Treatment - Endocrine Therapy

Tumors arising from the breast, prostate, and uterine endometrium may respond to hormonal manipulation of underlying cellular growth control mechanisms. Steroid hormones act by binding to specific receptors in the tumor cell cytoplasm to induce a conformational change that alters the shape of the receptor protein. The hormone-receptor complex is transported to the cell nucleus, where it interacts with cellular DNA, acting as a transcription factor to initiate specific messenger RNA and protein synthesis. After this interaction the cytoplasmic receptor concentration is restored and the cycle can be repeated. Receptors are known to exist for estrogens (ER), progesterones (PR), androgens, and adrenocorticosteroids. The latter also uniquely exert some antitumor effect on nonendocrine targets such as acute lymphocytic leukemic cells.

Estrogens. Breast and prostate cancers may be treated by removing sources of circulating hormones (ablation of endocrine organs) that stimulate or support tumor growth or by giving pharmacologic doses of estrogens, androgens, progesterones, or glucocorticoids to suppress tumor growth. Until recently, hormonal therapy has been empirical and based on menopausal status, disease-free interval, site of dominant disease, and response to prior endocrine therapy. The discovery of estrogen (ER) and progesterone (PR) receptors has placed such therapy on a more rational basis. In the case of breast cancer, 65 per cent of ER (+) patients respond to hormonal manipulation. The responses increase to 75 per cent if PR is also positive. In contrast, less than five per cent of patients who are ER (-) will respond to hormonal manipulation. Both ER and PR may be needed for optimum response, since nearly 40 per cent of ER (+) women still fail to respond to hormonal manipulation. Premenopausal women with breast cancer have a lower incidence of ER positivity and lower levels of binding protein in their tumor cell cytosol. In contrast, postmenopausal women have a higher incidence of ER positivity and quantitatively higher levels of ER protein in their tumor cell cytosol. Indeed, responsiveness to antiestrogens is directly related to the quantitative levels of hormone receptors in the tumor. ER (-) tumor cells may either be less well differentiated or have an increased growth (drug sensitive) fraction, so that ER (-) patients may respond better to cancer chemotherapy than ER (+) patients. Similar conditions of response to hormonal manipulation with the frequency and quantity of binding proteins have yet to be made for prostate and endometrial cancers.

Ablative surgery has been used in breast cancer. Chemotherapy is preferred for patients with ER (-) recurrent tumor, a short disease-free interval, hepatic metastases, lymphangitic spread to the lung, or refractoriness to prior hormone therapy. However, castration may benefit over 50 per cent of premenopausal women with ER (+) tumors that are slowly growing (long disease-free interval) or who have mainly osseous and soft tissue metastases. Patients not responding to castration are unlikely to respond to further endocrine manipulation and should be given chemotherapy. However, 50 per cent of ER (+) women who again relapse after a response to castration may again respond to adrenalectomy or hypophysectomy. Since the procedures are equally effective, the choice depends on the patient's condition and the available surgical expertise. Postmenopausal women who have responded to estrogen may also benefit. Responses last, on the average, 16 to 18 months.

Some 70 per cent of men with breast cancer also respond to castration, and 50 per cent of those who have recurrences will then respond to adrenalectomy or hypophysectomy.

Many men with prostatic cancer respond for 2 to 3 years after orchiectomy, which should be reserved for those requiring rapid response, since estrogens are equally effective. Estrogens provide an added benefit when castration is used. Indeed estrogen as diethylstilbesterol (DES) or ethinyl estradiol used to be the mainstay for the palliative treatment of disseminated cancer of the prostate.

Antiestrogens are estrogen analogues that antagonize estrogen stimulation of target tissues. They bind competitively to the estrogen receptor and function as a weak agonist/antagonist by translocating with it into the nucleus to initiate early estrogenic responses. It has a ling plasma half-life and requires 4 weeks or longer to reach steady state levels. A complete response does not develop, the antiestrogen retains the receptor in the nucleus for prolonged periods, and the genome remains refractory to the action of estrogens for a time. Up to 60 per cent of ER (+) patients with breast cancer respond to antiestrogens such as Tamoxifen, which help to avoid the need for so many ablative procedures.

The aromatase inhibitor aminoglutethimide is used for the palliative treatment of disseminated breast cancer. It blocks the enzymatic pathway that converts androgens to estrogens in peripheral tissues, and blocks the conversion of cholesterol to pregnenolone, which is a key step in the biosynthesis of steroid hormones. It thus produces a medical adrenalectomy that may require maintenance doses of hydrocortisone or mineralocorticoid.

Androgens may help postmenopausal women with breast cancer, particularly those with osseous metastases and ER (+) tumors. Response to therapy, including stimulation of erythropoiesis, may require 6 to 12 weeks; all androgen preparations are equally useful. Aside from bony metastases, however, androgens are less effective than estrogens for postmenopausal women.

Antiandrogens such as flutamide block the binding of androgen to its receptor in peripheral tissues. Tissue levels of the hormone decrease even though serum testosterone levels may rise. Metastatic prostate cancer is treated with flutamide, often in combination with leuprolide.

Progestins (progestational agents) such as medroxyprogesterone and megestrol acetate can be used to treat breast and endometrial cancers. They may produce responses in 30 per cent of women with metastatic endometrial cancer which can last several years. Progestins are related to progesterone produced by the corpus luteum and the placenta. Older women with slow growing, well differentiated tumors respond best. About 10 per cent of patients with metastatic renal cell and ovarian cancers may also respond. They act by interfering with the hypothalamic-pituitary-gonadal axis, and by altering the expression of estrogen receptors, and by having androgenic effects.
   
Thyroid nodules presumed to be cancer and 70 per cent of thyroid papillary adenocarcinomas, even when metastatic to the neck, can be suppressed for over 10 years with thyroid hormone given to tolerance.

Adrenal corticosteroids may produce complete remission in 60 per cent of patients with lymphoblastic leukemia and partial responses in 70 per cent of patients with chronic lymphocytic leukemia. These hormones are active in 10 per cent of women with breast cancer and against lymphomas and myeloma. They bind to a glucocorticosteroid receptor in lymphoid cells and then initiate apoptosis. The hormones also suppress mitosis and lyse normal and neoplastic lymphoid cells by inhibiting synthesis of cellular proteins. Their activity in breast cancer partly relates to suppression of estrogen production by the adrenal cortex. Prednisone, methylprednisone and dexamethasone are the agents most often used in cancer therapy.

Gonadotropin-Releasing Hormone Agonists. Leuprolide is a gonadotropin-releasing hormone (GnRH) agonist used to treat disseminated cancer of the prostate. Normally the pituitary is stimulated in a pulsatile fashion by GnRH. But when the stimulation is continuous eventually there is downregulation of the secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) that results in a decrease in the levels of androgen. During the first few weeks of therapy there may be increased release of LH and FSH with worsening of symptoms which is handled by adding an antiandrogen.

Somatostatin Analogues. Octreotide is used to treat the symptoms of functional endocrine tumors such as metastatic carcinoid or tumors secreting vasoactive intestinal peptide. Somatostatin analogues suppress the release of growth hormone as well as gastric and pancreatic peptides.

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