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Focusing on Testosterone
Supplement Article Focusing on Testosterone Judd W. Moul and Robert Dreicer Since Huggins and Hodges first established testosterone as the principal androgenic hormone responsible for the growth of prostate cancer in 1941, lowering the circulating testosterone to surgical castration levels (⬍50 ng/dL) has been a fundamental strategy for prostate cancer therapy. Until the 1980s, surgical castration (bilateral orchiectomy) and medical castration using estrogen (diethylstilbestrol) were the primary methods of testosterone suppression. However, during the past 30 years, newer agents that lower serum testosterone even more effectively have been approved and the indications for use of these newer agents re-evaluated. UROLOGY 78: S476 –S477, 2011. © 2011 Elsevier Inc.
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ccording to the National Cancer Institute,1 it was estimated that in 2010, ⬎217 000 men in the United States were diagnosed with prostate cancer (equating to a new case diagnosed every 2.7 minutes); ⬎2 million American men were living with prostate cancer, with approximately 32 000 of those men dying from the disease (equating to an American man dying of prostate cancer every 19 minutes). Although prostate cancer screening is widely practiced in the United States, the ultimate utility of this approach remains undefined. The past few decades have seen great progress in understanding the molecular mechanisms of prostate cancer, and, as a consequence, a series of new agents have recently received Food and Drug Administration approval. Among the most intriguing of these agents are those that target the androgen receptor, long recognized as the major therapeutic target in prostate cancer.
PRIMARY GOAL OF THERAPY: TESTOSTERONE AT CASTRATION LEVELS In 1941, Huggins and Hodges2 first demonstrated the key role of testosterone as the principal androgenic hormone stimulating tumor growth in prostate cancer, and a strategy of lowering circulating testosterone to castrate (ie, ⬍50 ng/dL) levels quickly became the therapeutic goal. Initially, testosterone suppression was achieved by surgical castration (bilateral orchiectomy) or medical castration with diethysilbestrol, also discovered by Huggins and
From the Department of Surgery, Division of Urologic Surgery, Duke University Medical Center, Durham, North Carolina; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; and Department of Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio Financial Disclosure: J. W. Moul is a member of the Speaker’s Bureau for Sanofi-Aventis, Astra-Zeneca, GSK, Ferring. R. Dreicer has received grant/research support from Millenium; and has worked as a consultant for Sanofi Aventis, Novartis, Astra Zeneca, GTX, EMD Serano, Boehringer Ingelheim, Centecor Ortho Biotech, and Millenium. Reprint requests: Judd Moul, M.D., Department of Urologic Surgery, Duke University Medical Center, Room 1573, Duke South DUMC 3707, Durham, NC 27710. E-mail: [email protected] Submitted: March 1, 2011, accepted (with revisions): June 4, 2011
S476
© 2011 Elsevier Inc. All Rights Reserved
Hodges2 in 1941. This approach to androgen deprivation remained the standard of care for ⬎40 years. In the late 1980s, these 2 simple approaches to lowering circulating testosterone levels were replaced when luteinizing hormone-receptor hormone agonists were introduced. Luteinizing hormone-receptor hormone agonists work by competitively binding to the endogenous receptors of the testosterone precursors (luteinizing hormone-receptor hormone and follicle-stimulating hormone); thus, lowering the testosterone levels without the debilitating physical and psychological side effects of orchiectomy or the biochemical side effects of diethysilbestrol. Androgen deprivation therapy (ADT) by blockade of the androgen receptors was an important advance, especially in terms of patient acceptance, but it still had 2 drawbacks: the initial stimulation of testosterone by an agonist at the androgen receptor and the eventual return of androgen receptor responsiveness. To treat these, concepts such as combined androgen blockade (the use of antiandrogens in combination) to both suppress the initial testosterone flare and account for adrenal production of steroid precursors that could be converted to testosterone became the subject of active clinical research.3,4 With the recent development of agents that directly antagonize the androgen receptors (gonadotropin-releasing hormone antagonists) and can effectively lead to even greater suppression of serum testosterone than that previously achieved with medical or surgical castration, we are now re-evaluating the roles of androgen receptor blockade and serum testosterone in the treatment of patients with advanced prostate cancer.
CONTEMPORARY QUESTIONS CONCERNING HORMONAL THERAPY FOR PROSTATE CANCER Achieving suppression of testosterone through blockade by binding the precursors to their receptors, also known as hormonal therapy, can be used in several situations: 0090-4295/11/$34.00 doi:10.1016/j.urology.2011.06.004
As primary therapy for localized or metastatic disease For biochemical or clinical recurrence after previous local therapy For biochemical or clinical recurrence after previous local therapy As an adjuvant to radiotherapy as the initial treatment if the patient is at intermediate or high risk of cancer recurrence Once the form of hormonal therapy has been chosen, the physician must determine whether the measurement of serum prostate-specific antigen and/or other imaging tests provide an accurate assessment of the prostate cancer status; must decide on the frequency of assessment; determine whether to periodically measure testosterone; and determine whether the results of the assays (eg, serum testosterone ⬍50 ng/mL or prostate-specific antigen progression) are clinically relevant. Finally, if the treatment strategy appears to be failing, the physician must determine what is happening biologically and/or physiologically, if the cancer indexes return; and the best therapeutic strategy for intervening to maintain biochemical and clinical remission, if the testosterone levels are not maintained in the castration range. This supplement to the Journal was based on a 2-day round table of leading investigators and practitioners
UROLOGY 78 (Supplement 5A), 2011
convened to assess where we are today in our understanding and current practices with pharmacologic ADT, especially in light of the new agents that are finally becoming available for the first time in many years. The following reports will be devoted to a review of the data from the large observational database, Cancer of the Prostate Strategic Urologic Research Endeavor, giving us a picture of the current applications of ADT in the community of physicians treating patients with prostate cancer, followed by reports on the physiology of the androgen receptor and androgen blockade, the various approaches to using ADT, and, finally, a brief review of some of the new agents becoming available. References 1. National Cancer Institute. Prostate cancer. Available from: http:// www.cancer.gov/cancertopics/types/prostate. Accessed February 2, 2011. 2. Huggins C, Hodges CV. Studies on prostatic cancer. I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1: 293-297. 3. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-424. 4. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet. 2000;355:1491-1498.
S477
A
ccording to the National Cancer Institute,1 it was estimated that in 2010, ⬎217 000 men in the United States were diagnosed with prostate cancer (equating to a new case diagnosed every 2.7 minutes); ⬎2 million American men were living with prostate cancer, with approximately 32 000 of those men dying from the disease (equating to an American man dying of prostate cancer every 19 minutes). Although prostate cancer screening is widely practiced in the United States, the ultimate utility of this approach remains undefined. The past few decades have seen great progress in understanding the molecular mechanisms of prostate cancer, and, as a consequence, a series of new agents have recently received Food and Drug Administration approval. Among the most intriguing of these agents are those that target the androgen receptor, long recognized as the major therapeutic target in prostate cancer.
PRIMARY GOAL OF THERAPY: TESTOSTERONE AT CASTRATION LEVELS In 1941, Huggins and Hodges2 first demonstrated the key role of testosterone as the principal androgenic hormone stimulating tumor growth in prostate cancer, and a strategy of lowering circulating testosterone to castrate (ie, ⬍50 ng/dL) levels quickly became the therapeutic goal. Initially, testosterone suppression was achieved by surgical castration (bilateral orchiectomy) or medical castration with diethysilbestrol, also discovered by Huggins and
From the Department of Surgery, Division of Urologic Surgery, Duke University Medical Center, Durham, North Carolina; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; and Department of Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio Financial Disclosure: J. W. Moul is a member of the Speaker’s Bureau for Sanofi-Aventis, Astra-Zeneca, GSK, Ferring. R. Dreicer has received grant/research support from Millenium; and has worked as a consultant for Sanofi Aventis, Novartis, Astra Zeneca, GTX, EMD Serano, Boehringer Ingelheim, Centecor Ortho Biotech, and Millenium. Reprint requests: Judd Moul, M.D., Department of Urologic Surgery, Duke University Medical Center, Room 1573, Duke South DUMC 3707, Durham, NC 27710. E-mail: [email protected] Submitted: March 1, 2011, accepted (with revisions): June 4, 2011
S476
© 2011 Elsevier Inc. All Rights Reserved
Hodges2 in 1941. This approach to androgen deprivation remained the standard of care for ⬎40 years. In the late 1980s, these 2 simple approaches to lowering circulating testosterone levels were replaced when luteinizing hormone-receptor hormone agonists were introduced. Luteinizing hormone-receptor hormone agonists work by competitively binding to the endogenous receptors of the testosterone precursors (luteinizing hormone-receptor hormone and follicle-stimulating hormone); thus, lowering the testosterone levels without the debilitating physical and psychological side effects of orchiectomy or the biochemical side effects of diethysilbestrol. Androgen deprivation therapy (ADT) by blockade of the androgen receptors was an important advance, especially in terms of patient acceptance, but it still had 2 drawbacks: the initial stimulation of testosterone by an agonist at the androgen receptor and the eventual return of androgen receptor responsiveness. To treat these, concepts such as combined androgen blockade (the use of antiandrogens in combination) to both suppress the initial testosterone flare and account for adrenal production of steroid precursors that could be converted to testosterone became the subject of active clinical research.3,4 With the recent development of agents that directly antagonize the androgen receptors (gonadotropin-releasing hormone antagonists) and can effectively lead to even greater suppression of serum testosterone than that previously achieved with medical or surgical castration, we are now re-evaluating the roles of androgen receptor blockade and serum testosterone in the treatment of patients with advanced prostate cancer.
CONTEMPORARY QUESTIONS CONCERNING HORMONAL THERAPY FOR PROSTATE CANCER Achieving suppression of testosterone through blockade by binding the precursors to their receptors, also known as hormonal therapy, can be used in several situations: 0090-4295/11/$34.00 doi:10.1016/j.urology.2011.06.004
As primary therapy for localized or metastatic disease For biochemical or clinical recurrence after previous local therapy For biochemical or clinical recurrence after previous local therapy As an adjuvant to radiotherapy as the initial treatment if the patient is at intermediate or high risk of cancer recurrence Once the form of hormonal therapy has been chosen, the physician must determine whether the measurement of serum prostate-specific antigen and/or other imaging tests provide an accurate assessment of the prostate cancer status; must decide on the frequency of assessment; determine whether to periodically measure testosterone; and determine whether the results of the assays (eg, serum testosterone ⬍50 ng/mL or prostate-specific antigen progression) are clinically relevant. Finally, if the treatment strategy appears to be failing, the physician must determine what is happening biologically and/or physiologically, if the cancer indexes return; and the best therapeutic strategy for intervening to maintain biochemical and clinical remission, if the testosterone levels are not maintained in the castration range. This supplement to the Journal was based on a 2-day round table of leading investigators and practitioners
UROLOGY 78 (Supplement 5A), 2011
convened to assess where we are today in our understanding and current practices with pharmacologic ADT, especially in light of the new agents that are finally becoming available for the first time in many years. The following reports will be devoted to a review of the data from the large observational database, Cancer of the Prostate Strategic Urologic Research Endeavor, giving us a picture of the current applications of ADT in the community of physicians treating patients with prostate cancer, followed by reports on the physiology of the androgen receptor and androgen blockade, the various approaches to using ADT, and, finally, a brief review of some of the new agents becoming available. References 1. National Cancer Institute. Prostate cancer. Available from: http:// www.cancer.gov/cancertopics/types/prostate. Accessed February 2, 2011. 2. Huggins C, Hodges CV. Studies on prostatic cancer. I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1: 293-297. 3. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-424. 4. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet. 2000;355:1491-1498.
S477