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THE MOSS REPORTS Newsletter (11/15/03)

 

 

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

Newsletter #107 11/15/03

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DISTURBING FINDING IN ANEMIA STUDY

 

 

 

Radiation therapy is one of the mainstays of

conventional cancer treatment. However, a common

complication of this kind of treatment is that many

patients who receive it go on to develop anemia.

(Anemia occurs when the hemoglobin concentration in the

blood falls below normal, usually because of a lowered

red blood cell count.) It has therefore become

standard practice to address radiation-induced anemia

as part of the overall strategy to improve the outcome

in many types of cancer.

 

 

The production of red blood cells is governed by a

hormone, erythropoietin (EPO), which is secreted by the

kidneys. Once scientists learned how to sequence the

gene that creates EPO they were able to use that

information to manufacture synthetic, or 'recombinant',

forms of the hormone. These are known collectively as

epoetins. Epoetin alpha is manufactured in the US by

Amgen, Inc. and marketed by Johnson & Johnson as

Procrit®, while the almost identical epoetin beta is

sold in Europe by Hoffmann-LaRoche, Ltd, under the

trade name NeoRecormon®.

 

 

There is some evidence to suggest that epoetin can

indeed reduce the severity of treatment-related anemia

and thereby improve the lives of patients undergoing

cancer therapy. Because of its beneficial effect on

blood hemoglobin levels, epoetin is now routinely

prescribed for cancer patients who are anemic due to

the side effects of their treatment.

 

 

It has long been known that fully oxygenated tumor

tissue is more susceptible to radiation than tissue

that is low in oxygen. Because of this, some

researchers have theorized that by improving the red

blood cell count in patients undergoing radiation

treatment, epoetin might actually also enhance the

sensitivity of tumors to radiation, leading to an

improvement in the outcome of the therapy. However,

this attractive idea had never been adequately tested

in clinical trials until a team of European

researchers, led by Dr. Michael Henke of Freibug,

Germany, undertook a rigorous study in cooperation with

Hoffmann-LaRoche. Their goal was to see if NeoRecormon

actually did improve cancer control and survival in

patients who were being given radiation treatment for head and neck

cancers. (They chose patients with head and neck

cancers because radiation-induced anemia is a

particularly common sequel of treatment in this type of

cancer.)

 

 

A total of 351 patients from Austria, France, Germany

and Switzerland were enrolled in this well designed,

placebo-controlled trial. They received 60 or 70 Grays

(Gy) of radiation, depending on the stage of their

disease, and were then randomly assigned to receive

subcutaneous injections either of epoetin or an inert

placebo. Injections took place three times per week,

beginning 10 days to two weeks before starting

radiation therapy and then continuing throughout the

duration of the treatment.

 

 

As hoped, the hemoglobin levels of 82 percent of

patients who were given epoetin were elevated into the

normal range, i.e., higher than 140 grams per liter

(g/L) in women or 150 g/L in men. However, just 15

percent of the patients receiving placebo had normal

hemoglobin scores. Inasmuch as epoetin unequivocally

improved blood hemoglobin concentrations, the treatment

seemed to work dramatically better than placebo - which

is what other studies have also shown

 

 

 

A Complete Reversal

 

 

 

However, in a complete reversal of what one might

logically have expected, patients in the treatment

group fared much worse in terms of overall survival

than did the controls. In fact, there was a significant

decline in their progression-free survival (the

interval during which the disease ceases to advance),

and also in their overall survival, which is defined as

the absence of death from any cause, a measure that

many scientists regard as the most significant proof of

true benefit. The epoetin group turned out to have a 62

percent greater chance of suffering a recurrence and a

339 percent greater chance of dying. Writing in The

Lancet, the authors concluded that epoetin beta

" corrects anemia but does not improve cancer control or

survival. Disease control might even be impaired "

(Henke 2003).

 

 

There were provocative findings, too, in terms of the

causes of these patients' deaths. Overall, 109 patients

(52 percent) in the epoetin-treated group died,

compared to just 89 patients (34 percent) in the

placebo group. What is particularly baffling is that

there were ten deaths from heart disease among the

epoetin-treated patients compared to just half that

number in the placebo group. In the placebo group there

was only one death from what the authors call " general

disorders " - but a total of nine such deaths in the

epoetin-treated group. Individual patients in the

epoetin group suffered " brain-stem infarction,

calf-vein thrombosis, and acute larynx edema, " which

the authors believe were all related to treatment.

 

 

It is known that certain tumor cells - for example,

those of breast cancer - have surface receptors for

erythropoeitin, and can apparently use this hormone to

promote cell growth and new blood vessel formation.

This raises the disturbing possibility that synthetic

forms of the hormone, such as epoetin, may have a

similarly stimulatory effect on receptive cancer cells.

 

 

Based on repeated studies showing the benefits of

epoetin in the treatment of cancer-related fatigue, the

drug has become almost universally recommended for that

purpose. But why is it that most previous studies of

epoetin failed to discern the association between the

drug and diminished survival? As the authors

themselves explain, earlier studies looked almost

exclusively at quality of life issues in the course of

palliative care, stopping short of examining epoetin's

possible effects on overall survival. Anecdotally, many

patients felt better after treatment with the drug, and

were grateful for the diminution of side effects. The

harder question, what impact epoetin treatment might

have on survival, was simply overlooked.

 

 

According to Dr. Henke and his colleagues, only two

studies have actually reported improved survival with

epoetin, and, there were serious methodological flaws

in both of them. One of these studies did not have a

proper control group (Glaser 2001), while the other was

missing crucial information (Littlewood 2001). In

addition, there was an earlier trial that did report

lower survival among patients with metastatic breast

cancer who were given erythropoietin (Leyland-Jones

2003), but it received little attention. The current

study, published in the October 18, 2003, issue of The

Lancet, is the most rigorous one so far - and certainly

the most devastating in terms of its conclusions.

 

 

 

Whom To Believe?

 

 

 

So here we have a major paradox - and another blow to the

standard strategy for dealing with cancer. Conventional

thinking goes something like this: Patients on

radiation and chemotherapy often become extremely ill

both during and after these therapies. Part of this is

due to treatment-induced anemia. By addressing the

anemia through the use of a synthetic red blood

cell-boosting hormone doctors stand a good chance of

making patients feel better and thereby reducing their

reluctance to persevere with treatment.

 

 

The safety and efficacy of these synthetic red blood

cell stimulating hormones has been heavily promoted by

pharmaceutical companies. For instance, Johnson &

Johnson markets Procrit (epoetin alpha) directly to the

consumer. Readers may have seen the recent series of

television advertisements for Procrit in which actors

portraying cancer patients - a doting grandfather, a

dressmaker, a fast-talking auctioneer, a charming Bed &

Breakfast owner - extol the virtues of this product,

recounting enthusiastically how it helped them to

resume their everyday activities in the midst of

rigorous cancer treatment.

 

 

Each ad has been carefully designed to encapsulate a

" moment of truth " for cancer patients and their loved

ones. Some of these scripts approach pure poetry. " I

was tired. Very, very tired, " says the grandfather in

" From the Heart, " the first commerical in the Procrit

campaign. " One time, my grandchildren were all over,

and they all went out and got ice cream….What a

photograph that had to be. I did not have the energy to

go upstairs to grab the camera. I missed the

photograph... to me, a once-in-a-lifetime opportunity. "

Madison Avenue analysts have called the Procrit

campaign a " groundbreaking and influential success….You

can see yourself in the brand, you feel recognized and

valued. You feel like they really know you. "

 

 

After seeing ads such as these, one could be forgiven

for assuming that this drug confers strength on cancer

patients, gives them a better mental attitude, and

possibly enables them to live considerably longer as

well. Thanks in part to such advertising, Procrit has

become Johnson & Johnson's top-selling drug. According

to the New York Times, global sales of EPO products

exceeded $13 billion in 2001, with Johnson & Johnson

alone accounting for $3.4 billion of that. EPO drugs

were J & J's best-selling pharmaceutical group, providing

more than 10 percent of its total revenue (Tagliabue

2002).

 

 

But last year, French regulators discussed pulling the

drug (called Eprex® in Europe) off the market entirely,

suspecting that it sometimes causes sudden deaths in

patients being treated for the anemia that accompanies

chronic kidney failure (Herper 2002). And last June,

the advertising campaign for the drug was criticized by

the Food and Drug Administration as " misleading " and

" inaccurate. "

 

 

Now comes this Lancet bombshell. True, the drug tested

in the present study was epoetin beta, not the nearly

identical epoetin alpha (Procrit). And true, the

patients in this study were receiving radiation

therapy, not chemotherapy (epoetin's more common use is

in chemotherapy-related anemia). Yet the implications

of this Lancet study should be clear to all. These

anemia-relieving drugs may not be safe for cancer

patients who are also taking cytotoxic treatments. The

authors have quite properly called for " further

erythropoietin trials " that would " carefully analyze

cancer control and survival. " The most urgent one would

be to rigorously test the safety of Procrit in the

treatment of chemotherapy-related anemia.

 

 

TO BE CONCLUDED, WITH REFERENCES, NEXT WEEK.

 

 

 

--Ralph W. Moss, PhD

 

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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.

 

 

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