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© 2000 American Society for Clinical Oncology
Prospective Trial of the Herbal Supplement PC-SPES in Patients With Progressive Prostate CancerFrom the University of California at San Francisco, San Francisco, CA; and Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Eric J. Small, MD, University of California at San Francisco, UCSF Comprehensive Cancer Center, 1600 Divisadero, 3rd Floor, San Francisco, CA 94115; email smalle{at}medicine.ucsf.edu ABSTRACT PURPOSE: PC-SPES is an herbal supplement for which there are anecdotal reports of anti–prostate cancer activity. This phase II study was undertaken to assess the efficacy and toxicity of PC-SPES in prostate cancer patients. PATIENTS AND METHODS: Thirty-three patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgen-independent prostate cancer (AIPCa) were treated with PC-SPES at a dose of nine capsules daily. Clinical outcome was assessed with serial serum prostate-specific androgen (PSA) level measurement and imaging studies.
RESULTS: One hundred percent of ADPCa patients experienced a PSA decline of CONCLUSION: PC-SPES seems to have activity in the treatment of both ADPCa and AIPCa and has acceptable toxicity. Further study is required to determine whether its effects exceed those expected with estrogen therapy. PC-SPES IS AN HERBAL preparation that has become popular among patients with prostate cancer as an alternative to conventional androgen-deprivation therapy and as second-line treatment for progressive androgen-independent disease.1-5 PC-SPES is sold as a dietary supplement and consists of extracts from eight different herbs, many of which have been reported to have antineoplastic or immunomodulatory activity.6-23 Preclinical prostate cancer models suggest that PC-SPES has some antitumor activity. In the androgen-dependent LNCaP human prostate cancer cell line, ethanolic extracts of PC-SPES inhibited proliferation in vitro.24 Decreased cell growth was accompanied by decreased expression of proliferating cell nuclear antigen (PCNA) and androgen receptor. In a second study, PC-SPES markedly inhibited clonal growth of LNCaP, PC-3, and DU-145 prostate cancer cells and seemed to induce cell cycle arrest.25 PC-SPES has also exhibited a dose-dependent inhibitory effect on tumorigenesis and cancer progression when provided as a dietary supplement in the Dunning R3327 rat prostate cancer model.26 DiPaola et al2 reported results in eight patients with androgen-dependent prostate cancer who were treated with PC-SPES and noted prostate-specific antigen (PSA) declines in all patients. Estrogenic side effects were seen in all eight patients, and serum testosterone concentrations declined to the castrate range in six of eight treated men. One patient developed a deep venous thrombosis. Preclinical testing in LNCaP cells had previously demonstrated that PC-SPES extracts resulted in downregulation of PSA secretion, so the significance of declining PSA values observed with PC-SPES therapy was unclear. Companion in vitro studies using a transcriptional activation assay in yeast and a biologic assay in mice demonstrated estrogenic activity of ethanolic extracts of PC-SPES. However, high-performance liquid chromatography, gas chromatography, and mass spectrometry failed to identify estradiol, estrone, or diethylstilbestrol (DES) in PC-SPES, suggesting that its putative estrogenic properties were not due to known physiologic estrogens.2 A case report of one patient with localized prostate cancer treated with PC-SPES also noted significant PSA decline and estrogenic side effects such as breast tenderness, gynecomastia, and decreased libido. Pfeifer et al4 reported on 16 patients with androgen-independent prostate cancer treated with PC-SPES and noted that 13 of 16 had a decline in PSA of more than 50%. Given the widespread use of PC-SPES in the community and early reports of anti–prostate cancer activity, a phase II study in patients with advanced prostate cancer was conducted. This clinical trial sought to evaluate the efficacy and toxicity of PC-SPES in a prospective, controlled setting in patients with androgen-dependent (hormone-sensitive) and androgen-independent prostate cancer. PATIENTS AND METHODS Eligible patients had histologically confirmed adenocarcinoma of the prostate, with evidence of disease progression defined by an increasing PSA level on at least three occasions 1 week or more apart, the development of new abnormalities on bone scan, or evidence of tumor growth on computed tomography (CT) scan. Patients with androgen-dependent prostate cancer had evidence of disease progression in the setting of non–anorchid testosterone levels, defined arbitrarily as more than 120 ng/mL. Prior androgen deprivation was permitted in the adjuvant and neoadjuvant setting, provided it was completed more than 6 months before study entry and was not used to treat progressive disease. Patients with androgen-independent prostate cancer had evidence of disease progression despite castrate levels of testosterone (< 50 ng/mL) and documented disease progression after antiandrogen withdrawal. Ongoing androgen deprivation with a luteinizing hormone-releasing hormone (LHRH) analog was required in those androgen-independent prostate cancer patients who had not undergone orchiectomy.
No new therapy was allowed within 30 days of study entry, including the use of investigational agents, chemotherapy, hormonal agents (including megestrol acetate or corticosteroids), or any herbal or dietary supplements. Required laboratory parameters for all patients included WBC Eligible patients underwent pretreatment laboratory evaluation, ECG, bone scan, and CT scan of the abdomen and pelvis. A transrectal ultrasound of the prostate was undertaken in patients who had not undergone prior prostatectomy or primary radiation therapy. Patients were evaluated with a history and physical examination at study entry and at weeks 1, 2, and 4. Thereafter, patients were seen once a month until month 3 and then every 3 months thereafter. In addition to a complete history and physical examination at each visit, patients were questioned about anticipated toxicities, including breast enlargement and tenderness, loss of libido and potency, leg cramps, and fatigue. Formal instruments evaluating sexual function or quality of life were not used. Prostatic acid phosphatase (PAP) was measured at baseline and, if elevated, was measured monthly thereafter. PSA and testosterone levels were checked pretreatment and monthly thereafter. Complete blood cell count and chemistries, including electrolytes, blood-urea nitrogen, creatinine, AST, ALT, alkaline phosphatase, total bilirubin, and lactate dehydrogenase, were checked at baseline and then monthly until month 3 and then every 3 months thereafter. If imaging studies (bone scan, CT scan, transrectal ultrasound) were positive at baseline, then they were repeated every 3 months. Patients received 320-mg capsules, one orally tid for 1 week. If there were no apparent adverse events, the dose was escalated to two capsules orally tid for a week and then once again to the maximum dose of three capsules orally tid. The maximum PC-SPES dose was empirically based on a regimen commonly used in the community. PC-SPES was purchased at cost from the manufacturer (Botanic Labs, Brea, CA) and provided at no cost to patients. All of the PC-SPES used in this study was obtained from a single lot. Because absorption characteristics are unknown, patients were asked to take PC-SPES on an empty stomach. Patients did not receive concomitant anticoagulants. At each visit, toxicity was graded according to the National Cancer Institute common toxicity criteria (CTC, version 2.0) and recorded. In the event of any grade 2 or higher toxicity (excluding anemia, alopecia, or effects associated with a low testosterone level, such as gynecomastia, gynecodynia, decreased libido, or impotence), PC-SPES therapy was held until toxicity resolved to grade 1 or less. At that time, PC-SPES therapy could be reinitiated at a decreased dose of two pills orally tid. In the event of any recurrent grade 2 or higher toxicity or persistent (> 3 weeks) grade 2 or higher toxicity after PC-SPES discontinuation, an additional dose de-escalation was permitted to one pill orally tid. Further grade 2 or higher toxicity or any thromboembolic event (deep vein thrombosis, pulmonary embolus, myocardial infarction, or stroke) at any dose level resulted in immediate discontinuation of therapy and withdrawal of the patient from the study.
End Points and Statistical Design Gehan’s two-stage design28 was used for each cohort individually to detect a response proportion of at least 15%. If no responses were seen in the first 19 patients, accrual to that cohort was to be stopped, whereas if at least one response was seen, then the study was to accrue to a total of 30 patients per cohort to allow the estimation of the response proportion with a 95% confidence interval of at most ± 17.9%. Overaccrual to 35 patients per cohort was permitted to allow for potentially unassessable patients. A second end point of this study was to describe the safety profile of PC-SPES. In particular, the true incidence of thromboembolic events was sought. With 30 patients in each cohort, this study had 80% power to reject a 20% rate of thromboembolic disease in favor of a 5% rate at the 5% significance level. The 5% target for the thromboembolic disease rate was felt to represent the natural incidence of thromboembolic disease in advanced prostate cancer patients. If the incidence of thromboembolic disease was pooled across both cohorts (60 assessable patients), then the study would have 80% power to reject a 15% rate in favor of a 5% rate. RESULTS
Patient Characteristics Patient characteristics of both cohorts are listed in Table 1. In the androgen-dependent group, the median pretreatment PSA level was 7.9 ng/mL (range, 0.9 to 81 ng/mL), the median age was 64 years (range, 48 to 86 ng/mL), and the median baseline testosterone level was 392 ng/mL (range, 127 to 664 ng/mL). (One ineligible androgen-dependent patient had a testosterone level of 64 ng/mL.) Two patients (6%) had bone metastases, one had a measurable mass (by CT) in the bladder, 12 patients (36%) had untreated localized disease, 10 patients (30%) had local recurrence, and eight patients (24%) had PSA recurrence only after primary local therapy. Of patients with locally recurrent disease, prior therapy consisted of radical prostatectomy alone in six patients, external-beam radiotherapy alone in seven patients, and radical prostatectomy plus radiation therapy in eight patients. Two patients had undergone prior cryosurgery. Seven patients had received prior neoadjuvant or adjuvant androgen deprivation for 3, 3, 4, 6, 6, 12, and 13 months 2 years or more before study enrollment. Four patients had received prior investigational therapy consisting of liarozole.
The patients with androgen-independent prostate cancer had more advanced disease. The median pretreatment PSA level in this cohort was 60.7 ng/mL (range, 1.8 to 3,433 ng/mL). Median age was 68 years (range, 43 to 89 years). Median testosterone level was 12 ng/mL (range, 0 to 40 ng/mL). (Two ineligible patients had testosterone levels of 58 and 81 ng/mL.) Twenty-seven patients had metastatic disease to bone; of these, one patient also had measurable disease (pulmonary nodules). Six patients had locally recurrent disease, and four had PSA-only recurrences. All patients had received prior therapy with combined-androgen blockade, and all had experienced disease progression despite antiandrogen withdrawal. Sixteen (43%) had received second-line ketoconazole, three (9%) had received prior chemotherapy, and 17 (50%) had received prior investigational therapy, consisting of immunotherapy (n = 14), radiolabeled monoclonal antibody (n = 2), or suramin (n = 1).
Clinical Outcome Androgen-independent cohort. Overall, 19 (54%) of 35 patients had a PSA decline of more than 50% (95% confidence interval [CI], 37% to 71%). The median PSA decline was 55% (range, 0% to 99%). Notably, in those patients who had previously developed progressive disease despite ketoconazole therapy, eight (50%) of 16 obtained a more than 50% decline in PSA on treatment with PC-SPES. The median time to PSA nadir for the entire cohort was 10 weeks. The median duration of PSA decline for all responders (including those who were removed from treatment for adverse events) was 18 weeks (range, 3 to 61+ weeks), and the median time to PSA progression for all assessable patients was 16 weeks (range, 2 to 69+ weeks). Nine patients had a baseline PAP elevated above the ULN along with an elevated PSA level. All nine patients experienced a more than 50% decline in both PSA and PAP on treatment with PC-SPES. Twenty-five assessable patients had positive bone scans at baseline. Improvement was seen in two patients, as evidenced by the resolution of multiple lesions in ribs and skull of one patient and of one rib lesion in a second patient. Five patients did not undergo repeat bone scanning because they had progressive disease by PSA criteria. The remaining 18 patients had stable bone scans, although ultimately, all but seven patients developed progressive disease. Seven patients have unchanged bone scans at 8, 10, 12, 12, 25, 36, and 49 weeks after starting therapy. The only patient with measurable disease (pulmonary nodules) had stable disease at 16 months. Of 35 androgen-independent patients who were assessable for response, 30 have been removed from therapy because of progressive disease or adverse events. The median duration of therapy was 16 weeks (range, 2 to 69+ weeks). Progressive disease was defined by changes on bone scan in 11 patients and by PSA changes in 13 patients. Six patients stopped therapy because of adverse events or by patient choice (see Toxicity). Five patients remain on therapy with ongoing PSA declines at 47 to 69 weeks (median, 55 weeks). The median actuarial survival in the 28 patients with metastatic androgen-independent prostate cancer has not been reached at a median follow-up of 13.3 months. Clinical outcome data are listed in Table 2.
Endocrine Effects Androgen-dependent cohort. In the androgen-dependent cohort of patients (Table 3), testosterone levels declined to less than 50 ng/mL in 31 (97%) of 32 patients and to less than 30 ng/mL in 30 patients. Only one patient’s testosterone level did not fall below 50 ng/mL, declining from 400 to 97 ng/mL. Although baseline sex hormone-binding globulin (SHBG) levels were not obtained, a one-time measurement was obtained in 29 hormone-naive patients at or near the point of PSA nadir. The median SHBG level was markedly elevated at 275 nmol/L (normal, 13 to 71 nmol/L), with a range of 109 to 499 nmol/L. At study entry, libido (defined as sex drive or an interest in sex) was reported by 24 patients (75%). During the course of therapy with PC-SPES, all 24 patients reported a complete or near-complete loss of libido. At study entry, 15 patients reported the ability to have an erection. All 15 reported losing the ability to have an erection after initiation of PC-SPES therapy. At baseline, no patient was experiencing hot flushes, breast tenderness, or breast enlargement. However, after initiation of therapy, 11 patients (34%) began to experience hot flushes, whereas 32 (100%) developed new breast tenderness and/or enlargement.
Androgen-independent cohort. All 35 assessable patients had a pretreatment testosterone level of less than 50 ng/mL. Twenty-four patients were experiencing hot flushes at baseline. Of these, 17 (71%) reported complete or near complete resolution of hot flushes after therapy with PC-SPES. Of the 13 patients who did not have hot flushes at baseline, eight (62%) developed new hot flushes during the course of treatment with PC-SPES. Thirty patients reported no gynecomastia or mastodynia at baseline, but of these nearly all (28 of 30, or 93%) subsequently developed breast enlargement or tenderness with PC-SPES treatment.
Toxicity
In the androgen-sensitive group, seven patients discontinued therapy. The reasons for discontinuation of therapy were thromboembolic disease (n = 2), breast tenderness (n = 1), leg cramps (n = 1), patient choice to pursue definitive local therapy (n = 1), loss of libido (n = 1), and hypertriglyceridemia (n = 1). In the androgen-independent group, 30 patients have discontinued therapy, 24 for progressive disease and six for adverse events. Adverse events necessitating treatment discontinuation included allergic reactions (n = 2), pulmonary embolism (n = 1), elevated liver transaminases (n = 1), congestive heart failure (n = 2; this was felt to be unrelated to PC-SPES), and acute renal insufficiency (n = 1 in one of the patients with congestive heart failure; this was also felt to be unrelated to PC-SPES). DISCUSSION This controlled prospective study has evaluated the clinical activity and safety of the herbal dietary supplement PC-SPES in prostate cancer patients with progressive disease. These data indicate that PC-SPES can produce PSA declines and improvement in bone scans in some patients with both androgen-dependent and androgen-independent prostate cancer.
In patients with androgen-dependent disease, PC-SPES produced PSA declines of Although the estrogenic nature of PC-SPES has been previously described in a small number of hormone-naive prostate cancer patients,2,3 the exact mechanism of action of PC-SPES remains unknown. In the present study, 97% of patients with androgen-dependent disease developed anorchid levels of testosterone while on PC-SPES, usually by 8 weeks. Libido and potency were assessed during each study visit, although formal quality-of-life instruments were not used, as this was not a primary aim of the study. Although it has been suggested that patients generally underreport sexual dysfunction to their physicians,30 the intent of this assessment was hypothesis generation and not accurate assessment of sexual dysfunction. Libido was present in 75% of patients at study entry, and 100% of these patients reported a loss in libido. Similarly, 15 of 32 androgen-dependent prostate cancer patients were potent at study entry, and all experienced total or near-total impotence after treatment with PC-SPES. These findings are consistent with the observation that the testosterone level fell to anorchid levels in virtually all androgen-dependent patients. Several clinical and laboratory features of this study support the contention that the androgen deprivation achieved by PC-SPES is mediated by estrogen-like effects. Like estrogens, PC-SPES resulted in gynecomastia or gynecodynia in 100% of hormone-naive patients. The development of hot flushes in one third of patients is consistent with androgen deprivation although not consistent with an estrogenic effect, which tends to be protective against hot flushes. It is possible that in some patients the androgen-depriving effects of PC-SPES outweigh its estrogenic effects. It has also been observed that exogenous administration of estrogen results in a five- to 10-fold increase in SHBG,31 which results in increased binding of testosterone, and reduction of free testosterone. It is not known whether this effect contributes to the anti–prostate cancer efficacy of estrogens. Nevertheless, it is of interest to note that of 28 patients with hormone-naive prostate cancer treated with PC-SPES who had SHBG levels measured, all had a large elevation of SHBG level at the time of PSA (and testosterone) nadir. Free testosterone levels were not measured. The mean SHBG level in PC-SPES patients was 275 nmol/L (normal, 13 to 71 nmol/L), compared with a mean level of 50.3 nmol/L in 16 control androgen-dependent prostate cancer patients who had anorchid testosterone levels as a consequence of LHRH agonist therapy (data not shown). These data suggest that PC-SPES therapy, like estrogens, results in increased SHBG levels. PC-SPES also induced PSA declines of more than 50% in 54% of patients with androgen-independent prostate cancer, with a median PSA decline duration of 4.5 months. However, there was a wide range of duration, with four patients experiencing PSA declines exceeding 1 year. Although changes in bone scan are difficult to use as markers of response, two androgen-independent patients demonstrated improvements in bone scan along with a PSA decline of more than 50%. The five patients who maintain unchanged bone scans have also had PSA declines of more than 50%. Of nine androgen-independent prostate cancer patients with PAP levels greater than the ULN, all had a more than 50% decline with PC-SPES therapy. The utility of PAP decline as a marker of outcome in androgen-independent prostate cancer patients has been previously described32 and was also used as confirmatory evidence of potential anticancer activity of PC-SPES. The proportion of androgen-independent patients experiencing a more than 50% decline in PSA and the duration of PSA declines that were observed with PC-SPES seem comparable to those of a secondary hormonal maneuver such as ketoconazole33 or estrogens.34 The efficacy of second-line estrogens has been appreciated for some time, although contemporary (PSA) assessment of estrogenic therapy in androgen-independent prostate cancer is less well documented. Smith et al34 treated 21 patients with metastatic androgen-independent prostate cancer with 1 mg of DES per day and noted PSA declines of more than 50% in 43% of patients (95% CI, 22% to 64%), overlapping with the results observed with PC-SPES in this study (54%; 95% CI, 37% to 71%). However, these investigators observed a response proportion of only 13% when DES was used in patients who had received more than one prior hormone treatment. In the comparable population in this study, of 16 patients who had previously been treated with ketoconazole and were subsequently treated with PC-SPES, eight (50%) experienced a more than 50% decline in PSA. The numbers of patients treated are small and represent a subset analysis. Nevertheless, these data raise the possibility that the responses observed with PC-SPES exceed those anticipated with estrogen alone and warrant further investigation. Few patients in this study had measurable disease, so that the effect of PC-SPES on bidimensionally measurable disease also needs further study. The use of complementary and alternative medical therapies, particularly in cancer patients, is common.35,36 However, few such therapies have been evaluated in a rigorous fashion, and attention has recently been drawn to the risks of untested and unregulated remedies.37 Additionally, there may exist literally hundreds of unique compounds in an herbal mixture such as PC-SPES, making it difficult to identify the active agent(s) and impossible to assure inter- and intralot variability. Nevertheless, PC-SPES is in wide use, and carefully conducted clinical trials are essential to evaluate the risk/benefit ratio associated with its use. This study evaluated not only the efficacy but also the potential toxicity of PC-SPES. In this study of 70 patients, PC-SPES was found to be generally well tolerated. Common side effects were those seen with androgen deprivation and/or estrogen therapy, including loss of libido and potency, gynecomastia, and gynecodynia. Other adverse events seen with PC-SPES therapy that are not commonly associated with androgen deprivation or estrogen therapy include grade 1 or 2 diarrhea in 39%, mild leg cramps in 68%, and grade 1 or 2 nausea in 13%. Of concern, three thromboembolic events were observed (4.3% incidence rate), two in patients with androgen-dependent disease and one in a patient with androgen-independent prostate cancer. Two additional patients developed grade 3 congestive heart failure and two patients had atrial arrhythmias (one grade 2 and one grade 3). The incidence of grade 3 or higher cardiovascular or thromboembolic toxicity was therefore 8.6% (six of 70 patients), compared with reported rates of 30% or more of patients treated with 2 or 3 mg of DES daily.38-40 Although a direct comparison requires a randomized trial, these data suggest that the thromboembolic toxicity of PC-SPES seems to be less than that seen with DES. Whether the thromboembolic events observed in this trial can be attributed to PC-SPES cannot be determined with certainty, because prostate cancer patients seem to be at increased risk of hypercoagulable events. In fact, one study of 209 men with a diagnosis of prostate cancer reported that 12 (5.7%) had an antecedent history of idiopathic deep vein thrombosis or pulmonary embolus, compared with 1.1% in control subjects with benign prostatic hypertrophy.41 Nevertheless, the possibility that PC-SPES is associated with an increased risk of thromboembolic events should be taken seriously, and the use of this herbal preparation in patients with a history of cardiovascular disease cannot be routinely recommended. The use of PC-SPES in patients with androgen-dependent prostate cancer, for whom safe and accepted conventional androgen-deprivation therapies exist, must be evaluated carefully in light of these toxicities. By contrast, the small risk of thromboembolism may be more acceptable for androgen-independent prostate cancer patients, particularly those who have developed progressive disease while receiving ketoconazole, for whom there exist few noncytotoxic therapeutic alternatives. The utility of prophylactic anticoagulation to prevent thromboembolic events in patients receiving PC-SPES is unknown and requires study before it can be routinely recommended. In summary, the effect of PC-SPES on PSA level and its toxicity were evaluated by this prospective, controlled study. PC-SPES seems to have potent hormonal effects that result in androgen deprivation and subsequent antitumor effects in patients with androgen-dependent prostate cancer. How such therapy compares with more conventional means of androgen deprivation is not known, but comparative trials may be worth pursuing. PC-SPES also seems to result in PSA declines in androgen-independent prostate cancer patients, including those who have developed progressive disease despite second-line hormone therapy with ketoconazole. In some patients, these PSA declines were associated with other measures of tumor response. Whether these effects exceed those expected with estrogens requires further investigation. These findings also suggest that future prospective trials of novel agents for the treatment of androgen-independent prostate cancer should control for the potentially confounding effect of concomitant PC-SPES therapy. NOTE ADDED IN PROOF One patient in the androgen-dependent group has developed objective progressive disease after initial PSA decline from 7.4 to 0.1 ng/mL with PC-SPES. Progressive disease developed after 15 months of PC-SPES and in the setting of an anorchid testosterone level.
ACKNOWLEDGMENTS Supported by CaP CURE, Santa Monica, CA. NOTES Presented in part at the Thirty-Fifth Annual Meeting of the American Society for Clinical Oncology, Atlanta, GA, May 15-18, 1999. REFERENCES 1. Porterfield H: Survey of UsToo members and other prostate cancer patients to evaluate the efficacy and safety of PC-SPES. Mol Urol 3: 333-337, 1999[Medline]
2.
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 3. 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 54: 319-324, 1999[Medline] 4. Pfeifer BL, Pirani JF, Hamann SR, et al: PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer. Br J Urology 85: 481-485, 1999 5. de la Taille A, Hayek OR, Buttyan R, et al: Effects of a phytotherapeutic agent, PC-SPES, on prostate cancer: A preliminary investigation on human cell lines and patients. Br J Urology 84: 845-850, 1999 6. Huang HC, Hsieh LM, Chen HW, et al: Effects of baicalein and esculetin on transduction signals and growth factor expression in T-lymphoid leukemia cells. Eur J Pharmacol 268: 73-78, 1994[Medline] 7. Chen X, Han R: Effect of glycyrrhetinic acid on DNA damage and unscheduled DNA synthesis induced by benzo(alpha)pyrene. Chin Med Sci J 10: 16-19, 1995[Medline] 8. Zani F, Cuzzoni MR, Daglia M, et al: Inhibition of mutagenicity in Salmonella typhimurium by Glycyrrhiza glabra extract, glycyrrhizic acid, 18 alpha and 18 beta-glycyrrhetinic acids. Planta Med 59: 502-507, 1993[Medline] 9. Okada K, Tmura Y, Yamamoto M, et al: Identification of antimicrobial and antioxidant constituents from licorice of Russian and Xinjiang origin. Chem Pharm Bull Tokyo 37: 252-258, 1989 10. Hasegawa H, Sung JH, Matsumiya S, et al: Reversal of daunomycin and vinblastine resistance in multi-drug resistant P388 leumemia in vitro through enhanced cytotoxicity by triterpenoids. Planta Med 61: 409-413, 1995[Medline] 11. Yun TK, Choi SY: Preventive effect of ginseng intake against various human cancers: A case-control of 1987 pairs. Cancer Epidemiol Biomarkers Prev 4: 401-408, 1995[Abstract] 12. Yun TK, Yun YS, Han IW: Anticarcinogenic effect of long-term oral administration of red ginseng on newborn mice exposed to various chemical carcinogens. Cancer Detect Prev 6: 515-525, 1983[Medline] 13. Lee YN, Lee HY, Chung HY, et al: In vitro induction of differentiation by ginsenoides in F9 teratocarcinoma cells. Eur J Cancer 32: 1420-1428, 1996 14. Mochizuki M, Yoo YC, Matsuzawa K, et al: Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside Rb2, 20 (R)- and 20 (S)-ginsenoside-Rg3, of red ginseng. Biol Pharm Bull Tokyo 18: 1197-1202, 1995 15. Sato K, Mochizuki M, Saiki I, et al: Inhibition of tumor angiogenesis and metastasis by saponin of Panax ginseng, ginsenoside-Rb2. Biol Pharm Bull Tokyo 17: 635-639, 1994 16. Wang G, Zhang J, Misuno T, et al: Antitumor active polysaccharides from the Chinese mushroom songshan lingzhi, the fruiting body of Ganoderma tsugae. Biosci Biotechnol Biochem 57: 894-900, 1993[Medline] 17. Shang J, Wang G, Li H, et al: Antitumor active protein-containing glycans from the Chinese mushroom songshan lingzhi, Ganoderma tsugae mycelium. Biosci Biotechnol Biochem 58: 1202-1205, 1997 18. Maruyama H, Yamazaki K, Murofushi S, et al: Antitumor activity of Sarcondon aspratus (Ber.) S. Ita and Ganoderma lucidum (Fr.) Karst. J Pharmacobiodyn 12: 118-123, 1989[Medline] 19. Chen WC, Hau DJ, Wang CC, et al: Effects of Ganoderma lucidum and krestin on cellular immunocompetence in gamma-ray-irradiated mice. Am J Chin Med 23: 71-80, 1995 20. Tanaka S, Ko K, Kino K, et al: Complete amino acid sequence of an immunomodulatory protein, ling Zhi-8: An immunomodulator from a fungus, Ganoderma lucidum, having similarity to immunoglobulin variable regions. J Biol Chem 264: 16272-16377, 1989 21. Austine CA, Patel S, Ono K, et al: Site-specific DNA cleavage by mammalian DNA topoisomerase II induced by novel flavone and catechin derivatives. Biochem J 282: 883-889, 1992 22. Matsuzaki Y, Kurokawa N, Terai S, et al: Cell death induced by baicalein in human hepatocellular carcinoma cell lines. Japan J Cancer Res 87: 170-177, 1996[Medline] 23. Motoo Y, Sawabu N: Antitumor effects of saikosaponins, baicalin, and baicalein on human hepatoma cell lines. Cancer Lett 86: 91-95, 1994[Medline] 24. Hsieh T, Chen SS, Wang X, et al: Regulation of androgen receptor (AR) and prostate specific antigen (PSA) expression in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation, PC-SPES. Biochem Mol Biol Int 42: 535-544, 1997[Medline] 25. 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[Medline] 26. 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]
27.
Bubley G, 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 28. Hanfelt JJ, Slack RS, Gehan EA: A modification of Simon’s optimal design for phase II trials when the criterion is median sample size. Control Clin Trials 20: 555-566, 1999[Medline]
29.
Eisenberger M, Blumenstein B, Crawford ED, et al: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339: 1036-1042, 1998
30.
Talcott JA, Rieker P, Clark JA, et al: Patient-reported symptoms after primary therapy for early prostate cancer: Results of a prospective cohort study. J Clin Oncol 16: 275-283, 1998 31. Burton RM, Westphal U: Steroid hormone binding proteins in a blood plasma. Metabolism 21: 253-276, 1972[Medline] 32. Steineck G, Kelly WK, Mazumdar M, et al: Acid phosphatase: Defining a role in androgen-independent prostate cancer. Urology 47: 719-726, 1996[Medline]
33.
Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: A shifting paradigm. J Clin Oncol 15: 382-388, 1997 34. Smith DC, Redman BG, Flaherty LE, et al: A phase II trial of oral diethylstilbestrol as a second-line hormonal agent in advanced prostate cancer. Urology 52: 257-260, 1998[Medline]
35.
Eisenberg DM, Kessler RC, Foster C, et al: Unconventional medicine in the United States: Prevalence, costs, and patterns of use. N Engl J Med 328: 246-252, 1993 36. 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[Medline]
37.
Angell M, Kassirer JP: Alternative medicine: The risks of untested and unregulated remedies [editorial]. N Engl J Med 339: 839-841, 1998 38. Klotz L, McNeill I, Fleshner N: A phase 1-2 trial of diethylstilbestrol plus low dose warfarin in advanced prostate carcinoma. J Urol 161: 169-172, 1999[Medline] 39. deVoogt HJ, Smith PH, Pavone-Macaluso M, et al: Cardiovascular side effects of diethylstilbestrol, cyproterone acetate, medroxyprogesterone acetate and estramustine phosphate used for the treatment of advanced prostatic cancer: Results from European Organization for Research on Treatment of Cancer trials 30761 and 30762. J Urol 135: 303-307, 1986[Medline] 40. Chang A, Yeap B, Davis T, et al: Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: Flutamide versus diethylstilbestrol. J Clin Oncol 14: 2250-2257, 1996[Abstract] 41. Oefelein MG, Brant M, Crotty K: Idiopathic thromboembolism as the presenting sign of occult prostate cancer. Urology 51: 775-780, 1998[Medline] Submitted April 19, 2000; accepted July 18, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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80%, with a median duration of 57+ weeks. No patient has developed PSA progression. Thirty-one patients (97%) had declines of testosterone to the anorchid range. Two ADPCa patients had positive bone scans; both improved. One patient with a bladder mass measurable on computed tomography scan experienced disappearance of this mass. Nineteen (54%) of 35 AIPCa patients had a PSA decline of 
1.5 times the upper limit of normal (ULN), bilirubin 
