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Originally published as JCO Early Release 10.1200/JCO.2004.10.195 on August 2 2004 © 2004 American Society of Clinical Oncology. Prospective, Multicenter, Randomized Phase II Trial of the Herbal Supplement, PC-SPES, and Diethylstilbestrol in Patients With Androgen-Independent Prostate CancerFrom the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute; Department of Chemistry, Northeastern University; Massachusetts General Hospital Cancer Center; Beth Israel Deaconess Medical Center, Boston, MA; Department of Food Science and Center for Advanced Food Technology, Rutgers University; University of Medicine and Dentistry of New Jersey, Piscataway, NJ; and University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA Address reprint requests to Eric J. Small, MD, UCSF Comprehensive Cancer Center, 1600 Divisadero St, A718, San Francisco, CA 94115; e-mail: smalle{at}medicine.ucsf.edu
PURPOSE: To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC). PATIENTS AND METHODS: A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES.
RESULTS: Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines CONCLUSION: PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.
Treatment options are limited in androgen-independent prostate cancer (AIPC).1,2 Secondary hormonal therapy and chemotherapy demonstrate activity in 20% to 70% of patients, but response duration is typically 6 to 12 months.1,2 Clinical trials demonstrate significant activity of diethylstilbestrol (DES) in AIPC. A phase II study of 1 mg oral DES in 21 patients with AIPC demonstrated a  50% decline in prostate-specific antigen (PSA) in 43% of patients.3 Other studies confirm that DES (1 to 4 mg daily) has substantial activity in AIPC, with PSA declines 50% in 29% to 66% of patients.4 Herbal therapies are used with increasing frequency by prostate cancer patients.5 A popular herbal combination called PC-SPES was commercially available from 1996 to 2002.6 PC-SPES was a combination of eight herbal compounds: Ganoderma lucidum, Scutellaria baicalensis, Rabdosia rubescens, Isatis indigotica, Dendranthema morifolium, Seronoa repens (saw palmetto), Panax pseudoginseng, and Glycyrrhiza uralensis (licorice root). PC-SPES inhibited growth of androgen-sensitive and androgen-independent prostate cancer cells, both in vitro and in animal models.7-10 Antitumor effects were dose- and time-dependent,7,8 and toxicity in rodents was limited.10 Growth inhibitory effects were seen in different cell types, ranging from the androgen-sensitive (LNCaP)9,10 to the androgen-independent (DU145)9 to the aggressive Mat-Ly-Lu rat prostate cancer.8
Several investigators studied PC-SPES in AIPC.11,12 One analysis of 23 patients reported significant efficacy.11 Eighteen patients had received prior secondary hormonal treatment, while 10 had received prior chemotherapy, signifying a heavily pretreated group of patients. Fifty-two percent of patients had a PSA decline While PC-SPES had anticancer effects, its estrogenic properties raised the question of whether the observed effects exceeded those anticipated with estrogens alone. In this context, if PC-SPES had antitumor activity independent of an estrogenic effect, it would represent an additional therapeutic option for AIPC patients.13 The current trial was designed to evaluate the efficacy of PC-SPES following DES therapy and conversely, DES following PC-SPES therapy in patients with AIPC. Though PC-SPES had potent estrogenic activity by an estrogen receptor assay, high-performance liquid chromatography (HPLC) and gas chromatography (GC) of extracts failed to identify DES, estrone, and estradiol.6 However, in the midst of this clinical trial, reports indicated that two laboratories detected DES in some lots of PC-SPES.13 We therefore performed chemical analyses of the four lots used in this clinical trial. Because the results demonstrated contamination with DES, the clinical trial was halted prematurely. This report summarizes our findings at study closure and the results of chemical analyses of PC-SPES.
This clinical trial was approved by the institutional review boards of Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, Massachusetts General Hospital (Boston, MA), and University of California San Francisco Medical Center/San Francisco Veterans Affairs Medical Center (San Francisco, CA). All patients provided written informed consent before participation.
Eligibility
Treatment Plan
Dose Modifications and Response Criteria For grade 3 or greater Common Toxicity Criteria (CTC) other than anemia, loss of libido, or breast enlargement or tenderness, the daily dosage of PC-SPES was held until toxicity resolved to grade 1 or less, and then PC-SPES was reduced to two capsules three times a day. If grade 3 toxicity recurred despite the dose reduction, treatment was held until toxicity resolved to grade 1 or less. The dose was further reduced to one capsule three times a day. If grade 3 or greater toxicity persisted, the patient was removed from the study. Any patient requiring a more than 4-week delay in therapy was also withdrawn. No dose modification of DES was permitted. For grade 3 or greater CTC other than anemia, loss of libido, or breast enlargement or tenderness, the daily dosage was held until toxicity resolved to grade 1 or less. The patient was then retreated with DES at the same dose. If grade 3 or greater toxicity recurred, the patient was removed from the study. Any patient requiring a more than 4-week delay in therapy was also withdrawn. Patients who experienced any thromboembolic event, including deep venous thrombosis, pulmonary embolism, stroke, or myocardial infarction, were removed from the study. Prothrombin time was monitored every 4 weeks and warfarin adjusted to maintain INR less than 1.5. Response and progression, as well as the time to progression, were defined per the PSA Working Group.14
Statistical Considerations
From previous experience, Two underlying assumptions of this trial were that (1) there was no DES present in PC-SPES and (2) there was minimal lot-to-lot variability of PC-SPES content. However, because chemical analyses demonstrated variable amounts of DES in each lot, it was decided that the primary outcome measure (cross-over response rate) was uninterpretable and the study was halted. At first, patients responding to treatment were allowed to remain on treatment. However, by February 2002, the manufacturer voluntarily recalled PC-SPES, at which point all patients were removed from treatment.13,16
Detection of DES in PC-SPES Analytic samples were prepared from the residue of the isolation by sonicating with acetonitrile (1.0 mL/100 mg residue) at 20°C for 5 minutes and filtered through a 0.4 micron polytetrafluoroethylene membrane. Quantitation was based on HPLC area counts against known standard concentrations. Standards were run at 0.05 mg/mL through 1.0 mg/mL concentrations. Calculated DES amounts were the average of three determinations. The identity of DES was confirmed by GC/MS.
Detection of Ethinyl Estradiol (EE) in PC-SPES
A total of 90 patients were registered onto this trial. Five patients, three initially assigned to PC-SPES and two to DES, received only 1 month of treatment at the time the study closed and were nonassessable for response but evaluated for toxicity. Thus, 85 patients are considered assessable for response, 43 patients in the initial PC-SPES arm and 42 patients in the initial DES arm. The two groups were well balanced in terms of baseline characteristics (Table 1). In general, patients had an excellent performance status. All patients had progression of disease despite androgen deprivation therapy. Most patients had bone metastases, but approximately one-fifth of the patients had progressive disease evidenced by a rising PSA only. No differences in baseline testosterone, dihydrotestosterone, estradiol, estrone, sex hormone-binding globulin, DHEA, DHEA-S, or androstenedione levels were seen between groups (data not shown).
Response to Initial PC-SPES or DES PSA declines of 50% or greater were noted in 17 (40%) of 43 patients (95% CI, 25% to 56%) of the PC-SPES group and 10 (24%) of 42 patients (95% CI, 12% to 39%) of the DES group. Characteristics of responding patients in each group are noted in Table 2. The mean percentage decrease in PSA was comparable, as was the median time to response. However, several significant differences are noted. At the time the study closed, median response duration was not reached for responding patients on initial PC-SPES, but was 3.8 months for responding patients on initial DES. The duration of response for responders in the initial PC-SPES arm was censored as of the last dose of treatment and will not change. Also, for all randomly assigned patients, median time to progression was 5.5 months in the initial PC-SPES group and 2.9 months in the initial DES group (Fig 2). No differences in baseline hormone levels were seen between responders and nonresponders in either the PC-SPES or DES treated groups (data not shown).
Toxicity for initial therapy was comparable between the two groups (Table 3). The most common toxicity was grade 1 fatigue, gynecomastia, and mastodynia. Grade 3/4 toxicities were rare. Two patients (4%) on PC-SPES developed grade 3 diarrhea. Grade 3/4 hemorrhage was noted in two patients (2%), one on each treatment. Five episodes of thromboembolism were noted, one (2%) in the PC-SPES arm and four (9%) in the DES arm. There were no treatment-related deaths. Seven (15%) of 46 patients in the PC-SPES arm and two (5%) of 44 patients in the DES arm stopped warfarin therapy because of an INR > 2.
Response to Cross-Over Treatment A total of 24 patients developed progressive disease and were assessable for the cross-over. Twelve additional patients were not assessable due to the early termination of the study (never started cross-over therapy, n = 3; received only 1 month of cross-over therapy, n = 9). Six of the 16 patients treated with PC-SPES at cross-over had decreases in PSA ranging from 3% to 82%, with one patient achieving a 50% PSA decline lasting 1 month before the study closed. All four patients who had initially responded to DES had decreases in PSA with PC-SPES, but only two of 12 initial nonresponders to DES had any decrease in PSA with PC-SPES. Two of eight patients treated with DES at cross-over demonstrated a decrease in PSA, though neither achieved a 50% PSA response. One of two patients who responded to PC-SPES had a decrease with DES, while one of six nonresponders to PC-SPES had a subsequent decrease with DES. Patients received between 2 to 5 months of cross-over therapy until the study closed. Time to progression was not different between the two groups (data not shown). The only grade 3/4 toxicity reported with cross-over therapy was grade 3 fatigue with DES. At the time of study closure, 20 (47%) of 43 of initial PC-SPES-treated patients and 11 (26%) of 42 initial DES-treated patients were still receiving their initial therapy. Twelve and 11 patients were receiving cross-over therapy with DES and PC-SPES, respectively.
Detection of DES in PC-SPES
Detection of EE in PC-SPES Three lots were tested, one of which (lot 5431219) was also used in the clinical trial. Of note, this lot contained barely detectable amounts of DES. According to the 1H NMR and electron ionization GC/MS, the retention time of GC, and comparison with a standard sample, a compound was identified as EE. To confirm the presence and quantity of EE in the sample, electron ionization mass spectroscopy was used. Table 4 lists the weights of EE determined in three lots of PC-SPES.
Given the few effective therapeutic options and short, often symptomatic median survival of hormone refractory prostate cancer patients, it is not surprising that PC-SPES was such a popular therapeutic option for patients and their physicians. An oral therapy with a modest toxicity profile, PC-SPES appeared to have antitumor activity as measured by PSA declines that were comparable to the best secondary hormonal and chemotherapies available. In addition, as a natural therapy, it had tremendous appeal to patients. On the other hand, it was extremely expensive, seldom covered by insurance plans, and was not regulated by the US Food and Drug Administration or any other governmental organization that was able to assure consistent production and proper labeling. Indeed the appeal of combination herbal therapy as cancer treatment was in fact the very problem with PC-SPES—it remained unclear how it worked and which particular component(s) accounted for its clinical benefits. To study this question, we undertook a randomized trial of PC-SPES and DES with a cross-over design to determine whether the active ingredient in PC-SPES mimicked the mechanism of action of DES itself. Based on prior studies and assurances from the manufacturer, we made several assumptions, which later were found to be untrue. First, we assumed a production process that created a consistent product across lots. In fact, initial publications describing PC-SPES, as well as the company's own literature, cited a process of "HPLC-standardization" which, it was claimed, led to consistent lots of PC-SPES. Second, we assumed that no synthetic agents were present in PC-SPES, in particular DES itself. The subsequent observation of the presence of DES and EE in PC-SPES makes it extremely difficult to interpret the results observed. Although this trial was discontinued early, results at study closure suggest that PC-SPES has moderate activity in the treatment of AIPC and that this activity was similar to 3 mg DES. However, this study was not designed to directly compare these treatments. Conclusive cross-over analysis was not possible, though these data suggested that patients might respond to sequential therapies. There are several possible explanations for these results. The first is that PC-SPES indeed represents combination therapy, and that although small amounts of DES and EE are present in the mixture, these are additive or synergistic with plant estrogens present in the mixture and together produce an effect better than synthetic estrogen alone. Another possibility is that a single active agent in PC-SPES (eg, DES, EE, or as-yet-unidentified compound) is responsible for the anticancer effects noted. No dose-finding studies have been undertaken with DES in prostate cancer, with the lowest reported doses being 1,000 µg. Thus it is difficult to know if 0.3 to 94.2 µg of DES could have anticancer activity, though this is unlikely. Recent reports confirm our findings.17,18 Sovak et al17 reported the presence of DES in PC-SPES lots manufactured from 1996 to 1999 at doses of 107 to 159 µg/g. In lots manufactured from 1999 to 2001, DES was noted in declining concentrations (0 to 46 µg/g). In addition, warfarin and indomethacin was detected. The California Department of Health Services (CDHS) detected warfarin, indomethacin, DES, and EE in various lots of PC-SPES.19 While in the present study, warfarin levels were not measured, these results are interesting in light of the fact that 15% of patients receiving PC-SPES required cessation of warfarin therapy because of an INR > 2, compared with 5% of DES patients. Furthermore, CDHS found significant lot-to-lot and within-lot variation in the concentration of the contaminants. Recent laboratory studies have further explored PC-SPES activity. In one study, cDNA microarray analysis was performed on LNCaP cells exposed to PC-SPES and DES.20 PC-SPES altered the expression of 156 genes, including marked downregulation of transcripts encoding alpha- and beta-tubulins, cell-cycle regulatory proteins, and androgen receptor. By comparison, DES altered expression of only 62 genes, only six (10%) of which were concordant with changes seen with PC-SPES. In another microarray study, the profile signatures of PC-SPES, DES, and another herbal combination (PC-CARE) were compared.21 Gene expression profiles induced by PC-SPES and DES were again different in LNCaP cells. However, PC-CARE and DES had similar profiles, though PC-CARE has the same component herbs as PC-SPES. These studies confirm the complex and uncertain nature of unregulated herbal combinations. Our experience demonstrates the difficulty of applying standard clinical trial design to the study of complex herbal combinations, especially when uniform production standards and quality control are not used.22 It remains to be seen whether the efficacy of such herbal combinations can be validated unless the purity of these treatments is assured.
The authors indicated no potential conflicts of interest.
Supported by a grant from the C. Brendan Noonan Jr. Charitable Foundation (to W.K.O.) and CaPCURE (to E.J.S.). Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18–21, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Gilligan T, Kantoff PW: Chemotherapy for prostate cancer. Urology 60:94–100, 2002 (3 suppl 1)[CrossRef][Medline] 2. Oh WK: Secondary hormonal therapies in the treatment of prostate cancer. Urology 60:87–93, 2002 (3 suppl 1)[CrossRef][Medline] 3. Smith DC, Redman BG, Flaherty LE, et al: A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer. Urology 52:257–260, 1998[CrossRef][Medline] 4. Oh WK: The evolving role of estrogens in prostate cancer. Clinical Prostate Cancer 1:81–89, 2002[Medline] 5. Nam RK, Fleshner N, Rakovitch E, et al: Prevalence and patterns of the use of complementary therapies among prostate cancer patients: An epidemiological analysis. J Urol 161:1521–1524, 1999[CrossRef][Medline]
6. 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 7. Halicka HD, Ardelt B, Juan G, et al: Apoptosis and cell cycle effects induced by extracts of the Chinese herbal preparation PC-SPES. Int J Oncol 11:437–448, 1997 8. Tiwari RK, Geliebter J, Garikapaty VP, et al: Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. Int J Oncol 14:713–719, 1999[Medline] 9. 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] 10. Kubota T, Hisatake J, Hisatake Y, et al: PC-SPES: A unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo. Prostate 42:163–171, 2000[CrossRef][Medline] 11. 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]
12. Small E, Frohlich M, 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 13. Oh WK, Small EJ: Complementary and alternative therapies in prostate cancer. Semin Oncol 29:575–584, 2002[Medline]
14. Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17:3461–3467, 1999 15. PC-SPES, Package insert. Botaniclab, Brea, CA 16. Press release: State health director warns consumers about prescription drugs in herbal products, February 7, 2002, No. 02-03. http://www.dhs.ca.gov.
17. 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 94:1275–1281, 2002 18. Guns ES, Goldenberg SL, Brown PN: Mass spectral analysis of PC-SPES confirms the presence of diethylstilbestrol. Can J Urol 9:1684–1688, 2002[Medline] 19. Ko R, Wilson RD, Loscutoff S: Letter to the editor: PC-SPES. Urology 61:1292, 2003[Medline]
20. Bonham M, Arnold H, Montgomery B, et al: Molecular effects of the herbal compound PC-SPES: Identification of activity pathways in prostate carcinoma. Cancer Res 62:3920–3924, 2002 21. Bigler D, Guilding KM, Dann R, et al: Gene profiling and promoter reporter assays: Novel tools for comparing the biological effects of botanical extracts on human prostate cancer cells and understanding their mechanisms of action. Oncogene 22:1261–1272, 2003[CrossRef][Medline]
22. White J: PC-SPES—a lesson for future dietary supplement research. J Natl Cancer Inst 94:1261–1263, 2002 Submitted October 31, 2003; accepted April 17, 2004. Related Editorial
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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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ABSTRACT
INTRODUCTION
2 statistic for categoric variables, a t statistic for continuous variables, and the nonparametric Mann-Whitney test to compare distributions. The duration of response and time to disease progression were estimated using the Kaplan-Meier product limit method. 
50% of the patients were expected to respond to initial PC-SPES or DES.
