SAN DIEGO — Adding etanercept to standard immunosuppressive treatment in Wegener's granulomatosis does not increase efficacy and may increase the risks for developing solid tumors, according to Dr. John H. Stone.
Most patients with Wegener's granulomatosis achieve remission if treated with glucocorticoids and cyclophosphamide, but flares are common, adverse effects are troublesome, and no successful long-term maintenance regimen as yet exists. Moreover, the use of cyclophosphamide carries with it a risk of cancer induction, and patients with this vasculitis already are at elevated risk for malignancy.
The Wegener's Granulomatosis Etanercept Trial (WGET) was a randomized study comparing standard treatment plus the TNF-α inhibitor etanercept, 25 mg twice weekly, or placebo in 180 patients from eight centers.
Standard treatment in the trial consisted of glucocorticoids plus cyclophosphamide for patients with severe disease, and glucocorticoids plus methotrexate for those with limited disease.
Cyclophosphamide was given in doses of 2 mg/kg per day, adjusted for renal dysfunction. Patients who reached remission in 3–6 months could be switched to methotrexate or, if their creatinine was elevated, to azathioprine, Dr. Stone said.
Methotrexate was given in doses up to 25 mg/week, continued for 12 months after remission was achieved, and then tapered at a rate of 2.5 mg/month.
Azathioprine, used in only a small number of patients, was given in doses of 2 mg/kg per day. This was decreased by 25 mg/month after 12 months of remission.
“There were no differences at all in any of the major efficacy parameters, including sustained remission,” Dr. Stone said at the annual meeting of the American College of Rheumatology.
Only 49.4% of patients in the combined groups achieved and maintained disease remission throughout the trial, he said.
But there was one important difference between the etanercept and placebo groups: During the trial's 25-month follow-up period there were six solid malignancies, all in the etanercept group, said Dr. Stone of the Johns Hopkins Vasculitis Center, Baltimore, who chaired WGET.
There were two cases of colon cancer, one breast cancer, on renal cell carcinoma, one cholangiocarcinoma, and one recurrent liposarcoma. All six patients had received cyclophosphamide during the trial, and several had also been treated with this agent previously.
There were no differences between the two treatment groups in terms of gender, disease severity, or history of cancer, though patients in the etanercept group were 4–5 years older at baseline, and less likely to be newly diagnosed with Wegener's granulomatosis.
Data on age- and gender-specific incidence rates for invasive solid malignancies in the Surveillance, Epidemiology, and End Results (SEER) Program suggest that a total of 1.92 solid tumors could be expected in this cohort. The standardized incidence ratio in the trial therefore was 3.12, which was highly statistically significant, he said.
Three additional cancers were seen in the 6 months after the study (N. Engl. J. Med. 2005;352:351–61). One was prostate cancer in a 70-year-old man in the etanercept group; he had not received any cyclophosphamide during the trial. A second was in a patient initially randomized to placebo, who dropped out after a second severe flare. This patient was subsequently treated with infliximab for 14 months and was diagnosed with disseminated renal cell carcinoma.
The third was a cholangiocarcinoma in a patient in the placebo group who had not received any cyclophosphamide during the trial.
There were no differences between the groups in terms of the percentage of patients who had received cyclophosphamide before the trial, who had ever used daily cyclophosphamide, in the mean duration of daily cyclophosphamide therapy, or in the maximum daily cyclophosphamide dose.
“All of this does not prove an association between TNF inhibition, cyclophosphamide, and malignancy. But there is a biologic plausibility for this association—[the abbreviation] TNF stands for tumor necrosis factor,” Dr. Stone said.
Like infliximab and adalimumab, etanercept blocks this cytokine, which was shown in the 1970s to lyse tumors in vitro and in mice.
In discussing his findings, Dr. Stone noted that a strength of the study was the fact that the malignancy data were completely unbiased and were only detected at the end of the trial, when the database was unlocked.
Also important was the fact that the data were collected in the context of a clinical trial. “We know that postmarketing studies are very good at detecting rare events but not so good at detecting events that are common. Most of these cancers, such as those of the colon and breast, are common, so the likelihood of detecting them in any setting other than a clinical trial would be quite small,” he said.