The Role of PC-SPES, Selenium, and Vitamin E in Prostate Cancer

March 1, 2002

The use of complementary and alternative medicine is a well-known phenomenon among cancer patients, and prostate cancer patients are no exception. The review article by Drs. Das and Kaplan nicely summarizes most of the data available on the use of PC-SPES, selenium, and vitamin E by prostate cancer patients. These three agents are probably the most widely used complementary approaches in prostate cancer, and they are the ones that have been studied most extensively. However, true data on efficacy, careful toxicity analyses, dose-response analysis, or pharmacokinetic analyses of these agents are extremely limited.

The use of complementary and alternative medicine is awell-known phenomenon among cancer patients, and prostate cancer patients are noexception. The review article by Drs. Das and Kaplan nicely summarizes most ofthe data available on the use of PC-SPES, selenium, and vitamin E by prostatecancer patients. These three agents are probably the most widely usedcomplementary approaches in prostate cancer, and they are the ones that havebeen studied most extensively. However, true data on efficacy, careful toxicityanalyses, dose-response analysis, or pharmacokinetic analyses of these agentsare extremely limited.

Perhaps the article’s first lesson is that the use of complementary andalternative medicine among prostate cancer patients is increasing. It is hard toknow exactly what percentage of patients use these therapies, although the exactpercentage probably depends on the sample surveyed. Support groups, urologypractices, and tertiary referral centers may include a larger proportion ofpatients who have explored the use of complementary medicine.

In any case, this article points out that it behooves us to take a carefulmedical history from our patients because published series suggest thatone-third or more of prostate cancer patients use some form of complementarymedicine. At our institution, for example, we no longer ask patients, "Whatmedicines are you taking?" We ask specifically, "Are you taking anysupplements, vitamins, herbal products, or other over-the-countercompounds?" A comprehensive questionnaire listing the most commonly usedagents is useful to this end.

Confounding Variables

Why should we care what over-the-counter products our patients take? First,we should not assume that these compounds are benign. (And even if they have notcaused any adverse events as single agents, they essentially represent blackboxes that may interact with other prescribed or nonprescribed medications.)Second, as we evaluate the efficacy of novel therapeutics for patients, we needto know if any confounding variables exist.

For example, we now know that PC-SPES is capable of modulating the expressionof prostate-specific antigen (PSA) in virtually all patients withhormone-sensitive disease and a majority of patients with hormone-refractory orandrogen-independent disease. If use of a novel agent is initiated and we areunaware that the patient has also recently started taking PC-SPES, we and ourpatients are blinded as to which agent or combination of agents is, in fact,providing clinical benefit.

This article provides physicians with a useful tool for discussing with theirpatients what is known about the use of PC-SPES, vitamin E, and selenium. Inaddition to the authors’ conclusion that it is extremely important thatphysicians and other health-care professionals understand the potential role andside effects of these therapies, the importance of relaying this information topatients as nonjudgmentally and objectively as possible also needs to beemphasized.

Hormonal Status and Treatment

The discussion of any novel agent used in the treatment of prostate cancershould be placed in the appropriate clinical context with regard to the hormonalstatus of the patient. It is important to understand whether an agent has beenused for the treatment of hormone-naive prostate cancer, androgen-independentprostate cancer, or overtly hormone-refractory prostate cancer. In thediscussion of PC-SPES, the authors have understandably mixed these clinicalstates together, as many (although not all) of the articles reviewed do thesame. However, in hormone-sensitive disease, virtually 100% of patients respondto PC-SPES. One of the most important observations we made in our clinical trialwas that PC-SPES uniformly dropped testosterone levels to anorchid levels.Hence, at a minimum, the mechanism of action of PC-SPES in hormone-sensitivepatients is androgen deprivation.

In androgen-independent prostate cancer, several series have clearly shownmodulation of PSA expression and clinical improvement in androgen-independentprostate cancer patients treated with PC-SPES.[1-3] The issue of estrogenicactivity as the underlying primary mechanism of activity remains controversial.Many investigators have recognized the estrogenic side effects of patients whotake PC-SPES, and it is probable that at least one (perhaps the only) mechanismof action involves an estrogenic effect. Several studies have shown thatdiethylstilbestrol (DES) itself has activity in androgen-independent prostatecancer, both in vitro and clinically.[4,5]

To address the question of cross-reactivity with standard estrogens, we arecurrently performing a randomized trial of PC-SPES vs DES. Patients withandrogen-independent prostate cancer are being treated with either PC-SPES at 9capsules per day or DES at 3 mg per day. They continue with their designatedregimen until treatment failure and cross over at that point to the othertherapy. Serologic studies will be performed to correlate response to serumandrogen and estrogen levels. Patients are asked to undergo biopsies on studyentry and at crossover to the second treatment, to be analyzed for expression ofestrogen receptor-alpha and -beta.

In androgen-independent prostate cancer studies, it has become standardpractice to report the percentage of patients with more than a 50% decline inPSA, because this benchmark is accepted as an intermediate end point in phase IItrials of novel agents for the disease.[6] In general, it appears thatapproximately 50% of patients treated with PC-SPES for androgen-independentprostate cancer will have a greater than 50% decline in PSA.

Selenium and Vitamin E Supplementation

Importantly, we need to tell patients that, to date, no controlled,prospective study has shown that selenium or vitamin E supplementation slows theprogression of established prostate cancer. Evidence supporting the use of theseagents for prostate cancer prevention is reviewed. It must be pointed out thatselenium levels are largely dependent on dietary intake and vary geographically.Thus, the study reported by Clark et al was specifically conducted in sevencities in low-selenium areas of the United States.[7,8] The investigators founda significantly lower incidence of prostate cancer in selenium-supplementedpatients, although there was no difference in overall survival.

Whether selenium supplementation will assume any role in prostate cancerprevention in patients who live in high-selenium areas (or in more contemporarytimes, where marketing has made all of our diets more uniform) is unknown.Although the Health Professionals Follow-up Study suggested that the meantoenail selenium level was significantly higher in subjects who did not developprostate cancer vs those who did, the 95% confidence interval of the odds ratioapproached 1.[9]

Similarly, data supporting the general use of vitamin E as a preventivemeasure are largely circumstantial. There certainly appears to be a reduction inprostate cancer risk among smokers who take vitamin E supplements. Whether thisobservation holds true for nonsmokers awaits completion of the nationalrandomized Selenium and Vitamin E Cancer Prevention Trial (SELECT).

Conclusions

What do we tell our patients? First, there is no evidence that the intake ofselenium and vitamin E will retard the growth of established prostate cancer.Second, no definitive data show that the use of vitamin E or selenium reducesthe likelihood of developing prostate cancer, although compelling trialsdescribed in the article suggest that they likely will play a role.

Participation in the SELECT trial should be encouraged. The biggest worryabout this trial is that, with a goal of more than 32,000 patients, there willbe so much use of these agents in the general population that it will beimpossible to identify an uncontaminated cohort of patients. Outside of aclinical trial, for patients who live in selenium-poor areas, low-levelsupplementation of selenium is a reasonable recommendation. Similarly, outsideof a clinical trial, vitamin E supplementation is also reasonable.

In sum, Drs. Das and Kaplan are to be congratulated for this timely andwell-presented review that integrates most of the reported data on these threecomplementary medicine approaches used by so many prostate cancer patients.

References:

1. Small E, Frohlich M, Bok R, et al: Prospective trial of the herbalsupplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol18(21):3595-3603, 2000.

2. 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 57(1):122-126, 2001.

3. de la Taille A, Buttyan R, Hayek O, et al: Herbal therapy PC-SPES: Invitro effects and evaluation of its efficacy in 69 patients with prostatecancer. J Urol 164:1229-1234, 2000.

4. Smith DC, Redman BG, Flaherty LE, et al: A phase II trial of oraldiethylstilbesterol as a second-line hormonal agent in advanced prostate cancer.Urology 52(2):257-260, 1998.

5. Rosenbaum E, Wygoda M, Gips M, et al: Diethylstilbestrol is an activeagent in prostatic cancer patients after failure to complete androgen blockade(abstract). Proc Am Soc Clin Oncol 19:1372, 2000.

6. Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelinesfor phase II clinical trials in androgen-independent prostate cancer:Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol17(11):3461-3467, 1999.

7. Clark LC, Combs GF, Turnbull BW, et al: Effects of seleniumsupplementation for cancer prevention in patients with carcinoma of the skin: Arandomized controlled trial. JAMA 2476:1957-1963, 1996.

8. Clark LC, Dalkin B, Krongrad A, et al: Decreased incidence of prostatecancer with selenium supplementation: Results of a double-blind cancerprevention trial. Br J Urol 81:730-734, 1998.

9. Yoshizawa K, Willett WC, Morris SJ, et al: Study of prediagnostic seleniumlevel in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst90:1219-1222, 1998.