Proven and Unproven Therapy for Benign Prostatic Hyperplasia
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《新英格兰医药杂志》
The desire to take medicine is one feature which distinguishes man, the animal, from his fellow creatures.
— William Osler1
The Food and Drug Administration (FDA) is the regulatory body charged with assessing the basic and clinical science underlying the introduction of new drugs into clinical practice and evaluating the efficacy and safety of new pharmaceutical agents, usually on the basis of data from phase 3 randomized trials. Almost always, the FDA initially limits the use of drugs it approves by requiring them to be prescribed by a physician.
In contrast, herbs and other botanical products, which are defined as dietary supplements by the 1994 Dietary Supplement and Health Education Act, are not held to the same standard as pharmaceutical agents and are sold without a prescription in the United States. Physicians, but not the general public, regard the usefulness of these remedies with considerable skepticism. The policy of applying separate regulations to two categories of medications, alternative and conventional, with different standards of efficacy and safety, is misguided — medicine of any kind, whether a botanical or a chemotherapeutic agent, requires rigorous testing to prove its efficacy and safety.2 Moreover, unlike the detailed information available for proven drugs, rigorous data and evidence-based guidance regarding the use of herbs and botanical agents are often lacking.
For these reasons, the study by Bent et al. in this issue of the Journal is a welcome contribution.3 Their clinical trial was funded by grants from the National Institutes of Health and the National Center for Complementary and Alternative Medicine (NCCAM). The investigators conducted a double-blind, placebo-controlled, randomized trial to determine whether an extract of the berry of saw palmetto was superior to placebo in ameliorating symptoms of benign prostatic hyperplasia. They randomly assigned 225 men with symptomatic benign prostatic hyperplasia to receive one year of treatment with either saw palmetto extract or placebo. The results of this well-designed and adequately powered study showed no significant difference between saw palmetto and placebo in terms of the primary end points, which were based on scores on the American Urological Association Symptom Index and maximal urinary flow rates. Bent and colleagues took special care to avoid the methodologic pitfalls of previous studies of saw palmetto in men with benign prostatic hyperplasia by treating the participants for a year, optimizing the consistency of the herbal product, and measuring the adequacy of blinding. In fact, through an advisory committee, the NCCAM helped select the product to be studied. These important factors have not always been taken into account in previous studies of saw palmetto and other botanical agents.4,5
A limitation of the study, however, is that Bent and colleagues tested a specific preparation of saw palmetto, leaving open the possibility that a different preparation or dose of saw palmetto might have been effective. The investigators discussed the similarities between the composition of the product they studied and the composition of many other products on the market, but without knowledge of how saw palmetto may work — if, indeed, it does — a true comparison of products is impossible. Furthermore, even if the study had demonstrated the superior effectiveness of saw palmetto as compared with placebo, the safety and efficacy of this product as compared with those of FDA-approved treatments for benign prostatic hyperplasia would remain in question.
Alpha-blockade and treatment with 5-reductase inhibitors to reduce the size of the prostate can decrease the symptoms and complications of benign prostatic hyperplasia, and widespread use of these FDA-approved medical therapies has reduced the number of surgeries required to treat benign prostatic hyperplasia.6,7 Studies of different preparations of saw palmetto have suggested that they ameliorate symptoms of benign prostatic hyperplasia, as compared with a placebo, and provide a clinical benefit similar to that of a 5-reductase inhibitor or alpha-blocker.4,5,8,9 These studies, taken together with the negative result obtained by Bent et al., raise questions about the variability of botanical products and indicate that additional rigorous, placebo-controlled studies are needed before firm conclusions can be made about the long-term effectiveness and safety of other preparations of saw palmetto.
Previous work has shown the danger of assuming that herbs are inherently safe because they are "natural." In studies of PC-SPES, an herbal product consisting of chrysanthemum, isatis, licorice, Ganoderma lucidum, Panax pseudoginseng, Rabdosia rubescens, saw palmetto, and scutellaria (skullcap), we and others demonstrated that its clinical activity in prostate cancer, side effects, and mechanism of activity were consistent with the presence of intrinsic estrogenic activity.10,11 Furthermore, some batches of the product were found to contain potentially harmful contaminants, including synthetic estrogens. As a result, PC-SPES was removed from the market. Estrogen is an effective treatment for prostate cancer, but it has a greater risk of adverse cardiovascular effects than most currently approved hormonal therapies.12 Studies of the mechanism of activity of saw palmetto are inconclusive but suggest there are several, including the inhibition of 5-reductase.13,14 Additional work would be important to clarify the role, if any, of saw palmetto and similar products in clinical practice and the need for drug development. Such investigations should follow the route taken by FDA-approved agents that were originally derived from herbs.
Approval of prescription drugs by the FDA, based on rigorous scientific evidence, has served our profession and the public by establishing clear methods and criteria for the safety and efficacy of drugs. Without the same oversight for herbal therapies, the public risks self-medication with substances that are potentially ineffective, toxic, or both. Lack of oversight also inhibits practitioners from appropriately informing and advising their patients about these agents. Rigorous phase 3 studies, such as the one by Bent et al., provide important and helpful data, but they leave questions about the efficacy of other products and preparations and the means to ensure the long-term quality and safety of these products. Perhaps the larger question is how patients can be better guided with respect to the issues surrounding the use of herbal therapies. We believe that these products should be studied as pharmaceutical agents have been that were approved by the FDA. Even with the best regulatory provisions for herbal products, reasonable assurance of their long-term efficacy and safety will require clinical trials of the same quality required for the approval of standard drugs and, possibly, the development of pure compounds. Until there is adequate research on an herbal or other botanical product, it is the responsibility of physicians to inform their patients and protect them from the inherent risks of unproven therapies.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Medicine (R.S.D.) and Surgery (R.A.M.), Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick.
References
Osler W. Aequanimitas. 2nd ed. Philadelphia: P. Blakiston's Son & Co., 1928.
Angell M, Kassirer JP. Alternative medicine -- the risks of untested and unregulated remedies. N Engl J Med 1998;339:839-841.
Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med 2006;354:557-566.
Wilt TJ, Ishani A, Stark G, MacDonald R, Lau J, Mulrow C. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998;280:1604-1609.
Wilt T, Ishani A, Stark G, MacDonald R, Mulrow C, Lau J. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2000;2:CD001423-CD001423.
Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335:533-539.
McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387-2398.
Carraro JC, Raynaud JP, Koch G, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate 1996;29:231-240.
Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol 2002;41:497-507.
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 1998;339:785-791.
Oh WK, Kantoff PW, Weinberg V, et al. Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 2004;22:3705-3712.
Malkowicz SB. The role of diethylstilbestrol in the treatment of prostate cancer. Urology 2001;58:Suppl 1:108-113.
Buck AC. Is there a scientific basis for the therapeutic effects of Serenoa repens in benign prostatic hyperplasia? Mechanisms of action. J Urol 2004;172:1792-1799.
Marks LS, Hess DL, Dorey FJ, Luz Macairan M, Cruz Santos PB, Tyler VE. Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens. Urology 2001;57:999-1005.(Robert S. DiPaola, M.D., )
— William Osler1
The Food and Drug Administration (FDA) is the regulatory body charged with assessing the basic and clinical science underlying the introduction of new drugs into clinical practice and evaluating the efficacy and safety of new pharmaceutical agents, usually on the basis of data from phase 3 randomized trials. Almost always, the FDA initially limits the use of drugs it approves by requiring them to be prescribed by a physician.
In contrast, herbs and other botanical products, which are defined as dietary supplements by the 1994 Dietary Supplement and Health Education Act, are not held to the same standard as pharmaceutical agents and are sold without a prescription in the United States. Physicians, but not the general public, regard the usefulness of these remedies with considerable skepticism. The policy of applying separate regulations to two categories of medications, alternative and conventional, with different standards of efficacy and safety, is misguided — medicine of any kind, whether a botanical or a chemotherapeutic agent, requires rigorous testing to prove its efficacy and safety.2 Moreover, unlike the detailed information available for proven drugs, rigorous data and evidence-based guidance regarding the use of herbs and botanical agents are often lacking.
For these reasons, the study by Bent et al. in this issue of the Journal is a welcome contribution.3 Their clinical trial was funded by grants from the National Institutes of Health and the National Center for Complementary and Alternative Medicine (NCCAM). The investigators conducted a double-blind, placebo-controlled, randomized trial to determine whether an extract of the berry of saw palmetto was superior to placebo in ameliorating symptoms of benign prostatic hyperplasia. They randomly assigned 225 men with symptomatic benign prostatic hyperplasia to receive one year of treatment with either saw palmetto extract or placebo. The results of this well-designed and adequately powered study showed no significant difference between saw palmetto and placebo in terms of the primary end points, which were based on scores on the American Urological Association Symptom Index and maximal urinary flow rates. Bent and colleagues took special care to avoid the methodologic pitfalls of previous studies of saw palmetto in men with benign prostatic hyperplasia by treating the participants for a year, optimizing the consistency of the herbal product, and measuring the adequacy of blinding. In fact, through an advisory committee, the NCCAM helped select the product to be studied. These important factors have not always been taken into account in previous studies of saw palmetto and other botanical agents.4,5
A limitation of the study, however, is that Bent and colleagues tested a specific preparation of saw palmetto, leaving open the possibility that a different preparation or dose of saw palmetto might have been effective. The investigators discussed the similarities between the composition of the product they studied and the composition of many other products on the market, but without knowledge of how saw palmetto may work — if, indeed, it does — a true comparison of products is impossible. Furthermore, even if the study had demonstrated the superior effectiveness of saw palmetto as compared with placebo, the safety and efficacy of this product as compared with those of FDA-approved treatments for benign prostatic hyperplasia would remain in question.
Alpha-blockade and treatment with 5-reductase inhibitors to reduce the size of the prostate can decrease the symptoms and complications of benign prostatic hyperplasia, and widespread use of these FDA-approved medical therapies has reduced the number of surgeries required to treat benign prostatic hyperplasia.6,7 Studies of different preparations of saw palmetto have suggested that they ameliorate symptoms of benign prostatic hyperplasia, as compared with a placebo, and provide a clinical benefit similar to that of a 5-reductase inhibitor or alpha-blocker.4,5,8,9 These studies, taken together with the negative result obtained by Bent et al., raise questions about the variability of botanical products and indicate that additional rigorous, placebo-controlled studies are needed before firm conclusions can be made about the long-term effectiveness and safety of other preparations of saw palmetto.
Previous work has shown the danger of assuming that herbs are inherently safe because they are "natural." In studies of PC-SPES, an herbal product consisting of chrysanthemum, isatis, licorice, Ganoderma lucidum, Panax pseudoginseng, Rabdosia rubescens, saw palmetto, and scutellaria (skullcap), we and others demonstrated that its clinical activity in prostate cancer, side effects, and mechanism of activity were consistent with the presence of intrinsic estrogenic activity.10,11 Furthermore, some batches of the product were found to contain potentially harmful contaminants, including synthetic estrogens. As a result, PC-SPES was removed from the market. Estrogen is an effective treatment for prostate cancer, but it has a greater risk of adverse cardiovascular effects than most currently approved hormonal therapies.12 Studies of the mechanism of activity of saw palmetto are inconclusive but suggest there are several, including the inhibition of 5-reductase.13,14 Additional work would be important to clarify the role, if any, of saw palmetto and similar products in clinical practice and the need for drug development. Such investigations should follow the route taken by FDA-approved agents that were originally derived from herbs.
Approval of prescription drugs by the FDA, based on rigorous scientific evidence, has served our profession and the public by establishing clear methods and criteria for the safety and efficacy of drugs. Without the same oversight for herbal therapies, the public risks self-medication with substances that are potentially ineffective, toxic, or both. Lack of oversight also inhibits practitioners from appropriately informing and advising their patients about these agents. Rigorous phase 3 studies, such as the one by Bent et al., provide important and helpful data, but they leave questions about the efficacy of other products and preparations and the means to ensure the long-term quality and safety of these products. Perhaps the larger question is how patients can be better guided with respect to the issues surrounding the use of herbal therapies. We believe that these products should be studied as pharmaceutical agents have been that were approved by the FDA. Even with the best regulatory provisions for herbal products, reasonable assurance of their long-term efficacy and safety will require clinical trials of the same quality required for the approval of standard drugs and, possibly, the development of pure compounds. Until there is adequate research on an herbal or other botanical product, it is the responsibility of physicians to inform their patients and protect them from the inherent risks of unproven therapies.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Medicine (R.S.D.) and Surgery (R.A.M.), Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick.
References
Osler W. Aequanimitas. 2nd ed. Philadelphia: P. Blakiston's Son & Co., 1928.
Angell M, Kassirer JP. Alternative medicine -- the risks of untested and unregulated remedies. N Engl J Med 1998;339:839-841.
Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med 2006;354:557-566.
Wilt TJ, Ishani A, Stark G, MacDonald R, Lau J, Mulrow C. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998;280:1604-1609.
Wilt T, Ishani A, Stark G, MacDonald R, Mulrow C, Lau J. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2000;2:CD001423-CD001423.
Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335:533-539.
McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387-2398.
Carraro JC, Raynaud JP, Koch G, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate 1996;29:231-240.
Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol 2002;41:497-507.
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 1998;339:785-791.
Oh WK, Kantoff PW, Weinberg V, et al. Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 2004;22:3705-3712.
Malkowicz SB. The role of diethylstilbestrol in the treatment of prostate cancer. Urology 2001;58:Suppl 1:108-113.
Buck AC. Is there a scientific basis for the therapeutic effects of Serenoa repens in benign prostatic hyperplasia? Mechanisms of action. J Urol 2004;172:1792-1799.
Marks LS, Hess DL, Dorey FJ, Luz Macairan M, Cruz Santos PB, Tyler VE. Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens. Urology 2001;57:999-1005.(Robert S. DiPaola, M.D., )