 |
 |
 |
 |
 |
 |
 |
HERBAL THERAPY PC-SPES: IN VITRO EFFECTS AND EVALUATION OFITS EFFICACY IN 69 PATIENTS WITH PROSTATE CANCERALEXANDRE DE LA TAILLE, RALPH BUTTYAN, OMAR HAYEK, EMILIA BAGIELLA, AHMAD SHABSICH, MARITH BURCHARDT', TATJANA BURCHARDT, DOMINIQUE K CHOPIN AND AARON E. KATZ From the Squier Urilogical Clinic, Department of Urology, Columbia University College Of Physicians and Surgeons, Columbia-Presbyterian Medical Center and Department of Biostatic, Columbia University, School of Public Health, New York, New York and Department of Urology, Henri MondorHospital, Creteil, France. ABSTRACT Purpose: We investigate the potential use of the phytotherapeutic PC-SPES to treat human prostate cancer, and evaluate its in vivo and in vitro activity, and clinical efficacy. Materials and Methods: PC-SPES was evaluated for its ability to induce apoptosis on prostate cancer cell lines LNCaP, PC3 and DU145. The effect of oral PC-SPES on growth of PC3 tumors present in male immunodeficient mice was studied. A total of 30 male nude mice were divided in 5 groups. In groups 1 control and 2 full dose therapy was started the sarne day of the tumor injection. In groups 3 control, 4 half dose and 5 full dose PC-SPES therapy was initiated 1 week after tumor injection. A total of 69 patients with prostate cancer were treated with 3 capsules of 320 mg PC-SPES daily. Serum prostate specific antigen (PSA) responses and side effects were evaluated. Results: All of the cultured prostate cancer cell lines had a significant dose dependent induction of apoptosis folIowing exposure to an alcoholic PC~SPES extract. Immunodeficient mice xe-nografted with the PC3 cell line had reduced tumor volume compared with sham treated controls when they were treated with a PC-SPES extract from the time of tumor cell implantation (931 ± 89 versus 1,424 ± 685 mm. p not significant) but not when the treatrnent was hegun 1week after tumor cell implantation. The testis, prostate, bladder and seminal vesicles of the treated mice were sigificantly reduced in weight compared with the sham treated animals. Of the patients with prostate cancer 82% had decreased serum PSA 2 months, 78% 6 rnonths and 88% 12 months after treatrnent with PC-SPES. Side effects in the treated patient population included nipple tenderness in 42% and phlebitis requiring heparinization in 2%. Conclusions: An extract of the phytotherapeutic agent PC-SPES proved to be active in inducing apoptosis of hormone sensitive and insensitive prostate cancer cells in vitro, and in suppressing the growth rate of a hormone insensitive prostate cancer cell line in vivo. The overwhelming majority of patients with prostate cancer treated with the agent experienced a decrease in serum PSA but also demonstrated a side effect profile comparable to estrogen treatmeant Key Words: prostatic neoplasms; hornones; medicine, herbal; prostate~specific antigen Prostate cancer is the most commonly diagnosed ancer in men and the second leading cause of male cancer deaths.¹ Epidemiological studies in the United States and other coun-tries suggest a strong dietary factor in the development of prostate cancer.² Such statistics also suggcst that dietary agents may have efficacy in preventing the occurrence or progression of this disease. These findings support the search for dietary or herbal agents that could be used In a combined regimen with contemporary' therapeutics to treat patients with prostate cancer. The concept of herbal therapies is pop-ular with the patient population1 and recent estimates suggest that some form of complementary therapy has been used by 27% of patients with prostate cancer.3 Of the more exciting herbal therapies that are currently being used to treat prostate cancer is the herbal amalgam PC-SPES. Phytotherapeutics, which are extracts of plants and herbs have been used to treat prostate disease for several years. PC-SPES has been commercially available since November 1998 and is a combination of 8 different herbs. Each herb individually seems to have some antitumoral ef-fect. Isatis indigotica contains ß-sitosterol, which is a phyt-osterol that is a constituent of legumes (bean family). Oral consumption of ß-sitosterol has been shown to reduce cancer growth in animal studies. Glycyrrhiza glabra and glycyrrhiza uralensis are Chinese herbs that contain saponin and quercetin. There is some evidence that saponin can stimulate the immune system, and quercetin has demonstrated anti cancer effects. This herb lowers serum testosterone levels and increases estrogen levels by inducing the enzymes 17 ß-hydroxysteroid dehydrogenase and aromatase.5 Panax pseudo-Ginseng contains dammaranc type saponins that are adaptagenic (possess nonspecific, antistress, homeostasis inducing properties), and is purported to enhance immunity by stimulating activity of natural killer cells. Ganoderm lucidum contains high moleculair weight polysaccharides and inhibits the growth of sarcoma. Scuttellaria baicalensis can. inhibit the growth of sarcoma and cervical cancer cell lines in vitro. The saponin Baicalein inhibits cancer cell multiplication and induces apoptosis in vitro,7 and has been shown to stimulate the immune system in vivo and possess antibacta-rial effects, dendranthema morifolium is less known with unspecified biological effects. Rabdosia rubesrens has multiple antitumor and analgesic effects and inhibits in vitro sarcoma cells, hepatoma cells, cervical cancer cells and lymphoma11 Analgesis and anti-anorexigenic properties have been observed in patients with primary liver cancer who received this therapy.11' Accepted for publication April 14, 2000. Supported by Grant R0ICA70769 from the Natiorial Institutes of Health and the National Cancer Institute, Washington, D. C. Editor's Note. This article is the fiflh of 5 published in this issue for which category 1 CME credits can be carned. Instructions for obtaining credits are givien with the questions on pages 1356 and 1357. Saw palmetto Is a natural product that decreases the bioavailability of testosterone in vivo and inhibits production of eicosanoids, which are Substances pro-duced during inflammation. This herb has also been demon-strated to have en effect on the symptoms of patients with benign prostatic hyperplasia.13 To assess the potential efficacy and determine the effects of PC-SPES we performed experiments on cultured prostate cancer cells (PC3) previously reported that an alcoholic extract of PC-SPES was able to reduce significantly the growth rate of prostate cancer cell lines LNCaP, PC3 LNCaP DU145.14 To assess whether this effect was due to a simple reduction in the rate of growth or tumor cell viability, we tested the potential of PC-SPES extract to induce apoptosis of these cell lines. Also, we studied whether PC-SPES therapy affects prostate cancer cells (PC3} grown as xenograft tumors in Immunodeficient mice. Finally, we report our clinical experi-ence with PC-SPES in patients with. prostate cancer. MATERIALS AND METHODS Prostate cancer cell line experiment. We tested the possi-bility that PC-SPES can induce apoptosis on human prostate cancer cell lines PC3, LNCaP and DU145. The cells were grown in RPMI-1640 medium supplemented with 10% fetal bovine serum, 2 mM. glutamine and 1x antibiotic/antimycotic solution (20 ug/ml streptomycin sulfate, 20 unit per ml. penicillin and 0.2S ug./mL amphotericin B). The cells were incubated at 37C in a humidified atmosphere of 5% carbon dioxide and 95% air. Cells were exposed for 8 days to PC-SPES at 2 concentrations of 4 ul. PC-SPES extract per ml. medium and 8 ul PC-SPES per ml. medium. A control was done using the same 4 and 8 ul volume of ethanol 70%, After 5 days of exposure the medium was removed and centrifuged. to collect cells in the medium, and trypsin was used to collect adherent cells. All cells were collected in the same tube, centrifuged on a slide and fixed on the slide with perafolmaldehyde 4% for 10 minutes. Apoptotic body stain-ing procedure was performed as recommended by the manufacturer using the in situ call death detection kit, phospha-tase alkaline TUNEL assay. Analysis of variance (ANOVA) was used to test the overall difference between. PC-SPES and the control. Separate analyses were conducted for the differ-ent call lines. Commercial software was used and p = 0.05 waa considered significant. Tumor xenografts. A total or 30, 6-week-old athymic male nude mice were housed aseptically 5 per cage- Mice were sterilely inoculated subcutaneously bilaterally with 1.5 million PC3 cells (hormone rafractory prostate cancer cell line) in 0.25 ml. basement rnembrane matrix and randomly divided into & groups of 6. PC-SPES therapy was initiated the same day as tumor injection in group 1- no PC-SPES and group 2—PC-SPES at 300 mg./kg. daily. PC-SPES therapy was initiated 1 week after tumor injection in group 3- no PC-SPES, group 4 — PC-SPES at a half dose of 150 mg/kg. daily and group 5 — PC-SPES at a full dose of 300 mg-/kg. daily. PC-SPES herbal preparation was administered as a sus-pension in 1,5% carboxymethylcellulose with 0.2% Tween 20 for 5 days a week as reported previously.15'16 In the control groups only the solution containing carboxymethylcellulose and Tween 20 was administered. The dose was based on body surface area of patients with prostate cancer taking PC-SPES. Tumors were measured twice a. week starting at week 4 with vernier calipers and calculated by the formula length x width X height: X 0.5S36. At 2 months after tumor infection bromodeoxyuridine was injected in the peritoneum 2 hours, before the mice were euthanized. Autopsies were performed, and tumors, testis, and en bloc prostate, bladder and Seminal vesicle were removed, weighed, fixed in 10% neutral buffered formalin and embedded in paraffin for Histological analysis, Fixed tissues were sectioned and immunostaining- proce-dures were performed as recommended by the manufacturer to evaluate the proliferative rate using the in situ cell proliferation kit, POD± and the apoptotic rate within the tissues was determined according to the TUNEL assay. Slides were examined by light microscopy at 200X magnification. For each tumor, seminal vesicle, prostate and testis 10 different fields were counted, but those containing necrotic tissue were not counted. Apoptotic bodies were defined by positive staining in the assay and the characteristic morphology of the apoptotic nucleus. The number of bromodeoxyuridine posi-tive cells per high power field was counted. Results were expressed as the mean number of positive cells per high power field. Statistical analyses were performed with com-mercial software, and apoptotic cell and proliferation counts were compared using Student's t test (independent variable or ANOVA. Patients. From September 1986 to June 1999, 69 patients with biopsy proved prostate cancer were treated with the herb mixture PC-SPES. The patients were completely eval-uated and disease was staged before inclusion in the study, and were carefully advised about the possible effects of the drug especially venous thrombosis. They received capsules of 320 mg. PC-SPES orally 3 times a day. The patients have been followed periodically through complete clinical evalua-tion with physical examination, radiological, studies when necessary, and prostate specific antigen (PSA) measurements at 2 and 6 months initially, and every 6 months thereafter. The known side effects of nipple tenderness, gy-necomastia, hot flashes, erectile dysfunction and thromboembolic events were evaluated. RESULTS Apoptosis induction in prostate cancer cell fines. Cultured prostate cancer cell lines (LNCaP. PC3 and DU145) were individually exposed to 4 or 6 Ul/mI. of an ethanol extract of PC-SPES for 5 days. Controls received normal medium or medium supplemented with 4 or 6 ul/ml. 70% ethanol alone. At the end of 5 days apoptosis was measured on the cells by the TUNEL assay that immunohistochemically detects cells with fragmented DNA in the nucleus, typical of apoptosis- No statistical differences were observed between the control groups (0, 4 or 6 (ul./ml. 70% ethanol) of any individual cell type (data not shown). Figure 1 demonstrates that PC-SPES extract had significant effects in inducing apoptosia in all cell Tumor xenografts. We evaluated the effects of PC-SPES in vivo using the hormone insensitive prostate cancer cell line PC3 injected subeutaneously in immunodeficient nude mice. During the study all mice were weighed weekly, and. mean weights of each experimental group were statistically similar to those of controle (data not shown)- Tumor volumes were estimated after 1 month and twice a week during a 1-month followup (fie. 2). Tumors weights at autopsy correlated well with the last tumor measurements (fig. 3). PC-SPES did not suppress tumor growth when therapy was initiated at 1 week after tumor injection (ANOVA p = 0.75). However, smaller
pain. local recurrence presenting as urinary obstruction, or positive bone scans. Using changes in serum PSA as a marker of biochemical response or progression of disease, we evaluated objective responses to PC-SPES therapy (de-creased serum PSA) in the patient cohort. Overall, 82% of patients had decreased serum PSA after 2 months of therapy, and at each followup more than two-thirds had a lower level of PSA compared to pre-PC-SPES therapy serum PSA. This ratio was observed in each patient group (table 3). Interest-ingly a large proportion of patients (74% at 6 months) with hormone refractory prostate cancer had decreased PSA levels at different followup times. Of the treated patients 9 had metastatic disease of whom 2 were in group B and 7 in group A. At 2-month follow-up all of these patients had decreased serum PSA, which was main-tained at 6 months in 87%. At 12-month followup PSA was lower than before PC-SPES therapy in 2 cases. Bone scans were not repeated because the patients had a decreased serum PSA and did not present with bone pain. After exclusion of patients with metastatic disease 63% of our patients had stage T1 (decreased serum PSA in 86%), 14% T2 (de-creased PSA to 60%) and 27% T3 decreased PSA in (100%) disease. Side Effects: Overall the treatment was well tolerated. Reported side effects were nipple tenderness in 42% of pa-tients, which did not require treatment interruption, gynecomastia in 88% hot flashes in 7% and deep venous thrombosis in 2% (1 patient who interrupted therapy concomitant with introduction of heparinization) No difference was observed among the 3 patient groups for the frequency of these side effects. discussion PC-SPES is a unique phytotherapeutic amalgam that is being used by patients with prostate cancer. In a previous study we showed that an alcoholic extract of PC-SPES has a potent dosage dependent effect of decreasing the growth rate of hormone sensitive (LNCaP) and insensitive (LNCaP-bcl-2, PC3 and DU145) prostate cancer cell lines. However, the growth suppressive effects of PC-SPES appeared to be less effective against the hormone insensitive lines compared with the hormone sensitive LNCaP These data suggest that PC-SPES has the potential for activity against hormone independent prostate cancers while showing that this effect can be at least partially suppressed by apoptotic inhibitory molecules, such as bcl-2, that are known to be expressed in some advanced prostate cancers. Other studies have shown that PC-SPES can inhibit the growth of PC3 and MCF-7 breast tumor cells in cell culture. In this study we confirmed that PC-SPES can induce apo-ptosis in hormone sensitive (LNCaP) and insensitive (PC3 and DU145) prostate cancer. Hsieh et al demonstrate'd that PC-SPES decreased the production of PSA and the expression of androgen receptors in a culture of LNCaP prostate tumor cells.19 DiPaole et al were unable to determine whether the effects of PC-SPES on cultured tumor cells were independent of estrogenic activity since estrogen alone in-duces apoptosis in tumor cell lines. PC-SPES has potent Estrogenic activity and contains multiple compounds but not the known estrogens, estrone, estradiol or diethylstilbestrol, or chemicals with similar structures and metabolites. In nude mice xenografts of PC3 cells tumor growth was de-creased by PC-SPES but did not reach the level of significance. In our in vivo experiment we observed a decrease in the weights of the combined prostate, seminal vesicle and bladder, and testis of treated mice after 2 months of PC-SPES therapy. There was also an increased apoptotic rate in these sexual accessory tissues in PC-SPES treated versus untreated mice, which would support the Estrogenic effect of PC-SPES. In a clinical trial DiPaola et al studied 8 patients taking PC-SPES and observed decreased testosterone and PSA within 2 to 6 weeks.19 PC-SPES effects have been similar to those of Diethylstilbestrol in terms of PSA decrease and side effects observed.
*Some patients (4 in group A and 1 in group B) missed serum PSA valuation at 2 months but had PSA evaluated at 6 months In our prospective clinical trial wo presented our results in 3 categories according to hormone sensitive status and prior therapy. Of the patients 4 received PC-SPES as pri-mary treatment of disease. The follow-up is short but in most of these patients serum PSA decreased. Also, of 22 patients who' received PC-SPES for hormone refractory prostate cancer, serum PSA decreased in 90% at 2-month follow-up and remained decreased at 6 months in 74%, Finally 48 patients had been treated previously with radiation therapy, cryo. therapy, radical prostatoctomy and/or hormone therapy but were considered to have hormone refractory prostate cancer. De-creased serum PSA was observed In 82% of the 43 patients at 2 months, 78% at 6 months and 82%- at 12 months of fol-low up. Compared to our previous report in the present study with longer followup and more patients, we confirmed that PC-SPES can decrease serum PSA in more than two-thirds of our patients. Our experience is similar to that reported by others. Mittelman et al reported that at 3 months 10 of 16 patients showed a decrease in PSA in excess of 50%. Kameda et al studied the in vivo affect of PC-SPES in a phase II study in which 34 patients received 9 capsules of PC-SPES daily. Of 20 patients with hormone naive disease 12 and of 14 with androgen independent prostate cancer 12 were available for 1-month followup and PSA decreased greater than 50% in 75% and 70%, respectively. Testosterone level decreased to anorchid levels by 1 month in 33% of the patients. As a result of phyto-estrogenic properties, the risk of po-tential side effects of PC-SPES are theoretically the same as those seen with diethylstilbestrol especially thromboembolic phenomena, end caution must accompany its use We also observed side effects, such as tender gynecomastia in 43% of patients, hot flashes in 7% and venous thrombosis in 2%, which would be typical of estroggenic therapy. Kameda et al reported that 60% of patients with previously normal testos-terone levels had lost libido and other side effects, including tender gynecomastia in 71% (if grade 1 nausea in 12% and grade 1 diarrhea in 33%-21 To date there is no Pood and Drug Administration approval for PC-SPES or for any other herbal therapy. In the litera-ture most studies reporting the use of herbal therapies did not randomize the cases. However, as emphasised by Fair, the basis traditional medicine is the practical use of herbs for more than 3,000 years "by intelligent people with a strong history" of interest in healing common diseases.22 CONCLUSIONS The effect of PC-SPES On prostate cancer cell lines as well as its clinical activity is an interesting phenomenon. Based on the results of our study and those reported in the litera-ture, we can confirm an estrogen-like activity of this herbal amalgam on prostate cancer cell lines and prostate cancer. However, Our observation that this agent has a clinical effect on patients with hormone resistant prostate cancer suggests that estrogen-like activity is not its sole mechanism of action. PC-SPES extract preparations were obtained from Dr. Sophie Chen. New York Medical College, New York. New York. PC-SPES capsules were obtained from Botaniclab, Brea, California. REFERENCES 1. Landia, S. H., Murray, T., Bolden, S. et al; Cancer statistics, 1999.- CA Cancer J Clin. 49; 8, 1999 2. Ross, R. K. and Henderaon. B. E.; Do diet and androgens alter prostate cancer risk via a common etiologic pathway? J Natl Cancer Inst, 86: 252. 1994 3. Nam. R. K , FIeshner, N., Rakovitch, E. et al: Prevalence and patterns of the use of complementary therapies among pros-tate Cancer patients an epidermological analysts. J Urol, 161;1521, 1999 4. Kellis, J. T,, Jr. and Vickery, L. E.; Inhibition of human estrogen synthetic (aromatase) by flavones. Science, 225, 1082. 1984 5. Agarwal, K., Wang. Z. Y, and Mukhtar, H.; Inhibition of mouse skill tumor-initiating activity of DMBA by chronic oral. feeiling of glycyrrhizin in drinking water. Nutr Cancer, 15s 187, 1991 6. Smith, R., E,, Donachie. A M. and Mowat, A. M.: Immune stimulating compIexes as mucosal vaccines. Immunol Cell Biol. 76;268,1998 7. Wang, S- Y., Hsu, M. L., Hsu, H. 0. et al: The anti-tumor effect of Ganoderma lucidum is mediated by cytokines released from activated macrophages and T lymphocytes. Int J Cancer, 70: 688,1997 8. Matsuzaki, Y.. Kurokawa, N., Terai. S, et al: Cell death induced by baicalein in human hepatocellular carcinoma cell lines. Jpn J Cancer Res, 87; 170. 1998 9. Ghosh, J. and Myers, C. E.: Inhlbition of arachidonate -lipoyygenese triggers massive apoptosis in human prostate cancer cells, Proc Natl Acad Sci U S A, 95; 131.82. 1898 10. Kyo. R, Nakahata, N., Sakakibara I. et al Effects of Shosoiko-to, San'o-shashin-to and Scutellariae Radix on intracellular Ca2+ mobilization in. C6 rat glioma cells. Biol Pharm Bull, 21;1067, 1998 11. Kubo, I.: Structural basis for bitterness based on Rabdosis Deterpenes, Phygiol Behav, 56; 1203, 1994 12. Nagao, Y., Ito, N., Kohno, T, et al; Antitumor activity of Rabdosia and Teuctium diterpenoids against P 388 lymphocytic leukemia in mice- Chem Pharm Bull (Tokyo), 30: 727, 1982 13. Wilt, T. J.. Ishani, A., Stark, G.- et ah Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic re-view. JAMA. 280; 1604.1999 14 de la Taille, A., Hayek, 0. R,. Buttyan, R. et al Effects of a phytothorapeutio agent, PC-SPES, on prostate cancer: a preliminary investigation on human cell lines and patients. BJU Int, 84; 845, 1999 15. Kubota, T., Hisatake, J,, IIisatake. Y- et al: PC-SPES: a unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo Prostate, 42; 163,2000 16. Tiwari, R. K., Geliebter, J., Garikapaty, V. P- et al: Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. Int. J Oncol, 14: 713. 1999 17. Halicka, H. D,. Ardelt, B., Juen, G. et al: Apoptosis and cell cycle effects induced by extracts of the chinese herbal preparation PC-SPES Int J Oncol, 11; 487. 1997 18. ft. Hsieh, T.. Chen. S. S:, Wang, X. et al; Regulation of androgen receptor (AR) and prostate specific antigen (PSA) suppresion in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation PC-SPES. Biochem Mol Biol Int. 42; 535,1997 19. DiPaola, R. S., Zhang, H., Lambert, G. H, et al: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med, 889: 785,1998 20. Mittelman, A., Tiwari, R. K. Chen, S. et al: Preclinical analysis of the in vivo and in vitro effects of PC-SPES on rat prostate cancer cells. J Clin Oncol, vol. 18, 1999 21. Kamada, H,, Small, E. J., Reese. D. M, et al: A phase II study of PC-SPES, an herbal compound, for the treatment of advanced prostate cancer (PCa). J din Oncol, vol 18, 1999 22. Fair, W_ R.: Back to the future—the role of complementary medicine in urology. J Urol. 162; 411,1999 EDITORIAL COMMENT Complementary and alternative medicine is used by .more than 40% of patients in the United States, and urology patients are no exception.1 Patients seek complementary and alternative medicine for a variety of reasons including failure or traditional therapy, avoidance of side effects, desire for a more natural approach to healing and desire to maintain control over therapy Thus, it is not surprising that men with prostate cancer have sought out such an approach because hormonal therapy fails with time, has multiple and protean side effects if prescribed and administered by physicians, and often leads to poly pharmacy. Into this environment moves PC-SPES, & combination of 1 Amer-ican and 7 Chinese herbs. This study and others demonstrate un-equivocally that this amalgam has activity in prostate cancer. and clinically causes a decrease in PSA, In this study PSA decreased greater than 50% in two-thirds of the patients with hormone naive and hormone refractory disease. In the authors' previous report of 33 patients 87% had a decrease in PSA (reference 14 in article) and in another small series of 8 patients all exhibited a decrease in PSA (reference 19 in article}. Finally in a recent sorties of 34 patients with hormone naive and hormone refractory disease 75% of patients in both groups had a PSA decrease of greater than 50% (Reference 21 in article), The authors have forthered our knowledge regarding this agent, and demonstrated that significant apoptosis is soon in PC3, DU145 and LNCaP cell cultures, of which 2 cell lines are hormone insensitive, Nevertheless in the PC3 xonograft no significant difference in tumor volumes or proliferation rates was noted. Of interest was a lower apoptosis rate in the prostate and a significant proliferation rate in the testis. The cause for these changes remains unknown, in the mixed population of men with prostate cancer responses in PSA Were the rule with about three quarters exhibiting a PSA decrease of greater than 50%, which is a threshold often used to declare significant activity of antincoplastic agents. Most intriguing was the observation that the degree of response appeared to be similar in hormone naive and hormone resistant disease. The results of this study, especially the clinical results, should prompt more interest in PC-SPES, However I am disturbed by several observfations. The mechanism action of the agent remains unknown, and the specific component(s) of the agent that cause this effect remains unknown. Also the appropriate dose is unknown, and the side effects are significant despite the lack of regulation of the use of the agent. It is of interest that in a previous study by the authors of patients who were treated in what appears to be a similar protocol (I presume that the current study is a longer followup with a large number of patients but includes the original 33) DVT devel-oped in 2 of 88 (Reference 14 in article). In the present study only 1 of 69 patients had deep venous thrombosis. Breast tenderness with PC-SPES has now been reported in 6% to 100% of patients (references 14 and 19 in article). The sterols in this agent, although dissimilar to estrone. estradiol and Diethylstilbestrol are nevertheless estrogens and can be expected to cause other cardiovascular side effects (reference 19 in article), Without large scale, detailed, clinical trials we will not know if the degree of cardiovascular mortality is Iess than or greater than that previously wen with diethylstilbestrol.1 The findings of this report are exciting and disturbing. We have evidence that some or all of the compounds in this mixture have an effect on hormone refractory prostate cancer that may be highly significant. The prospect of lives saved in an otherwise incurable disease is an electrifying development It comes at a risk, however, of a serious side effect. If this agent undergone appropiate testing by a pharmaceutial manufacturer we would know an appropriate dose, have a tailored combination of agents and have detailed infor-mation regarding side effects and methods to possibly prevent them. Because of the lack of regulation of agents such as these, physicians and patients must take the place of the agency that provides over-sight for regulated pharmaceuticals. Cardiovascular and thrombo-embolic deaths attributable to this agent can be expected as its popularity grows. Could deaths be averted through appropriate over-sight? Could a better agent have been designed if each component had been appropriately tested? With the significant cost of the agent, which is $162 to $486 a month. and Since it is not on traditional formularics, one must question whether patients arc being denied a potentially effective treatment. In the current environment we may never know. The efficacy and toxicity of PC-SPES should be a call to action for elected officials to demand testing of agents, such as these, that by any other definition are truly pharmaceuticals We cannot allow less for our patients. Ian. M. Thompson Jr. Division of Uro!ogy The University of Texas Health Science Center at San Antonio San Antonio, Texas |
