing a high dose of radiation to be administered to a concentrated area of prostatic tissue. This procedure is attractive for many patients because it is minimally invasive and allows for faster recovery with some studies citing lower sexual and urinary side effects
(100). Long-term survival data on patients treated with EBRT or brachytherapy suggests cancer-free survival rates that are similar to men treated with surgical resection at least for the first ten years (101). Currently, combinations of external beam radiotherapy and brachytherapy are becoming the standard of care.
Because each of the therapies described above have inherent risks and potential complications, for some men watchful waiting is the treatment of choice. This option is particularly reasonable for men who are elderly and /or have other medical issues where aggressive therapy may be too hazardous and the life expectancy is limited.
Additionally, although prostate cancer is a common diagnosis, most men diagnosed with prostate cancer will die from causes unrelated to prostate cancer, therefore older men who are asymptomatic may comfortably choose conservative treatment and pursue more interventions only if clinically indicated (102, 103).
After an initial diagnosis of cancer, many patients feel motivated to change their lifestyle or dietary behaviors with the hope of either reducing the risk of cancer progression or to help with the psychological stress associated with a life-threatening illness (104). It has been documented that cancer patients are more likely to use
32 complementary and alternative medications (CAM) than relatively healthy people (104-
106). Many newly-diagnosed cancer patients begin to investigate diet and nutritional adaptations that they can make to improve their treatment outcome and overall health, and between 20% and 70% of cancer patients consume nutritional supplements during cancer therapy (104, 107, 108). While this phenomenon of increased CAM use in cancer patients is well documented, the impact of diet, nutrients and dietary supplements on prostate cancer treatment modalities has rarely been investigated.
A few studies have evaluated the influence of dietary compounds on men diagnosed with prostate cancer who have chosen to undergo a prostatectomy. Bowen et al., conducted a feeding study with 32 men scheduled for surgery (109). The men consumed one serving of tomato sauce (30 mg of lycopene/day), each day for three weeks prior to surgery. Serum and prostate tissue lycopene concentrations, serum PSA and tissue DNA 8-OH-deoxyguanosine (8-OHdG, a measure of DNA oxidative damage) were measured at the time of prostate biopsy and three weeks later at the time of surgery.
A significant reduction in serum PSA and serum leukocyte 8-OhdG was reported following dietary intervention. Also, the concentration of lycopene tripled within the prostate following dietary intervention with tomato sauce. The mean concentration of lycopene at the time of biopsy was 0.279 ± 0.450 nmol/g versus a mean concentration following dietary intervention with tomato sauce of 0.820 ± 0.119 nmol/g (p = 0.001).
This study provides strong evidence that prostate tissue lycopene will change in parallel with dietary interventions (109, 110).
33 A second intervention study investigated lycopene supplements, rather than tomato products, in men scheduled to undergo a prostatectomy (111). Kucuk and colleagues randomized 26 men with prostate cancer to either 30 mg of lycopene per day or a daily placebo for three weeks prior to surgery (111). Post-surgical prostate tissue specimens were obtained and compared between the two groups. Men in the lycopene groups were more frequently found to have no involvement of surgical margins (73% v.
18% of subjects, p = 0.02) and less frequently found to have diffuse high grade PIN (67% v. 100%, p = 0.05). Additionally, the intervention group was found to have smaller tumors, a greater reduction in PSA over the 3-week study period, and a higher expression of the gap junction protein, connexin 43, however these differences did not reach statistical significance. Although much more research is needed, these important human intervention studies suggest that tomato foods and lycopene may have an impact on early prostate cancer biology.
There have been many publications dedicated to managing the side effects associated with traditional cancer treatment modalities including chemotherapy and radiation therapy. It is not the goal of this section to discuss this important topic. Rather, the objective here is to address the potential of dietary components, specifically nutritional supplements, to impact the treatment of early stage prostate cancer. Because chemotherapy is not typically used in this population, this review will focus on radiation therapy.
34 Nutrition support during radiation therapy
Radiation therapy acts by inducing oxidative damage to the DNA of malignant cells and arresting cell proliferation. Because radiation therapy acts through oxidative processes, many theories related to dietary antioxidant supplements have been propagated including: 1) antioxidant supplements may provide protection to normal tissue surrounding the tumor and reduce toxicity to radiation therapy, 2) high dose antioxidants may enhance the ability of radiation therapy to kill cancer cells, and 3) high doses of antioxidants may be harmful because they may protect the tumor and interfere with the efficacy of radiation therapy (112). The antioxidant compounds which are most commonly hypothesized to impact radiation therapy include: vitamin E, selenium, vitamin C, and plant polyphenols and carotenoids. Human studies investigating the potential mechanisms and efficacy are extremely limited and need to be conducted.
It is difficult to apply much of the animal research investigating antioxidants and radiation therapy to humans. Most animal studies employ whole-body radiation or are investigating the role of UV sunlight on epidermal inflammation. Additionally, many animal studies do not use animals with tumors, so extrapolating this data to the effects of antioxidants on a human tumor is problematic (113-115). The notion that antioxidants can either augment therapy or protect healthy tissue needs to be investigated. It is logical to speculate that if antioxidants may protect adjacent healthy tissue, they may also protect the tumor and render radiation treatment less effective.
35 The belief that radiation therapy depletes blood antioxidant status in both animals and humans has been demonstrated in several studies (116). Several human studies suggest that radiation therapy enhances oxidant stress and decreases plasma antioxidant levels, but few intervention studies have determined whether supplementation restores plasma levels to baseline values or if antioxidants can reduce side effects of therapy or improve treatment outcome. In a study of 89 radiation therapy patients with varying malignancies blood samples collected during therapy had elevated levels of malondialdehyde and nitric oxide radicals compared with 33 healthy controls (117). A recent study randomized 53 patients receiving radiation therapy for head and neck cancer to either an oil mouth rinse with vitamin E, or a placebo mouth rinse. A major side effect of radiation to the head and neck is mucositis, a painful inflammation of the epithelial tissue. After 5 to 7 weeks of therapy, the group receiving vitamin E had a 36% lower risk of developing symptomatic mucositis (p = 0.038) and had significantly less mouth- related pain (p = 0.0001) (118).
There are no published intervention studies of dietary antioxidant supplements and prostate cancer patients, but a few studies have surveyed prevalence of supplement use. A prospective study enrolled 84 prostate cancer patients presenting for initial consultation to a radiation oncologist and questioned them about the use of unconventional therapies, including nutritional supplements. After an initial history and physical, specific questions were asked about use of vitamins, herbals, and other natural supplements. In this study, meditation was considered to be an unconventional medical therapy however, prayer and exercise were not. Thirty-seven percent (n = 31) of men
36 reported using some form of unconventional medical therapy with mega-vitamins (24%), herbs (18%), antioxidant supplements (19%) and other natural supplements (7%) being the most common types of therapies (119). It is important to note that the men in this study had not yet started radiation therapy and this may not reflect typical supplement habits during therapy since some radiation oncologists or nursing staff may suggest that patients stop nutritional supplements during therapy (120).
In a second study conducted in Pennsylvania, a survey was used to assess CAM practices, including nutritional supplement use, among 50 consecutive patients at a veteran’s medical center. After excluding men with metastatic disease, 46 men completed the survey. Thirty-seven percent (n = 17) reported participating in at least one
CAM therapy. Herbal supplements were consumed by 22% (n = 10) and high dose vitamin/ mineral supplements were consumed by 15% (n = 7). Supplements were categorized into broad groups and no information on individual nutrients or doses was reported in this study. Interestingly, the investigators also surveyed the physicians treating these patients and reported that the physicians estimated fewer than 5% of their patients participated in CAM practices (107). This supports previous findings that cancer patients frequently do not report nutritional supplement use to health care providers, either because the health care provider does not inquire about use or, because patients do not want to be dissuaded from use and therefore are not forthcoming. Both the American
Institute of Cancer Research and the American Cancer Society have published guidelines for nutrition and supplement use during cancer therapy. Both groups caution that use of
37 supplements may be harmful and suggest avoiding nutritional supplements at levels which exceed the Dietary Reference Intake values (121, 122).
There is very little data quantifying the use of nutritional supplements among men being treated for localized prostate cancer. Obtaining prevalence data is an important initial step in determining if nutritional supplements can be useful or harmful during radiation therapy and to plan future intervention trials. Since nutritional supplement use is frequently underreported, meticulous questioning and documentation is particularly important to obtain accurate estimates.
2.6. Nutrition and Advanced Prostate Cancer
After initial therapy for localized prostate cancer, the majority of men will be cured. For these men, serum PSA values will rapidly decline after treatment eventually reaching a nadir of 0 ng/mL after prostatectomy and typically < 4 ng/mL after radiation therapy. However, approximately 30% of patients treated for localized prostate cancer will experience a prostate cancer recurrence. This is often preceded by a PSA relapse where serum PSA gradually increases over time (123, 124). This increase in PSA indicates either a local or systemic recurrence. Although increasing PSA is indicative of disease progression, many patients do not have any clinical symptoms of disease for many months or years. Indeed, the most sensitive scans including ProstaScint, CT scans, bone scans and MRI fail to detect metastatic disease for month or years while the PSA begins to rise. This extended phase (often years) from biochemical failure (rising PSA)
38 as the first sign of recurrence to the onset of clinical symptoms is another unique characteristic of prostate cancer. For other cancers sub-types such as breast or lung, a recurrence frequently manifests itself as some type of clinical symptom and often necessitates prompt treatment since biomarkers such as PSA are not available.
One of the hallmarks of prostate cancer is its dependence on testosterone for carcinogenesis. This phenomenon is best characterized by the early studies of Dr.
Charles Huggins and colleagues in the 1930’s and 1940’s. He noted that surgical removal of the testes (bilateral orchiectomy) in men with metastatic prostate cancer, dramatically decreased pain from metastatic disease in the bone (125-127). This landmark research marked the beginning of hormone therapy for prostate cancer that is still commonly used today for advanced disease. When clinical symptoms become present, treatment with castration or gonadotropin-releasing hormone antagonists
(GnRH) are the current standard therapies. GnRH analogues block gonadotropin release from the hypothalamus and therefore decrease the synthesis of androgens. Men treated with GnRH analogues frequently respond favorably; their clinical symptoms usually abate and their PSA precipitously drops to zero over the course of several months.
Hormone therapy is not without side effects, however and many men on GnRH analogues will experience hot flashes, erectile dysfunction, muscle wasting, gynecomastia, a decline in cognitive function, depression and osteoporosis (128, 129).
Unfortunately, the benefit of hormone therapy is transient, and the vast majority of prostate cancers eventually transform to become hormone independent. This is
39 another period during the prostate cancer continuum where PSA begins to rise and men are usually asymptomatic for many months. Thus, this is another opportunity for nutrition intervention research. Most studies report that the time from initiation of hormone therapy, to the onset of hormone failure when the PSA begins to rise again, is approximately two years (130). Once a man has failed hormone therapy, other methods to control the disease are available including biologic therapy and chemotherapy but there is no cure for metastatic prostate cancer, and the average life expectancy after hormone failure is 10 to 24 months (131-136).
PSA has emerged as a useful biomarker of prostate cancer disease progression and data continues to accumulate showing that PSA is useful to assess the efficacy of interventions. Recently, several studies have evaluated the relationship of serial PSA velocity, slope and doubling-time and disease progression (137, 138). A mathematical formula to derive PSA doubling time (figure 2.7) was first reported in 1993 by D’Amico and Hanks (139). Several studies have evaluated PSA doubling time after primary therapy (radiation or surgery) and the majority (140-146) report that it is a helpful predictor of aggressive disease. D’Amico et al., reported that PSA doubling time of less than 12 months was predictive of greater likelihood of death from prostate cancer versus death from other causes, compared with a PSA doubling time ≥12 months in 94 men who had a rising PSA after radiation therapy (median follow up 4 years). The relative risk for death from prostate cancer in this group was 5.1 (95%CI = 2 to 8.9, p < 0.03) for the faster PSA doubling time (≤ 12 months) compared with the slower doubling time (> 12 months) (144).
40
natural log(2) x time interval PSADT = log final PSA – log initial PSA
Figure 2.7 Mathematical equation for PSA Doubling Time (PSADT)
41 Compared with prostate cancer prevention efforts, there are even fewer studies that have investigated the role of diet and nutrients in men with advanced (either hormone naïve or hormone refractory) prostate cancer. Interestingly, cell culture studies frequently use the hormone insensitive prostate cancer cell lines (either DU 145 or PC-3 cells) to study hormone refractory disease. Many cell-culture studies have found isoflavones, particularly genistein, reduce cancer cell proliferation through inhibition of epidermal growth factor (42, 147). Other possible mechanisms include upregulation of the endogenous, selenium-dependent, antioxidant enzyme glutathione peroxidase. In a cell culture study of both LNCaP (hormone sensitive) and PC-3 cells, proliferation of both cell lines was inhibited by genistein in a dose-dependent manner (0, 50, 100, 150 and 200 mmol genistein). On cDNA microarray analysis, genistein appeared to significantly upregulate the production of glutathione peroxidase more than other gene products(148). Several cell-culture studies have also investigated the effect of lycopene on prostate cancer cell lines. A recent study by Tang, et al, found lycopene inhibited the growth of the hormone-insensitive cells more effectively than in the hormone naïve line
(50% inhibitory concentration = 26.6 mmol/L for DU145, 40.3 mmol/L for PC-3, and
168.5 mmol/L for LnCaP cells) (149). The authors injected the DU145 cells into male nude mice and fed the mice for 8 weeks with 3 different doses of lycopene (0, 10, 100 or
300 mg/kg). There was a dose-dependent inhibitory effect of lycopene on tumor growth.
Mice fed the 110 gm/kg or the 300 mg/kg doses had a tumor growth rate 55% and 76% less than the control group (149). Based on these laboratory and rodent studies, there appears to be some mechanistic evidence that components in tomatoes and soy foods may influence advanced prostate cancer.
42 Several human studies have focused on the impact of individual dietary supplements during advanced prostate cancer, and there are far fewer food-based dietary intervention studies. Several dietary supplements have been reported to have a beneficial effect for advanced prostate cancer. PC-SPES (product name) is an example illustrating several important points. In the late 1990’s PC-SPES gained a lot of public and scientific attention as a potential treatment for metastatic disease. PC-SPES is a Chinese herbal preparation which purportedly contained eight different plant products (Dendranthema morifolium Tzvel, Panax pseudo-ginseng, Glycyrrhiza uralensis Fisch, Rabdosia rubescens Hara, Scutellaria baicalensis Georgi, Ganoderma lucidum Karst, Isatis indigotica Fort, Serenoa repens) (150). Early animal studies and human testimonials reported remarkable reductions in PSA in both hormone responsive and hormone resistant men (135, 151-153). Small et al., conducted a prospective clinical trial and found that men consuming nine PC-SPES capsules per day (320 mg / capsule) experienced an 80% reduction in PSA if they were hormone naïve, and a 54% reduction in men who were hormone resistant (135). Sovak et al., investigated the active components of PC-SPES and found that multiple lots of the supplement were tainted with three prescription medications: diethylstilbesterol (an estrogen drug that is known to decrease PSA), indomethacin (a non-steroidal anti-inflammatory drug), and warfarin (a blood thinner) resulting in an FDA ban of this product (154). These results highlight the difficulty of conducting research on dietary supplements. Regulatory loopholes created with the 1994 passage of the Dietary Supplement and Health Education Act has resulted in the production and marketing of hundreds of products for which purity and safety are not rigorously reviewed or maintained.
43
Researchers in India recently investigated the effect of lycopene supplements in
20 men with hormone refractory metastatic prostate cancer (155). The men consumed a lipid extract of tomatoes containing 10 mg of lycopene (Lycored softules) each day for three months. PSA data and performance status (using the Eastern Cooperative
Oncology Group Performance Status questionnaire) were collected at baseline and at the end of the study. At baseline, the median PSA was 50.1 ng/mL and the range was 8.2 to
960 ng/mL. The authors reported that one man had a complete response (defined as PSA
< 4 ng/mL and disappearance of any sign of disease for at least 8 weeks), 6 men had a partial response (> 50% decrease in PSA for at least 8 weeks and no worsening of pain or performance status), 10 men had stable disease (less than 50% decrease, or < 25% increase in PSA and no worsening of pain or performance status) and 3 men had disease progression (155). Response to lycopene (either complete or partial) was strongly related to tumor grade and baseline PSA. It is interesting to note that this study used a relatively low dose of lyopene (10 mg / day) which is not significantly different from the mean lycopene intake reported in epidemiologic cohorts (2). Unfortunately, serum lycopene measures were not collected in this group, so the absorption and plasma response to this supplement could not be interpreted.
One of the very few food-based diet intervention studies for advanced prostate cancer investigated the effect of a low fat, high fiber, plant-based diet in addition to a stress management program on absolute PSA and PSA doubling time in 10 men with recurrent (hormone-naïve) prostate cancer (156). Unfortunately, this was an extremely
44 small (n = 10) study and the intervention was not randomized or controlled. After a four month intervention, PSA doubling time had slowed in 8 of the 10 men, and there was a decrease in absolute PSA in three of the men. In this study, increases in dietary fiber consumption, increase in minutes of exercise per day, and reduction in body mass index were all significantly associated with a slower PSA doubling time (p = 0.02, p = 0.04, and p = 0.04, respectively) (156). Although this study had a limited sample size, the results are provocative.
The role of diet and nutrients during the early phase of advanced prostate cancer has not been adequately studied, yet this time period is a valuable opportunity for nutrition research. Men who are asymptomatic, but have a rising PSA are often anxious about their recurrent disease. Because hormone therapy only offers temporary regression in PSA, it is generally prudent to hold off on initiation of therapy until a man shows measurable disease on scans, shows a more rapid rise in PSA, or develops symptoms.
Determining if diet and nutrient interventions could lower the absolute PSA or slow the increase in PSA would offer men with advanced prostate cancer valuable time with good quality of life before more aggressive therapy is required. This approach is particularly attractive for several reasons: 1) many diet and nutrition therapies have a low toxicity, 2) men who proactively participate in interventions experience less stress (124) 3) diet and nutrition therapies can have several overlapping health benefits (eg., weight loss may also result in improved blood glucose control), and 4) new therapies for advanced prostate cancer are constantly being developed so delaying the initiation of aggressive therapy may result in additional cancer treatment options.
45 2.7. Summary
The hallmarks of prostate cancer: high prevalence, long latency, clearly defined stages of progression, and the availability of PSA as a biomarker provide promising opportunities for clinical nutritional investigators. Nutrition research investigating the areas of prostate cancer prevention, treatment, and survivorship are both feasible and of interest to patients and the community. In the three chapters that follow, research focusing on nutrition and clinical prostate cancer at three time points along the prostate cancer continuum are described.
46 CHAPTER 3
CONSUMPTION OF NUTRITIONAL SUPPLEMENTS, ALTERNATIVE MEDICATIONS, AND PRESCRIPTION MEDICATIONS IN MEN PARTICIPATING IN THE PROSTATE CANCER PREVENTION TRIAL (PCPT)
3.1. Abstract
Purpose: Human and laboratory studies strongly suggest that dietary patterns, individual nutrients, and some prescription medications may influence prostate carcinogenesis.
Little information is available regarding the use of these products among men participating in prostate cancer prevention trials.
Materials and Methods: We completed a detailed evaluation of the use of prescription medications, alternative medications and dietary supplements in men participating in the
Prostate Cancer Prevention Trial (PCPT) at a large academic medical center.
Results: We collected data on 86 of 92 evaluable men (mean age = 69) and found 85% regularly consume at least one nutritional supplement. The mean number of
47 supplement products per man was 3.3 ± 3.5 with a range of 0 to 21 different supplement products per man. The most common supplement consumed was a multivitamin and multimineral (73%). Several single-nutrient supplements were regularly (≥ 3x per week) consumed, including: vitamin E (48%), vitamin C (31%), calcium (24%), and selenium
(7%). Thirty-six percent of men reported consumption of herbal products. Forty-four percent of men were consuming at least 400 IU of vitamin E and 12 % were consuming at least 200 µg of selenium. These doses equal or exceed the amount currently being studied in a large chemoprevention trial called SELECT. Prescription medications consumed by the cohort of 86 men at any point during the study period that may influence prostate carcinogenesis included: NSAIDS (57%), antihypertensives (49%), and lipid lowering agents (27%). Aspirin was the most frequently consumed over-the- counter medication (64%).
Conclusions: Our data show that men volunteering to participate in the PCPT at an academic center have a high propensity for supplement use. In addition, many of the supplements consumed, such as selenium and vitamin E, are hypothesized to influence the risk of prostate cancer. Furthermore, several of the medications commonly consumed, including aspirin, NSAIDS, and statins are being investigated as chemopreventive agents. Investigators designing prostate cancer chemoprevention trials should consider including detailed documentation of exposure to supplements, alternative medications, and prescription medications that may influence study outcomes.
48 3.2. Introduction
Prostate cancer is the most common visceral malignancy in American men with over 230,000 men diagnosed each year and accounting for an excess of 29,000 annual cancer deaths (3). Prostate carcinogenesis is a long process encompassing many years or decades prior to diagnosis (8). Thus, opportunities exist to define long-term, low-risk interventions that will inhibit prostate carcinogenesis, slow progression, delay diagnosis until later ages, or perhaps prevent the development of clinically significant disease. The
Prostate Cancer Prevention Trial (PCPT) was initiated in 1993 and enrolled over 18,000 men. The PCPT is a phase III, randomized, double-blinded intervention (finasteride v. placebo) for the prevention of prostate cancer. The intervention phase of the PCPT was terminated in 2003 after an interim analysis and review by a data safety and monitoring committee suggesting that men randomized to the finasteride group experienced a 25% lower risk of prostate cancer than men in the placebo group (25). This landmark study firmly established the feasibility of prostate cancer chemoprevention, providing a stimulus for future efforts to establish even more effective strategies with additional agents or combinations.
Evidence from epidemiological and laboratory studies support the hypothesis that several nutritional components influence prostate carcinogenesis risk and that interventions hold promise for disease prevention. Energy balance and obesity, dietary lipids, tomato products, broccoli, vitamin D, calcium, and zinc are actively being examined (157). Among the many possible relationships, those for selenium and alpha-
49 tocopherol have received significant interest in part due to the relative safety of these agents in many clinical trials focusing on various disease outcomes. In addition, several laboratory and clinical studies suggested that selenium and vitamin E have potential chemopreventive activity for prostate cancer (29, 30, 33, 34). In 2001, the NCI initiated the Selenium and Vitamin E Cancer Trial (SELECT) for prostate cancer prevention, the largest prostate chemoprevention trial to date. The trial has enrolled over 35,000 men and is expected to provide results within 12 years.
An accumulating body of research suggests that over-the-counter medications and prescription medications may also influence prostate cancer risk. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDS), and dietary fatty acids may all influence patterns of prostaglandin and bioactive lipid metabolism which may in turn, influence prostate carcinogenesis (158). HMG CoA-reductase inhibitors (3-hydroxy-3-methylglutaryl- coenzyme A) or “statins” used for the treatment of hypercholesterolemia have antioxidant properties (159) and also inhibit growth-factor stimulated intracellular signal transduction pathways (160). An increased risk of prostate cancer has also been associated with sympathetic tone, hypertension, and higher resting pulse rate, suggesting that antihypertensive medications may lower risk of prostate cancer (161). In addition to nutrient supplements and prescription medications, a rapidly expanding array of alternative medications, herbals (such as PC SPES and saw palmetto) and functional foods are available to consumers with the goal of altering prostate function and disease processes (135, 152, 162, 163). Clearly, the widespread exposure to these prescription
50 and non-prescription drugs could influence prostate carcinogenesis, suggesting that monitoring exposure is potentially important in chemoprevention trials.
It is critical that large-scale prostate cancer prevention trials are supported so that evidence-based public health recommendations and risk-based tailored medical interventions can be employed to reduce the burden from this malignancy. However, we hypothesize that the exposure of study participants to a vast array of nutritional supplements, prescription and non-prescription medications, as well as the growing number of alternative products, may be important confounding variables in prevention trials. The purpose of this study was to precisely document in men participating in the
PCPT at an academic medical center, the exposure to nutritional supplements, alternative agents, and medications.
3.3. Materials and Methods
PCPT Recruitment
The cohort consisted of men enrolled in the PCPT at The James Cancer Hospital and Solove Research Institute at The Ohio State University in Columbus, Ohio.
Recruitment to the PCPT occurred from 1994 to 1997 and was in response to local advertisements. Enrollment criteria included: age 55 or older, no history of prostate cancer, no history of other malignancies for the past five years, no history of a myocardial infarction for the past 3 months, a prostate specific antigen (PSA) of < 3.0 ng/mL and a normal digital rectal exam (DRE). We randomized 140 men to either the
51 finasteride group or the placebo group. Since 1993, 48 participants have been removed from intervention due to the development of prostate cancer, moving to a new location, discontinuation of the study drug due to perceived side effects, or death, resulting in a total of 92 men who were undergoing active follow-up during the period our survey was conducted. This study was approved by the Institutional Review Board of The Ohio
State University (Appendix A).
Data Collection
The PCPT participants were contacted by telephone one week prior to their scheduled annual visit and asked to bring the containers of all medications and each nutritional, herbal, botanical or other alternative medication regularly consumed to his upcoming appointment. At the appointment the label from each container was photocopied. In addition, the participant was asked specific questions about each supplement including: the number of times per day the supplement or medication is consumed, the number of pills taken from each bottle at one time, and the number of months/ years each product has been consumed. Each man was also asked if he followed a specific dietary pattern (e.g., a low-fat diet), if he regularly took aspirin, how many times per month (if any) he consumed soy foods, and where he obtained information on supplements and nutrition (see Appendix A for outline of patient questions). A thorough chart review was also completed and any prescription medication documented in the medical record since the participant’s enrollment in the PCPT was recorded.
52 Data Management
Excel spreadsheets, were created for data entry and analysis. Supplements were categorized into groups according to type, including: multivitamin / mineral, single vitamins, single minerals, supplements for weight loss, supplements for mental function, antioxidant blends, herbal supplements, soy supplements, fatty acid supplements, supplements for vascular function, supplements for joint health and miscellaneous supplements. Prescription medications were categorized into the following categories: antihypertensives, cholesterol lowering agents, non-steroidal anti-inflammatory drugs
(NSAIDS), antihistamines, antibiotics, antivirals, decongestants, diabetic medications, pulmonary medications, anxiolytics, antidepressants, antiarrhythmics, acid suppressants, and other. The data file contained the name and category of each different supplement and the dose taken by each participant. A dictionary file was created as a detailed list of the amount of every major ingredient in every commercial supplement consumed, based upon the contents listed on the label. If an ingredient listed on the label was not quantified, it was included in the database and given a value of zero.
The data file and the dictionary file were linked together for calculation of the amount of specific components from various sources. Through multiple looping processes, a complete profile quantifying the components consumed for each of the men in the study was created. We calculated both the dose and frequency of single-nutrient supplements (eg., 400 IU of vitamin E) and the total amount of each nutrient from multi- component supplements consumed (eg., 400 IU vitamin E, plus vitamin E from a multivitamin).
53 Statistical Analysis
Descriptive statistics were used to describe the specific characteristics of supplement and medication use in the cohort. Data was presented as mean ± standard deviation (SD) and median. For the comparison of the number of dietary supplements among subgroups, Wilcoxon signed rank tests were used for hypothesis testing. All of the analyses were conducted using STATA Statistical Software: Release 7.0 (Stata
Corporation, College Station, TX). STATA is a complete statistical software package with a full range of statistical and graphical capabilities.
3.4. Results
Of the 92 men scheduled for their annual PCPT visit, six were either unable to make their appointment, or did not bring in their bottles of nutrient supplements or alternative medications for precise documentation. Therefore, we collected data on 86 men. Height averaged 70 ± 3 (SD) inches with a range of 64 to 78 inches. Weight averaged 90 kg ± 20 kg with a range of 57 to 205 kg. Twenty-three percent of our cohort had a body mass index (BMI) within a healthy range of 18 - 24.9 kg/m2, 50% were overweight (BMI = 25 - 29.9 kg/m2) and 26% were obese (BMI ≥ 30 kg/m2), while one individual (1%) had a BMI of 17 kg/m2. Supplement use stratified by participant demographics are shown in table 3.1. Of the 86 men who participated in this study, 73
(84.9%) were taking at least one dietary supplement or alternative medication. The average number of supplements per PCPT participant was 3.3 ± 3.5 with a median of 2.5.
54 When we excluded the men who were not consuming any dietary supplements (n = 13), the mean number of products consumed per supplement user was 3.9 ± 3.5 and the median was 3.0. There were 232 different commercial nutritional supplements / alternative medications consumed among the 86 men interviewed. We did not detect a statistically significant association between supplement use and age, education, race, or marital status. The distribution of the number of supplements consumed per man is shown in figure 3.1 illustrating that the majority of men consume between 1 and 4 different dietary products. The frequently consumed dietary supplements are shown in figure 3.2, with a multivitamin / mineral product being the most popular and consumed by 63 (73%) of the 86 men. We found 36% of participants were consuming an herbal product with the most common herbal supplements being, garlic (10%), ginkgo biloba
(6%) and echinacea (3%,).
We also calculated the total amount of specific nutrients derived from all supplement sources. For instance, men frequently consumed vitamin E from several different supplements such as a multivitamin / multimineral (73%), a single vitamin E supplement (48%) and an antioxidant blend (7%). Table 3.2 shows the total daily nutrient consumption from all supplemental sources for several selected nutrients that are hypothesized to influence prostate cancer risk. Many of the men consumed specific nutrient supplements at doses that exceeded the Recommended Dietary Allowance
(RDA) even without considering food sources of nutrients. For example, when we summed the total consumption of a specific nutrient from each supplement consumed by
55
Number of Dietary Supplement Products Kruskal-Wallis N Mean Median SD Minimum Maximum P-Value Race White 82 3.32 2.50 3.56 0.00 21.00 Other 4 2.50 2.50 2.08 0.00 5.00 0.860 Age 60-65 23 3.17 3.00 2.31 0.00 9.00 66-70 29 3.79 3.00 4.30 0.00 21.00 70+ 34 2.91 2.00 3.45 0.00 16.00 0.349 Education Graduate School 47 3.83 4.03 3.00 0.00 21.00 College Graduate 21 2.86 2.92 2.00 0.00 11.00 Other 18 2.33 2.28 1.50 0.00 9.00 0.675 Marital Status Married 72 3.25 3.61 2.00 0.00 21.00 Other 14 3.43 2.98 3.00 0.00 9.00 0.275
Table 3.1 The number of dietary supplement (nutrients, herbals, botanicals and alternative medications) products consumed and demographic characteristics of 86 participants in the PCPT at The Ohio State University.
56
18 17 16 15 14 13 12 11 10 9 8 7
Number Men of 6 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 101112131415161718192021 Number of Dietary Supplement Products
Figure 3.1 Frequency of nutritional supplement use among 86 men enrolled in the PCPT at The Ohio State University.
57
10 20 30 40 50 60 70
Diet Supplements
Mulitvitamin / mineral Vitamin E Herbal Supplements Vitamin C Calcium Selenium
Pharmaceuticals
Aspirin Anti-hypertensive Cholesterol lowering NSAIDS Antiarrhythmic Diabetes Control
Figure 3.2: Percent of men participating in the PCPT at The Ohio State University consuming dietary supplements or specific prescription drugs potentially related to prostate cancer risk.
58
Supplement Amount N (% of cohort)
Vitamin E♣ None 15 (17%) 400 IU 33 (38%) 401 – 799 IU 30 (35%) 800 – 999 IU 5 (6%) 1000 IU 3 (3%)
Selenium* None 31 (36%) 55 µg 37 (43%) 56 – 199 µg 8 (9%) 200 µg 10 (12%)
Calcium∞ None 23 (27%) 250 mg 33 (38%) 251 – 1000 mg 24 (28%) 1001 - 1999 mg 5 (6%) 2000 mg 1 (1%)
Folic Acid# None 22 (26%) 400 µg 50 (58%) 401 – 699 µg 6 (7%) 700 – 999 µg 8 (9%) 1000 µg 0 (0%)
Vitamin Cψ None 17 (20%) 90 mg 31 (36%) 91 – 500 mg 15 (17%) 501 – 1000 mg 17 (20%) 1001 – 1999 mg 5 (6%) 2000 mg 1 (1%)
♣ Vitamin E: RDA = 22 IU natural vitamin E, or 33 IU synthetic vitamin E UL = 1500 IU natural vitamin E, or 1100 IU synthetic vitamin E * Selenium: RDA = 55 µg, UL = 400 µg ∞ Calcium: RDA = 1000 mg (≤age 50), UL = 2.5 g # Folic Acid: RDA = 400 µg, UL = 1000 µg ψ Vitamin C: RDA = 90 mg, UL = 2000 mg
Table 3.2 Intake of selected nutrients from all supplemental sources for 86 men participating in the PCPT at The Ohio State University.
59 individual participants, 83% of the 86 men surveyed consumed vitamin E at doses higher than the RDA (RDA = 22 IU natural vitamin E or 33 IU synthetic), 21% of men consumed supplemental selenium in excess of the RDA (55 µg / day), while 16% took folic acid above the RDA (400 µg / day), and 44% of the cohort exceeded the RDA for vitamin C (90 mg / day). The ongoing SELECT has randomized men in a 2x2 factorial, placebo-controlled design to vitamin E at 400 IU and/or 200 µg of selenium. Forty-four percent of the men in our cohort were consuming at least 400 IU of vitamin E from one or more supplements and 12% were consuming at least 200 µg of selenium. When all dosages of vitamin E and selenium were included, 72 out of 86 men (84%) were taking either vitamin E, selenium or both.
Based on a thorough review of each participant’s medical record since 1993 with annual updates, we quantitated all prescription medications for each patient during the seven-year follow-up study period (Figure 3.2). Fifty-seven percent of 86 participants consumed NSAIDS, 49% of men were taking antihypertensive medications, and 36% of men consumed cholesterol-lowering agents at some point during seven-year PCPT study period (26 men consumed statin agents, 5 men consumed non-statin agents). Other categories of medications that were consumed less frequently included: antacids (17%), antidepressants (12%) medications for benign prostatic hyperplasia (9%), antidiabetics
(8%), anxiolytics (5%) and antibiotics (5%).
Men provided information regarding aspirin use, intake of soy foods and sources of nutrition information. Fifty-five men (64%) reported that they take aspirin daily.
60 Twenty-four (30%) of 83 men regularly consume foods containing some soy protein components with a mean frequency among soy consumers of 2.6 times per week.
Common soy foods cited were soy nuts, soy milk, soy bars and soy burgers/breakfast meats. We questioned participants about the primary and secondary resources they use for information on diet or nutritional supplements. The most common primary sources of nutrition information were the participant’s spouse (28%) and physician (18%). The popular press (newspaper articles, magazines, etc.) was the most common secondary source of nutrition information (16%). Other answers included: the internet (11%), a registered dietitian (5%), supplement company literature (4%), and pharmacists (3%).
3.5. Discussion
The results of the PCPT, showing a 25% reduction in prostate cancer incidence over seven years among the men taking finasteride, clearly demonstrates that prostate cancer represents an excellent malignancy for intense efforts to reduce incidence through chemoprevention and dietary interventions (25). Prevention trails, by necessity, require large numbers of participants in order to achieve the statistical power necessary to detect potential benefits of interventions, but also to accurately assess risks. These cohorts are established and monitored at an enormous cost and we should consider options to obtain as much valuable information as possible regarding prostate carcinogenesis, screening, and modifying factors such as genetics and lifestyle variables. We observed that volunteers enrolled in the PCPT at an academic medical center frequently consume nutritional supplements, alternative medications, and prescription and non-prescription 61 medications that are hypothesized to influence prostate cancer risk. Thus, we support efforts to consider this information when designing inclusion and exclusion criteria for future prevention trials. Furthermore, in large studies where supplement intake is permitted, funds should be provided for investigators to collect detailed information on supplements and prescription medicine use, so that this data can be used in statistical models to assess their independent effects and potential interactions between supplements
/medications with study agents under investigation, for both efficacy and toxicity.
Our detailed evaluation suggests that the prevalence of nutritional supplement use by participants in the PCPT exceeds estimates for the general population. Large, cross- sectional studies such as the National Health and Nutrition Examination Survey
(NHANES)-III estimate that approximately 63% adult men and women over age 60 consume at least one dietary supplement per day (105), and has increased significantly over previous evaluations by NHANES-I and NHANES-II. Indeed, men volunteering for chemoprevention studies may be even more likely to consume supplements since they exhibit other characteristics previously associated with supplement use, including: being more highly educated, have overall good health, and may be more likely to engage in screening programs (164).
Data describing the use of herbal, botanical and other non-nutrient/ non-vitamin / non-mineral supplements is predominantly limited to studies in persons undergoing cancer therapy, and there is very little research on the use of these substances in relatively healthy populations participating in prevention trails. Prior to 2004, the two major
62 nutritional monitoring surveys, the National Health and Nutrition Examination Survey
(NHANES) and the Continuing Survey of Food Intakes by Individuals (CSFII), collected very limited data on non-vitamin, non-mineral supplement use, however, there are efforts to more accurately capture dietary supplement information in these cross-sectional studies (165). It has been estimated that approximately 3 - 14% of adults regularly consume herbal or other non-vitamin / non-mineral dietary supplements (166).
When the PCPT began in 1993, men who enrolled completed a health history questionnaire and a food frequency questionnaire that included questions about supplement use. Participants completed the questionnaires at home and were asked to look at their supplement bottles to correctly quantify a limited range of specific nutrients and phytochemicals of interest to the investigators at that time (vitamins E and C, ß- carotene, calcium, and zinc). For other nutrients and non-nutrient compounds (including
B-complex, vitamin D, selenium, fish oil capsules, and garlic pills) the participant simply noted whether they were consumed regularly or not (regular use was defined at three times per week or more). Of the 15,387 participants who had completed the enrollment assessment, 60% reported regularly using a nutritional supplement in the previous year with 44% of the men consuming multivitamins regularly. Vitamins C and E were each consumed regularly by 35% of the men, calcium was consumed by 20%, and antioxidant mixtures, B-complex mixtures and other single supplements were consumed by 7 to 15% of the cohort. These reported results are lower for the PCPT cohort than the incidence observed in our PCPT-subgroup (73% consume a daily multivitamin / mineral, 48% consume vitamin E, 31% consume vitamin C and 24% consume calcium supplements).
63 There are several reasons why our subgroup may have slightly different supplement habits than the PCPT cohort as a whole. Our population may not accurately reflect the entire cohort, due to the nature of the population served by an academic medical center with the recruitment of more educated and health conscious men. Seventy-seven percent of the large national cohort had attended college and 53% attended graduate school, whereas in our subgroup 89% of the men had at least some college and 55% attended graduate school. Our sub-group only had 3% African American representation and no one of Hispanic or Asian origin. The entire PCPT also only has 3% African Americans, with 2% Hispanic and 1% Asian population.
Our approach to quantitating supplement consumption was much more detailed, thorough, and labor intensive, than would be practical in a large cohort study. When we exclude the 13 men who did not consume any nutritional supplements, the 73 supplement-takers in our study consumed in total, 232 different products indicating how difficult it is to design a questionnaire that includes all possible products.
Two other prospective cohort studies have investigated supplement use among persons who are at high risk for cancer or who are enrolled in a chemoprevention trial.
The Colorectal Adenoma Prevention Study (CAPS), is a three-year study investigating daily use of aspirin and risk of recurrent colorectal adenomas among individuals with a history of colorectal carcinoma (160). Nutritional supplement data was collected by self- report from 622 men and women. Fifty-five percent (n = 341) of the CAPS cohort reported consuming one or more nutritional supplements with a mean number of
64 supplements per subject of 2.6 (± 1.7). Although this supplement use is lower than our subgroup, it is difficult to compare the two groups because the CAPS cohort had history of cancer and therefore is fundamentally different from our chemoprevention cohort.
A second study (VITamins And Lifestyle Cohort Study, or VITAL) is prospectively evaluating supplement use, diet, other lifestyle habits and cancer risk in over 77,000 men and women in Washington state (167). Over the next several years cancer outcomes will be documented through computerized linkages with the National
Cancer Institute’s Surveillance Epidemiology and End Results (SEER) cancer registry, and relationships between diet, supplements and cancer risk will be assessed.
Information on current supplement use (including common herbs and specialty products) and supplement use 10 years prior to baseline was also collected (167). Although enrollment in this study was not restricted to non-users, the cover letter targeted people who were supplement users, therefore, the prevalence of use is likely to be higher than other studies which use a random sampling procedure. In this cohort, 79% used at least one nutritional supplement. Sixty-six percent of the participants regularly consumed a multivitamin, 46% consumed vitamin C, 46% consumed calcium, and 47% consumed vitamin E in the 10 years prior to baseline and approximately one-third of this cohort regularly used an herbal or specialty supplement. It is interesting to note that although supplement users were targeted for recruitment into the VITAL study, the prevalence of supplement use is similar to our PCPT sub-group.
65 Our study suggests that there is probably a selection bias towards over representation of supplement users in recruiting participants for chemoprevention trials at academic medical centers. Surveys of several populations have elucidated some of the common characteristics of supplement users and these may be more prevalent in populations served by many academic institutions. Persons who regularly consume nutritional supplements and alternative medications tend to be: female, older, have more than 12 years of education, have a lower body mass index (BMI), consume more nutrient- dense diets, participate in regular physical activity, and have never been smokers (26).
Another key finding in this study was that even though this population of men was largely college educated, they most frequently cited the insistence of their spouse as the major reason for consuming supplements. Many men reported that they had little knowledge regarding the proposed health benefits of the product and consume them simply because the spouse purchased the product and monitored intake. This observation suggests that education of men regarding supplement use and recruitment strategies for nutritional supplement studies must include the family unit.
It is particularly interesting that 84% of the men in our cohort were consuming supplemental tocopherols or selenium. These nutrients are the interventions for the
SELECT trial that has recruited over 35,000 men for a 12-year prostate cancer chemoprevention trial. Based on the evidence cited to justify investment in the SELECT trial, these nutrients may clearly be important in reducing prostate cancer incidence.
66 Surprisingly, almost one-third of the men in our study consumed soy-containing foods on a regular basis (mean intake among men who consumed soy = 2.56 servings per week). Diets rich in soy foods have been hypothesized to reduce the risk of several types of cancer, including prostate cancer, a relationship that is supported by in vitro, rodent studies, and human studies (46, 168). The average soy intake in Asian countries, where prostate cancer is uncommon, is between 30 and 55 grams per day, whereas soy intake in the United States is less than 5 grams per day (169). One study of 98 healthy American men and women (ages 18 – 37) estimated dietary soy intake to be between 1 and 2 grams per day with no significant differences in intake noted between men and women (170).
The public is also becoming more aware of studies suggesting that a diet rich in tomatoes, tomato products, or the carotenoid lycopene is associated with a lower risk of prostate cancer (2). In our cohort, five men (6%) were consuming lycopene as either an individual supplement or as an ingredient in a more complex supplement. The potential of lycopene supplements to reduce risk of prostate cancer is intriguing but remains very speculative at this point in time. Other compounds found in tomatoes, including tomato polyphenols, may also be important in prostate carcinogenesis (59).
In addition to dietary and nutritional variables, evidence has gradually accumulated that medications used for the treatment of several disease processes could influence the risk of prostate cancer. For example, non-steroidal anti-inflammatory drugs
(NSAIDS) are associated with a reduced risk of certain cancers based on laboratory and clinical trials. NSAIDS are a class of agents exhibiting varying specificity regarding the
67 inhibition of cyclooxygenase (COX)-1 and -2, enzyme systems that are crucial to the production of prostaglandins and related mediators that regulate various cellular and tissue processes. The expression of COX-1 and 2 in prostate cancer has been documented leading many to hypothesize that NSAIDS may have a role in chemoprevention or augment the benefits of other therapeutic agents. NSAIDS are commonly consumed for pain control, especially for degenerative joint disease and related arthritic conditions that are common in older men. We observed that 57% of men consumed NSAIDS at some point during the PCPT. This is slightly higher than the results of a study where researchers used random digit dialing to assess medication and nutritional supplement use among 2,590 ambulatory adult men and women. Forty-three percent of men over the age of 45 reported using an NSAID during the week before the interview (166). White et al., recently reported that 27% of the VITAL cohort regularly used NSAIDS in the 10-years prior to enrollment. In the VITAL cohort, NSAID use was associated with dietary supplement use (167).
Hyperlipidemia is a major risk factor contributing to cardiovascular disease in
Americans. The recent development and rapid incorporation of HMG CoA-reductase inhibitors or “statins” into the schema for the medical management of hypercholesterolemia has significantly influenced cardiovascular outcomes. There is increasing evidence that intermediates in this pathway are also components of intracellular signal transduction pathways that regulate tumor cell proliferation, such as the farnesylation of the ras oncogene. Statins have been shown in preclincial and case-
68 control studies to have anticancer or antioxidant properties and are being considered for further evaluation as preventive agents (171, 172).
Another class of commonly consumed pharmaceutical agents that have been hypothesized to influence prostate cancer risk are antihypertensive medications. A study analyzing data from the Cardiovascular Health Study cohort investigated associations between hypertension, heart rate and use of antihypertensive medications among 2,442 men (161). No association was found between enrollment/incident blood pressure, however there was an association with resting heart rates above 80 beats per minute vs. heart rates of 60 and under (HR: 1.6, 95% CI =1.03-2.5). There was also an inverse relationship found between the use of any antihypertensive agents and prostate cancer incidence (HR: 0.7, 95% CI: 0.5-0.9) (161). In our PCPT subgroup, 49% consumed an antihypertensive medication at some point during follow-up.
Conclusions
In conclusion, men recruited to participate in the PCPT at an academic institution exhibit a high frequency of consumption of dietary supplements and alternative medications. Furthermore, many prescription and over-the-counter medications consumed by the majority of PCPT participants have been hypothesized to influence prostate cancer risk. This data supports the concept that large chemoprevention trials, such as the PCPT and SELECT, should consider detailed assessment of supplements and medications as possible important co-variables in assessing risk of prostate cancer.
69 Furthermore, details regarding product use may require directing questionnaires to spouses of participants. We recognize that our subgroup will not be representative of the entire PCPT due to the demographics of the participants at our institution, thus, these findings cannot be extrapolated to the entire cohort. However, this work highlights some of the issues of concern regarding the “background noise” that may influence risk in prostate cancer prevention trials and compromise the ability to detect benefits of the intervention agent. Furthermore, this study suggests an opportunity to develop more specific and precise tools to assess agents that influence prostate cancer risk as components of large intervention trials.
70 CHAPTER 4
USE OF NUTRITIONAL SUPPLEMENTS AND CAM (COMPLEMENTARY AND ALTERNATIVE MEDICNE) BY PROSTATE CANCER PATIENTS UNDERGOING RADIOTHERAPY
4.1. Abstract
Background: Nutritional supplements are increasingly consumed among the cancer population to enhance health, and are perceived by many to be a useful adjunct in the treatment of disease. Prevalence data on the use of nutritional supplements among men with prostate cancer is lacking. This data is important for future studies investigating the impact of nutritional supplements on radiation therapy.
Materials and Methods: We surveyed 48 men undergoing radiation therapy for localized prostate cancer at an academic medical center. The men were asked questions about nutritional supplement use and were asked to bring all bottles of nutritional supplements consumed. The labels from each bottle were photocopied and all supplemental ingredients were entered into a database for statistical analysis and quantification.
71 Results: Over half of our study cohort (58%) consumed at least one nutritional supplement during radiation therapy and the mean number of supplements per man was
2.2 ± 3.5. The most common categories of supplements consumed were: multivitamin / mulitmineral supplements (29%), antioxidants, (54%), multivitamin / mineral (29%), and herbal preparations (23%). When nutrients from all supplemental sources were summed, we found between 13% and 46% of men were exceeding the RDA for specified antioxidant nutrients.
Conclusions: Using a comprehensive approach, our findings suggest that use of nutritional supplements among men undergoing radiation therapy for localized prostate cancer is more common than previously reported. Many of the supplements consumed by this population are hypothesized to influence the efficacy of radiation therapy.
Research investigating the impact of nutritional supplement use on the efficacy of radiation therapy in men with localized prostate cancer is warranted given the frequency of supplement consumption in this cohort.
72 4.2. Background
The use of complementary and alternative medicine (CAM) has become significantly more prevalent in the U.S. over the past decade (173). The National
Institutes of Health defines CAM as a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine (174). CAM includes both clinical approaches (such as herbal remedies, dietary supplements and acupuncture) and behavioral techniques (such as spiritual techniques and relaxation methods) that can be used individually or in combination. A landmark study by Eisenberg et al., reported that in 1990, Americans made an estimated 425 million visits to alternative health practitioners with expenditures exceeding $13 billion
(175). A follow-up study in 1997 reported that in the 7 years since the original publication, visits to alternative medicine practitioners increased to 629 million and expenditures were estimated to be $21.2 billion (176). These studies imply that people are becoming increasingly interested in and are willing to pay out-of-pocket for a variety of CAM therapies.
Nutritional supplements are among the most commonly utilized type of CAM therapies. This includes vitamin and mineral supplements and herbal and botanical supplements (such as Gingko biloba and St. Johns Wort). Cross-sectional surveys have reported that between 40 and 60 percent of Americans regularly use at least one nutritional CAM therapy (105, 173, 177). Interestingly, a recent study reported that use of herbal and other non-vitamin/ non-mineral supplements had not significantly changed
73 among younger subjects between 1998 and 2002. However, during this same time period, herbal supplement use doubled among men and women aged 65 and older (62).
The use of CAM therapies, specifically nutritional supplements, is reported to be significantly more common among cancer patients than among the general public (178).
Some studies have reported that approximately 80% of cancer patients participate in
CAM practices, with nutritional supplements being the most common type of CAM used
(179). There appears to be some variability in CAM use among different cancer sub- types. Women with breast cancer report high usage, whereas patients with head and neck cancers report relatively low CAM use (106, 180). Cancer patients indicate several reasons for taking nutritional supplements. Two of the most common reasons are to minimize the adverse effects of conventional treatment and to augment the efficacy of conventional therapy, such as chemotherapy and radiation therapy (107). Unfortunately, there are very few human studies that have investigated the role of nutritional CAM practices during cancer treatment. A few case reports and clinical trials have described the influence of individual nutritional supplements (usually a particular herb or botanical) on patients receiving chemotherapy (181, 182). However, human studies investigating the impact of nutritional supplement use on radiation therapy have not been adequately investigated.
Radiation therapy is a common treatment for prostate cancer. Approximately
25% of men diagnosed with prostate cancer will choose radiation therapy for primary 74 treatment (183). There are two major types of radiation therapy, external beam radiation therapy or brachytherapy. External beam radiation therapy administers a focused beam of radiation to the prostate gland. Each treatment lasts less than 5 minutes and men generally receive radiation therapy five days per week for approximately 4 to 6 weeks
(184). Brachytherapy involves the surgical insertion of radioactive beads directly into the prostate tissue. This is an outpatient procedure and men usually recover quickly (184).
Combinations of external beam radiation therapy and brachytherapy are also becoming standard treatment for localized prostate cancer (184). The ten-year survival data suggests that each of these forms of radiation therapy are similar to surgical resection and that the rate of sexual and urinary side effects may be lower (100, 101).
The impact that nutritional supplements may have on radiation therapy is unknown. Radiation arrests tumor cell growth, in part, by causing irreparable oxidative damage to tumor cells. Since antioxidant nutrients and many non-nutrient phytochemicals found in plants can quench free radicals and prevent oxidative damage, it is plausible that supplementation with high levels of certain nutrients or herbs may interfere with the efficacy of radiation therapy. Conversely, it has also been hypothesized that nutritional supplements may reduce radiation-induced damage to normal tissue surrounding the malignant area, and therefore mitigate the side effects of radiation therapy. The health implications of supplementation with nutrients and alternative medications during radiation therapy have not been extensively studied and further research is clearly needed.
75 To date, there have only been two studies that have specifically investigated CAM use among men with prostate cancer who were undergoing radiation therapy. The studies were completed at the same treatment center in Pennsylvania and both reported that 37% of men with prostate cancer regularly used some form of CAM (107, 119). The first study surveyed 50 consecutive prostate cancer patients (localized, non-metastatic disease) seen in the radiation oncology department. In this group, herbal supplements were consumed by 22% (n = 10) of the men and high-dose vitamin supplements were consumed by 15% (n = 7). A few years later, the same group surveyed 84 patients with prostate cancer (stage of cancer not reported). Their results were similar to the earlier study with 23% of men reporting use of high-dose vitamin and mineral products, 17% reporting herbal use and 18% reported consuming antioxidant supplements (119). Each of these studies categorized supplements into broad categories (eg antioxidant, herbal, megavitamin) but neither quantified consumption of individual nutrients, the dose of any individual nutrient, or dietary sources of nutrients (107, 119). Additionally, each of these studies reported supplement use in men who were seen in the radiation oncology clinic for a consultation. It is not known whether the men actually went on to receive treatment, and if they continued consuming nutritional supplements.
There are no published reports which quantify detailed nutritional supplement information among men actively undergoing radiation therapy for prostate cancer. This study will provide detailed descriptive data summarizing the use of nutritional supplements among men undergoing radiation therapy for prostate cancer. This effort is being undertaken with the goal of initiating future intervention studies designed to alter
76 antioxidant status of the patient in order to enhance treatment efficacy with less toxicity.
We can only begin interventions after we have clearly defined the current use of these products. We hypothesize that men with newly diagnosed prostate cancer who are actively undergoing radiation therapy are commonly taking nutritional supplements that may impact the efficacy or toxicity of treatment.
Objectives
The major objective of this study was to precisely quantify CAM and nutritional supplement use in men undergoing either external beam radiation therapy or brachytherapy for primary treatment localized prostate cancer.
4.3. Materials and Methods
Study Design
Forty-eight men with clinically localized prostate cancer were enrolled between
November 2002 and May 2005 in the Department of Radiation Oncology at Arthur G.
James Hospital and Richard J. Solove Research Institute in Columbus, Ohio. Patients were recruited from the clinics of OSU faculty. Prior to enrolling, all men had chosen to undergo external beam radiation, brachytherapy or a combination of both for primary cancer treatment. Men with known metastatic disease or a history of any prior malignancy (except non-melanomatous skin cancer) were excluded from this study. All men scheduled for radiation therapy were contacted, in person, at their first radiation therapy appointment. After informed consent was obtained, study participants were
77 queried about their nutritional supplement use and given a questionnaire which asked brief personal and demographic information (Appendix B). Participants were verbally queried about several different types of supplement use including multivitamins, minerals, herbal, or other “natural” products. Participants who reported consumption of any type of nutritional supplement were asked to bring the bottles with them to their next appointment in radiation oncology so the labels could be photocopied. After photocopying each label, we carefully inquired about the dose taken from each supplement bottle. If the serving size stated on the label of a supplement was 3 pills per day, we would specifically ask if the participant consumed the recommended 3 pills, or if he took more or less than three to document the accurate daily serving size consumed from each supplement. Nutrient data was summarized for this population providing direct comparison to the National Academy of Sciences Dietary Reference Intakes. This study was approved by The Ohio State University Institutional Review Board
(Appendix B).
Statistical Analysis
A supplement database using Microsoft Excel spreadsheet was created to organize the information for analysis. This supplement database included the supplement name, manufacturer and/or brand name, and the nutrient content in standardized units per serving size as noted on the supplement label. Supplement products were entered into the database individually, and they were also categorized into broad groups including: multivitamin / multimineral, antioxidant, individual vitamin/ mineral, herbal, anti- arthritic, and miscellaneous. Examples of supplements categorized in each of these
78 groups are listed in table 4.1. A separate database included the dose of each product consumed by each study participant. Multiple looping procedures were used to link the databases together and provide descriptive data on frequency of supplement use and summations of individual nutrients or other dietary compounds. SAS software (Cary,
NC) was used to generate all descriptive statistical analyses.
4.4. Results
Of the 48 men who enrolled in the study, all 48 completed the survey and provided bottles of supplements for photocopying and documentation. Participant anthropometrics and descriptive data are listed in table 4.2. The mean age (±SD) of this cohort is 63 (± 8) years and the mean number of months since prostate cancer diagnosis was 3.5 (± 3.8) months (median = 2 months) (table 4.2). Of the 48 men in this study, 28
(58%) were taking at least one nutritional supplement and the mean (±SD) number of supplements per man was 2.2 ± 3.5 supplements per day (range = 0 to 19 different nutritional supplement products per man, median = 1). Figure 4.1 illustrates the frequency of nutritional supplement use among the entire cohort and figure 4.2 illustrates the frequency of multiple supplement use among the 28 men who consumed supplements.
79
Multivitamin Herbal “One-A-Day” type supplement Alfalfa Echinacea Antioxidant Garlic Vitamin C Ginkgo biloba Vitamin E Ginseng Selenium Hawthorn ß carotene Saw Palmetto Any combination of above St. John’s Wort
Single Vitamin / Mineral Anti-Arthritic Vitamin A Glucosamine Vitamin D Chondroitin Vitamin B 1 Vitamin B 6 Miscellaneous Vitamin B 12 Juice Plus Calcium, Linoleic Acid Zinc Shark Cartilage
Table 4.1 Categories of nutritional supplements and examples of representative products
80
N (%) Mean ± SD
Race Age (years) 63 ± 7.7 Caucasian 37 (77)
African American 8 (17) Other 3 (6) Height (inches) 70 ± 2.9
Education < High School 5 (10) Weight (lb) 198 ± 32 High School 20 (42) College 13 (27) Graduate School 10 (21) BMI (kg/m2) 28 ± 4
Employment Status Paid 20 (43) Months since Retired 25 (53) PCa diagnosis 3.5 ± 3.8 Unemployed 0 (0) Other 2 (4)
Income <$20,000 5 (13) $20,000-$39,999 12 (30) $40,000-$59,000 11 (28) $60,000-$99,000 5 (13) >$100,000 7 (18)
Marital Status Single 1 (2) Married 42 (89) Widowed 0 (0) Divorced 4 (9)
Tobacco use 5 (11)
Alcohol use 24 (52)
Table 4.2 Descriptive and anthropometric data of men with prostate cancer undergoing radiation therapy (n = 48)
81
30
25
20 Number of Men 15
10
5
0 Yes No
Supplement Use
Figure 4.1 Frequency of nutritional supplement use among men with prostate cancer undergoing radiation therapy (n = 48)
82
10
9 8
Number 7 of Men 6 5
4 3 2 1
0 1 2 3 4 5 6 7 8 9 10111213141516171819
Number of Dietary Supplement Products
Figure 4.2 Frequency of nutritional supplement use among 48 men undergoing radiation therapy for localized prostate cancer
83 Types of Supplements Consumed
The most common type of supplement was a multivitamin / mineral which was consumed by 14 men (29%), followed by supplements categorized as antioxidants and herbal supplements. Twenty-six (54%) men were consuming 23 different supplements products which can be categorized as “antioxidant” compounds (this does not include multivitamins / minerals which may also contain putative antioxidant nutrients). An individual vitamin E supplement was consumed by 14 men (29%) and an individual vitamin C supplement was consumed by 10 men (21%). One man was taking an individual ß-carotene pill and one man was taking a selenium pill. Herbal products were consumed by 11 (23%) men and there were 19 different herbal products consumed across the group.
Among men who were taking herbal supplements, the mean (SD) was 1.7 products per man (1.6) with a range of 1 – 6 supplements per man. The most commonly consumed herbal supplement among the men was garlic (n = 6, 13%) followed by saw palmetto (n = 4, 8%) (figure 4.3). The most common individual nutrient supplement was calcium (n = 8, 17%) followed by B12 (n = 4, 8%). Three men (6%) were consuming a
B complex mixture. The remaining supplements were consumed by 2 or fewer men in our study.
Among the 28 men who consumed at least one nutritional supplement, we summed the total intake of selected nutrients from each product consumed (e.g., vitamin
84
6
5
4
3
2
1 Number of men consuming herbal products herbal consuming men of Number
0 Garlic Saw Echinacea Alfalfa Ginkgo Ginseng Hawthorn St. Johns Palmetto Biloba Wort
Figure 4.3 Frequency of herbal supplement use among men with prostate cancer undergoing radiation therapy
85
Supplement Amount N (% of cohort)
Vitamin E♣ None 26 (54%) 400 IU 15 (31%) 401 – 799 IU 6 (13%) 800 – 999 IU 1 (2%) 1000 IU 0 (0%)
Selenium* None 35 (73%) 55 µg 7 (15%) 56 – 199 µg 4 (8%) 200 µg 2 (4%)
Calcium∞ None 28 (58%) 250 mg 13 (27%) 251 – 1000 mg 5 (10%) 1001 - 1999 mg 2 (4%) 2000 mg 0 (0%)
Folic Acid# None 32 (67%) 400 µg 1 (2%) 401 – 699 µg 15 (31%) 700 – 999 µg 0 (0%) 1000 µg 0 (0%)
Vitamin Cψ None 26 (20%) 90 mg 7 (36%) 91 – 500 mg 7 (17%) 501 – 1000 mg 5 (20%) 1001 – 1999 mg 2 (6%) 2000 mg 1 (1%)
Vitamin A** None 32 (67%) 999 IU 0 (0%) 1000 – 2500 IU 2 (6%) 2501 14 (29%)
♣ Vitamin E: RDA = 22 IU natural vitamin E, or 33 IU synthetic vitamin E UL = 1500 IU natural vitamin E, or 1100 IU synthetic vitamin E * Selenium: RDA = 55 ug, UL = 400 ug ∞ Calcium: RDA = 1200 mg (≤age 70), UL = 2.5 g # Folic Acid: RDA = 400 ug, UL = 1000 ug ψ Vitamin C: RDA = 90 mg, UL = 2000 mg ** Vitamin A: RDA = 900 µg RE, UL = 3,000 µg, 1 IU = 0.30 µg retinol
Table 4.4 Quantification of select nutrient intake summed from all dietary supplements, among men undergoing radiation treatment for localized prostate cancer 86 E from a multivitamin + a vitamin E pill) and then compared them to the Dietary
Reference Intakes for each nutrient (table 4.4).
4.5. Discussion
We found that over half (58%) of men with localized prostate cancer who are undergoing radiation therapy at an academic medical center are consuming nutritional supplements. Our estimate is two-times higher than previous reports which have published information on this population (107, 119), but similar to reports of healthy men over age 60 in large cross-sectional studies such as NHANES (62, 105). Additionally, we found that many men (n = 26, or 54%) are consuming antioxidant nutrients either as part of a multivitamin / multimineral, or as an individual nutrient supplement, which have been hypothesized to impact the efficacy of radiation therapy. The database we created allowed us to sum total nutrient consumption from all supplemental sources for each man. We compared these values to the Dietary Reference Intake RDA’s and found that
46% of men exceeded the RDA for vitamin E, 13% for selenium, and 31% for vitamin C.
We found 23% of the men in our cohort were consuming herbal preparations which is similar to the previous reports by the Pennsylvania group (107, 119). Other categories of supplements including “anti-arthritic” and “miscellaneous” were much less common and products in these categories were consumed by two and four men, respectively.
This study has several limitations and strengths. Although this report provides the first detailed description of nutritional supplement use among men undergoing radiation
87 therapy for localized prostate cancer, we recognize that the sample size is small, and that broad generalizations to other prostate cancer patients or other cancer patients undergoing radiation therapy are not possible. Additionally, it is possible that men who agreed to participate in the study were more or less likely to be supplement users than men who declined to participate. We believe this is improbable because very few men who were approached, declined to participate (10 – 15% of men). One of the strengths of this study is that we did not rely on self-report to estimate nutrient consumption. By photocopying the labels, we were able to record all nutritive and non-nutritive compounds for each supplemental product. The accuracy and detail of our methods provides important descriptive data that can be used in future interventional studies. Research investigating the impact of nutritional supplement use on the efficacy of radiation therapy in men with localized prostate cancer is warranted given the frequency of supplement consumption in this cohort.
88 CHAPTER 5
DIET INTERVENTION WITH LYCOPENE-RICH FOODS OR SOY PROTEIN IN MEN WITH RECURRING, ASYMPTOMATIC PROSTATE CANCER
5.1. Abstract
Background: Tomato products and soy foods are hypothesized to reduce the risk of prostate cancer or enhance the efficacy of treatment. We completed a study designed to determine if men with prostate cancer will adhere to a diet rich in tomato products to achieve a lycopene intake of >25 mg / day and a soy supplement providing 40 g soy protein (80 mg isoflavones) per day.
Materials and Methods: We enrolled 41 men (age mean, SD = 70 ±7) with recurrent, but asymptomatic prostate cancer characterized by a rising serum prostate specific antigen
(PSA) following primary therapy. The study included an initial one-week washout
(weeks -1 to 0, no tomato foods or soy protein). The men were then randomized to one of two groups. Men in Group A were advised to consume tomatoes / tomato products (no soy) for weeks 0 - 4 and combine tomato products with 40 grams soy protein (tomato +
89 soy) for weeks 4 - 8. Group B consumed soy (no tomatoes) for weeks 0 - 4 and the tomato-rich diet with soy for weeks 4 - 8.
Results: Reported side effects of the treatments were few (7%, grade I constipation, and
(2%, grade I gout). There were no changes in complete blood counts, blood chemistry,
IGF-1 or testosterone. During weeks 0 - 4, mean (± SD) lycopene intake for Group A was 43 mg (± 15 mg) and mean soy intake for Group B was 39 g (± 1 g). During weeks
4 - 8 adherence remained high (>97%) and consistent with blood/urine phytochemicals.
Serum lycopene increased (p < 0.0001) and urinary isoflavone excretion increased (p <
0.05) in response to diet changes for weeks 0 - 4 and 4 - 8. Total cholesterol decreased
7% between weeks 0 - 8 for both groups (p < 0.001). Absolute serum PSA levels decreased between week 0 and week 8 for 14 / 41 men (34%).
Conclusions: This study demonstrates that men with active prostate cancer can successfully adhere to a diet and consume tomato products and soy together with excellent adherence and minimal toxicity. Further studies combining tomato and soy foods to determine efficacy and health benefits should be undertaken.
90 5.2. Background
Prostate cancer is the most common visceral malignancy in men with 230,000 new diagnoses and 30,000 deaths estimated for 2005 (3). Epidemiology studies strongly suggest that several dietary factors, including soy and tomato foods, may modulate prostate cancer risk (157, 185).
Soy and Prostate Cancer
The risk of prostate cancer in Asian countries is at least 10-fold lower than in the
United States (17, 18). Migrant studies suggest that when men of Asian ancestry move to the United States, within a few generations, the risk of prostate cancer is similar to the host country implicating lifestyle and environmental factors, rather than genetics in prostate cancer etiology (20, 21).
Dietary patterns of Asian populations have been studied in an attempt to determine potential components associated with prostate cancer. Among these, soy protein is a common component of the diet for Asian men and it contains many substances hypothesized to inhibit prostate cancer. Active agents in soy products include: phytoestrogens (isoflavones and lignans), protease inhibitors, saponins, and phytic acid (186). Laboratory studies have described many biological actions of soybean components that may modulate carcinogenesis including: steroid hormone receptor antagonism, tyrosine kinase inhibition, protease inhibition, cell cycle arrest, and increased apoptosis (39, 186-190). A rodent study by Zhou et al., found that soy protein plus a 91 soy phytochemical concentrate significantly reduced tumor cell proliferation, microvessel density and increase apoptosis in 48 mice inoculated with LNCaP tumors (190).
Although animal and cell-culture research generally supports the hypothesis that soy compounds may be cancer protective, human studies investigating soy and prostate cancer are less consistent. Most of the published case-control studies have not found a significant association between soy foods and prostate cancer (53, 55, 191, 192). Some of the strongest evidence for an anticarcinogenic role of soy comes from two epidemiologic studies (51, 52). The first study used a food-frequency questionnaire and
24-hour dietary recall records to estimate the diet habits of almost 8,000 Japanese men living in Hawaii. After 21 years of follow-up, the authors reported that men in the highest tertile of tofu consumption had a 65% reduced risk of prostate cancer compared with men in the lowest tertile (RR = 0.35, 95% CI = 0.08-1.43, p = 0.054) (51, 54, 193).
Several years later, over 12,000 Seventh-day Adventists in California were enrolled in a second study. The men completed diet records throughout the study and were followed for 6 years. The findings suggested that men who consumed soy milk at least one time per day had a 70% reduced risk of prostate cancer (RR = 0.3, 95% CI = 0.1-0.9, p for trend = 0.02) (52, 54, 193). These two studies in addition to laboratory data have encouraged recent clinical trial studies with soy-based interventions.
Human intervention studies with soy compounds have produced somewhat mixed results. A recent study by Spentzos et al., enrolled 18 men with asymptomatic, recurrent prostate cancer who had not received hormone therapy (194). The men were instructed
92 to consume a low-fat diet (< 15% total calories) from enrollment until PSA progression
(increase of 50% from baseline). At the time of PSA progression, a soy protein supplement was added to the low fat diet intervention. Although the authors reported a trend toward a longer PSA doubling time during the intervention, this study was significantly compromised by a very small sample size and high withdrawal rate (194).
The results of a randomized and blinded diet intervention study were recently reported in which in which a soy-enriched bread, a soy enriched bread with added flaxseed (also known as linseed) or a placebo bread (wheat) were studied in 28 Australian men scheduled to undergo a prostatectomy (92). The soy-enriched breads provided a total of 117 mg of soy isoflavones per day. At the end of the intervention (length not disclosed), total PSA decreased 12.7% in the group consuming the soy-enriched bread, and increased 21.3% and 40% in the soy + linseed and placebo groups, respectively (p =
0.02 for soy v. placebo groups)(92). Like the Spentzos study (193), these results are provocative, but significantly compromised by a small sample size and the fact that the authors did not disclose the duration of the intervention.
These studies highlight some important limitations that are common in studies of soy protein and prostate cancer. Many of the clinical trials and case-control studies have very small sample sizes, making data interpretation difficult (55, 191, 192, 194).
Second, many of the older studies did not use diet questionnaires that queried about a variety of soy foods. Therefore, assessment of total soy exposure has been limited and
93 many publications have reported on the effects of only one soy food (eg., soy milk, or tofu). Finally, in many studies, especially studies conducted in Western societies where soy is not a commonly consumed food, overall soy consumption is very low. Recently, a study of habitual isoflavone consumption in Dutch women was found not to be protective against breast cancer. However, the median isoflavone consumption in this study was
0.67 mg/day which is strikingly less than the 50 mg per day typically consumed by
Japanese women (37, 195, 196).
Overall, the evidence derived from epidemiologic studies, rodent experiments, and in vitro studies provide the support necessary for clinical investigations focusing upon dietary interventions with soy products for the prevention or treatment of prostate cancer.
Tomatoes and Tomato Products
A series of studies published over the past decade support the hypothesis that the intake of tomatoes and tomato products may reduce the risk of prostate cancer. It is proposed that lycopene, the carotenoid providing the familiar red color to tomatoes, may be one of the key components in tomato products that reduces risk of prostate tumor progression. Lycopene has been shown in vitro to be a potent antioxidant (197, 198) and to upregulate expression of gap junction proteins involved in cell:cell communication and differentiation (199, 200). In their landmark 1995 study, Giovannucci and co-workers (2) demonstrated that American men consuming >10 servings of tomato products versus
94 <1.5 servings per week had a significant 35% reduction in advanced prostate cancer risk.
Ten servings of tomato-based foods per week is approximately equivalent to 150 mg of lycopene per week, or 21 mg lycopene per day (60). The mean lycopene consumption in the highest quintile of lycopene intake was 10 mg per day (2).
More recently, human and rodent studies have added support to the hypothesis that lycopene is important in prostate cancer prevention. Gann et al., analyzed pre- diagnostic blood antioxidants and subsequent prostate cancer diagnosis in the Physicians’
Health Study cohort (578 cases, 1294 controls) (201). The authors reported that of all the antioxidants measured, only blood lycopene was related to prostate cancer risk (201).
Lycopene concentrations were significantly lower in men who subsequently developed prostate cancer than in men who remained disease-free (201). Additionally, Clinton et al., and others have demonstrated that lycopene is found in the human prostate which further supports a putative direct role for lycopene in prostate carcinogenesis (58, 202,
203). Emerging data from animal studies also supports a role for both whole tomatoes and lycopene in suppression of prostate cancer progression (59, 61). While most studies of tomato phytochemicals have focused upon lycopene, tomatoes contain many other phytochemicals, including polyphenolics such as quercitin, rutin, and kaempherol which may also have an anticarcinogenic role (41).
Natural History of Advanced Prostate Cancer
Although many men whose prostate cancer is properly staged and who undergo curative treatment (usually surgery or radiation therapy) will have no evidence of prostate
95 cancer in the years following treatment, approximately 30% of men will develop a prostate cancer recurrence within ten years (124, 137, 204). In the early stages of recurrent disease, many men are asymptomatic and aggressive treatment is frequently not initiated due to the potential for side effects and because therapies for advanced cancer
(including hormone therapy or chemotherapy) are only effective for a finite period of time. Generally, starting aggressive therapy for prostate cancer when a patient becomes symptomatic, rather than treating an asymptomatic biochemical recurrence (as indicated by a rising PSA) is the preferred course of action. Upon diagnosis with recurrent prostate cancer, many men become understandably anxious and feel uncomfortable accepting that there is little chance of cure and pursuing a monitoring approach. This anxiety is worsened by a gradual, but relatively predictable increase in PSA. Because men with a rising PSA are likely to be motivated to participate in their healthcare, and because most men are asymptomatic, studies of diet and nutrition are ideally suited for this population.
Hypothesis
Tomato products and soy foods each may influence prostate cancer and should be further investigated with regards to their ability to prevent prostate cancer, reduce the rate of progression, or serve as an adjunct to prostate cancer therapy. A combination of tomatoes and soy may be an ideal intervention for large clinical trials. We hypothesize that men with active, asymptomatic prostate cancer will be adherent to a diet rich in tomato products (to provide > 25 mg lycopene per day) and soy protein (40 grams soy protein and 80 mg isoflavones per day) without evidence of significant toxicity (as
96 measured by standard laboratory tests including complete blood counts and blood chemistry). Additionally, we hypothesize that these dietary changes will increase blood lycopene levels, increase urinary isoflavone excretion and the interventions may result in alterations in biomarkers associated with prostate cancer progression including a slowing in the rise of PSA, and a reduction in serum IGF-1.
5.3. Subjects and Methods
Subjects
Participants were men with histologically diagnosed prostate cancer (n = 41). All men had completed primary therapy (prostatectomy, external beam radiation therapy, brachytherapy, watchful waiting, or hormone therapy) and were currently demonstrating biochemical failure as evidenced by at least two consecutive increases in serum PSA.
Based on clinical judgment, the men were asymptomatic and likely to remain asymptomatic for at least three months. Men were asked to discontinue use of all alternative medications and nutritional supplements. All men were given a multivitamin / multimineral supplement (Kroger brand One Daily) which provided 100% of the
Recommended Dietary Allowance (RDA) for most nutrients. Men who met any of the following criteria were excluded: currently receiving chemotherapy, radiotherapy or biological therapy for any internal malignancy (including prostate cancer), abnormal kidney or liver enzymes, history of a malabsorptive disorder or other metabolic disorder requiring special diet modifications (type I or type II diabetes excepted). There were no minimum or maximum PSA limits for this study and there were no age restrictions. This
97 study was approved by the Biomedical Sciences Institutional Review Board of The Ohio
State University, Columbus, Ohio (Appendix C). The objectives, requirements, and risks/benefits of the study were clearly outlined and informed written consent was obtained for each subject.
Study Design
Once men were deemed clinically eligible and informed consent was obtained, all men participated in a one-week washout where they abstained from foods containing tomatoes / tomato products and any sources of soy protein. After the one-week washout, men were randomized to one of two dietary intervention groups: Group A: consumption of tomatoes / tomato products to provide at least 25 mg lycopene per day (no soy), or
Group B: consumption of 40 grams soy protein isolate per day from a powdered supplement (no tomatoes) for four weeks. After the four week intervention, men were then instructed to consume both 25 mg lycopene from tomatoes / tomato foods and 40 grams soy protein for an additional 4 weeks. Blood and urine samples were obtained at randomization, after 4 weeks of intervention on single agents, and after 4 weeks on combined product intervention (figure 5.1).
98
Group A
Tomato Group Tomato + Soy
R A Washout N D O M Group B I Z E
Soy Group Tomato + Soy
-1 0 4 8
week
diet blood blood diet blood record urine urine record urine
Figure 5.1 Study design
99 Enrollment and standardization
All 41 men were counseled by a registered dietitian and encouraged to follow a diet which included the USDA Dietary Guidelines. This diet is designed according to the standards recommended by USDA that includes at least five servings of a variety of fruits and vegetables / day, <30% calories from fat, replacing refined carbohydrates with complex carbohydrates, >20 g fiber / day. It is proposed that the men will continue with this regimen throughout the study and perhaps incorporate these changes into a general healthy lifestyle. To further standardize the study, all men will discontinue other dietary vitamin and mineral supplements and consume a multivitamin /multimineral supplement that approximates the RDA of essential nutrients. All men were asked to complete a 3-day diet record (two non-consecutive week days and one weekend day) at two different time points, during washout and during weeks 4 – 8 (see Appendix D for diet record forms and other education materials used in this study). Additionally, all men were encouraged to participate in daily physical activity. Physical activity recommendations were tailored according to the patient’s baseline activity level. Patients were asked to report the time they spent participating in physical activity, above their normal activities of daily living, to the study dietitian during the scheduled meetings. Patients would recall the number of minutes per day spent in physical activity and the number of days per week. This information was used to calculate and record an estimate of total minutes per week spent in physical activities. Patients were queried about physical activity at all three clinical visits
(weeks 0, 4 and 8). No formal questionnaires or record logs were used for physical activity documentation.
100 Patient Education - Washout Phase
All 41 men were asked to consume a diet devoid of tomato products or soy products for 7 days. This was necessary to establish a new baseline for blood lycopene and urinary soy isoflavones. Men were asked to avoid lycopene-rich fruits and vegetables
(tomatoes and tomato products, watermelons, red grapefruit) and soy products (tofu, soymilk and shakes, and soy nutritional supplements). Earlier studies in our lab have shown that lycopene concentrations will decrease by approximately 50% in 7 to 14 days of washout (205). Men were then randomized after 1 week of the washout phase to one of the two dietary interventions
Patient Education – Tomato Intervention
To assist the men in achieving 25 mg of lycopene per day, a tomato worksheet was developed (figure 5.2). This worksheet listed standard serving sizes for a variety of tomato-based foods and assigned a “score” based on previously published values for the lycopene content of these foods (60). The score for each tomato food approximated the milligrams of lycopene per serving. Subjects were asked to check the number of servings consumed from the foods listed on the tomato worksheet and add up their individual score at the end of each day. Men were permitted to accumulate a score greater than 25 per day if desired. One “Tomato Worksheet” was completed each day for weeks 0 through 4 for the men in Group A, and each day for weeks 4 through 8 for both groups.
Men who were randomized to Group A were asked not to consume any foods containing soy protein for weeks 0 through 4.
101 Tomato Worksheet
Name:______Week ___ Day ______
The foods below have been assigned points according to portion size and nutrient content. Each day, your goal is to consume combinations of the foods listed below so that you accumulate 25 points. You may use any combination of foods, as long as you adhere to the portion sizes and point system below. You may eat the same food more than one time each day, just make sure you check the appropriate number of boxes on the worksheet.
Food Serving Size # of servings Points / svg. 1 2 3 4 5 Tomato, raw 1 whole x 4 =
Tomato, raw, slice 2 slices x 1 =
Tomato, raw, chopped ½ cup x 3 =
Tomatoes, ckd / stewed 1/2 cup x 5 =
Tomato, canned / whole 1/2 cup x 13 =
Tomato Sauce ½ cup x 21 =
Tomato Paste 1 Tbsp. x 9 =
Tomato Juice 1 cup / 8 fl. oz x 21 =
Tomato Soup ½ cup (condensed) x 12 =
Catsup 2 tsp x 3 =
Chili 1 cup x 5 =
Pizza Sauce (canned) ½ cup x 16 =
Pizza slice 1 slice x 3 =
Salsa 2 Tbsp. x 4 =
Steak Sauce 1 Tbsp. x 3 =
Vegetable Juice ½ cup x 10 =
Goal = 25 points, Total = _____
Figure 5.2 Study participant daily lycopene log sheet
102 Patient Education – Soy Intervention
Men were given a powdered soy protein supplement formulated and manufactured by DuPont Technologies (St. Louis, MO). The nutrient and isoflavone content for each package of soy protein is described in table 5.1. Men were asked to consume two packages of the soy protein powder each day. The soy protein could be mixed with any liquid or mixed into any soft food (eg., oatmeal) and could be consumed in small frequent doses if desired. Men were also asked to document soy protein consumption (figure 5.3). Men randomized to Group B for weeks 0 – 4 were asked to abstain from consuming any tomatoes or tomato products. For weeks 4 – 8, all men were asked to consume 2 packages of soy protein and document consumption with lycopene consumption on the Tomato Worksheet.
Blood Sampling
Venous blood samples were obtained by trained phlebotomists at The Ohio State
University Medical Center, Columbus, Ohio. Blood was collected in 10 mL EDTA tubes and 8 mL CPT tubes with sodium heparin gel. Blood samples were centrifuged at 24 degrees C and 2700 rpm for 20 minutes in a Beckman centrifuge. Plasma was aliquoted into 2 mL sample tubes and subsequently stored at -70 degrees C.
Urine Sampling
Subjects collected urine for 24-hours before each clinic visit. Urine was stored in a cool location, thoroughly mixed, aliquoted into 4 ml tubes and subsequently stored at
-70 degrees C.
103
Nutrients per % Daily serving* Value (1 package) Calories 100 - Carbohydrate (g) 4 1 Fiber 0 0 Sugars 2 - Protein (g) 20 40 Total Fat 1 2 Saturated Fat 0 0 Cholesterol 0 0 Vitamin A (IU) 500 10 Vitamin C (mg) 0 0 Vitamin D (IU) 100 25 Vitamin B 2 (mg) 0.4 25 Vitamin B 12 (mcg) 0.9 15 Folate (mcg) 60 15 Calcium (mg) 700 70 Iron (mg) 3.6 20 Phosphorous (mg) 500 50 Magnesium (mg) 40 10 Isoflavones (mg) 40 - Genestein (mg) 24 - Other (mg) 16 -
* Subjects consumed two servings per day
Table 5.1 Nutrient analysis of soy protein powder
104
Soy Group
Please keep track of each package of soy powder consumed using the table below.
Date Pkg 1 Pkg 2 Comments (optional) Tues, 25 November X X Mixed with milk
Figure 5.3 Study participant daily log for soy protein consumption
105 Carotenoid extractions from plasma
Extraction followed the method of Nomura et al. (206). Aliquots (150 µL) of plasma were transferred into microcentrifuge tubes and equal amounts of water and ethanol (300 µL) containing 0.1% BHT were added. After vortexing, 1 mL hexane containing 0.02 % BHT was added, vortexed and centrifuged at 5600 x g for 1 min
(Corning-Costar 10 MVSS Microcentrifuge, New York, NY). The hexane extraction was repeated twice and the combined hexane layers were dried under nitrogen, reconstituted in 300 µL of MTBE:MeOH (1:1, v/v), filtered and 25 µL aliquots were analyzed by
HPLC.
Quantification of carotenoids by HPLC
All-trans standards of β-carotene and lycopene were purchased from Sigma (St.
Louis, MO), while α-carotene was obtained from Fluka Chemie AG (Buchs,
Switzerland). Stock solutions of carotenoids were prepared in hexane and their concentrations were determined spectrophotometrically. All-trans standards were used for the quantitation since cis isomers are not commercially available. Identification of cis isomers was based on the comparison to previously reported UV-VIS and electrochemical methods (205, 207). HPLC-grade solvents and water were used throughout the experiments.
The HPLC system consisted of a Hewlett Packard model 1050 (Santa Clara, CA) solvent delivery system. An eight-channel 5600 Coularray™ electrochemical detector
(ESA, Chelmsford, MA) with cell potentials set from 200 to 620 mV in 60 mV
106 ™ increments was used. Separations were achieved using a YMC C30 column (150 mm x
4.6 mm, 5µm particle size). The separation method developed by Ferruzzi et al. (207) was modified and used for the quantification of carotenoids. The volumetric proportions of methanol:MTBE:water:ammonium acetate buffer (pH = 4.6; 1.0 mol/L) was used in the preparation of mobile phase A (88:5:5:2) and mobile phase B (28:70:0:2). The linear gradient was: 0 min 100% A, from 0 to 7 min 15% A and 85% B; 7 to 18 min 100% B at a flow rate of 1 mL/min.
Isoflavone extractions from urine
Extraction of urine samples for isoflavones was performed as described by
Kulling et al. (208). Briefly, after thawing, aliquots (2.0 mL) of urine were mixed with
0.4 mL sodium acetate buffer (pH=5.5), 50 µL internal standard (2’,4’ dihydroxy-2- phenylacetophenone), 0.1 mL 10% aqueous ascorbic acid solution, 0.1 mL beta- glucuronidase/arylsulfatase, and 50 µL 2 M/L MgCl2 solution. Following incubation at
37oC for 2 hours, the suspension was extracted twice with 5 mL diethylether. After evaporated to dryness under nitrogen, the extract was resolubilized in 350 µL methanol, filtered, and 10 µL aliquots were injected to the HPLC.
Quantification of isoflavones by HPLC
Standards of daidzein, genistein, and glycitein were purchased from LC
Laboratories (Woburn, MA); dihydrodaidzein, O-desmethylangolensin, dihydrogenistein from Plantech (Reading, UK); equol, and 2’,4’-dihydroxy-2-phenylacetophenone
107 (internal standard) from Sigma (St. Louis, MO), β-glucuronidase/arylsulfatase from
Roche (Mannheim, Germany).
A Waters 2690 HPLC system (Milford, MA) equipped with a Waters 996 photo- diode array detector was used. Reverse phase separations were carried out by using an analytical C18 Hydrobond (100mm x 3 mm, 3µm particle size) column coupled to a C18 guard column and filter. HPLC method described by Franke et al., (209) was used with some modifications. Mobile phase was composed of methanol, acetonitrile, and 1% aqueous acetic acid and the gradient used changed from 10:15:75 to 15:20:65 linearly within 5 min, then to 20:20:60 until 10 min, then to 25:25:50 until 13 min, then to
45:45:10 until 14 min, then to 45:50:5 until 18 min, then to 10:15:75 until 20 min, followed by holding for the next 5 min (total of 25 min). The flow rate was 0.55 mL/min.
5.4. Statistical Analysis
General Data Management
The purpose of this study was to examine adherence and safety of a diet intervention rich in tomatoes / tomato products and soy foods in 41 men with asymptomatic, recurrent prostate cancer. We also analyzed differences in plasma levels of carotenoids between patients who received tomato for four weeks followed by four weeks of tomato+soy versus soy for four weeks followed by tomato+soy for four weeks and changes in biochemical measures associated with prostate cancer including PSA, testosterone, and IGF-1. All data was entered into an Excel spreadsheet and SPSS 13.0
108 (SPSS Inc., Chicago, IL) was used to compute descriptive statistics. For all analyses, p- values ≤ 0.05 were considered significant.
Adherence to Interventions
Descriptive statistics were used to determine mean ± SD for lycopene and soy protein consumption and to calculate mean servings per week for various tomato products.
Clinical Laboratory Data and Vital Signs
Descriptive statistics and paired t-tests were used to determine changes in blood chemistries, blood counts and vital signs.
Plasma Carotenoids and Urinary Isoflavones
The analysis involved testing whether group and time are important factors in determining the plasma carotenoid levels. Time is a repeated factor in this experiment; therefore special care was taken in the analysis to account for the correlation in responses across time. A repeated measures analysis of variance was used to model the data.
Because there is incomplete data at some time points, the parameters for the model were estimated using maximum likelihood. An unstructured correlation was assumed for the errors. The PROC MIXED procedure in SAS Version 9.0 was used to analyze the data.
If significant effects were found, then multiple comparisons were performed using
Tukey’s method for pairwise comparisons in SAS. This procedure uses an approximate t-test to test whether the differences are equal to zero.
109 Two model assumptions assessed are normality of the residuals and equal variances of the residuals. Residual plots and tests were examined to evaluate these assumptions. If either assumption did not hold, then a square-root transformation was applied to the outcome data.
Diet Analysis and Physical Activity Data
Diet records were analyzed with ESHA Diet Analysis Plus software (version 6.0,
ESHA Research, Salem, Oregon). Paired t-tests were conducted for each group to determine dietary changes between baseline and end of study. Physical activity data was collected in minutes per week and paired a t-test was used to determine change from baseline to end of study for the entire cohort.
5.5. Results
Of the 41 men enrolled, all 41 completed the study. Baseline demographic and clinical characteristics are described in table 5.2.
Adherence
Patient Records
Table 5.3 details the mean intake of lycopene and soy protein at each time point based on each patient’s daily recorded consumption of tomato products and soy. The
110
Both Both Groups Groups mean ± SD mean ± SD
Randomization n = 41 Laboratory Values Chemistry ± Clinical State BUN (mg/dL) 18 7 No Hormone Therapy n = 21 Cr (mg/dL) 1 ± 0.2 Hormone Insensitive n = 20 ALT (U/L) 21 ± 6 ± AST (U/L) 24 5 ± Anthropometrics Bili (mg/dL) 0.7 0.3 Age (years) 70 ± 7 Hematology Height (inches) 70 ± 2 WBC (k/uL) 7 ± 3 Weight (pounds) 198 ± 32 Hct (%) 42± 4 ± BMI (kg/m2) 29 4 Hgb (g/dL) 14 ± 1 † ± Adjusted BMI (kg/m2) 30 3 Platelets (K/uL) 249 ± 70 Lipid Profile ± Vitals T. Cholesterol (mg/dL) 189 36 ± Resting Pulse (beats / min) 74 12 HDL (mg/dL) 49 ± 26 Systolic BP (mm Hg) 139 ± 16 LDL (mg/dL) 108 ± 32 Diastolic BP (mm Hg) 78 ± 9 Triglycerides (mg/dL) 164 ± 84
† excludes 2 men with BMI 2 SD below mean * p < 0.01 ** p < 0.05
Table 5.2 Baseline characteristics of men enrolled in study (n = 41)
111
Group A Group B Tomato – Combined Soy – Combined All Men
week week week week week 0 – 4 4 – 8 0 – 4 4 – 8 4-8
Lycopene 43 ± 15 40 ± 17 0 36 ± 11 38 ± 14 (mg / day)
Soy protein 0 36 ± 8 39 ±1 39 ± 2 38 ± 6 (g / day)
Table 5.3 Mean lycopene and soy protein intake
112 mean lycopene consumption exceeded the targeted goal of 25 mg per day. The range of average lycopene consumption for Group A was 28 - 82 mg / day for weeks 0 - 4 and 21 -
89 mg/ day for weeks 4-8. For men in Group B, the range of lycopene intake was 27 –
74 mg / day for weeks 4 – 8 (no tomato consumption for weeks 0 - 4). Mean intake of soy protein was slightly lower than the goal of 40 grams per day (table 5.3). The range of soy protein intake in Group A was 11 – 40 grams / day for weeks 4 – 8 (no soy for weeks 0 - 4). The range of soy protein consumption in Group B was 36 – 40 grams / day for weeks 0 – 4 and 32 – 40 grams /day for weeks 4 – 8.
To determine the products that were most commonly consumed to meet the daily lycopene goal, we summed each participants’ data from the daily “Tomato Worksheet.”
Tomato juice (including tomato juice and vegetable juice) were consumed most frequently at 10.7 servings (8 fl. ounces / serving) per week followed by 4 servings of raw tomatoes per week (figure 5.4).
Plasma Carotenoids
Mean plasma levels of total lycopene, lycopene isomers, beta carotene and alpha carotene are shown in table 5.4. We conducted pairwise comparisons for the plasma carotenoid values for each time point and each group.
Group A changes from week 0 to week 8 Total plasma lycopene, lycopene isomers, and
ß-carotene increased significantly in Group A from week 0 to week 4, but did not significantly increase from week 4 to 8.
113
10.00
8.00
6.00
4.00 Mean servings per per week servings Mean
2.00
0.00 juice raw catsup salsa pizza sauce soup chili other
Figure 5.4 Mean servings per week from various tomato products
114
Group A Group B Plasma P-values from 2x3 ANOVAs Carotenoids Tomato – combined Soy – combined mean µmol/L ±SEM Week 0 Week 4 Week 8 Week 0 Week 4 Week 8 Group Time Interaction
Total lycopene 0.72±0.09bc 1.27±0.09e 1.21±0.10de 0.59±0.07b 0.35±0.05a 0.91±0.10cd <0.0001 <0.0001 <0.0001
Trans-lycopene 0.15±0.02bc 0.30±0.02df 0.27±0.03ef 0.12±0.02b 0.07±0.01a 0.22±0.03cf <0.0001 0.0003 <0.0001
Total cis-lycopene 0.57±0.07bc 0.97±0.06d 0.94±0.07def 0.47±0.06b 0.28±0.04a 0.69±0.07cf <0.0001 <0.0001 <0.0001
5-cis-lycopene 0.20±0.03bcfg 0.36±0.03dgi 0.33±0.04ehi 0.19±0.04b 0.10±0.03fa 0.25±0.04cgh <0.0001 0.0031 <0.0001 115
cis-lycopene E 0.14±0.01bc 0.18±0.01de 0.18±0.01ce 0.10±0.02b 0.07±0.01a 0.14±0.01c <0.0001 <0.0001 <0.0001
cis-lycocpene D 0.20±0.03bc 0.37±0.02d 0.37±0.03def 0.15±0.02b 0.09±0.01a 0.27±0.03cf <0.0001 <0.0001 <0.0001
cis-lycopene B 0.03±0.00cef 0.05±0.01b 0.06±0.01dg 0.03±0.00abc 0.02±0.00ae 0.04±0.00bfg <0.0001 0.0015 0.0055
Total β-carotene 0.61±0.08cg 0.98±0.9dhjl 1.03±0.12eikl 0.91±0.13abcde 1.02±0.15afghi 1.17±0.14bfjk <0.0001 0.2269 0.0015
Trans-β-carotene 0.42±0.06cg 0.64±0.07dhjl 0.67±0.09eikl 0.61±0.10abcde 0.67±0.11afghi 0.77±0.10bfjk <0.0001 0.2841 0.0057
9 cis-β-carotene 0.2±0.02c 0.34±0.03dgik 0.36±0.04ehjk 0.30±0.03abde 0.34±0.04afgh 0.40±0.04bfij <0.0001 0.1531 0.0035
% cis-lycopene 79.96±6.6cfil 76.88±4.7dgjln 78.45±5.0ehkmn 80.2±6.1abcde 82.07±7.8afgh 77.85±6.4bijk 0.1479 0.3000 0.0099
α-carotene 0.08±0.01 0.11±0.02 0.14±0.02 0.13±0.02 0.16±0.02 0.16±0.03 0.0664 0.0001 0.6639
* Means with different superscript letters are significantly different by pairwise comparisons
Table 5.4 Plasma carotenoid values*
115 Group B changes from week 0 to week 8 Total lycopene, and most of the lycopene isomers were statistically different from one another during each of the three time points.
The only exception to this was cis-lycopene B which was not statistically different from week 0 to week 4, but significantly increased from week 4 to week 8. Total ß-carotene, trans- ß-carotene and 9-cis- ß-carotene similarly were not different from week 0 to week
4, but significantly increased from week 4 to week 8.
Comparison of Group A to Group B After the one-week washout, plasma carotenoid levels for Group A and Group B were not significantly different with the exception of 9 cis- ß-carotene which was higher in group B. The week 4 time point is dramatically different for all lycopene measures between the two groups, however the percent of cis- lycopene and the ß –carotene measures were not different between groups.
We analyzed the main effects across each group, across time and the interactions between group and time. Those data are summarized below. For all of the analyses, except for percent cis-lycopene, the residuals were examined and neither the normality assumption nor the equal variance assumption appeared valid. Therefore, a square-root transformation was applied to the outcome data. The assumptions appeared to be met after transforming the data.
Total lycopene: The group x time interaction was statistically significant (p < 0.0001).
The results from the multiple comparisons procedure that was performed within each group indicate that all pairs of time were significantly different for the soy group. For the
116 tomato group, baseline was significantly different from weeks 4 and 8; however weeks 4 and 8 were not significantly different. For the group comparisons, soy and tomato were significantly different at week 4 only.
Trans-lycopene: The group x time interaction was statistically significant (p< 0.0001).
The results from the multiple comparisons procedure that was performed within each group indicate that all pairs of time were significantly different for the soy group. For the tomato group, baseline was significantly different from weeks 4 and 8; however weeks 4 and 8 were not significantly different. For the group comparisons, soy and tomato were significantly different at week 4 only.
Total cis-lycopene: The group x time interaction was statistically significant (p < 0.0001).
The results from the multiple comparisons procedure that was performed within each group indicate that all pairs of time were significantly different for the soy group. For the tomato group, baseline was significantly different from weeks 4 and 8; however weeks 4 and 8 were not significantly different. For the group comparisons, soy and tomato were significantly different at week 4 only.
5-cis-lycopene: The group x time interaction was statistically significant (p < 0.0001).
The results from the multiple comparisons procedure that was performed within each group indicate that all pairs of time were significantly different for the soy group. For the tomato group, baseline was significantly different from weeks 4 and 8; however weeks 4
117 and 8 were not significantly different. For the group comparisons, soy and tomato were significantly different at week 4 only.
cis-Lycopene E: The group x time interaction was statistically significant (p < 0.0001).
The results from the multiple comparisons procedure that was performed within each group indicate that all pairs of time were significantly different for the soy group. For the tomato group, baseline was significantly different from weeks 4 and 8; however weeks 4 and 8 were not significantly different. For the group comparisons, soy and tomato were significantly different at week 4 only.
cis-Lycopene D: The group x time interaction was statistically significant (p< 0.0001).
The results from the multiple comparisons procedure that was performed within each group indicate that all pairs of time were significantly different for the soy group. For the tomato group, baseline was significantly different from weeks 4 and 8; however weeks 4 and 8 were not significantly different. For the group comparisons, soy and tomato were significantly different at week 4 only.
cis-Lycopene B: The group x time interaction was statistically significant (p = 0.0055).
The results from the multiple comparisons procedure that was performed within each group indicate that baseline and week 8 and weeks 4 and 8 were significantly different for the soy group. For the tomato group, baseline was significantly different from weeks
4 and 8; however weeks 4 and 8 were not significantly different. For the group comparisons, soy and tomato were significantly different at week 4 only.
118
Total beta-carotene: The group x time interaction was statistically significant (p =
0.0015). The results from the multiple comparisons procedure that was performed within each group indicate that there were no significant time differences within the soy group.
For the tomato group, baseline was significantly different from weeks 4 and 8; however weeks 4 and 8 were not significantly different. For the group comparisons, soy and tomato did not differ at any time points.
Trans-beta-carotene: The group x time interaction was statistically significant (p =
0.0057). The results from the multiple comparisons procedure that was performed within each group indicate that there were no significant time differences within the soy group.
For the tomato group, baseline was significantly different from weeks 4 and 8; however weeks 4 and 8 were not significantly different. For the group comparisons, soy and tomato did not differ at any time points.
Urinary Isoflavones
Urinary excretion of soy isoflavones and isoflavone metabolites are shown in table 5.5. During the washout period (week 0) and at the 4 week time point for Group A, urinary isoflavone excretion was not detectable (noted as ND in table 5.5) by HPLC. A
Wilcoxon Rank Sum test revealed significantly different urinary isoflavone excretion when comparing the week 8 time point for Group A and Group B. A Wilcoxon Signed
Rank test compared both Group A and Group B from week 4 to week 8 revealed significantly lower isoflavone excretion at the week 8 time point compared with week 4
119
Group A Group B Statistics Tomato – combined Soy - combined
week week week week week week Urine Isoflavones A week B week A vs. B mean µmol/L ± SEM 0 4 8 0 4 8 † † †† 4 vs. 8 4 vs. 8 week 8
Total Isoflavones ND ND 54.3±4.6 ND 69.5±7.2 54.1±5.7 < 0.0001 0.0296 0.7291
Total native ND ND 32.0±3.6 ND 41.6±5.5 30.2±3.7 < 0.0001 0.0266 0.5168
Total metabolites ND ND 22.3±2.9 ND 27.8±3.7 23.8±3.0 < 0.0001 0.1429 0.9640
Genistein ND ND 8.5±1.7 ND 11.3±2.2 7.8±1.4 < 0.0001 0.0826 0.7519
Daidzein ND ND 20.2±2.2 ND 26.4±3.1 20.1±2.9 < 0.0001 0.0532 0.4785 120 Glycitein ND ND 3.21±0.6 ND 3.9±1.0 2.4±0.4 < 0.0001 0.0266 0.1103
Equol* ND ND 4.0±2.2 ND 1.5±1.5 1.4±1.4 0.0497 0.3421 0.1240
ODMA ND ND 8.9±2.5 ND 12.7±3.0 8.0±1.2 0.0004 0.0042 0.5729
DHD ND ND 9.5±2.1 ND 13.6±2.5 14.4±2.7 0.0004 1.0 0.1582 † p-value computed using an exact Wilcoxon Sign Rank test †† p-value computed using an exact Wilcoxon Rank Sum test * 5 men were equol producers, 1 in tomato group, 4 in soy group ND = not detectable
Table 5.5 Urinary isoflavone levels
120 for all isoflavones and metabolites in Group A and all isoflavones and metabolites in
Group B except for glycitein, equol and DHD.
Diet Analysis and Physical Activity
Diet analysis data for both groups are shown in tables 5.6 and 5.7. There were several nutrients in each group which were significantly different from the first diet analysis to the second diet analysis. The mean (± SD) minutes of physical activity for all men at baseline was 44 (± 68) minutes / week. By the end-of-study visit, the mean minutes of exercise per week had increased to 93 (± 83) minutes / week (p < 0.01)
Safety
There were no grade II or III toxicities during this study (Appendix C). Only 3
(7%) men complained of constipation while consuming the soy protein and one man
(2%) indicated a flare-up of gout (grade I toxicity). There were no significant changes between week 0, week 4 or week 8 in any laboratory or clinical measure of toxicity including: kidney and liver enzymes, other blood chemistries, complete blood counts, circulating hormones or vital signs.
Prostate Cancer Related Biomarkers and Serum Lipids
Serum Testosterone and Insulin-like Growth Factor I (IGF-I)
Data for testosterone and IGF-I were stratified according to hormone status (naïve or refractory). There were no significant changes in testosterone or IGF-1 during the course
121
Washout Weeks 4 - 8 RDA†
Calories / d 2020 ± 546 2198 ± 501 n/a
Protein (g / d) 86 ± 24 126 ± 31*** n/a
Fiber (g / d) 25 ± 9 28 ± 8 38 g
Fat (g / d) 64 ± 21 67 ± 25 n/a
Cholesterol (mg / d) 238 ± 98 263 ± 142 < 200
% CHO 54 ± 7 50 ± 8 45-65
% Protein 17 ± 4 23 ± 5*** 10-35
% Fat 28 ± 7 26 ± 6** 20-35
Folate (mcg / d) 357 ± 114 502 ±120** 400
Vitamin C (mg / d) 147 ± 83 221 ± 82*** 90
Vitamin D (mcg / d) 4.9 ± 28 6.4 ± 5.3 10
Vitamin E (mg / d) 7.5 ± 4 9.7 ± 4 15
Calcium (mg / d) 1000 ± 536 2298 ± 556*** 1200
Iron (mg / d) 18 ± 5 26 ± 5*** 8
Phosphorous (mg /d) 1407 ± 504 2289 ± 530*** 700
Potassium (mg / d) 3118 ± 1085 3864 ± 1196* 4700
Sodium (mg / d) 3260 ± 2091 4182 ±1308** 1200-1300
Vegetable (svg / d) 3.6 ± 1.8 6.4 ± 2*** 3-4
Fruit (svg / d) 3.9 ± 2.8 2.8 ±1.6 2-3
† if no RDA established, then value is AI * p < 0.05 ** p < 0.01 *** p < 0.001
Table 5.6 Group A diet analysis data
122
Washout Weeks 4 - 8 RDA†
Calories (kcal / d) 1999 ± 561 2073 ± 522 n/a
Protein (g / d) 89 ± 24 119 ± 32*** n/a
Fiber (g / d) 23 ± 7 25 ± 9 38 g
Fat (g / d) 68 ± 26 61 ± 23 n/a
Cholesterol (mg / d) 297 ±149 275 ± 129 < 200
% CHO 50 ± 9 49 ± 7 45-65
% Protein 18 ± 4 23 ± 5 10-35
% Fat 30 ± 7 25 ± 6 20-35
Folate (mcg / d) 379 ±137 466 ± 144* 400
Vitamin C (mg / d) 144 ± 88 218 ± 83*** 90
Vitamin D (mg / d) 4.5 ± 3.9 5.5 ± 4.3 10
Vitamin E (mg / d) 8.7 ± 6.2 9.3 ±3 15
Calcium (mg / d) 863 ± 461 1977 ± 719*** 1200
Iron (mg / d) 17 ± 5 24 ± 7*** 8
Phosphorous (mg / d) 1354 ± 471 2099 ± 665*** 700
Potassium (mg / d) 3240 ±1086 3825 ± 1123* 4700
Sodium (mg / d) 2983 ±1639 3971 ± 1118*** 1200-1300
Vegetable (svg / d) 4 ± 2 6.2 ±2*** 3-4
Fruit (svg / d) 3.6 ± 1.7 2.7 ±1.7 2-3
† if no RDA established, then value is AI * p < 0.05 ** p < 0.01 *** p < 0.001
Table 5.7 Group B diet analysis data
123 of the study for either group. There was a statistically significant decrease in serum total cholesterol and non-significant reductions in both HDL and LDL cholesterol (table 5.8).
Serum PSA
Because we enrolled men with highly variable PSA values, we have presented the data several different ways. Table 5.9 details absolute PSA changes over the course of the study according to intervention group, and the entire cohort.
We also stratified PSA changes based on pre-enrollment doubling time of 0 to 3.9 months = fast, 4 to 8 months = moderate, and 8 months or longer = slow). We used a
Fisher’s Exact test to compare the proportion of men in each group prior to enrollment to the actual and expected values at the end of the study. There was a statistically significant difference in the proportions for the entire group and, after multiple comparisons, more men in the “fast” group experienced a slower doubling time than men in the “slow” group (table 5.10).
To normalize the highly variable PSA data, we calculated PSA slope at week 0 and at week 8. PSA slope is the log of the relationship between PSA velocity and time.
Figures 5.5 and 5.6 are graphic representations of this data.
124
Week 0 Week 8
Testosterone (ng/dL) Hormone therapy (n = 20) 2.5 ± 7 5.2 ± 10 Hormone naïve (n = 21) 90 ± 174 90 ± 170
IGF-1 (ng/mL) Hormone therapy (n = 20) 167 ± 86 185 ± 83 Hormone naïve (n = 21) 155 ± 74 157 ± 76
† Total Cholesterol (mg/dL) 186 ± 36 175 ± 35
LDL (mg/dL) 108 ± 33 99 ± 35
HDL (mg/dL) 49 ± 26 45 ± 19
Table 5.8 Testosterone, IGF-1 and lipid values
125
Group A Group B All Men
(n = 20) (n = 21) (n = 41)
% with rising PSA prior to 20 / 20 21 / 21 41 / 41 enrollment (100%) (100%) (100%)
% showing slower doubling time 13 / 20 10 / 20* 23 / 40 compared with pre-enrollment (65%) (43%) (58%)
% showing faster doubling time 7 / 20 10 / 20 17 / 40 compared with pre-enrollment (35%) (50%) (43%)
% showing same or lower PSA at 6 / 20 9/21 15 / 41 end of study than at enrollment (30%) (43%) (37%)
* Not enough data to determine pre-study doubling time in 1 man
Table 5.9 Change in PSA and PSA doubling time from week 0 to week 8
126
No. of men with No. of men with equal slower rate of rise or faster rate of rise at week 8 v. before at week 8 v. before Enrollment PSA enrollment enrollment doubling time
0 – 3.9 months a 13 / 15 2 / 15 (n = 15) (87%) (13%)
4 – 8 months 5 / 11 6 / 11 (n = 11) (45%) (55%)
> 8 months a 5 / 14 9 / 14 (n = 14) (36%) (64%)
* overall p-value = 0.01 a multiple comparisons with Bonferroni correction: PSA 0 – 3.9 v. > 8 ng/ mL, p < 0.01
Table 5.10 PSA rate of rise stratified by PSA doubling time at enrollment*
127
1.00
0.50
0.00 Slope log / month -0.50
-1.00 1 2 3 4 5 6 7 8 9 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 Individual Participants
Figure 5.5 PSA slope for each individual, prior to randomization. PSA slope is defined as the log of PSA / time.
128
1.00
0.50
0.00
Slope / month Slope log -0.50
-1.00
1 2 3 4 5 6 7 8 9 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 Individual Participants
Figure 5.6 PSA slope for each individual at the end of the study (week 8). PSA slope is defined as the log of PSA / time.
129 5.6. Discussion
This study provides several important findings regarding a diet intervention with a combination of tomato and soy products for men with asymptomatic, recurrent prostate cancer.
Adherence to tomato intervention
Our study suggests that men with recurrent prostate cancer are motivated and capable of adhering to dietary interventions with tomatoes and soy. The average lycopene consumption (> than 36 mg lycopene / day for all groups) in this study was significantly higher than the minimum targeted goal of 25 mg/ day and almost three times higher than the amount of lycopene found to be associated with a lower risk of prostate cancer in epidemiological studies (2, 67). We also were able to construct a useful tool
(the “Tomato Worksheet”) to assist men in tracking lyocpene consumption. We believe this tool is valid because the plasma lycopene levels were increased in parallel with the documented lycopene intake from the “Tomato Worksheet” during weeks 0 – 8 for
Group A and during weeks 4 – 8 for Group B. Additionally, the 3-day diet records completed during the weeks 4 – 8 reflected a statistically significant increase in nutrients typically found in tomato foods including vitamin C, sodium (from processed tomato foods) and potassium, when compared with the baseline diet record completed during the washout period when no tomatoes were consumed.
130 Adherence to soy intervention
Men were also adherent to the soy intervention and consumed 95% of the targeted goal. The amount of soy protein (40 grams / day) and isoflavones (80 mg / day) is similar to the amounts that have been used in other studies (194, 210) and slightly higher than the amount consumed in a typical Asian diet (193). The men in our study found the powdered soy supplement to be tolerable and were able to individually find ways to consume the product without significant difficulty. Isoflavone and isoflavone metabolite excretion were significantly higher at week 4 for Group B when compared to washout.
Interestingly, isoflavone excretion was slightly, but significantly, lower at week 8 than week 4 for Group B which is in agreement with participant documentation of soy intake and indicates that the men in this group consumed slightly less soy during the second 4 weeks of the study. Soy isoflavone excretion also increased in Group A at week 8 compared with week 0 and week 4. The 3 day diet records during weeks 4 – 8 also reflected adherence to the soy product. Nutrients which are derived from the soy protein powder formulation (protein, calcium, phosphorous) were significantly increased compared with the diet record completed at washout when no soy was consumed.
Adherence to tomato plus soy intervention
For weeks 4 – 8, the men in our study were again adherent to the targeted goals with both interventions simultaneously. This is the first time to our knowledge that these products have been combined together in a dietary intervention for recurrent prostate cancer. The most common tomato product chosen by men during our study was tomato juice. The popularity and convenience of tomato juice in this study make it an attractive
131 option for the future development of a functional food with added isoflavones which could be used in larger phase II/ III studies.
Safety
This is the first study to document the safety of a diet enriched in lyocpene from tomato foods with the addition of soy protein for 8 weeks. Each of the interventions, consumed separately or in combination, did not change any clinical measure of toxicity including kidney or liver enzymes, complete blood counts and vital signs. There were no issues related to safety in the tomato group. Three men consuming the soy powder reported constipation (grade I). Other studies utilizing a soy protein powder have also reported gastrointestinal complaints (211, 212) and close monitoring of tolerance needs to be considered for future studies which utilize a soy protein powder supplement. One man
(2%) in the soy group reported symptoms of foot pain similar to a previous episode of gout, although when brought to the attention of the study physician, there were no physical findings to confirm the diagnosis. Although recent studies suggest that uric acid levels are not increased by vegetable protein, we cannot dismiss the possibility that the soy protein powder in our study contributed to this incident (187). Future studies with soy protein should monitor study participants for gout-related symptoms.
Lycopene isomers
Lycopene consumed in foods is predominantly found in the all-trans-form (58,
213). However, many studies have reported that cis-isomers of lycopene account for greater than 50% of total lycopene in the blood, and 75% of total lycopene in prostate
132 tissue (58). It has been proposed that different lycopene isomers may confer different biological effects, however the complexities of lycopene isomerization are still poorly understood. In our study the increase in plasma lycopene and the distribution of various isomers was similar to previous reports (205, 214). We found the percentage of cis- lycopene isomers to be close to 80% of total lycopene at all time points for both groups which is consistent with other reports (58, 214).
Soy isoflavones and metabolites
Urinary excretion of the major soy isoflavones (genestein, diadzein and glycitein) were similar to previous soy intervention studies with comparable soy isoflavone consumption (Hadley, CW unpublished data). Equol is a metabolite of the isoflavone daidzen which is produced by colonic bacteria. The impact of equol on human health is poorly understood, however there are many hypotheses including a lower risk of breast cancer, prostate cancer and osteoporosis associated with this metabolite (215). Previous reports suggest that 30 to 50% of generally healthy people are equol producers, and that conversion of diadzein to equol may be influenced by age, ethnic background and habitual dietary practices (216, 217). Interestingly in our study, only 5 men (12%) produced equol which is significantly lower than published reports in population-based studies (215, 216). The potential relationship between equol and prostate cancer may warrant more investigation.
133 Biomarkers of prostate cancer
We found no changes in circulating testosterone or IGF-1 during this study in men who were either hormone naïve or hormone refractory. This is in contrast to a recent study of rats fed a lycopene-supplemented diet for 8 weeks, followed by gene chip analysis of prostate tissue gene expression (61). Gene chip analysis revealed a reduction in tissue IGF-1 production and a reduced activation of testosterone into the more active metabolites. Several previous studies evaluating the influence of soy protein and isoflavones have generally reported no significant alterations in circulating testosterone or IGF-1 levels (92, 218, 219). However, a recent mouse study did report that a combination of green tea and soy phytochemical concentrate significantly reduced serum levels of IGF-I (220). Our findings do not support a significant influence of soy on these biomarkers with an 8 week intervention.
Finally, we found that in a proportion of men in this study (58%), the rate of PSA increase (as measured by PSA slope and PSA doubling time) was slower than it had been at enrollment. When we stratified the men according to doubling time at enrollment, we found that men with the fastest doubling time (0 to 3.9 months) were significantly more likely to experience a slower doubling time than men who had a slower doubling time at the start of the study. This could indicate a time period during prostate cancer progression where diet interventions may have the most significant impact. While the clinical utility of temporarily modulating PSA values in this population of men would be considerable, it is premature to suggest any influence of these interventions on PSA due
134 to our small sample size and lack of control for other variables which may modulate PSA, such as calorie restriction.
Conclusion
In conclusion, this study demonstrates that men with active prostate cancer can successfully change their diet and consume tomato products and soy together with excellent adherence and minimal toxicity. Further studies combining tomato and soy foods to determine efficacy and health benefits should be undertaken. We propose combining tomato juice with an isoflavone-rich soy fraction to achieve a convenient phytochemical-rich product for larger clinical trials.
135 CHAPTER 6
CONCLUSION
An overwhelming amount of human, animal and cell-culture research indicates that diet can influence various points along the cancer continuum, including prevention, active treatment, cancer survivorship, and cancer recurrence. Prostate cancer is a unique cancer sub-type because it is very commonly diagnosed, it has a protracted time course, and because it has a biomarker (PSA) which may be used to monitor progression. These characteristics make prostate cancer an opportune disease model for nutrition research.
The studies which comprise this dissertation have contributed to understanding the nutrition-related issues at various time points during prostate carcinogenesis. Our first study suggests that men who participate in prostate cancer chemoprevention trials are likely to be consuming nutritional supplements. Several of these supplements, including vitamin E and selenium, may play a role in prostate carcinogenesis and therefore could influence study outcomes. Accurate documentation and a detailed assessment of nutritional supplement use is important for future chemoprevention studies.
136 Our second study suggests that nutritional supplements are also commonly used among men undergoing radiation therapy for prostate cancer. There is very little documentation of nutritional supplement and alternative medication use among men undergoing radiation treatment for prostate cancer. Our study contributes to this area of research and suggests that use of supplements, specifically antioxidants, may be much more common than previously reported. Because the influence of nutritional supplements on the efficacy of radiation therapy is not known, this study provides important data illustrating prevalence of use and provides a foundation for future observational or interventional studies.
Finally, men who have been diagnosed with metastatic prostate cancer can be asymptomatic for several months, and many of these men are motivated to make diet and lifestyle changes which may impact disease progression. Although there are several different foods and food components which have been studied, tomatoes, tomato products and soy foods have been reported to have some benefit in large, epidemiological studies.
Our study has demonstrated that men with asymptomatic, recurrent prostate cancer are able to consume a diet rich in tomato products and soy protein without significant toxicity. Additionally, this diet intervention appears to have had a beneficial impact on
PSA in a proportion of men. We have provided the preliminary data necessary for the development of tomato juice product with added soy that can be used in a larger, more definitive trial.
137
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200. Stahl, W., Nicolai, S., Briviba, K., Hanusch, M., Broszeit, G., Peters, M., Martin, H. D., and Sies, H. Biological activities of natural and synthetic carotenoids: induction of gap junctional communication and singlet oxygen quenching. Carcinogenesis, 18: 89-92, 1997.
201. Gann, P. H., Ma, J., Giovannucci, E., Willett, W., Sacks, F. M., Hennekens, C. H., and Stampfer, M. J. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res, 59: 1225-1230, 1999.
202. Freeman, V. L., Meydani, M., Yong, S., Pyle, J., Wan, Y., Arvizu-Durazo, R., and Liao, Y. Prostatic levelsof tocopherols, carotenoids and retinol in relation to plasma levels and self-reported usual dietary intake. Am J Epidemiol, 151: 109-118, 2000.
203. Rao, A. V., Fleshner, N., and Agarwal, S. Serum and tissue lycopene and biomarkers of oxidation in prostate cancer patients: a case-control study. Nutr Cancer, 33: 159-164, 1999.
204. D'Amico, A. V., Chen, M. H., Roehl, K. A., and Catalona, W. J. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med, 2004: 125-135, 2004.
205. Hadley, C. W., Clinton, S. K., and Schwartz, S. J. The consumption of processed tomato products enhances plasma lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage. J Nutr, 133: 727-732, 2003.
206. Nomura, A. M., Stemmermann, G. N., Lee, J., and Craft, N. E. Serum micronutrients and prostate cancer in Japanese Americans in Hawaii. Cancer Epidemiol Biomarkers Prev, 6: 487-491, 1997.
207. Ferruzzi, M. G., Nguyen, M. L., Sander, L. C., Rock, C. L., and Schwartz, S. J. Analysis of lycopene geometrical isomers in biological microsamples by liquid
156 chromatography with coulometric array detection. J Chromatogr B Biomed Sci Appl, 760: 289-299, 2001.
208. Kulling, S. E., Honig, D. M., and Metzler, M. Oxidative metabolism of the soy isoflavones daidzein and genistein in humans in vitro and in vivo. J Agric Food Chem, 49: 3024-3033, 2001.
209. Franke, A. A., Custer, L. J., Wilkens, L. R., Le Marchand, L. L., Nomura, A. M., Goodman, M. T., and Kolonel, L. N. Liquid chromatographic-photodiode array mass spectrometric analysis of dietary phytoestrogens from human urine and blood. J Chromatogr B Analyt Technol Biomed Life Sci, 777: 45-59, 2002.
210. Acharya, S., Maskarinec, G., Williams, A. E., Oshiro, C., Hebshi, S., and Murphy, S. P. Nutritional changes among premenopausal women undertaking a soya based dietary intervention study in Hawaii. J Hum Nutr Diet, 17: 413-419, 2004.
211. Kreijkamp-Kaspers, S., Kok, L., Grobbee, D. E., de Haan, E. H., Aleman, A., Lampe, J. W., and van der Schouw, Y. T. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA, 292: 65-74, 2004.
212. Albertazzi, P., Pansini, F., Bonaccorsi, G., Zanotti, L., Forini, E., and De Aloysio, D. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol, 91: 6-11, 1998.
213. Porrini, M., Riso, P., and Testolin, G. Absorption of lycopene from single or daily portions of raw and processed tomato. Br J Nutr, 80: 353-361, 1998.
214. Allen, C. M., Schwartz, S. J., Craft, N. E., Giovannucci, E. L., De Groff, V. L., and Clinton, S. K. Changes in plasma and oral mucosal lycopene isomer concentrations in healthy adults consuming standard servings of processed tomato products. Nutr Cancer, 47: 48-56, 2003.
215. Atkinson, C., Frankenfeld, C. L., and Lampe, J. W. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med, 230: 155-170, 2005.
216. Frankenfeld, C. L., Atkinson, C., Thomas, W. K., Goode, E. L., Gonzalez, A., Jokela, T., Wahala, K., Schwartz, S. M., Li, S. S., and Lampe, J. W. Familial correlations, segregation analysis, and nongenetic correlates of soy isoflavone-metabolizing phenotypes. Exp Biol Med, 229: 902-913, 2004.
217. Valentin-Blasini, L., Sadowski, M. A., Walden, D., Caltabiano, L., Needham, L. L., and Barr, D. B. Urinary phytoestrogen concentrations in the U.S. population (1999- 2000). J Expo Anal Environ Epidemiol, 2005.
157
218. Adams, K. F., Newton, K. M., Chen, C., Emerson, S. S., Potter, J. D., White, E., and Lampe, J. W. Soy isoflavones do not modulate circulating insulin-like growth factor concentrations in an older population in an intervention trial. J Nutr, 133: 1316-9, 2003.
219. Goldin, B. R., Brauner, E., Adlercreutz, H., Ausman, L. M., and Lichtenstein, A. H. Hormonal response to diets high in soy or animal protein without and with isoflavones in moderately hypercholesterolemic subjects. Nutr Cancer, 51: 1-6, 2005.
220. Zhou, J. R., Yu, L., Mai, Z., and Blackburn, G. L. Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice. Int J Cancer, 108: 8-14, 2004.
158
APPENDIX A
INSTITUTIONAL REVIEW BOARD BIOMEDICAL SUMMARY SHEETS AND CONSENT FORM AND STUDY QUESTIONNAIRE
159 BIOMEDICAL SCIENCES SUMMARY SHEETS
ADDRESS EACH ITEM IN A COMPLETE AND CONCISE MANNER. (Do not leave any item blank with "See attached.) Use continuation pages when necessary.
1. Abstract (overview of research)
Background: The use of dietary supplements, including vitamins, minerals, herbs, botanicals and other miscellaneous products, has become significantly more prevalent over the past decade. Dietary supplements are used for a variety of reasons such as; disease treatment or prevention, to increase energy, and most commonly, to promote overall health (Mayo Clinic Proceedings 1999). We believe that people who enroll in clinical trials for prevention of cancer are perhaps a unique subpopultion with a greater frequency health conscious behaviors and therefore may be more likely than others to consume dietary supplements. This information is important because the safety and efficacy and potential long-term benefits or adverse effects of dietary supplements is largely unknown and could affect the outcome of cancer prevention research. Furthermore, little effort has focused upon men with prostate cancer and the use of supplements to promote the efficacy of therapy and survivorship.
Objective: Our objective is to describe dietary supplement use in men who are currently enrolled in a cancer prevention trial (the Prostate Cancer Prevention Trial or PCPT) and those with prostate cancer that are followed in the Medical Oncology, Urology, and Radiation Therapy clinics at OSU.
Design: This study will consist of a medical chart review and a brief interview of a total of 395 men. There are 95 men currently enrolled in the PCPT plus we will enroll an additional 100 men from each of three clinics (radiation oncology, medical oncology and urologic oncology). We will ask all men to bring their supplements to clinic where we will photocopy the labels for our data base. Descriptive statistics will be completed to provide information on the frequency of consumption of different types of products and the intake of specific nutrients that may be related to prostate cancer risk or survivorship.
2. Describe the requirements for a subject population and explain the rationale for using in this population special groups such as prisoners, children, the mentally disabled or groups whose ability to give voluntary informed consent may be in question. Address means of pregnancy screening for females.
None of the special groups mentioned above will be enrolled in this study. Women will not be enrolled in this study because they are not at risk for prostate cancer. The requirements include the following; study participants must be:
• Currently enrolled in the Prostate Cancer Prevention Trial or • A cancer patient who is being seen for any reason in the Medical Oncology, Radiation Oncology, or Urology clinics at The James Cancer Hospital.
3. Describe and assess any potential risks - physical, psychological, social, legal, financial, or other - and assess the likelihood and seriousness of such risks. If methods of research create potential risks, describe other methods, if any, that were considered and why they will not be used.
Physicians should document the use of nutritional supplements as part of a standard medical work-up. Unfortunately, this is often not done. The study coordinator will call the patient before his scheduled clinic visit, and ask him to bring in all nutritional supplements to his next clinic appointment. Patients who do not wish to disclose their use of nutritional supplements will not be included in the study. However, in Dr. Clinton’s experience where documentation of supplement and alternative medications is routine, he has never encountered a patient who was unwilling to discuss the use of these products. This study consists only of a medical chart review and/or a brief patient interview, therefore, there is no risk to the patient for this study. Indeed, if products are consumed that have known risks at the doses taken, Dr. Clinton will discuss the risks and safety issues with the patient.
4. Describe consent procedures to be followed, including how and where informed consent will be obtained. (The use of a finder's fee for recruiting subjects is not permitted.)
All patients will undergo an informed consent process. The study coordinator will meet with each patient at his regularly scheduled clinic visit and will describe the purpose of the survey. Patients will be informed that there is no risk to them and no additional visits to the clinic are required. Patients who do not wish to participate in the study will still be encouraged to report their dietary supplement use to their physician because many supplements can interact with medications or other therapeutic treatments and should be part of the medical record of all patients. HS-029B (Rev. 7/93)
160 BIOMEDICAL SCIENCES SUMMARY SHEETS
ADDRESS EACH ITEM IN A COMPLETE AND CONCISE MANNER. (Do not leave any item blank with "See attached.) Use continuation pages when necessary.
5. Describe procedures (including confidentiality safeguards) for protecting against or minimizing potential risks and an assessment of their likely effectiveness.
Ideally, the procedures for this trial will consist only of a medical chart review. However, since there is almost uniformly not an accurate documentation of nutritional supplement use, patients will be asked to bring in the bottles of any nutritional supplements they regularly take. We will not advise or recommend any changes to the patients regimen of nutritional supplementation unless there is a clear interaction with prescription medication the patient is taking, or if they are taking a dose of a nutrient / herb which may be toxic.
This study poses no obvious risk to the patient.
Patient names will not be used in any publication resulting from this study.
All records will be kept in a locked file cabinet in Starling Loving Hall and only persons directly involved in the study (Steven K. Clinton and Elizabeth Miller) will have access to the study files.
6. Assess the potential benefits to be gained by the individual subject, as well as benefits which may accrue to society in general as a result of the planned work.
The individual subject may not benefit from this study unless the investigator identifies supplement use that is of risk to the patient. In those cases, Dr. Clinton will discuss the issue with the patient. For example, if patient has a history of DVT and is taking Coumadin as an anticoagulant along with a megadose of vitamin E, Dr. Clinton may discuss with the patient data suggesting that vitamin E supplements may be associated with a greater risk of hemorrhagic stroke.
There is no obvious risk of this study because it is simply a review of the medical records or a collection of information that should be included in each patient’s medical record.
The benefits to society may be large. This study will describe nutritional supplement use in men who are enrolled in a cancer prevention trial and men who are undergoing prostate cancer therapy. This information will be useful for the interpretation of the PCPT effort and may stimulate the leadership of this trial to undertake a more detailed documentation of supplement use for their final analysis. This information will also help us effectively plan recruiting strategies for an upcoming cooperative group (SWOG) study called Selenium and Vitamin E Cancer Prevention Trial (SELECT). Men who enroll in SELECT will be asked to discontinue the use of specific nutritional supplements such as vitamin E and selenium that may interfere with study outcomes. In addition, the description of supplement use by men undergoing prostate cancer therapy will provide many new hypotheses regarding future research on nutritional support of cancer therapy and prostate cancer survivorship.
7. Compare the risks versus the benefits.
The risk to the patient is minimal while the potential benefits to our society are large.
8. Will the subjects for the study be paid for participating in this study? Yes No X If yes, how much?
Will subjects be paid for selected activities (e.g., blood drawing) or for general participation in the study? * NOTE: All information concerning payments, including the amount and schedule of payment, must be included in the consent form.
Is there any other inducement? Yes No X If so, please describe.
9. Will advertising be used to recruit subjects? Yes No X If yes, attach a copy of the proposed advertisement.
161 THE OHIO STATE UNIVERSITY Protocol No. ______
CONSENT TO INVESTIGATIONAL TREATMENT OR PROCEDURE
I, ______, hereby authorize or direct Steven K. Clinton, MD, Ph.D., associates or assistants of his choosing, to perform the following treatment or procedure (describe in general terms),
To review my medical chart and record all of the nutritional supplements (vitamins, minerals, herbs, botanicals, etc.) I take regularly.
To ask me questions about my use of nutritional supplements.
To allow the investigators to photocopy ingredient content of supplements consumed.
Examples of questions that I may be asked include questions about the dose, formulation, brand name, and the number of years I have taken a specific nutritional supplement. These questions should take no more than ten (10) minutes to answer.
upon ______. (myself or name of subject)
The experimental (research) portion of the treatment or procedure is:
Approximately 395 men will be enrolled in this study.
If I decide to participate in this study, I will permit the study coordinators to review my medical chart, record my use of nutritional supplements, and photocopy the labels on all nutrient supplement bottles.
Participation is voluntary. Refusal to participate will involve no penalty or loss of benefits to which I am otherwise entitled.
I will not be paid for my participation in this study, nor will this study result in any extra cost to me.
The study is entitled:
Nutritional Supplement Use by Men Enrolled in the Prostate Cancer Prevention Trial (PCPT) in Comparison with Men Undergoing Treatment for Prostate Cancer
1. Purpose of the procedure or treatment:
To evaluate the use of nutritional supplements among men participating in a prostate cancer prevention trial or are undergoing prostate therapy.
2. Possible appropriate alternative procedure or treatment (not to participate in the study is always an option):
Because this study involves reviewing my medical chart and recording the nutritional supplements I regularly take, there is no alternative treatment.
I may choose not to participate without affecting my current or future medical care.
3. Discomforts and risks reasonably to be expected:
There are no risks associated with participation in this study.
4. Possible benefits for subjects/society:
I may not benefit in any way from this study, nor is there any risk to me. If the medical team identifies that any of the supplements are of risk to my health they will discuss this with me. The possible benefits to society include a better understanding of nutritional supplement use in men my age with similar health concerns.
162 5. Anticipated duration of subject's participation (including number of visits):
This study consists of a review of my medical chart or a brief interview during my regularly scheduled appointment.
No additional visits to the clinic are required for this study.
I hereby acknowledge that ______have provided information about the procedure described above, about my rights as a subject, and he/she answered all questions to my satisfaction. I understand that I may contact him/her at Phone No. 614.293.8396 should I have additional questions. He/She has explained the risks described above and I understand them; he/she has also offered to explain all possible risks or complications.
I understand that, where appropriate, the U.S. Food and Drug Administration may inspect records pertaining to this study. I understand further that records obtained during my participation in this study that may contain my name or other personal identifiers may be made available to the sponsor of this study. Beyond this, I understand that my participation will remain confidential.
I understand that I am free to withdraw my consent and participation in this project at any time after notifying the project director without prejudicing future care. No guarantee has been given to me concerning this treatment or procedure.
I understand in signing this form that, beyond giving consent, I am not waiving any legal rights that I might otherwise have, and I am not releasing the investigator, the sponsor, the institution, or its agents from any legal liability for damages that they might otherwise have.
In the event of injury resulting from participation in this study, I also understand that immediate medical treatment is available at University Hospitals of The Ohio State University and that the costs of such treatment will be at my expense; financial compensation beyond that required by law is not available. Questions about this should be directed to the Office of Research Risks at 292-5958.
I have read and fully understand the consent form. I sign it freely and voluntarily. A copy has been given to me.
AM Date: Time PM Signed (Subject)
Witness (es) if required (Person Authorized to Consent for Subject if Required)
I certify that I have personally completed all blanks in this form and explained them to the subject or his/her representative before requesting the subject or his/her representative to sign it.
163
NAME: DATE:
Prostate Cancer Prevention Trial 1. Do you currently take multiple vitamins? Yes □ No □ (Photocopy bottle label)
1a. What is the brand name? ______1b. How many do you take per week? 2 or less □ 3 to 5 □ 6 to 9 □ 10 or more □
2. EXCLUDING MULTIVITAMINS please indicate if you take any of the following individual nutrient supplements.
2a. Vitamin A (retinol, retinal, retinaldehyde, retinoic acid) No □ Yes, seasonal only □ Yes, most months □ If yes what dose per day? ______IU If yes, how many years? 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
2b. β-Carotene No □ Yes □ If yes, what dose per day? ______mg If yes, how many years?
164 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
2c. Vitamin C (ascorbic acid, ascorbate) No □ Yes, seasonal only □ Yes, most months □ If yes, what dose per day? ______mg or ______g If yes, how many years? 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
2d. Vitamin B6 (pyridoxal, pyridoxine, pyridoxamine) No □ Yes □ If yes, what dose per day? ______mg If yes, how many years? 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
165 2e. Vitamin E (tocopherol or tocotrienol) No □ Yes □ If yes, what dose per day? ______mg □ or IU □ What type of vitamin E (alpha or gamma tocopherol)______If yes, how many years? 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
2f. Folic Acid (folate) No □ Yes □ If yes, what dose per day? ______micrograms If yes, how many years? 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
2g. Selenium (Se, selenite, selenite, selenide, selenomethionine, or selenocysteine) No □ Yes □ If yes, what dose per day? ______micrograms If yes, how many years? 0 to 1 year □ 2 to 4 years □ 166 5 to 9 years □ 10 + years □ Don’t know □
2h. Iron (Fe, ferrous sulfate) No □ Yes □ If yes, what dose per day? ______mg If yes, how many years? 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
2i. Zinc (Zn) No □ Yes, seasonal only □ Yes, most months □ If yes, what dose per day? ______mg If yes, how many years? 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
167 2j. Calcium (Ca, forms include: calcium carbonate, citrate, dolomite, gluconate, malate, phosphate) No □ Yes □ If yes, what dose per day?______mg If yes, how many years? 0 to 1 year □ 2 to 4 years □ 5 to 9 years □ 10 + years □ Don’t know □
2k. Other individual vitamin-mineral supplements: □______daily dose:______□______daily dose:______□______daily dose:______□______daily dose:______□______daily dose:______
3. Do you take any of the following non-vitamin / mineral supplements?
□ Alfalfa daily dose:______□ Aloe vera daily dose:______□ Amino Acids daily dose:______□ Bee pollen daily dose:______□ Brewer’s yeast daily dose:______□ Cod Liver or other fish oils daily dose:______□ Co-enzyme Q-10 daily dose:______□ Creatine Monohydrate daily dose:______□ DHEA (dehydroepiandosterone) daily dose:______
168 □ Echinacea daily dose:______□ Evening Primrose Oil daily dose:______□ Flakseed oil daily dose:______□ Flakseeds daily dose:______□ Garlic (pill form only) daily dose:______□ Gingko Biloba daily dose:______□ Ginseng daily dose:______□ Glucosamine Chondroitin daily dose:______□ Glutamine daily dose:______□ Goldenseal daily dose:______□ Kava Kava daily dose:______□ Kelp daily dose:______□ Lecithin daily dose:______□ Leutein daily dose:______□ Lycopene daily dose:______□ Milk Thistle daily dose:______□ PC Spes daily dose:______□ Rose Hips daily dose:______□ Royal Jelly daily dose:______□ Saw Palmetto daily dose:______□ Shark Cartilage daily dose:______□ St. Johns Wort daily dose:______□ Tomato extract daily dose:______□ Valerian daily dose:______
169
Other non-vitamin, non-mineral supplements: □ ______daily dose:______□ ______daily dose:______□ ______daily dose:______□ ______daily dose:______□ ______daily dose:______□ ______daily dose:______
4. Please list any over-the-counter medications you take regularly (include aspirin, Tylenol, Advil, Bayer etc.) ______How many times per week? ______How many times per week? ______How many times per week? ______How many times per week? ______How many times per week? ______
5. Do you regularly drink a nutritional supplement beverage such as Carnation Instant Breakfast Drink, Ensure, Ensure Plus, Boost, or Resource? No □ Yes □
If yes, please list the name brand and the number of cans per day. ______cans per day: ____
6. Do you eat soy foods? No □ Yes □ How many times per week? ______
7. If you had a question about nutrition, who would you ask or where would you look to find the answer? (list primary and secondary sources) ______
8. What type of diet do you follow? ______
170
APPENDIX B
PERSONAL AND DEMOGRAPHIC INFORMATION FORM AND INSTITUTIONAL REVIEW BOARD BIOMEDICAL SUMMARY SHEETS AND CONSENT FORM
171 Radiation Therapy Questionnaire
This brief questionnaire should take no more than 10 minutes to complete. You can choose to fill it in now and return it to the study coordinator immediately OR return the questionnaire the next day before your scheduled radiation therapy (radiotherapy patients) or before your next clinical appointment (brachytherapy patients).
Where is your cancer? Prostate Breast
What is the date of your cancer diagnosis? ______(month/ year)
What is your age? ≤ 30 yr 31- 40 yr 41- 50 yr 51- 60 yr 61- 70 yr ≥70 yr
What is your race/ ethnicity? Caucasian African American Hispanic Others
What is your height? _____Ft_____ in
What is your weight? ______lb
What is your highest level of education? < High School High School College Graduate School
What is your current status of employment? Paid Retired Unemployed Other
172
What is your level of income? < $20,000 $20,000 - $39,999 $40,000 - $59,999
$60,000 - $99,999 ≥ $100,000
What is your marital status? Single Married Widowed Divorced or Separated
Do you smoke? Yes
No
Do you drink any alcohol? Yes
No
173 BIOMEDICAL SCIENCES SUMMARY SHEETS
ADDRESS EACH ITEM IN A COMPLETE AND CONCISE MANNER. (Do not leave any item blank with "See attached.) Use continuation pages when necessary.
1. Abstract (overview of research)
Background: The use of complementary and alternative medicine (CAM) has become significantly more prevalent over the past decade, and it may be more common among cancer patients. CAM are used for a variety of reasons such as; minimizing the effect of conventional treatment, enhancing quality of life or the desire to take control of health (Kao, 2000). The effects of CAM use during cancer treatment are largely unstudied, and it is possible that certain types of CAM, such as nutritional supplements and alternative medications, may impact the efficacy of radiation treatment. There are very few studies investigating the prevalence of CAM use among persons undergoing radiation treatment. This information is critical for future trials to investigate the effects of CAM therapies on cancer treatment, clinical outcomes, and quality of life.
Objective: Our objective is to quantify the use of CAM therapies in men with prostate cancer and women with breast cancer who are currently undergoing radiation therapy at The James Cancer Hospital and Solove Research Institute. We will collect information on the use of many different CAM therapies with an emphasis on nutritional supplement and alternative medication use. We will also determine if patients change their patterns of supplement and alternative medication use during or after radiation treatment and we will use a reliable and valid questionnaire to measure quality of life. Finally, we will evaluate any relationships between the use of CAM and radiation toxicity 0as evaluated by the Oncology Nursing Society criteria currently used in the Department of Radiation Oncology.
Design: This study will consist of a brief interview and a take-home questionnaire at three different time points for a total of 50 men with prostate cancer and 50 women with breast cancer who are scheduled to begin radiation therapy at The James Cancer Hospital and Solove Research Institute. We will ask all eligible patients to answer a few questions and to bring their supplement bottles to the clinic where we will photocopy the labels for our records. Descriptive statistics will be completed to provide information on the frequency of different types of CAM therapies and associations between specific CAM therapies and demographic characteristics and quality of life. Radiation therapy toxicity using standardized criteria will also be assessed to determine if there is a correlation between CAM use and quality of life.
2. Describe the requirements for a subject population and explain the rationale for using in this population special groups such as prisoners, children, the mentally disabled or groups whose ability to give voluntary informed consent may be in question. Address means of pregnancy screening for females.
None of the special groups above will be enrolled in this study. Pregnant women will not be enrolled in this study. The requirements include the following; study participants must:
• Currently be scheduled to undergo external beam radiation therapy or brachytherapy at The James Cancer Hospital and Solove Research Institute for primary treatment for newly diagnosed prostate or breast cancer. • Not have known metastatic disease.
3. Describe and assess any potential risks - physical, psychological, social, legal, financial, or other - and assess the likelihood and seriousness of such risks. If methods of research create potential risks, describe other methods, if any, that were considered and why they will not be used.
There are no significant risks involved with participating in this study. Eligible patients who do not wish to disclose their use of nutritional supplements will not be included in the study.
4. Describe consent procedures to be followed, including how and where informed consent will be obtained. (The use of a finder's fee for recruiting subjects is not permitted.)
All patients will undergo an informed consent process. The study coordinator will call eligible patients prior to the initiation of radiation therapy and brachytherapy and will describe the purpose of the survey. Patients will be informed that there is no risk to them and no additional visits to the clinic are required for the purposes of this study. Patients who do not wish to participate will not be included in the study. Radiotherapy patients will be asked to sign the informed consent form during their simulation visit, before the initiation of radiation therapy, while patients scheduled for brachytherapy will sign the informed consent form prior to their therapy. HS-029B (Rev. 7/93)
174 BIOMEDICAL SCIENCES SUMMARY SHEETS
ADDRESS EACH ITEM IN A COMPLETE AND CONCISE MANNER. (Do not leave any item blank with "See attached.) Use continuation pages when necessary.
5. Describe procedures (including confidentiality safeguards) for protecting against or minimizing potential risks and an assessment of their likely effectiveness.
We will review each patient’s medical chart to obtain demographic information. Additional demographic characteristics will be obtained from the administered questionnaires. This information in addition to the study documents will be kept in a locked filing cabinet in Starling Loving Hall and only persons directly involved in the study (Steven K. Clinton, Elizabeth Miller and Eileen Ang) will have access to the study files.
The study poses no obvious risk to the patient.
Patient names will not be used in any publication resulting from this study.
6. Assess the potential benefits to be gained by the individual subject, as well as benefits which may accrue to society in general as a result of the planned work.
The individual subject may not benefit from this study. There is no obvious risk of this study because it is simply a collection of information at three different time points, consisting of a brief interview and a take-home questionnaire.
The benefits to the society may be large. This study will describe nutritional supplement and alternative medicine use in men with prostate cancer and women with breast cancer who are undergoing radiation therapy and to determine the association between supplement usage patterns with demographic characteristics and reported quality of life. This information will be useful for future trials to investigate the effects of CAM therapies on cancer treatment, clinical outcomes and quality of life.
7. Compare the risks versus the benefits.
The risk to the patient is minimal while the potential benefits to our society are large.
8. Will the subjects for the study be paid for participating in this study? Yes No X If yes, how much?
Will subjects be paid for selected activities (e.g., blood drawing) or for general participation in the study? * NOTE: All information concerning payments, including the amount and schedule of payment, must be included in the consent form.
Is there any other inducement? Yes No X If so, please describe.
9. Will advertising be used to recruit subjects? Yes No X If yes, attach a copy of the proposed advertisement.
175 THE OHIO STATE UNIVERSITY Protocol No. ______
CONSENT TO INVESTIGATIONAL TREATMENT OR PROCEDURE
I, ______, hereby authorize or direct Steven K. Clinton, MD, Ph.D., associates or assistants of his/her choosing, to perform the following treatment or procedure (describe in general terms),
To ask me questions about my use of nutritional supplements (vitamins, minerals, herbs, botanicals, etc.) and for me to fill in a questionnaire on quality of life and alternative therapies I use.
To allow the investigators to photocopy ingredient content of supplement consumed.
Examples of questions that I may be asked include questions about the dose, formulation, brand name, and the number of years I have taken a specific nutritional supplement, the types and frequency of alternative therapies I use and general quality of life questions. These questions should take no more than ten (10) minutes to answer.
upon ______. (myself or name of subject)
The experimental (research) portion of the treatment or procedure is:
Approximately 50 men and 50 women will be enrolled in this study.
If I decide to participate in this study, I will answer a brief questionnaire about my use of Complementary and Alternative Medicine practices and a quality of life questionnaire. In addition I will bring in the bottles of all of the nutritional supplements and alternative medications I currently use to be photocopied by the study coordinator.
This process will be repeated three times over the course of approximately two to three months: For radiation therapy patients: at the beginning of radiation treatment, at the end of radiation treatment, and at my first follow up appointment. For brachytherapy patients: before brachytherapy, 5 weeks after brachytherapy and 11 weeks after brachytherapy during their clinical visits with Dr. Clinton.
Participation is voluntary. Refusal to participate will involve no penalty or loss of benefits to which I am otherwise entitled.
I will not be paid for my participation in this study, nor will this study result in any extra cost to me.
This is done as part of an investigation entitled:
Use of nutritional supplements and CAM (complementary and alternative medicine) by prostate and breast cancer patients undergoing radiotherapy
1. Purpose of the procedure or treatment:
To evaluate the use of complementary and alternative medicine practices among men with prostate cancer and women with breast cancer who are currently undergoing radiation therapy at The James Cancer Hospital and Solove Research Institute.
To determine if the use of complementary and alternative medicine is related to quality of life in breast cancer and prostate cancer patients undergoing radiation therapy.
2. Possible appropriate alternative procedure or treatment (not to participate in the study is always an option):
I may choose not to participate without affecting my current or future medical care.
3. Discomforts and risks reasonably to be expected:
There are no risks associated with participation in this study.
176 4. Possible benefits for subjects/society:
I may not benefit in any way from this study, nor is there any risk to me.
The possible benefits to society include a better understanding of complementary and alternative medicine use in men with prostate cancer or women with breast cancer who are undergoing radiation therapy.
5. Anticipated duration of subject's participation (including number of visits):
This study consists of a brief interview during my regularly scheduled appointment and a take home questionnaire.
No additional visits to the clinic are required for this study.
I hereby acknowledge that ______has provided information about the procedure described above, about my rights as a subject, and he/she answered all questions to my satisfaction. I understand that I may contact him/her at Phone No. 614.293.8396 should I have additional questions. He/She has explained the risks described above and I understand them; he/she has also offered to explain all possible risks or complications.
I understand that, where appropriate, the U.S. Food and Drug Administration may inspect records pertaining to this study. I understand further that records obtained during my participation in this study that may contain my name or other personal identifiers may be made available to the sponsor of this study. Beyond this, I understand that my participation will remain confidential.
I understand that I am free to withdraw my consent and participation in this project at any time after notifying the project director without prejudicing future care. No guarantee has been given to me concerning this treatment or procedure.
I understand in signing this form that, beyond giving consent, I am not waiving any legal rights that I might otherwise have, and I am not releasing the investigator, the sponsor, the institution, or its agents from any legal liability for damages that they might otherwise have.
In the event of injury resulting from participation in this study, I also understand that immediate medical treatment is available at University Hospitals of The Ohio State University and that the costs of such treatment will be at my expense; financial compensation beyond that required by law is not available. Questions about this should be directed to the Office of Research Risks at 292-5958.
I have read and fully understand the consent form. I sign it freely and voluntarily. A copy has been given to me.
AM Date: Time PM Signed (Subject)
Witness (es) if required (Person Authorized to Consent for Subject if Required)
177
APPENDIX C
INSTITUTIONAL REVIEW BOARD BIOMEDICAL SUMMARY SHEETS AND CONSENT FORM AND NCI TOXICITY CRITERIA
178 BIOMEDICAL SCIENCES SUMMARY SHEETS
ADDRESS EACH ITEM IN A COMPLETE AND CONCISE MANNER. (Do not leave any item blank with "See attached.) Use continuation pages when necessary.
1. Abstract (overview of research)
Background: Epidemiologic studies strongly suggest that nutrition plays a critical role in the etiology and progression of prostate cancer. Geographic studies show that men living in different parts of the world have dramatic differences in risk. Furthermore, migrant studies indicate that environment (including diet and nutrition) rather than genetics is most important. For example, Asian men have among the lowest death rates from prostate cancer, and it has been hypothesized that high consumption of soy-based products may be one of the factors reducing prostate cancer progression in this population. Soy products are rich sources of isoflavones as well as other phytochemicals that are proposed to influence prostate cancer risk. Many other dietary factors have also been proposed to enhance prostate cancer risk in American men. In a large prospective trial, Giovannucci and co-workers have shown that men who consumed >10 servings of tomato products per week had a 35% reduction in prostate cancer compared with men who consumed <1.5 servings per week. It is proposed that lycopene, a potent antioxidant primarily derived from tomato products, is one of the critical components of tomatoes that lowers risk. Preclinical laboratory studies in cell culture and animal models support the hypothesis that soy isoflavones and lycopene may independently influence prostate carcinogenesis. We have observed that soy isoflavones, such as genistein, inhibit prostate tumor cell proliferation, cause a G2M cell cycle arrest, enhance apoptosis, and reduce the growth of transplantable prostate tumors in mice. Dietary tomato polyphenols and lycopene enhanced the survival of rats in a prostate carcinogenesis model.
Objectives: This study is designed to determine if men with prostate cancer will consume a soy-based dietary supplement (40 g protein / day to provide approximately 80 mg isoflavones / day for 4 weeks), tomato products (to provide 25 mg lycopene / day for 4 weeks), or both (for 4 weeks) following a low-intensity and cost effective dietary instruction program. Compliance to either a lycopene-rich tomato product diet, soy protein supplemented diet, and a combination of both diets (soy + tomato products) will be measured by classical methods (food diaries and interviews) and by biochemical markers of lycopene or soy intake (e.g., blood lycopene concentrations and urinary excretion of soy isoflavones). In addition, secondary goals of this study are to determine the effects of dietary interventions on (a) overall carotenoid profile, (b) antioxidant status, (c) blood testosterone and insulin-like growth factor I (IGF-I) concentrations and (d) serum prostate specific antigen (PSA).
Design: The study will require 40 men that will have one week of “washout” without consumption of tomato products or soy products prior to randomization to one of two dietary interventions with 20 men per group, (a) tomato products providing 25 mg lycopene per day, or (b) soy protein at 40 g per day. These will be consumed for 4 weeks. At that time all men will receive both products for an additional 4 weeks. Blood and urine samples will be obtained at randomization, after 4 weeks of intervention on single agents, and after 4 weeks on combined product intervention.
2. Describe the requirements for a subject population and explain the rationale for using in this population special groups such as prisoners, children, the mentally disabled or groups whose ability to give voluntary informed consent may be in question. Address means of pregnancy screening for females.
None of the special groups mentioned above will be recruited to this trial.
This is a prostate cancer study and all subjects will be men.
To be eligible for this study, participants must: • Have histologically confirmed prostate cancer diagnosis. • Have completed primary therapy (radical prostatectomy, external beam radiation, brachytherapy) or chosen “watchful-waiting” and are currently demonstrating biochemical failure (rising PSA). • Have not received ongoing hormonal therapy of “alternative” medications such as PC-SPES that can influence hormone profiles. • Be asymptomatic and based on clinical judgement will remain so for at least 3 mo.
179 • Have demonstrated a rise in PSA on two serial samples after a nadir following primary therapy. If the patient has chosen “watchful waiting” two consecutive increases in PSA will allow enrollment. There is no minimal concentration of PSA required or maximum PSA allowed. • Not be receiving ongoing chemotherapy, radiotherapy, or biological therapy for an internal malignancy including prostate cancer. Patients must not undergo changes in hormonal therapy during the study. • Have kidney and liver enzymes within normal limits. • Have no history of malabsorptive disorders or other metabolic disorders requiring special diet recommendations. Men with type I or type II diabetes mellitus will be permitted to participate.
Note: there are no age restrictions for this trial
3. Describe and assess any potential risks - physical, psychological, social, legal, financial, or other - and assess the likelihood and seriousness of such risks. If methods of research create potential risks, describe other methods, if any, that were considered and why they will not be used.
The risks associated with this protocol are minimal.
The soy product (or very similar products) employed in this study has been employed in dozens of studies of cholesterol lowering and cancer prevention in the past. In the last several years, soy protein supplementation has been studied in both men and women as a potential dietary intervention for hypercholesterolemia. Based on the landmark meta-analysis by Anderson and co-workers [Anderson, 1995] and other more recent studies [Teixeira, 2000], the United States Food and Drug Administration has approved a health claim stating that consumption of 25 grams soy protein / day may lower blood cholesterol and reduce risk for heart disease. Teixeira and colleagues showed that 40 of soy protein per day is optimal to saturate blood isoflavone concentrations and achieve levels similar to those reported in Asian populations. On the basis of the approved health claim and the consumption of soy products at this level by Asian populations, it can be assumed that risks associated with this intervention are minimal.
The increase in tomato product consumption to provide 25 mg of lycopene per day has been completed in our laboratory with healthy volunteers consuming single products daily (tomato sauce, tomato juice, and tomato soup) for 4-8 wks without evidence of toxicity (manuscripts and abstracts submitted). Toxicity associated with consumption of dietary tomato products at this rate has not been reported in the epidemiologic, nutrition, or toxicologic literature.
The protocol has been designed so that it will easily integrate into the standard clinical practice of the participating physician and should not alter treatment plans for the prostate cancer. Blood draws and urine collections are the only procedures that may be done with more frequency that the standard course of care. The major risk of the additional sampling of peripheral blood may be mild bruising.
4. Describe consent procedures to be followed, including how and where informed consent will be obtained. (The use of a finder's fee for recruiting subjects is not permitted.)
Patients will undergo an informed consent process. Patients will be recruited from the urology, radiation therapy, and medical oncology clinics at the James Cancer Hospital and Solove Research Institute. Dr. Clinton and the study coordinator (Beth Miller, R.D.) will meet with the patient, review the medical chart to determine eligibility, give verbal and written information about the study, and answer any questions. A copy of the consent form will be given to the patient. The patient may sign the consent form at the initial evaluation, or he may take a copy home for further consideration and sign it at a later clinic visit if he decides to enroll in the study.
180 BIOMEDICAL SCIENCES SUMMARY SHEETS
ADDRESS EACH ITEM IN A COMPLETE AND CONCISE MANNER. (Do not leave any item blank with "See attached.) Use continuation pages when necessary.
5. Describe procedures (including confidentiality safeguards) for protecting against or minimizing potential risks and an assessment of their likely effectiveness.
No invasive procedures are involved in this study beyond peripheral blood draws and urine collection.
The risk of toxicity from dietary tomato products at any level of consumption has not been documented. Additionally, toxicity from the soy product provided in this study has not been reported.
Participants will have routine blood analysis (complete metabolic panel and CBC) and clinical evaluations that should identify patients developing any signs or symptoms of toxicity. Any patient showing new abnormalities will be withdrawn from the study. Patients may also choose to withdraw from the study at any time for any reason, such as an inability to consume the dietary soy product or high levels of tomato products.
If a patient shows signs of disease progression that warrants any intervention with hormonal agents, chemotherapy, radiation, or other treatments, the patient will be removed from the study.
All medical records will be maintained in confidence according to the rules and regulations of the James Cancer Hospital and The Ohio State University.
6. Assess the potential benefits to be gained by the individual subject, as well as benefits which may accrue to society in general as a result of the planned work.
It is critical that we determine if dietary interventions can serve as an adjunct to current therapy of prostate cancer. This study will allow us to assess if a low-intensity and cost effective dietary instruction program will lead to significant compliance with dietary regimens incorporating soy products and tomato products. Since both of these interventions reduce prostate carcinogenesis in laboratory studies it is possible that disease progression may be slowed in these patients.
The potential benefits to the individual subject include a $200 gift certificate for Kroger grocery stores as an incentive to complete the trial. The gift certificate will be provided within two weeks of each participant’s completion of the study.
The potential benefits to society are large. If this study is successful in showing high compliance rates we will be able to move forward with definitive studies to determine if dietary interventions enhance the efficacy of prostate cancer therapy. The study also has potential public health implications since current therapies for men with recurring prostate cancer are not curative and new strategies to enhance the efficacy of treatment is necessary.
7. Compare the risks versus the benefits.
The risks of participation in the trial are low since no significant toxicity of the dietary interventions have been reported.
The potential benefits to the individual and to our society are large.
8. Will the subjects for the study be paid for participating in this study? Yes X No If yes, how much?
Subjects will be given donated tomato products from manufactures to help with consumption of 25 mg/lycopene per day.
Subjects will be given the soy protein supplement without charge.
Subjects who complete all nine weeks will be given a $200 gift certificate for Kroger grocery stores as an incentive to
181 complete the trial. The gift certificate will be provided within two weeks of each participant’s completion of the study.
Will subjects be paid for selected activities (e.g., blood drawing) or for general participation in the study? No
*NOTE: All information concerning payments, including the amount and schedule of payment, must be included in the consent form.
Is there any other inducement? Yes No X If so, please describe.
9. Will advertising be used to recruit subjects? Yes No X If yes, attach a copy of the proposed advertisement.
182 THE OHIO STATE UNIVERSITY Protocol No. 01H0007 Approved: 01/08/01 version D CONSENT TO INVESTIGATIONAL TREATMENT OR PROCEDURE
I, ______, hereby authorize or direct Steven K. Clinton M.D., Ph.D. (phone 293-8396) associates or assistants of his/her choosing, to perform the following treatment or procedure (describe in general terms),
To evaluate my eligibility for an investigational study entitled Comparison of Dietary Tomato Products or Soy Protein to Enhance Blood Antioxidant Status and Modify Hormonal Profiles in Men with Recurrent Prostate Cancer. My eligibility will be determined by a personal interview, a review of my medical record, and my willingness to comply with a change in my diet.
I will attempt to adhere to anti-cancer dietary guidelines provided by the study coordinator for the entire nine weeks of this study. These guidelines involve increasing fruit and vegetable intake to at least five servings per day, to reduce total fat intake to approximately 30 % of energy intake, to increase consumption of dietary fiber to greater than 20 grams per day. In addition, I will not consume dietary or nutritional supplements other than the multivitamin or soy products provided by the study coordinator.
I will be randomly assigned to a study group where I agree to consume either a specified amount of lycopene from tomato products or, a soy protein beverage everyday for four weeks. After this four-week dietary intervention, I will consume both a lycopene-rich diet and the soy protein beverage for an additional four weeks.
I will agree to regular clinic visits, physical exams, and blood draws as required for the study and as routine standard care for prostate cancer.
upon ______. (myself or name of subject)
The experimental (research) portion of the treatment or procedure is:
If I choose to enroll in this study, I will answer dietary interview questions (which will take no more than 10 minutes) and agree to meet with a dietitian receive instructions regarding the necessary dietary interventions.
Throughout the duration of this study, I will follow anti-cancer diet guidelines, which recommend controlled amounts of fat and fiber, and at least five fruits and vegetables each day. This diet recommended by the National Institutes of Health and the National Cancer Institute. For the first one week of the study, I will follow the anti-cancer diet and abstain from all tomato and soy foods. During the following four weeks of the study, I will be randomly assigned to consume either specific amounts of tomato products or a soy product. The last four weeks of the study will require me to eat both tomato products and soy in specified amounts in addition to the anti-cancer diet guidelines.
I agree to visit the medical oncology clinic on the second floor of the James Cancer Hospital at the end of weeks one, five, and nine (three times total) for blood draws and collect my urine for 24 hours on three separate occasions.
It is the expert opinion of the physician in charge of this study that both treatments are just as likely to benefit me as a cancer patient.
The study is undertaken as part of an investigation entitled:
Comparison of Dietary Tomato Products or Soy Protein to enhance Blood Antioxidant Status and Modify Hormonal Profiles in Men With Recurrent Prostate Cancer
183 1. Purpose of the procedure or treatment:
Studies conducted in large populations of men suggest that elevated intakes of either tomato products or soy protein may decrease risk of prostate cancer or perhaps enhance the efficacy of treatment. The study I am joining is designed to test if enriching my diet in tomato products or supplementing my diet with a soy protein powder can be achieved in men with prostate cancer. In addition, the study will determine if the dietary changes can improve my antioxidant status or alter hormone profiles and potentially delay or even inhibit prostate cancer progression based on PSA changes.
2. Possible appropriate alternative procedure or treatment (not to participate in the study is always an option):
If I enroll in the study, I may quit at any time without affecting my future medical care.
If I do not wish to enroll in the study, I will continue with regular medical follow-up appropriate for my disease.
I understand that my participation in this study is voluntary and refusal to participate will not affect my future medical care.
3. Discomforts and risks reasonably to be expected:
There are minor risks associated with venipuncture (taking blood from a vein) including mild discomfort or bruising. Less commonly, a small clot, swelling of the vein, infection, or bleeding may occur at the site of puncture.
There are no known health risks associated with the portion sizes of tomato or soy foods provided by this study. I will be asked if I am allergic to tomato products or soy. If I am, I will not be able to participate in this study.
4. Possible benefits for subjects/society:
It is possible that I will not receive any benefit from this study beyond the routine medical care and regular monitoring of my prostate cancer. The benefits for society include a better understanding of the role that dietary changes may have in health and disease. Participation in the study may help to slow the growth of my prostate cancer.
If I decide to enroll in this study, some of the tomato products and all of the soy protein supplements will be provided at no cost to me.
If I decide to enroll in this study and complete all nine weeks, I will receive a $200 gift certificate as an incentive to complete the study. This gift certificate will be given to me within two weeks after I have completed the study.
5. Anticipated duration of subject's participation (including number of visits):
This study is designed enroll 40 men and will last nine weeks. During the study, I agree to give blood samples during weeks one, five and nine, (a total of three blood samples) and collect a 24-hour urine sample on three different occasions.
There are certain circumstances under which the primary investigator may terminate my participation in this study without my consent including severe side effects from the experimental treatment or if my disease becomes worse and requires medical intervention.
I hereby acknowledge that ______or associates of his choosing have provided information about the procedure described above, about my rights as a subject, and he/she answered all questions to my satisfaction. I understand that I may contact him/her at Phone No. 614.293.8396 should I have additional questions. He/She has explained the risks described above and I understand them; he/she has also offered to explain all possible risks or complications.
184
I understand that, where appropriate, the U.S. Food and Drug Administration may inspect records pertaining to this study. I understand further that records obtained during my participation in this study that may contain my name or other personal identifiers may be made available to the sponsor of this study. Beyond this, I understand that my participation will remain confidential.
I understand that I am free to withdraw my consent and participation in this project at any time after notifying the project director without prejudicing future care. No guarantee has been given to me concerning this treatment or procedure.
I understand in signing this form that, beyond giving consent, I am not waiving any legal rights that I might otherwise have, and I am not releasing the investigator, the sponsor, the institution, or its agents from any legal liability for damages that they might otherwise have.
In the event of injury resulting from participation in this study, I also understand that immediate medical treatment is available at University Hospitals of The Ohio State University and that the costs of such treatment will be at my expense; financial compensation beyond that required by law is not available. Questions about this should be directed to the Office of Responsible Research Practices at 614-688-4792.
I have read and fully understand the consent form. I sign it freely and voluntarily. A copy has been given to me.
A M P Date: Time M Signed (Subject)
Witness (es) if required (Person Authorized to Consent for Subject if Required)
185
186 187 188 189
APPENDIX D
PARTICIPANT EDUCATION MATERIALS
190 Instructions for 3 Day Diet Record Book
This three-day diary will be used to estimate your typical nutrient intake. The dietary information you provide is an important component of the research study.
To estimate your nutrient intake accurately, we need a complete record of what you eat and drink.
Keep a record of everything you eat and drink (including water) for three days. You should choose two non-consecutive weekdays (e.g. Monday and Wednesday) and one weekend day (Saturday or Sunday). Fill in all information requested and choose days that you consider to be “normal.” For instance, you may not want to record what you eat on a holiday such as Thanksgiving or Christmas, because you may eat larger portions and significantly different foods than normal.
It is best to record what you eat and drink immediately after you consume it. However, if you recall something at a later time, add it to the diet diary.
Be very specific in describing the foods that you eat. For example:
• Types of foods:
Milk - Is it whole, non-fat, 2% or 1% lowfat? Bread - Is it rye, whole wheat, raisin, etc.? Cereal - Brand name? Cookies - Chocolate chip, oatmeal, peanut butter, etc.? Pop - Diet or Regular?
*please note any low-fat, reduced-fat or fat-free versions of food items
• Food preparation:
Eggs - Fried, poached, scrambled (with what), etc.? Chicken - Roasted, fried, barbecued, etc.? Skin on or off?
• Additions to your food:
Coffee - Cream, milk, sugar, artificial sweeteners, etc.? Toast - Butter, margarine, jelly, etc.? Vegetables - Butter, cheese, margarine, dips, etc.? Sandwich - Mayonnaise, mustard, butter, etc.? Salad - Dressing? What type? Croutons, other toppings?
191
• Amounts consumed: (also see Common Portions Sizes handout)
Eggs - How many? Milk - How much? 1 cup? ½ cup? (1 cup = 8 fl. ounces) Meat/Cheese - How many ounces? Check package labels for total amount and estimate how much you are eating Peanuts - Approximately how many? Salted or unsalted? If you ate a package, record the weight of the package. Candy bars - How many bars and how many ounces? Cereal - How much? 1 cup? ½ cup? Check package labels. (Don’t forget the milk!)
• Mixed dishes:
You will need to break down certain combination items in your food record using two or more separate lines. For example, a turkey and Swiss cheese sandwich might be:
• Two slices of whole wheat bread • Three slices turkey • Two slices Swiss cheese • One tablespoon mayonnaise
• Example:
Time Meal Place Eaten Amount Food Description 7 AM B Home 1 cup Cheerios 6 fl. ounces 2% milk 2 large Strawberries 5 ½ oz can V8 11 AM S At desk 2 inch diam Cherry Danish 12 fl. ounces Coffee 2 packets Sugar 4 packets Half & half 1 PM L School cafeteria 1 ½ cups Chicken noodle soup 20 Goldfish 12 fl. ounces Diet Pepsi 7 PM D Boston Market 1 medium Chicken leg and thigh w/skin, roasted ¾ cup Stuffing ½ cup Glazed carrots 3 inch square Corn bread 12 fl. ounces Rolling Rock beer
192
DIET RECORD
Name:______Day / Date:______
*** Start a new page each day. *** Please be as specific as possible. Note any low fat or reduced fat items. Time Meal Place Eaten Amount Food Description
193
Appointments and Instructions for Diet Study
Week of: ______avoid all tomatoes, tomato products and soy foods (see attached list for examples).
First Appointment:
Date:______Time:______Begin 24 hour urine collection
Date:______Time:______Arrive at 2nd floor James Hospital for blood draw
Second Appointment:
Date:______Time:______Begin 24 hour urine collection
Date:______Time:______Arrive at 2nd floor James Hospital for blood draw
Third Appointment:
Date:______Time:______Begin 24 hour urine collection
Date:______Time:______Arrive at 2nd floor James Hospital for blood draw
194
Patiient Demographiics
Name:______
Address:______
______
MRN: ______
Age: ______Date of Birth:______
Phone: ______e-mail: ______
Date Enrolled:______
Date Randomized:______
Group Randomized:______
195 Mistake Sheet
Do not worry if you accidentally eat a food (tomato and/or soy) that is prohibited on the study. As long as you write it down, we will be able to account for the mistake in your blood and urine samples.
Please record any mistakes on this sheet and give it to Beth when at your next appointment.
Date Time Amount of Food Description of food June 3 12 Noon (lunch) ½ cup Salsa at Mexican restaurant
196
OSU NUTRITION STUDY GENERAL DIET INFORMATION
Eat at least five fruits and vegetables each day: A diet rich in fruits and vegetables has been associated with many health benefits. Your goal each day is to eat at least five fruits and vegetables from a variety of sources. What counts as a serving? 1 small raw fruit or vegetable (orange, apple, or tomato) 1 cup chopped raw fruits or vegetables (lettuce or watermelon) ½ cup fruit or vegetable juice ½ cup cooked or canned fruits or vegetables By following this recommendation every day, the other recommendations will be much easier to achieve. Fruits and vegetables can be fresh, frozen or canned.
Consume a diet with plenty of fiber: Fruits, vegetables and whole grains are good sources of fiber. A diet high in fiber can help lower cholesterol and keep the gastrointestinal system fit. What’s more, foods high in fiber frequently induce a feeling of fullness, which reduces the desire to overeat. Check the food label to determine if a food is a good source of fiber. Good sources of fiber have at least 3 grams of fiber per serving. You should try and eat approximately 20 grams of fiber each day. A good way to get a jump on fiber intake is to start the day off with a high fiber cereal such as Raisin Bran, Wheaties, or Frosted Mini Wheats.
Reduce fat to 25 – 30% of total calories: Fats such as oils, margarine, butter and other sauces/condiments, add additional calories but do not provide many nutrients. You do not need to eliminate your favorite foods in order to follow a low-fat diet, just balance them with the rest of your meal and eat them in moderation. The food label can help you determine if a food is low in fat. Low-fat foods have 3 grams of fat (or less) per serving. A good rule of thumb is to only have one food per meal that is high in fat. The following example demonstrates how to change a high fat meal to a low fat meal. The items in boldface are foods that have more than 3 grams of fat per serving.
High Fat Meal Low Fat Meal 3 to 4 ounces beef 3 to 4 ounces beef garden salad with: garden salad with: shredded cheese green peppers, tomatoes Italian dressing light Italian dressing 3 slices French bread 1 cup wild rice 3 t. butter ½ cup fruit cocktail Ice Cream Orange Sherbet
Reduce intake of simple sugars: Oftentimes when people try to follow a low fat diet, they substitute fatty foods with sugary foods, like fat-free candy, cookies and soft drinks. Just like with fat, sugar provides extra calories, but few nutrients. By focusing on eating more whole fruits, vegetables, and grains, it is likely that you will naturally reduce the amount of sugar you eat each day. However, if you drink several cans of regular soda each day or eat a sugary dessert after both lunch and dinner, then you need to cut back.
197 Common Soy Foods
Thank you for participating in our diet study. Your participation will enable us to develop the next phase of our ongoing effort to define the optimal dietary intervention for men with prostate cancer. We encourage you to continue the improved dietary habits you have established over the past 9 weeks. In addition to soy powder there are many other food products which are excellent sources of soy protein. Below is a list of foods with soy protein that are available at your local grocery store.
Soy Milk There are many different types of soy milk (sweetened, unsweetened, extra calcium or protein, etc). You may find it necessary to try several different brands to find the one you prefer. If you find the taste of soy milk is too strong, try it in cereal, milkshakes, or pudding.
Soy Nuts Soy nuts are roasted mature soybeans. Most grocery stores carry one or more brands of soy nuts. You can buy them salted or unsalted and some brands have added oil.
Soy Powder Soy powder, like the one used in the study, can be added to most beverages without dramatically changing the taste. They are especially good in fruit smoothies. Generally, soy powder comes in canisters and can be found in the health food section of the grocery store. Brand names include: Health Source (this brand is very similar to what was used in the study) Genisoy
Soy Burgers, Hot Dogs, Bacon, Sausage If you have never tried a soy burger, you will be amazed at how good they are. Some are indistinguishable from beef, others have a great taste all their own. The other soy “meats” vary in quality and soy content and you may need to try various brands. Soy burgers can be found in the freezer section of most grocery stores and are becoming more popular at restaurants. The other soy products are found near their meat-based counterparts. Be cautious if you follow a salt restricted diet, many of these meat substitutes are very high in sodium. Brand names include: Boca Burgers Morningstar Farm Soy Burgers Yves Veggie Chili dogs Bratos Sausages (pork and tofu)
198
Edamame Edamame (ed ah mom ay) are immature (green) soybeans. They taste like lima beans and can be easily prepared by steaming them in the microwave for a few minutes. Add a little salt and / or butter and edamame makes a great snack. Edamame comes in a bag and can be found in the frozen foods section of the grocery store.
Soy Flour For anyone who makes homemade bread, soy flour is a great ingredient to try. Soy flour can be found in a number of different places in the grocery store. It may be near the other baking ingredients, in the health foods section, or with the bread machine and quick breads. Brand names include: Bobs Soy Flour Red Arrow Soy Flour
Cereal with Soy Most of these cereals include soy as a minor component and thus do not provide as much soy protein as many other sources. A standard serving only provides about 2 grams of soy protein (compared to 20 grams per package consumed in our study!). Adding a little soy milk will significantly increase this amount. These cereals can be found with the other cereals or in the health food section of the grocery store. Brand names include: Harmony (Kelloggs) GoLean (Kashi) Apple Cinnamon Soy O’s (Health Valley)
Soy Energy Bars Energy bars are a lot like candy bars but are found in the health food or dietetic food section of most grocery stores. Check the label, because many of these bars are high in calories (over 200 per bar) and rarely will satiate your hunger. Brand names include: Balance Bar Luna Bar Genisoy Bar Health Source Bar
199
Tofu Tofu is soybean curd. It has between 9 and 20 grams of soy protein per cup and can be crumbled into spaghetti, or lasagna, or stir-fried with vegetables in place of meat. Usually, tofu can be found in the produce, ethnic or health food section of the grocery store. Brand names include: Mori-Nu tofu
Other soy foods: These foods are harder to find in most standard grocery stores and are less popular than those mentioned above. If you really love soy, you may want to give some of these a try, but many people find these products a bit distasteful. Soy Cheese Soy Ice Cream Soy Margarine Soy Butter (similar to peanut butter) Soy Yogurt Tempeh (fermented soy, used as a meat substitute)
200