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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

 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)
Antioxidants

 Vitamins A, C, E
 Beta-carotene
 Lutein
 Selenium
 Zinc
 Lycopene
 CoQ10

 Colored vegetables and fruits


Richest Food
Sources of Antioxidants

 Small red beans (dried)  Strawberries


 Wild blueberries  Red delicious apples
 Red kidney beans  Granny Smith apples
 Pinto beans  Pecans
 Blueberries (cultivated)  Sweet cherries
 Cranberries  Black plums
 Artichokes (cooked)  Russet potatoes
 Blackberries (cooked)
 Prunes
 Black beans (dried)
 Raspberries
 Plums
 Gala apples
 Dark Chocolate
Avoid Antioxidants?
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?)
Pre-Chemo/Rad
Oxidative 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
Pre-Chemo/Rad
Oxidative 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
This assumes that
antioxidants protect cancer cells
from apoptosis.

Is that, in fact, the truth?


9/05 D’Andrea Article in
CA: 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
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
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.”
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”
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
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.
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
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
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
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.
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
Vitamin A and
Chemotherapy

 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
Vitamin A and
Chemotherapy

 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
Vitamin A and
Radiation

 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)
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)
Melatonin and
Chemotherapy
 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
Melatonin and
Radiation

 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
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
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
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
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
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.
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.
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
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
Chinese Medicine
and 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
Chinese Medicine
and 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
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.
Whole Food
vs. 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
Multifocal
curcmin, artemsia,
mistletoe, ginger VEGFR
scutellaria,

Angiostatic
resveratrol, EGCG, silymarin,
grapeseed extract, quercetin,
green tea, gingko, curcmin, resveratrol, soy

Therapy
ginger isoflavones,
squalamine, Vit D scutellaria,
artemsia curcumin, EPA
silymarin, glycine, cartilege,
mistletoe
silymarin, Cu antagonists
curcumin
green tea
scutellaria

bFGFR and TNF-1:


Cu antagonists
Growth
Factors
NFkB VEGF, AKs, bFGF, IL8, MMPs,
COX-2
TNF-1, heparinases, collagenases

Silymarin,
Glycine, Ginger

Anti- NFkB: poria,


Anti GFs:
coriolus, ginger,
green tea
resveratrol, green tea,
quercetin
Anti-COX-2: quercetin, scutellaria, artemsia, quercetin,
magnolia
EPA/DHA, licorice, ginger, carnosol, panax ginseng,
resveratrol,
resveratrol, grapeseed extract, silymarin, salicylates,
soy, curcumin
curcumin, salicylates, garlic, green curcumin, picentannol,
holy basil
tea, panax ginseng, silymarin, basil, Cu antagonists
rosemary
bilberry, antioxidants, boswellia, rosemary
ganoderma
aloe
licorice Vit E
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?