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, Ph.D.

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