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Nutrition and Orthomolecular Supplementation in Lung Cancer Patients Diana Campos, Carlos Austerlitz, Ron R. Allison, Helion Póvoa and Claudio Sibata Integr Cancer Ther 2009; 8; 398 DOI: 10.1177/1534735409344333 The online version of this article can be found at: http://ict.sagepub.com/cgi/content/abstract/8/4/398

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Nutrition and Orthomolecular Supplementation in Lung Cancer Patients

Integrative Cancer Therapies 8(4) 398–408 © The Author(s) 2009 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav DOI: 10.1177/1534735409344333 http://ict.sagepub.com

Diana Campos,1 Carlos Austerlitz,1 Ron R. Allison,1 Helion Póvoa,2 and Claudio Sibata1

Abstract This article reviews updates and provides some data related to nutritional and orthomolecular supplementation in oncology patients with an emphasis on lung cancer, a commonly diagnosed tumor with significant nutritional disturbances. Cancer and its treatment play a significant role in nutritional imbalance which likely has negative impact on the patient both in terms of quality and quantity of life. Nutritional supplementation may correct these imbalances with significant clinical benefit both physiologically and psychologically.This review will help assist in providing clinically useful data to assess the cancer patient’s nutritional status and to guide nutritional intervention to assist these patients’ recovery. Keywords orthomolecular, supplementation, nutrition, lung cancer, questionnaire

Introduction At least one third of all cancers may be influenced by nutrition.1 Dietary intake effects metabolism, which in turn affects both physiological and psychological homeostasis. Furthermore, response to cancer treatment may also be influenced by adequate intake of nutritional components, both in terms of healing from therapy and recovery from the cancer itself. For many patients, cancer leads to great difficulties in achieving a nutritionally appropriate diet. The tumor may secrete myriad factors that interfere with eating or absorption. Appetite, taste, smell, and the ability to consume, digest, and absorb food are affected. In addition, treatment for cancer may lead to the same outcomes. For example, chemotherapy is generally associated with loss of appetite, diminished taste, nausea, and weakness among other morbidities. Radiation therapy also may promote a generalized weakness and malaise, and radiation treatment portals generate specific side effects such as mucositis or enteritis, each with a negative effect on nutrition intake and absorption.2 Surgery may promote significant imbalances in nutrition as wound healing requires great caloric intake, sometimes beyond the capacity of the individual with cancer. This nutritionally compromised state will then further diminish the patient’s immune system, ability to heal, fight infection, and maintain an acceptable quality of life. These nutritional compromises are pronounced in lung cancer.

This review will provide an update of peer-reviewed scientific data related to the impact and outcome of orthomolecular nutritional supplements, with an emphasis on lung cancer patients.

Background Oxidative Stress and Disease A free radical is an atom or molecule that has at least 1 unpaired electron and is therefore unstable and highly reactive. Free radicals are generated during cancer treatment and are responsible for cellular damage and killing malignant cells. Oxygen radicals are also generated in the human body by a variety of mechanisms and exposures, including thermolysis; photolysis; redox reactions; the Fenton reaction; ionizing radiation; sun light; chemical toxins (carbon tetrachloride, paraquat, benzo, pyrene), aniline dyes, and toluene; chemotherapeutic

1 The Brody School of Medicine, East Carolina University, Greenville, NC, USA 2 Clinice, Rio de Janeiro, Brazil

Corresponding Author: Carlos Austerlitz, East Carolina University, 600 Moye Blvd, Greenville, NC 27834, USA Email:[email protected]


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Campos et al

O2 (100%)

Mitochondrial

H2O2 (95-98%)

2-5% O2+ e

-

Superoxide dismutase (Cu, Zn, Mn)

Yes Terminate

No Endogenous defense

H2O2

Glutathione redutcase (B2)

Cell Catalase (Fe), Glutathione peroxidase (Se) Ionizing radiation

Terminate Yes

No Haber Weiss

Fenton

OH*

Fatty acid

No endogenous defense

Figure 1. Oxidation pathways within the human body for oxygen metabolism and ionizing radiation

agents (carboplatin, taxol, cisplatin, gemcitabine, navelbine, irinotecan, etoposide, vinorelbine adriamycin, bleomycin, mitomycin C, nitrofurantoin, chlorpromazine); air pollution (carbon monoxide, nitric oxide, aldehydes, alkyl nitrates); ingested substances (alcohol, smoked and barbecued food, peroxidized fats in meat and cheese, deep-fried foods); occupational and environmental exposures to metals; and emotional stress.3 Antioxidants are molecules that neutralize free radicals before vital molecules are damaged. Antioxidants include (a) nutrients (vitamins A, C, and E, carotenoids, selenium, flavonoids/polyphenols, lycopene, lutein, lignans, coenzyme Q10, glutathione); (b) enzymes synthesized in the body (superoxide dismutase, catalase, glutathione peroxidase); although there are several enzyme systems within the body that scavenge free radicals, the body cannot use these enzymes without micronutrients (ie, Cu, Fe, Mn, Zn, and Se), so they must be supplied in the diet.4 Oxygen

free-radical formation caused by oxygen metabolism and ionizing radiation is shown in Figure 1. Approximately 95% to 98% of the oxygen in the human body is converted to water. The electron transport chain, which is found in the inner mitochondrial membrane, uses oxygen to generate energy in the form of adenosine triphosphate.5 Oxygen acts as the terminal electron acceptor within the electron transport chain, but anywhere from 2% to 5% of the total oxygen intake has the ability to form the highly damaging superoxide anion (O2−) radical via electron escape. In the presence of Cu, Zn, and Mn, superoxide dismutase converts O2− to hydrogen peroxide (H2O2) or the hydroxyl radical (OH·). The H2O2 can then be neutralized by the enzymes catalase and glutathione peroxidase. During this process of neutralization, glutathione peroxidase becomes oxidized and is regenerated by the glutathione reductase enzyme. These enzymes can only work in the presence of Fe (catalase), Se (glutathione peroxidase), and


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vitamin B2 (glutathione reductase). When the H2O2 is not neutralized, it can interact with copper or iron to produce OH· by the Haber Weiss reaction, or with Fe++ to produce OH· by the Fenton reaction. These reactions are significant as the substrates are found abundantly within the body.3 The hydroxyl radical has no endogenous neutralizing enzyme and can interact with fatty acids to form lipidic peroxide (COOH-) or with nitric oxide (NO) to form a peroxynitrite anion (ONOO-). Because the human body consists of more than 75% water, free radicals are produced from water by hydrolysis when exposed to ionizing radiation. Singlet oxygen is formed after water is exposed to ionizing radiation. Singlet oxygen is not a true free radical but can transfer its energy to a new molecule and act as a catalyst for free radical formation. Table 1 outlines exogenous antioxidants that can be used against all the free radicals listed. The enzymes superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase, which constitute endogenous protection against free radicals, can only act against the superoxide anions and hydrogen peroxide free radicals if supplied with Mn, Zn, Cu, Fe, Se, and B2. Melatonin is formed endogenously by the pineal gland and by the intestinal cells. When these cells are damaged, for example, during a radiation treatment, there will be a decrease in melatonin formation.6 Oxidative stress is defined as a disturbance in the equilibrium between reactive oxygen species (ROS) and detoxifying antioxidant systems7 and can be involved in the pathophysiology of many diseases. Examples of conditions linked to OS include the following: anemia and tumor hypoxemia8; cardiomyopathy; bone and joint pain; bone marrow depletion; cardiopulmonary damage9; endocrine and reproductive impairment and dysfunction; normal tissue damage from radiotherapy10; fatigue and compromised nutritional status,11 gastrointestinal dysfunction,9 and immunological complications12; local ischemia13; lung tissue injury; muscular atrophy14; musculoskeletal sequelae9; myelodysplastic syndromes; numbness and tingling; osteopenia10; osteoporosis15; pain; renal impairment9; respiratory complications16; malignancy10; thyroid abnormalities10; inflammation17; and aging.18 All these may influence response to cancer treatment and outcome.

Antioxidants and Lung Cancer Prevention Even though antioxidants have been associated with cancer prevention, the cancer prevention community was stunned in the early 1990s when the Alpha Tocopherol, Beta-Carotene Cancer Prevention Study Group19 failed to show that b-carotene could prevent lung cancer in older male smokers. In this study, Finnish smokers who were supplemented with synthetic b-carotene (20 mg 33 000 UI/d) developed lung cancer

at significantly higher rate (18%) than those using a placebo. An analysis of this study was presented by Gonzáles et al in 1997.20 Out of 14 560 men on b-carotene, 474 developed lung cancer, whereas of the 14 573 men on placebo, 402 developed lung cancer. The incidence increased from 2.76% in the control group to 3.26% for the treated group. There was an 18% relative increase in lung cancer in the b-carotene group. However, the overall mortality from cerebrovascular disease was reduced by 10% in those receiving antioxidants, and the overall mortality was reduced by 7% in the supplemented group, which may also confound results. The most relevant issues addressed by Gonzáles et al about the Finnish antioxidant and lung cancer study were related to the form of supplementation—low doses, short duration of supplementation—and other additional risks factors such as the continuation of smoking. The form of supplement was synthetic and contained other ingredients (B-carotene and vitamin E) and a-tocopherol/acetate from which some animals have increased tumor rates. Doses were only 1/8 to 1/40 of the intake used in previous clinical studies. Alcohol consumption was not taken into account. A recent review of the effect of b-carotene intake on lung cancer development was published by Brar.21 It concluded that the current literature concerning b B-carotene supplementation and lung cancer incidence may best be summarized as inconclusive. In a study done by Wright et al,22 the effects of a-tocopherol and b-carotene supplementation did not provide a protective effect against upper aerodigestive tract cancers. Nevertheless, subgroup analysis for larynx showed a protective effect of b-carotene supplementation on the incidence of early stage malignancies.22 Additionally, the lack of overall benefit of single agent b-carotene and a-tocopherol supplementation contrasts with the strong inverse findings for baseline dietary and serum antioxidants in relation to esophageal and laryngeal cancers. These discrepancies might have arisen because dietary antioxidants are likely to exert their protective effects through interactions with other vitamins and cofactors. The effect of multiple (b-carotene, vitamin E, and selenium) vitamins and minerals in the prevention of esophageal cancer in a population with the highest known rate for this disease in the world (China) is the subject of an ongoing study.23 Early results have shown that such supplementation reduced total mortality, total cancer mortality, stomach cancer incidence and mortality, and premalignant lesions. Therefore, supplementation with only a single antioxidant might be insufficient to achieve a beneficial effect. Furthermore, pharmacological doses of antioxidants may modulate the biological pathways differently than through dietary means. It is also hypothesized that antioxidant trials in patients who take a supplement for relatively short periods of time might not reflect the maximum benefit of


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Campos et al Table 1. Free Radicals, Antioxidant Defense Network Antioxidant Free Radical

Exogenous (O2-)

Superoxide anions Hydrogen peroxide (H2O2)

b-Carotene, a-lipoic acid Vitamin C, bioflavonoids, Se, N-acetylcysteine, carnosine, melatonin39

Hydroxyl (OH-) Oxygen, singlet (O2) Lipidic peroxide (COOH-)

a-Lipoic acid, carnosine, melatonin39 b-Carotene, a-lipoic acid, carnosine, melatonin39 Vitamin E, a-lipoic acid

antioxidants compared with habitual consumption over many decades.

Nutritional Supplementation in Lung Cancer Patients Lung cancer has one of the lowest survival outcomes of any cancer. Published international 5-year survival for patients with lung cancer varies from 5% to 16%.24 A variety of treatment modalities are used to treat lung cancer, including chemotherapy and radiation, both of which can increase oxidative stress.24 Both nutrition and antioxidants influence oxidative stress levels, and both may play an important role in the prevention of cancer and treatment of cancer patients. Data support the use of antioxidants in the prevention of gastrointestinal cancer,25 prostate cancer,26 and breast cancer. The use of antioxidant and nutritional supplementation in cancer patients has been reported to decrease inflammation, infection,27 cancer growth,28 mutation,29 malignant cell proliferation and inducing differentiation,30 and dedifferentiation.31 In addition, supplementation has been associated with palliation of pain32 and improved the quality of life of terminal cancer patients.33 A study was conducted by Jatoi and collegues34 on the use of voluntary vitamin and mineral supplementation on non-small-cell lung cancer (NSCLC) patients from the Mayo Clinic. A cohort of 1129 patients responded to a questionnaire on vitamin and mineral intake, which was then used to assess survival and quality of life. The results show that median survival was 4.3 years versus 2.0 years for vitamin/ mineral users and nonusers, respectively. The Lung Cancer Symptom Scale showed better quality of life among vitamin/ mineral users (mean difference in score of 3 (95% confidence interval = 0.8, 5.1; P < .01), and after adjusting for related variables, there remained a trend in favor of vitamin/mineral use with a mean difference of 1.8 (95% confidence interval = 0.2, 3.9; P = .08). A similar study was done for small-cell lung cancer by Jatoi and collegues.35 Based on a cohort of 178 patients, it was stated that the median survival increased to 38% in those who took vitamin and mineral supplements compared with those who did not. However, there were no significant improvements in the patients’ quality of life.

Endogenous Superoxide dismutase (Mn, Zn, Cu) Catalase (Fe), glutathione peroxidase (Se), glutathione reductase (Vitamin B2), melatonin Melatonin39 Melatonin39

Simone and collaborators36 examined the interference of antioxidants and other nutrients with chemotherapy or radiation therapy. The work involved 280 peer-reviewed published studies (62 in vitro and 218 in vivo), including 50 human clinical studies that used nonprescription antioxidants and other nutrients (8521 patients, 5081 of whom were given nutrients) and 50 studies on prescription antioxidants. It was concluded that published studies have consistently shown that nonprescription antioxidants and other nutrients do not interfere with cancer therapeutic modalities. In addition, nonprescription antioxidants and other nutrients enhance the killing of cancer therapeutic modalities, decrease their side effects, and protect normal tissues, and in 15 human studies, 3738 patients actually had prolonged survival. There are few findings in the scientific literature related to dietary intervention and supplementation specifically for lung cancer patients.37 Sun and colleagues examined the effect of the intake of 30 g daily of Sun Farm soup freezedried powder (DSV) for NSCLC (stages III and IV) on 24 patients. The soup contains water, soybean, shiitake mushroom, mung bean, red date, scallion, garlic, lentil bean, leek, hawthorn fruit, onion, American ginseng, angelica root, licorice, dandelion root, senegal root, ginger, olive, sesame seed, and parsley. The primary endpoint of this study was death or survival measured up to 24 months from date of entry. Median and mean survival was 4 and 4.8 months in control patients and 15.5 and 15 months in treatment patients (P < .01). Weight maintenance and Karnofsky performance status were also improved. Another report by Sun et al,38 involved a small openenrollment trial to evaluate the survival of 18 volunteer, stage IIIB and IV NSCLC patients consuming 283 g daily of thawed selected vegetables (FSV) alone or as an adjuvant to conventional therapy, compared with historical controls. The mean and median survival times of eligible NSCLC patients using FSV were 23.7 and 33.5 months, respectively. The historical mean survival time is 7 months. One-year survival of FSV patients was 71%. In summary, effective dietary intervention and supplementation has been associated with less weight loss and improved survival in lung cancer patients.37,38 Quality of life measured by the quality-of-life index increased significantly, and weight loss was decreased for advanced lung


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cancer patients undergoing aggressive chemotherapy with supplemented diets for 2 months.39 A multivariate analysis demonstrated that lung cancer patients on a diet with 25% of calories from protein and supplemented with zinc and magnesium had less weight loss and higher serum albumin concentrations, which were also significant and independent prognostic variables for survival duration.39 Although these are promising results, there is a need for large randomized placebo-controlled trials.

Complication of Treatment and Nutritional Intervention Lung cancer treatment is often aggressive and may induce morbidity. The clinical consequences of lung cancer treatment may lead to complications including: oral mucosa and intestinal lining damage, leading to oral or esophageal candidiasis, inflammation, taste loss, nausea, vomiting, diarrhea, and anorexia. All these symptoms constitute a heavy burden for the patients and their caregivers. When proper oral nutrition is impaired, it can be replaced by means of supplementation (vitamin, minerals, amino acids, etc).

Orthomolecular Supplementation Many lung cancer survivors have low blood nutrient levels even before diagnosis as a result of inadequate diets and/or the adverse effects of smoking.40 For example, the Food and Nutrition Board of the National Academy of Sciences recommends that individuals who smoke consume an additional 35 mg of vitamin C per day. Mahdavi et al7 have determined the levels of oxidative stress, serum total antioxidants, and vitamin C in a cohort of 57 cancer patients and 22 healthy participants. The level of oxidative stress was measured by malondialdehyde (end product of lipid peroxidation). Cancer patients as compared with controls, showed a significant increase in lipid peroxidation with a concomitant decrease in the antioxidant defense system. In addition, low serum levels of vitamin C in spite of adequate daily intake may be because of increased use in scavenging lipid peroxides as well as their sequestration by tumor cells. Levels of oxidative stress in patients with lung cancer have also been measured by Esme and coauthors.41 In this study, a cohort of 49 lung cancer patients, who had not received any cancer therapy, and 20 healthy participants were evaluated. Serum nitrite, nitrate, ascorbic acid, retinol, b-carotene and ceruloplasmin levels, and whole-blood malondialdehyde, reduced glutathione levels, and catalase activity were measured. Statistically significant differences between the patient group and the control group were detected for all biochemical parameters. It was advocated that with advancing stage of lung cancer, the levels of oxidative stress increase, and levels of antioxidant molecules decrease. Patients with squamous cell carcinoma had higher

oxidative stress as reflected by higher levels of malondialdehyde and nitrite. Cachexia is clinically characterized by progressive weight loss, anorexia, metabolic alterations, asthenia, depletion of lipid stores and severe loss of skeletal muscle proteins. It is present in about 50% of cancer patients and accounts for 20% of all cancer deaths. Proinflammatory cytokines and oxidative stress/antioxidant parameters characterize the biohumoral profile of early cachexia in lung cancer patients. This has been reported by Fortunati et al.42 The findings of ROS, reduced glutathione and vitamin E, and elevated a-proinflammatory cytokines allows the identification of a lung cancer patient developing cancer-related cachexia. Todisco et al43 in an early study reported on the treatment of cancer with a combination of chemotherapy and nutrition supplements. They combined cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and adrenocorticotropic hormone. In a phase II trial, the abovementioned medications were well tolerated and effective in treatment of low-grade non-Hodgkin lymphoma at an advanced stage. The response of somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced NSCLC patients with low performance status has been published by Norsa and Martino.44 From this study of 28 patients, it was concluded that the combined regimen of such medications is active in the treatment of chemotherapy-naïve patients with advanced NSCLC and poor performance status, in terms of both survival and quality of life, and presents very mild side effects. The rationale for this pharmacological association was based on the following: (a) both growth hormone and prolactin are released, which are 2 hormones involved in neoplastic growth that are inhibited by somatostatin and bromocriptine,45 respectively; (b) retinoids, such as vitamin A and its analogs, regulate cell growth, and immune function46; (c) melatonin is endowed with immunostimulant properties47; and (d) each of the proposed biotherapeutical agents has specific antitumoral effects. A similar study was performed by the same authors using a group of 23 pretreated patients with advanced lung adenocarcinoma and low performance status.48 In this case, vitamin E was added to the above-mentioned combined regime. It was concluded that this combined regimen is also well tolerated and can be effective in improving disease-related symptoms in heavily pretreated patients with late-stage lung adenocarcinoma. A study was conducted by Jaakkola et al49 on small-cell lung cancer in humans using combination chemotherapy of cyclophosphamide, Adriamycin (doxorubicin), and vincristine with radiation and a combination of antioxidants, vitamins, trace elements, and fatty acids. The conclusion was “antioxidant treatment, in combination with chemotherapy and radiation, prolonged the survival time of patients” compared with expected outcome without the composite oral therapy.


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Campos et al Another study involving small-cell lung cancer patients and effects of vitamin intake and folate status on disease-free survival has been performed by Jatoi et al.50 In this study, supplemental vitamin usage, dietary vitamin intake (Willett Food Frequency Questionnaire), red blood cell folate, and serum folate concentrations were assessed. In this cohort of patients, it was concluded that those who took vitamin supplements were more likely to be long-term survivors (41 months vs 11 months; P = .002). A similar trend toward long-term survival was seen among patients with higher circulating folate concentrations. The effect of chemotherapy alone versus chemotherapy plus a high dose of multiple antioxidants in patients with advanced NSCLC have been published by Pathak and collaborators.51 In this study, 136 patients with stage IIIB to IV NSCLC were randomized to receive chemotherapy (paclitaxel and carboplatin) alone (chemotherapy arm, n = 72) or chemotherapy in combination with ascorbic acid 6100 mg/d, dl-a-tocopherol (vitamin E) 1050 mg/d, and b-carotene 60 mg/d (combination arm, n = 64). It was reported that antioxidant supplementation during paclitaxel/carboplatin-containing chemotherapy in NSCLC appears to be safe and does not compromise the efficacy of standard chemotherapy. Although all these results indicate a potential benefit for supplementation, large-scale randomized trials will be required before supplementation is accepted as a standard of care in this patient population.

Clinical Aspects of Supplementation During and after treatment, lung cancer survivors may benefit from eating foods that provide concentrated calories that are easy to swallow. Small, frequent meals may be easier to manage than 3 large meals per day. Omega-3 fatty acid supplements and additional nutritional support may be helpful for those patients experiencing weight loss. If nutrient deficiencies are present or patients cannot eat enough to adequately meet micronutrient needs, a multivitamin– mineral supplement is advisable, either in pill or liquid form. Recommendations for nutrition and physical activity for persons who are living with lung cancer are best made based on individual needs. Striving toward a healthy weight by adjusting food intake and physical activity is a reasonable goal, as is ensuring that micronutrient needs are met with a well-balanced diet and a multivitamin–mineral supplement, if needed.52 In addition, intestinal absorption, which could be affected by radiation, chemotherapy, or poor nutrition may be improved by using the amino acid glutamine and lactobacillus.53 Because many lung cancer patients die from cachexia malnutrition, a basic list of orthomolecular supplements and a nutritional protocol with emphasis on this disease are given in Table 2 and Table 3, respectively. For a supplementation to be effective, various factors need to be considered,

including (a) the patient’s medical history, (b) clinical and laboratory tests (including mineral hair analysis), (c) the appropriate antioxidant dose for prevention and treatment, (d) use of chelated mineral supplements to improve their absorption, (e) use of combinations of antioxidants for potential synergy, and (f) the patient’s food intake and lifestyle. In addition, knowledge of the patient’s intestinal absorption status (ie, pH, and permeability) is imperative because intestinal malabsorption may compromise the effectiveness of supplementation.

Antioxidant Protocol and Nutritional Questionnaire for Lung Cancer Patients Lung cancer is largely related to cigarette smoking, but diets low in vegetables and fruits have also been associated with increased lung cancer risk, even after accounting for tobacco use.54 Both these risk factors are associated with increased oxidative stress. As previously discussed, enzymes, minerals, and vitamins play an important role in oxidative stress control. However, the response to treatment may also be influenced by the patient’s comorbidities, which can offset the oxidative status, such as hypertension, obesity, diabetes, and intestinal dysfunctions. Unfortunately, there are no studies in the literature exploring a customized orthomolecular protocol for oncological patients, including antioxidant combinations and nutritional aspects. In addition, studies analyzing lung cancer patients’ blood, feces, and minerals from, for example, hair during chemoradiotherapy to determine the level of oxidative stress are lacking.

Lung Cancer Patient Status via Questionnaire and Lab Analysis We have previously reported results from profiles of vitamins, minerals, and amino acids in lung cancer patients undergoing radiation therapy.55 This was based on analytical laboratory tests and nutritional questionnaires from a cohort of 10 NSCLC patients. The analytical tests included hair elements analysis of toxic elements (Al, Sb, As, Be, Ca, Bi, Cd, Pb, Hg, Pt, Tl, Th, U, Ni, Ag, Sn, and Ti) and essential elements (EEs; Ca, Mg, Na, K, Cu, Zn, Mn, Cr, V, Mo, B, I, P, Li, Se, Sr, S, Ba, Co, Fe, Ge, Rb, and Zr), amino acids profile on plasma (alanine, a-amino adipic acid, a-amino butyric acid, arginine, asparagine, aspartic acid, b-amino isobutyric acid, b-alamine, citruline, cystathione, ethanolamine, g-amino butyric acid, glycine, glutamic acid, glutamine, hydroxyproline, histidine, homocystine, isoleucine, leucine, lysine, methionine, ornithine, phenylalamine, proline, sarcosine, serine, taurine, threonine, tyrosine, tryptophan, valine, 1-methylhistidine, 3-methylhistisdine), fecal analysis (ova and parasites may impair medication and nutrient absorption), whole blood analyses


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Table 2. Antioxidant and Micronutrients to Help Prevent and Mitigate Treatment-Related Toxicities in Lung Cancer Patients Action: Supplementationa

Action: Supplementationa

Allergies:Vit. C, methionine Anemia: iron, folic acid,Vit. B12,Vit. C,Vit. E, Se, L-glutamine, lactobacillus Anxiety: L-5-hydroxytryptophan, L-taurine, B-complex Antiherpes: lysine, Zn,Vit C Anti-inflammatory: carnosine, omega-3, omega-6 Antimyelodysplastic: melatonin Antiangiogenic:Vit. E Appetite:Vit. B1 Bleeding gums: bioflavonoids,Vit. C Blood: pressure—Vit. E,Vit. B3. Ca, Cr, arginine, PH (K); circulation— Vit. B3, Gingko biloba; clotting—Ca; vessel permeability—bioflavonoids; red cell formation—Vit. B12, Folic acid; coagulation—Vit. K Bone marrow toxicity: melatonin Cisplatin toxicity: glutathione Dehydration: K Cholesterol breakdown: Mn, methionine,Vit. A Circulatory system: biotin,Vit. E Collagen: bioflavonoids Detoxification: glutathione, silymarin Digestive system:Vit. B3, L-glutamine, lactobacillus, digestive enzymes Fatigue:Vit. E, iron,Vit. C, B-complex Glycosylation: inhibition—melatonin; protection—V, carnosine

Glucose metabolism:V, Cr Hair loss:Vit. E, methionine, biotin,Vit. B2 Heart: N-acetylcysteine,Vit. E,Vit C Hemoglobin formation: iron,Vit. C Hepatic detoxification: cysteine, methionine, silymarin Hypertension: coenzyme Q-10, Mg, omega-3 Insomnia: melatonin, l-taurine, inositol, Ca, Mg, L-5-hydroxytryptophan Immune boosting: carnosine, melatonin, lactobacilus, lycopene Lung:Vit. A, cysteine Muscle:Vit. B1; growth—L-carnitine; pain—biotin; metabolism— arginine; function—Ca, K Neuropathy: K, Ca, Mg, a-lipoic acid,Vit. B6, glutathione Nervous system:Vit. B3,Vit. D,Vit. B1 Oxidative stress:Vit. C, Zn, Mn, Se,Vit B2, glutathione, Cu Periodontal disease: coenzyme Q-10,Vit. C Prostaglandin synthesis: Glutathione Protein synthesis: Zn, Glutathione Tissue regeneration: folic acid,Vit. A,Vit. B2,Vit. B3, biotin, K, methionine, erythema (grape seed oil, external use) Wound healing: Se; regeneration—Vit. C, Cu, Zn Yeast infection: Lactobacillus, Zn

Abbreviation:Vit., vitamin. a Chelated metal should be used to improve absorption.

Table 3. Basic Protocol to Modulate Cancer Cachexia Objective Nutrition

Physical activity Supplementation (tailoring to the individual)

Breakfast: whole grains cereal with yogurt, whole grain bread with cream To increase calories and gain weight, cheese, or cooked cage free eggs. Green tea or coffee with whole milk decrease glycemic index, mitigate Morning snacks: natural blended fruit juice (apple, plums, peaches, banana, inflammation (foods rich in omega-3 pear) with honey and nuts (eg, walnuts and macadamia) fatty), facilitate swallowing and Lunch: fish and vegetable soufflé or sweet mashed potatoes with cooked stimulate the immune system chicken breast. Spinach cream with soy meat Afternoon Snacks: Soft peanut cookie, pudding with fruit jelly or milkshake Dinner: vegetable soup made with fish/chicken/soy broth; whole rice and vegetable soufflé Night Snacks:Yogurt or dark chocolate pudding Remark: Whatever it is possible, include in the meal nutraceutical foods (rosemary, soybean, shiitake mushroom, mung bean, garlic, lentil bean, leek, pomegranate, onion, American ginseng, angelica root, licorice, dandelion root, ginger, extra virgin olive oil, sesame seed, tomatoes, nuts, and parsley) Walk, stretch and respiratory exercise. To increase appetite, reduce constipaPassive movement or physiotherapy for bed confined patients tion, prevent muscular weakness, and counteract fatigue L-glutamine, Zn and lactobacillus Stimulate gut absorption and decrease yeast infection Melatonin, L-taurine, L-5-hydroxytryptophan, L-taurina, B-complex Insomnia and anxiety Coenzyme Q-10 and Vit. C Periodontal disease Mitigate nutritional deficiencies Vit. E, omega-3, Ca, Mg, Cr, Cu, Zn,Vn, B vitamins,Vit. A, a-lipoic acid,Vit. D3, glutathione, carnosine and beta-carotene

Abbreviation:Vit.Vitamin. Downloaded from http://ict.sagepub.com at EAST CAROLINA UNIV on January 4, 2010

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Campos et al (WBC, RBC, HgB, Hct, MCV, MCH, MCHC, RDW, platelet count), serum chemistries (Na, K, Cl, CO2, Ca, glucose, BUN, total protein, Alb, T bili, ALK phosphatase, SGOT, SGPT, Cr, anion gap, uric acid), lipid panel (cholesterol, HDL, LDL, triglyceride), and others (vitamin B12, ferritin, folate, HbA1C, c-reactive protein [CRP], and homocysteine). The nutritional questionnaire included patient data (name, sex, date of birth, present weight, usual body weight and height); supplement intake (b-carotene, thiamin, riboflavin, niacinamide, vitamin B6, cobalamin, amygdaline, biotin, folic acid, ascorbic acid calciferol, cholecalciferol, tocopherol menadione, phylloquinone); minerals intake (magnesium, iron, calcium, zinc, manganese, chromium, potassium, copper, selenium, and vanadium); amino acid intake (lysine, carnosine, cysteine, arginine, methionine, glutamine l-carnitine); lactobacillus (acidophilus, bulgaricus, rhamnosus); others (coenzyme Q-10, omega 3, omega 6, resveratrol, gingko biloba, bioflavonoids, glutathione, and melatonin); food allergies/aversion; intake barriers (depression, dental problems, difficulty chewing, pain, reflux, nausea, vomiting, diarrhea, constipation, altered sense of smell and taste, dysphasia); alcohol use; medication use; gastrointestinal problems; domestic and/or economic difficulties, kind of meal, and frequency (breakfast, morning and afternoon snacks, lunch/dinner and night snacks); and drugs intake. The study was performed in the radiation oncology department of East Carolina University with a cohort of 10 NSLC patients (ages 40-86) randomly selected during a period of time of 6 months. The results show increased levels of PTEs identified in this cohort (Pt, As, Sn, Cd, Sb, Pb, and Al). High total toxic representation was identified in 20%, and very high total toxic representation was found in 30% of patients. An imbalance for all EEs was identified in 100% of patients. Abnormal ferritin levels were found in 50% of patients, as also abnormal levels of homocysteine (70%), HbA1C (50%), ultrasensitive CRP (US-CRP) (60%), and amino acids (60%). None of the patients met the minimum daily required intake of fruits and vegetables on the nutritional questionnaire. The presence of PTE and imbalance of EEs can lead to a disruption of protein synthesis, catabolism, neurotoxicity, myopathy, hemolytic anemia, renal failure, inflammatory processes, and disruption of ability to produce antioxidant enzymes. High levels of homocysteine, HbA1C, and US-CRP may lead to inflammation, increased probability of clot formation, proliferation of tumor cells, oxidative stress, and aggravated immunological response. From these data, we concluded that all patients showed evidence of nutritional imbalance, presence of toxic elements, and imbalance of EEs, which could lead to increased oxidative stress. Clinical correlation of these levels prior to, during, and after oncological therapy may assist in designing a rational intervention, which may include nutritional intervention, chelation of potential toxic elements, and mineral and vitamin supplementation to

improve outcomes and quality of life. However, variables that may influence the levels of biological indicators independently of exposure (eg, geographical areas to identify air pollution, source of water supply) were not taken into account. The present study provides initial compelling data about the potential benefits of the use of vitamin/mineral supplements as adjunctive therapy for cancer patients. However, there is a need to standardize a nutritional questionnaire and to implement an individualized regime of antioxidants for lung cancer patients according to the treatment protocol and the particular patient’s life condition, with clinical correlation and evaluation of both the benefits and consequence of this approach.

Conclusions Enzymes, minerals, and vitamins play an important role in oxidative stress control. Vitamins in combination with other nutrients promote normal metabolism and interact with each other to facilitate absorption within the body Most lung cancer patients die with nutritional imbalances that are difficult to correct by dietary intake alone. A nutrition questionnaire together with specific laboratory panels can be implemented for lung cancer patients. These tools may serve in providing data to assess the patient’s nutrition oxidative stress and clinical status, and directing nutrition intervention to treatment-related complications. This may result in improved quality of life, decreased morbidity, and prolonged survival. Declaration of Conflicting Interests The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding The authors received no financial support for the research and/or authorship of this article.

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Author Bios: Diana Campos MD, Federal University of Pernambuco, Brazil. Physician specialized in Radiation Pathology (REAC/TS, Oak Ridge, USA), Homeopathy (Brazilian Hahnemanniano Institute) and Orthomolecular Medicine (Center of Orthomolecular Medicine of Rio de Janeiro, Brazil). Physician from the Brazilian Nuclear Energy Commison (1980-2006). Founder and Director of the Orthomolecular Study Center, Recife, Brazil (2005-currently). Visiting Professor, Department of Radiation Oncology and Photodynamic Therapy, East Carolina University (2006-currently) Has published 6 scholarly scientific papers in peer-reviewed journals, authored 2 books (Homeopathy in HIV Patients and Treatment of overexposure to Ionizing Radiation), 26 scientific presentations in congresses and other peer reviewed meetings., and has made numerous invited presentations about medical subjects of public interest in Brazilian broadcast (radio, newspaper and TV). At her private Clinical in Recife, Brazil, she provides consultation for about 900 patients yearly. C Austerlitz Ph.D. degree in nuclear engineering from the Georgia Institute of Technology (1990). M.S degree in health physics (GaTech 1988), M.S. degree Biology (State University of Rio de Janeiro, Brazil, 1982), Research Instructor, Department of Radiation Oncology, East Carolina University, Has received several honors, including fellowships from the Brazilian Nuclear Energy Commission, the Brazilian National Division of Cancer, the German Government for advanced training in Metrology of Ionizing Radiation, and from the French Government for advanced training in dosimetry. Member of both the Brazilian and American Association of Physicists. Has served as an independent consultant for the National Institute for Metrology Standard and Industry Quality in the areas of infant phototherapy equipment, diagnostic and therapeutic laser equipment, and automatically-controlled brachytherpay afterloading. Has published 25 papers in pee-reviewed journals and over 80 scientific presentations in congresses and other peer reviewed meetings. Ron R Allison M.D. Professor and Chairman of the Department of Radiation Oncology and Clinical Director of the Photodynamic Therapy Program. Physician specialized in Radiation Oncologist, board certified in my specialty by the American Board of Radiology, 1992, and diplomat of the National Board of Medical Examiners in 1991. Served as Associate Professor at the State University of New York at Buffalo form 1996-2001 and Professor at East Carolina


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University from 2001 to present. Has conduct manuscript reviews for 15 scientific journals. Has published over 65 scholarly scientific papers in peer-reviewed journals. Has authored 5 book chapters in radiation oncology and photodynamic Therapy. Has made numerous invited presentations in national and international events and has been awarded 7 extramural funded grants. Has received several awards and honors and I am listed in the Who’s Who in Fluorescence 2006, and Who's Who in Medicine Academia, since 2006. Helion Póvoa MD, Federal University of Rio de Janeiro, Brazil. Researcher from the Osvaldo Cruz Foundation. Visiting professor of nutrition in the school of public health from Harvard, Professor of clinical biochemistry in post-graduate of the Pontificia Catholic University of Rio de Janeiro, Brazil. Has published overr 400 research papers in journals congresses and meetings. He is a member of the National Academy of Medicine and the founder and director of Center for Advanced Medicine, CLINICE, Rio de Janeiro, Brazil. Has authored 4 book in the field of orthomolecular. Claudio H Sibata Ph.D. degree in Medical Physic from the University of Wisconsin in Madison in 1984. Professor and

Vice-Chairman in the Department of Radiation Oncology and Science Director of the Photodynamic Therapy Center of the Brody School of Medicine at East Carolina University. Received several awards and honors, including Inventor of the Year Award in 2009, East Carolina University and Fellow of the American Association of Physicists in Medicine. Member of the International Photodynamic Association, American Association of Physicists in Medicine, American Society for Therapeutic Radiology and Oncology, Brazilian Association of Physicists in Medicine, European Society for Therapeutic Radiology and Oncology, and Argentinean Society of Physicists in Medicine. Have supervised more than 35 graduate and post graduate students and fellows. Has served as examiner for the American Board of Radiology since 2000. Physics surveyor sine 2002 for American College of Radiation Oncology and have surveyed over 150 radiation oncology departments since then, Serve as reviewer in several editorial boards of scientific journals such as the Physics in Medicine and Biology, the Medical Physics, the Lancet Oncology, and the International Journal of Radiation Oncology Biology Physics. Has published over 100 scholarly scientific articles in peer-reviewed journals and co-authored 5 chapters in medical physics books and 6 books/monographs.
