International Symposium on Nutrition in Cancer
Report on International Symposium on Nutrition in Cancer, sponsored by Cancer Treatment Research Foundation; NOAT, Society for Nutritional Oncology Adjuvant Therapy; UCLA Center for Human Nutrition; Division of Nutrition, Harvard Medical School; Bristol-Myers Squibb
This meeting was attended by oncologists, nutritionists, dietitians, researchers in these field and by me as patient/activist. The following is from the statement of purpose: “The link between cancer and nutrition has generated increased interest and support from the medical scientific community… Scientists now estimate that 40-60% of cancers are directly related to our dietary choices. Nutritional Oncology is a new field that will develop evidence on the role of nutrition in preventing cancer and improving the quality of life, and will continue to develop scientific approaches to the treatment of malnutrition which often accompanies cancer.”
I. Donald Nixon, M.D.Director of Cancer Prevention and Control, spoke about the research being done at the Hollings Cancer Center, Medical University of South Carolina, Charleston, S.C. They are currently running a Phase I trial for elegiac acid(from raspberries) as a preventive for colon cancer, with encouraging results. Using many objective measurements researchers were able to detect responses in vitro. The hypothesis presented suggests that this natural substance is acting on the P53 pathways(a gene substance present in many cancers). It is believed that their laboratory(in conjunction with the Agriculture Department)can develop a super-potent raspberry which can be used to arrest growth and restore cell differentiation in cervical, prostate, colon, pancreatic and breast cells. Dr. Nixon presented a paper in which he stated “Emerging knowledge about the relationships between diet, nutrition and cancer has generated new clinical trials targeted at specific cancers earlier in the course of disease.” Examples include restriction of nutrients such as fat; addition of ingredients including fiber, vitamins and trace minerals. He also mentioned numerous non-nutrient phytochemicals showing tumor suppressive or host supportive mechanisms. In breast cancer trials, “cost and duration are reduced by using the… known relapse rate of breast cancer over time as a surrogate marker.”
II. Ernst Wynder. M.D., President of the American Health Foundation spoke about the need to educate Americans on reducing fat and increasing fiber. This organization is conducting an intervention studies on postmenopausal women and fat/dietary habits. WIN, Women’s Intervention on Nutrition.
There are 33 centers participating but very few oncologists have any
understanding of the importance of nutrition. “We must look to a day when nutrition will be a treatment for many disease, we have as least as good an answer as many of the therapies conducted today.” Dr. Wynder was the researcher who first made the connection between smoking and lung cancer. He suggests that our best weapon against breast cancer will come when we develop a biomarker for breast cancer, thus allowing truly early detection.
III. David Heber, M.D., PhD. Director of the UCLA Center for Human Nutrition discussed how to get oncologists to pay attention to nutrition. He runs a center which is somewhat unique. They offer training and information to the medical profession, nutritional research, education for public health and international nutritional issues as well as clinical programs for the consumer. He suggested that public health interventions have always played a major role in reducing disease. A specific example was the fact that antibiotics helped but the biggest reduction came when the water system was separated from sewage. He also mentioned that Americans now get less heart disease and at later ages, due to nutritional and lifestyle changes.
One recent result of their research has been the locating of a gene that allows the protective value of broccoli to be utilized in the body.
Those without this gene apparently do not benefit from broccoli(whose active ingredient is suspected to be indole carbinol-3. But as Dr. Heber reminded the audience, in order for the gene to work, one must eat broccoli.
Ever since the multi-stage model of colon cancer was mapped showing the progression of abnormal tissue to carcinogenic tissue, it has been used for epithelial cancers (breast is one). The point is that scientists now know that many years exist between initiation and actual malignancy. It is believed that nutritional intervention (chemo prevention) may be able to affect this progression.
Studies in California have shown that only 10% of the population meet the goal to eat 5 portions of vegetables and fruit a day. 20% eat NO fruit or veggies. The UCLA Center for Human Nutrition has developed the California Cuisine Food Pyramid. It includes fat content at 20%. Soy was
discussed as a complete protein source. Fish was recommended above meat or chicken.
Dr. Heber suggested that genestein (active ingredient in soy)is a weak binder for estrogen and may occupy receptor sites in the breast, somewhat like tamoxifen. There are many active substances in soy such as daidzein, daidzin, glycitein, gycitin, genestin, etc. Therefore, eating whole food soy products may be more beneficial than a single active substance product.
IV. Judah Folkman, M.D., Children’s Hospital, Boston, MA. spoke eloquently about his work on angiogenesis (blood vessels to a tumor). This presentation was also given, in part, at the Era of Hope conference for DoD participants as well.
Angiogenesis has been studied for over 30 years. They have identified over 14 angiogenic proteins. Most human cancers seem to use this group of proteins. There are 8 factors than can stimulate new blood vessel growth in breast cancer tumors. Ten years ago they identified the first molecule that could turn off angiogenesis or at least slow the growth. They observed that there was NO drug resistance and this has held true. Four years ago they found proteins in the body that turn off angiogenesis completely. These have now been isolated and are being tested as therapy (at least in animal studies).
10-20% of tumor cells seem to be responsible for ‘recruiting’ blood vessels. By the time a tumor is found by mammography, it has already developed its blood supply system. Earlier detection is obviously an advantage here. IL-6 has been identified as a paracrine factor, it stimulates tumor cells to travel.
Angiostatin and Endostatin are two compounds that have been shown to inhibit capillary endothelial proliferation. In other words, they are specifically able to stop blood vessel development to breast tissue tumors.
Folkman then discussed the fact that certain tumors, when removed, are followed by ‘explosive’ spread of disease. This is true mostly with sarcoma(breast cancer is adenocarcinoma), particularly lung. Such a factor leads to theories of concomitant immunity, resistance and idiopathic resistance. This needs to be further explored.
He then made some rather startling statements about research publication parameters. He was discussing the results of their latest animal studies and showing the phenomenal response of the laboratory mice. When using chemotherapy, drug resistance usually develops and the larger the tumor, the faster it can develop. Using angiostatin or endostatin, they have not found any type of tumor they could not regress. Since there is no drug resistance, nor dosage intolerance, they can increase it where necessary. The mice were treated for 190 days in an on/off pattern (called pulsing). After the initial treatment period, the tumors did not return. The researchers did not know why this happened. They were uncomfortable about publishing these results since the hypthesis was exceeded. Apparently it is not only negative results which are withheld from publication (publication bias), it can also be exceedingly positive results as well. Luckily in this case, the laboratory decided to submit their article for publication and it has been accepted by Nature.
Dr. Folkman believes that angiostatin and endostatin will become first line cancer drugs in the future. Pharmaceutical labs are slow to make the antiangiogenesis proteins. Right now it is created in his laboratory and takes overnight to accomplish. His current thinking is that human subjects may be treated for a year with dormancy or even a “cure” as a result.
In 1994 studies with angiostatin were done in humans showing an 87% inhibition response. In 1995, a 99% rate was shown in mice and a 1996 mouse study with endostatin also produced a 99% inhibition. He discussed a patient who has taken angiostatin for cervical cancer with mets to the lung. She took the therapy much longer than it was originally intended for-February 1995 to January 1997(an extra year). She is now off and has no tumor. She is only one patient, but she was the first to use the drug! Folkman suggested that there is a toxic dose, but he did not discuss the level. He did say that a patient could retreat off of the toxic level with no permanent effect. He said it may be used as a new ovarian therapy.
Leukemia is also angiogenesis dependent and may therefore be treated with the products.
Folkman then said that they are now doing dog studies using animals from a hospital in Boston. Most of the dogs have metastatic disease and their owners have given up on their recovery. They therefore created ‘canine’ angiostatin and endostatin. The dogs cannot easily tolerate chemotherapy so have not been treated with any cytoxic drugs.
They have also begun treating pet rats and as a consequence have been able to determine that naturally occurring tumors are even more responsive to treatment than tumors induced in laboratory-bred rodents.
Lastly, Folkman said that genestein at low levels taken over a long time can also induce anti-angiogenetic changes.
V. Peter Greenwald, M.D., Dr. PH. Division of Cancer Prevention, NCI,NIH was the recipient of a public service aware by NOAT. He began his presentation by a discussion of twin studies and cancer. Dr. Greenwald compared the rate of breast cancer in the United States and Japan in a novel way. He said that if the U.S. had the same incidence rate as Japan, 14,000 women would die of breast cancer this year(as opposed to the 46,000+ estimated). He further said that if we had the same rate as Japan had in the 1950’s, deaths would have numbered around 8,000. Unfortunately, this shows that our rates and theirs are both increasing. He then spoke about many types of cancers and the interventions being studied. For colon cancer, which is connected to breast cancer in many ways, a diet high in fiber and low in fat, and filled with fruits and vegetables is recommended. He mentioned a study being done in Kansas using nipple aspiration to check the effect of dietary changes after biomarkers for breast changes have been found. Dr. Greenwald suggested that the disease we need to fight is carcinogenesis since it may be more easily prevented and certainly should be detected in the decades-long stages before cancer occurs.
He discussed bio-engineered foods and suggested that many products will soon be available. Calling this process an inevitable trend, he pointed to the tomato that had a gene put in backward(anti-sense) which allowed the fruit to stay ripe without softening as soon.
Dr. Greenwald has often argued for a need to build cancer prevention into the mainstream of major research institutions.
VI. Steve Clinton, M.D., Ph.D., Dana Farber Cancer Institute spoke about the efforts to integrate molecular and cell biology with the discipline of nutrition and cancer. There has been a separation in educational institutions which has left biochemists, epidemiologists, chemists, physicists and other researchers too far apart. He discussed the burden of “grantsmanship”-having to incorporate the currently “happening” research area into one’s own in order to get funding. He suggested that funding should be based on a sound rationale, a novel hypothesis and good scientific tools only.
Dr. Clinton discussed an often-heard theme of cancer heterogenicity. In other words, a family of diseases we have agreed to call breast cancer. He pointed to metastatic presentation, local disease, very slow spread time and other factors. Mentioning the fact that leukemia is now understood to be chronic or acute with many subdivisions in each category. He mentioned a form of leukemia that has a 20-30% survival with chemotherapy but has yielded to retinoic acid (Vitamin A) therapy. This substance somehow allows the cells to develop normally. This treatment was applied after discovery that there were cellular changes in the retinoid receptors (with this disease). It is certainly possible that molecular defects may be identified in other cancers and may yield to nutritional interventions as well.
He reminded the audience that over 100 single genes that involve cancer have been identified and 17 have been cloned. Studies with high-risk populations may yield strong benefits since the group is more motivated, more willing to follow dietary rules, etc. We need biomarkers and some surrogate endpoints for nutritional intervention studies, i.e. dietary and nutritional footprints like changes in target tissue receptors, changes in serum modulator, etc.
In animal studies, energy(calorie) restriction has been shown to greatly increase apoptosis (cell death) and decrease micro-vessel density.
Dr. Clinton stated that while understanding mechanisms yield great intellectual satisfaction, it is not necessary in order to establish effective recommendations for cancer prevention. He suggested that researchers look to the time between a (needle)biopsy and full surgery to devise important studies on nutritional intervention. He mentioned prostate patients who often have a gap of 4-6 weeks prior to surgery. At that juncture, new needle biopsies could compare for changes from such nutritional interventions.
VII. Sue Ingles, Ph.D., Norris Comprehensive Cancer Center, USC, Los Angeles, CA. spoke about molecular epidemiology and genetic susceptibility studies using biomarkers of exposure. She suggested that genetic susceptibility offered low to moderate relative risk with a potentially high ability to intervene. She spoke about a Vitamin D study that had shown a ecologic association between breast cancer and sunlight exposure. Deltoids(Vitamin D) induces regression of breast cancer in rat model according to a 1992 study by Colson. A study by Anzano in 1994 showed that deltoids could prevent breast cancer induction in rat models. P21, a cell cycle inhibitor is responsive to this vitamin. Interestingly, it has been found that the genetic marker conveys protection against breast cancer but may provide a higher risk of prostate cancer.
VII. Maret Traber, Ph.D., University of California at Berkeley, Berkeley, CA. spoke about oxidant stress and host oxidant defense mechanisms. (She took a lot of teasing about “free radicals” at Berkeley). Free radical damage is thought to be involved in initiation and promotion of cancer. They tend to react very rapidly with other molecules. This is mostly kept to a minimum due to the high efficiency of enzyme mediated electron transfers. Free radicals cause protein and DNA damage and can even directly damage membranes through a process known as lipid peroxidation.
Dr. Traber is an expert on Vitamin E and spoke about the 8 naturally occurring types. She recommended d-alpha tocopherol acetate and not synthetic dl. She firmly stated that anti-oxidants during radiation treatment can only be helpful. They may enhance the immune system without interfering and help protect the up to 20% of patients who develop sarcomas as a result of radiation. The only caveat to Vitamin E usage was that the succinate** and acetate forms of the vitamin may be cancer promoting in the presence of UVB rays. Most people absorb 40-50% of the vitamin through food.
VIII. David Kritchevsky,Ph.D., WISTAR Institute, Philadelphia, PA. spoke about the fundamentals of (good)nutrition. He said water is important to our health. He strongly stated that a high fiber diet is NOT achieved by adding fiber to a low fiber diet. One has to eat whole grain products, fruits and vegetables regularly. Fiber is a combination of cellulose, plant sterols, bran, gums, legumes etc. He said that dietary fiber may reduce circulating estrogen, and wheat bran may do it best.
Corn oil contains linoleic acid which is a growth factor for tumors.
In rat studies, those fed twice as much fat but on calorie restricted diets had fewer and smaller tumors. When more fat was added, each group had larger tumors. A question from the floor raised the issue of rats who continue to grow during most of their life span and may therefore be compared best to children and adolescents.
One of the biggest changes world-wide has been the sedentary nature of our lifestyles. People eat as much but do less physical exercise. Still, all disease since 1950 have shown a mortality rate decrease (including some types of cancers). But cancer deaths in general are up 6%, with lung cancer leading the way. Deaths by heart disease, by contrast, have decreased by 53%.
IX. Diane F. Birt, Ph.D., Iowa State University, Ames, IA discussed the comparison between rats fed freely and continuously versus those on restricted diets. Energy restricted animals are found to be more active. This study is looking at epithelial cancers using skin cancer but may be applicable to breast, prostate and colon. It was found that corticosteroids from the adrenal gland seemed to affect the number of tumors. When the adrenal gland was removed, there were more tumors.
X. Kent Erickson, Ph.D., University of California, Davis, Davis, CA. discussed invasion and metastatic biology. Despite all advances in chemotherapy adjuvant treatment, etc. most patients die from metastatic disease. Single cells leave the primary tumor to colonize new sites. This is a powerful cell since it evades many defense mechanisms. Angiogenesis is important in this process. Then a secondary tumor is formed. Lamin receptors are found on metastatic cells that allow it to bind to other cell locations(adhesion). Many different molecules are involved in cellular adhesion-enzymes for extra-cellular matrix degeneration, metalloproteinase, etc.
Tumor cells set themselves up to block the effects of cytolytic T-cells ability to kill targets. Is the immune system blocked? If the T-cell binds to a tumor cell, it may enhance its ability within the immune system.
Where a tumor cell goes is not necessary to the first capillary bed. It is usually through the lymph node to the lung or liver. A glycoprotein CD44 gene is expressed on the surface and is a homing device for the lymph node.
In a study of rats to determine if dietary fat effected metastases, it was found that it did not. It is possible that prostaglandins in linoleic acid enhanced metastatic mammary tumor cells but they did not affect primary tumorgenesis. It seems there is a needed threshold for metastatic events. It may be possible to find the specific receptors on cells that lead to specific sites.
Mice fed safflower oil had faster tumor growth than those fed with fish oil. The rats that got EPA/DHA had one half the metastatic results as the other rats. Additionally, there was four-fold less tumor vasculization found within the fish oil group.
Other findings showed that an increased production of cholesterol may enhance metastatic progression.
XI. Edward Giovannucci, M.D.Harvard Medical School, Boston, MA. said that epidemiological evidence about a relationship between fat and breast cancer is still unproven. Post-menopausal weight gain has been linked to an increase in breast cancer. However, the Nurses study while providing an association between animal fat and colon cancer, has not done so with breast cancer. There is a stronger association between dairy products and prostate and breast cancer than for animal fat.
A recent study(unpublished) on dietary supplementation with calcium has raised the risk of increased prostate cancer and the same may be true for breast cancer. A statement from the audience suggested that calcium always needs magnesium for proper absorption.
A study of tomatoes and prostate cancer has shown an association with risk reduction. Cooked tomatoes seem to be best (tomato sauce is recommended).
In the Nurses study, vitamin use seemed to reduce the risk colon cancer but took a full fifteen years to demonstrate.
Dr. Giovannucci finished his remarks by stating that selenium was recommended because many studies have shown a 50% cancer risk reduction with its use.
XII. David Albers, M.D., Arizona Cancer Center, Tucson, AZ. speaking about colon cancer said that 25% is family risk-related. It is known that males in Shanghai, China have the same colon cancer risk as U.S. males but incidence is much lower in China. A similar study was done in Nigeria and in the Japanese-American population in Hawaii.
Dr. Albers also mentioned that when cooking meat (including chicken and fish) over a barbecue or grill, there is an increased risk of creating carcinogens. He recommended microwaving for 3 minutes, then grilling or barbecuing.
XIII. Rachel Ballard-Barbash, M.D., MPH, National Cancer Institute, NIH, Bethesda, MD suggested that heavier women with breast cancer show shorter times to or are more likely to recur. Conversely, studies show a decreased risk of lung cancer for with more body fat. Additionally, she noted that weight cycling has not been studied relative to cancer outcome.
Dr. Ballard spoke about studies indicate that pre-menopausal women who are tall and lean are at a higher risk for breast cancer, but have no worse prognosis. She suggested that thin women with late stage disease whether ER+/- or PR+/- may have worse prognosis than other women. Conversely heavier post-menopausal women have increased risk. And heavier women with family history may be at the highest risk. Weight if located in the central part of the (around the waist and stomach) seems to put post-menopausal women at greater risk. Fat distribution may play a role in risk of ovarian cancer as well. There is no data to date concerning diabetes and breast cancer, a concern since insulin and IGF (insulin growth factor) increase the risk of malignant breast cells.
XIV. Stephen Hustings, PhD, MPH, UT, MD Anderson Cancer Center, Houston, TX stated that DHEA and its analog (8453?) cut cancer incidence in P53 mice by 50% or more(lymphoma and sarcoma). Caloric restriction showed increased survival and decreased proliferation. DHEA increased survival, decreased proliferation and increased apoptosis. The next studies will be on Wrt-1 transgenic mice which develop mammary tumors.
XV. Mathhew Longnecker, MD, ScD discussed alcohol and cancer raising the question of whether dose patterns of consumption influence the risk of breast cancer. There is some evidence that a decrease in consumption may decrease risk of breast cancer.
XVI. Gary Kelloff, PhD, National Cancer Institute, NIH, Rockville, MD is the head of the Chemoprevention Department. This is the area that studies the inhibition or reversal of carcinogenesis by intervention with chemical agents (either synthetic drugs or chemical entities in the food chain ). To
develop these substances, they look at mechanistic studies, enzyme structure analysis, animal studies, drug developers in other areas and epidemiological studies. As soon as they can identify the earliest stages of carcinogenesis, A short intervention may be able to be used to slow mutagens or speed up apoptosis (cell death).
Several populations have been identified for study with these substances, including general population, high risk population, subjects with pre-cancerous conditions, patients who have been previously treated and cancer patients.
Substances currently under investigation include: curcumin, Fluasterone, indole-carbinol 3(cruciferous vegetables), isoflavones(soy), peryll alcohol(lavender), SERM, sulindac sulfone, limonene(citrus fruits family), selenomethione/E, aromatase inhibitors, DHEA, Vitamin D analog(deltoids) NAC & DFMO(anti-proliferative agents)and 4 HPR +oltipraz(an enhancing agent).
XVII. Carolyn Clifford, PhD, National Cancer Institute, NIH, Rockville,MD. discussed the methodology of conducting food-based epidemiological research. In contrast to other opinions ,she expressed great concern about the changes to come in bio-engineering the food supply.
XVIII. James F. Holland, MD, Mount Sinai Medical Center, NY, Professor of Neoplastic Diseases defined the stages of breast cancer as curable, sub-curable requiring two modalities, pre-curable(unknown treatment will work) and metastatic. He suggests that all than can be done for women with mets is to help with quality of life, freedom from pain, dysfunction and anxiety of depression. In discussing the side effects of current treatment, he suggested that all or any can lead to malaise, diabetes and abnormalities of taste. His suggestions for nutritional intervention included: encouragement(coaching, cutting-up food) and dietary supplements which don’t require extensive chewing(but should not substitute for food).
He spoke of the dangers of total parental nutrition (tube feeding) from contamination, vomiting, pneumonia, diarrhea and the risk of bacterial or viral infection. He suggested pear nectar as a good drink in these situations!
Dr. Holland told the audience that he believes that chemotherapy alone is not enough for metastatic disease but he forsees treatment that works directly on anti-body receptors.
XIX. Abby Bloch, PhD, RD, Memorial Sloan-Kettering Cancer Ctr, NY offered a method for nutritional assessment of the cancer patient as follows:
Check out reasons for diminished intake-pain, swallowing difficulties, effort to consume food, difficulty with process of eating, ability to position self, anxiety, depression and drug response. She mentioned cannabinoids (Marinol ), Decadron, Benadryl, Kyrol, Reglan, Zofran and Compazine.
XX. Judith Ashley, PhD, RD, UCLA Center for Human Nutrition spoke about the new RDA to be called Dietary Reference Intake(DRI). The emphasis is on change in the risk of chronic disease. She indicated that 50% of all Americans consumed supplements in 1994. It is likely that a high degree of cancer patients are among those people. The supplement market is $6.5 billion. UCLA actually has a researcher Dr. Huey(sp??) who is looking into herbal interactions. She mentioned Astralagus, echinacea, cat’s claw, Essiac, Hoxsey, Mistletoe, Kombucha, Laetrile, milk thistle, Pau d’arco, Pycnogenol, and shitake mushrooms.
Also discussed was the trends in food science-possibly manufacturing to healthy specifications; true food component knowledge; agricultural developments and a world-wide sharing of resources.
XXI. Richard Rivlin, MD, Memorial Sloan-Kettering, NY spoke about Phytochemical and Cancer Prevention and discussed current research at Sloan. Their team is looking at isoflavones (legumes, beans, peanuts) to block estrogen receptors and inactivate oncogenes; garlic to conjugate carcinogens, retard tumorgenesis (many other healthy properties) ; lignans(flax seeds); indoles which inactivate estrogen and blunt promotion of breast cancer; terpenes(citrus fruits) to stimulate enzymes to block the action of carcinogens and polyactylenes (parsley) to block prostaglandin in biosysnthesis.
Dr. Rivlin reminded the audience that a second malignancy is always possible especially with cases of breast cancer. He suggested chemoprevention (the above-mentioned products) to prevent onset or slow or prevent growth or minimize toxicity. He mentioned a study in England that showed that dietary and supplemental garlic reduced the incidence of prostate cancer. Certainly many in-vitro studies using breast cell lines have show inhibition with aged garlic extracts or SAC and SAMC (garlic elements). These products work even in cells which have lost sensitivity to estrogen(ER-).
**The 2000 NOAT conference had a talk on Vitamin E succinate and its value in helping potentiate radiation therapy while protecting normal cells.
This meeting was attended by oncologists, nutritionists, dietitians, researchers in these field and by me as patient/activist. The following is from the statement of purpose: “The link between cancer and nutrition has generated increased interest and support from the medical scientific community… Scientists now estimate that 40-60% of cancers are directly related to our dietary choices. Nutritional Oncology is a new field that will develop evidence on the role of nutrition in preventing cancer and improving the quality of life, and will continue to develop scientific approaches to the treatment of malnutrition which often accompanies cancer.”
I. Donald Nixon, M.D.Director of Cancer Prevention and Control, spoke about the research being done at the Hollings Cancer Center, Medical University of South Carolina, Charleston, S.C. They are currently running a Phase I trial for elegiac acid(from raspberries) as a preventive for colon cancer, with encouraging results. Using many objective measurements researchers were able to detect responses in vitro. The hypothesis presented suggests that this natural substance is acting on the P53 pathways(a gene substance present in many cancers). It is believed that their laboratory(in conjunction with the Agriculture Department)can develop a super-potent raspberry which can be used to arrest growth and restore cell differentiation in cervical, prostate, colon, pancreatic and breast cells. Dr. Nixon presented a paper in which he stated “Emerging knowledge about the relationships between diet, nutrition and cancer has generated new clinical trials targeted at specific cancers earlier in the course of disease.” Examples include restriction of nutrients such as fat; addition of ingredients including fiber, vitamins and trace minerals. He also mentioned numerous non-nutrient phytochemicals showing tumor suppressive or host supportive mechanisms. In breast cancer trials, “cost and duration are reduced by using the… known relapse rate of breast cancer over time as a surrogate marker.”
II. Ernst Wynder. M.D., President of the American Health Foundation spoke about the need to educate Americans on reducing fat and increasing fiber. This organization is conducting an intervention studies on postmenopausal women and fat/dietary habits. WIN, Women’s Intervention on Nutrition.
There are 33 centers participating but very few oncologists have any
understanding of the importance of nutrition. “We must look to a day when nutrition will be a treatment for many disease, we have as least as good an answer as many of the therapies conducted today.” Dr. Wynder was the researcher who first made the connection between smoking and lung cancer. He suggests that our best weapon against breast cancer will come when we develop a biomarker for breast cancer, thus allowing truly early detection.
III. David Heber, M.D., PhD. Director of the UCLA Center for Human Nutrition discussed how to get oncologists to pay attention to nutrition. He runs a center which is somewhat unique. They offer training and information to the medical profession, nutritional research, education for public health and international nutritional issues as well as clinical programs for the consumer. He suggested that public health interventions have always played a major role in reducing disease. A specific example was the fact that antibiotics helped but the biggest reduction came when the water system was separated from sewage. He also mentioned that Americans now get less heart disease and at later ages, due to nutritional and lifestyle changes.
One recent result of their research has been the locating of a gene that allows the protective value of broccoli to be utilized in the body.
Those without this gene apparently do not benefit from broccoli(whose active ingredient is suspected to be indole carbinol-3. But as Dr. Heber reminded the audience, in order for the gene to work, one must eat broccoli.
Ever since the multi-stage model of colon cancer was mapped showing the progression of abnormal tissue to carcinogenic tissue, it has been used for epithelial cancers (breast is one). The point is that scientists now know that many years exist between initiation and actual malignancy. It is believed that nutritional intervention (chemo prevention) may be able to affect this progression.
Studies in California have shown that only 10% of the population meet the goal to eat 5 portions of vegetables and fruit a day. 20% eat NO fruit or veggies. The UCLA Center for Human Nutrition has developed the California Cuisine Food Pyramid. It includes fat content at 20%. Soy was
discussed as a complete protein source. Fish was recommended above meat or chicken.
Dr. Heber suggested that genestein (active ingredient in soy)is a weak binder for estrogen and may occupy receptor sites in the breast, somewhat like tamoxifen. There are many active substances in soy such as daidzein, daidzin, glycitein, gycitin, genestin, etc. Therefore, eating whole food soy products may be more beneficial than a single active substance product.
IV. Judah Folkman, M.D., Children’s Hospital, Boston, MA. spoke eloquently about his work on angiogenesis (blood vessels to a tumor). This presentation was also given, in part, at the Era of Hope conference for DoD participants as well.
Angiogenesis has been studied for over 30 years. They have identified over 14 angiogenic proteins. Most human cancers seem to use this group of proteins. There are 8 factors than can stimulate new blood vessel growth in breast cancer tumors. Ten years ago they identified the first molecule that could turn off angiogenesis or at least slow the growth. They observed that there was NO drug resistance and this has held true. Four years ago they found proteins in the body that turn off angiogenesis completely. These have now been isolated and are being tested as therapy (at least in animal studies).
10-20% of tumor cells seem to be responsible for ‘recruiting’ blood vessels. By the time a tumor is found by mammography, it has already developed its blood supply system. Earlier detection is obviously an advantage here. IL-6 has been identified as a paracrine factor, it stimulates tumor cells to travel.
Angiostatin and Endostatin are two compounds that have been shown to inhibit capillary endothelial proliferation. In other words, they are specifically able to stop blood vessel development to breast tissue tumors.
Folkman then discussed the fact that certain tumors, when removed, are followed by ‘explosive’ spread of disease. This is true mostly with sarcoma(breast cancer is adenocarcinoma), particularly lung. Such a factor leads to theories of concomitant immunity, resistance and idiopathic resistance. This needs to be further explored.
He then made some rather startling statements about research publication parameters. He was discussing the results of their latest animal studies and showing the phenomenal response of the laboratory mice. When using chemotherapy, drug resistance usually develops and the larger the tumor, the faster it can develop. Using angiostatin or endostatin, they have not found any type of tumor they could not regress. Since there is no drug resistance, nor dosage intolerance, they can increase it where necessary. The mice were treated for 190 days in an on/off pattern (called pulsing). After the initial treatment period, the tumors did not return. The researchers did not know why this happened. They were uncomfortable about publishing these results since the hypthesis was exceeded. Apparently it is not only negative results which are withheld from publication (publication bias), it can also be exceedingly positive results as well. Luckily in this case, the laboratory decided to submit their article for publication and it has been accepted by Nature.
Dr. Folkman believes that angiostatin and endostatin will become first line cancer drugs in the future. Pharmaceutical labs are slow to make the antiangiogenesis proteins. Right now it is created in his laboratory and takes overnight to accomplish. His current thinking is that human subjects may be treated for a year with dormancy or even a “cure” as a result.
In 1994 studies with angiostatin were done in humans showing an 87% inhibition response. In 1995, a 99% rate was shown in mice and a 1996 mouse study with endostatin also produced a 99% inhibition. He discussed a patient who has taken angiostatin for cervical cancer with mets to the lung. She took the therapy much longer than it was originally intended for-February 1995 to January 1997(an extra year). She is now off and has no tumor. She is only one patient, but she was the first to use the drug! Folkman suggested that there is a toxic dose, but he did not discuss the level. He did say that a patient could retreat off of the toxic level with no permanent effect. He said it may be used as a new ovarian therapy.
Leukemia is also angiogenesis dependent and may therefore be treated with the products.
Folkman then said that they are now doing dog studies using animals from a hospital in Boston. Most of the dogs have metastatic disease and their owners have given up on their recovery. They therefore created ‘canine’ angiostatin and endostatin. The dogs cannot easily tolerate chemotherapy so have not been treated with any cytoxic drugs.
They have also begun treating pet rats and as a consequence have been able to determine that naturally occurring tumors are even more responsive to treatment than tumors induced in laboratory-bred rodents.
Lastly, Folkman said that genestein at low levels taken over a long time can also induce anti-angiogenetic changes.
V. Peter Greenwald, M.D., Dr. PH. Division of Cancer Prevention, NCI,NIH was the recipient of a public service aware by NOAT. He began his presentation by a discussion of twin studies and cancer. Dr. Greenwald compared the rate of breast cancer in the United States and Japan in a novel way. He said that if the U.S. had the same incidence rate as Japan, 14,000 women would die of breast cancer this year(as opposed to the 46,000+ estimated). He further said that if we had the same rate as Japan had in the 1950’s, deaths would have numbered around 8,000. Unfortunately, this shows that our rates and theirs are both increasing. He then spoke about many types of cancers and the interventions being studied. For colon cancer, which is connected to breast cancer in many ways, a diet high in fiber and low in fat, and filled with fruits and vegetables is recommended. He mentioned a study being done in Kansas using nipple aspiration to check the effect of dietary changes after biomarkers for breast changes have been found. Dr. Greenwald suggested that the disease we need to fight is carcinogenesis since it may be more easily prevented and certainly should be detected in the decades-long stages before cancer occurs.
He discussed bio-engineered foods and suggested that many products will soon be available. Calling this process an inevitable trend, he pointed to the tomato that had a gene put in backward(anti-sense) which allowed the fruit to stay ripe without softening as soon.
Dr. Greenwald has often argued for a need to build cancer prevention into the mainstream of major research institutions.
VI. Steve Clinton, M.D., Ph.D., Dana Farber Cancer Institute spoke about the efforts to integrate molecular and cell biology with the discipline of nutrition and cancer. There has been a separation in educational institutions which has left biochemists, epidemiologists, chemists, physicists and other researchers too far apart. He discussed the burden of “grantsmanship”-having to incorporate the currently “happening” research area into one’s own in order to get funding. He suggested that funding should be based on a sound rationale, a novel hypothesis and good scientific tools only.
Dr. Clinton discussed an often-heard theme of cancer heterogenicity. In other words, a family of diseases we have agreed to call breast cancer. He pointed to metastatic presentation, local disease, very slow spread time and other factors. Mentioning the fact that leukemia is now understood to be chronic or acute with many subdivisions in each category. He mentioned a form of leukemia that has a 20-30% survival with chemotherapy but has yielded to retinoic acid (Vitamin A) therapy. This substance somehow allows the cells to develop normally. This treatment was applied after discovery that there were cellular changes in the retinoid receptors (with this disease). It is certainly possible that molecular defects may be identified in other cancers and may yield to nutritional interventions as well.
He reminded the audience that over 100 single genes that involve cancer have been identified and 17 have been cloned. Studies with high-risk populations may yield strong benefits since the group is more motivated, more willing to follow dietary rules, etc. We need biomarkers and some surrogate endpoints for nutritional intervention studies, i.e. dietary and nutritional footprints like changes in target tissue receptors, changes in serum modulator, etc.
In animal studies, energy(calorie) restriction has been shown to greatly increase apoptosis (cell death) and decrease micro-vessel density.
Dr. Clinton stated that while understanding mechanisms yield great intellectual satisfaction, it is not necessary in order to establish effective recommendations for cancer prevention. He suggested that researchers look to the time between a (needle)biopsy and full surgery to devise important studies on nutritional intervention. He mentioned prostate patients who often have a gap of 4-6 weeks prior to surgery. At that juncture, new needle biopsies could compare for changes from such nutritional interventions.
VII. Sue Ingles, Ph.D., Norris Comprehensive Cancer Center, USC, Los Angeles, CA. spoke about molecular epidemiology and genetic susceptibility studies using biomarkers of exposure. She suggested that genetic susceptibility offered low to moderate relative risk with a potentially high ability to intervene. She spoke about a Vitamin D study that had shown a ecologic association between breast cancer and sunlight exposure. Deltoids(Vitamin D) induces regression of breast cancer in rat model according to a 1992 study by Colson. A study by Anzano in 1994 showed that deltoids could prevent breast cancer induction in rat models. P21, a cell cycle inhibitor is responsive to this vitamin. Interestingly, it has been found that the genetic marker conveys protection against breast cancer but may provide a higher risk of prostate cancer.
VII. Maret Traber, Ph.D., University of California at Berkeley, Berkeley, CA. spoke about oxidant stress and host oxidant defense mechanisms. (She took a lot of teasing about “free radicals” at Berkeley). Free radical damage is thought to be involved in initiation and promotion of cancer. They tend to react very rapidly with other molecules. This is mostly kept to a minimum due to the high efficiency of enzyme mediated electron transfers. Free radicals cause protein and DNA damage and can even directly damage membranes through a process known as lipid peroxidation.
Dr. Traber is an expert on Vitamin E and spoke about the 8 naturally occurring types. She recommended d-alpha tocopherol acetate and not synthetic dl. She firmly stated that anti-oxidants during radiation treatment can only be helpful. They may enhance the immune system without interfering and help protect the up to 20% of patients who develop sarcomas as a result of radiation. The only caveat to Vitamin E usage was that the succinate** and acetate forms of the vitamin may be cancer promoting in the presence of UVB rays. Most people absorb 40-50% of the vitamin through food.
VIII. David Kritchevsky,Ph.D., WISTAR Institute, Philadelphia, PA. spoke about the fundamentals of (good)nutrition. He said water is important to our health. He strongly stated that a high fiber diet is NOT achieved by adding fiber to a low fiber diet. One has to eat whole grain products, fruits and vegetables regularly. Fiber is a combination of cellulose, plant sterols, bran, gums, legumes etc. He said that dietary fiber may reduce circulating estrogen, and wheat bran may do it best.
Corn oil contains linoleic acid which is a growth factor for tumors.
In rat studies, those fed twice as much fat but on calorie restricted diets had fewer and smaller tumors. When more fat was added, each group had larger tumors. A question from the floor raised the issue of rats who continue to grow during most of their life span and may therefore be compared best to children and adolescents.
One of the biggest changes world-wide has been the sedentary nature of our lifestyles. People eat as much but do less physical exercise. Still, all disease since 1950 have shown a mortality rate decrease (including some types of cancers). But cancer deaths in general are up 6%, with lung cancer leading the way. Deaths by heart disease, by contrast, have decreased by 53%.
IX. Diane F. Birt, Ph.D., Iowa State University, Ames, IA discussed the comparison between rats fed freely and continuously versus those on restricted diets. Energy restricted animals are found to be more active. This study is looking at epithelial cancers using skin cancer but may be applicable to breast, prostate and colon. It was found that corticosteroids from the adrenal gland seemed to affect the number of tumors. When the adrenal gland was removed, there were more tumors.
X. Kent Erickson, Ph.D., University of California, Davis, Davis, CA. discussed invasion and metastatic biology. Despite all advances in chemotherapy adjuvant treatment, etc. most patients die from metastatic disease. Single cells leave the primary tumor to colonize new sites. This is a powerful cell since it evades many defense mechanisms. Angiogenesis is important in this process. Then a secondary tumor is formed. Lamin receptors are found on metastatic cells that allow it to bind to other cell locations(adhesion). Many different molecules are involved in cellular adhesion-enzymes for extra-cellular matrix degeneration, metalloproteinase, etc.
Tumor cells set themselves up to block the effects of cytolytic T-cells ability to kill targets. Is the immune system blocked? If the T-cell binds to a tumor cell, it may enhance its ability within the immune system.
Where a tumor cell goes is not necessary to the first capillary bed. It is usually through the lymph node to the lung or liver. A glycoprotein CD44 gene is expressed on the surface and is a homing device for the lymph node.
In a study of rats to determine if dietary fat effected metastases, it was found that it did not. It is possible that prostaglandins in linoleic acid enhanced metastatic mammary tumor cells but they did not affect primary tumorgenesis. It seems there is a needed threshold for metastatic events. It may be possible to find the specific receptors on cells that lead to specific sites.
Mice fed safflower oil had faster tumor growth than those fed with fish oil. The rats that got EPA/DHA had one half the metastatic results as the other rats. Additionally, there was four-fold less tumor vasculization found within the fish oil group.
Other findings showed that an increased production of cholesterol may enhance metastatic progression.
XI. Edward Giovannucci, M.D.Harvard Medical School, Boston, MA. said that epidemiological evidence about a relationship between fat and breast cancer is still unproven. Post-menopausal weight gain has been linked to an increase in breast cancer. However, the Nurses study while providing an association between animal fat and colon cancer, has not done so with breast cancer. There is a stronger association between dairy products and prostate and breast cancer than for animal fat.
A recent study(unpublished) on dietary supplementation with calcium has raised the risk of increased prostate cancer and the same may be true for breast cancer. A statement from the audience suggested that calcium always needs magnesium for proper absorption.
A study of tomatoes and prostate cancer has shown an association with risk reduction. Cooked tomatoes seem to be best (tomato sauce is recommended).
In the Nurses study, vitamin use seemed to reduce the risk colon cancer but took a full fifteen years to demonstrate.
Dr. Giovannucci finished his remarks by stating that selenium was recommended because many studies have shown a 50% cancer risk reduction with its use.
XII. David Albers, M.D., Arizona Cancer Center, Tucson, AZ. speaking about colon cancer said that 25% is family risk-related. It is known that males in Shanghai, China have the same colon cancer risk as U.S. males but incidence is much lower in China. A similar study was done in Nigeria and in the Japanese-American population in Hawaii.
Dr. Albers also mentioned that when cooking meat (including chicken and fish) over a barbecue or grill, there is an increased risk of creating carcinogens. He recommended microwaving for 3 minutes, then grilling or barbecuing.
XIII. Rachel Ballard-Barbash, M.D., MPH, National Cancer Institute, NIH, Bethesda, MD suggested that heavier women with breast cancer show shorter times to or are more likely to recur. Conversely, studies show a decreased risk of lung cancer for with more body fat. Additionally, she noted that weight cycling has not been studied relative to cancer outcome.
Dr. Ballard spoke about studies indicate that pre-menopausal women who are tall and lean are at a higher risk for breast cancer, but have no worse prognosis. She suggested that thin women with late stage disease whether ER+/- or PR+/- may have worse prognosis than other women. Conversely heavier post-menopausal women have increased risk. And heavier women with family history may be at the highest risk. Weight if located in the central part of the (around the waist and stomach) seems to put post-menopausal women at greater risk. Fat distribution may play a role in risk of ovarian cancer as well. There is no data to date concerning diabetes and breast cancer, a concern since insulin and IGF (insulin growth factor) increase the risk of malignant breast cells.
XIV. Stephen Hustings, PhD, MPH, UT, MD Anderson Cancer Center, Houston, TX stated that DHEA and its analog (8453?) cut cancer incidence in P53 mice by 50% or more(lymphoma and sarcoma). Caloric restriction showed increased survival and decreased proliferation. DHEA increased survival, decreased proliferation and increased apoptosis. The next studies will be on Wrt-1 transgenic mice which develop mammary tumors.
XV. Mathhew Longnecker, MD, ScD discussed alcohol and cancer raising the question of whether dose patterns of consumption influence the risk of breast cancer. There is some evidence that a decrease in consumption may decrease risk of breast cancer.
XVI. Gary Kelloff, PhD, National Cancer Institute, NIH, Rockville, MD is the head of the Chemoprevention Department. This is the area that studies the inhibition or reversal of carcinogenesis by intervention with chemical agents (either synthetic drugs or chemical entities in the food chain ). To
develop these substances, they look at mechanistic studies, enzyme structure analysis, animal studies, drug developers in other areas and epidemiological studies. As soon as they can identify the earliest stages of carcinogenesis, A short intervention may be able to be used to slow mutagens or speed up apoptosis (cell death).
Several populations have been identified for study with these substances, including general population, high risk population, subjects with pre-cancerous conditions, patients who have been previously treated and cancer patients.
Substances currently under investigation include: curcumin, Fluasterone, indole-carbinol 3(cruciferous vegetables), isoflavones(soy), peryll alcohol(lavender), SERM, sulindac sulfone, limonene(citrus fruits family), selenomethione/E, aromatase inhibitors, DHEA, Vitamin D analog(deltoids) NAC & DFMO(anti-proliferative agents)and 4 HPR +oltipraz(an enhancing agent).
XVII. Carolyn Clifford, PhD, National Cancer Institute, NIH, Rockville,MD. discussed the methodology of conducting food-based epidemiological research. In contrast to other opinions ,she expressed great concern about the changes to come in bio-engineering the food supply.
XVIII. James F. Holland, MD, Mount Sinai Medical Center, NY, Professor of Neoplastic Diseases defined the stages of breast cancer as curable, sub-curable requiring two modalities, pre-curable(unknown treatment will work) and metastatic. He suggests that all than can be done for women with mets is to help with quality of life, freedom from pain, dysfunction and anxiety of depression. In discussing the side effects of current treatment, he suggested that all or any can lead to malaise, diabetes and abnormalities of taste. His suggestions for nutritional intervention included: encouragement(coaching, cutting-up food) and dietary supplements which don’t require extensive chewing(but should not substitute for food).
He spoke of the dangers of total parental nutrition (tube feeding) from contamination, vomiting, pneumonia, diarrhea and the risk of bacterial or viral infection. He suggested pear nectar as a good drink in these situations!
Dr. Holland told the audience that he believes that chemotherapy alone is not enough for metastatic disease but he forsees treatment that works directly on anti-body receptors.
XIX. Abby Bloch, PhD, RD, Memorial Sloan-Kettering Cancer Ctr, NY offered a method for nutritional assessment of the cancer patient as follows:
- Weight status (anthropometics)
- Food intake patterns: appetite
- Metabolic changes: the derivation
- Med/surgical treatment programs
- Impact on nutritional status
- Funct’l stat-quality of life/activities
- Body composition measures
- Biochemical indices
- Complementary/alternative therapies
Check out reasons for diminished intake-pain, swallowing difficulties, effort to consume food, difficulty with process of eating, ability to position self, anxiety, depression and drug response. She mentioned cannabinoids (Marinol ), Decadron, Benadryl, Kyrol, Reglan, Zofran and Compazine.
XX. Judith Ashley, PhD, RD, UCLA Center for Human Nutrition spoke about the new RDA to be called Dietary Reference Intake(DRI). The emphasis is on change in the risk of chronic disease. She indicated that 50% of all Americans consumed supplements in 1994. It is likely that a high degree of cancer patients are among those people. The supplement market is $6.5 billion. UCLA actually has a researcher Dr. Huey(sp??) who is looking into herbal interactions. She mentioned Astralagus, echinacea, cat’s claw, Essiac, Hoxsey, Mistletoe, Kombucha, Laetrile, milk thistle, Pau d’arco, Pycnogenol, and shitake mushrooms.
Also discussed was the trends in food science-possibly manufacturing to healthy specifications; true food component knowledge; agricultural developments and a world-wide sharing of resources.
XXI. Richard Rivlin, MD, Memorial Sloan-Kettering, NY spoke about Phytochemical and Cancer Prevention and discussed current research at Sloan. Their team is looking at isoflavones (legumes, beans, peanuts) to block estrogen receptors and inactivate oncogenes; garlic to conjugate carcinogens, retard tumorgenesis (many other healthy properties) ; lignans(flax seeds); indoles which inactivate estrogen and blunt promotion of breast cancer; terpenes(citrus fruits) to stimulate enzymes to block the action of carcinogens and polyactylenes (parsley) to block prostaglandin in biosysnthesis.
Dr. Rivlin reminded the audience that a second malignancy is always possible especially with cases of breast cancer. He suggested chemoprevention (the above-mentioned products) to prevent onset or slow or prevent growth or minimize toxicity. He mentioned a study in England that showed that dietary and supplemental garlic reduced the incidence of prostate cancer. Certainly many in-vitro studies using breast cell lines have show inhibition with aged garlic extracts or SAC and SAMC (garlic elements). These products work even in cells which have lost sensitivity to estrogen(ER-).
**The 2000 NOAT conference had a talk on Vitamin E succinate and its value in helping potentiate radiation therapy while protecting normal cells.
