Cytoxan Offers Modest Sclerosis Lung Benefits: The
first RCT assessing the drug for interstitial lung disease
showed a slowing in functional decline
Colin Nelson, Contributing Writer
"Rheumatology News," Volume 4, Issue 9, Page
16 (September 2005)
 The
immunosuppressant drug cyclophosphamide may attenuate
the decline in lung function that comes with scleroderma,
according to a recent multicenter trial.
The investigation findings suggest that differences
in lung function as small as 2%–3% may brighten
the quality of life among scleroderma patients.
Loss of vital capacity in scleroderma “shortens
life and increases morbidity,” coauthor of the
trial, Philip Clements, M.D., of the University of California,
Los Angeles, said in an interview. Although lung function
did not improve in patients taking cyclophosphamide
(Cytoxan) in the trial, it deteriorated less than in
those who took placebo, he said.
Some 60%–70% of patients with scleroderma die
within 10 years. Most develop interstitial lung disease
(ILD). Some 15% of patients will go on to severe lung
disease with forced vital capacity (FVC) of less than
50% of normal.
The new trial, known as the Scleroderma Lung Study,
is the first large, randomized, controlled, double-blind
trial to investigate the influence of cyclophosphamide
on lung function in scleroderma patients with ILD. The
goal is to see whether cyclophosphamide is effective
early in the course of ILD, before the disease does
irreversible damage.
Dr. Clements and his colleagues enrolled 156 patients
with scleroderma of less than 7 years' duration, who
had shortness of breath, the appearance of “ground
glass” on lung CT scans, and FVC less than 85%
of predicted normal.
The researchers randomized patients to receive either
cyclophosphamide or placebo (1 mg/kg per day initially,
followed by increases of 25 mg every 4 weeks until the
daily dose reached 2 mg/kg per day or was limited by
toxicity). On average, the subjects were 48 years old
and had had scleroderma for 3 years; 71% were female.
Their FVC was 68%, total lung capacity was 70%, and
diffusing capacity was 47%.
Of the 80 patients in the cyclophosphamide group,
72 were available for FVC measurements at either 9 or
12 months, as were 70 of 76 patients in the placebo
group.
The authors recently presented the 12-month results
of their 2-year study during a symposium at the 2005
annual meeting of the American Thoracic Society in San
Diego.
The results suggest that cyclophosphamide is modestly
effective. Decline in FVC was 2.3% better in the cyclophosphamide
group than in the placebo group.
The difference in lung function between groups is
statistically significant, said Dr. Clements. “But
whether it is clinically significant could be argued,”
he acknowledged.
Dr. Clements pointed out that cyclophosphamide might
not help patients with long-standing, chronic disease.
“The caveat here is that we looked only at early
disease.” Fibrosis in later disease may be more
intractable, he suggested.
Results of the study's secondary outcomes were encouraging.
Patients taking cyclophosphamide scored significantly
better on the Transition Dyspnea Index, a measure of
changes in breathlessness over time.
“It's pretty clear that the people who got Cytoxan
had less shortness of breath,” said Dr. Clements.
“The people who took placebo got worse. It was
a very strong effect.” Skin thickening scores
also improved significantly more in patients with diffuse
scleroderma who received cyclophosphamide.
Cyclophosphamide appeared to provide significant improvements
in subtle, subjective measures of self-rated health—in
vitality and peppiness (as scored by the SF-36 scale)
as well in health over time. Changes in the Health Assessment
Questionnaire disability index scores were significantly
better in the cyclophosphamide group at the 12-month
mark, although these were considered “minimally
clinically significant.”
The news was not all good, however.
Dropouts in both groups were substantial. In the cyclophosphamide
group, 26 of 80 patients (33%) stopped taking the drug
by 12 months, according to Dr. Clements. In the control
group, 21 of 76 patients (28%) stopped taking placebo.
Two side effects—a decreased white blood cell
count and blood in the urine—were significantly
higher in the cyclophosphamide group (at 19% and 11%)
than in the placebo group (0% and 4%).
Patients taking cyclophosphamide had a higher number
of serious adverse events (17 vs. 11), but the difference
was not statistically significant. There was also no
significant difference in the number of patients who
developed pneumonia (five vs. one).
The authors attributed many of the adverse events
to the natural course of the illness. “Scleroderma
is a nasty disease,” said Dr. Clements.
“You have not only potential lung disease, but
also gut disease, heart disease, and kidney disease
that are part of the scleroderma disease.” With
the exception of low white blood cell counts, he said,
“The events are not necessarily related to the
drug but to the disease.”
Dr. Clements pointed out that some observers believe
cyclophosphamide might be more effective than this trial
suggests. Many patients with severe disease would simply
not enroll in a placebo-controlled trial.
The decline in lung function among untreated patients
with severe disease might have been greater than was
seen in this trial, and thus would lead to a more pronounced
difference between groups, these observers argue.
The best therapy for lung disease in scleroderma remains
unknown.
According to Dr. Clements, preliminary results of
a trial in the United Kingdom by Athol Wells, M.D.,
of Royal Brompton Hospital, London, and colleagues show
dramatic improvements in lung function among patients
receiving intravenous cyclophosphamide for 6 months—a
3% boost, compared with a 3% decline among those receiving
placebo. After 6 months, the patients in the U.K. trial
are switched to Imuran (azathioprine), a lesser immunosuppressive.
“In that context we have a confirmation that
Cytoxan works and that immunosuppression helps,”
said Dr. Clements. Nevertheless, he added, less noxious
drugs would clearly be preferable.
Cyclophosphamide is “a sledge hammer,”
he said. “Whether it is the right drug, we're
still not sure.”
© 2005 Elsevier Inc.. All rights reserved.
|
