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Cancer Decisions

THE MOSS REPORTS Newsletter (11/05/03)

 

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Ralph W. Moss, Ph.D. Weekly CancerDecisions.com

Newsletter #106 11/05/03

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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:

 

 

" 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 © (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./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

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