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Corticosteroids in Advanced Cancer

Corticosteroids in Advanced Cancer

ABSTRACT: Despite the fact that there are only a few controlled trials demonstrating the benefits associated with the use of corticosteroids in specific situations, these agents are administered frequently to patients with advanced cancer. Corticosteroids may be used alone or as adjuvants in combination with other palliative or antineoplastic treatments. For example, corticosteroids may help prevent nausea, vomiting, and hypersensitivity reactions to treatment with chemotherapy or radiation. They are also commonly used as appetite stimulants in patients with advanced cancer. In the adjuvant setting, corticosteroids help to alleviate pain in advanced cancer patients, including specific situations such as back pain related to epidural compression. This article reviews the evidence supporting the use of corticosteroids in a broad range of situations seen in patients with advanced cancer. [ONCOLOGY 15(2):225-236, 2001]

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, prednisolone, methlyprednisolone, dexamethasone, and
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 (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, 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 (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.

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