Femara is the trade name for a new drug, letrozole, which has been undergoing clinical trials as a follow-up to tamoxifen. After five years or so, tamoxifen loses its effectiveness as an agent to reduce the risk of recurrence of breast cancer. Researchers have been looking for a product that can be administered to women after this five-year period, in order to extend the risk reduction. Tamoxifen is a SERM (selective estrogen receptor modulator) which means that it prevents the binding of estrogens to the estrogen receptors of cancer cells, therefore blocking the stimulation of the tumour. In contrast, Femara is an aromatase inhibitor, a product that limits the ability of an enzyme (aromatase) to create estrogen. Aromatase inhibitors almost completely suppress estrogen levels in post-menopausal women.

Letrozole is thus in the same family as anastrozole (Arimidex), a product developed by AstraZeneca and tested against tamoxifen (also an Astra-Zeneca product) over the last few years. In fact, Arimidex was also hailed as a significant breakthrough — at a press conference — just a few weeks before news broke about Femara.

Femara is targeted solely to post-menopausal women who have been diagnosed with early-stage, hormone-dependent breast cancer. The director of Cancer Control Policy of the Canadian Cancer Society estimates that slightly more than half of the women diagnosed with breast cancer in 2003 will thus eventually be eligible for this drug.

Femara was tested in a clinical trial involving over 5,000 post-menopausal women who had initially taken tamoxifen for 4 to 6 years after diagnosis and treatment of their original cancer. Roughly half of these 5,000 women were given letrozole and the other half a placebo, each in the form of a daily pill. The women were followed in the customary way — seen every six months for the first year and then annually. At each visit, a history was taken and physical examination performed; they also had an annual mammogram.

The study was halted about half-way through its projected duration, i.e., after an average of 2.4 years (although some women participated for the full five years). The halt was called to herald the good news that only 75 women on Femara had a recurrence versus 132 in the control group (i.e., those taking a placebo). Over the four-year period of the study, 17 women in the control group died of breast cancer (and 25 from other causes), as compared to nine women who died of breast cancer while taking Femara (and 22 of other causes).

The principal investigator, Paul Goss, of the Princess Margaret Hospital, Toronto, commented that this study "ushers in a new era of hope by cutting these ongoing recurrences and deaths from breast cancer after tamoxifen by almost one half." Other commentators have been as lavish with their praise. Not only does this add to the armamentarium of "pills for prevention" but it may be a gold mine for Novartis, the pharmaceutical company that brought it to market. As is often the case these days, several of the researchers (including the principal investigator) have received consulting fees, lecture fees, and/or research support from Novartis.

We welcome good news but should we have any reservations? Perhaps.

Should the trial have been continued? An editorial in the New England Journal of Medicine has criticized the early halt to the Femara trial, commenting that "although the results demonstrate a meaningful biologic effect of letrozole therapy after tamoxifen therapy, they do not demonstrate a significant survival benefit, nor do they convey information about the optimal duration of treatment beyond two or three years." From a marketing standpoint, however, the sales of Femara over the next two to three years may well justify Novartis' decision to halt the trial halfway through. [This is reminiscent of the preliminary results from the tamoxifen trials. It took some time before news of the adverse side effects of tamoxifen (increased risks of endometrial cancer and blood clots) was noted and acted upon, and even more time before it was recognized that tamoxifen's beneficial effects dissipated after five years.]

Many of us are becoming wary of this pattern of early halts to clinical trials — particularly early halts in conjunction with a press conference called by the manufacturer of the product, in advance of or coincident with the publication of an article in a medical journal. In this case, the press conference was called at the same time as an online version of the article was posted while the relevant article was published only a month later. In effect, many major pharmaceutical companies no longer rely on doctors to read and absorb the medical literature. Instead, they "sell" the new product to potential users in the hope that patients will ask about it and perhaps coax their doctors into prescribing it. (This is also the modus operandi of direct-to-consumer advertising of prescription drugs.)

Secondly, early-stage, estrogen-dependent breast cancer in post-menopausal women is rarely an aggressive disease. If there is a recurrence, it is usually successfully treated much like the initial diagnosis (i.e., excision, radiation and/or chemotherapy). Because post-menopausal women with estrogen-dependent early-stage cancers are less likely to have a recurrence than are similar women with estrogen-negative tumours, the women who fulfil the criteria for use of Femara are the very ones who are least likely to have a recurrence in the first place — perhaps 10% in the ten years after initial diagnosis. And less than 1% will die of the disease. This does not, unfortunately, take into account the anxiety that is experienced when a recurrence is found, but it does highlight the positive prognosis in such cases.

Although there may be women who feel vulnerable to a recurrence of their breast cancer when told to discontinue tamoxifen, there may be others who feel that they can now put the experience behind them. And there will be many, many post-menopausal women who simply cannot afford to use Femara. The cost of this product, in my local Jean Coutu pharmacy, is $175.30 for 30 pills — or $5.86 a day. This is not chicken feed.

A third area of concern is the way in which letrozole (Femara) works — by inhibiting the body's production of estrogen. The result is an upsurge in menopausal symptoms. The Novartis website warns that "approximately one-third of the patients treated with Femara can be expected to experience adverse reactions. The most frequently reported adverse reactions ... were hot flashes, nausea and hair thinning." Other reported side effects are pain in bones and muscles, headaches and fatigue.

Low estrogen levels are known to contribute to the risk of osteoporosis. Again, because of the early halt to the trial, we don't have adequate information about either of these potential concerns. However, we do know that more women in the Femara group reported a diagnosis of osteoporosis, and that more of these women also experienced bone fractures. On top of the cost of Femara, women who choose to go this route may also have to take Fosamax (a bisphosphonate to combat the bone-thinning effects of low estrogen). The most common dose of Fosamax is a 70mg tablet taken once a week. The cost, locally, would be $46.93 for a month.

Low levels of estrogen also contribute to coronary artery disease. The authors of the Femara study found an increase in the number of "cardiovascular events" (e.g., heart attacks and strokes) in the Femara group as compared to the placebo group. This could have happened by chance but, as they themselves state, "longer follow-up is needed to rule out the possibility that letrozole has adverse cardiovascular effects." Again, only time will tell.

Lastly, there is no attempt to measure the putative positive effects of Femara against other viable and less expensive methods of heading off a recurrence of breast cancer, like regular exercise and/or a low-fat diet. As Dr. Ralph Moss comments, "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." We will try to keep you informed.

References:

  • Advanced breast cancer more responsive to letrozole than anastrozole. www.medscape. com/viewarticle/464233_print
  • Bryant J, Wolmark N. Letrozole after tamoxifen for breast cancer — What is the price of success? New England Journal of Medicine, Nov. 6/2003; 349:19
  • 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. New England Journal of Medicine, Nov. 6/2003; 349 (19): 1793-1802
  • Moss RW, Newsletter #106, Nov. 5, 2003
  • New treatment significantly improves long-term outlook for breast cancer survivors. http://www.cancer... /content_nav_print. aspx? viewid=3a2c5ec5-6525-4950-99aa-a5c4b25d89e (invalid link)
  • Questions and Answers: Clinical trial comparing letrozole (Femara) to placebo following tamoxifen therapy to reduce the risk of cancer recurrence among post-menopausal women originally diagnosed with early-stage breast cancer. http://cancer. gove/newscenter/pressreleases/letrozoleQandA (invalid link)