Corticosteroids in the Treatment of Neoplasms
Mechanism of Glucocorticoid Action
The majority of the biologic effects of steroid hormones are mediated by intracellular receptors specific for each class of steroid.
The glucocorticoid receptor (GR), a cytoplasmic protein, is present in all tissues that are targets of glucocorticoid action.
Activation of GR à involve a conformational change in GR, increased phosphorylation of the receptor, and release of associated regulatory proteins. Activated steroid-receptor complex translocates to the nucleus, binds as a homodimer to specific DNA sequences called glucocorticoid-responsive elements (GREs), and alters the transcription rate of specific genes associated with the GRE. lead to changes in the amount of messenger RNA and, ultimately, the level of protein that is synthesized from these genes, and thus alters cellular functions.
Neoplasms Treated with Corticosteroids
Acute Lymphoblastic Leukemia
- Early studies: (ALL) treated with prednisone alone showed that 50% of the affected children responded with prompt clinical improvement and remission.
- However, remission was short (1 year), and relapse, often coinciding with the appearance of steroid resistance, was inevitable.
- For these reasons, multiple drug therapy was initiated, which involves combining prednisone with other cytotoxic agents.
- With the advent of regimens that contain vincristine and prednisone or prednisolone, more than 90% of children and 60 to 80% of adults achieve remission.
- In one study, prednisone pretreatment before initiation of combination therapy improved the rate of complete remission in adult patients.
Acute Myeloid Leukemia
Little value in the treatment of acute myeloid leukemia. While they have been included in some combination chemotherapies, their importance in such regimens is unclear
Chronic Lymphocytic Leukemia
Corticosteroids are particularly useful if the neoplasm is associated with autoimmune hemolytic anemia, neutropenia, and thrombocytopenia with hemorrhagic complications. Glucocorticoids alleviate the lymphadenopathy and hepatosplenomegaly that are often associated with this condition.
Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML) in the chronic phase presents no indication for corticosteroids.
Hodgkin lymphoma is a solid tumor that is now considered curable by chemotherapy.
Corticosteroids alone can achieve worthwhile objective results in 66% of Hodgkin lymphoma patients resistant to alkylating agents.
Corticosteroids used as single-agent therapy produce temporary responses in patients with non-Hodgkin lymphoma; they are therefore included in virtually every complex regimen used for the treatment of non-Hodgkin lymphoma.
Patients with disseminated lymphomas à intensified CHOP regimen
One study indicates that the use of interferon-α2b in combination with a typical glucocorticoid-containing drug regimen produces good results (85% overall response rate and 86% 3-year survival rate). For tumors within the central nervous system, dexamethasone is preferred instead of prednisone to decrease tumor swelling.
The standard therapy for multiple myeloma, melphalan, and prednisone, results in a 50% response rate. Complete remission is rare, however, and the median survival is only 24 to 30 months. A combination of vincristine, Adriamycin, and dexamethasone (VAD) is also effective, especially in refractory disease.
The use of interferon-α along with a glucocorticoid for maintenance therapy appears to prolong remission duration. Thalidomide produces a response in about 30% of patients with refractory disease and is being investigated in combination with dexamethasone as initial therapy.
Although never used as the sole treatment for breast cancer, glucocorticoids are included in various combination chemotherapies. Cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-type regimens, with and without prednisone, resulting in tumor regression in 50 to 80% of patients and complete response in 15 to 20%.
For metastatic breast cancer patients who do not consent to aggressive cytotoxic chemotherapy, the alternative combination of mitoxantrone, leucovorin, 5-fluorouracil, and prednisone induced tumor regression in 67% of patients with a complete response in 25%.
Hydrocortisone replacement (approximately 40 mg/d) is indicated after surgical or medical (via steroid synthesis inhibitors) adrenalectomy.
Such adrenalectomy eliminates circulating steroids in cases of breast cancer, prostate cancer, and ectopic ACTH excess. Hemangiomas in infants are often treated with injections of glucocorticoids. Thymomas are often treated with glucocorticoids either alone or in combination with cytotoxic drugs. Other tumors that have been treated with combination chemotherapy involving a glucocorticoid include medulloblastoma, primitive neuroectodermal tumors, and ependymomas.
Symptomatic Uses of Corticosteroids
- Glucocorticoid treatment produces rapid symptomatic improvements in critically ill patients, including relief of fever, sweats, lethargy, weakness, and other nonspecific effects of cancer.
- Glucocorticoids also cause mild euphoria, a general feeling of well being, and stimulation of appetite.
- These effects are transient, and only short-term treatment is possible due to the side effects of the high doses. In addition, glucocorticoid withdrawal can result in adrenocortical insufficiency.
- For these reasons, corticosteroid treatment is appropriate only for patients whose life expectancy is brief (a few weeks or less).
- Although doses of 25 mg/d prednisolone can be used, with a decrease to 7.5 to 15 mg/d for maintenance of effects, other options for pain management in terminally ill patients make the use of glucocorticoids in this context relatively rare.
Hypercalcemia, a common complication of many malignancies, is often caused by increased bone resorption and renal calcium reabsorption.
This effect is thought to be a consequence of factors secreted by tumors, particularly tumors of lymphoid origin.
Although glucocorticoids do not lower normal calcium levels, high-dose glucocorticoid has efficacy in the treatment of hypercalcemia (100 mg/d prednisolone, 400 mg/d hydrocortisone).
Glucocorticoids are most effective on hypercalcemia that is secondary to high vitamin D levels, and least effective in patients with solid tumors. Results in the treatment of multiple myeloma patients are inconsistent. Therefore, glucocorticoids are a poor treatment modality except in cases of vitamin D-mediated hypercalcemia.
Central Nervous System Tumors
Neurologic symptoms from primary and metastatic brain and spinal cord tumors are partially caused by peritumoral edema.
Glucocorticoids can ameliorate these symptoms in approximately 70 to 80% of cases after several days of treatment, likely by inducing both decreased edema production and increased edema reabsorption.
Dexamethasone is the recommended steroid for this treatment because it contains no mineralocorticoid activity and is highly potent. A dose of 16 mg/d is used with an increase to 100 mg/d if no response occurs.
This dose is continued until the maximum response is obtained, then decreased gradually and maintained at the lowest effective dose.
Glucocorticoids decrease the severity of chemotherapy-induced emesis. Both dexamethasone (8 to 20 mg) and methylprednisolone (125 to 250 mg) are employed for this indication, with vomiting episodes reduced by as much as 74%.
Glucocorticoids are most effective when used at low doses to enhance the antiemetic efficacy of other drugs.
Recent findings suggest that the combination of glucocorticoids with serotonin receptor antagonists (eg, ondansetron, granisetron, tropisetron) is extremely effective.
The mechanism of glucocorticoid-mediated antiemesis is unknown. The effect may be associated with decreases in prostaglandin synthesis, or glucocorticoids may act directly on the chemoreceptor trigger zone by modifying capillary permeability or stabilizing lysosomal membranes.
Dyspnea Caused by Lymphangitic Carcinomatosis
Dyspnea in lymphangitic carcinomatosis may be a result of tumor edema and is effectively relieved in most cases, at least temporarily, by glucocorticoid treatment.
Prednisone is given at a dose of 60 to 100 mg/d and then reduced rapidly to the minimum level that maintains a response. If the primary tumor is chemosensitive, then cytotoxic agents are also given.
Other Uses of Glucocorticoids
- Acute upper airway obstruction can result from direct tumor growth or by compression from thyroid, lung, and esophageal cancers. This obstruction can be reduced by glucocorticoid treatment, either alone or in combination with radiotherapy.
- Other cancer-related obstructions and mass effects, including superior vena cava syndrome; lymphedema; liver metastases; masses in the pelvis, mediastinum, or retroperitoneum; and blockages of the large bowel or ureter, can be partially controlled by glucocorticoids.
- Therapeutic effects are a result of a reduction in peritumoral inflammation and edema. Pain from bone metastases or metastatic arthralgia from solid tumors often responds to glucocorticoid treatment.
- Several chemotherapeutic agents (mitomycin, bleomycin, busulfan, carmustine), as well as radiotherapy, are associated with pulmonary toxicity. Preventive glucocorticoid administration during chemotherapy, for example, dexamethasone administration during mitomycin chemotherapy for nonsmall-cell lung cancer, can prevent lung injury. However, decreased antineoplastic effects of mitomycin in such a context suggests that further study of this application is warranted.
- Loss of vision associated with pseudotumor cerebri can be treated with glucocorticoids.