Inez's comment: When I'm reading research papers, I quickly scan the article for keywords that are of interest to me; for example, brain tumor, acoustic neuroma, vestibular schwannoma, lipid, cholesterol,and dietary supplements of any kind. I'll underline these and then go back for a more careful reading. Sometimes I'll spend several hours reading, pondering, and highlighting information. But here's the important part--then I sit back and determine if any of what I read might apply to me. Even though this paper addresses cancerous tumors and has some information on chemotherapy, there is much information which is very meaningful to me. I hope this post has some "food for thought" for you . . . and your doctor. If he poo-poos the importance of dietary supplements and nutrition, then show him the long list of references.

Note: This article comes from the International Journal of Integrative Medicine; a subscription costs about $68/year and is well worth it; order by calling 1-800-477-2995 (USA) or 1-888-292-2229 (Canada).

graphic of brain for article entitled

CONTENTS:
INTRODUCTION
A COMPLEMENTARY APPROACH
DIETARY STRATEGIES
COMPLEMENTING ALLOPATHIC TREATMENTS
Complementing Surgery
Complementing Radiation Therapy (RT)
Enhancing the Efficacy of Radiation Therapy
RT Side Effects and Post-RT Healing
SUPPORT DURING CHEMOTHERAPY
Enhancing Efficacy and Reducing Resistance (RT)
BIOLOGICAL RESPONSE MODIFERS
CONCLUSION
Table 1 - Summary of Case Studies
Table 2 - Natural Agents for Chemotherapy Side Effects
Resources for Brain Tumor Patients
References 		KEYWORDS (bold or red to make them easy to locate):
surgery, radiation, chemotherapy
nutrient-dense diet
high-quality multi-vitanin/mineral supplement
impaired intestinal permeability
hepatic detoxification, redox homeostasis
Omega-3 fatty acids, eicosapentanoic acid (EPA), docosahexanoic acid (DHA)
Omega-6 fatty acids
stabilized fish-oil product (Tyler Eskimo-3)
Alkylglycerols, Bromelain, Eicosapentanoic Acid
Gingko Biloba, Hypericin,
Inositol Hexaphosphate (IP-6) Melatonin, Niacin, nicotinamide, Selenium
Glutamine, Taurine, glutathione (GSH), whey
Vitamin C, Bioflavonoids
Vitamin E, d-alpha tocopheryl succinate
Vitamin A, zinc, Proteolytic enzymes,
Echinacea, Astragalus, Ashwaganda, Panax or Siberian Ginseng, Oregon Grape Root, Goldenseal, Silymarin

Anaplastic astrocytoma (AA III) and Ghoblastoma multiforme (GBM IV), neoplasms arising from the brain's supportive glial cells, are particularly aggressive malignant brain tumors. They affect some 20,500 individuals every year.1 Approximately 15,000 deaths occur annually in the United States from brain tumors.2

Glioblastoma multiforme (GBM IV) has been called the "ultimate expression of anaplasia."3 Capable of doubling as rapidly as every 7-10 days, these aggressive tumors spread by forming tendrils, or "roots," which infiltrate surrounding tissues. Complete surgical resection is nearly impossible. Mimicking invasive garden weeds, a single errant root portion can allow the tumor to regrow, despite attempts at eradication. As a brain tumor grows within the confines of the skull, normal brain tissue is displaced and intracranial pressure intensifies, depriving the patient of neurological function. Headaches, seizures, loss of motor function, cognitive impairment, and personality changes may occur, depending on the tumor location.

Morbidity and mortality rates associated with these tumors are unacceptably high. Median survival time for adult glioblastoma patients is generally less than 6 months.4 Only 10% survive for two years, and only 1% for five years.5 For tumors that have progressed in size before diagnosis and surgery, the prognosis is considerably worse.

Conventional approaches--surgery, radiation, and chemotherapy--are designed to preserve function and lengthen survival time. However, they may negatively impact quality of life. This article explores the role of adjuvant nutritional and botanical support for improving the quality of life, and perhaps survival time, of these patients.
 

Research in this area is not abundant, and this approach is purely experimental. However, delaying care for want of more research does not serve the interests of brain tumor patients. These individuals face prognoses of short duration and have much to gain from the incorporation of natural agents, which pose little risk of adverse effect. This complementary approach is to be undertaken in collaboration with a qualified oncologist.

A COMPLEMENTARY APPROACH

The objectives of a comprehensive complementary protocol for brain tumors are multi-faceted:

  • Selective and judicial use of conventional treatments-- surgery, radiation, chemotherapy, and/or clinical trials-chosen by the patient and neuro-oncology team working in partnership;
  • Provision of natural agents that may enhance the efficacy and reduce the undesirable side effects of allopathic treatments (the focus of this article);
  • Use of natural and pharmacological agents to influence various biological mechanisms of the cancer process (e.g., angiogenesis, invasion, differentiation, apoptosis); and
  • Adoption of a systemic approach. Cancer is not a localized phenomenon but a systemic event. Identify and address imbalances throughout the body (e.g., impaired intestinal permeability, hepatic detoxification, and redox homeostasis).

    DIETARY STRATEGIES

    A nutrient-dense diet and high-quality multi-vitanin/mineral supplement provide an excellent foundation. Two additional dietary strategies are important: regulating blood sugar and modulating Prostaglandins.

    Cancer cells are obligate sugar feeders and have increased glucose uptake. In fact, brain tumor cells may consume as much as 10-15 times more glucose than normal brain cells.6 A diet emphasizing complex carbohydrates, fiber, adequate protein, and essential fatty acids- while minimizing sweets and processed foods-helps regulate normative blood glucose levels. While most cancer diets advocate low fat intake (less than 20% of calories), higher fat diets may offer some benefit to brain tumor patients. indeed, a ketogenic diet decreased glucose uptake to tumors by 20%, impairing tumor metabolism and significantly improving clinical status in astrocytoma patients.7 Seizure control may also improve on this diet.

    Careful attention to the quality of dietary fats is essential. Omega-3 fatty acids, particularly fish and flaxseed oils (precursors of tumor-fighting and immune-boosting 3- series eicosanoids) should be emphasized. Saturated, hydrogenated, trans-, and Omega-6 fatty acids (precursors of tumor-promoting and immune-suppressing eicosanoids) should be restricted.

    Cholesterol may play an important role in the metabolism of malignant brain tumors. Recent research shows the growth of human glioblastoma can be arrested by drugs that inhibit cholesterol synthesis at the mevalonate pathway.8 This finding suggests a supportive role for dietary and nutritional strategies to control cholesterol. Supplementation wthh pantethine (which inhibits cholestrol synthesis via the mevalonate pathway)9 may offer some benefit. Further research into thismechanism is indicated.

    NATURAL AGENTS FOR USE WITH BRAIN TUMORS
  • Alkylglycerols: Protect healthy tissue from radiation injury, impede glioma growth and invasion, improve response to chemotherapy by increasing delivery of chemo drugs to cells, reduce thrombocytopenia, and stimulate immune function.
  • Bromelain: Speeds wound healing, reduces pain, swelling, and post-surgical complications, reduces inflammation, boots immunity, improves circulation, and modulates eicosanoids involved in the inflammatory response and required for tumor growth.
  • Eicosapentanoic Acid: Improves the efficacy of chemotherapy, reduces tumor resistance to chemotherapeutic agents (vincristine), enhances immune function, destroys cancer cells in vitro, inhibits tumor growth, and reduces inflammation.
  • Gingko Biloba: Increases blood flow and oxygenation to the brain, functions as an anti-oxidant, protects against invasion via its flavonoid content, protects against radiation-induced damage, reduces cerebral edema, may reduce seizure activity, helps with post-chemo memory loss, may help alleviate depression.
  • Hypericin: Provides cytostatic effect on gliomas, enhances effect of radiation, may reduce depression, inhibits protein kinase C, and currently the focus of clinical trials on brain tumors.
  • Inositol hexaphosphate (IP-6): enhances cell-to-cell communication, induces differentiation, increases NK (natural killer) cell activity, helps inhibit tumor growth, and works well with chemotherapy
  • Melatonin: Increases survival when given with radiation, functions as an effective adjunct to chemotherapy, addresses insomnia, reduces radiation and steroid-related toxicities, combats inflammation, boosts immune function, and provides anti-oxidant activity.
  • Niacin: Increases blood flow and oxygenation to rumors, enhancing their vulnerability to radiation and chemotherapy.
  • Taurine: Replaces depletion of Taurine associated with chemotherapy and radiation, aids conjugation of steroid drugs, and helps regulate brain activity, thereby reducing seizures.
  • .Vitamin E: Enhances effect of BCNU, reduces side effects of radiation and chemotherapy, protects against myelo-suppression and lowered WBC counts, lessens fatigue, induces apoptosis and differentiation, and protects against cerebral edema.

    • COMPLEMENTING ALLOPATHIC TREATMENTS

    Complementing Surgery

    Numerous published protocols confirm the importance of nutrition in speeding post-surgical healing and reducing pain, swelling, and complications. 10 11 Supplement protocols begun 1-2 weeks prior and continuing 3-4 weeks post-surgery-commonly include a daily intake of Vitamin C (3,000 mg, tid), Bioflavonoids (1,500 mg),Vitamin E (400 IU), Vitamin A (25,000 IU), and Zinc (30 mg). Proteolytic enzymes--well researched in cancer treatment--are particularly helpful in reducing swelling and enhancing wound healing. The author has observed greater benefits in brain tumor patients with the use of Bromelain than with digestive enzyme preparations. Bromelain has several actions that make it an ideal adjunct for surgery and for the care of brain tumor patients. It combats inflammation and tumors, modulates cytokines, boosts immunity, promotes wound healing, improves circulation, and enhances the absorption of substances taken with it.12 The recommended dose of Bromelain is 500-750 mg (2,400 mcu strength), three times daily on an empty stomach.

    Complementing Radiation Therapy (RT)

    Radiation therapy (RT) is generally palliative, not curative, in astrocytonia and gliolastoma. As many as 30% of GBMs do not respond to RT, and the tumor may even continue to grow despite the treatment. Adjuvant nutrition and phytotherapy during radiotherapy have at least 3 objectives: selectively enhancmg the cytotoxic effects on neoplastic cells while protecting healthy cells, reducing unwanted side effects, and supporting post-treatment repair of healthy tissues. Radiation therapies for which adjunctive nutritional and botanical support are indicated include the following:

  • Localized stereotactic or conformal radiation therapy
  • Gamma Knife radiosurgery
  • Brachytherapy (placement of radioactive seeds in the tumor bed).

    Enhancing the Efficacy of Radiation Therapy (RT)

  • Niacin: Oxygen is a potent radiation sensitizer. Hypoxic (oxygen-deficient) tumors are resistant to radiation. Natural agents that increase blood flow may improve radiation response by delivering oxygen to tumors, thereby increasing tumor vulnerability to radiation. Niacin (500 mg to 6,000 mg of nicotinamide) is an effective radio-sensitizer, while producing little or no radio-sensitization of normal tissues.13-17 However, prolonged intake of larger doses of niacin may lead to liver damage. Inositol hexaniacinate may be a preferable form. It is safer, well-tolerated, and effectively improves circulation and oxygenation.18
  • Anti-oxidants: Radiotherapies are believed to achieve their cytotoxic effect by generating free radical-mediated DNA damage to the tumor. The use of anti-oxidants during radiation therapy appears counter-indicated in theory. However, research published over the past 30 years supports the adjunctive use of anti-oxidant nutrients, with improved radiation treatment results and protection of healthy tissues. 19- 24
  • Vitamin C: Increases tolerance to radiation therapy without reducing tumor control.25 Although the appropriate ascorbate dose is debated, the author advises 3-5 gm/day buffered Vitamin C, in divided doses, with one dose taken one hour prior to radiation therapy.
  • Vitamin E: is also an effective adjunct to radiation.26-27 It protects against brain edema,28 a side effect of brain irradiation. Vitamin E intake (800 IU/day) can be divided between d-alpha tocopheryl succinate which does not act as an anti-oxidant and provides some anti-tumor effects,29 and a mixed tocopherol product.
  • Melatonin: Recent advances in brain tumor biology suggest tumor growth is partially under neuroendocrine (including pineal) control. GBM patients receiving radiation therapy in conjunction with oral metatonin (20 mg/day) demonstrate increased survival at one year, compared to those receiving RT alone (6% vs 43%).30 Melatonin reduced radiation and steroid-related toxicities in this study. It also offers immune-boosting, anti-inflammatory, and anti-proliferative effects.31-32
  • Alkylglycerols: A component of shark liver oil, alkylglycerols can protect healthy tissue from radiation injury,33 slow tumor growth,34-35 and stimulate immune function.36 The recommended dose is 100 mg of alkylglycerols, two to three times daily with meals. Because excessive use can stimulate overproduction of platelets, a 10-day rest period between 30-day cycles is recommended. Select a product purified of excess Vitamins A and D, pesticides, and heavy metals.
  • Taurine: The amino acid Taurine is severely depleted during RT and chemotherapy.37 Taurine compounds administered during and after RT offer protective effects.38 Other research shows Taurine plays a role in reducing seizure activity. 39-40 Daily supplementation of 2,000 mg, in divided doses, is recommended.
  • Hypericin: A constituent of the herb St. John's wort (Hypericum perforatum), hypericin has been investigated for its effects on depression. Clinical trials are currently investigating the effect of hypericin on brain tumors. Researchers at the University of Southern California investigated the effects of hypericin on three human glioblastonia cell lines. They report enhanced radiosensitivity and significantly reduced tumor cell survival rates with hypericin plus RT, over RT alone (50% versus 26% reduced tumor cell survival).41-42 Current clinical trials are employing high doses of synthetic hypericin (0.25-0.50 mg/kg). Use of high dose St.Johns wort is limited by photosensitivity reactions, which resolve upon discontinuation. The author has had some success in reducing this reaction with beta-carotene loading (12 ounces of fresh carrot juice daily).
  • Ginkgo Biloba Extract (GBE): Known for its ability to increase blood flow and oxygenation to the brain, 43-44 appears ideally suited for use in preparation for and recovery from brain irradiation. However, no formal studies have examined it as an adjunctive treatment to RT. Ginkgo Biloba is an anti-oxidant that protects lipids against peroxidation,45-46 protects against radiation damage, 47 reduces cerebral edema, 48-49 suppresses neurological impairment, and reduces seizure activity.50 Ginkgo Biloba may not be appropriate for use in those at risk for hemorrhage, or those taking anticoagulant medications.

    RT side effects and post-RT healing.

    Side effects commonly associated with brain irradiation include loss of hair, skin burn, loss of taste, and pervasive fatigue.

    Radiation damage to salivary glands and tastebuds can result in a dry, irritated mouth and loss of taste perception. This can decrease the desire and ability to eat, seriously impacting nutritional status. Zinc supplementation (15-45 mg, tid, as lozenges or liquid zinc sulfate) at onset of loss of taste can restore taste perception.51 Supplementation with antioxidant nutrients--from 14 days prior through 12 days post-RT---can reduce damage to salivary glands.52 Water extracts of flaxseed can provide relief of dry, irritated mouth and replace lost saliva.53 Topical vitamin E is effective in oral mucositis.54

    Topical application of 100% concentrate of Aloe Vera after daily RT treatments can be helpful for radiodermatitis.55 Vitamin E supplementation (1,600 IU/day), begun one week prior to RT, allowed more than half the patients to keep their hair, and dramatically reduced fatigue.56

    Astragalus can help address radiation-induced fatigue. Panax or Siberian Ginseng is also indicated and works synergistically with Astragalus. However, Ginseng is best restricted to recuperation following RT (15-30 days post-RT), because it stimulates DNA repair.57-58

    Over the course of several months, radiation causes the death of brain tumor cells (necrosis). As intracranial necrotic tissue cannot be adequately resorbed, irritation can lead to headaches, inflammation, edema, and seizures, which may necessitate surgical removal of necrotic tissue. Bromelain,Vitamin E, and Ginkgo Biloba appear to address the effects of necrosis (see Table 2). Their use in this application should be researched.

    SUPPORT DURING CHEMOTHERAPY

    The decision whether to utilize chemotherapy can be agonizing. The efficacy of chemotherapy in glioblastoma and astrocytoma is debatable. Although a plethora of literature compares the efficacy of various chemotherapy drugs against one another, no literature has compared the drugs to supportive care alone. In his work, Questioning Chemotherapy, Ralph Moss quotes a prominent surgeon: "Chemotherapy [of malignant gliomas] adds little if anything to post-surgical irradiation in terms of median and/or mean survival." 59

    While it is beyond the scope of this paper to fully address the pros and cons of chemotherapy for brain tumors, patients are encouraged to investigate the topic before committing to a course of action. For those who choose chemotherapy, adjunctive nutrition may improve the efficacy of the drugs, reduce side effects and after- effects, and lessen the negative impact on quality of life.

    The most commonly employed agents against AA III and GBM IV are the nitrosoureas: BCNU (carmustine) and FVC (procarbazine, vincristine, CCNU/Lomustine). Clinical trials are currently exploring dozens of other agents. A major obstacle is the blood-brain barrier, which limits concentration of chemotherapeutic agents in the brain, thereby limiting their effectiveness. New strategies are being explored to surmount this problem and make chemo more selective.

    Clinical trials are also investigating the use of blood brain barrier-disrupting agents, such as mannitol. Other new approaches involve the direct application of chemotherapeutic agents via intra-arterial delivery, intracranial pumps, or placement of Gliadel wafers (chemo wafers surgically implanted in the tumor bed). Chemosensitivity testing also shows promise. While in vitro testing cannot ascertain how well a drug will work in vivo, it may help screen out agents that are clearly ineffective or to which the tumor cells are resistant.

    Enhancing Efficacy and Reducing Resistance

  • Omega-3 fatty acids: The Omega-3 fatty acids-- particularly eicosapentanoic acid (EPA) and docosahexanoic acid (DHA)--improve chemotherapy's tumor-destroying ability by altering cancer cell membranes, thereby increasing uptake of the drugs.60 EPA and DHA potentiate the cyto-toxicity of a variety of anti-cancer drugs in vitro, including vincristine,61 even reversing vincristine-resistance. Additionally, Omega-3 fats reduce inflammation, significantly enhance immune function, inhibit tumor growth, and provide cyto-toxic effects in vitro .62 Alkylglycerols also enhance drug penetration through tumor cell membranes.63 Provision of adequate Vitamin E to protect these oils from oxidation, or selection of a stabilized fish-oil product, counteracts the rise in blood glucose associated with the administration of fish oil.64 Daily intake of two to four or more grams of Omega-3 fatty acids is recommended.
  • Whey: Intracellular concentrations of Glutathione (GSH) in tumor cells are higher than in adjacent normal cells. This difference in Glutathione status is believed to be an important factor in tumor resistance to chemotherapy. Whey protein concentrate can selectively deplete tumor GSH concentrations, while maintaining GSH levels in normal tissue.65 This selective depletion of tumor GSH may make the tumor more vulnerable to the actions of chemotherapy, while protecting normal tissue from its deleterious effects. The recommended dose is 30 to 60 grams of whey protein concentrate daily.
  • Antioxidants: Despite prevailing cautions regarding use of antioxidants during chemotherapy, a comprehensive review article on the topic (264 references) exposed virtually no evidence that antioxidants interfere with chemotherapy. It did provide substantial evidence that certain antioxidants protect against chemo-induced side effects, and improve qualityof life. 66 For example, Melatonin has potent anti-oxiddant properties, and it augments the anticancer effect of chemotherapeutic drugs, while decreasing toxic side effects .67 The effect of BCNU is enhanced when administered along with beta-carotene and Vitamin E.68 These nutrients may protect against BCNU-associated pulmonary toxicity.
  • Berberin: Berberine is the primary alkaloid in Goldenseal, Barberry, and Oregon Grape Root. Combining Berberine with BCNU yields additional cytotoxicity and enhanced tumor kill at 10 mg/kg in animals.69 Berberine alone also shows potent antitumor activity against human glioma.

    BIOLOGICAL RESPONSE MODIFIERS

    Additional agents can be utilized to complement allopathic care, to provide a therapeutic approach when the patient has exhausted conventional treatment options, or to use between treatment cycles. Rather than directly attacking the tumor cytotoxically, these agents are selected to impact a wide variety of biological mechanisms of the cancer process (e.g., angiogenesis, invasion, differentiation, apoptosis). While a discussion of these agents is beyond the scope of this article, some examples should be mentioned.

    Shark cartilage appears to inhibit invasion and angiogenesis.85 Shark cartilage is currently the focus of clinical trials on malignant primary intracranial tumors.86 Phenylacetate stimulates differentiation and blocks the mevalonate pathway, reducing the production of sterols and isoprenoids vital for glioma growth.87-88 Inositol hexaphosphate (IP-6) has shown growth-inlubiting, differentiating, and immune-stimulating capacities.89-90 Vitamin A induces differentiations, 91 Vitamin C, proanthocyanindins, and anthocyanidins reduce invasion via collagen strengthening.92 Vitamin E (d-alpha tocopheryl succinate) induces apoptosis and differentiation.93

    Side effects common to chemotherapy agents used for brain tumors include fatigue, nausea, vomiting, constipation or diarrhea, myelo-suppression, leukopenia (decreased white blood cell counts), thrombocytopenia (decreased platelets), and anemia. Table 2 shows the use of various natural agents in addressing many of these side effects.

    Antioxidants play a key role in protecting against many chemotherapy-induced side effects.70 Silymarin (140 mg of milk thistle containing 80% silyrnarin, tid) protects the liver against damage during chemotherapy, and may help protect the immune system. Glutamine supports the immune system, maintains intestinal integrity, and reduces gastrointestinal side effects from chemo.71 Siberian Ginseng (1,000 mg/day), Astragalus (500 mg),72-73 and Ashwaganda (Withania somnifers) are particularly beneficial adjuncts to chemotherapy (refer to Table 2).

    CONCLUSION

    Adjunctive nutrition and botanical therapies are a growing field. A complementary approach appears to provide a signifciant contribution to the management of primary brain tumors. Further research into this area is clearly warranted.

    TABLE 1.
    TUMOR PATIENTS UTILIZING COMPLEMENTARY NUTRITION AND PHYTOTHERAPY
    SUMMARY OF CASE STUDIES (details omitted due to complexity and size)
    Table 1 presents survival data on 23 brain tumor patients who have utilized various, individually tailored nutritional and botanical agents during their oncological care. While no statiscally significant relationship can be certain, the intent of this table is to suggest an association compelling enough to inspire credible scientific research in this area.
    TABLE 2.
    NATURAL AGENTS FOR CHEMOTHERAPY SIDE EFFECTS
    Nausea/vomiting Ginger (2-4 gm/day)," acupuncture
    Mucositis Topical Vitamin E 75
    Maldigestion Digestive bitters, digestive enzymes, pancreatin, bromelain, glutamine, slippery elm
    Diarrhea Carob powder (2 Tbsp, bid)," Lactobacillus acidophilus'
    Constipation Flaxseed meal, increased fiber (>30 gm/day), magnesium (400 mg HS)
    Myelosuppression Vitamin E succinate (400 to 800 IU/day)," ashwaganda
    Leukopenia Vitamins C and E, zinc, selenium, astragalus" Panax ginseng (1,000 mg, tid)," Siberian ginseng," echinacea," alkylglycerols (100 mg, tid), ashwaganda, Oregon grape root or goldenseal (500 mg, fid), glutamine (2-4 gm/day)
    Thrombocytopenia Alkylg@cer-ols (I 00mg, fld)" ashwaganda
    Anemia Liquid liver extract, alkylglycerols (I 00 mg, tid), folate (400-800 mcg/day), vitamin B[2 (1,000- 3,000 mcg/day)
    Fatigue Astragalus, vitamin E (up to 1,600 IU/day)l
    Depression St. John's Wort (300 mg @ 0.3% hypericin, tid)
    RESOURCES FOR BRAIN TUMOR PATIENTS
    American Brain Tumor Association
    2720 River Rd, Des Plaines, IL 60018, 800-886-2282    		 National Brain Tumor Foundation
    785 Market Street, Suite 1060, San Fran, CA 94103
    , 800-934-CURE
    Al Musella's Brain Tumor website
    www.virtualtrials.com
    (includes a listing of clinical trials, links, survivor stories)    		 Libutti R: That's Unacceptable
    Krystal Publishing 1997
    PO Box 221, Martinsville, NJ 08836,
    908-889-6038
    Ovist D: Second Chance, Eureka, MT:
    Danashan Publishing, 1997    		 Rolof T (ed): Navigating Through a Strange Land: A Book for Brain Tumor Patients and Their Families
    West Fork, AR: Indigo Press, 1995

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