LOS ANGELES - The alkylating chemotherapy agent Cytoxan (cylcophosphamide) can produce small but significant improvements in lung function in patients with scleroderma, but its toxicities must be weighed against its potential benefits.
LOS ANGELES, June 21 - The alkylating chemotherapy agent Cytoxan (cylcophosphamide) can produce small but significant improvements in lung function in patients with scleroderma, investigators here confirmed.
In a randomized placebo-controlled trial, those with scleroderma-related alveolitis and interstitial lung disease who received Cytoxan for one year had better forced vital capacity than patients on placebo, a difference still seen at two-year follow-up, according to Donald P. Tashkin, M.D., of the University of California at Los Angeles, and colleagues in the Scleroderma Lung Study Research Group.
In addition, patients who had taken Cytoxan had modest improvement of dyspnea, skin thickening, functional ability, and some health-related quality-of-life measures, the investigators reported in the June 22 issue of New England Journal of Medicine.
"The favorable effect of cyclophosphamide on forced vital capacity was sustained for the two years of the study," the investigators wrote. "Although treatment with cyclophosphamide resulted in a greater number of adverse events than did placebo, the risk-benefit ratio appears to be favorable. Caution regarding the use of cyclophosphamide is still warranted, since potential long-term consequences were not evaluated,"
Adverse events, always of concern with Cytoxan, were higher in the active treatment group and caused more patients to drop out during the treatment phase, but there were no significant differences in the rate of serious adverse events between the treatment and placebo groups, said Dr. Tashkin and colleagues.
In an accompanying editorial, Fernando J. Martinez, M.D., and W. Joseph McCune, M.D., of the University of Michigan Health System in Ann Arbor, commented that "this well-designed trial will be regarded as a sentinel study confirming a beneficial response to cyclophosphamide in highly selected patients with scleroderma-related interstitial lung disease."
"In the absence of long-term follow-up data on mortality and the development of malignant diseases, however, the modest therapeutic response and the potential for significant toxic effects do not, in our opinion, support the conclusion that one year of daily cyclophosphamide should be considered routine therapy for all such patients," the editorialists added.
Clinically significant interstitial lung disease is a cause of significant morbidity and mortality in about 40% of patients with scleroderma. Only Cytoxan has been shown, in retrospective studies, to slow decreases in forced vital capacity or to possibly improve lung function, Dr. Tashkin and colleagues noted.
Investigators at 13 centers throughout the United States enrolled 158 patients with scleroderma who had restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease either on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both.
The patients were randomly assigned to oral Cytoxan at a dose of ≤2 mg/kg/day or matching placebo for one year, and were followed for an additional year. Treatment of any type at the discretion of the treating physician was allowed any time during the second year.
Participants were assessed for pulmonary function every three months during the first year. The primary study endpoint was forced vital capacity expressed as a percentage of the predicted value at 12 months after adjustment for baseline measures.
A total of 158 patients (79 in each group) were randomized at the start of the study, but only 145 completed at least six months of treatment (73 in the Cytoxan group and 72 in the placebo group), and these patients were all included in the analysis.
The authors found that the mean absolute difference in adjusted 12-month forced vital-capacity percent predicted was 2.53% (95% confidence interval, 0.28% to 4.79%) in favor of Cytoxan (P<0.03). The difference was maintained after 24 months of treatment.
They also found a significant difference between the active treatment and placebo groups for total lung capacity at 12 months, with an absolute difference in the percentage of the predicted value of 4.09% (95% CI, 0.49% to 7.65%, P = 0.026) in favor of Cytoxan.
Patients in the Cytoxan group also had small but significantly better skin thickness scores, cough, and improved scores on the Health Assessment Questionnaire disability index.
"There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant," the authors reported.
In all, 20 patients taking Cytoxan and 13 on placebo withdrew from the study, mostly because of side effects. Three patients on Cytoxan and five on placebo had treatment failure, which was defined as an absolute decrease from baseline in forced vital capacity of at least 15% of the predicted value occurring at least three months after treatment was initiated, and lasting for at least one month.
During the first year there were five deaths: two patients on Cytoxan and three on placebo.
The authors concluded that "one year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study."
In their editorial, Dr. Martinez and Dr. McCume acknowledged that Cytoxan appears to have a beneficial effect on lung function in patients with scleroderma, particularly those with more fibrotic abnormalities at baseline.
But they also cautioned that "an important consideration when interpreting these limited therapeutic benefits of treatment with cyclophosphamide is the need for a thorough assessment of the risks of the drug, arguably the most toxic immunosuppressive agent currently used to treat autoimmune diseases."
They argued that study follow-up wasn't long enough to evaluate the effects of the drug on survival or on the rate of secondary malignancies.
"When cyclophosphamide is used as an immunosuppressive agent in the treatment of other rheumatologic diseases, the risks of cancer and gonadal failure increase with cumulative doses and are greater when the drug is administered daily, rather than as an intermittent monthly bolus," they wrote.
They called for further analysis of the data from the current study, as well as new studies, to help clinicians better identify which patients with scleroderma are most likely to benefit from therapy with Cytoxan.