Corticosteroids in Advanced Cancer

Introduction

Corticosteroids are commonly used in the treatment of patients with advanced cancer. However, much of this use stems from the experience of practitioners rather than from data collected in controlled clinical trials.[1] Although little is known about the actual mechanisms by which corticosteroids exert their effects in patients, a substantial amount of evidence supports their monitored use in specific situations. This article will review the available evidence on the use of corticosteroids in advanced cancer, including treatment of refractory malignancies, use as premedication with chemotherapy, and symptom palliation.

Background Information

The most commonly used corticosteroids in the United States include prednisone(Drug information on prednisone), prednisolone(Drug information on prednisolone), methlyprednisolone, dexamethasone(Drug information on dexamethasone), and hydrocortisone(Drug information on hydrocortisone), all of which were approved by the Food and Drug Administration in the 1950s. There does not appear to be evidence to support the use of one corticosteroid over another in any given situation, although physicians have their preferences.

Corticosteroids exhibit varying glucocorticoid and mineralocorticoid effects (Table 1).[2,3] More potent glucocorticoid effects are desirable in inflammatory states, whereas mineralocorticoid effects are needed to treat adrenal insufficiency. Corticosteroids inhibit inflammatory and immune responses, most likely through alteration of cellular transcription and protein synthesis as well as through effects on lipocortins, which inhibit the release of arachidonic acid. The use of corticosteroids in advanced cancer revolves around their glucocorticoid effects, combined with an avoidance of the salt-retaining properties that characterize mineralocorticoids.

That said, it is important to remember that patients previously treated with corticosteroids may have some degree of adrenal suppression and, therefore, may require supplemental corticosteroid therapy during stressful situations. In this setting, mineralocorticoid properties are desired.

Effects of Long-Term Use

Chronic use of corticosteroids causes adrenal suppression and may blunt or prevent normal adrenal response to physiologic stress. To avoid this effect, many cancer patients may receive intermittent doses of steroids as antiemetics to prevent hypersensitivity reactions, or as adjuvants for pain control. Spiegel and colleagues performed adrenocorticotropic hormone (ACTH)-stimulation tests in 14 patients receiving high-dose prednisone for emesis prophylaxis prior to chemotherapy.[4] Adrenal function was suppressed in 13 patients at 24 hours and remained suppressed in 5 patients for more than 1 week.

Investigators at the University of Rochester performed ACTH-stimulation tests in nine women with ovarian cancer before and during chemotherapy in which dexamethasone premedication was used.[5] They noted effects on the hypothalamic-pituitary axis for up to 8 days, but reported no long-term suppression. It is probably not necessary to taper steroids when they are administered in brief, intermittent doses, but adrenal suppression should be considered when patients who have received such treatment present with hypotension and severe illness. The use of replacement-dose steroids in patients with cancer who are undergoing surgery was recently reviewed by Lefor.[6]

The risks associated with corticosteroid use in patients with advanced cancer have been reviewed extensively.[2] Acute side effects include dyspepsia, peptic ulcer disease, insomnia, oral and vaginal candidiasis, anxiety, and glucose intolerance. Side effects from chronic use include development of a cushingoid appearance, weight gain, edema, cataracts, osteoporosis, proximal myopathy, thinning of the skin, infection, and impaired wound healing. Corticosteroids can also lead to neuropsychiatric changes including depression, agitation, and delirium.[6]

It is important, therefore, to carefully weigh the potential benefits of corticosteroid therapy against potential side effects, and to closely monitor the efficacy of therapy. If no improvement is noted, treatment should be adjusted or discontinued.

Corticosteroids as Anticancer Agents

Corticosteroids have been used as anticancer agents since the 1940s,[8] with activity reported in a wide variety of solid tumors, including breast and prostate cancer, and the lymphoid hematologic malignancies. They are commonly found in regimens for acute lymphocytic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, myeloma, and chronic lymphocytic leukemia. This section will focus on the use of corticosteroids as palliative anticancer treatment once chemotherapeutic options have been exhausted or abandoned.

Multiple Myeloma

Several studies have been reported suggesting a benefit with the use of corticosteroids in refractory multiple myeloma. Alexanian et al reported the use of pulse prednisone therapy in patients with myeloma refractory to melphalan(Drug information on melphalan) (Alkeran).[9] Prednisone was administered at 60 mg/m²/d for 5 of 8 days, for three pulses followed by a 3-week rest, with the cycle repeated. The investigators noted a greater than 50% reduction in tumor mass in 5 of 16 patients, and found that responding patients benefited clinically with less pain, improved performance status, and increased hemoglobin.

Norfolk and Child performed a similar study in 17 patients with relapsed or refractory disease. Patients in this study received prednisolone, 60 mg/m²/d for 5 days, followed by a 9-day rest.[10] Fourteen patients completed six cycles of treatment, and 10 had more than a 25% reduction in serum paraprotein or a 50% reduction in urinary light-chain excretion. An overall improvement in quality of life was also noted. Notably, two of the nonresponders demonstrated an improvement in performance status. Median survival for the group was more than 19 months.

In 1991, the Eastern Cooperative Oncology Group reported a pilot study of high-dose, pulsed dexamethasone in patients with relapsed or refractory disease.[11] Patients received dexamethasone, 40 mg/d, 4 days a week for 8 weeks. Of 32 patients enrolled, 13 (40%) achieved objective responses and 28.5% showed improvement in pain or performance status. The study also reported significant toxicity, with 19 patients experiencing side effects assessed as at least grade 2. Median survival was 19 weeks, and the authors suggested that less frequent administration at longer intervals should be considered.

Alexanian also reported on the use of intermittent, high-dose dexamethasone, noting a 27% response rate in patients who did not respond to their prior treatment.[12] The Southwest Oncology Group reported a trial of alternate-day administration of corticosteroids (oral prednisone, 100 mg every other day for 2 weeks, then 50 mg every other day for 10 weeks) in 121 patients with relapsed or refractory myeloma. They measured glucocorticoid receptors from patient samples and found an improved response, but no change in overall survival among patients with a moderate number of receptors, compared with patients with a low number of receptors. They reported a 10% partial response rate (defined as a 50% to 75% decrease in M-protein), although 81 patients maintained stable disease while enrolled in the study.

Prednisone, as used in this study, was well tolerated and appeared to be associated with response and median survival rates (12 months) similar to those reported with other drug schedules used in myeloma.

Non-Hodgkin’s Lymphoma

In 1996, Newcom reported on the outcome of two patients with refractory, poorly differentiated lymphocytic lymphoma who had been treated with continuous corticosteroids (prednisone, 60 to 100 mg/d).[13] Both patients improved within 3 weeks of the initiation of single-agent prednisone, and both reportedly experienced regression of nodes and organomegaly as well as an improvement in function. However, the patients died 14 and 15 months after initiation of therapy with prednisone.

Breast Cancer

have been used in the primary treatment of breast cancer in elderly women after failure of front-line hormonal therapy.[8] Minton et al followed 91 women aged 65 years and older in whom disease progressed following initial hormonal therapy with estrogens(Drug information on estrogens), tamoxifen(Drug information on tamoxifen) (Nolvadex), or androgens.[14] A treatment-free period of 1 month was recommended to control for a withdrawal response. The majority of patients received prednisolone, 15 mg daily, and 10 patients received hydrocortisone acetate, 75 mg daily. Objective responses were noted in 13 patients (14%). Another 19 (21%) achieved stable disease for at least 6 months. There was no correlation with any prior response to endocrine therapy, and toxicity was felt to be acceptable. Unfortunately, the authors did not report a clinical benefit as subjectively reported by the patients.

Mercer and colleagues reported a prospective randomized trial of aminoglutethimide (Cytadren, 125 mg twice daily) vs hydrocortisone (20 mg twice daily) in advanced breast cancer.[15] All patients were postmenopausal and had experienced disease progression on tamoxifen. Of 61 patients entered into the trial, 56 were included in the analysis. Three patients who received aminoglutethimide achieved a partial response (11%), while one partial and five complete responses (21%) were reported in the hydrocortisone group. Although this difference was not statistically significant, it does serve as evidence that corticosteroids have activity in breast cancer. The authors did not report on clinical benefit.

Prostate Cancer

Hormone therapy is well established in the treatment of prostate cancer. However, progressive disease after failure of hormone therapy is a difficult problem for patients in this setting. Tannock and colleagues from the Princess Margaret Hospital in Toronto have reported their experience with prednisone in the treatment of hormone-refractory disease.[16] In an informative study, these investigators prospectively treated 37 men with symptomatic bone metastases with 7.5 to 10 mg of prednisone daily. Pain scores were assessed by three different measures at monthly intervals.

An improvement in all three pain scales without an increase in opiate dosages was reported for a minimum of 1 month in 14 (38%) patients. Responses did not correlate with alkaline or acid phosphatase measures, but did appear to correlate with suppression of adrenal androgens. Although the median duration of response was only slightly more than 4 months, the investigators concluded that there was improvement in quality of life with little toxicity or expense. These investigators have now reported on the superiority of the combination of mitoxantrone(Drug information on mitoxantrone) (Novantrone) and prednisone as palliation for a similar group of patients; however, this therapy was not associated with a survival advantage.[17] Some patients will opt not to receive chemotherapy, although corticosteroids alone may be beneficial.

Sartor and colleagues assessed the effects of prednisone, 10 mg twice daily, on prostate-specific antigen (PSA) in 29 men with progressive, hormone-refractory prostate cancer.[18] Twenty-six of the patients were symptomatic. PSA levels declined by at least 25% in 14 (48%) of the patients, and 23 of 26 reported an improvement in appetite, weight gain, or pain control. The median progression-free survival was 2 months; however, median overall survival was 12.8 months after initiation of therapy with prednisone. The duration of symptom control and any correlation with PSA measurements were not reported, but would be of interest as patients lived an average of 10 months beyond the development of progressive disease.