Chapter 081. Principles of Cancer Treatment (Part 17)

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. ...
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Chapter 081. Principles of Cancer Treatment (Part 17) 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 todownregulate hypothalamic luteinizing hormone (LH) production results indecreased elaboration of testosterone by the testicle. For this reason, orchiectomyis equally as effective as moderate-dose DES, inducing responses in 80% ofpreviously untreated patients with prostate cancer but without the prominentcardiovascular side effects of DES, including thrombosis and exacerbation ofcoronary artery disease. In the event that orchiectomy is not accepted by thepatient, testicular androgen suppression can also be effected by luteinizinghormone–releasing hormone (LHRH) agonists such as leuprolide and goserelin.These agents cause tonic stimulation of the LHRH receptor, with the loss of itsnormal pulsatile activation resulting in decreased output of LH by the anteriorpituitary. Therefore, as primary hormonal manipulation in prostate cancer, one canchoose orchiectomy or leuprolide, but not both. The addition of androgen receptorblockers, including flutamide or bicalutamide, is of uncertain additional benefit inextending overall response duration; the combined use of orchiectomy orleuprolide plus flutamide is referred to as total androgen blockade. Tumors that respond to a primary hormonal manipulation may frequentlyrespond to second and third hormonal manipulations. Thus, breast tumors that hadpreviously responded to tamoxifen have, on relapse, notable response rates towithdrawal of tamoxifen itself or to subsequent addition of an aromatase inhibitoror progestin. Likewise, initial treatment of prostate cancers with leuprolide plusflutamide may be followed after disease progression by response to withdrawal offlutamide. These responses may result from the removal of antagonists frommutant steroid hormone receptors that have come to depend on the presence of theantagonist as a growth-promoting influence. Additional strategies to treat refractory breast and prostate cancers thatpossess steroid hormone receptors may also address adrenal capacity to produceandrogens and estrogens, even after orchiectomy or oophorectomy, respectively.Thus, aminoglutethimide or ketoconazole can be used to block adrenal synthesisby interfering with the enzymes of steroid hormone metabolism. Administration ofthese agents requires concomitant hydrocortisone replacement and additionalglucocorticoid doses administered in the event of physiologic stress. Humoral mechanisms can also result in complications of an underlyingmalignancy. Adrenocortical carcinomas can cause Cushings syndrome as well assyndromes of androgen or estrogen excess. Mitotane can counteract these bydecreasing synthesis of steroid hormones. Islet cell neoplasms can causedebilitating diarrhea, treated with the somatostatin analogue octreotide. Prolactin-secreting tumors can be effectively managed by the dopaminergic agonistbromocriptine. Targeted Therapies A better understanding of cancer cell biology has suggested many newtargets for cancer drug discovery and development. These include the products ofoncogenes and tumor-suppressor genes, regulators of cell death pathways,mediators of cellular immortality such as telomerase, and molecules responsiblefor microenvironmental molding such as proteases or angiogenic factors. Theessential difference in the development of agents that would target these processesis that the basis for discovery of the candidate drug is the a priori importance ofthe target in the biology of the tumor, rather than the initial detection of drugcandidates based on the phenomenon of tumor cell regression in tissue culture orin animals. The following examples reflect the rapidly evolving clinical researchactivity in this area. Figure 81-4 summarizes how FDA-approved targeted agentsact. Figure 81-4