BARCELONA — Evidence from placebo-controlled trials now exists confirming that both oral and intravenous cyclophosphamide are beneficial in the treatment of scleroderma lung disease.
However, there are no head-to-head data identifying which route of administration is more effective or less toxic, so to address this question Dr. Daniel E. Furst reviewed the data for both in a presentation at the annual European Congress of Rheumatology.
Oral cyclophosphamide was evaluated in a double-blind study at 13 clinical centers throughout the United States. “We asked very simple questions: Would oral cyclophosphamide work in the lung and would it be worth the side effects of such a drug?” said Dr. Furst, who is Carl M. Pearson Professor in Rheumatology, University of California at Los Angeles, and who was one of the study investigators.
A total of 158 patients with diffuse or limited scleroderma were enrolled and randomized to receive oral cyclophosphamide, 2 mg/kg or less per day, or placebo for 1 year.
The primary end point was the percentage of predicted value of forced vital capacity (FVC) at 12 months.
At 1 year, the adjusted mean absolute difference in FVC between the cyclophosphamide and placebo groups was 2.53%, favoring cyclophosphamide (N. Engl. J. Med. 2006;354:2655–66).
The difference was significant but quite modest, the investigators pointed out. “These are very small changes, and all we can say about this outcome is that there is a statistical difference but not necessarily a clinical difference,” Dr. Furst said.
Greater differences were seen on a secondary end point, the transitional dyspnea index. Scores improved by 1.4 points in the cyclophosphamide group and worsened by 1.5 points in the placebo group, which was quite significant and a large enough difference to be clinically important, he said. Favorable effects also were seen on total lung capacity, functional ability, and Rodnan skin scores.
More adverse events were seen in the active treatment group, with leukopenia being the principal one. There were no statistical difference in numbers of serious adverse events between the two groups, and those that are attributable to cyclophosphamide also occurred in the placebo group, Dr. Furst said.
No information is available yet on possible long-term adverse events such as bladder cancer.
“We are following these patients but we have no answers yet,” he said.
Intravenous cyclophosphamide was evaluated in the Fibrosing Alveolitis in Scleroderma trial (FAST), which included 45 patients from five centers in the United Kingdom. They were randomized to receive low-dose prednisone plus placebo or cyclophosphamide, approximately 1,000 mg/month for 6 months, and then oral azathioprine in doses of 2.5 mg/kg per day as maintenance therapy.
The FVC decreased about 5% in the placebo group and was stable in the cyclophosphamide group. The difference in change in FVC between the groups trended toward, but did not achieve, statistical significance (Arthritis Rheum. 2006;54:3962–70).
However, only about 60% of patients completed the trial. “And with such small numbers, it would have been a great surprise to see statistical differences,” Dr. Furst said.
“In this case, you have to think differently—if it comes close that's very encouraging,” he said.
The FAST investigators wrote, “We would suggest that a trend for improvement, intuitively better than a trend for decline, is hugely encouraging for the patient, and this must not be ignored.”
They also noted that many patients with severe or deteriorating disease were excluded from the trial and that the small therapeutic effects they saw in patients with milder disease might be greater in more progressive disease.
Adverse events associated with the active treatment were few, resulting in withdrawal in only two cases. There were no cases of hemorrhagic cystitis or bone marrow suppression.
“So you can see that both drugs work, but data from lupus and Wegener's trials tell us that, in general, if the intravenous administration is handled carefully, it is a little safer than the oral drug. So, for my patients, if they can tolerate the intravenous drug, I tend to go with that,” Dr. Furst said.
It's important to provide clear instructions about increased fluid intake, to be cognizant of the potential for cardiovascular toxicity, and not to treat for too long, he said.
With regard to the duration of treatment, Dr. Furst said in response to a question from the audience that he tends to treat for about 6 months to 1 year and then give the patient a rest period for about 6–8 months.
“But in real life, sometimes patients only begin to respond at 3–6 months, and you might be reluctant to stop. If you go longer than a year, you have to discuss it with the patient, because of the possibility that 5 years down the road they may have a serious problem,” he said.