Are Corticosteroids Effective in All Patients With Cancer-Related Pain?
+ Author Affiliations
- Corresponding author: James F. Cleary, MB, FAChPM, K6/546 CSC, 600 Highland Ave, Madison, WI 53792; e-mail: jfcleary@wisc.edu.
Corticosteroids are commonly used in cancer
medicine. Many chemotherapy regimens, especially those used in the
treatment of
hematologic malignancies, often include
corticosteroids, sometimes at high-doses. Often the impact of the sudden
cessation
after 5 days of high-dose corticosteroids was the
major adverse effect reported by patients. Even more recently,
corticosteroids
were included in the treatment of prostate cancer,
prompting some to ask whether corticosteroids were active agents in this
disease.1
While not included in many newer chemotherapy regimens, corticosteroids
are often administered at significant doses as antiemetics
for moderately and highly emetogenic chemotherapy
regimens. In fact, the optimal value of 5-HT3 antagonists as
antiemetics seems strongly related to their concurrent use with
corticosteroids. In addition, the use of prednisone
in combination with calcitonin was standard practice
for management of hypercalcemia, before the development of
bisphosphonates.
There have been many questions raised as to
the value of corticosteroids in cachexia and appetite stimulation.
Although studies
have shown mixed results, it has been the experience
of many physicians that corticosteroids may be beneficial in patients
with refractory cachexia for stimulation of appetite
and improvement in quality of life. However, the use of corticosteroids
was recommended for short (maximum 2 weeks), periods
as longer duration of treatment may increase the likelihood of adverse
effects including deterioration in muscle strength.2
Corticosteroids are used commonly when it is
felt that inflammation may be contributing to the patient's symptoms.
For brain
metastases and spinal cord compression,
corticosteroids have always been an effective option to relieve edema.
Some have suggested
that a response to corticosteroids in brain metastases
and metastatic cord compression may even indicate the disease's
response
to radiotherapy, but with little evidence to support
the claim. Corticosteroids are listed as emergent therapy for cord
compression
and superior vena syndrome often with dramatic
responses. Clinical experience suggests that corticosteroids might also
be
highly effective for liver capsular pain and for
pain-related to nerve compression. However, in a recently published
systematic
literature review, there was little evidence for an
analgesic effect of corticosteroids in the treatment of cancer pain.3
Recommendations for the use of corticosteroids in cancer and palliative care have since been supported by reports and guidelines
from various organizations.4 A study of corticosteroid use in Swedish patients with cancer demonstrated that corticosteroids were used commonly; 50% of
patients with cancer in the palliative care setting received corticosteroids.5 The most common indications for starting corticosteroids in this survey were appetite loss (37%), fatigue (36%), and poor
well-being (33%) while pain was an indication in 25%. A recent report from New Zealand6
showed that of almost 1,200 patients receiving care from seven
inpatient hospices, two thirds had received at least one course
of corticosteroids during that care. The reasons for
corticosteroids were a nonspecific indication (40%), neurologic symptoms
(25.3%), and soft-tissue infiltration symptoms
(14.4%). Detailed information was recorded for a sample of 260 patients
with
the agent of choice being dexamethasone with a median
dose of 8 mg (dose range, 1 mg-40 mg). Corticosteroids were prescribed
for a median duration of 29 days per course. Abrupt
stopping occurred in 72 (23.2%) cases; of these 35 (49%) had been on a
course of corticosteroids for more than 3 weeks.
Corticosteroid-prescribing guidelines, including cessation titration,
were
only available in one hospice. Adverse effects were
recorded in 82 (32%) but only 52% of the 260 had regular monitoring,
thus
suggesting that adverse events were in fact much more
common than reported.
But do corticosteroids make a difference?
The study by Norwegian investigators in the article that accompanies this editorial7
uses high level evidence from a randomized, double-blind,
placebo-controlled trial. Using well-validated tools, they measured
the effect of methylprednisone (16 mg twice daily) on
pain, fatigue, and appetite over a 1-week period. The study showed no
difference in pain scores between the two groups when
measured as absolute or percentage differences, and this negative
finding
was not changed by regression analysis. The study did
find significant differences in appetite stimulation, fatigue, and
overall
satisfaction in favor of the corticosteroid group.
Will this level of evidence change practice
in use of corticosteroids in oncology? Perhaps it will, but not
necessarily in
the direction expected. All could agree that the study
provides evidence to support the use of short course of
methylprednisone
with the goal of improving appetite and fatigue in the
short term. Fatigue and appetite are significant issues for patients
with advanced cancer and a common cause of distress
for both patients and families. However, based on other evidence,2,6 caution needs to be taken with balancing adverse effects and benefits when corticosteroids are used for longer than a week
in this setting.
Another important consideration involves a
careful examination of the population treated in this study, to ensure
that the
results are generalizable to most patients treated in
daily practice. The average morphine dose for patients with cancer has
been quoted as being 60 mg/d.8
The average morphine equivalent dose for this study was 220 mg per day
and the medications were morphine, oxycodone, and
fentanyl. No methadone was used in these patients,
possibly a reflection of practice in Norway, while it is a commonly used
drug in the United States for patients needing higher
doses of opioids, especially those with neuropathic pain. Patients had
to have stable pain for at least 48 hours before study
entry, although they could be taking extra doses for breakthrough pain.
Most patients with severe pain (pain scores > 7)
were excluded from enrollment on the study. There were nonstatistically
significant
differences in the presence of neuropathic pain in the
active care group with both higher opioids doses and greater use of
gabapentin. To show how atypical this population may
be, the study took some four years to accrue given difficulties in
enrolling,
and many patients were excluded if they in fact had
had a previous dose of corticosteroids so we may in fact have some
selection
bias. The authors note all of these issues in the
discussion, and acknowledge an earlier study by Bruera,9 in which an average daily opioid dose of 20 mg/d was associated with a beneficial effect of corticosteroids on pain.
So, what is the bottom line? Short courses of
corticosteroids seem to have an impact on fatigue and appetite and may
continue
to be useful in pain relief in patients on lower doses
of opioids who have a possible inflammatory component to their pain.
However, this study suggests that we not rely on
corticosteroids as a coanalgesic in patients with cancer who have used
them
previously, and who are receiving higher doses of
opioids. Other approaches for pain relief are clearly needed to better
serve
our patients experiencing cancer-related pain.
AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org.
AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Are Corticosteroids Effective in All Patients With Cancer-Related Pain?
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