OOll-972X/92/7503-0665$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society
CLINICAL Endocrine RICHARD
Vol. 75, No. 3 Printed in ill S.A.
REVIEW Treatment
37 of Prostate
Cancer
J. SANTEN
Department of Medicine, Division Hershey, Pennsylvania 17033
of
Endocrinology,
P.O. Box 850, The Milton
Prostate Cancer Background
Prostate cancer follows breast cancer as the most common type of hormone-dependent neoplasm in the United States with 122,000 new casesdiagnosed per year. Clinical staging of this tumor (Fig. 1) provides the major meansof determining prognosisand is used for making treatment decisions(1). In 80% of patients with metastatic prostate cancer, tumor cells are dependent upon androgens for continued viability (androgen-dependent cells) or are stimulated to grow more rapidly by androgens but do not regress upon androgen withdrawal (androgen sensitive cells). The major androgenic effects on tumor growth are mediated through dihydrotestosterone, the 5a-reduced product of testosterone. Approximately 7,000 PLgtestosterone are secreted daily by the testes and 500 pg of this are converted into dihydrotestosterone in various peripheral tissues, Notably, a large fraction of the dihydrotestosterone present in benign and malignant prostatic tissue is produced locally in the prostate gland from testosterone. The adrenal gland provides an additional 5% of the androgen produced in adult men. Testosterone as well as preandrogens such as androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate originate in the adrenal and are converted in peripheral tissues and in the prostate into dihydrotestosterone. No specific hormonal or receptor measurementsare currently available that allow the precise biochemical characterization of tumors as androgen dependent, androgen sensitive, or androgen independent. Whereas estrogen receptor measurements are useful in patients with breast cancer, androgen receptors in prostate cancer patients have not been established as a practically useful method of predicting responsesto endocrine therapy. When to initiate
hormonal
treatment
The decision when to begin hormonal therapy is a major question in patients with prostate cancer. Becausecure with hormones is not possible, the two goals of treatment are to Received February 27, 1992. Address all correspondence and requests for reprints to: Richard J. Santen, Department of Medicine, Division of Endocrinology, P.O. Box 850, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033.
S. Hershey Medical
Center,
increaselife expectancy and to relieve symptoms. If treatment were to be advocated in asymptomatic patients, the therapy should improve the length of patient survival. Rigorously controlled seriesfrom the Veterans Administration Cooperative Urological ResearchGroup (VACURG) trials during the 1960s indicated no clear survival benefit from endocrine therapy at the time of diagnosis.Since then, standard practice involves withholding hormonal therapy until metastatic (stage D) diseaseis present. Patients with stage Al disease are observed, and patients with stage A2 and B tumors are treated either with radical prostatectomy or radiation therapy. Stage C patients receive radiation therapy, although some clinicians advocate initiating hormonal therapy for these patients before the development of symptoms (2, 3). Prospective randomized trials are required to determine the optimal management of stage C disease,and this remains an area of some controversy. Considerations regarding hormonal therapy for asymptomatic patients with stage D diseaseare logically based upon the survival benefit which accrues from this treatment. Unfortunately, it is unclear whether endocrine therapy prolongs survival in stageD disease.Respondersto therapy live longer than nonresponders, but this may reflect differences in biological aggressivenessof tumors and not treatment (3). Placebo-controlled trials conducted by the VACURG in the 1960s provided only equivocal evidence of survival benefit from hormonal therapy. Basedupon these considerations, all symptomatic patients with stage D disease should receive hormonal therapy in order to improve the quality of life and relieve symptoms. Asymptomatic patients who are younger and have high grade tumors might also experience prolongation of survival by hormonal therapy at the time of diagnosis(3) and should, perhaps, also be treated. This recommendation is basedupon post hoc multivariant analyses from the VACURG studies (3) but not upon prospective trials designed to substantiate this finding. Other asymptomatic patients might reasonably be observed until they develop complaints referable to the cancer. The choice of endocrine
treatment
Which endocrine therapy to useinitially representsa major question (Fig. 2). In the VACURG study, various doses of estrogen were compared with orchiectomy and with the combination of orchiectomy plus estrogen therapy (3). The results show that orchiectomy is as effective in inducing tumor regression as is an optimal dose of estrogen. In addi-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 15 November 2015. at 03:50 For personal use only. No other uses without permission. . All rights reserved.
SANTEN
686 CLINICAL
STAGING
AND
JCE & M .1992 Vol75.No3
PROGNOSIS
Ketoconazole Ketocxmazole
Tumor bat Palpable
Rectally
I
Local
Extension
I
Extraprosistic
Spread
Clinical staging system in general use. Stage A represents occult disease found at the time of transurethral resection of the prostate for the suspected clinical diagnosis of benign prostatic hypotrophy. The subsets Al and A2 depend upon the number of tissue chips found to contain cancer. Stage B disease is palpable clinically and is divided into subsets representing various stages of involvement of the prostate. Stage C represents local extraprostatic metastasis contiguous to the gland and stage D distant lymph node, bone, or other metastases. Approximate percentage of patients not treated or treated conservatively, dead at 5 yr is indicated by the heavy squares containing percentages drawn for each category. Prognostic data represent a compilation of information from varying time intervals [summarized from Catalona WJ (ed) 1984 Prostate Cancer. Grune and Stratton, New York, p 401. FIG.
1.
tion, orchiectomy is not associated with accelerated cardiovascular disease or other indirect complications of therapy that can occur with estrogens. The operative risks, especially when local anesthesia is used, are minimal. Impotence occurs as frequently after castration (i.e. nearly always) as with other standard endocrine therapies. Patient compliance is not a consideration once an adequate orchiectomy has been performed. The clinician can be assured that testicular androgens are completely suppressed provided that a total and not subcapsular orchiectomy is performed.
Before recent studieswith the GnRH superagonistanalogs, estrogen was the preferred form of “medical castration.” The rationale is to inhibit LH releaseby the pituitary and, thereby, lower plasma androgens to castrate levels. The VACURG (3) studies identified several problems with estrogen therapy and emphasized the critical dependence of these upon the dosage administered. Excessive amounts of estrogen [i.e. 5.0 mg of diethylstilbestrol (DES) daily] accelerate cardiovascular morbidity and mortality, whereas insufficient doses (i.e.
CLINICAL Endocrine RICHARD
Vol. 75, No. 3 Printed in ill S.A.
REVIEW Treatment
37 of Prostate
Cancer
J. SANTEN
Department of Medicine, Division Hershey, Pennsylvania 17033
of
Endocrinology,
P.O. Box 850, The Milton
Prostate Cancer Background
Prostate cancer follows breast cancer as the most common type of hormone-dependent neoplasm in the United States with 122,000 new casesdiagnosed per year. Clinical staging of this tumor (Fig. 1) provides the major meansof determining prognosisand is used for making treatment decisions(1). In 80% of patients with metastatic prostate cancer, tumor cells are dependent upon androgens for continued viability (androgen-dependent cells) or are stimulated to grow more rapidly by androgens but do not regress upon androgen withdrawal (androgen sensitive cells). The major androgenic effects on tumor growth are mediated through dihydrotestosterone, the 5a-reduced product of testosterone. Approximately 7,000 PLgtestosterone are secreted daily by the testes and 500 pg of this are converted into dihydrotestosterone in various peripheral tissues, Notably, a large fraction of the dihydrotestosterone present in benign and malignant prostatic tissue is produced locally in the prostate gland from testosterone. The adrenal gland provides an additional 5% of the androgen produced in adult men. Testosterone as well as preandrogens such as androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate originate in the adrenal and are converted in peripheral tissues and in the prostate into dihydrotestosterone. No specific hormonal or receptor measurementsare currently available that allow the precise biochemical characterization of tumors as androgen dependent, androgen sensitive, or androgen independent. Whereas estrogen receptor measurements are useful in patients with breast cancer, androgen receptors in prostate cancer patients have not been established as a practically useful method of predicting responsesto endocrine therapy. When to initiate
hormonal
treatment
The decision when to begin hormonal therapy is a major question in patients with prostate cancer. Becausecure with hormones is not possible, the two goals of treatment are to Received February 27, 1992. Address all correspondence and requests for reprints to: Richard J. Santen, Department of Medicine, Division of Endocrinology, P.O. Box 850, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033.
S. Hershey Medical
Center,
increaselife expectancy and to relieve symptoms. If treatment were to be advocated in asymptomatic patients, the therapy should improve the length of patient survival. Rigorously controlled seriesfrom the Veterans Administration Cooperative Urological ResearchGroup (VACURG) trials during the 1960s indicated no clear survival benefit from endocrine therapy at the time of diagnosis.Since then, standard practice involves withholding hormonal therapy until metastatic (stage D) diseaseis present. Patients with stage Al disease are observed, and patients with stage A2 and B tumors are treated either with radical prostatectomy or radiation therapy. Stage C patients receive radiation therapy, although some clinicians advocate initiating hormonal therapy for these patients before the development of symptoms (2, 3). Prospective randomized trials are required to determine the optimal management of stage C disease,and this remains an area of some controversy. Considerations regarding hormonal therapy for asymptomatic patients with stage D diseaseare logically based upon the survival benefit which accrues from this treatment. Unfortunately, it is unclear whether endocrine therapy prolongs survival in stageD disease.Respondersto therapy live longer than nonresponders, but this may reflect differences in biological aggressivenessof tumors and not treatment (3). Placebo-controlled trials conducted by the VACURG in the 1960s provided only equivocal evidence of survival benefit from hormonal therapy. Basedupon these considerations, all symptomatic patients with stage D disease should receive hormonal therapy in order to improve the quality of life and relieve symptoms. Asymptomatic patients who are younger and have high grade tumors might also experience prolongation of survival by hormonal therapy at the time of diagnosis(3) and should, perhaps, also be treated. This recommendation is basedupon post hoc multivariant analyses from the VACURG studies (3) but not upon prospective trials designed to substantiate this finding. Other asymptomatic patients might reasonably be observed until they develop complaints referable to the cancer. The choice of endocrine
treatment
Which endocrine therapy to useinitially representsa major question (Fig. 2). In the VACURG study, various doses of estrogen were compared with orchiectomy and with the combination of orchiectomy plus estrogen therapy (3). The results show that orchiectomy is as effective in inducing tumor regression as is an optimal dose of estrogen. In addi-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 15 November 2015. at 03:50 For personal use only. No other uses without permission. . All rights reserved.
SANTEN
686 CLINICAL
STAGING
AND
JCE & M .1992 Vol75.No3
PROGNOSIS
Ketoconazole Ketocxmazole
Tumor bat Palpable
Rectally
I
Local
Extension
I
Extraprosistic
Spread
Clinical staging system in general use. Stage A represents occult disease found at the time of transurethral resection of the prostate for the suspected clinical diagnosis of benign prostatic hypotrophy. The subsets Al and A2 depend upon the number of tissue chips found to contain cancer. Stage B disease is palpable clinically and is divided into subsets representing various stages of involvement of the prostate. Stage C represents local extraprostatic metastasis contiguous to the gland and stage D distant lymph node, bone, or other metastases. Approximate percentage of patients not treated or treated conservatively, dead at 5 yr is indicated by the heavy squares containing percentages drawn for each category. Prognostic data represent a compilation of information from varying time intervals [summarized from Catalona WJ (ed) 1984 Prostate Cancer. Grune and Stratton, New York, p 401. FIG.
1.
tion, orchiectomy is not associated with accelerated cardiovascular disease or other indirect complications of therapy that can occur with estrogens. The operative risks, especially when local anesthesia is used, are minimal. Impotence occurs as frequently after castration (i.e. nearly always) as with other standard endocrine therapies. Patient compliance is not a consideration once an adequate orchiectomy has been performed. The clinician can be assured that testicular androgens are completely suppressed provided that a total and not subcapsular orchiectomy is performed.
Before recent studieswith the GnRH superagonistanalogs, estrogen was the preferred form of “medical castration.” The rationale is to inhibit LH releaseby the pituitary and, thereby, lower plasma androgens to castrate levels. The VACURG (3) studies identified several problems with estrogen therapy and emphasized the critical dependence of these upon the dosage administered. Excessive amounts of estrogen [i.e. 5.0 mg of diethylstilbestrol (DES) daily] accelerate cardiovascular morbidity and mortality, whereas insufficient doses (i.e.
