Ralph W. Moss, Ph.D. Weekly CancerDecisions.com Newsletter #106 11/05/03 NOTE TO READER: This week we present a special investigative report on a recently announced clinical trial of Femara (letrozole). Although this is rather lengthy, we felt it was important to put all of this information in your hands at one time, rather than breaking it up into weekly installments. Consequently, there will be no newsletter next week, but we intend to return to our regular schedule after that. -R.W.M. FEMARA TAKES THE CANCER WORLD BY STORM It is being hailed as the biggest breakthrough in the treatment of breast cancer in years. An anti-estrogen drug called Femara (letrozole) has been found to decrease the risk of recurrences in post-menopausal women who have been treated for early-stage hormone-sensitive breast cancer. Leaders of an international clinical trial called off the trial when analysts found a big difference in responses between the two 'arms' of the study. The women who were already on Femara were advised to continue taking the drug, while those who had been given an inert placebo were offered the chance to start on Femara. In the wake of this finding, most leaders of the cancer field have agreed that all post-menopausal women with a history of treated early-stage hormone-sensitive breast cancer should take this new drug after completing five years of treatment with the standard anti-hormonal drug, tamoxifen. "If you fit the profile it's very, very clear," said James Doroshow, MD, chairman of the division of medical oncology and therapeutics at City of Hope Cancer Center in Duarte, Calif (Gardner 2003). The decision could affect 100,000 women per year in the US alone, and hundreds of thousands more around the world. The study was greeted with a barrage of enthusiasm the likes of which has not been seen in a quite some time. "This is up with the biggies, it is up with the major majors," enthused Larry Norton, MD, chief of medical oncology at Memorial Sloan-Kettering Cancer Center in New York and one of the study authors (Kolata 2003). "I think it's exciting," said Dr. C. Kent Osborne, director of the Breast Center at Baylor College of Medicine and the Methodist Hospital in Houston (ibid.). Dr. Harold J. Burstein of the Dana-Farber Cancer Institute, Boston, described the findings as an "unexpected and robust difference in the rate of events" (ibid.). "Everyone thought letrozole would have a modest effect," said Dr. James N. Ingle, the principal investigator for the United States in the study. "Everyone was surprised" (ibid.). The US government was quick to embrace the study. It is a "very important advance in breast cancer treatment," which will "improve the outlook for many thousands of women," according to Andrew von Eschenbach, MD, director of the National Cancer Institute, which led the study in the United States. The study was featured prominently at the government's website, www.cancer.gov In the often bleak landscape of cancer therapeutics, new treatments are always welcome. But amidst the outpouring of celebratory news stories, I wish to interject a few words of caution. Let us see if we can figure out what exactly Femara did--and did not do--for the women who were enrolled in this important clinical trial over a four-year period. As stated, the 5,187 women who took part in this Canadian-led trial were all post-menopausal, and had been treated for early-stage breast cancer. All had already taken the standard drug tamoxifen for a period of 4.5 to 6 years following their initial treatment. It has been found that the protective effect of taking tamoxifen wanes over time, levelling off after about five years. Thus, the essential purpose of the present study was to find out if Femara could be given as a long-term therapy in place of tamoxifen after the latter had begun to lose its effectiveness. And, make no mistake, the study DID indeed show that there was a significant reduction in the risk of breast cancer recurrences in women who received Femara compared to those who received only an inert placebo In total, during the four-year period of the study, 132 women taking the placebo experienced recurrences compared to just 75 who were taking Femara. Understandably, press reports have focused on the fact that Femara significantly reduced the occurrence of new tumors, which is true. However, we need to be quite clear on our terms of reference here. Femara reduces the risk of recurrence by 43 percent, but this is not the same thing as reducing deaths by 43 percent. Put another way, Femara was shown to increase the period of "disease-free survival," or the length of time before the disease recurs, during which period the patient shows no evidence of disease (NED). In real terms the study demonstrated that after an average of four years 13 percent of women on the placebo, but only 7 percent of those on Femara, had suffered a recurrence. Impact on Deaths "Our study ushers in a new era of hope by cutting these ongoing recurrences and deaths from breast cancer after tamoxifen by almost one half," said the lead author, Paul E. Goss, MD. The reader can see that this statement is technically true, but its significance is easily inflated. In this study, there were 2,594 women in the control group and 2,593 women in the Femara group. Over the four-year period in question, 17 women taking the placebo pills died of breast cancer compared to 9 taking Femara, for a total of 26. Thus, there was an overall reduction of 8 deaths from breast cancer. Statistical abstractions such as relative risk and absolute risk can be extremely confusing. Studies have found that many doctors do not clearly understand the difference between relative risk and absolute risk, and frequently confuse the two, basing treatment decisions on mistaken interpretations of the term 'risk'. Click on or go to the address listed below for an excellent discussion of the ways in which these statistical concepts are used in clinical medicine: http://www.annieappleseedproject.org/relrisverabr.html I read these figures differently from most commentators. What the figures say to me is that, for post-menopausal women, the risk of dying from early-stage breast cancer after undergoing conventional therapy is very small to start with. Even in the placebo group the death rate was under one percent over the duration of the study. Stated this way the results seem somewhat less spectacular than suggested by Dr. Goss's dramatic claim that the death rate had been cut in half. That the overall death rate should be so low may initially seem surprising: we are accustomed, after all, to thinking of breast cancer as a relentlessly deadly disease. However, early-stage, post-menopausal, estrogen-receptor-positive breast cancer is generally not as aggressive a disease as many people fear. Naturally, after a first bout one needs to remain vigilant for any sign of a recurrence. But if a tumor does recur, either in the same or in the opposite breast, it can usually be adequately treated with conventional methods, such as further excisional surgery (as apparently happened to most of the women who experienced recurrences during this study). According to surgeon Richard Evans, MD, in his thought-provoking book "The Cancer Breakthrough You've Never Heard Of," this watch-and-wait strategy, followed whenever necessary by conservative surgery, is generally effective at removing the tumor before it spreads to internal organs (provided that the recurrent tumor is found before it becomes bigger than the original growth). Review the website of Texas Cancer Center for a fuller explanation of Dr. Evans' views by clicking or going to: http://www.texascancercenter.com/ In the Femara study, there was an excess of 29 cases of distant metastases in the placebo group compared to the group receiving the drug over the four years of the study. Unfortunately the authors do not state whether this figure reached statistical significance, a crucial point. A true picture of the impact of treatment on the incidence of distant metastases is one of several important things that were lost through early termination of the study. Most importantly, we should be absolutely clear on the fact that in this study Femara was NOT shown to increase overall survival in a statistically significant way. A total of 42 women in the placebo group died of all causes while taking part in the trial compared to 31 in the Femara group. While the trend was in Femara's favor, this difference did not reach statistical significance (technically, it had a "p" value of =0.25). In other words, even the relatively small survival advantage conferred by Femara in this regard may simply have been due to chance. Some oncologists see the drug's positive impact on "disease-free survival" as a sure-fire indicator that the drug will eventually be shown to increase actual survival. For instance, Dr. Larry Norton, MD said he was confident Femara would save lives. "Disease-free survival predicts survival," he asserted. "It always has. And there is a very big decrease in cancer incidence so there will be a survival difference." However, not everyone sees it that way. For instance, in a leading cancer textbook, Principles and Practice of Radiation Oncology (3rd edition), Dr. Thomas Pajak, past Director of Statistics of the American College of Radiology, argued that "there is no general agreement about what constitutes a treatment failure or how NED [no evidence of disease, ed.] survival is to be estimated." In his view, there is no substitute for proof of effectiveness based upon the actual survival of everyone in the trial. "Absolute survival," he wrote, "is usually the most objective measure of treatment because a patient is either alive or dead. It calls for no interpretation" (p. 233). This is the view I ascribe to. Disease-free survival is a somewhat arbitrary measure, referring to a decrease in deaths due specifically to a particular kind of cancer over a limited period of time. It refers only to deaths that are directly attributable to the extension and progression of the disease. But deciding on a cause of death is somewhat subjective. It also does not take into account the possibility that the treatment itself may shorten the survival of some patients through its own adverse effects on the body. As we shall see, Femara is not without risks and side effects, the impact of which may only become apparent after patients have been followed for a considerably longer time than they were in the present truncated study. Ethical Concerns It has become a common practice to call a halt to a clinical trial if one arm of the treatment appears in an interim analysis to be yielding significantly better results than a competing arm. In this case, the trial was terminated about half way through its projected duration, after independent analysts noted that the Femara patients were having fewer recurrences of their breast cancer. Although I understand and respect the ethical concerns that prompted this decision, I think it was wrong to halt the study at this time. Because of this decision, the long-term effects of the treatment remain uncertain. The public may never discover through a rigorous trial whether Femara treatment actually increases overall survival, or what its possible long-term side effects may be. Meanwhile, hundreds of thousands of women will receive a treatment whose full effects remain obscure. Those women will, in effect, become unwitting participants in an open-ended experiment. To me, that in its own way is just as unethical as withholding a promising treatment. A similar point of view was expressed by John Bryant, PhD, and Norman Wolmark, MD, in an accompanying editorial in the New England Journal of Medicine. "[T]he primary aim of the study was not fully achieved - namely, "to determine the disease-free survival and overall survival for women who have previously received ~5 years of adjuvant tamoxifen randomized to receive either letrozole 2.5 mg daily or placebo daily for five years," they wrote. "Thus, 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 to three years" (Bryant 2003). Early closure of a clinical trial can also "freeze" a desirable result in time, before it has a chance to trend downward. In other words, trials may be abruptly halted at the point that the treatment in question is still showing superiority (in this case over the placebo). A crude way of putting this is "quitting while you're ahead." A full-term trial might have yielded less dramatic results or even negative results concerning overall survival. What About the Cost? I now wish to turn my attention to the economic impact of using this drug. Nowadays, a new treatment cannot be launched into the world without considering its overall cost. Many thousands of post-menopausal 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 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 Oct. 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 [than three years, ed]," 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…and Their Cost The financial consequences of long-term Femara prescription are 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 will 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 new-onset 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 [Femara] 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 under way 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 proportionately. (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 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. Is Femara A Conceptual Breakthrough? Femara is an aromatase inhibitor, a type of drug that limits the ability of an enzyme called aromatase to create estrogen, which is a major growth factor in hormone-receptor positive breast cancers. Aromatase inhibitors have been shown to effectively suppress estrogen levels in post-menopausal women. Dr. Andrew Eschenbach, MD, director of the US National Cancer Institute, has hailed this class of drugs as a conceptual breakthrough. "This is one more example of the ability to interrupt the progression of a cancer using a drug that blocks a crucial metabolic pathway in the tumor cell." However, the idea of arresting breast cancer progression by curtailing the amount of estrogen in the body is nothing new. It has been known for decades that estrogen fuels the growth of many breast tumors. For that reason doctors have long practiced "ovarian ablation," the surgical removal of the ovaries from pre-menopausal women with breast cancer. The use of drugs such as tamoxifen and Femara is simply a pharmacological way of accomplishing the same thing. It does not represent a breakthrough in thinking, although a breakthrough is indeed desperately needed in the fight against cancer. 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 or her 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 judgment 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 mankind. In the 1930s, one of my mentors, Albert Szent-Györgyi, 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. Nowadays, 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 wide scale illusions are not fostered in a public that is desperate for cures? --Ralph W. Moss, PhD ======================= References: 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: http://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/hl_hsn/newbreastcancerdrugleavesquestions Goss PE, Ingle JN, Martino S, et al. A Randomized Trial of Letrozole in post-menopausal 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 post-menopausal 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 post-menopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998;13:763-73. 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 IMPORTANT DISCLAIMER The news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice. Source:www.cancerdecisions.com Remember we are NOT Doctors and have NO medical training. This site is like an Encyclopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.