Femara

In last month's column I began a discussion of a major clinical trial of the new drug Femara. This showed that although Femara did have a positive impact on recurrences in early-stage breast cancer in postmenopausal women, it did not have a statistically significant effect on overall survival. Now I wish to turn my attention to the economic impact of using this drug.

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Today, a new treatment cannot be launched into the world without considering its overall cost. Many thousands of postmenopausal women will undoubtedly be convinced by this study to take Femara in order to ward off the possibility of a breast cancer recurrence. They are understandably eager to have any edge at all in the fight against this frightening disease. But the rush to prescribe Femara as a long-term treatment comes at a time when the US and other countries are struggling with the problem of runaway drug costs. Many Americans are already desperately trying to cope with the inflated price of prescription drugs, and are looking to decrease those costs by shopping on the Internet or by buying from Canadian or Mexican pharmacies. Thus, the imperative to take Femara could be a serious economic blow to many older women and their families, who are trying to survive in perilous economic times.

What Will be the Cost of Taking this Medication, Both to the Individual and to Society?

I have seen a quoted figure of $200 per month for this new treatment. Perhaps one can find it for such a price. But when I called the local branch of a national pharmacy chain, I was told that the cost of 60 Femara pills was $487.99, in other words, $8.13 per day (since the dosage is normally one 2.5 milligram pill per day). At this rate, the cost per patient will be closer to $250 per month or about $3,000 per year at the retail level.

Some women have insurance that will cover some or all of this cost. Others do not. Those who are on Medicare will only get limited reimbursement. Femara has until now only been approved by the FDA for use in treating post-menopausal women with advanced breast cancer; it has not yet been approved for long-term secondary prevention in women with early breast cancer. The company says it will be filing for this new indication with both the European authorities and the US Food and Drug Administration--probably in the second half of next year (Gardner 2003). Despite reassuring words from the manufacturer, Novartis, some insurance companies may balk at paying.

Furthermore, because of the early termination of the study it is unclear how long women are supposed to take this drug in order to receive benefit. The women on the study were given Femara for a period averaging 2.4 years (after they had already spent five years taking tamoxifen). Many women will probably wind up taking Femara for five years, and quite possibly longer. So, at retail, we're talking about a cost of around $15,000 per woman. And what happens after five years? The problem is that there is no cut-off point at which the recurrence of breast cancer stops being a threat, so they may be advised to take the drug indefinitely.

How much will this new use of Femara add to the US national health bill? This is more difficult to calculate. Of the 211,000 US women who get invasive breast cancer each year, at least 100,000 are post-menopausal women with early stage estrogen-receptor positive tumors and therefore potential candidates for the drug. Simple math tells us that the retail cost of this will be around $300,000,000 annually.

However, that only accounts for this year's "class" of US breast cancer patients. There is already a huge backlog of individuals who have completed tamoxifen treatment but eagerly want to do something now to prevent a possible recurrence of their disease. They are being told that Femara fills that void. These patients can be expected to create an enormous demand for this new "miracle drug" in the months ahead.

At a press conference on October 9, Dr. Goss advocated Femara for many of these women: "There isn't any plausible biological reason to think that the drug would not work if there had been a greater gap from tamoxifen for three months," Dr. Goss said. "It is my belief that any woman who had receptor-positive tumors could be accepted but ... trying to individualize that patient's risk will be important" (Gardner 2003).

This attitude, if accepted, will open a floodgate of demand for Femara in the US. And this is in addition to the huge international market for the drug. It is simply a gold mine for Novartis, Femara's Swiss manufacturer. I would not be surprised if, with all this favorable publicity, Femara becomes a billion-dollar-a-year seller forNovartis ... medicine's equivalent of "going platinum."

Adverse Effects

The financial consequences of long-term Femara prescription is not the only alarming aspect of the current rush to medicate. There is, in addition, a distinct possibility that women taking Femara may experience serious adverse effects from the drug itself. Because Femara works by directly inhibiting the body's production of estrogen, taking it is often associated with an upsurge in menopausal symptoms. According to the manufacturer's website, "approximately one-third of the patients treated with Femara can be expected to experience adverse reactions. The most frequently reported adverse reactions in the clinical trials were hot flushes, nausea and hair thinning. Many adverse reactions can be attributed to the normal pharmacological consequences of estrogen deprivation."

According to the American Cancer Society website, other reported side effects are pain in bones and muscles, headache and fatigue. These symptoms can be extremely debilitating, as women going through menopause know only too well. For women who thought they had finally finished with the unpleasant process of menopause, the return of these symptoms will undoubtedly cause considerable psychological as well as physical distress, and lead to a significant loss in well-being and productivity.

More Threatening Consequences

Femara may also contribute to more threatening conditions associated with low estrogen, such as coronary artery disease and osteoporosis.

Osteoporosis is a condition in which the bones become extremely porous, are subject to fracture, and heal slowly. Estrogen deficiency has been clearly linked to menopausal osteoporosis (Riggs 1998). Femara and similar drugs have been shown to increase bone resorption, i.e., the loss of the bone's substance through pathologic or physiologic means (Harper-Wynne 2001). In the present study, more women in the Femara group than in the placebo group reported a diagnosis of newonset osteoporosis, and fractures occurred in more women in the Femara group than in the placebo group (3.6 percent and 2.9 percent, respectively). The authors themselves state: "Because of the early discontinuation of our study, however, these data may underestimate the long-term effects of letrozole on bone metabolism." This is an extremely important point--and another example of why stopping a study prematurely may yield an unrealistically favorable view of the treatment.

Separate studies are underway to evaluate whether women given long-term Femara should at the same time, be given drugs called bisphosphonates (such as the FDA-approved agent Fosamax) in order to counteract the bone-thinning effects of the estrogen-lowering drug. If this is found to be warranted, then the cost to the individual and to society will increase proportionally. (My local pharmacy sells 35 milligram Fosamax pills for $21 apiece.)

There is also a concern that, again because of its anti-estrogenic action, Femara may contribute to an increased incidence in cardiovascular disease, a condition that in the past has been clearly associated with lowered estrogen levels. Indeed, the authors of the present study did find an increase in the number of "cardiovascular events" (such as heart attacks and strokes) between the Femara group (88 events, or 4.1 percent) over the placebo group (77 events or 3.6 percent). This difference did not reach statistical significance. However, as the authors themselves state, "longer follow-up is needed to rule out the possibility that letrozole [Femara] has adverse cardiovascular effects." If Femara does indeed cause even a small increase in heart attacks and strokes, this alone could outweigh its positive impact on breast cancer recurrences.

Media Promotion

Finally, I wish to comment on the general way in which Femara has been promoted in the media worldwide. There was a time when scientists maintained a discreet distance from the treatments that they researched. They were careful to avoid any semblance of being promotional. A scientist's role was to question everything, especially his own pet theories and projects. Now, the news surrounding each new cancer "breakthrough" seems to become more and more frenetic in tone. Doctors and scientists, once noted for their sobriety, are now often enthusiastic ringleaders in this media circus.

Richard P. Feynman, PhD, the Nobel laureate who gained universal fame for exposing the defective "O-ring" in the Challenger shuttle disaster, memorably expressed his thoughts on scientific objectivity and integrity thus:

"[S]cientific integrity [is] ... a kind of utter honesty--a kind of leaning over backwards. For example, if you're doing an experiment, you should report everything that you think might make it invalid--not only what you think is right about it: other causes that could possibly explain your results .... [T]he idea is to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgement in one particular direction or another" (Feynman 1985).

A generation or two ago, scientists would often refuse to profit individually from their involvement in medical research. Prof. Wilhelm C. Roentgen renounced the patent on X-rays in order to make his discovery available to all. In the 1930s, one of my mentors, Albert Szent-Gyorgyi, MD, PhD, refused to take a patent on his discovery of ascorbic acid (vitamin C) but instead donated his meager supply of the compound to prevent scurvy in Scandinavian children (Moss 1987). This sort of altruism has become exceedingly rare.

These days, it is sometimes difficult to tell the difference between statements coming from researchers and those originating in the public relations departments of Big Pharma. More and more scientists are making their initial presentations of data not at medical meetings, but at company press conferences. If you read the fine print at the end of this Femara paper (Goss, et al., 2003) you learn that Drs. Goss, Norton and several others received consulting and lecture fees, and/or research support from Novartis. They have also been among the most outspoken advocates of the wider use of Femara.

It is hard to escape the conclusion that the public is being stampeded into accepting this new treatment before all the salient facts have been sifted and digested. When scientists themselves become financially entangled with huge pharmaceutical companies, who is left to look out for society's interests? Who can make sure that data is interpreted in a cool and dispassionate way, and that widescale illusions are not fostered in a public that is desperate for cures?

More information on aromatase inhibitors can be found at: http://cancer.gov/clinicaltrials/developments/aromatase-inhibitors-digest and http://www.femara.com/home/index.jsp

Bibliography

Eastell R, Adams J. Results of the 'Arimidex' (anastrozole, A), tamoxifen (T), alone or in combination (C) (ATAC) trial: effects on bone mineral density (BMD) and bone turnover (ATAC Trialists' Group). Ann Oncol 2002;13:Suppl 5:32.

John Bryant, Ph.D., and Norman Wolmark, M.D. Letrozole after Tamoxifen for Breast Cancer--What Is the Price of Success? N Engl J Med 2003;349;19, at: www.nejm.org

Feynman Richard P. Surely You Must Be Joking, Mr. Feynman. New York: Bantam, 1985.

Gardner, Amanda. New Breast Cancer Drug Leaves Questions. HealthDay, Fri Oct 17, 2003. http://story.news.yahoo.com/news?tmpl=story&cid=97&ncid=751&e=11&u=/hsn/20031017/h1_hsn/newbreastcancerdrugleavesquestions

Goss PE, Ingle JN, Martino S, et al. A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer. N Engl J Med. 2003 Oct 9.

Harper-Wynne C, Ross G, Sacks N, et al. A pilot prevention study of the aromatase inhibitor letrozole: effects on breast cell proliferation and bone/lipid indices in healthy postmenopausal women. Breast Cancer Res Treat 2001;69:225.

Kolata, Gina. New Drug Regimen Greatly Cuts Risk of Recurring Breast Cancer Published: Oct. 10, 2003. http://www.nytimes.com/2003/10/10/health/10CANC.html?hp

Moss, Ralph W. Free Radical. New York: Paragon House, 1987 (out-of-print).

Riggs BL, Khosla S, Melton LJ III. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998;13:763-73.

by Ralph W. Moss, PhD, Director, The Moss Reports

[c]2004 Ralph W. Moss, PhD. All Rights Reserved

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