MIAMI BEACH—Why would tamoxifen, a breast cancer therapy, be considered for treating patients with amyotrophic lateral sclerosis (ALS)?
Benjamin Rix Brooks, MD, Professor of Neurology at the University of Wisconsin Hospitals and Clinics in Madison, cited several reasons in discussing the impetus for his own clinical trial of this cancer therapy for ALS.
First, he observed that one of his ALS patients with breast cancer seemed to improve neurologically and that tamoxifen was somehow slowing the rate of progression. Preliminary evidence by other investigators suggested that tamoxifen may be neuroprotective in stroke and hypoxia. And, he said, tamoxifen had proven to be a protein kinase inhibitor – a kinase that is increased in the spinal cord of ALS patients.
Finally, experimental studies of tamoxifen in a murine retrovirus-induced motor neuron disease mouse model showed a benefit for tamoxifen on survival and function in the retrovirus-induced ALS model, he said (Amyotroph Lateral Scler Other Motor Neuron Disord 2003;4(Suppl 1):138).
At the AAN Annual Meeting here, Dr. Brooks presented the results of a dose-finding trial, which he said, showed that tamoxifen appeared to prolong survival in a cohort of patients with ALS treated with doses of 20, 30, and 40 mg/day over a two-year period.
Eighty-seven percent of the patients included in the study were already taking riluzole, the only drug approved by the Food and Drug Administration for the treatment of ALS, and the survival benefit of tamoxifen was observed on top of that of riluzole.
Riluzole extends survival in ALS by three months, and in this study, the survival benefit extended an additional six months, said Dr. Brooks. Dr. Brooks was careful to point out that the patients taking tamoxifen did not experience functional benefits in their arms measured by isometric muscle strength or overall function measured by the ALS FRS [ALS Functional Rating Scale], “but they remained alive.”
The dose-ranging study evaluated five dose levels of tamoxifen: 10 mg weekly (the lowest dose chosen because only one pill was needed), and 10, 20, 30, and 40 mg daily (the highest dose and the dose used in Europe as adjuvant hormonal therapy in patients with breast cancer). Sixty patients entered the study (34 men and 26 women), with a mean age of 51 years.
ASSESSMENT OF SURVIVAL BENEFIT
Patients were evaluated every three months with computerized isometric muscle strength testing. During the first eight weeks of treatment, patients were assessed for side effects via telephone. The study design matched groups by age, gender, and site of disease onset – for example, bulbar or limb. Other criteria were also used for matching groups to be block-randomized [within each group of five], including time from ALS onset to treatment, and vital capacity. Median age of onset was 50.7 years, median time from onset to diagnosis of ALS was 1.3 years, and time from onset to treatment with tamoxifen was 3.5 years. Eleven patients had bulbar onset and 49 had limb-onset of symptoms.
The survival benefit was observed for those treated with the higher doses of tamoxifen – 20 mg/day, 30 mg/day, and 40 mg/day – compared with those treated at lower dose of tamoxifen – 10 mg weekly or 10 mg daily. Survival results were similar in both men and women for patients with bulbar or limb onset, and for patients at all levels of vital capacity.
The main side effect was hot flashes, which were typically transient and resolved after four to six weeks. Persistent hot flashes were observed at the highest dose level of tamoxifen, he said. The only serious adverse event was deep vein thrombosis, which occurred in two patients treated at the lowest dose level of tamoxifen.
“We included a similar group of ALS patients – in terms of age, sex, type of disease, and length of disease before treatment – as those studied in the original riluzole trials. The survival benefit observed in this study was as good or better as the improved survival for riluzole-treated patients compared with placebo-treated patients in the original riluzole trials,” Dr. Brooks said. In the tamoxifen clinical trial, however, the five experimental groups were compared to each other with no placebo arm.
Dr. Brooks noted that his trial enrolled patients who did not meet enrollment criteria for other randomized clinical trials, either because of the length of disease, the severity of disease, or the vital capacity at entry. This is an important group in which to show treatment benefit, he continued, because they reflect the majority of patients in the community.
When asked why he did not include a placebo arm, he said that a dose-ranging trial with multiple treatment arms is as good as a placebo-controlled trial, because the lower dose arms may serve as the control arm if the higher doses are effective. In ALS, patients want to receive the treatment and not placebo, he added.
This study is interesting and provocative, said Hiroshi Mitsumoto, MD, Wesley J. Howe Professor of Neurology at Columbia University Medical Center in New York. “I admire the willingness of Dr. Brooks to test a new medication in patients with an advanced stage of ALS. ALS is such a difficult disease with many challenges that we can't ignore any positive finding, such as the safety of tamoxifen reported by Dr. Brooks,” he commented.
But, he said, while the findings are interesting, there are too few patients to draw any conclusions. Dr. Brooks says that the highest dose level prolonged survival, but this needs to be investigated in larger trials,” Dr. Mitsumoto commented.
Dr. Mitsumoto also noted that Dr. Brooks did not test tamoxifen in the SOD [superoxide dismutase] mouse model of ALS, but rather in a retrovirus mouse model that develops motor neuron weakness similar to ALS.
The SOD mouse model itself is problematic, Dr. Mitsumoto continued, because it is a model for familial ALS and not the more common sporadic form of the disease. Another problem is that positive findings for medications tested to date in SOD mice have not been reproduced in humans with ALS.
“The SOD model may not be a perfect model for ALS, but it is the only model we currently have. If investigators could find a breakthrough in SOD mice, it may be a breakthrough in humans as well,” Dr. Mitsumoto said. It is difficult to develop another mouse model for ALS because the cause of the disease is unknown, he added.
Dr. Brooks said that tamoxifen has been tested in the SOD mouse model and Neil Cashman, MD, reported the data at the 2003 Milan ALS-MND meeting. Dr. Cashman and colleagues found tamoxifen effective in female mice at a dose similar to the lower doses used by Dr. Brooks in the retrovirus mouse studies, but not at higher doses (Amyotroph Lateral Scler Other Motor Neuron Disord 2003;4 (Suppl 1):137–138).
Dr. Brooks plans to study tamoxifen at higher doses in a larger group of ALS patients. He does not plan to include a placebo arm in the next series of studies. He received no industry support for these trials, except for the provision, at no cost, of tamoxifen by Astra Zeneca. The Muscular Dystrophy Association – ALS Division, provided administrative support for the tamoxifen studies.
ARTICLE IN BRIEF
- ✓ In a preliminary dose-finding study, Dr. Benjamin Rix Brooks reported that tamoxifen seemed to extend by several months the lives of ALS patients.
©2005 American Academy of Neurology
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