Ralph Moss on Cancer--Expert Guidance for Crucial Decisions

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THE FLAP OVER ANGIOSTATIN & ENDOSTATIN

The Cancer Chronicles, Spring, 1998

© May, 1998 by Ralph W. Moss,Ph.D.

"Every day almost, we read startling headlines in the daily press of some doctor who has discovered a cure for cancer. Truly a wonderful discovery! But do not get excited over it, for I remember that over ONE HUNDRED remedies have been EXPLOITED as a cure for cancer, within the last forty years; they are now obsolete and numbered among the has-beens." --Eli Jones, MD, 1912.

The recent spate of newspaper articles and television programs about the new antiangiogenic drugs, angiostatin and endostatin, has created a tremendous amount of excitement and anxiety all over the world. The hopes of millions of cancer patients have been raised, cruelly in our opinion. We deplore the cynical manipulation of the hopes and fears of cancer patients by self-interested individuals.

Our criticism does not extend to Dr. Judah Folkman of Harvard University, discoverer of these agents. By all accounts he is ethical, determined, and brilliant. We wrote favorably about this work in "Angiostatin: A New Approach" in 1996. But while we share an appreciation for his work, we need to emphasize certain things about this current situation:

1) So far, the excellent results reported have only been in mice. It is well known that there are often outstanding results in mice that never translate into advances in the treatment of human cancer. As just one of many examples, tumor necrosis factor (TNF) also had excellent results in mice and made tumors literally fall off over night. But it has had extremely disappointing results in humans.

Similarly, when the useful drug camptothecin (derived from the Camptotheca acuminata tree) was first tested in animals it cured 36 out of 36 human tumors growing in nude (athymic) mice. However, when this same compound was put into patients the results were quite different: two "partial responses" (temporary tumor shrinkages) out of 61 patients with GI intestinal tract! (Moertel, CG, et al. Cancer Chemotherapy Report 1972;56:95.)

Many other examples could be given. It needs to be emphasized that the real test is the human, clinical situation and to date this mixture of angiostatin/endostatin has not been tried in a single human.

2) The manufacturer EntreMed does not have enough of either agent on hand to launch a clinical trial. It may be a year or more before they do and another year before the results of a Phase I-II trial would be announced. (It took almost 20 years to take TNF from the laboratory to the clinic.) Even if the Phase I-II trial was deemed positive that is not enough. It would still have to be tested in Phase III (large-scale randomized clinical trial). And even then it would probably be necessary to repeat this test at another institution, just to be sure. This could take years (presuming the company has the ability to isolate and produce this amount of these rare substances).

3) Some related products have already been tried in people, with less than startling results.

At the 1998 ASCO meeting, T. Eisen and colleagues at the Royal Marsden Trust in London reported that they gave thalidomide, an anti-angiogenic drug, to 48 patients with advanced solid tumors. These included patients with melanoma, ovarian, kidney, and breast cancer. Each recived 100 mg per day until progression. The results were that 3 of the 48 patients (6.25%) had a "differential response." Ten patients had stable disease for up to 25 weeks (with a median of 12 weeks), and 8 patients continued on the treatment. There was also an improvement in appetite and sleeping. The scientists concluded that further studies were warranted at higher doses. By all means...but this far from the "cure" that many patients believe is in the offing.

Another Phase I study has been carried out on a product called VITAXIN, which is a kind of monoclonal antibody directed against a chemical found on the blood vessels of tumor. Fifteen patients with stage IV disease were treated. They had many different types of cancer. There was one early death, which researchers ascribed to tumor progresson "and unrelated to VITAXIN therapy." Several patients developed fevers. Out of the 12 patients, there was one partial response (8.3%). Six patients appeared to have stable disease and five had progressive disease. Phase II studies are being planned. (Gutheil, JC, et al. Phase I study of Vitaxin, an anti-angiogenic humanized monoclonal antibody to vascular Integrin alpha-nu-beta-3, ASCO abstract 1998, #832.)

4) When the Phase I-II trial of Angiostatin/Endostatin is launched it is likely that around 50 patients will be treated. The Phase III trial may involve 100 or so, but half of these will have to be "randomized" to another treatment regimen, and will not receive angiostatin/endostatin. By that time there will literally be millions of people clamoring to get into this trial, and I would not be surprised if the company selects people by way of a lottery of some sort. And so one's chances of getting in will be literally like winning the sweepstakes.

5) The main appeal of Angiostatin/Endostatin is that they apparently overcome the problem of drug resistance. However, as a lead comment by Atul Gawande in the New Yorker (5/18/98) wisely pointed out (but the New York Times failed to mention), "drug resistance is just one of many factors that stymie anti-cancer drugs." Cancer in humans is a far more complex phenomenon that just the creation of new blood vessels. These are not affected by this drug. Nor does this drug combination address the multifaceted nature of cancer nor its causes. Also, angiogenesis itself is probably more complex than indicated in the newspapers, and is dependent on multiple factors in the body, such as IL-1, IL-8, bFGF, TGF-alpha, TGF-beta, PD-EGF, VPF, PAF, TNF, etc.

6) Inhibiting angiogenesis (new blood vessel formation) may not be without serious consequences or side effects. For example, angiogenesis is also present in other bodily processes, including benign diseases and normal processes as well. It is present during wound healing, ovulation, menstruation and pregnancy. It is a complex process about which we know very little. Researcher John Boik (author of Cancer and Natural Medicine) points out that "in spite of active angiogenesis, the blood supply in a solid tumor is relatively limited compaerd to that of normal tissue." In a Phase I study of SU5416, a novel angiogenesis inhibitor, various forms of toxicity were seen, including fatigue, change in voice, pain at infusion site and an allergic reaction. In rats and dogs, injury to the liver was seen (Rosen, LS, et al. UCLA School of MEdicine, 1998 ASCO abstract #843).

7) It has been known for over 100 years that tumors contain abnormally dense blood vessels networks. In the 1960s scientists realized that tumors induce their own blood supply. In 1972 Folkman and Hochberg reported that tumors implanted in the eyes of rabbits grew only to one cubic millimeter before developing their own blood supply. Antiangiogenesis was first proposed as a cancer therapy in 1971. In fact, a story about the latest work appeared in the New York Times on November 27, 1997 and was featured where it belonged, back on page A28.

This original Times article by Nicholas Wade said said what is true: these new drugs "may well prove relevant to the treatment of human cancer." Naturally, it sparked little follow-up since the same can be said about many drugs only tested in mice. Then on Sunday, May 3, 1998 basically the same story appeared on the front-page of The New York Times with the headline, "A CAUTIOUS AWE GREETS DRUGS THAT ERADICATE TUMORS IN MICE." As the New Yorker said, however, "the article...was longer on awe than on caution. A media frenzy ensued." It turns out that the author of the second article, science reporter Gina Kolata, had sat next to a famous scientist, James Watson, at a dinner party, where he regaled her with extravagant praise of Judah Folkman, such as "Judah is going to cure cancer in two years." It was an unguarded moment of overenthusiasm. You should also understand that cancer drug development is not Dr. Watson's field.

"...a handful of élite science journalists hold more power
over medicine than any doctor in America does."

Kolata apparently thought she had the story of the century, and decided to run with it. She got other cancer research leaders (such as NCI Director Klausner) to corroborate these enthusiastic appraisals. I do not know what Dr. Klausner is thinking, but Dr. Watson himself has been deeply embarrassed by these statements and has written a letter to the Times claiming he was misquoted. It then turned out that Gina Kolata's literary agent circulated a book proposal the day after the story appeared to write a book about the "cancer breakthrough." She withdrew the proposal after she was criticized for exploiting her position for personal gain. As the New Yorker notes, "...a handful of élite science journalists hold more power over medicine than any doctor in America does."

UGLIEST ASPECTS

The flap over Angiostatin/Endostatin has unleashed some of the ugliest aspects of our culture. The stock of EntreMed quadrupled and about a billion dollars changed hands. (It would be interesting to see a list of all the people who made money speculating on this stock. It might prove enlightening.) In addition, a media frenzy ensued which dwarfed any curemongering we have seen before, such as the earlier furors over interferon and then interleukin-2 . The New York Daily News carried a gigantic front-page screamer, "OUR BEST HOPE." Columnist (and cancer patient) Mike McAlary wrote, "Maybe we don't have to die." Not to be outdone, the New York Post countered with an editorial congratulating Dr. Folkman and then (in the words of the New Yorker, which deserves a prize for its salutory coverage of these events) "used him as a club with which to clobber, among other villains, non-Western medicine, 'New Age witch-doctory,' political correctness, the animal-rights movement, and the 'quasi-terrorism' of AIDS activists."

With the growth of the media, Internet, CNN, email, etc. news of "the cure" quickly swept over the entire globe. I have a friend in a remote town in Norway who knew about these developments as soon as I did in New York. In fact, he happened to see Kolata's article in a copy of The New York Times, which he picked up at the train station. Just a decade or so ago it would have taken weeks or months for this news to be disseminated.

It is particularly important to pay attention to the link between the promotion of angiostatin and endostatin and the attack on complementary and alternative medicine (CAM). Many people are going to try to deliver a killing blow to CAM with any new advance in conventional medicine. However, this theory of angiogenesis inhibition has been most popular in CAM and is in fact the theory behind the widespread use of shark and bovine cartilage. It might be a good idea to use plain cartilage as the control group in any Phase III clinical trial of angiostatin/endostatin. Dr. Folkman has said that he thinks these agents are too weak to exert any clinical benefit. It would be interesting to find out by a head-to-head comparison with the new, patented agents. The results would be enlightening.

Before defenders of conventional medicine start to celebrate the demise of CAM (dreaming, perhaps, of what the Salk vaccine did to Sister Kenney's treatment for polio), they should consider the implications of Judah Folkman's work. These particular angiogenesis inhibitors are produced by the tumor itself. Their discovery stems from the heretical observation that when primary tumors are removed their previously silent metastases sometimes erupt into explosive growth. Sometimes cancer modulates its own growth and surgical removal does not cure but inadvertently kills. These observations (which even Kolata mentions in passing) is hardly likely to reinforce public confidence in conventional medicine.While I still favor surgery for early-stage tumors, I think these studies show up the limitations and uncertainties inherent in all ablative treatments, which are practiced without a real understanding of the dynamics of tumor growth.

SOME PRACTICAL SUGGESTIONS

To summarize: angiostatin and endostatin are not available today and are unlikely to be available in the forseeable future. For those seeking treatment along these lines, however, there are a number of possibilities:

1) There are some clinical trials already underway with anti-angiogenic agents such as thalidomide, TNP-470, matrix metalloproteinase inhibitors, carboxyamidotriazole, and tecogalan sodium. Although I am not a great "fan" of clinical trials (which I feel rarely offer much chance of benefit to today's patients) we are providing a list of such trials as a public service.

2) There are also a number of dietary or natural factors that may work along the same lines, although of course they are far less concentrated that pure drugs and may not have a significant effect on established cancers. These include:

cartilage extracts, including collagenase inhibitors
genistein, found primarily in soy
gold thiomalate
hydrocortisone and heparin complexes
interferon-alpha
Magnolia liliflora (xin yi hua)
Penicillamine-D (a copper chelator)
Platelet factor IV
Protamine
SCM-chitin
Thiol compounds, such as glutathione and Allium species (garlic, onion, etc.)
Vitamin A
Vitamin D3 metabolites

Of all these, garlic is probably the least expensive, safest and most readily available. It would make sense for many individuals to take two cloves or more of lightly cooked fresh garlic per day for a variety of reasons. Soy in various forms (miso, tofu, sprouts, etc.) and reasonable amounts of vitamins A and vitamin D should also exert antiangiogenic effects. Although many doubt this, I believe that shark and bovine cartilage also operate along the same lines and occasionally seem to exert a valuable anticancer effect.

Ralph W. Moss, Ph.D. is director of the The Moss Reports for cancer patients. Dr. Moss is the author of eleven books and three documentaries on cancer-related topics. He is or has been an advisor on alternative cancer treatments to the National Institutes of Health, the National Cancer Institute, the American Urological Association, Columbia University, the University of Texas, the Susan G. Komen Foundation and the German Society of Oncology. He wrote the first article on alternative medicine for the Encyclopedia Britannica yearbook. He is listed in Marquis Who's Who in America, Who's Who in the World, Who's Who in the East, and Who's Who in Entertainment (as a film documentarian). This Web site does not advocate any particular treatment for cancer. We urge you to always seek competent medical advice for all health problems, especially cancer. Before consulting our site please read our full Disclaimer statement.