Vitamin chemotherapy New Weapons in an Old Fight

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NEW WEAPONS IN AN OLD FIGHT

What scientists know--and don't know--about treating cancer with nutrients

HYDROXYUREA. MERCAP-topurine. Cyclophosphamide. One thing all cancer drugs seem to have in common is their hard-to-spell names.

Or do they? How about A? D? E? These aren't fancy new drugs--they're plain old vitamins. Yet when administered by scientists in large doses, some vitamins may act like drugs, or work with standard cancer-fighting drugs. It isn't clear vet whether the research into this futuristic notion of vitamin chemo-therapy will ever pan out. But if the research is successful, chemotherapy could be much easier to take--and a lot easier to spell.

Here's the latest on what scientists have learned so far:

RETINOIDS AGAINST SKIN CANCER
Several synthetic forms of vitamin A, collectively called retinoids, have been tested as treatments for skin cancer. They've mostly been pitted against the two skin cancers known as basal-cell and squamous-cell carcinoma. In several tests--just in the experimental stage--oral doses of retinoids have been effective against these carcinomas because retinoids accumulate primarily in the skin.

Most of the studies performed so far have been small, but the results are encouraging. These skin cancers, like all the others that retinoids have been used against, are unlikely to regress on their own. So researchers think that even though their tests are preliminary and have no control groups, the retinoids are probably responsible for the positive effects.

The retinoids etretinate (eh-TRET-tin-ate) and isotretinoin (EYE-so-tret-in-OH-in) have been used to treat basal-cell carcinoma. In three separate studies on a total of 56 people, 23 showed a partial regression of cancer (the tumors shrank), and five showed complete regression (disappeared). This is an overall response rate of 50 percent, meaning rhat half the people experienced some decrease in the number or size of tumors.

Once treatment was completed, though, many of the cancers returned. This suggests that regular doses of retinoids may be required for a "cure." Among other things, doctors are conducting studies to determine the best maintenance dose: one that minimizes skin and mucous-membrane drying, the main side effect.

Researchers are having better luck using oral retinoids against squamous-cell carcinoma. In four small studies, a total of 14 squamous-cell patients were treated with etretinate (4 patients), isotretinoin (9), or arotinoid (1). Six of the 14 had partial remission (tumors reduced in size) or temporary remission (tumors shrank or stopped growing for a short time); another 4 had complete, sustained remissions of the squamous-cell tumors. That adds up to a 71 percent response from an admittedly small sample.

Both basal-cell and squamous-cell carcinomas are relatively easy to cure with surgical removal (used in 90 percent of cases), radiation therapy or tissue destruction with extreme heat or cold. So why all this fuss about retinoids?

Surgery and other tissue-destroying therapies leave scars. That's not a big problem for a person with one tumor on the back of a hand. But a majority of people with carcinoma have several tumors on areas of the body that are regularly exposed to the tumor-inducing ultraviolet rays of the sun: not only the hands, but the head and neck as well.

Retinoids don't leave scars: Tumors shrink away and normal tissue fills in. That's especially valuable in advanced disease. "One patient had severe, disfiguring tumors on his neck and nose. After six months on isotretinoin, the neck tumor had shrunk to a small, flat lesion. And the nose tumor had shrunk by 70 percent, with preliminary rebuilding of his all-but-eroded nose," explained Scott M. Lippman, M.D., of the hematology/oncology department of M.D. Anderson Cancer Center at the University of Texas, in Houston.

Retinoids have also been tested against malignant melanoma, a more serious form of skin cancer. Preliminary results from a small study of 20 people with advanced melanoma showed some shrinkage of tumors in three people. It's far from a cure, but it's a glimmer of hope against a type of cancer that has been resistant to drugs.

A rare skin cancer called mycosis fungoides (my-KOH-sis fung-GOY-dees) has shown good response to retinoid therapy. In five preliminary studies, a total of 78 people with the disease were put on oral isotretinoin. More than half showed at least a partial response. The National Cancer Institute is currently sponsoring a clinical study of isotretinoin in combination with other substances against this cancer.

BATTLING IN THE BLOODSTREAM
Synthetic versions of vitamins A and D seem to hold promise in the treatment of myeloid leukemia, a cancer of the white blood cells. Both are currently being tested in preliminary trials.

The main problem in leukemia is that immature white blood cells proliferate in the bloodstream, crowding out normal red and white cells. This causes severe anemia and compromises the immune system. But through a hormonal interaction, vitamins A and D seem to make the immature cells grow up. Mature cells appear to stop their rapid reproduction and are able to carry out their immune-system functions.

Initially the active form of vitamin D was tested, but in high doses this has the unfortunate side effect of causing the body to retain calcium. That could cause complications, including hardening of the vital organs and death. But the synthetic version of vitamin D has a more powerful maturing influence on leukemic cells--and a much-lowered calcium-loading mechanism. In studies on leukemic lab mice, this synthetic compound achieved much better results than pure vitamin D. "Some of the mice treated with synthetic D may actually be cured of their leukemia," reports H. Phillip Koeffler, M.D., professor of medicine at UCLA and one of the leading researchers in this field. However promising that may sound, further studies need to be done before this compound is tested in humans.

Synthetic vitamin A has been tested in humans against leukemia, but not on a widespread scale in this country. A few years ago, American researchers at several centers were involved in a doubleblind, randomized trial of 13-cis retinoic acid (a retinoid compound) in patients with a preleukemic condition called myelodysplastic (MY-low-dis-PLAS-tik) syndrome. Problems with the study--including many patients quitting the trial--cast suspicion on the results, according to Dr. Koeffler.

One of the researchers, however, continued the study on his own after the trial ended, and found a significant response. Was the original trial too short? It's hard to say without attempts to duplicate those results. The study also showed physicians that the side effects of retinoid therapy drying can be reduced with doses of vitamin E. More reports have come from abroad. Researchers in China and France have reportedly achieved promising results using transretinoic acid against acute promyelocytic leukemia (APL). Up to 75 percent of patients in Chinese studies went into remission. A French researcher has reportedly duplicated their results.

Other research shows that of seven APL patients (from four different studies) treated with isotretinoin, four had what a review article termed "remarkable responses." Clearly; there's enougk evidence to warrant further research on both synthetic A and D.

FIGHTING WITH FOLATE
Leucovorin (loo-koh-VOR-rin) is a synthetic form of the B vitamin folate. It's being used in combination with a cancer drug called fluorouracil (floor-oh-YOOR-a-sill), commonly referred to as 5-FU. Right now 5-FU/leucovorin is in clinical trials against several types of cancer. Researchers hope that someday it may become a standard therapy.

By itself, 5-FU has been used against colon cancer for more than 30 years. It interferes with cancer growth by binding to an enzyme needed for cell reproduaion. (Some cancer cells reproduce much faster than normal cells. That's how some tumors grow in relation to surrounding tissue.) But 5-FU alone is only moderately effective.

Leucovorin, though, seems to strengthen the bond between 5-FU and the enzyme. The drug/vitamin combination holds onto the enzyme for a longer period than the drug alone. Fewer free enzymes mean slowed or stopped tumor growth.

5-FU/leucovorin has recently passed a series of clinical trials to determine its effectiveness against advanced, inoperable colon cancer. ln five out of seven studies, 5-FU/ leucovorin resulted in tumor shrinkage in two to three times as many patients as 5-FU. In two studies patients lived three to five months longer than patients on the standard treatment.

That may not seem like a giant leap forward, but it paves the way for studies in people with earlier (and more treatable) stages of colon cancer. "That's where we hope to have a real impact on the survival rates," says Susan G. Arbuck, M.D., a research clinician at Roswell Park Memorial Institute, in Buffalo, New York. Dr. Arbuck encourages patients who have surgery for colon cancer (and are at high risk for recurrence) to participate in the National Cancer Institute high-priority clinical trials for colon and reaal cancer.

5-FU/leucovorin is being tested against a variety of other malignancies, including cancers of the stomach, breast, pancreas, head and neck. To find out more about any of these clinical trials (including your eligibility if you've been diagnosed with cancer), call the National Cancer Institute hotline: (800) 4-CANCER.

COLORECTAL PROTECTORS?
Colorectal polyps are easy to remove but may recur. That prompted researchers at the Ludwig Institute for Cancer Research, in Toronto, to test the effect of vitamins C and E on polyp recurrence.

Two hundred people who were free of polyps after surgery were split into two groups. One was given daily supplements of 400 milligrams of vitamin C and 400 mg. of vitamin E. The other got blank look-alikes .

After about two years, all the patients were checked for polyp recurrence. The researchers noted a slight reduction in polyp recurrence among the patients receiving vitamins C and E. They stressed that further studies should be performed to rule out the possibility that this was a chance finding.

A further study is presently under way at six research centers in the United States. About 865 people are enrolled in the trial. The patients are split into four groups: The first gets supplements of vitamins C and E; the second group gets beta-carotene (the plant substance our bodies turn into vitamin A); the third gets C, E and beta-carotene; and the fourth group gets none of the above. Results from this trial are not expected for three years.

VITAMIN A FOR ORAL HEALTH
Two years ago, a report from the British Columbia Cancer Research Center, in Vancouver, announced that vitamin A could heal oral leukoplakias (precancerous sores inside the mouth). The study involved 21 people who chew a tobacco and betel-nut mixture known to cause an abundance of leukoplakias. After six months of taking vitamin A supplements, 57 percent of the people showed no detectable disease. And none of the tobacco/betel chewers developed new sores while on the vitamin A. Experts estimate that normally only 5 percent of such sores disappear on their own.

Now word comes from the University of California (Irvine) Clinical Cancer Center and the University of Arizona Cancer Center that a milder form of vitamin therapy has the same effect. Seventeen people with oral leukoplakias were given beta-carotene. Each person took 30 ma. of supplemental beta-carotene per day for three months. Those whose leukoplakias responded to the treatment were kept on it for an additional three months.

At the end of the study, two patients had complete remission of their leukoplakias, and 12 others had partial remissions. Of the remaining three, one shovved no change and the other two got worse. Overall, that's an 82 percent positive response rate.

The exciting aspect of this study is that beta-carotene, rhe safest source of vitamin A, was so effective. Pure vitamin A is toxic in high doses, and even the retinoids have unpleasant side effects (primarily skin problems). But beta-carotene is virtually problem-free, even in high doses. That's because the body converts only as much beta-carotene into vitamin A as is needed at the moment. The excess is excreted harmlessly.

WHAT THE GOOD NEWS MEANS
Vitamin chemotherapy is a seductive idea: The ultimate goal is an effective natural cancer treatment with no pain and minimal expense. But it's not quite that simple--yet.

Scientists are going full bore to see if any of these treatments will turn out to be effective. And even for the vitamins showing the greatest potential, questions of dosage and side effects must be resolved.

Note, too, that several of the vitamin therapies don't use pure vitamins. Leucovorin and Isotretinoin are synthetic chemical equivalents of folate and vitamin A, respectively. Slight alterations in their chemistry make them more efficient treatments and/or reduce dangerous side effects seen in high doses of the original vitamin. These synthetic vitamins are different enough to be treated as drugs by the Food and Drug Administration. They're available by prescription only.

Until scientists nail down the facts, the best course is to go with what we know. Opt for the proven medical treatments. Have suspected cancer checked by a physician. And try a good defense: There's good scientific evidence that a healthy diet can help prevent the start of certain types of cancer. To use this evidence to your fullest advantage, eat a well balanced, nutrient-dense diet that is low in fat. This includes low-fat meats and poultry, fish, whole-grain products,. and generous amounts of fresh fruits and vegetables. If you're on a restricted diet--or need added assurance that you're getting the Recommended Dietary Allowance for vitamins and minerals--you may want to consider taking a multiple supplement.

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By Steven Lally

VITAMINS VS. BLADDER CANCER: HOW TO BE A PART OF THE RESEARCH
Bladder polyps, which can become cancerous, are fairly easy to treat by surgical removal. But mere's a 70 percent risk of recurrence or that new polyps will form. To prevent that, researchers at Wed Virginia Uni" versity are testing megadoses of four vitamins as an adjunct to conventional therapy after bladder surgery.

Patients are being divided into two groups: People in one group take multiple vitamins at the recommended daily alowance levels; those in the omer group get the same, but with megadoses of vitamins A, B6, C and E. Vitamin B6 has been tested with good results in other preliminary bladder-cancer studies in humans. Vitamins A and C have been tried against bladder cancer in animal studies, will early encouraging re" sults. Vitamin E hasn't been tested specifically against bladder polyps before but has shown promise in other cancer tHals.

About 120 people are now enrolled in Ws WVU study. Preliminary resuHs are expected h be published in a year, according to Donald L. Lamm, M.D., professor and chairman of the department of urology at WVU. And it's not too late to join up. Patients around the country who will be undergoing polypremoval wrgery can get information about signing up by calling Dr. Lamm's office at (304) 293-2706.

OUR SOURCES
Daniel M. Albert M.D., director, David G. Cogan Eye Pathology Laboratory, and associate chief for academic affairs, Massachusetts Eye and Ear Infirmary, Harvard Medical School.

Susan G. Arbuck, M.D., cancer research clinician, Roswell Park Cancer Institute. Buffalo, N.Y, and assistant professor of medicine, SUNY at Buffalo;

E. Robert Greenberg, M.D., professor of community and family medicine and clinical medicine, Norris Cotton Cancer Center, Dartmouth--Hitchcock Medical Center, Hanouer, N.H.

Peter R. Holt, M.D., chief of gastroenterology at St. Luke's--Roosevelt Hospital Center (St. Luke's site), professor of medicine, College of Physicians and Surgeons, Columbia University, New York, N.Y.

Keith A. Hruska, M.D., Ira M. Lang professor of medicine and associate professor of cell biology, and physiology and chief of renal diuision, Jewish Hospital at Washington University Medical C.enter, .5t. Louis; H.

Phillip Koeffler, M.D., professor of medicine, University of California, Los Angeles.

Donald L. Lamm, M.D., professor and chairman of urology, West Virginia University, Morgantown.

Scott M. Lippman, M.D., assistant professor of medicine, hematologyloncology department, M.D. Anderson Cancer Center, University of Texas, Houston.

Gail E. McKeown-Eyssen, Ph.D., associate professor, preventive medicine and biostatistics, University of Toronto.

Frank L. Meyskens Jr., M.D., director, Clinical Cancer Center, University of California (Irvine).

Mukta M. Webber, Ph.D. professor of zoology and medicine, Michigan State University, East Lansing.

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