- Email: [email protected]
Prostate cancer and selenium
Urol Clin N Am 29 (2002) 67–70
Prostate cancer and selenium Mark A. Nelson, PhD*, Mary Reid, Anna J. Duffield-Lillico, James R. Marshall Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA
Prostate cancer is the second leading cause of cancer deaths in men. The lifetime risk of death owing to prostate cancer is 3.4% for US men. An estimated 244,000 new cases of prostate cancer with 40,400 deaths were reported in 1995. Since 1995 the incidence rate has declined. In 1999 it was estimated that there would be approximately 179,000 new cases. This decline has been attributed, in part, to the advent of the prostate-specific antigen test (PSA), which may be responsible for the substantial decrease in the number of prevalent presymptomatic cases of prostate cancer in the United States [6]. The number of deaths owing to prostate cancer is low relative to the number of incident cases, in part, because prostate cancer tends to occur among older men, and because prostate cancer generally progresses slowly [6,7,12,21]. Current modalities of therapy include watchful waiting for clinically localized stage T1 or T2 prostate cancer. Watchful waiting is an appropriate modality for men who have an estimated life expectancy of less than 10 to 15 years [24,25]. This approach is less applicable to healthier (life expectancy >10 years) and younger men (<70 years old), who could benefit from potentially curative therapies. The current recommendation for men who have clinically localized prostate cancer and a life expectancy of more than 10 years is to treat with the intention of eradicating the tumor. Current therapeutic options include radical and
Work for this article was supported in part by Cypress Systems, the American Institute for Cancer Research, and Department of Defense grants PC970441, CA49764, CA79080, and CA77789. * Corresponding author. E-mail address: [email protected] (M.A. Nelson).
nerve-sparing prostatectomy, radiotherapy, and brachial radiotherapy [18,25]. A primary goal of prevention of prostate cancer is to identify individuals at substantial risk for the disease, such as men with a family history of prostate cancer at a young age and AfricanAmerican men who present with more advanced stage. Regular screening with digital rectal examination and PSA testing should detect disease at earlier more treatable stages. Ultimately, prevention efforts should identify lifestyle factors, especially dietary patterns, which are associated with increased risk. It is hoped that intervention in these factors will decrease the risk for cancer development. Recently, several extensive general reviews of selenium and cancer have been published [11,16]. This review focuses mainly on clinical trials underway at the authors’ center that are designed to extend understanding of the role of selenium supplementation in prostate cancer chemoprevention. Selenium levels and the risk for prostate cancer In the United Kingdom, selenium intakes have fallen over several decades owing mainly to a decrease in the use of imported flour from North America. Recent studies show that the average intake of selenium may be as low as 30 to 40 lg/ day [20]. During this time period of reduced selenium intake, the age-adjusted prostate cancer incidence and mortality have increased dramatically in England and Wales [17]. Further studies are warranted to determine whether the decrease in selenium intake has contributed to the increase in prostate cancer. In the United States, lower age-specific death rates for some cancers are seen in states with higher soil selenium levels [8,23]. Several studies
0094-0143/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 9 4 - 0 1 4 3 ( 0 2 ) 0 0 0 1 8 - 6
68
M.A. Nelson et al. / Urol Clin N Am 29 (2002) 67–70
based on prediagnostic serum selenium levels support an inverse association between lower levels of selenium and an increased risk of various cancers [23]. In a double-blind, placebo-controlled clinical trial in which baker’s yeast containing 200 lg of selenium or a matched placebo were administered daily to individuals with a history of nonmelanoma skin cancer, Clark and co-workers [9] found that selenium had no significant effect on skin cancer recurrence; however, individuals in the experimental group experienced sizable decreases in the risks for primary cancers of the colorectum, prostate, and lung. The prostate cancer incidence decreased by a striking 63%, lung cancer by 46%, and colorectal cancer by 58%. Total cancer mortality was decreased by 50% in the supplemented group [9]. One of the limitations is that prostate cancer was not an a priori hypothesis of the study [7,10,13,14], and that interpretation requires caution [19]. Not all male participants had a PSA or digital rectal examination. In addition, because not all men with an elevated PSA underwent a prostate biopsy, a number of cancers may not have been detected. Other criticisms include the limited generalizability of the results to men living outside of a low-selenium area and the use of the selenized baker’s yeast, which contains many undefined selenoproteins. In the Health Professionals Follow-up Study, investigators evaluated the association between the risk of prostate cancer and the prediagnostic level of selenium in toenails, a surrogate marker for long-term selenium intake [26]. The results from this study indicated that a reduced risk of advanced prostate cancer was associated with higher selenium levels. Both studies observed more than a 60% reduction in prostate cancer incidence between the high- and low-selenium groups, despite the fact that the Nutritional Prevention of Cancer trial used a nutritional supplement in a clinical trial design, and the Health Professionals Follow-up Study observed differences in dietary intakes in a cohort study. Taken together, these data support a role for selenium in reducing the risk of prostate cancer. These studies provide rationale for the further evaluation of this relationship. Clinical trials with selenium in prostate cancer The four studies underway at the authors’ center seek to extend understanding of the relationship between selenium and the risk for prostate cancer. Designed as randomized, placebo-controlled, double-blind trials, these studies will offer
opportunities to confirm Clark’s results and explore mechanisms by which selenium compounds might work. These complementary trials involve interventions at different phases of the development of clinical prostate cancer. One trial is using only selenomethionine, whereas the other trials are using high-selenium baker’s yeast, a mixture of several selenium compounds. This contrast offers an opportunity to explore, in limited fashion, whether the primary compound in selenized yeast, selenomethionine, has different effects than the broader range of selenium compounds in selenized yeast. The four studies include the Phase III Trial of Selenium for Prostate Cancer (Negative Biopsy), the Selenium-Based Chemoprevention in HighGrade Prostatic Intraepithelial Neoplasia Patients (HGPIN) trial, the Chemoprevention Trial of Selenium and Prostate Cancer (Preprostatectomy), and the Phase II Chemoprevention Trial of Selenium and Prostate Cancer (Watchful Waiting). They range from evaluations of the responses to selenium of high-risk individuals who have not been diagnosed with prostate cancer to attempts to alter the course of clearly invasive prostate cancer. All of the trials are coupled with efforts to identify biologic changes associated with possible effects of selenium on prostate cancer risk and progression. Negative biopsy trial Men with persistently elevated PSA with or without an abnormal digital rectal examination are at a significantly elevated risk for prostate cancer [15] and represent a high-priority target for prostate cancer chemoprevention studies. In the negative biopsy trial, subjects are required to have a recent negative biopsy of the prostate, ensuring to the greatest degree possible that they do not already have clinical prostate cancer. Although many of these men have early prostate cancer, the randomization procedure will ensure that they are equally distributed between the treatment groups. A total of 700 men with negative biopsies but elevated PSA will be randomized to placebo, 200 lg/day, or 400 lg/day of selenium in highselenium baker’s yeast. Follow-up is expected to last up to 57 months. Outcome measures will include prostate cancer incidence and the rate of rise in the PSA and chromogranin A before the end of treatment and follow-up. This trial will evaluate the ability of selenium supplementation to halt or slow the preclinical progression of
M.A. Nelson et al. / Urol Clin N Am 29 (2002) 67–70
prostate cancer and to decrease the incidence of clinical disease. The results will be directly generalizable to patients at high risk for prostate cancer but who have not yet been diagnosed. HGPIN trial The HGPIN study is being carried out by the Southwest Oncology Group (SWOG) under the leadership of the Arizona Cancer (authors’) Center. The primary premise of this study is that HGPIN is a premalignant lesion for prostate cancer [3–5,22]. A total of 470 men with HGPIN who have had two or more biopsies that indicate no invasive prostate cancer will be assigned to placebo or 200 lg/day of selenium in the form of selenomethionine. These subjects will be followed up for at least 3 years. Men who have not had additional biopsies will be scheduled for biopsy at the end of the follow-up period. The primary endpoint in this study is the diagnosis of biopsyproven prostate cancer. The secondary endpoints, or biomarkers of change, include pretreatment and posttreatment measurement of apoptosis and proliferation. Machine vision imaging will also be used to evaluate change in nuclear characteristics and degradation of basal cell integrity in the glands and ducts [1,2]. The ability of these markers to signal the effects of selenium and to predict prostate cancer risk will be carefully evaluated. This study will evaluate the activity of selenium immediately before neoplastic growth becomes transformed into invasive growth. Preprostatectomy trial The preprostatectomy trial will enroll 110 men with biopsy-diagnosed, localized prostate cancer who have selected prostatectomy as treatment. All of the subjects must agree to take a selenium supplement or placebo during the period just before surgery. Subjects will be assigned to placebo, 200 lg/day, or 400 lg/day of selenium in the form of high-selenium baker’s yeast. Followup evaluations will occur during the 6- to 8-week period between biopsy and prostatectomy. Because of the short time period available, no run-in period has been included in the trial design. Study endpoints will include immunohistochemical biomarkers of change in healthy tissue, such as proliferation, apoptosis, thioredoxin, thioredoxin reductase, and glutathione peroxidase. Fresh prostate biopsy specimens will be obtained from prostatectomy for evaluation of tissue selenium levels.
69
This clinical trial will also assess whether selenium administration can change the biochemistry of the prostate within a brief period and will evaluate whether two important mechanisms of carcinogenesis—proliferation and apoptosis and the balance between these two processes—can be altered by short-term treatment with selenium. Watchful waiting trial Evidence suggests that, for men with localized disease and low-grade tumors and a life expectancy less than 10 years, watchful waiting is a reasonable alternative to aggressive treatment [7,12]. A nontoxic chemopreventive agent such as selenium would be an attractive adjuvant treatment. In the watchful waiting trial, a total of 264 men with localized prostate cancer (PSA < 50 m/ml) who have chosen not to undergo prostatectomy, irradiation, or hormonal treatment will be given placebo, 200, or 800 lg/day of selenium in the form of high-selenium baker’s yeast. Patients will be observed for up to 4 years. Endpoints of this study will include selenium toxicity, the rates of increase in PSA, the indications to commence hormonal treatment, and the development of regional and distant metastases. A principle advantage of this study is that by limiting the sample to men with biopsy-confirmed prostate cancer, misclassification bias will be minimized. One of the most important outcomes of this study will be the evidence accrued on the impact of the doses of selenium. At these levels, this trial will contribute significant information on the safety and chemotherapeutic effects of long-term selenium supplementation. To date, no evidence of toxicity has been observed.
Summary The important progress achieved in the treatment of prostate cancer comes by exacting significant costs [11,16–18,20,23,25]. Currently, there is incomplete evidence that the radical interventions at hand significantly reduce the human costs of the disease. Surgery and radiotherapy induce substantial risks of incontinence and impotence. The PSA test has probably decreased the stage at which prostate cancer is diagnosed [15]. Nonetheless, the PSA is a means of earlier detection; it does not elucidate quantitatively distinct modes of treatment. The PSA test is not a means of prostate cancer prevention. The continuing incidence,
70
M.A. Nelson et al. / Urol Clin N Am 29 (2002) 67–70
morbidity, and mortality imposed by this disease strongly indicate that preventive strategies for its control are necessary. Chemoprevention with selenium and other agents offers a promising approach that is undergoing intensive investigation. Randomized trials underway at the authors’ center are building on the important clinical trial results reported by Dr. Larry C. Clark. These studies will evaluate the activity of selenium at several points along a continuum ranging from cancerous prostatic tissue in men with diagnosed cancer to premalignant tissue in men with high-grade PIN to healthy tissue in high-risk men with negative biopsy to long-term effects on cancerous tissue in men with frank cancer. These trials will also offer an opportunity for preliminary evaluation of the mechanisms by which selenium treatment could result in the slower development or progression of prostate cancer.
[10]
[11] [12]
[13]
[14]
[15]
Acknowledgments This article is dedicated to the memory of Dr. Larry C. Clark.
[16] [17]
References [1] Bartels PH, da Silva VD, Montironi R, et al. Chromatin texture signatures in nuclei from prostate lesions. Anal Quant Cytol Histol 1998;20:407–16. [2] Bartels PH, Montironi R, Thompson D, et al. Statistical histometry of the basal cell/secretory cell bilayer in prostatic intraepithelial neoplasia. Anal Quant Cytol Histol 1998;20:381–8. [3] Bostwick DG. Progression of prostatic intraepithelial neoplasia to early invasive adenocarcinoma. Eur Urol 1996;30:145–52. [4] Bostwick DG. Prospective origins of prostate carcinoma: prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia. Cancer 1996;78: 330–6. [5] Bostwick DG, Brawer MK. Prostatic intraepithelial neoplasia and early invasion of prostate cancer. Cancer 1987;59:788–94. [6] Facts Cancer & Figures—1999. Atlanta, American Cancer Society, 1999. [7] Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. [see comments] N Engl J Med 1994; 330:242–8. [8] Clark LC, Cantor KP, Allaway WH. Selenium in forage crops and cancer mortality in US countries. Arch Eviron Health 1991;46:37–42. [9] Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention
[18]
[19] [20] [21]
[22]
[23]
[24] [25]
[26]
in patients with carcinoma of the skin: a randomized controlled trial. Nutritional Prevention of Cancer Study Group [see comments]. JAMA 1996;276: 1957–63. [Published erratum appears in JAMA 1997;277(19):1520.] Colditz GA. Selenium and cancer prevention: promising results indicate further trials required. JAMA 1996;276:1984–5. Combs GF Jr, Gray WP. Chemopreventive agents. Selenium Pharmacol Ther 1998;79:179–92. Fleming C, Wasson JH, Albertsen PC, et al. A decision analysis of alternative treatment strategies for clinically localized prostate cancer: Prostate Patient Outcomes Research Team [see comments]. JAMA 1993;269:2650–81. Fleet JC. Dietary selenium repletion may reduce cancer incidence in people at high risk who live in areas with low soil selenium. Nutr Rev 1997;55: 277–86. Fleshner NE, Klotz LH. Diet, androgens, oxidative stress and prostate cancer susceptibility. Cancer Metastasis Rev 1999;17:325–30. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer [see comments]. JAMA 1995;273:289–94. Ip C. Lessons from basic research in selenium and cancer prevention. J Nutr 1998;128:1845–54. Majed FA, Buirgess TA. Trends in death rates and registration rates for prostate cancer in England and Wales. Br J Urol 1994;73:377–81. Majur DJ, Hickam DH. Patient preferences for management of localized prostate cancer. West J Med 1996;165:26–30. Pocock S, Hughes M. Estimation issues in clinical trials and overviews. Stat Med 1990;9:657–71. Rayman MP. Dietary selenium: time to act. BMJ 1997;314:387–8. Ross R, Schottenfeld D. Prostate cancer. In: Schottenfeld D, Fraumeni J Jr, editors. Cancer epidemiology and prevention, 2nd edition. New York: Oxford University Press; 1996. p. 1180–206 Sakr WA, Grignon DJ. Prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia: relationship to pathologic parameters, volume and spatial distribution of carcinoma of the prostate. Anal Quant Cytol Histol 1998;20:417–23. Shamberger RJ, Frost DV. Possible protective effects of selenium against human cancer. Can Med Assoc J 1969;100:82. Small SJ. Prostate cancer incidence management and outcomes. Drugs Aging 1998;13:71–81. Steinberg GD, Bales GT, Brendler CB. An analysis of watchful waiting for clinically localized prostate cancer. J Urol 1998;159:143–6. Yoshizawa K, Willet WC, Morris SJ, et al. Study of the prediagnostic selenium level in toenail and the risk of advanced prostate cancer. J Natl Cancer Inst 1998;990:1219–24.
Prostate cancer and selenium Mark A. Nelson, PhD*, Mary Reid, Anna J. Duffield-Lillico, James R. Marshall Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA
Prostate cancer is the second leading cause of cancer deaths in men. The lifetime risk of death owing to prostate cancer is 3.4% for US men. An estimated 244,000 new cases of prostate cancer with 40,400 deaths were reported in 1995. Since 1995 the incidence rate has declined. In 1999 it was estimated that there would be approximately 179,000 new cases. This decline has been attributed, in part, to the advent of the prostate-specific antigen test (PSA), which may be responsible for the substantial decrease in the number of prevalent presymptomatic cases of prostate cancer in the United States [6]. The number of deaths owing to prostate cancer is low relative to the number of incident cases, in part, because prostate cancer tends to occur among older men, and because prostate cancer generally progresses slowly [6,7,12,21]. Current modalities of therapy include watchful waiting for clinically localized stage T1 or T2 prostate cancer. Watchful waiting is an appropriate modality for men who have an estimated life expectancy of less than 10 to 15 years [24,25]. This approach is less applicable to healthier (life expectancy >10 years) and younger men (<70 years old), who could benefit from potentially curative therapies. The current recommendation for men who have clinically localized prostate cancer and a life expectancy of more than 10 years is to treat with the intention of eradicating the tumor. Current therapeutic options include radical and
Work for this article was supported in part by Cypress Systems, the American Institute for Cancer Research, and Department of Defense grants PC970441, CA49764, CA79080, and CA77789. * Corresponding author. E-mail address: [email protected] (M.A. Nelson).
nerve-sparing prostatectomy, radiotherapy, and brachial radiotherapy [18,25]. A primary goal of prevention of prostate cancer is to identify individuals at substantial risk for the disease, such as men with a family history of prostate cancer at a young age and AfricanAmerican men who present with more advanced stage. Regular screening with digital rectal examination and PSA testing should detect disease at earlier more treatable stages. Ultimately, prevention efforts should identify lifestyle factors, especially dietary patterns, which are associated with increased risk. It is hoped that intervention in these factors will decrease the risk for cancer development. Recently, several extensive general reviews of selenium and cancer have been published [11,16]. This review focuses mainly on clinical trials underway at the authors’ center that are designed to extend understanding of the role of selenium supplementation in prostate cancer chemoprevention. Selenium levels and the risk for prostate cancer In the United Kingdom, selenium intakes have fallen over several decades owing mainly to a decrease in the use of imported flour from North America. Recent studies show that the average intake of selenium may be as low as 30 to 40 lg/ day [20]. During this time period of reduced selenium intake, the age-adjusted prostate cancer incidence and mortality have increased dramatically in England and Wales [17]. Further studies are warranted to determine whether the decrease in selenium intake has contributed to the increase in prostate cancer. In the United States, lower age-specific death rates for some cancers are seen in states with higher soil selenium levels [8,23]. Several studies
0094-0143/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 9 4 - 0 1 4 3 ( 0 2 ) 0 0 0 1 8 - 6
68
M.A. Nelson et al. / Urol Clin N Am 29 (2002) 67–70
based on prediagnostic serum selenium levels support an inverse association between lower levels of selenium and an increased risk of various cancers [23]. In a double-blind, placebo-controlled clinical trial in which baker’s yeast containing 200 lg of selenium or a matched placebo were administered daily to individuals with a history of nonmelanoma skin cancer, Clark and co-workers [9] found that selenium had no significant effect on skin cancer recurrence; however, individuals in the experimental group experienced sizable decreases in the risks for primary cancers of the colorectum, prostate, and lung. The prostate cancer incidence decreased by a striking 63%, lung cancer by 46%, and colorectal cancer by 58%. Total cancer mortality was decreased by 50% in the supplemented group [9]. One of the limitations is that prostate cancer was not an a priori hypothesis of the study [7,10,13,14], and that interpretation requires caution [19]. Not all male participants had a PSA or digital rectal examination. In addition, because not all men with an elevated PSA underwent a prostate biopsy, a number of cancers may not have been detected. Other criticisms include the limited generalizability of the results to men living outside of a low-selenium area and the use of the selenized baker’s yeast, which contains many undefined selenoproteins. In the Health Professionals Follow-up Study, investigators evaluated the association between the risk of prostate cancer and the prediagnostic level of selenium in toenails, a surrogate marker for long-term selenium intake [26]. The results from this study indicated that a reduced risk of advanced prostate cancer was associated with higher selenium levels. Both studies observed more than a 60% reduction in prostate cancer incidence between the high- and low-selenium groups, despite the fact that the Nutritional Prevention of Cancer trial used a nutritional supplement in a clinical trial design, and the Health Professionals Follow-up Study observed differences in dietary intakes in a cohort study. Taken together, these data support a role for selenium in reducing the risk of prostate cancer. These studies provide rationale for the further evaluation of this relationship. Clinical trials with selenium in prostate cancer The four studies underway at the authors’ center seek to extend understanding of the relationship between selenium and the risk for prostate cancer. Designed as randomized, placebo-controlled, double-blind trials, these studies will offer
opportunities to confirm Clark’s results and explore mechanisms by which selenium compounds might work. These complementary trials involve interventions at different phases of the development of clinical prostate cancer. One trial is using only selenomethionine, whereas the other trials are using high-selenium baker’s yeast, a mixture of several selenium compounds. This contrast offers an opportunity to explore, in limited fashion, whether the primary compound in selenized yeast, selenomethionine, has different effects than the broader range of selenium compounds in selenized yeast. The four studies include the Phase III Trial of Selenium for Prostate Cancer (Negative Biopsy), the Selenium-Based Chemoprevention in HighGrade Prostatic Intraepithelial Neoplasia Patients (HGPIN) trial, the Chemoprevention Trial of Selenium and Prostate Cancer (Preprostatectomy), and the Phase II Chemoprevention Trial of Selenium and Prostate Cancer (Watchful Waiting). They range from evaluations of the responses to selenium of high-risk individuals who have not been diagnosed with prostate cancer to attempts to alter the course of clearly invasive prostate cancer. All of the trials are coupled with efforts to identify biologic changes associated with possible effects of selenium on prostate cancer risk and progression. Negative biopsy trial Men with persistently elevated PSA with or without an abnormal digital rectal examination are at a significantly elevated risk for prostate cancer [15] and represent a high-priority target for prostate cancer chemoprevention studies. In the negative biopsy trial, subjects are required to have a recent negative biopsy of the prostate, ensuring to the greatest degree possible that they do not already have clinical prostate cancer. Although many of these men have early prostate cancer, the randomization procedure will ensure that they are equally distributed between the treatment groups. A total of 700 men with negative biopsies but elevated PSA will be randomized to placebo, 200 lg/day, or 400 lg/day of selenium in highselenium baker’s yeast. Follow-up is expected to last up to 57 months. Outcome measures will include prostate cancer incidence and the rate of rise in the PSA and chromogranin A before the end of treatment and follow-up. This trial will evaluate the ability of selenium supplementation to halt or slow the preclinical progression of
M.A. Nelson et al. / Urol Clin N Am 29 (2002) 67–70
prostate cancer and to decrease the incidence of clinical disease. The results will be directly generalizable to patients at high risk for prostate cancer but who have not yet been diagnosed. HGPIN trial The HGPIN study is being carried out by the Southwest Oncology Group (SWOG) under the leadership of the Arizona Cancer (authors’) Center. The primary premise of this study is that HGPIN is a premalignant lesion for prostate cancer [3–5,22]. A total of 470 men with HGPIN who have had two or more biopsies that indicate no invasive prostate cancer will be assigned to placebo or 200 lg/day of selenium in the form of selenomethionine. These subjects will be followed up for at least 3 years. Men who have not had additional biopsies will be scheduled for biopsy at the end of the follow-up period. The primary endpoint in this study is the diagnosis of biopsyproven prostate cancer. The secondary endpoints, or biomarkers of change, include pretreatment and posttreatment measurement of apoptosis and proliferation. Machine vision imaging will also be used to evaluate change in nuclear characteristics and degradation of basal cell integrity in the glands and ducts [1,2]. The ability of these markers to signal the effects of selenium and to predict prostate cancer risk will be carefully evaluated. This study will evaluate the activity of selenium immediately before neoplastic growth becomes transformed into invasive growth. Preprostatectomy trial The preprostatectomy trial will enroll 110 men with biopsy-diagnosed, localized prostate cancer who have selected prostatectomy as treatment. All of the subjects must agree to take a selenium supplement or placebo during the period just before surgery. Subjects will be assigned to placebo, 200 lg/day, or 400 lg/day of selenium in the form of high-selenium baker’s yeast. Followup evaluations will occur during the 6- to 8-week period between biopsy and prostatectomy. Because of the short time period available, no run-in period has been included in the trial design. Study endpoints will include immunohistochemical biomarkers of change in healthy tissue, such as proliferation, apoptosis, thioredoxin, thioredoxin reductase, and glutathione peroxidase. Fresh prostate biopsy specimens will be obtained from prostatectomy for evaluation of tissue selenium levels.
69
This clinical trial will also assess whether selenium administration can change the biochemistry of the prostate within a brief period and will evaluate whether two important mechanisms of carcinogenesis—proliferation and apoptosis and the balance between these two processes—can be altered by short-term treatment with selenium. Watchful waiting trial Evidence suggests that, for men with localized disease and low-grade tumors and a life expectancy less than 10 years, watchful waiting is a reasonable alternative to aggressive treatment [7,12]. A nontoxic chemopreventive agent such as selenium would be an attractive adjuvant treatment. In the watchful waiting trial, a total of 264 men with localized prostate cancer (PSA < 50 m/ml) who have chosen not to undergo prostatectomy, irradiation, or hormonal treatment will be given placebo, 200, or 800 lg/day of selenium in the form of high-selenium baker’s yeast. Patients will be observed for up to 4 years. Endpoints of this study will include selenium toxicity, the rates of increase in PSA, the indications to commence hormonal treatment, and the development of regional and distant metastases. A principle advantage of this study is that by limiting the sample to men with biopsy-confirmed prostate cancer, misclassification bias will be minimized. One of the most important outcomes of this study will be the evidence accrued on the impact of the doses of selenium. At these levels, this trial will contribute significant information on the safety and chemotherapeutic effects of long-term selenium supplementation. To date, no evidence of toxicity has been observed.
Summary The important progress achieved in the treatment of prostate cancer comes by exacting significant costs [11,16–18,20,23,25]. Currently, there is incomplete evidence that the radical interventions at hand significantly reduce the human costs of the disease. Surgery and radiotherapy induce substantial risks of incontinence and impotence. The PSA test has probably decreased the stage at which prostate cancer is diagnosed [15]. Nonetheless, the PSA is a means of earlier detection; it does not elucidate quantitatively distinct modes of treatment. The PSA test is not a means of prostate cancer prevention. The continuing incidence,
70
M.A. Nelson et al. / Urol Clin N Am 29 (2002) 67–70
morbidity, and mortality imposed by this disease strongly indicate that preventive strategies for its control are necessary. Chemoprevention with selenium and other agents offers a promising approach that is undergoing intensive investigation. Randomized trials underway at the authors’ center are building on the important clinical trial results reported by Dr. Larry C. Clark. These studies will evaluate the activity of selenium at several points along a continuum ranging from cancerous prostatic tissue in men with diagnosed cancer to premalignant tissue in men with high-grade PIN to healthy tissue in high-risk men with negative biopsy to long-term effects on cancerous tissue in men with frank cancer. These trials will also offer an opportunity for preliminary evaluation of the mechanisms by which selenium treatment could result in the slower development or progression of prostate cancer.
[10]
[11] [12]
[13]
[14]
[15]
Acknowledgments This article is dedicated to the memory of Dr. Larry C. Clark.
[16] [17]
References [1] Bartels PH, da Silva VD, Montironi R, et al. Chromatin texture signatures in nuclei from prostate lesions. Anal Quant Cytol Histol 1998;20:407–16. [2] Bartels PH, Montironi R, Thompson D, et al. Statistical histometry of the basal cell/secretory cell bilayer in prostatic intraepithelial neoplasia. Anal Quant Cytol Histol 1998;20:381–8. [3] Bostwick DG. Progression of prostatic intraepithelial neoplasia to early invasive adenocarcinoma. Eur Urol 1996;30:145–52. [4] Bostwick DG. Prospective origins of prostate carcinoma: prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia. Cancer 1996;78: 330–6. [5] Bostwick DG, Brawer MK. Prostatic intraepithelial neoplasia and early invasion of prostate cancer. Cancer 1987;59:788–94. [6] Facts Cancer & Figures—1999. Atlanta, American Cancer Society, 1999. [7] Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. [see comments] N Engl J Med 1994; 330:242–8. [8] Clark LC, Cantor KP, Allaway WH. Selenium in forage crops and cancer mortality in US countries. Arch Eviron Health 1991;46:37–42. [9] Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention
[18]
[19] [20] [21]
[22]
[23]
[24] [25]
[26]
in patients with carcinoma of the skin: a randomized controlled trial. Nutritional Prevention of Cancer Study Group [see comments]. JAMA 1996;276: 1957–63. [Published erratum appears in JAMA 1997;277(19):1520.] Colditz GA. Selenium and cancer prevention: promising results indicate further trials required. JAMA 1996;276:1984–5. Combs GF Jr, Gray WP. Chemopreventive agents. Selenium Pharmacol Ther 1998;79:179–92. Fleming C, Wasson JH, Albertsen PC, et al. A decision analysis of alternative treatment strategies for clinically localized prostate cancer: Prostate Patient Outcomes Research Team [see comments]. JAMA 1993;269:2650–81. Fleet JC. Dietary selenium repletion may reduce cancer incidence in people at high risk who live in areas with low soil selenium. Nutr Rev 1997;55: 277–86. Fleshner NE, Klotz LH. Diet, androgens, oxidative stress and prostate cancer susceptibility. Cancer Metastasis Rev 1999;17:325–30. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer [see comments]. JAMA 1995;273:289–94. Ip C. Lessons from basic research in selenium and cancer prevention. J Nutr 1998;128:1845–54. Majed FA, Buirgess TA. Trends in death rates and registration rates for prostate cancer in England and Wales. Br J Urol 1994;73:377–81. Majur DJ, Hickam DH. Patient preferences for management of localized prostate cancer. West J Med 1996;165:26–30. Pocock S, Hughes M. Estimation issues in clinical trials and overviews. Stat Med 1990;9:657–71. Rayman MP. Dietary selenium: time to act. BMJ 1997;314:387–8. Ross R, Schottenfeld D. Prostate cancer. In: Schottenfeld D, Fraumeni J Jr, editors. Cancer epidemiology and prevention, 2nd edition. New York: Oxford University Press; 1996. p. 1180–206 Sakr WA, Grignon DJ. Prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia: relationship to pathologic parameters, volume and spatial distribution of carcinoma of the prostate. Anal Quant Cytol Histol 1998;20:417–23. Shamberger RJ, Frost DV. Possible protective effects of selenium against human cancer. Can Med Assoc J 1969;100:82. Small SJ. Prostate cancer incidence management and outcomes. Drugs Aging 1998;13:71–81. Steinberg GD, Bales GT, Brendler CB. An analysis of watchful waiting for clinically localized prostate cancer. J Urol 1998;159:143–6. Yoshizawa K, Willet WC, Morris SJ, et al. Study of the prediagnostic selenium level in toenail and the risk of advanced prostate cancer. J Natl Cancer Inst 1998;990:1219–24.