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Controversies over Concurrent Use of Supplements and Foods During Chemotherapy and Radiotherapy Dr. Tom Archie, MD, DAB

Controversies over Concurrent Use of Supplements and Foods During Chemotherapy and Radiotherapy Dr. Tom Archie, MD, DABFP, DABMA Wood River Cancer Guides - Hailey, ID Updated as of 2006 www.drtomsalchemy.com. Antioxidants.

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Controversies over Concurrent Use of Supplements and Foods During Chemotherapy and Radiotherapy Dr. Tom Archie, MD, DAB

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  1. Controversies over Concurrent Use of Supplements and Foods During Chemotherapy and Radiotherapy Dr. Tom Archie, MD, DABFP, DABMA Wood River Cancer Guides - Hailey, ID Updated as of 2006 www.drtomsalchemy.com

  2. Antioxidants • The main area of controversy deals with the concurrent use of Antioxidants • Reduce oxidative stress (stealth of electrons from a stable molecule to an oxidizing substance) • Increases availability of unstable “free radicals” • Damage nearby DNA, increase inflammation and mutations • Not all foods and supplements have antioxidant properties • Important not to confuse antioxidants with all supplements and foods, although many foods have some antioxidant properties (many fruits/veggies)

  3. Antioxidants • Vitamins A, C, E • Beta-carotene • Lutein • Selenium • Zinc • Lycopene • CoQ10 • Colored vegetables and fruits

  4. Small red beans (dried) Wild blueberries Red kidney beans Pinto beans Blueberries (cultivated) Cranberries Artichokes (cooked) Blackberries Prunes Raspberries Dark Chocolate Strawberries Red delicious apples Granny Smith apples Pecans Sweet cherries Black plums Russet potatoes (cooked) Black beans (dried) Plums Gala apples Richest Food Sources of Antioxidants

  5. Avoid Antioxidants?

  6. Avoid Antioxidants? • R Salganik, MD, PHD UNC-Chapel Hill • Argues for studying AO-depleted diet in humans • Mice w/ brain tumors fed normal diet vs. AO-depleted diets • AO-depleted diets assoc w/ higher ROS (reactive oxygen species), more apoptosis of cancer cells (vs. normal), and smaller tumors • No study of survival changes (malnutrition risk?)

  7. Pre-Chemo/RadOxidative Stress Screening? • R Salganik, MD, PHD UNC-Chapel Hill • Argues for screening populations for ROS (reactive oxygen species) • Argues that some level of ROS is necessary • Hyper-producers of ROS • Higher CA risk (and coronary dz, dementia, etc) • Better use of AO • Hypo-producers of ROS • Lower CA risk • Use of AO possibly unnecessary or at worst harmful

  8. Pre-Chemo/RadOxidative Stress Screening? • Hypo-producers of ROS with high carcinogenic exposure (smoker, industrial chemicals) • AO might prevent apoptosis of CA cells (smokers and beta-carotene) Salganik. JACN. 2001;20(5):464S

  9. This assumes that antioxidants protect cancer cells from apoptosis. Is that, in fact, the truth?

  10. 9/05 D’Andrea Article inCA: A Cancer Journal for Clinicians • “Use of Antioxidants During Chemotherapy and Radiotherapy Should Be Avoided” • Poor and biased review • Basis for D’Andrea’s argument • Theory of antioxidant mechanism vs “therapeutic” oxidative stress by chemo/rad • Selective group of trials re: negative interaction • Studies against antioxidant efficacy in general but having nothing to do with concurrent use

  11. Agreement • Absence of adequate RCT evidence on concurrent use • Use or non-use could be harmful • Cancer patients should not self-medicate with antioxidants • Cancer not a self-help disease • Not all antioxidants likely to be beneficial • Some may interfere with chemotherapy or radiotherapy

  12. Vitamin C Moertel Studies • D’Andrea: Neither study showed improvement vs placebo and possibly worse survival in Vit C group • 1st Study • Patients had chemo first, followed by oral Vit C • Vit C given to immunocompromised pts (NOT CONCURRENT and not even Vit C as initial therapeutic trial vs cancer) • 2nd Study • No Chemo – NOT A CONCURRENT STUDY • Vit C 10 grams oral (no IV Vit C – Pauling had shown efficacy of IV Vit C) • NIH’s Levine: “Efficacy of Vit C cannot be judged from clinical trials that use only oral dosing.”

  13. Vitamin C • D’Andrea speculates on Golde’s findings • Vit C enters cancer cells via glucose transporters • Assumes that this Vit C “feeds” cancer cell • Assumes Vit C interferes with chemo/rad • Levine at NIH proved (vs. speculation) • IV Vit C selectively kills variety of CA cells • “By acting as a pro-drug to deliver hydrogen peroxide to malignant tissues”

  14. Lesperance Study • 90 women early-stage breast cancer • Standard therapy with or without • B-carotene, niacin, Vit C, selenium, CoQ10, zinc • NOT RCT • Retrospective review matched cases from one physician’s practice (Dr. Adam Hoffer, MD, PhD) • Patients took 3-6 supplements • Doses varied widely • CoQ10 – does never recorded • Selenium 1-750 mcg • Zinc 0-50 mg • Vit C 1-24 grams • AO group had lower disease-free survival, breast cancer-specific survival, but same overall survival rate as non-AO group

  15. Lesperance Study What does it mean? • D’Andrea: • “Although many confounding factors may explain these differences in survival, the data should concern any oncologist who has patients considering antioxidant therapy.” • Archie: • The data should concern any oncologist that the data are meaningless. • D’Andrea should be careful not to inappropriately bias the readership of CA: A Cancer Journal for Clinicians against supplements which may actually be helpful and not harmful.

  16. Vitamin C and Radiation • Radiation for variety of cancers • 50 patients randomized • +/- Vit C 1 gram orally 5x per day • 4 month follow-up (meaningful?) • 63% vs. 45% complete remission • Fewer side effects Hanck. Prog Clin Biol Res. 1988;259:307

  17. CoQ10 and Breast Cancer • Blocks COX-2 • High dose of CoQ10 associated with fewer deaths in women with metastatic breast cancer Lockwood, Biochem Biophys Res Commun 1995 July 6;212(1):172

  18. CoQ10 and Tamoxifen • May 2005 Study. Rats with mammary tumors were given tamoxifen, coenzyme Q10, tamoxifen plus coenzyme Q10, or no therapy. • Addition of CoQ10 increased the susceptibility of cancer cells to tamoxifen. Perumal et al. Mol Cell Biochem. 2005 May;273(1-2):151-60. • February 2005 study: mammary tumor proliferation in rats was prevented by the administration of tamoxifen plus CoQ10, niacin, and riboflavin. Perumal et al. Chem Biol Interact. 2005 Feb 28;152(1):49-58

  19. Co Q10 and Adriamycin • Doxorubicin (Adriamycin) • Increased risk for congestive heart failure • CoQ10 protects against this risk without interfering with the cytotoxic effect of the drug Konklin. J Nutr. 134(11) 3201S.

  20. CoQ10 and Radiation • No interference with radiation in mouse studies at 10mg/kg dose • There was interference at 40mg/kg, but a standard “high dose” human dose is 400mg (about 5-8mg/kg in human adult) Lund. Folia Microbiol. 1998;43:505

  21. Vitamin A andChemotherapy • Small Cell Lung Cancer • efficacy of etoposide in vitro • efficacy of doxorubicin in vitro • Sarcoma • efficacy of doxorubicin, cisplatin, vincristine • Head and Neck cancer • Synergistic with cisplatin

  22. Vitamin A andChemotherapy • Pancreatic Cancer • Vitamin A palmitate 50,000 iu orally twice per day plus b-interferon and combined chemotherapy (epirubicin, mitomycin C, and 5-fluorouracil) • Prolonged symptom palliation in 35%pts • Fairly toxic combination, however only toxic effect attributed to Vit A was hepatic • Also helpful in non-lymphocytic leukemia

  23. Vitamin A andRadiation • Radiotherapy +/- Vit A 150,000iu or beta-carotene 90mg/kg in mice with xenografted breast cancer • survival • tumor size • Adv squamous cell CA mouth (human) • mucositis • No change in survival (no interference)

  24. Beta-Carotene • Decreased efficacy of antimetabolites • 5-FU • Methotrexate • Increased efficacy of radiotherapy • Increased efficacy of some chemotherapy • Alkylating (cyclophosphamide, ifosamide) • Anthracycline (Adriamycin, bleomycin) • Platinum-containing (cisplatin)

  25. Melatonin andChemotherapy • 100 people with metastatic Non-small cell Lung cancer randomized to chemo alone vs. chemo plus melatonin 20mg/day • 5-year survival higher in melatonin group • (6% vs. 0%) • Chemotherapy better tolerated in melatonin group. • Similar effects seen in RCTs of colorectal cancer and effective vs cancer-related thrombocytopenia Lissoni. J Pineal Res 2003;35:12 Cerea et al. Anticancer Res.2003;23:1951 Lissoni et al. J Pineal Res 2001;30:123

  26. Melatonin andRadiation • RCT Glioblastoma • Radiation +/- melatonin 20mg • Increased 1 year survival in melatonin group • 6/14 vs 1/14 still alive • Fewer side effects in melatonin group Lissoni. Onc. 1996;53:43

  27. N-acetylcysteine • efficacy of anthracycline-type drugs in animal studies • Doxorubicin (Adriamycin) • Bleomycin • No known reduction of Adriamycin-associated cardiotoxicity • No effect on alkylating agents • Cyclophosphamide • hematuria associated with cyclophosphamide • efficacy of cisplatin vs bladder cancer cells in vitro • But NAC is used to treat cisplatin-associated renal failure

  28. Glutatione, Cisplatin and Neurotoxicity • Fear: Thiol-containing antioxidants might interfere with platinum-containing drugs • N-acetylcysteine blunts efficacy of cisplatin vs. bladder cancer cells in vitro • Glutatione is a thiol-containing substance • Glutathione does not interfere with cisplatin

  29. Glutathione, Cisplatin and Neurotoxicity • Glutathione found in Phase 3 clinical trials to decrease adverse effects of cisplatin • Gastric, ovarian, colorectal, NSCCLung, head/neck • Neurotoxicity, need for transfusion, hair loss, difficulty concentrating, anemia, thrombocytopenia • No decrease in efficacy of cisplatin • Patients able to tolerate more cisplatin treatments • Same effects seen for oxilaplatin Smyth et al. Ann Oncol. 1997;8:569 Cascinu et al. J Clin Oncol. 1995;13:26-32 Cascinu et al. J Clin Oncol. 2002;20:3478-83 Smidinger et al. Wien Klin Wochenschr. 2000;112:617-23

  30. Glutamine • Protects GI tract vs. radiation and chemotherapy toxcity • Preserves glutathione levels • Prevents Adriamycin cardiac toxcicity Cao. J Surg Res. 1999;85:178 Decker-Baumann. Eur J Cancer. 1999;35:202 Jensen et al. Ann Surg Oncol. 1994;1:157 • Some studies fail to replicate this Bozzetti et al. Nutr. 1997;13:748

  31. Tangeretin • Flavanoid found in citrus fruit • efficacy of platinum drugs (cisplatin, carboplatin) • efficacy of hormonal agent tamoxifen • Bracke et al. J Natl Cancer Inst. 1999;91:354.

  32. Green Tea • concentration of Adriamycin in two tumor types but not in normal tissue • anti-tumor efficacy by 2.5x vs. ovarian sarcomas Sadzuka. Clin Cancer Res. 1998;4:153. Sugyama. Cancer Letter. 1998;133:19.

  33. Malnutrition • NCI website: “Side effects of cancer and cancer treatments make it difficult to eat well…Malnutrition can result, causing the patient to be weak, tired, and unable to resist infections or withstand cancer therapies.” • Yale University“In addition to weight lost prior to the diagnosis of head and neck cancer, the patient may lose an additional 10% of pre-therapy body weight during radiotherapy or combined- modality treatment.” “A reduction of greater than 20% of total body weight results in an increase in toxicity and mortality.” Colasanto et al. Onc. 2005;19:371

  34. Immunosuppression • One of the most common dose-limiting complications of chemotherapy • Melatonin • Improved WBC and platelet counts in NSCCLung with etoposide and cisplatin • Astragalus • Cochrane Collaborative • leukopenia, nausea, vomiting and overall side effects of chemotherapy

  35. Chinese Medicineand Radiation • Fu-Zheng pattern (correct predisposing patterns of deficiency and stagnation) • Symptom management and increase in survival • 197 pts Stage III and IV ENT cancers randomized to radiation with or without TCM herbs (Yi Qi Yang Yin Tang). 3-year survival 67% vs. 33%. Sun. Rec Results in Cancer Research 1988:108:327

  36. Chinese Medicineand Chemotherapy • 303 patients with Stage III and 63 with Stage IV gastric cancer with chemo randomized to additional Pishen Fang herbal formula or to control group. • 5yr survival 53% Stage III with herbs and 10% Stage IV with herbs • 10yr survival 47% Stage III with herbs Yu. J Trad Chin Med 1993;13(1):31. • 2001 first US FDA-approved clinical study of extract of Coix lachryma-jobi called Kanglaite for refractory solid tumors (Lung CA mentioned). Study ongoing. Previous Chinese studies show inhibition of mitosis of tumour cells during G2/M phase of the cell cycle, tumor cell apoptosis, increased gene expression of FAS and Apo-1, inhibits angiogenesis www.clinicaltrials.gov/ct/show/NCT00031031?order=1 www.annieappleseedproject.org/kanglaite.html

  37. Concurrent Use – Both Chemo and Rad • Finish study SCCLung with chemo and radiation +/- antioxidant supplement • Concurrent antioxidants survival • Vit A 15,000 IU, B-carotene 10,000 IU, a-tocopherol 300 IU, Vit C 2000mg, and selenium 800mcg • 2yr survival >33% vs <15% historical controls • Non-randomized study of 18 people compared to historical controls • (Not much unlike the Lesperance study, except that the doses were the same for each person) Jaakkola. Anticancer Research. 1992;12:599.

  38. Whole Foodvs. Synthetic • Juice Plus is first supplement endorsed by the Center for Advancement in Cancer Education (CACE) • 1. apples, oranges, pineapple, cranberries, peaches, acerola cherries, papaya • 2. carrots, parsley, beets, kale, broccoli, cabbage, spinach, tomatoes, barley, oat fibers • 3. blueberries, blackberries, bilberries, raspberries, cranberries, elderberries, black currants, red currants, and Concord grapes • oxidative stress, DNA damage, homocysteine, immune function markers

  39. curcmin, artemsia, mistletoe, ginger scutellaria, resveratrol, grapeseed extract, green tea, gingko, squalamine, Vit D silymarin, glycine, Multifocal Angiostatic Therapy VEGFR EGCG, silymarin, quercetin, resveratrol, soy isoflavones, curcumin, EPA Cu antagonists curcmin, scutellaria, cartilege, silymarin, green tea ginger artemsia mistletoe curcumin scutellaria bFGFR and TNF-1: Cu antagonists Growth Factors NFkB COX-2 VEGF, AKs, bFGF, IL8, MMPs, TNF-1, heparinases, collagenases Silymarin, Glycine, Ginger Anti- NFkB: poria, coriolus, ginger, resveratrol, green tea, artemsia, quercetin, carnosol, panax ginseng, silymarin, salicylates, curcumin, picentannol, basil, Cu antagonists rosemary Anti GFs: green tea quercetin magnolia resveratrol, soy, curcumin holy basil rosemary ganoderma licorice Vit E Anti-COX-2: quercetin, scutellaria, EPA/DHA, licorice, ginger, resveratrol, grapeseed extract, curcumin, salicylates, garlic, green tea, panax ginseng, silymarin, bilberry, antioxidants, boswellia, aloe

  40. We’ve all been waiting, wondering, Will we ever know the truth? What it’s like washing windows When you know that there are pigeons on the roof?

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