INNOVATIVE USES OF CONVENTIONAL CANCER TREATMENTS
Presenters: James Anthony Boyle, M.D., Glen Hyland, M.D., and Robert Nagourney, M.D.
Moderator: Robert Gerard, M.D.
Session: Su8; June 13, 1999| Conference Home Page | Presenter Bios | CMBM Home Page |
I. Abstract
As we approach the turn of the century, the search for cancer "penicillin" continues. While scientists vigorously look for a cure, the disease takes the life of millions each year. Standard treatments exist for each type of cancer, yet innovative uses of conventional treatments are the key to future advancements. Many clinical trials investigate the efficacy of such therapies, whether it is a new combination of compounds or a more efficient drug delivery mechanism. This session's presenters focused on cutting edge uses of standard cancer treatments, such as developing treatments based on the concept of cell death rather than the inhibition of cell growth and less toxic means of drug delivery throughout the body.
II. The Cancer-Related Issues Addressed
Tony Boyle, M.D., Ph.D., Internist and Endocrinologist and Senior Vice President of The Lisosome Co., began the session focusing on reduction of the toxic side effects of adriomycin via more efficient and safer delivery mechanism. Glen Hyland, M.D., Radiation Oncologist Clinical Associate Professor at the Medical University of Bismarck, ND discussed glyconutrients. Robert Nigourney, M.D., Medical and Laboratory Director of Rational Therapeutics, focused on topics in cancer research. He presented data from experiments conducted by Rational Therapeutics. Gabriel Feldman, M.D., Ph.D, Director of colon and prostate cancer at the American Cancer Society provided the concluding remarks. Robert Gerard, M.D., Center for Mind Body Medicine opened the session.
III. The Program Presented by Dr. Boyle A. Background
Adriamycin, or Doxorubicin, is an effective drug in the treatment of many types of cancer, such as leukemia and breast cancer. The anticancer activity arises from its ability to bind to nucleic acids and interfere with DNA synthesis. Unfortunately, there are some serious cardiac and gastrointestinal toxicities related to the drug. The heart damage often proves to be fatal for the patient and is cumulative. Adriamycin also causes severe tissue necrosis. It is administered intravenously and if any of the drug leaks out, serious tissue damage leading to ulceration may occur. In some cases the damage is so extensive that a patient can no longer move their arms and often are referred to a plastic surgeons for tissue repair. Many physicians continue to use Adriamycin despite the toxicities because it is one of the most effective treatments.
Thirty-five years ago a scientist in England mixed phospholipids with water and looked at them under polarizing light. Under higher magnification the strange structure appeared to be stratified layers of material. With the use of an electron microscope the strata were even more visible and resembled an onion-like structure. The structure was composed of many liposomes. Liposomes are formed by phospholipids. Phospholipids contain two parts, a fat-loving and a water-loving component. The fat, or lipid, portion seeks and binds to other fats and the water portion seeks and binds water molecules. The stratified layers of material are formed spontaneously by the physical and chemical attraction of fat-fat and water-water interactions.
B. Details
Dr. Boyle and his colleagues at The Liposome Company are working on ways to force Adriamycin into a liposome to make it a safer, yet as effective, drug. The phospholipids are put through filters, broken up and recollected. The procedure divides the liposomes into individual cell units, rendering them pharmaceutically useful. Adriamycin is then loaded into these "fatty bubbles." The drug is forced into the liposomes via a pH gradient and once inside, does not escape. Adriamycin, or Doxorubicin, exists in two forms. One form consists of many hydrogen ions but can be altered to a second, less acidic form with a carbonate buffer. The second form can then be forced into the liposome while the buffer remains outside. Inside the Doxorubicin-citrate compound is a hydrogen rich species. Dr. Boyle claims the entire procedure is about ninety percent efficient. Scientists can actually see the success of their efforts due to the characteristic pink color of Doxorubicin, which is visible inside the capsule. The compound forms different shapes and complexes inside the liposome. The Doxorubicin-citrate complex turns 60 degrees every 50 nanometers and forms bundles. The Liposome Company has named their product TLC-D99.
C. Research
Conclusive studies on Doxorubicin, or DOX, in liposomes have been conducted in both animals and humans. In animals there was a decrease in cardiotoxicity with DOX in liposomes. The drug also retained its anticancer activity. Dr. Boyle showed slides comparing animal tissue injected with unencapsulated DOX and capsulated DOX. The cells treated with unencapsulated DOX showed ulceration and tissue necrosis. The other tissue showed some redness but no ulceration. Slides of cardiac muscles of animals treated with TLC-D99 and ones with free DOX contrasted the abnormality between the test arms. The cardiac muscle of the heart injected with free DOX looked deformed and the fibers were not arranged in straight bundles. The heart injected with TLC-D99 looked normal.
Encapsulating the Doxorubicin alters the way the body sees the drug. Dr. Boyle presented slides showing reduced amounts of free Doxorubicin enter the heart and blood, thereby reducing cardiotoxicities. Twelve dogs, six receiving TLC-D99 and six receiving free DOX, were assessed for toxicity over a six month period. The TLC-D99 arm experienced less GI toxicity, cardiotoxicity and no hemorrhaging. Finally, a graph of DOX per gram of tumor was presented to assess amount of DOX uptake into tumor. The results again favored TLC-D99. In conclusion, animals injected with TLC-99 experienced less cardiac and GI side effects and less tissue damage. The antitumor activity proved to be comparable to that of free DOX.
The Liposome Company then advanced the study to patients. Three phase III randomized comparative studies in women with metastatic breast cancer were presented. The group assessed two primary endpoints. First, TLC-D99 produced less cardiotoxicites and reduced the risk of congestive heart failure and second, the antitumor activity was not inferior to that of free DOX. The first two studies compared TLC-D99 against Doxorubicin, both in combination with cyclophosphamide, another antitumor drug. Dr. Boyle presented the data using tables and Kaplan-Meyer plots, which showed highly significant differences between free DOX and the test agent. In both studies the number of patients with heart damage and heart failure in the TLC-D99 group were significantly less than those receiving free DOX. The response rates in both groups were identical and the survival was slightly better in the patients receiving TLC-D99. In combination with cyclophosphamide a decrease in grade four neutropenia, but an increased risk of hand-foot syndrome was also observed.
The third study compared TLC-D99 with Epirubicin, a compound similar to Doxorubicin used in Europe. Data of time to disease progression and time to treatment failure were significantly better for the TLC-D99 cohort. These patients also showed better duration of response.
In conclusion, TLC-D99 produced less cardiotoxic effects, less cases of stomatitis, mucositis and diarrhea than free doxorubicin. The antitumor effects of the test compound were equal to or greater than DOX. The Liposome Company's product being reviewed by the Food and Drug Administration.
III. The Program Presented by Dr. Hyland
A. Background
Dr. Hyland spoke on glyconutritional, vitanutritional and phytochemical agents. These include primarily eight monosaccharides. Other examples include dried fruits and vegetables, aloe vera extract and shark cartilage. Dr. Hyland is an internist who now practices radiation oncology. He emphasizes nutrition in his practice and refers all patients to the American Dietetic Association for consultation.
He presented five cases of patients he has evaluated over the past months. The patients began taking eight monosaccharides at various stages in their disease and all responded with clinical improvement. Dr. Hyland desires to further investigate the cases to determine if the results are "real" and if the compounds would stand up under testing in clinical trials. Dr. Hyland personally takes glyconutritional agents.
B. Mechanism of Action
The glycoproteins consist of eight monosaccharides with aloe extract in polyamines. Most people receive sugars as simple sugars such as glucose and fructose. Through enzymatic changes, the body can convert polysaccharides to monosaccharides. Eight monosaccharides form molecules with amino acids, thus becoming a glycoprotein. The complex forms cell surface receptors. The receptors are important means of communication in the body with compounds such as antibodies and hormones. This upregulation of cellular communication is especially important in abnormal cancer cells. Dr. Hyland did not further expand upon the biochemistry, nor mechanisms of action of the glycoproteins.
C. Research
There have been no clinical trials conducted to date on the efficacy of glycoproteins or phytonutrients in cancer patients. Dr. Hyland presented the five patient cases he has seen in his office, however he did not have any conclusive data or extensive research on the topic. After review of the cases, he proposed a double-blinded, randomized cross-over study to investigate the efficacy of glycoproteins to the Institutional Review Board (IRB). The IRB posed too many limitations on patient eligibility, and argued that it was too difficult to accrue patients to a study with a placebo arm. Furthermore, nutritional companies did not want to participate. They felt that if the trial succeeds, their nutritional agents would then be called drugs and that would result in new manufacturing regulations and marketing approaches.
One nutritional company did agree to administer a survey created by Dr. Hyland to assess clinical symptoms of those patients taking glycoproteins. The survey questioned 127 patients in three states from 1996-98. The patients were followed for 1-12 months, with a mean of 4-5 months. Many primary care physicians instructed their patients to discontinue use of glycoproteins and in the end, 100 responses were gathered. The questions addressed quality of life issues such as fatigue, appetite, level of physical activity, pain control and therapy tolerance. Dr. Hyland reported an 85% improvement in a majority of the categories for patients taking the supplements. The survey, however, was truncated and the results are inconclusive. Dr. Hyland looked to the audience for personal experiences with the agents or more information on the role of glycoproteins in cancer patients. He is also looking for any contact names listeners (or readers) might know.
III. The Program Presented by Dr. Nagourney
A. Background
Dr. Robert Nagourney, a medical oncologist-hematologist spoke on a few selected cancer topics. Dr. Nagourney is from Rational Therapeutics, a company that tests the sensitivity of an individual's cancer cells against a wide range of drugs. He claimed his company will cure and expand lives with their approaches. He is a proponent of keeping an open mind when one chooses a treatment. Dr. Nagourney first proposed the question, "What do cancer cells do that make them different?" Cancer is considered a disease that is a proliferation of cells that lost control. Cancer is actually a disease of cell death; the cells have forgotten how to die. Apoptosis, programmed cell death, is an important consideration in developing cancer therapies. Dr. Nagourney suggested designing drugs with the concept of cell death in mind. Cancer cells need to be stopped in their growing and commit suicide, so to speak. Rational Therapeutics uses cell death measures to discover new treatments. They expose extracted cancer cells in culture to a collection of drugs and examine the response.
Dr. Nagourney outlined a set of background principles to explain the rationale behind Rational Therapeutics developments. They support the innovative cell culture therapy over standard treatments. The biological principles include: the best active drugs induce cell death; the best model for human cancer is human cancer; cancer cells die "too little". The statistical principles include: many standard pharmaceutical trials are just a collection of statistically significant anecdotes; insignificant improvements in populations tend to obscure statistically significant improvements in sub-populations. The pharmacological principles are: more is not always better; new is not always better; drugs do not know what they were invented for and should not be limited to one type of disease; there are no good or bad chemotherapy drugs, rather patient variation determines efficacy. Rational Therapeutics operates following guidelines of simple solutions, individuality and "one size does not fit all". Dr. Nagourney's personal motto is, "whatever works, use it".
B. Research
Dr. Nagourney presented 1556 published peer reviewed clinical correlations to date. Tissue samples from 1556 patients were treated with a spectrum of drugs and studied in culture. Seventy two percent were drug sensitive and 91 percent were drug specific. Dr. Nagourney then discussed a study of children with leukemia treated with dexamethasone. The children's cancer cells were tested for drug sensitivity at the beginning of treatment and the patients were followed for 15 years. The children whose cells proved to be drug sensitive survived, while most of the children whose cells were resistant had died. The results were statistically significant, with a p-value for response rate equal to 0.007.
One study of 24 ovarian cancer patients treated with cisplatin and gemcitabine, showed 29% of women with a complete response and 21% showed partial response. Cell samples of the patients were collected and tested in culture prior to treatment. The lab sensitivity and resistivity profiles correlated with the outcomes in all cases. The same drug combination was used in a phase II breast cancer study population of 30 women. The results were as follows: 3/30 showed complete response; 12/30 showed partial response; 11/30 had stable disease. Again, the lab sensitivity profiles correlated with the clinical outcomes.
Dr. Nagourney closed with a brief list of a few novel therapies he foresees as future promises. Betulin or betulinic acid is an extract from the white birch bark tree and a member of the terpine family. It is a non-toxic substance that is thought to induce apoptosis. It has shown activity against lymphoma and other cancers. Limonene, extract from lime, lemon or orange peels, is also a non-toxic member of the terpine family. Limonene is combined with a second compound known to down-regulate ras oncogene activity. Garlic contains an active compound called allicin. Research on its efficacy has been published in 1300 papers. Dr. Nigourney plans to test garlic extract as an antitumor agent in vitro.
Dr. Nagourney believes that the success of future advancements depends on applying all available resources and evaluating patient distribution and individualization. Patients and practitioners alike should think globally in the search to find the most effective way to get specific tumors to undergo apoptosis.
IV. Comments
In closing, Dr. Feldman commented on a few of the major therapies presented. He felt that the liposomal based therapy "looks promising" and has been used previously in tuberculosis trials; Although encapsulated, Adriamyocin remains an extremely toxic drug. Glycoproteins, or simple sugars, should be used in combination with chemotherapy or radiation in patients with favorable prognoses or, for extremely sick patients who may show faster results. However, there are no prospective trials going on currently and glycoproteins are sold over the counter. Dr. Feldman stressed that, at best, glycoproteins might be a helpful addition. Individualization of patient care, the ultimate goal of Rational Therapeutics, is a practical, yet unrealistic idea. Doctors, nurses and health care professionals have limited time for each patient, which is one reason people turn to alternative medicine. Randomized trials, Dr. Feldman stressed, remain a promising area of treatment options. Dr. Feldman also stressed the importance of learning as much as one can about the disease and which treatment works best for ‘me.’ Patients and families heed caution and be selective of the wealth of information on cancer topics available today.
V. Audience Questions
(Directed to Dr. Nigourney, regarding his program,) Does a patient have to have fresh tumor to participate in your program?
Dr. Nigourney: Yes, if the cells are not alive, they can not be killed for study. The drugs are used as probes to determine what the cancer cells do or do not respond to.
Clinical trials are important but they take a long time, what other forms of inquiry or methodology are there, how does one expand the level of inquiry?
Dr. Nigourney: Alternatives and supplements are a good start. Clinical trials are crude.
Dr. Feldman: All clinical trials are not superb, however scientists and doctors need evidence and the only way to test conventional (proven) treatments against non-conventional is with trials. The studies are need to find cures otherwise we have questions without answers. Trials are better than any other means to get data and answers so do not give up.
Audience comment: Double-blinded randomized clinical trials are a gold standard. There are not enough people enrolling currently in clinical trials and without people we can not find data on survival. Nutritional studies are another issue because there is no control group and there is not enough money in the field.
(Directed to Dr. Nigourney) What is the cost of your treatment? What does the patient tell the surgeon before extracting cells?
A formal analysis costs $2500. There are funds available for patients who can not afford the procedure. The tissue must be fresh and shipped overnight to the company.
VI. Resources
The American Cancer Society
http://www.cancer.orgThe Liposome Company Inc.
http://www.lipo.comRational Therapeutics
http://www.rational-t.comThe Center for Mind-Body Medicine
http://www.cmbm.org/ or (202)966-7338