Guest guest Posted September 13, 2004 Report Share Posted September 13, 2004 > 12 Sep 2004 19:50:10 -0000 > " Cancer Decisions " > < > THE MOSS REPORTS Newsletter (09/12/04) > ---------------------- > Ralph W. Moss, Ph.D. Weekly CancerDecisions.com > Newsletter #149 09/12/04 > ---------------------- > > 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. > > -------------- > > IMPORTANT NOTICE: > > Please do not REPLY to this letter. All replies to > this email address are automatically deleted by the > server and your question or concern will not be > seen. If you have questions or concerns, use our > form at > http://www.cancerdecisions.com/contact.html > Thank you. > > To SUBSCRIBE TO OUR FREE NEWSLETTER: Please go to > http://cancerdecisions.com/list/optin.php?form_id=8 > and follow the instructions to be automatically > added to this list. > Thank you. > > ===== Quote Link to comment Share on other sites More sharing options...
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