THE MOSS REPORTS Newsletter (09/12/04)

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> 12 Sep 2004 19:50:10 -0000

> " Cancer Decisions "

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> THE MOSS REPORTS Newsletter (09/12/04)

>

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

> Newsletter #149 09/12/04

>

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>

> THE MOSS REPORTS

>

> " Those who assume hypotheses as first principles of

> their speculations...may indeed form an ingenious

> romance, but a romance it will still be. " So wrote

> Roger Cotes, seventeenth century British astronomer

> and mathematician in his preface to Sir Isaac

> Newton’s legendary Principia Mathematica.

>

> Although it was written almost three hundred years

> ago, Cotes’ aphorism still rings true today because

> it speaks of the fallibility of human nature, and

> the tendency of scientists and philosophers alike to

> confuse hypothesis with fact. It was not only in

> Newton’s day that scientists fell blindly in love

> with ideas and selectively ignored data that might

> have shaken their convictions. Contemporary

> scientists are human, too, and just as capable of

> clinging to theories and dismissing or ignoring

> evidence that might undermine those basic

> assumptions.

>

> This week I begin a two-part discussion of the

> latest findings of the National Surgical Adjuvant

> Breast and Bowel Project, an influential clinical

> trials collaborative organization sponsored by the

> National Cancer Institute. The group’s findings,

> published in the Journal of the National Cancer

> Institute, cast grave doubt on the value of

> post-operative chemotherapy for colon cancer.

>

> That the group came to this conclusion is laudable.

> Chemotherapy for colon and most other kinds of

> cancer has come to be seen as an unassailably

> worthwhile treatment – an " ingenious romance " , to

> use Cotes’ expression. But, as you will see, even

> though a group as prominent and respected as NSABP

> was able to cast doubt on the value of this form of

> treatment in early colon cancer, many other equally

> prominent medical voices have been raised in defense

> of the status quo. For the past thirty years I have

> been studying the world of cancer therapeutics,

> weighing the evidence and writing about the best

> treatment choices that conventional and alternative

> medicine have to offer. The fruits of this work are

> embodied in The Moss Reports, a comprehensive series

> of reports on the treatment options for more than

> 200 different cancer diagnoses.

>

> If you or someone you love has received a diagnosis

> of cancer, a Moss Report can provide you with the

> key to understanding the best that conventional and

> alternative medicine have to offer. You can order a

> Moss Report on your specific cancer type by calling

> Diane at 1-800-980-1234 (814-238-3367 from outside

> the US), or by visiting our website:

> http://www.cancerdecisions.com

>

> We look forward to helping you.

>

>

>

> NEW DOUBTS ABOUT ADJUVANT CHEMOTHERAPY FOR COLON

> CANCER – PART 1

>

>

> A common form of chemotherapy does not improve the

> long-term survival of patients with stage II and III

> colon cancer. This was the conclusion of a long-term

> follow-up report by the prestigious research group,

> the National Surgical Adjuvant Breast and Bowel

> Project (NSABP). It was published August 4 in the

> Journal of the National Cancer Institute (Smith

> 2004).

>

> " The disease-free and overall survival benefit

> associated with chemotherapy in this patient

> population is of limited duration, disappearing

> after 10 years, " the authors wrote.

>

> The new study throws doubt on the value of a form of

> chemotherapy that has been an important part of

> colon cancer treatment over the last several

> decades. The regimen in question is called MOF and

> contains 5-fluorouracil, or 5-FU, still the most

> commonly used anti-colon cancer agent. It also

> includes two other powerful drugs, MeCCNU

> (semustine) and vincristine. While this particular

> combination is rarely used today, it is similar to

> other 5-FU-containing regimens that are still in

> use.

>

> 5-FU has long been a mainstay of treatment for

> various stages of colon cancer, particularly when

> given after surgery as a so-called ‘adjuvant’

> (helper) therapy. Although it is moderately

> effective at inducing shrinkage in existing tumors,

> such shrinkages are almost always temporary.

> Questions have remained, therefore, as to whether

> adjuvant chemotherapy with 5-FU really extends the

> lives of colon cancer patients. This rigorous Phase

> III randomized, controlled trial conducted by NSABP

> set out to answer just that question.

>

>

> Some Background

>

>

> 5-FU was discovered in 1957 by Dr. Charles

> Heidelberger of the University of Wisconsin. By the

> time the war on cancer began in 1971, 5-FU had

> already been in use for a decade in the treatment of

> colon cancer. Despite initial enthusiasm, however,

> long-term results were generally disappointing.

> " Many early trials of adjuvant chemotherapy failed

> to show a significant improvement in either overall

> or disease-free survival for patients receiving

> treatment, " according to the National Cancer

> Institute’s Physician Data Query (PDQ) report (NCI

> 1994).

>

> Then, in 1975, came the dramatic announcement by

> Charles G. Moertel, MD, of the Mayo Clinic,

> Rochester, MN, that a combination of 5-FU and the

> drug levamisole had been found to extend the lives

> of Dukes C (stage III) colon cancer patients

> significantly (Moertel 1975).

>

> It is perhaps difficult for readers who were not

> following news about cancer at that time to realize

> just how exciting Moertel’s announcement sounded.

> Chemotherapy for the common solid tumors of adults

> was still in its infancy, and much of the medical

> profession was still skeptical of the treatment. For

> instance, I remember one scientist at Memorial

> Sloan-Kettering Cancer Center, New York, telling me

> that destroying a tumor with drugs would be like

> " making a person’s right ear disappear while leaving

> the left ear intact. " In making his announcement

> concerning 5-FU and levamisole Dr. Moertel was in

> effect endorsing chemotherapy with the full weight

> and prestige of his world-famous organization, as

> well as the North Central Cancer Treatment Group

> (NCCTG).

>

>

> The Levamisole Puzzle

>

>

> In that landmark Mayo Clinic study, patients who

> were treated with a combination of 5-FU and

> levamisole were compared to patients who were

> treated using levamisole alone, and to a third

> group, a control group, that received no adjuvant

> treatment at all.

>

> The study claimed a 41 percent decrease in the rate

> of recurrence of colon cancer, and, more

> importantly, an impressive 33 percent decrease in

> the death rate compared to stage III patients who

> did not receive chemo after surgery (Laurie 1989).

>

> Levamisole, originally developed as a worming agent

> for livestock, was hailed in the 1970s as a

> remarkable discovery in human cancer treatment.

> However, it gradually slipped out of fashion and is

> no longer routinely used in cancer therapy. (There

> are, for example, no current trials using levamisole

> in the www.clinicaltrials.gov database.)

>

>

> NSABP Study

>

>

> In 1988, NSABP issued a report stating that patients

> with stages II and III (then called Dukes B and C)

> colon cancer who were given 5-FU and a different

> drug, leucovorin, after standard surgery had a

> statistically significant increase in both their

> five-year disease-free survival and their overall

> survival (Wolmark 1988). Since chemotherapy had only

> very rarely been shown to increase actual survival

> time this was also big news, and was treated as a

> watershed event in the history of cancer treatment.

>

> In April, 1990, the concept of adjuvant chemotherapy

> for colon cancer was officially endorsed by a

> high-level National Institutes of Health (NIH)

> Consensus Conference on Colon Cancer. The consensus

> conference lauded the Mayo clinic study as " high

> quality…excellent…mature, " etc. This august body

> concluded that stage III colon cancer patients

> " should be offered adjuvant 5-FU and levamisole as

> administered in the intergroup trial unless medical

> or psycho-social contraindications exist. "

>

> (The Consensus Statement, available online, also

> gives a good history of the clinical trials leading

> to this position {NIH 1990}.}

>

> This Consensus Conference received clamorous

> publicity and led to an enormous increase in the use

> of chemotherapy for colon cancer. However, as I

> noted in my book Questioning Chemotherapy (1995),

> there were a number of problems with this treatment,

> including both short- and long-term toxicity. Doubt

> was thrown on its validity by the fact that

> levamisole did not work in any other kind of cancer.

> Its mechanism of action was unknown. There was also

> the troublesome fact that neither 5-FU nor

> levamisole had individually been proven to have a

> beneficial effect on survival. Indeed, in my book I

> concluded that " it would be odd if one drug that

> does not increase survival (5-FU), added to another

> which actually decreases survival (levamisole),

> together prolonged people’s lives. Certainly,

> stranger things have happened, but caution is

> advised both in interpreting the data and in taking

> this treatment " (p103).

>

> At that time I was one of very few commentators who

> drew attention to the weaknesses in the data being

> used to support the use of adjuvant chemotherapy for

> colon cancer. In the following years, while we were

> continually being told that adjuvant chemotherapy

> prolonged life, there were growing signs of its

> ineffectiveness.

>

> By the mid-1990s there seemed to be some hedging

> over the significance of the original 5-FU protocol.

> In a statement dating from that time, for instance,

> NCI still upheld the idea that a " significant

> improvement in disease-free survival was observed, "

> but added that " overall survival benefits were of

> borderline statistical significance. "

>

>

> JNCI Review

>

>

> It is that borderline significance that has now

> disappeared. Fourteen years after the NIH Consensus

> Conference, one of the key clinical trials that has

> been constantly cited in support of adjuvant

> chemotherapy has been refuted, according to the

> latest report in the Journal of the National Cancer

> Institute.

>

> This 10-year follow up study included a total of

> 1166 patients who were randomized into three groups.

> A group of 375 patients was treated with surgical

> resection alone. A group of 349 patients was

> assigned to be treated postoperatively with

> so-called MOF chemotherapy, and a further group of

> 372 was treated with adjuvant Bacillus

> Calmette-Guerin (BCG) immunotherapy after resection.

>

> There were no differences in the chemotherapy and

> surgery-alone groups in terms of either 10-year

> disease-free or overall survival, according to Dr.

> Roy E. Smith and colleagues of the NSABP in

> Pittsburgh. The survival curves were very close to

> begin with and they simply converge at around eight

> years as if nothing happened. But on the basis of

> the false assumption that adjuvant chemotherapy

> extended life, tens of thousands of patients have

> been given this treatment, with all its attendant

> toxicity and side effects.

>

> Some oncologists, such as first author Smith, have

> tried to salvage something positive from this

> conclusively negative finding. Dr. Smith concedes

> that this form of adjuvant chemotherapy does not

> prolong life. However he believes that it may

> " attenuate " the course of colon cancer. Perhaps what

> Dr. Smith means by this is that chemotherapy with

> 5-FU may have prevented some patients from

> succumbing specifically to colon cancer for a number

> of years. As the NSABP article put it, " There may

> have been an early delay in recurrence. "

>

> However, Dr. Smith admits that this interpretation

> is essentially speculative. Meanwhile the stark

> fact remains that overall survival does not increase

> as a result of adjuvant chemotherapy. Moreover, it

> is important to consider the possibility that

> chemotherapy may itself damage patients’ immune or

> other bodily systems such that they succumb to other

> diseases. Perhaps chemotherapy does temporarily

> halt the progression of colon cancer in some

> patients, but it may concurrently open the door to

> other fatal diseases, such as a second cancer. At

> least one of the drugs in this regimen, MeCCNU, is

> known to cause leukemia (Boice 1986). That doesn’t

> seem like a very desirable trade-off.

>

>

> BCG to the Rescue?

>

>

> To the surprise of investigators, the most

> encouraging result of the NSABP study was the

> performance of the patients in the immunotherapy

> group, who were given Bacillus Calmette-Guerin, or

> BCG, which has been used in cancer treatment for

> many years as an immune-modulating agent. BCG is the

> standard vaccine for tuberculosis, and it is widely

> used for that purpose in Europe and elsewhere. It is

> also routinely used to treat one form of bladder

> cancer and is still occasionally used as a treatment

> for other cancers as well. But it is a stepchild of

> American oncology—officially approved but generally

> ignored. That is probably because it is an

> inexpensive agent in the public domain. BCG is not

> even mentioned in the National Cancer Institute’s

> PDQ statement on colon cancer, although it

> frequently shows better results than chemotherapy.

>

> In the present study, BCG immunotherapy was the only

> treatment that did in fact have a beneficial effect

> on overall survival after 10 years. There was a

> significant 27 percent increase in overall survival

> in the group that received immune support after

> surgery. But there was no increase in disease-free

> survival. In other words, BCG did not appear to kill

> colon cancer cells per se but boosted the patients’

> own immune competence to such a degree that it was

> able to protect them from premature death due to

> " comorbidities " (other medical conditions).

>

> This is surely something worth exploring, since it

> seems to confirm the idea that boosting the immune

> system is crucial for cancer patients. But far from

> heralding the success of BCG in prolonging patients’

> lives, the study authors, in a curious turn of

> phrase, wrote that BCG’s benefit may be a " chance

> finding because it was an unanticipated effect. "

>

> Are we to doubt significant findings because they

> are " unanticipated " ? Most of the great discoveries

> of medicine were not anticipated in advance of their

> chance discovery. Serendipity was, and remains, a

> crucial part of science. As Louis Pasteur said in

> 1854, " chance favors the prepared mind. " Perhaps

> one has to be mentally prepared for the idea that

> the immune system is a crucial element in fighting

> cancer in order to recognize the importance of these

> findings. As a firm believer in the power of the

> immune system, I don’t find the benefits of BCG in

> this study surprising in the least. But to those who

> consider the health of the immune system to be

> irrelevant to the treatment and outcome of cancer, I

> suppose that such findings would indeed be

> " unanticipated. "

>

> At least the NSABP study included a comparison group

> of patients who received immunotherapy as well as a

> no-further-treatment (or observation) arm. This is

> no longer typical of US clinical trials. Of the 13

> clinical trials of adjuvant chemotherapy for colon

> cancer listed at www.clinicaltrials.gov, only one

> contains an ‘observation’ arm. And only a single

> study involves adjuvant immunotherapy, using an

> immune modulator called P40, derived from the

> Corynebacterium granulosum microbe. But this one

> study is being conducted only in Buenos Aires,

> Argentina.

>

>

> Moving Goalposts

>

>

> Another disturbing reaction is typified by the

> editorial accompanying the paper’s publication in

> the Journal of the National Cancer Institute. In

> that editorial, Dr. Jean Grem of the University of

> Nebraska Medical Center in Omaha acknowledges that

> the study did not reflect well on adjuvant

> chemotherapy. But as though unable to accept the

> obvious conclusion that chemo had been oversold, she

> proposes that in future, researchers in this field

> should adopt the yardstick of three-year

> disease-free survival, instead of the current

> five-year overall survival, as the standard of

> benefit. This would allow, she opined, " more timely

> completion of trials, and more rapid implementation

> of new trials testing promising new therapies. "

>

> Yes, trials would be completed more rapidly and,

> yes, they might allow the introduction of more

> drugs. But what she really seems to be saying is

> that we should stop worrying about whether patients

> as a whole actually survive five (much less ten)

> years after they receive treatment. (That is what is

> measured by overall survival.) Let us shorten the

> time span of our experiment and look instead at

> whether they have succumbed to colon cancer, and

> exclusively to colon cancer, after a waiting period

> of just three years.

>

> If this " surrogate " standard recommended by Dr. Grem

> had been adopted as the end point of this particular

> NSABP trial it would have made the current drug

> regimen seem like a success rather than the dismal

> failure it has now been conclusively shown to be.

> " Promising new therapies " (which don’t pan out in

> the real world) could then be " rapidly implemented "

> (i.e., rushed to market) to the detriment of tens of

> thousands more patients.

>

> In other words, when all else fails, move the

> goalposts.

>

>

> (To be concluded, with references, next week.)

>

> --Ralph W. Moss, PhD

>

> ---------------

> 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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