Sirolimus therapy in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis was associated with a reduction in angiomyolipoma volume of nearly 50% and, in the patients with lymphangioleiomyomatosis, improvements in airflow and gas trapping (measured as residual volume). The renal and pulmonary benefits of treatment with sirolimus tended to reverse after the drug was withdrawn, though the improvements were persistent in some patients.
In patients with the tuberous sclerosis complex, renal disease is a leading cause of death or disability, second only to neurologic disease.24
Angiomyolipomas are slow-growing hamartomas that can lead to renal failure or spontaneous hemorrhage and do not spontaneously regress. Although nephron-sparing surgical and interventional radiologic techniques have largely supplanted nephrectomy for the management of problematic angiomyolipomas, there is a clear need for less-invasive therapies. The identification of tuberous sclerosis complex genes and the implication of their role in pathogenic cell signaling have suggested inhibition of the activity of the mammalian target of rapamycin (mTOR) as a potential pharmacologic approach to managing angiomyolipomas in patients with the tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. Preclinical studies have suggested that angiomyolipomas might respond to sirolimus therapy.10,11
Case reports of sirolimus-induced reduction in angiomyolipoma size were published while this article was in press.25,26
The observation that angiomyolipoma size correlates with the risk of hemorrhage suggests that pharmacotherapy that maintains or reduces angiomyolipoma size may reduce the risk of bleeding.27
We speculate that the regression in angiomyolipoma size found in our patients might be related to apoptosis or cell-volume reduction. The variable recurrence of tumors, ranging from a rapid return to baseline dimensions to a sustained reduction in size, after the withdrawal of sirolimus might be consistent with both processes.
Eleven patients with lymphangioleiomyomatosis were evaluated for pulmonary outcomes. The typical rate of change in FEV1
for such patients is reported to be -75 ml per year.23
After 1 year of sirolimus therapy, the FEV1
increased by 118 ml, and the FVC increased by 390 ml. It is unlikely that these spirometric responses can be explained by the reversal of airflow obstruction alone, given that the increase in FVC was more than three times the increase in FEV1
. The most likely explanation for the observed increase in FVC is the relief of gas trapping, indicated by the reduction in residual volume that occurred with the use of sirolimus. A decrease in the infiltration of smooth-muscle cells, or in lung remodeling, in association with the reduction in cyst volume may have contributed to this response. The volumetric CT data revealed a trend toward a reduction in cyst size, but the results were not significant. The lack of a significant response in total lung capacity suggests that sirolimus does not markedly affect the elastic recoil of the lung. DlCO
, which reflects the integrity of the pulmonary capillary bed and is considered a sensitive indicator of lymphangioleiomyomatosis progression, did not change significantly during the period of sirolimus therapy, probably because the destruction of the pulmonary parenchyma in lymphangioleiomyomatosis is irreversible. The lack of a significant increase in the 6-minute walk distance suggests that improvement in lung function was not accompanied by an increase in exercise capacity. However, the high exercise tolerance of our patients at baseline might have confounded detection of a treatment effect. Among the pulmonary responses, FVC and residual volume remained the most improved, significantly so, 1 year after sirolimus was stopped, as compared with the baseline values.
There was no change in neuroimaging results or neurologic status during the study. Tubers, the most prevalent neurologic lesions in the study, are dysplastic rather than neoplastic, and may not be responsive to antiproliferative treatment strategies. However, sirolimus appears to have activity in the central nervous system, on the basis of reports of its effects on subependymal giant-cell astrocytomas28
and recurrent glioblastoma multiforme.29
Reported adverse effects of sirolimus include leukopenia, thrombocytopenia, hypertriglyceridemia, hypercholesterolemia, aphthous ulcers, edema, joint pain, interstitial pneumonia, delayed wound healing, and infection.30-34
Montalbano et al. reported that sirolimus had to be discontinued because of side effects in 24% of liver-transplant patients who were receiving multidrug immunosuppressive therapy and that there were sirolimus-related deaths.35
The sirolimus monotherapy used in our trial also resulted in a high rate of adverse events. Approximately 50% of patients had elevations in their serum lipid levels requiring dietary or pharmacologic intervention. Oral ulcers occurred to some degree in the majority of patients but typically resolved with topical therapy or a short-term reduction in sirolimus dose. There were six serious adverse events while patients were receiving sirolimus, as well as four during follow-up after the therapy was stopped. Sirolimus was discontinued in five patients, in four because of side effects and in one because of nonadherence to protocol. The use of sirolimus did not appear to be associated with an increased risk of convulsions, and pneumothorax did not occur after sirolimus was initiated. One patient with severe sporadic lymphangioleiomyomatosis, who withdrew from the trial to be able to receive the sirolimus off-label, later died suddenly at home. No autopsy was performed, and the cause of death was presumed to most likely have been arrhythmia or pulmonary embolism. Further research regarding the safety, efficacy, and dosing of sirolimus is indicated in this population of patients who typically have chronic, slowly progressive disease.
In conclusion, treatment with sirolimus for 1 year resulted in a decrease in the size of angiomyolipomas and an improvement in lung function in adults with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. One year after the drug was discontinued, the angiomyolipoma size and the FEV1 approached, but did not completely return to, the baseline values, and the effects on residual volume and FVC were durable in most patients. Our study has important limitations, including the open-label design, the lack of a control group, the small number of patients, and the effort-dependent nature of pulmonary-function tests. Collectively, the data suggest that mTOR inhibition may hold promise for treating the tuberous sclerosis complex and sporadic lymphangioleiomyomatosis and that sirolimus monotherapy is associated with clinically important side effects. Additional trials will be needed to define the relative risks and benefits of the use of sirolimus in patients with these diseases.