A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with LAM
By Calvin Lu, MD, University Of Pennsylvania
Lymphangioleiomyomatosis (LAM) predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, which suggested an important role for estrogen in the development and progression of this disease.
In preclinical laboratory studies, estrogen appeared to promote the growth and spread of LAM-like cells, while suppression of estrogen reduced the survival of LAM cells. In other human clinical trials, there has been a suggestion that lung function declines more slowly in LAM patients after menopause, although this was not clear when this clinical trial was being developed.
Although estrogen is no longer produced by the ovaries in postmenopausal women, estrogen is still produced by conversion (by aromatase) from other hormones produced by the adrenal glands and fat cells. The action of aromatase can be blocked by medications which are aromatase inhibitors (e.g. letrozole), which lower the blood levels of estrogen.
The goals of this clinical trial clinical trial were to evaluate the safety of treatment of postmenopausal women with LAM with the aromatase inhibitor letrozole, and to assess the effect of letrozole on lung function, especially the rate of change in FEV1 over 12 months.
From May, 2011 to August, 2014, a total of 19 postmenopausal patients with LAM consented to participate in the study. Of these, 17 patients were considered eligible and were randomly assigned to receive either letrozole (9) or placebo (8). Five patients in each group were taking sirolimus. One patient receiving treatment with letrozole withdrew after the 6-month visit, and one patient in the placebo group withdrew after the 3-month visit. All the other patients completed all 12 months of assigned treatment, including all patients already taking sirolimus.
Although estrogen levels were adequately suppressed, there was no significant difference in change of lung function between the group of patients on letrozole compared to the group on placebo, including rate of change in FEV1, FVC, TLC, RV, DLCO, and 6-minute walk distance. At the same time, there was also no significant difference in side-effects or quality of life between the 2 groups.
Therefore, this clinical trial would be considered negative in terms of effectiveness. There may be several reasons for this. Enrollment in the study was less than the target of 25 patients in each group, probably because of the rarity of LAM, and restriction of enrollment to a minority (i.e., postmenopausal) subgroup. To compound the problem, the MILES trial reported that sirolimus was effective for the treatment of LAM just as TRAIL enrollment opened. It was our impression that many symptomatic patients with LAM subsequently opted to take the proven drug (i.e., sirolimus) instead of enrolling in a double-blind placebo-controlled trial with a previously untested therapy. In view of retrospective reports of slowing of lung function decline after menopause, the trial period of 1 year may have been too short to see a benefit of estrogen suppression in this relatively stable group of patients.
At the same time, this clinical trial suggests that letrozole is safe for use in postmenopausal patients with LAM.
Of interest, serum VEGF-D showed a significant decline in patients taking letrozole after 1 year, suggesting that estrogens may play a role in maintaining serum levels of the lymphangiogenic growth factor.
Also, this was the first controlled trial of hormone therapy in LAM, the first trial conducted within the LCRN, and the third randomized controlled trial for LAM published in the literature. One benefit of conducting the trial in the LCRN was that it facilitated the evolution of the network to become the National Institutes of Health/National Center for Advancing Translational Sciences Rare Lung Diseases Consortium, which will be a durable platform for future trials.