The increasing role of CAM in prostate cancer

Gabrielle Zecha, PA-C; Daniel W. Lin, MD; R. Bruce Montgomery, MD

Ms. Zecha works at the University of Washington, Seattle. Dr. Lin is in the Department of Urology and Dr. Montgomery in the Department of Oncology, University of Washington Medical Center, Seattle VA Puget Sound Healthcare System. The authors have indicated no relationships to disclose related to the content of this article.

Diet, antioxidants, COX-2 inhibitors, and certain herbs are among the numerous CAM interventions available for prostate cancer. Some show promise, but additional research is needed.

As the most common cancer in men, prostate cancer was diagnosed in more than 198,000 American men and was responsible for 30,000 deaths in 2001.¹ The disease strikes African-American men twice as often as Caucasian men, tends to affect older men, and typically progresses slowly.² Autopsy studies have shown that many men die with some evidence of clinically undetected prostate cancer.³

Mounting epidemiologic evidence suggests that many factors play a role in the development of prostate cancer, including age, race, diet, and genetics. Among ethnic and racial groups, African-American men have the highest prostate cancer mortality rate.⁴ Recent genetic studies suggest that a strong familial predisposition may be responsible for 5% to 10% of prostate cancers.¹ Because dietary factors appear to be protective, chemoprevention trials are under way to identify specific modifiable risk factors that would prevent or reduce the number of prostate cancer deaths. Cyclooxygenase-2 (COX-2) inhibitors, dietary fat, soy, lycopene, selenium, and vitamin E are currently under clinical investigation to explore their roles in the prevention and development of prostate cancer.

Anatomy and pathology of prostate cancer

The prostate produces 20% of the seminal fluid and other substances that facilitate sperm motility and penetration but are not essential for fertility. In adults, epithelial cell proliferation and cell death in the prostate are regulated by androgens, of which dihydrotestosterone is the major circulating form.⁵ Tumorigenesis is initiated when this balance of cell proliferation becomes unregulated and apoptosis (programmed cell death) is blocked.

Prostatic intraepithelial neoplasia (PIN) has been increasingly implicated as a premalignant lesion for prostate cancer⁶ and may be a point in the disease where interventions are most likely to slow or prevent disease progression. PIN is a noninvasive lesion that is morphologically dysplastic and has genetic abnormalities, a loss of cellular control functions, and some of the phenotypic characteristics of invasive cancer. PIN predicts a substantially increased likelihood of developing invasive cancer.⁷ In patients with isolated PIN, more than 50% of subsequent prostate biopsies detect prostate cancer, suggesting that PIN is a marker for prostate carcinoma.⁸ Autopsy studies reveal that PIN is found in association with cancer in as many as 94% of malignant and 43% of benign prostates.⁹ PIN has been identified as a clinically strategic point to initiate chemoprevention.

Prostate cancer is graded histologically using the Gleason scoring system. This is the combined score of the two most prevalent patterns present in a biopsy (each of which has a score of 1 to 5), with a total possible score of 10. Once a lesion has progressed to malignancy, a number of clinical and pathologic factors become important indicators of potential cure with local therapy. Prostate-specific antigen (PSA) level and clinical staging provide important data regarding the potential outcome after treatment with radiation or prostatectomy.

The degree of risk for postoperative or postradiation prostate cancer recurrence in patients with clinically localized disease is based on the patient's PSA level, biopsy, Gleason score, and 1992 American Joint Committee on Cancer stage.

Conventional standards of care

Treatment decisions are based on the patient's Gleason score, clinical stage, PSA level, patient preferences, age, comorbidities, and life expectancy. Conservative management or watchful waiting is a reasonable choice in older patients with low-grade, clinically localized tumors, particularly patients who have an average life expectancy of less than 10 years.^10,11 Treatment decisions are more complex in younger patients or those with intermediate or high-grade tumors because of the wide range of treatment options and the significant side effects of those treatments. Treatments for localized disease include surgery, external beam radiation, brachytherapy, and hormone manipulation. Because the approach to localized disease is controversial, this article will not discuss in detail the treatment choices, their side effects, and the clinical situations in which they would be utilized. Although chemotherapy has been shown to have a palliative benefit in patients with painful metastatic disease, it has not been shown to prolong life. Investigators are focusing on novel approaches to chemotherapy with the hope of prolonging life in this patient population.

Complementary and alternative medicine

Complementary and alternative medicine (CAM) is a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine. Conventional medical treatments are those that are widely accepted and practiced by the mainstream medical community. Complementary practices combine easily with conventional medicine; examples include aromatherapy, mental imagery, and massage. Alternative medicine is used in place of conventional medicine and includes both homeopathic and naturopathic medicine.¹²

CAM is used much more widely than most mainstream medical providers realize. In 1997, 42% of patients reported using at least one unconventional therapy in the previous year, up from 34% in 1990.¹³ Conservative estimates are that Americans spent more than $34 billion for CAM in 1997.¹³ The rate of use was highest for back problems, anxiety, headaches, chronic pain, and cancer. The modes of therapy most commonly used include relaxation techniques, herbal medicine, chiropractic, and massage.¹⁴

Why patients turn to CAM—and why you should be concerned

There are many reasons why patients use CAM. They most frequently cite distrust or dissatisfaction with conventional medicine, the need for personal control, philosophical congruence (treatments are seen as more compatible with the patient's personal values), and the desire for transformational experiences.¹⁵ CAM users tend to be better educated and to have a holistic attitude toward health. Not surprisingly, patients categorized as primarily reliant on alternative health care are more likely to be dissatisfied with and distrust conventional medicine and to be desirous of maintaining exclusive control over their health care decisions.¹⁵

Among patients with prostate cancer, CAM therapies used commonly include vitamins (34% of patients), prayer or religious practices (25%), and herbal medicines (13%). As many as 72% of patients do not inform their physician about their use of CAM.¹⁶ For example, one study found that only 33% of prostate cancer patients revealed their use of CAM when they were asked about medication use during the history. When questioned specifically about CAM use, however, 81% of the same group disclosed their use of CAM.¹⁷ This discrepancy in reporting is believed to occur because patients fear disapproval by providers and because patients may not regard CAM as a medication.

Prostate cancer patients who use CAM tend to be younger, better educated, and have higher Gleason grades; less hope of cure may be communicated to these patients, leading them to explore other treatments in addition to conventional therapy.¹⁶ Currently, many prostate cancer patients also use CAM to diminish the side effects associated with conventional hormonal therapy, including osteoporosis, vasomotor flushing, and depression. Complementary treatments for vasomotor symptoms include black cohosh and soy. Depression is commonly treated with St. John's wort. Osteoporosis is more complicated because of the possible connection between high calcium intake and prostate cancer, although the skeletal benefits of calcium and vitamin D supplementation may outweigh any theoretic risks.¹⁸ High-dose vitamin therapy, acupuncture, diet, massage, and prayer and other religious practices are used individually or, more commonly, in combination. Saw palmetto is used to ameliorate urinary symptoms and is commonly taken for benign prostatic hypertrophy.^18,19

The clinician's awareness of CAM use is important in patients with prostate cancer. For example, St. John's wort decreases plasma levels of the chemotherapy drug irinotecan (Camptosar) by an average of 42%, potentially compromising the efficacy of irinotecan in the treatment of cancer.²⁰ The antagonistic effect of the herbal supplement PC-SPES on conventional prostate cancer treatments such as the taxanes (paclitaxel [Taxol] or docetaxel [Taxotere]) is a concern because PSA levels and tumor response may be altered.²¹ PC-SPES also antagonizes the effect of taxane-based chemotherapies at their molecular target. The risk of undesirable effects is significant because CAM therapies may have a potential for biological impact on tumor behavior and drug metabolism.

Patient safety and product efficacy are significant concerns when CAM products are used. Many patients believe that these products are safe and reasonably well controlled, even though the Dietary Supplement Health and Education Act of 1994 exempts dietary supplements from FDA premarket safety evaluations. Very few alternative medicines available to consumers have undergone well-designed, randomized clinical trials. The importance of documented efficacy and safety cannot be overstated, and such documentation is essential to confirming the future use of these medicines in any setting.

CAM use may also cause patients to delay seeking standard medical care. The medical literature includes reports of dangerous side effects, such as an acquired bleeding disorder in a patient taking PC-SPES for prostate cancer and myocardial infarction, and stroke and even death in patients taking ephedra.^22-29 Contamination and inconsistent levels of potency of dietary supplements have been problems as well.^22-29 PC-SPES was withdrawn from the market by the manufacturer in February 2002 after it was found to contain possible contaminants.

CAM and prostate cancer prevention

Epidemiologic studies suggest that consumption of soy products, vegetables (particularly cruciferous vegetables), and tomatoes and other lycopene-containing foods is associated with a lower risk of developing prostate cancer,^30-32 while consumption of red meat, dairy products, and dietary fat—particularly saturated fat—is associated with an increased prostate cancer risk; total fat consumption is directly related to the risk of advanced prostate cancer.^33,34 Although the data are fascinating, they are inadequate thus far to draw clinically useful conclusions. Interventions for prostate cancer chemoprevention show great promise and are currently the subject of large clinical trials.³⁵

Selenium and vitamin E An essential trace mineral found in plant foods and in some meats and seafood,³⁶ selenium has been found to inhibit tumorigenesis and induce apoptosis in animal models.^37,38 Selenium inhibits cell cycle progression in human prostate cancer cell lines; interestingly, the antiproliferative properties of this mineral appear to be dependent on the presence of a functioning androgen receptor.³⁹ Clark and coworkers found that men who received selenium supplementation had a 63% reduction in prostate cancer incidence and a decrease in the overall incidence of prostate, colorectal, and lung cancers.^40,41 Low plasma selenium levels are associated with an increased risk of prostate cancer, especially among smokers.^42-44 Plasma selenium levels decrease with age. These factors support future research into the use of selenium for prostate cancer prevention.

Vitamin E is fat soluble and exists in eight different forms. Alpha-tocopherol is the most active form of vitamin E in humans and is a powerful biological antioxidant commonly found in vegetable oils, nuts, green leafy vegetables, and fortified cereals.³⁶ Vitamin E acts as an anticarcinogen by scavenging free radicals and enhancing the body's immune response.⁴⁵ It has been shown to inhibit the growth of prostate cancer cells and can suppress the expression of prostate-specific antigen and androgen receptors.⁴⁶ In a lung cancer prevention study, vitamin E supplementation reduced prostate cancer incidence by 32% and mortality by 41% in a study of 29,000 male smokers.⁴⁷ Although changes in prostate cancer incidence and mortality were found in secondary analyses, the study population was restricted to men with current tobacco use—no prostate examination was necessary for entry into the study, and the results have not been confirmed by other studies.

Some evidence suggests that selenium and vitamin E have a synergistic effect. The mechanism is undefined in humans, although evidence in animal models is clear. Vitamin E provides a more favorable climate against oxidative stress, thereby potentiating the action of selenium.⁴⁸ The use of these supplements, both individually and together, is being studied for prostate cancer prophylaxis and PIN in two large cooperative multicenter studies.^35,49

PC-SPES The use of the herbal supplement PC-SPES in the treatment of prostate cancer is particularly instructive regarding the risks and benefits of CAM. ("PC" stands for prostate cancer, and "spes" is Latin for hope.) PC-SPES is a combination of eight herbs including Isatis indigotica Fort, Glycyrrhiza glabra L, Glycyrrhiza uralensis Fisch, Panax pseudoginseng Wall, Ganoderma lucidum Karst, Scutellaria baicalensis Georgi, Dendranthema morifolium Tzvel, Rabdosia rubescens Hara, and Serenoa repens.

Evidence suggests that PC-SPES has antineoplastic as well as immunomodulating effects,⁵⁰ and it has shown significant therapeutic efficacy against androgen-dependent and androgen-independent prostate cancer in clinical trials, achieving response rates that were as good as or better than standard approaches.^51-53 The mechanism of action was initially thought to be a phytoestrogen because the compound had many estrogenic effects, which are thought to be distinctly different from diethylstilbestrol, estrone, or estradiol. Clinically significant reductions in serum testosterone concentrations, decreases in PSA levels, and a side effect profile similar to pharmacologic doses of estrogen have all been seen with PC-SPES.^51-56 Because PC-SPES has activity against androgen-independent as well as androgen-dependent prostate cancers, multiple pathways are probably involved. Tumor responses may result both from estrogen-mediated central androgen suppression and from direct cytotoxicity via estrogen-independent mechanisms. PC-SPES alters the expression of several genes involved in cell cycle regulation and cell proliferation and has been shown to initiate an apoptotic response in prostate cancer cells.^{51, 57}

The remarkable clinical effects of PC-SPES were offset by initial reports that it could induce hypercoagualability, probably mediated by estrogens, or hemorrhagic diatheses, which was unexplained but potentially mediated by a compound similar to warfarin.⁵⁸ PC-SPES lots manufactured during this period contained warfarin, licochalcone A (a licorice flavonoid that appears to have antineoplastic and estrogenic activities), baicalin (a flavonoid from Scutellaria baicalensis, a principal ingredient of PC-SPES), indomethacin (an NSAID) and diethylstilbestrol (DES, a synthetic estrogen). A concern with PC-SPES is that it contains several potentially active substances, which makes the study of its effects more complex. Progressively lower amounts of both indomethacin and diethylstilbestrol were found in succeeding lots, with a corresponding decrease in antineoplastic activity and estrogenicity.⁵⁹

PC-SPES was withdrawn from the market by the manufacturer in February 2002 after the FDA warned that it was contaminated with warfarin.^60,61 The story of PC-SPES illustrates how CAM products may indicate the direction for new and innovative studies that could potentially reveal new molecular mechanisms of tumorigenesis suppression. It also shows the risks associated with compounds whose manufacture is not regulated and which are contaminated with drugs whose toxicities cannot be anticipated by patients or providers.

COX-2 inhibitors Selective cyclooxygenase-2 (COX-2) inhibitors are a relatively new class of drugs that show promise in the area of chemoprevention. Cyclooxygenase catalyzes the synthesis of prostaglandin from arachidonic acid. Prostaglandins play many roles in the human body, but when overexpressed in tissues, they have been associated with tumorigenesis. Of the two isoforms (COX-1 and COX-2), COX-2 is frequently overexpressed in premalignant lesions and neoplasms.⁶² Increased COX-2 expression is well documented in PIN and prostate cancer.^62-64 The level of overexpression has been shown to significantly correlate to invasiveness, prognosis, and survival.⁶⁵ The role of COX-2 in carcinogenesis is thought to be related to its ability to increase the production of prostaglandins, convert procarcinogens to carcinogens, increase cell proliferation, inhibit apoptosis, promote angiogenesis, modulate inflammation and immune function, and increase tumor cell invasiveness.^63,66

Some studies have demonstrated that COX-2 inhibitors and some NSAIDs can potentially decrease the incidence of many malignancies, including prostate cancer.^63,66 COX-2 inhibitors have been shown to inhibit the proliferation of prostate cancer cells via apoptosis and to reduce angiogenesis.^67,68 They may also act synergistically with cytotoxic and molecularly targeted agents.⁶⁵ COX-2 inhibitors do not affect platelet function and have a better GI side effect profile than other NSAIDs, making them a relatively safe chemopreventive agent. The existing data for COX-2 inhibitors is compelling, and future clinical trials will further delineate their place in chemoprevention and therapy.

Conclusion

Complementary and alternative medicine offers options for both prevention and treatment that may appeal to many men. Research is needed to ensure the safety and efficacy of these interventions before clinicians can recommend them. Asking patients about CAM use and providing unbiased, nonjudgmental information in your response promotes a strong clinician-patient relationship and will help patients to avoid ineffective and sometimes dangerous therapies.

 

Online resources for complementary and alternative medicine information National Center for Complementary and Alternative Medicine www.nccam.nih.gov Describes CAM and how to select a CAM practitioner. Provides alerts and advisories on drug interactions and information by treatment or disease. Supplement Watch www.supplementwatch.com Provides a summary of relevant data, including a description of the supplement, what it claims to do, scientific support, and safety data. Quackwatch www.quackwatch.com Takes a conservative approach to alternative medicine. Its mission is to "combat health-related frauds, myths, fads and fallacies."

 

KEY POINTS in this article Patients with prostate cancer may use complementary therapies to diminish the effects associated with conventional therapy. Patients have easy access to information on CAM, not all of which is reliable. Clinicians can steer patients to Web sites that provide balanced information with patient safety and efficacy in mind. The existing data for COX-2 inhibitors is compelling, and future clinical trials will further delineate their place in chemoprevention and therapy.

 

Acknowledgement The authors acknowledge the assistance of Hilde Wette, RD, PhD.

REFERENCES

1. American Cancer Society. Cancer Facts and Figures 2001. Atlanta, Ga: 2001.

2. Newschaffer CJ, Otani K, McDonald MK, Penberthy LT. Causes of death in elderly prostate cancer patients and in a comparison nonprostate cancer cohort. J Natl Cancer Inst. 2000;92:613-621.

3. Breslow N, Chan CW, Dhom G, et al. Latent carcinoma of prostate at autopsy in seven areas. The International Agency for Research on Cancer, Lyons, France. Int J Cancer. 1977;20:680-688.

4. American Cancer Society. Cancer Facts and Figures for African Americans 2000-2001. Atlanta, Ga; 2000: 7-8.

5. DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001.

6. Sakr WA, Grignon DJ, Haas GP, et al. Epidemiology of high grade prostatic intraepithelial neoplasia. Pathol Res Pract. 1995;191:838-841.

7. O'Shaughnessy JA, Kelloff GJ, Gordon GB, et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res. February 2002;8:314-346.

8. Brawer MK. Prostatic intraepithelial neoplasia and prostate-specific antigen. Urology. 1989;34(6 suppl):62-65.

9. Sakr WA, Partin AW. Histological markers of risk and the role of high-grade prostatic intraepithelial neoplasia. Urology. 2001;57(4 suppl 1):115-120.

10. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med. 1994;330:242-248.

11. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA. 1998;280:975-980.

12. National Center for Complementary and Alternative Medicine. What is complementary and alternative medicine (CAM)? Available at: http://nccam.nci.nih.gov/ health/whatiscam/. Accessed January 20, 2004.

13. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-1575.

14. Eisenberg DM, Kessler RC, Foster C, et al. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med. 1993;328:246-252.

15. Astin JA. Why patients use alternative medicine: results of a national study. JAMA. 1998;279:1548-1553.

16. Lippert MC, McClain R, Boyd JC, Theodorescu D. Alternative medicine use in patients with localized prostate carcinoma treated with curative intent. Cancer. 1999;86:2642-2648.

17. Jones HA, Metz JM, Devine P, et al. Rates of unconventional medical therapy use in patients with prostate cancer: standard history versus directed questions. Urology. February 2002;59:272-276.

18. Smith MR. Complementary and alternative therapies for advanced prostate cancer. Hematol Oncol Clin North Am. 2001;15:559-571.

19. Kao GD, Devine P. Use of complementary health practices by prostate carcinoma patients undergoing radiation therapy. Cancer. 2000;88:615-619.

20. Mathijssen RH, Verweij J, de Bruijn P, et al. Effects of St. John's wort on irinotecan metabolism. J Natl Cancer Inst. 2002;94:1247-1249.

21. Bonham MJ, Galkin A, Montgomery B, et al. Effects of the herbal extract PC-SPES on microtubule dynamics and paclitaxel-mediated prostate tumor growth inhibition. J Natl Cancer Inst. 2002;94:1641-1647.

22. Nelson L, Perrone J. Herbal and alternative medicine. Emerg Med Clin North Am. 2000;18:709-722.

23. Herbal Rx: the promises and pitfalls. Consum Rep. March 1999;64:44-48.

24. Monmaney T. Remedy's U.S. sales zoom, but quality control lags; St. John's wort: regulatory vacuum leaves doubt about potency, effects of herb used for depression. Los Angeles Times; August 31, 1998:A1.

25. Graham-Brown RA, Bourke JF, Bumphrey G. Chinese herbal remedies may contain steroids. BMJ. 1994;308:473.

26. Slifman NR, Obermeyer WR, Aloi BK, et al. Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med. 1998;339:806-811.

27. Routledge PA, Spriggs TL. Atropine as possible contaminant of comfrey tea. Lancet. 1989;1:963,964.

28. Weinrobe MC, Montgomery B. Acquired bleeding diathesis in a patient taking PC-SPES. N Engl J Med. 2001;345:1213,1214.

29. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343:1833-1838.

30. Cohen JH, Kristal AR, Stanford JL. Fruit and vegetable intakes and prostate cancer risk. J Natl Cancer Inst. January 5, 2000;92:61-68.

31. Gann PH, Ma J, Giovannucci E, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res. 1999;59:1225-1230.

32. Jacobsen BK, Knutsen SF, Fraser GE. Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control. 1998;9:553-557.

33. Giovannucci E, Rimm EB, Colditz GA, et al. A prospective study of dietary fat and risk of prostate cancer. J Natl Cancer Inst. 1993;85:1571-1579.

34. Michaud DS, Augustsson K, Rimm EB, et al. A prospective study on intake of animal products and risk of prostate cancer. Cancer Causes Control. 2001;12:557-567.

35. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. Selenium and Vitamin E Cancer Prevention Trial. J Urol. 2001;166:1311-1315.

36. NIH Clinical Center, National Institutes of Health [Web site]. Facts about dietary supplements. Available at: http://www.cc.nih.gov/ccc/supplements/intro.html. Accessed January 23, 2004.

37. Thompson HJ, Wilson A, Lu J, et al. Comparison of the effects of an organic and an inorganic form of selenium on a mammary carcinoma cell line. Carcinogenesis. February 1994;15:183-186.

38. Zhu Z, Jiang W, Ganther HE, Thompson HJ. Mechanisms of cell cycle arrest by methylseleninic acid. Cancer Res. January 1, 2002;62:156-164.

39. Venkateswaran V, Klotz LH, Fleshner NE. Selenium modulation of cell proliferation and cell cycle biomarkers in human prostate carcinoma cell lines. Cancer Res. 2002;62:2540-2545.

40. Clark LC, Combs GF Jr, Turnbull BW, et al. E. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996;276:1957-1963.

41. Clark LC, Dalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol. 1998;81:730-734.

42. Brooks JD, Metter EJ, Chan DW, et al. Plasma selenium level before diagnosis and the risk of prostate cancer development. J Urol. 2001;166:2034-2038.

43. Yoshizawa K, Willett WC, Morris SJ, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst. 1998;90:1219-1224.

44. Duffield-Lillico AJ, Reid ME, Turnbull BW, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev. 2002;11:630-639.

45. Packer L. Protective role of vitamin E in biological systems. Am J Clin Nutr. 1991;53(4 suppl):1050S-1055S.

46. Zhang Y, Ni J, Messing EM, et al. Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells. Proc Natl Acad Sci U S A. 2002;99:7408-7413.

47. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440-446.

48. Horvath PM, Ip C. Synergistic effect of vitamin E and selenium in the chemoprevention of mammary carcinogenesis in rats. Cancer Res. 1983;43:5335-5341.

49. Marshall JR, Wood DP Jr, Alberts DS, et al. L-Selenium-based chemoprevention of prostate cancer among men with high grade prostatic intraepithelial neoplasia. Southwest Oncology Group, 2002. Available at: http://www.swog.org. Accessed January 24, 2004.

50. Chenn S. In vitro mechanism of PC-SPES. Urology. 2001;58(2 suppl 1):28-35.

51. de la Taille A, Buttyan R, Hayek O, et al. Herbal therapy PC-SPES: In vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol. 2000;164:1229-1234.

52. Oh WK, George DJ, Hackmann K, et al. Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology. January 2001;57:122-126.

53. Small EJ, Frohlich MW, Bok R, et al. Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol. 2000;18:3595-3603.

54. DiPaola RS, Zhang H, Lambert GH, et al. Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med. 1998;339:785-791.

55. Moyad MA, Pienta KJ, Montie JE. Use of PC-SPES, a commercially available supplement for prostate cancer, in a patient with hormone-naive disease. Urology. August 1999;54:319-323.

56. Small EJ, Corry M, Frohlich MA, et al. Effects of PC-SPES, an herbal compound, in patients with androgen dependent prostate cancer. Proc ASCO. 2000;19:1316.

57. Bonham M, Arnold H, Montgomery B, Nelson PS. Molecular effects of the herbal compound PC-SPES: identification of activity pathways in prostate carcinoma. Cancer Res. 2002;62:3920-3924.

58. Weinrobe MC, Montgomery B. Acquired bleeding diathesis in a patient taking PC-SPES. N Engl J Med. 2001;345:1213,1214.

59. Sovak M, Seligson AL, Konas M, et al. Herbal composition PC-SPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst. 2002;94:1275-1281.

60. Sovak M, Seligson AL, Konas M, et al. PC-SPES in prostate cancer: an herbal mixture currently containing warfarin and previously diethylstilbestrol and indomethacin. Proc AACR. 2002. Abstract no. LB152.

61. California Department of Health Services, Office of Public Affairs. State health director warns consumers about prescription drugs in herbal products. February 2002. Available at: http://www.applications.dhs.ca.gov/pressreleases/store/pressreleases/ 02-03.html. Accessed February 6, 2004.

62. Dang CT, Shapiro CL, Hudis CA. Potential role of selective COX-2 inhibitors in cancer management. Oncology (Huntingt). 2002;16(5 suppl 4):30-36.

63. Kirschenbaum A, Liu X, Yao S, Levine AC. The role of cyclooxygenase-2 in prostate cancer. Urology. 2001;58(2 suppl 1):127-131.

64. Hughes L, Heydon K, Edmonds P, et al. Cyclooxygenase 2 (COX-2) expression in locally advanced prostate cancer: secondary analysis of radiation therapy oncology group (RTOG) 86-10. Int J Radiat Oncol Biol Phys. 2002;54(2 suppl 1):271-272.

65. Koki AT, Masferrer JL. Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer Control. 2002;9(2 suppl):28-35.

66. Xu XC. COX-2 inhibitors in cancer treatment and prevention, a recent development. Anticancer Drugs. February 2002;13:127-137.

67. Liu XH, Kirschenbaum A, Yao S, et al. Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo. J Urol. 2000;164(3 pt 1):820-825.

68. Kamijo T, Sato T, Nagatomi Y, Kitamura T. Induction of apoptosis by cyclooxygenase-2 inhibitors in prostate cancer cell lines. Int J Urol. July 2001;8:S35-S39.

© 2007 Haymarket Media, Inc. and the American Academy of Physician Assistants. All rights reserved.
Use of jaapa.com subject to License agreement. Please read our Disclaimer and Privacy policy.