Sirolimus Reduces Size of Angiomyolipoma Tumors

Zosia Chustecka

January 10, 2008

January 10, 2008 — Year-long treatment with the immunosuppressive drug sirolimus led to shrinkage of angiomyolipoma tumors, with volume reduced by nearly 50%, along with improvement in lung function in patients with tuberous sclerosis complex and/or lymphangioleiomyomatosis. However, the benefits of treatment receded once treatment stopped, and further trials are needed to explore the use of this drug in these diseases, the researchers conclude.

The results come from an uncontrolled trial of 25 patients and are reported by John Bissler, MD, from Cincinnati Children's Hospital, in Ohio, and colleagues in the January 10 issue of the New England Journal of Medicine. An accompanying editorial agrees that further trials are necessary.

Sirolimus — also known as rapamycin (Rapamune, Wyeth) — is approved for use in transplant recipients to prevent organ rejection. It was tested in patients with tuberous sclerosis complex and/or lymphangioleiomyomatosis because both are associated with gene mutations that result in inappropriate activation of mTOR (mammalian target of rapamycin), and the drug acts as an inhibitor of mTOR signaling.

Both diseases are rare. Tuberous sclerosis complex is a genetic multisystem disease characterized by hamartomas in many organs, and about 80% of patients develop angiomyolipomas — tumors rich in fat, muscle, and blood vessels that infiltrate the kidney and lead to renal failure. Some patients also develop lymphangioleiomyomatosis, which affects the lungs and leads to respiratory problems, but this condition also occurs sporadically.

The trial was conducted in 7 patients with tuberous sclerosis complex, 6 patients with sporadic lymphangioleiomyomatosis, and 12 patients with both conditions. All 25 patients took sirolimus for a year: 20 completed the therapy, 4 discontinued because of adverse effects, and 1 did not adhere to the protocol. Patients were then monitored for another year, and 18 patients completed the 24-month evaluation. The other 2 elected to continue sirolimus therapy because of a self-perceived benefit.

At the end of the year of therapy, the mean volume of angiomyolipoma tumors was significantly reduced, to about half (53.2% ± 26.6%; P < .001). However, after the second year without treatment, the volume increased again and was back to 85.9% ± 28.5% of the baseline value (P = .005). Nevertheless, 5 of 18 patients evaluated at 24 months had a persistent reduction in tumor size of 30% or more. These tumors do not spontaneously regress, the researchers comment, and renal disease is a leading cause of death or disability in these patients.

"A drug that maintains or shrinks tumor size may reduce the need for procedures such as surgery," Dr. Bissler commented. "There are still many questions that need to be answered, but such drug therapies would be very welcome to those patients who are headed for serious complications because of their angiomyolipomas," he told Medscape Oncology. "Currently our most involved patients require surgical treatments and kidney transplants."

Patients with lymphangioleiomyomatosis showed pulmonary benefits, with improvements in airflow and gas trapping, but these benefits also tended to reverse after the drug was withdrawn, the researchers comment. Nevertheless, some of the effects on pulmonary function were durable.

Sirolimus was associated with serious adverse effects, including diarrhea, pyelonephritis, stomatitis, and respiratory infection, and 9 patients were hospitalized. Patients also developed mouth ulcers and joint pain.

Dr. Bissler and colleagues conclude that mTOR inhibition "may hold promisefor treating tuberous sclerosis complex and sporadic lymphangioleiomyomatosis" by offering ameliorative treatment. His group is planning further studies, including a placebo-controlled trial. Several other groups are also conducting trials investigating mTOR inhibition, and some of these include a placebo group.

However, the authors of the accompanying editorial, Elahna Paul, MD, PhD, and Elizabeth Thiele, MD, PhD, from the Massachusetts General Hospital, in Boston, offer some words of caution. It is difficult to assess the clinical importance of the tumor shrinkage, because only a minority of angiomyolipomas in the kidney cause serious complications, say the editorialists. To Medscape Oncology, Dr. Bissler said that the editorialists are correct to point out that the trial was not designed to look for a major clinical improvement; rather, it was a proof-of-concept study. Further research might eventually show that drugs such as sirolimus reduce the lesion size and also reduce the risk for bleeding, but a trial designed to show, for example, that renal failure could be avoided would take a very large number of patients and a very long time, he said.

The editorialists comment that the pulmonary data are "more encouraging." The prognosis for patients with lymphangioleiomyomatosis can be grim, and the fact that the improvement in pulmonary function was partially sustained after a year of therapy is encouraging, particularly because the changes in some patients are large enough to improve quality of life, they write.

"Unfortunately, enthusiasm about these pulmonary-function–related results should be tempered" by results reported by another group in the same issue of the journal, the editorialists add. In contrast to the positive results of Dr. Bissler, a letter in the same issue of the journal reports interim results from an ongoing prospective trial of sirolimus in the United Kingdom, in which the researchers saw deterioration of pulmonary function in 3 of 4 patients with lymphangioleiomyomatosis. The UK group, headed by Mark Davies, MB, from Cardiff University, in Wales, also reports that in the 9 patients treated to date, shrinkage of angiomyolipomas was seen in every patient, but no clear improvement in lung function was observed.

In a press release about these UK results, Prof. Julian Sampson, director of the Institute of Medical Genetics at Cardiff University, said: "This is a small-scale study, and we will be treating patients for another year before it is completed. However, what we have seen so far is very promising and already justifies progression to a larger study in many more patients. The findings offer new hope for what is a very serious and distressing genetic disease."

"I do not think the results are that different," Dr. Bissler commented to Medscape Oncology. He pointed out that not all of the patients in his group responded, and the difference in results might be due to the "limited sample size in both studies." He said that ongoing clinical trials should help to answer some of the questions that remain about this therapeutic approach. The editorial adds that data from these larger studies should help to determine whether sirolimus should become a standard of care for patients with tuberous sclerosis complex or lymphangioleiomyomatosis.

Dr. Bissler reports receiving grant support from Novartis; some of the coauthors report receiving grants or lecture fees from Wyeth, OncoImmune, Abbott Laboratories, and Novartis. Dr. Thiele reports receiving lecture fees from Athena Diagnostics. Dr. Davies reports receiving grant support and lecture fees from Wyeth.

N Engl J Med. 2008;1358:140-151, 190-192, 200-202.


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