Fwd: THE MOSS REPORTS Newsletter (02/22/04)

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22 Feb 2004 20:00:07 -0000

" Cancer Decisions "

THE MOSS REPORTS Newsletter (02/22/04)

 

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

Newsletter #121 02/22/04

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COLORECTAL CANCER

 

 

Despite advances in the screening, early detection and

treatment of colorectal cancer, it remains the third

most common cancer in the US. About 147,500 people

will be diagnosed with cancers of the colon or rectum

this year and some 57,000 will die from the disease.

 

 

The announcement this week that the drug Erbitux had

been approved for the treatment of advanced colorectal

cancer will surely have raised many people's hopes.

Since much of medicine's ability to hold cancer in

check depends on early diagnosis, it is especially

heartening when we hear that there is a new treatment

specifically designed for advanced cases. Yet, as this

week's newsletter shows, Erbitux, far from being a

breakthrough, is in essence another vivid example of

the way in which the politics and economics of cancer

have come to overrule the basic science of cancer

research.

 

 

A cancer patient's best hope of success is to arm him

or herself with as much detailed, objective information

as possible so that he or she can carefully weigh the

choices and decisions that lie ahead. To that end,

for the remainder of the month of February we are

offering our Moss Reports on colon and rectal cancer at

a special discounted price of $247, a savings of $50.

 

 

You can order reports via our website,

www.cancerdecisions.com, or reach us at 1-800-980-1234

(814-238-3367 when calling from outside the US).

 

 

 

ERBITUX APPROVED

 

 

Erbitux (cetuximab), the drug at the center of the

Martha Stewart stock trading scandal, was approved by

the US Food and Drug Administration (FDA) on Thursday,

February 12, 2004. Erbitux is considered a last-ditch

treatment for cancers of the colon or rectum, which

have spread to other parts of the body. In its approval

announcement, FDA specified that Erbitux should be used

in combination with a commonly used chemotherapy drug,

irinotecan (Camptosar or CPT-11), in patients who have

not responded to that drug alone. Erbitux was also

recommended for patients who cannot tolerate irinotecan

(Pollack 2004).

 

 

Erbitux was the latest beneficiary of FDA's accelerated

approval program, which allows the agency to approve

products for the treatment of cancer and other serious

diseases based on what they consider to be " early

evidence " of effectiveness. Despite the fact that the

evidence for Erbitux's effectiveness turned out to be

exceedingly slender, the approval was greeted with

expressions of enthusiasm from the oncology and

investment communities.

 

 

" This has enormous potential, " said Robert Mayer, MD,

director of gastrointestinal oncology at the

Dana-Farber Cancer Institute in Boston. " And this is

only the first wave. There are several more [such

drugs, ed.] underway. That's why this is such a very

exciting time. "

 

 

" This is tremendous vindication for the company, " said

Cory William Kasimov, a biotechnology analyst with Ryan

Beck & Co, speaking of the drug's developer, ImClone.

" All these years they were right - this was an effective

drug. "

 

 

But is it really an effective drug? Let us try to

clarify what Erbitux does - and does not - do. This

task is complicated by the fact that the clinical

trials on which approval was based have not yet been

published in peer-reviewed medical journals. (A search

of PubMed reveals only two published clinical trials of

Erbitux, neither of which relates to colorectal

cancer.) So when all is said and done we have only the

company's and the FDA's word on the safety and

effectiveness of this drug.

 

 

But by the FDA's own admission, the drug is of limited

effectiveness. The approval itself states that Erbitux

has NOT been proven to increase cancer patients'

survival time. Nor is there any mention of complete

responses. And although some scientists have talked in

hopeful terms about Erbitux possibly improving cancer

patients' quality of life, there is no proof of this,

either. " Currently, " said a statement from

Bristol-Myers Squibb, which has an agreement to

distribute the drug, " no data are available that

demonstrate an improvement in disease-related symptoms

or increased survival with Erbitux. " This seems

unambiguous.

 

 

So, if Erbitux doesn't improve quality of life or

increase survival, what use is it? According to the

FDA, what the drug can do is temporarily shrink some

tumors, especially when used in conjunction with

irinotecan. In studies, when Erbitux was given in this

way, the combination partially shrank tumors in 23

percent of selected patients, with an average response

duration of 4 months. Used alone, Erbitux shrank tumors

in only 12 percent of patients with a duration of

response of one-and-a-half months. It was on the basis

of these less than impressive results that the drug was

approved.

 

 

But isn't the whole point of cancer treatment to

increase overall survival rather than to temporarily

shrink tumors? Absolutely. But so far, Erbitux has

failed that crucial test. Also note that in this trial,

there was no control group. The only comparison made

was between Erbitux alone and Erbitux plus

chemotherapy. We therefore do not really know how

survival with Erbitux compared to the use of other

treatments, or to giving just supportive care.

 

 

 

Side Effects

 

 

Erbitux is one in a generation of so-called " targeted "

therapies for cancer that emerged in the 1990s. One of

the promises of targeted therapies was that they would

be far less toxic than standard chemotherapy. Prior

studies claimed that Erbitux is " well tolerated and

adverse events are mild and manageable " (Hollywood

2002). But in the current clinical trials Erbitux,

alone or in combination, was responsible for many

disturbing adverse events.

 

 

According to Bristol-Myers, the most common of these

was an acne-like rash, which occurred in fully 90

percent of patients. This may sound like a minor

complication, but it is not always so. In fact, this

rash was rated grade 3-4 (i.e., serious to severe) in

12 percent of patients.

 

 

But the side effects of Erbitux, alone or in

combination, are more than skin-deep. In fact, the FDA

reports that in trials, 10 percent of patients receiving

Erbitux plus irinotecan and 5 percent of patients

receiving Erbitux alone discontinued treatment

primarily because of adverse events (FDA 2004). In the

study that led up to FDA approval, 73 percent of

patients who completed treatment with the combined

Erbitux/irinotecan regimen exhibited weakness and

malaise, 72 percent experienced diarrhea, 55 percent

suffered nausea, 41 percent experienced vomiting and 45

percent had abdominal pain. Meanwhile, 34 percent of

patients experienced fever, and 30 percent suffered

constipation. In addition, skin problems such as

dryness and fissuring were common, and inflammatory or

infectious conditions, especially of the eyes, were

also seen.

 

 

Bristol-Myers concedes that some patients suffered even

more severe reactions: " ...severe infusion reactions,

rarely fatal, and characterized by rapid onset of

airway obstruction (bronchospasm, stridor, hoarseness),

hives, and low blood pressure, occurred in 3 percent

with the administration of Erbitux. " Ninety percent of

these reactions, including the drop in blood pressure

and difficulty breathing, came after the first infusion

of the new agent. While the risk of such severe

reactions might be justified if the drug extended life

significantly, it seems an unwarranted risk when the

agent is so manifestly ineffective and the anticipated

gains so modest.

 

 

Interstitial lung disease (ILD) has also been reported

after use of this drug. This is a condition that occurs

when the lungs become inelastic due to scarring of the

tissue between the air sacs. The FDA, making a fine

distinction, said that it is difficult at this time to

determine if ILD was actually caused by Erbitux, or was

merely found in association with the treatment. They

therefore chose to give Erbitux the benefit of the

doubt. However, the same lung disease has been clearly

associated with the administration of a similar

targeted agent, Iressa, leading to that drug's

withdrawal from the market in Japan.

 

 

 

Sensationalist Hoopla

 

 

So here we have yet another drug winning approval after

showing only minor activity of dubious significance.

This is a far cry from all the sensationalist hoopla

that greeted Erbitux's appearance just a few years ago.

At that time, Dr. Sam Waksal was the toast of

Manhattan, throwing lavish caviar and champagne parties

in his Picasso-adorned Soho loft and cultivating a

social circle that eventually included Mick Jagger,

Martha Stewart, and other celebrities (Agovino 2002).

 

 

The cure for cancer seemed at hand! Today, of course,

the unfortuante Dr. Waksal is serving out a seven-year

prison sentence for insider trading on ImClone's stock.

Martha Stewart is on trial for her alleged involvement

in that same scandal. Now, too, we know that Erbitux is

of minimal significance in the fight against advanced

colorectal cancer. But back in those halcyon days, Time

magazine ran a cover story on the new generation of

anti-cancer drugs, including the rising star Erbitux

(then called IMC-C225). Time claimed that the drug was

" effective in treating colon tumors " and said that

" just this year researchers at Sloan-Kettering showed

that the drug could dramatically boost the

effectiveness of standard colorectal cancer

chemotherapy… " (Lemonick 2001).

 

 

Dr. Leonard Saltz, a celebrated colorectal cancer

specialist at Memorial Sloan-Kettering Cancer Center in

New York, was quoted as saying the results were

" staggering. " Erbitux " weakens the tumor enough for

chemotherapy to finish it off, " he enthused. Combined

with chemotherapy agents, we were assured, Erbitux

would " pack a triple punch " . Time's reporters gushed on

like this for nearly eight pages! (Lemonick 2001) In

July 2001, Erbitux was touted on the cover of Business

Week, and the New York Times called it the " two billion

dollar molecule. " Wall Street stock analysts posted

" buy " ratings and the stock price soared. There were

few dissenters from this triumphalist chorus. Critics

who warned that most of these anti-cancer drugs were

being oversold were either ignored or dismissed as

habitual naysayers (Moss 2002).

 

 

However, Dr. Saltz, the erstwhile enthusiast for

Erbitux, has apparently reconsidered his position.

After the drug's recent approval, he told New York

Newsday that, in reality, the drug is only a " modest

step forward….You can't call it a breakthrough and you

can't call it revolutionary. " Dr. Saltz added, " we

still have an awful lot of patients who are dying of

this disease, and I see them every day " (Marshall

2004).

 

 

Although, as Bristol Myers readily acknowledges,

Erbitux does not extend life, doctors still extol its

ability to shrink the size of tumors. Reducing the size

of a tumor could alleviate pain and discomfort, said

Daniel Laheru, MD, an oncologist at the Johns Hopkins

Kimmel Cancer Center, Baltimore. One certainly hopes

so. But no evidence for this indication appears in the

FDA's or Bristol-Myers' statement on the approval…and

the data itself is so far unavailable for independent

scrutiny. There is therefore no proof that Erbitux

actually alleviates pain and discomfort. On the

contrary, it appears to cause considerable side effects

(some of them serious) in many of those who receive it.

 

 

Another hope is that Erbitux may shrink previously

inoperable tumors so that doctors can then remove them

surgically. But this indication is also speculative.

After all, the drug has been approved specifically for

the treatment of advanced colorectal cancer, which has

recurred or spread throughout the body. The rationale

for using it to assist in the removal of isolated

tumors therefore is hard to fathom. In any case, this

would only be of benefit to a small minority of

patients.

 

 

 

Targeted Receptors

 

 

Erbitux is certainly different from standard

chemotherapy in that it targets specific proteins that

are involved in cancer growth. It is a specially

manufactured type of protein called a monoclonal

antibody, which blocks a molecule called " epidermal

growth factor receptor " (EGFR) that spurs cancer cells

to grow. This genetically engineered molecule actually

contains both human and mouse components. Very high

tech.

 

 

While chemotherapy could be compared to saturation

bombing, targeted drugs are intended to be more like

'smart bombs.' Such therapies are supposed to be more

effective than chemo and to have fewer side effects

because they are so well focused on just the malignant

cells. The dream of Sam Waksal and many others was that

by targeting cancer-specific proteins they would be

able to pinpoint the malignancy but leave normal cells

unharmed….in other words, to create the long-sought

" magic bullet " for cancer. However, to date very few of

these targeted treatments seem to be panning out. Most

are turning in surprisingly mediocre performances.

Cancer once again turns out to be able to survive and

work its way around such attacks.

 

 

 

A Financial Bonanza

 

 

Now that it has gained approval, however, Erbitux will

be rushed into full-scale production and made available

for advanced colorectal cancer patients in just a few

weeks. If history is a guide, we will start to see

Erbitux advocated and then used 'off label' for the

treatment of other stages of colorectal cancer as well

as for other kinds of cancer entirely, such as cancers

of the pancreas, ovaries, fallopian tubes, peritoneal

cavity and lung (all of which are currently in clinical

trials with this drug).

 

 

As of this writing, ImClone and its Big Pharma partner,

Bristol-Myers Squibb, have not specified a price for

the agent, but according to the New York Times it will

be " comparable to other biotechnology drugs, which can

cost tens of thousands of dollars a year " (Pollack

2004), Newsday speculates that the cost will be $20,000

per year per patient (Marshall 2004). Others believe it

will be even higher, between $25,000 and $30,000 per

year (Coghill 2004). (A similar drug, Gleevec, costs

over $25,000 per year per patient.)

 

 

There is a huge market at stake. Approximately 147,500

Americans will be diagnosed with the disease this year

and 57,000 people will die of it. Since Erbitux targets

EGFR, it is only supposed to be given to patients who

test positive for that marker. But that will prove to

be no hardship for the company, since EGFR is expressed

in up to 77 percent of all colorectal cancers. The

number of US patients eligible for Erbitux will thus

be in the tens of thousands. This fact has not escaped

Andrew G. Bodnar, a senior vice president of

Bristol-Myers. The Erbitux approval, he said, " begins

our return to the position that we intend to occupy in

the field of oncology, which is one of pre-eminence. "

 

 

FDA's approval of Erbitux was accompanied by bizarre

gyrations in the price of ImClone stock, reminiscent of

the 2001 scandal that led to Waksal's and Stewart's

legal troubles. The drug agency broke with its usual

practice and released its announcement in the midst of

Wall Street's trading day, rather than before or after

the stock market's close. When word came that FDA was about

to announce its decision, ImClone's stock's price

plunged by more than $9 per share, on rumors that the

drug would once again be rejected, as it was in

2001. The sell-off was so intense that the Securities

and Exchange Commission (SEC) had to stop all trading

in the company's stock. When trading resumed after

hours, and the favorable news had been digested,

ImClone's shares surged by 30 percent, to more than

$45. Lucky the person who guessed that Erbitux would in

fact be approved! The SEC is investigating this latest

financial imbroglio.

 

 

 

Political Payback

 

 

This approval could be seen as a gift from the Bush

Administration to Bristol-Myers Squibb, a company that

was among the President's top ten donors in 2000.

According to an online public interest newsletter:

 

 

" Executives at drug giant Bristol-Myers Squibb were

pressured to make maximum donations to the Bush

campaign in 2000. Reluctant donors were warned that CEO

Charles A. Heimbold, Jr. would be informed if they

failed to give. Bush later named Heimbold as Ambassador

to Sweden. More importantly, since 1999 the

pharmaceutical industry pooled $42.1 million for Bush

and other GOP candidates… " (Aaron 2004).

 

 

" For Bristol-Myers, " the New York Times said, " the

approval represents a delayed payoff for the

unprecedented $2 billion deal it signed with ImClone

for marketing rights in September 2001. Bristol was

desperate for a new product to replace its cancer drug

Taxol, which began facing generic competition "

(Pollack, 2004). The approval sends a clear message

that the Bush Administration will never stand in the

way of the drug industry's headlong rush for

megaprofits.

 

 

(To be completed, with references, next week.)

 

 

 

--Ralph W. Moss, PhD

 

 

=======================

 

Where to find it...

 

 

To order my book The Cancer Industry please click or go to:

 

http://www.amazon.com/exec/obidos/ASIN/1881025098/cancerdecisio-20/103-4018872-4\

386244

 

 

To order my book Questioning Chemotherapy please click or go to:

 

http://www.amazon.com/exec/obidos/ASIN/188102525X/cancerdecisio-20/103-4018872-4\

386244

 

 

To order my book Cancer Therapy please click or go to:

 

http://www.amazon.com/exec/obidos/ASIN/1881025063/cancerdecisio-20/103-4018872-4\

386244

 

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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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