Hormonal Treatment - Introduction
L. Bressler
November, 1997
OBJECTIVES
1. Discuss the settings for use of different hormones and hormone-related treatments in oncology.
2. Discuss common side effects of hormonal therapy in cancer patients.
REQUIRED READING
NONE
SUGGESTED READING
NONE
HORMONAL TREATMENT - INTRODUCTION
Hormonal therapy is used extensively in the treatment of breast cancer, prostate cancer and lymphoid malignancies, as well as in the management of several complications of cancer (eg. brain metastases). Occasionally, hormonal therapy is incorporated into chemotherapeutic regimens for other solid tumors, on the basis that the tumor may have some hormone dependency.
Many steroid hormone effects are mediated through interaction with HORMONE RECEPTORS. The steroid binds to a specific receptor in the cytoplasm. The STEROID/RECEPTOR COMPLEX is then translocated to the nucleus of the cell where it alters cell function through interaction with RNA. Some effects of steroids are non-receptor mediated (ie. direct steroid binding to nucleic acids). The significance of such effects is not completely understood, but may have implications especially as regards the role of glucocorticoids in leukemias, lymphomas and multiple myeloma.
The following is a brief overview of the use of pharmacologic agents for hormonal treatment of breast cancer and prostate cancer. It is not to be interpreted as a review on the treatment of these cancers.
About 30% of patients with breast cancer respond to various hormonal manipulations. This figure almost doubles when patients are selected on the basis of positive ESTROGEN RECEPTORS. Positive PROGESTERONE RECEPTORS in addition to positive estrogen receptor status increases the response rate even further. (Hormone receptor positivity is a quantitative measurement, not merely presence or absence.) Patients with higher estrogen receptor positivity tend to be OLDER and have SLOWER GROWING tumors than receptor negative patients. Tumors that have estrogen (progesterone) receptor positivity may respond to various hormonal manipulations, additive or ablative:
TAMOXIFEN - Tamoxifen is an ANTIESTROGEN that binds to estrogen receptors. It is very well tolerated. Usual dose is 10mg BID. There is little evidence for a dose-response relationship, although occasional patients will respond to higher doses after progressing on a lower dose. Ocular toxicity has been reported, primarily when high doses have been used. Menopausal symptoms may be seen, especially in premenopausal women.
DIETHYLSTILBESTROL (DES) - DES is as effective as tamoxifen in advanced breast cancer, but with more side effects. Thus, tamoxifen is commonly the first line hormonal agent. The usual dose of DES in breast cancer is 5mg TID. This may be associated with nausea/vomiting, so treatment can be initiated with a lower dose (5mg/day) and gradually increased to full dose over 1-2 weeks. Other side effects include SODIUM and WATER RETENTION and THROMBOEMBOLIC complications.
AMINOGLUTETHIMIDE (AG) - AG may be used as a second (occasionally first or third) line hormonal agent in breast cancer. AG blocks the conversion of cholesterol to delta-9-pregnenolone, an early step in adrenal steroid synthesis. More important in breast cancer, AG blocks the peripheral (eg. in fat, muscle) conversion of androstenedione to estrogen. With continued use of AG, the former mechanism is overridden by a compensatory increase in ACTH, thus AG is used in conjunction with HYDROCORTISONE (HC) (to suppress the reflex increase in ACTH). The latter mechanism, however, continues. And this mechanism is probably more important in breast cancer. Most side effects of AG are seen within the first six weeks of treatment. These include LETHARGY, DIZZINESS and RASH. In most cases, the drug need not be discontinued. A common dosing schedule is: AG 250mg BID + HC 100mg/day x 2 weeks, then, AG 250mg QID + HC 40mg/day. AG dose is increased, as the drug induces its own metabolism. Higher initial doses of HC may help minimize occurrence of the rash due to AG.
Newer agents (eg. ANASTROZOLE) are selective aromatase inhibitors. They work by the second mechanism noted above, and don't affect adrenal steroid synthesis. Their relative place in therapy remains to be determined.
PROGESTINS (eg. MEGESTROL 40mg QID) and ANDROGENS (eg. FLUOXYMESTRONE) may be used as second or third line hormonal agents. Megestrol is usually very well tolerated, frequently causing subjective improvement (eg. patients feel better). The major side effects of megestrol are weight gain (which is often desirable) and sweating. (The occurrence of weight gain with megestrol has lead to its use in cancer and AIDS cachexia.) Androgens are more likely to be associated with adverse side effects such as masculinization.
PRINCIPLES OF USE OF HORMONE TREATMENT IN BREAST CANCER
Responsive tumors commonly respond to subsequent hormonal manipulations after response, then progression, with a previous hormone therapy.
Response to hormonal therapy is slow (ie. it can't be evaluated for about 6-8 weeks).
Fast growing tumors and/or visceral involvement respond less well to hormones.
All hormonal agents have the potential to cause a "FLARE" of the disease, an apparent worsening with increased bone pain, hypercalcemia, etc. This is not necessarily an indication to discontinue the drug, although manifestations (eg. hypercalcemia) should be corrected. Flare reactions, when they occur, do so with in the first few weeks of therapy. WITHDRAWAL RESPONSES (ie. response seen when hormone therapy is discontinued) may also be seen in hormonally responsive tumors.
Most of the above applies to the use of hormones in advanced breast cancer. Tamoxifen is also used as adjuvant treatment (ie. to prevent recurrence after primary breast cancer) in certain populations.
Hormones (or orchiectomy) are generally used in symptomatic STAGE D PROSTATE CANCER.
DES - 1mg/day - This dose causes less cardiovascular toxicity (edema, thrombosis, phlebitis) and is as effective as higher doses that have been tested. Sometimes 3mg/day is used in an attempt to decrease testosterone to castrate levels. The CLINICAL BENEFIT of 3mg versus 1mg is not clear. IMPOTENCE and DECREASED LIBIDO are associated with DES. Other side effects include NAUSEA, HOT FLASHES, and GYNECOMASTIA. Gynecomastia can be prevented by local irradiation to the breasts prior to starting treatment.
LEUPROLIDE - Leuprolide was reported to be as effective and have less toxicity than 3mg/day of DES. Leuprolide is a long-acting analog of luteinizing hormone releasing hormone (LHRH), which inhibits gonadotropin (and thus testosterone) secretion with chronic use. Leuprolide is given by daily subcutaneous injection or monthly (or longer) depot IM injections. Leuprolide is also associated with IMPOTENCE. Another common side effect is HOT FLASHES. Some non-hormonal treatments used to treat menopausal hot flashes in women (eg. clonidine) may be useful.
GOSERELIN - Goserelin is another LHRH analog. It is administered monthly as a subcutaneous implant into the upper abdominal wall. Side effects are similar to those seen with leuprolide.
FLUTAMIDE - Flutamide is an ANTIANDROGEN that inhibits either androgen uptake into cells or the binding of androgen in the nucleus of target cells. Flutamide thus blocks the effects of both testicular and adrenal androgen. It may thus be used in combination with an LHRH agonist to achieve "TOTAL ANDROGEN BLOCKADE". Initial treatment with LHRH agonists results in an increase in gonadotropin secretion. This can cause a "flare", which can be dangerous in patients with IMPENDING SPINAL CORD COMPRESSION or URINARY TRACT OBSTRUCTION. Flutamide is used to BLOCK this INITIAL FLARE. Flutamide may also be used ALONE as hormonal therapy in symptomatic Stage D prostate cancer. The dose of flutamide is 250mg TID. In contrast to other hormonal therapies, flutamide appears to PRESERVE LIBIDO and SEXUAL POTENCY. (This benefit is not seen when flutamide is combined with an LHRH agonist.) The only side effect reported to occur more often with flutamide in combination with LHRH agonist than with LHRH agonist alone is DIARRHEA. Other antiandrogens include NILUTAMIDE and BICALUTAMIDE.
High doses of KETOCONAZOLE (ie. 400mg q 8 hours) have been used to treat prostate cancer. This is based on the ability of ketoconazole to block adrenal and testicular androgen synthesis.
In contrast to breast cancer, responses to sequential hormonal therapies in prostate cancer are less common.
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