Chapter 081. Principles of Cancer Treatment (Part 17) Prostate cancer is classically treated by androgen deprivation. Diethylstilbestrol (DES) acting as an estrogen at the level of the hypothalamus to downregulate hypothalamic luteinizing hormone (LH) production results in decreased elaboration of testosterone by the testicle. For this reason, orchiectomy is equally as effective as moderate-dose DES, inducing responses in 80% of previously untreated patients with prostate cancer but without the prominent cardiovascular side effects of DES, including thrombosis and exacerbation of coronary artery disease. In the event that orchiectomy is not accepted by the patient, testicular androgen suppression can also be effected by luteinizing hormone–releasing hormone (LHRH) agonists such as leuprolide and goserelin. These agents cause tonic stimulation of the LHRH receptor, with the loss of its normal pulsatile activation resulting in decreased output of LH by the anterior pituitary. Therefore, as primary hormonal manipulation in prostate cancer, one can choose orchiectomy or leuprolide, but not both. The addition of androgen receptor blockers, including flutamide or bicalutamide, is of uncertain additional benefit in extending overall response duration; the combined use of orchiectomy or leuprolide plus flutamide is referred to as total androgen blockade. Tumors that respond to a primary hormonal manipulation may frequently respond to second and third hormonal manipulations. Thus, breast tumors that had previously responded to tamoxifen have, on relapse, notable response rates to withdrawal of tamoxifen itself or to subsequent addition of an aromatase inhibitor or progestin. Likewise, initial treatment of prostate cancers with leuprolide plus flutamide may be followed after disease progression by response to withdrawal of flutamide. These responses may result from the removal of antagonists from mutant steroid hormone receptors that have come to depend on the presence of the antagonist as a growth-promoting influence. Additional strategies to treat refractory breast and prostate cancers that possess steroid hormone receptors may also address adrenal capacity to produce androgens and estrogens, even after orchiectomy or oophorectomy, respectively. Thus, aminoglutethimide or ketoconazole can be used to block adrenal synthesis by interfering with the enzymes of steroid hormone metabolism. Administration of these agents requires concomitant hydrocortisone replacement and additional glucocorticoid doses administered in the event of physiologic stress. Humoral mechanisms can also result in complications of an underlying malignancy. Adrenocortical carcinomas can cause Cushing's syndrome as well as syndromes of androgen or estrogen excess. Mitotane can counteract these by decreasing synthesis of steroid hormones. Islet cell neoplasms can cause debilitating diarrhea, treated with the somatostatin analogue octreotide. Prolactin- secreting tumors can be effectively managed by the dopaminergic agonist bromocriptine. Targeted Therapies A better understanding of cancer cell biology has suggested many new targets for cancer drug discovery and development. These include the products of oncogenes and tumor-suppressor genes, regulators of cell death pathways, mediators of cellular immortality such as telomerase, and molecules responsible for microenvironmental molding such as proteases or angiogenic factors. The essential difference in the development of agents that would target these processes is that the basis for discovery of the candidate drug is the a priori importance of the target in the biology of the tumor, rather than the initial detection of drug candidates based on the phenomenon of tumor cell regression in tissue culture or in animals. The following examples reflect the rapidly evolving clinical research activity in this area. Figure 81-4 summarizes how FDA-approved targeted agents act. Figure 81-4 . Chapter 081. Principles of Cancer Treatment (Part 17) Prostate cancer is classically treated by androgen deprivation. Diethylstilbestrol (DES) acting as an estrogen at the level of the. notable response rates to withdrawal of tamoxifen itself or to subsequent addition of an aromatase inhibitor or progestin. Likewise, initial treatment of prostate cancers with leuprolide plus flutamide. understanding of cancer cell biology has suggested many new targets for cancer drug discovery and development. These include the products of oncogenes and tumor-suppressor genes, regulators of cell