Chapter 63

### INTRODUCTION

The growth of a number of cancers is hormone dependent or regulated by hormones. Research in the fields of fertility, birth control, and menopause has yielded valuable hormone analogs and antagonists for the treatment of both breast and prostate cancer. These molecules interrupt the stimulatory axis created by systemic pools of androgens and estrogens, inhibit hormone production or binding to receptors, and ultimately block the complex expression of genes that promotes tumor growth and survival. These drugs have proven effective in extending survival and delaying or preventing tumor recurrence in breast cancer and prostate cancer.

### GLUCOCORTICOIDS

The pharmacology, major therapeutic uses, and toxic effects of the glucocorticoids are discussed in Chapter 42. Only the applications of these drugs in the treatment of neoplastic disease are considered here. Glucocorticoids act through their binding to a specific physiological receptor that translocates to the nucleus and induces anti-proliferative and apoptotic responses in sensitive cells. Because of their lympholytic effects and their ability to suppress mitosis in lymphocytes, glucocorticoids are used as cytotoxic agents in the treatment of acute leukemia in children and malignant lymphoma in children and adults.

In acute lymphoblastic or undifferentiated leukemia of childhood, glucocorticoids may produce prompt clinical improvement and objective hematological remissions in ≤30% of children. Although these responses frequently are characterized by complete disappearance of all detectable leukemic cells from the peripheral blood and bone marrow, the duration of remission is brief. Remissions occur more rapidly with glucocorticoids than with antimetabolites, and there is no evidence of cross-resistance to unrelated agents. For these reasons, therapy is initiated with prednisone and vincristine, often followed by an anthracycline or methotrexate, and l-asparaginase. Glucocorticoids are a valuable component of curative regimens for other lymphoid malignancies, including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and chronic lymphocytic leukemia (CLL). Glucocorticoids are extremely helpful in controlling auto-immune hemolytic anemia and thrombocytopenia associated with CLL.

The glucocorticoids, particularly dexamethasone, are used in conjunction with radiotherapy to reduce edema related to tumors in critical areas such as the superior mediastinum, brain, and spinal cord. Doses of 4-6 mg every 6 hours have dramatic effects in restoring neurological function in patients with cerebral metastases, but these effects are temporary. Acute changes in dexamethasone dosage can lead to a rapid recrudescence of symptoms. Dexamethasone should not be discontinued abruptly in patients receiving radiotherapy or chemotherapy for brain metastases. Gradual tapering of the dosage may be undertaken if a clinical response to definitive antitumor therapy has been achieved. The antitumor effects of glucocorticoids are mediated by their binding to the glucocorticoid receptor, which activates a program of gene expression that leads to apoptosis.

Several glucocorticoids are available and at equivalent dosages exert similar effects (see Chapter 42). Prednisone, e.g., usually is administered orally in doses as high as 60-100 mg, or even higher, for the first few days and gradually reduced to levels of 20-40 mg/day. A continuous attempt ...

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