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Originally published as JCO Early Release 10.1200/JCO.2004.06.920 on August 2 2004 © 2004 American Society of Clinical Oncology.
PC-SPES: Hope or Hype?Division of Hematology/Oncology, Scripps Clinic, La Jolla, CA Herbal medicines have always held an attraction for patients. Often used unmodified, or only slightly modified from their natural state, they are considered by many to be a pure, safe, and reasonable alternative to traditional, potentially more toxic treatments. Approximately 25% of prescription medicines are derived from plants. Examples in oncology include morphine, vinca alkaloids, and the taxanes. From a regulatory perspective, herbal products fall under the Dietary Supplement Health Education Act, enacted in 1994. Herbals are considered safe unless they "present a significant risk of illness or injury" under the conditions or use recommended in the labeling. While many herbal supplements are safe, there can be interactions with prescription medicines. An example is St John's wort (hypericum perforatum), the agent of choice for depression in Europe, outselling Prozac 20-fold. St John's wort is an inducer of cytochrome P-450, which can increase the clearance of irinotecan by 42%, thereby decreasing efficacy.1 It also induces p-glycoprotein, enhancing drug efflux of the taxanes, anthracyclines, and vinca alkaloids, thereby potentially decreasing efficacy. It has long been recognized that there can be great inconsistency among what appear to be identical natural substances. Examples include different vintages of wine, and different teas or coffees. Growing conditions, time of harvest, conditions of handling, and storage all potentially introduce variability in potency that might affect efficacy and toxicity. Caveat emptor. PC-SPES is a proprietary formulation that was marketed by Botanic Lab (Brea, CA)2 from 1966 through 2002. PC stands for prostate cancer, and spes is Latin for hope. Each capsule of PC-SPES contains 320 mg of eight herbs in a proprietary formulation. The recommended dose for "prostate health" is three to six capsules per day on an empty stomach. The 2002 cost was $108 for a bottle of 60 capsules. The eight herbs included in PC-SPES are listed in Table 1. In preclinical studies, most of these agents have in vitro properties ranging from stimulation of natural killer-cell activity to growth inhibitory effects across a range of cell lines. Other components exhibit estrogenic activity (Isatis indigotica, Glycyrrhiza uralensis) or inhibit 5-alpha reductase (Seronoa repens).3
The clinical activity of PC-SPES had been previously demonstrated in four small phase II studies in patients with androgen-insensitive prostate cancer (AIPC).4-7 The response rate, as measured by a prostate-specific antigen (PSA) decline of  50%, ranged from 50% to 81%. In one phase II study of patients with both androgen-sensitive and androgen-insensitive prostate cancer, PC-SPES, at a dose of nine pills per day, decreased the PSA by 50% in 100% of androgen-dependent tumors and 54% of androgen-insensitive tumors. Interestingly, eight of 16 patients with tumors who progressed on adrenal androgen suppression, a very difficult group of patients to treat, had a PSA decline of 50%. In this and other studies, gynecomastia was near universal (90% to 97%); leg cramps were common (69%) and nausea and vomiting occurred in 14%, and thromboembolism occurred in approximately 5% of patients.6 Another important factor driving the study of PC-SPES was the fact that, in 2002, approximately 10,000 patients with prostate cancer were using PC-SPES.8 Many patients were using this therapy in addition to standard therapy directed by their physician, while others with advanced prostate cancer were using PC-SPES as the sole treatment, often without close medical supervision. In these patients, estrogenic side effects, such as gynecomastia, were frequent, and sporadic reports of deep vein thrombosis were noted. The apparent clinical activity, wide spread clinical use, and a suggestion of an estrogenic mechanism of action9 made the comparison study of PC-SPES to an estrogen a reasonable next step in the analysis of this interesting compound. In patients with advanced prostate cancer failing primary hormonal therapy, diethylstilbestrol (DES) has a biochemical response rate from 29% to 66%. While not commonly used, DES remains a viable hormonal option for patients with progressive AIPC.
In this issue of the Journal of Clinical Oncology, Oh et al10 report a study that was designed to assess the response to either PC-SPES or DES in patients with AIPC, as measured by a decline in PSA. At either clinical or biochemical progression, patients were planned to be crossed over to the second agent. In this study, patients were randomly assigned to receive PC-SPES at a dose of nine pills per day (the accepted therapeutic dose of the drug) versus 3 mg per day of DES. Because of the known thrombotic complications of DES and reports of thrombotic complications associated with PC-SPES, all patients were treated with warfarin at a dose of 2 mg per day, adjusted to keep the INR at less than 2. All patients had castrate levels of testosterone, and prior hormonal therapy was stopped 1 month before initiation of the study treatment. On progression, patients were to be crossed over to the other agent to determine whether PC-SPES had a mechanism of action that was independent of its estrogenic properties. The biochemical response rate to initial therapy as measured by a PSA decline of Analysis of four lots of PC-SPES used in this study had measurable quantities of DES and ethinyl estradiol. These results were confirmed in two separate laboratories. This was in contradistinction to earlier studies of different lots of PC-SPES which failed to confirm any evidence of DES or other therapeutic estrogens; however, others have noted a variety of contaminants in multiple lots of the supplement.11 In February 2002, the State of California12 issued a public health advisory after warfarin was detected in PC-SPES at a concentration of 0.211 mg per capsule, or 1.27 mg per six capsules. Aprazolam was also detected in a companion compound, SPES. A product recall of PC-SPES was issued by Botanic Labs on February 8, 2002; however, analysis by their labs failed to detect any DES. On April 1, 2002, patients were notified by Botanic Labs that PC-SPES production had been moved from California to China to be closer to the suppliers of the raw material and maintain better quality control; however, the first Chinese batch was reportedly of a poor quality. Botanic Labs ceased business on June 1, 2002. The unanswered questions relating to PC-SPES include the impact of the identified contaminants, primarily DES and warfarin, and their effect on the therapeutic efficacy of herbal supplements. As noted by the authors, it is possible that the warfarin detected in PC-SPES accounted for the large number (15%) of patients receiving PC-SPES who discontinued warfarin therapy because of overanticoagulation. This had been previously reported13 in a patient who developed a retroperitoneal bleed while taking twelve capsules of PC-SPES daily. Warfarin was also detected in this patient's PC-SPES. It is important to understand that approximately 40% of prostate cancer patients, and between 26% and 80% of cancer patients, use some form of complementary or alternative therapy. Approximately 40% of the time, patients disclose use of these therapies to their physicians.14 In the United States, patients spend $250 million more on complementary and alternative therapies than on traditional primary care medicine. The conundrum of PC-SPES is that it was a drug widely and enthusiastically embraced by patients.15 It appeared to be a potentially useful intervention in patients with androgen-insensitive prostate cancer and the therapeutic index of the drug appeared to be acceptable, particularly when compared with similar medications, such as DES. However, the uniformity of the lots was uncertain. There were contaminants detected which had both the potential to increase toxicity and impact efficacy. Most importantly, the fact that potentially dangerous compounds, such as warfarin, were found in PC-SPES, led to withdrawal of the product from the market. This resulted in a loss of confidence in PC-SPES, and, possibly, other alternative therapies, by patients and medical professionals alike. The studies of PC-SPES clearly demonstrate the difficulties in doing clinical trials that employ natural compounds. It also emphasizes the absolute necessity for doing such studies. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
REFERENCES
1. Mathijssen RH, Verweij J, de Bruijn P, et al: Effects of St. John's wort on irinotecan metabolism. J Natl Cancer Inst 94:1247–1249, 2002 2. Anonymous: PC SPES® For Prostate Health: Product information. Brea, CA, BotanicLab, 2000 3. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com/Last accessed on July 2, 2004. 4. Pfeifer BL, Pirani JF, Hamann SR, et al: PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer. BJU Int 85:481–485, 2000[CrossRef][Medline] 5. 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 164:1229–1234, 2000[CrossRef][Medline]
6. 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 18:3595–3603, 2000 7. 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 57:122–126, 2001[Medline] 8. Burton T: Recall of Herbal Supplement Highlights Gaps in Regulations. WSJ, March 26, 2002
9. 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 339:785–791, 1998
10. Oh WK, Kantoff PW, Weinberg V, et al: A prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 22:3705-3712, 2004
11. Sovak M, Seligson AL, Knoas M, et al: Herbal composition PC-SPES for management of prostate cancer: Identification of active principles. J Natl Cancer Inst 94:1275–1281, 2002 12. Press release: State health director warns consumers about prescription drugs in herbal products, February 7, 2002, No. 02-03. http://www.dhs.ca.gov
13. Weinrobe MC, Montgomery B: Acquired bleeding diathesis in a patient taking PC-SPES. N Engl J Med 345:1213–1214, 2001
14. Eisenberg DM, Davis RB, Etner Sl, et al: Trends in alternative medicine use in the United States, 1990-1997: Results of a follow-up national survey. JAMA 280:1569–1575, 1998 15. Porterfield H: Survey of US-TOO members and other prostate cancer patients to evaluate the efficacy and safety of PC-SPES. Mol Urol 3:333–336, 1999[Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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