Transcript No decrease in efficacy of cisplatin

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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The main area of controversy deals with the
concurrent use of Antioxidants
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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
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Vitamins A, C, E
Beta-carotene
Lutein
Selenium
Zinc
Lycopene
CoQ10
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Colored vegetables and fruits
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Richest Food
Sources of Antioxidants
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Small red beans (dried)
Wild blueberries
Red kidney beans
Pinto beans
Blueberries (cultivated)
Cranberries
Artichokes (cooked)
Blackberries
Prunes
Raspberries
Dark Chocolate
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Strawberries
Red delicious apples
Granny Smith apples
Pecans
Sweet cherries
Black plums
Russet potatoes
(cooked)
Black beans (dried)
Plums
Gala apples
Avoid Antioxidants?
Avoid Antioxidants?
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R Salganik, MD, PHD UNC-Chapel Hill
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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?)
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Pre-Chemo/Rad
Oxidative Stress
Screening?
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R Salganik, MD, PHD UNC-Chapel Hill
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Argues for screening populations for ROS
(reactive oxygen species)
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Hyper-producers of ROS
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Argues that some level of ROS is necessary
Higher CA risk (and coronary dz, dementia, etc)
Better use of AO
Hypo-producers of ROS
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Lower CA risk
Use of AO possibly unnecessary or at worst harmful
Pre-Chemo/Rad
Oxidative Stress
Screening?
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Hypo-producers of ROS with high
carcinogenic exposure (smoker, industrial
chemicals)
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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
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“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
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Agreement
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Absence of adequate RCT evidence on
concurrent use
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Cancer patients should not selfmedicate with antioxidants
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Use or non-use could be harmful
Cancer not a self-help disease
Not all antioxidants likely to be
beneficial
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Some may interfere with chemotherapy or
radiotherapy
Vitamin C
Moertel Studies
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D’Andrea: Neither study showed improvement vs
placebo and possibly worse survival in Vit C group
1st Study
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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
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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
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D’Andrea speculates on Golde’s findings
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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)
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IV Vit C selectively kills variety of CA cells
“By acting as a pro-drug to deliver
hydrogen peroxide to malignant tissues”
Lesperance Study
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90 women early-stage breast cancer
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Standard therapy with or without
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B-carotene, niacin, Vit C, selenium, CoQ10, zinc
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Retrospective review matched cases from one physician’s
practice (Dr. Adam Hoffer, MD, PhD)
NOT RCT
Patients took 3-6 supplements
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Doses varied widely
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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?
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D’Andrea:
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“Although many confounding factors may explain these
differences in survival, the data should concern any
oncologist who has patients considering antioxidant
therapy.”
Archie:
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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
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Radiation for variety of cancers
50 patients randomized
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+/- Vit C 1 gram orally 5x per day
4 month follow-up (meaningful?)
63% vs. 45% complete remission
 Fewer side effects
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Hanck. Prog Clin Biol Res. 1988;259:307
CoQ10 and
Breast Cancer
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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
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May 2005 Study. Rats with mammary tumors
were given tamoxifen, coenzyme Q10,
tamoxifen plus coenzyme Q10, or no therapy.
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Addition of CoQ10 increased the susceptibility of
cancer cells to tamoxifen.
Perumal et al. Mol Cell Biochem. 2005 May;273(1-2):151-60.
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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
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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
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No interference with radiation in mouse
studies at 10mg/kg dose
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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
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Small Cell Lung Cancer
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Sarcoma
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efficacy of etoposide in vitro
efficacy of doxorubicin in vitro
efficacy of doxorubicin, cisplatin,
vincristine
Head and Neck cancer
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Synergistic with cisplatin
Vitamin A and
Chemotherapy
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Pancreatic Cancer
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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
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Radiotherapy +/- Vit A 150,000iu or
beta-carotene 90mg/kg in mice with
xenografted breast cancer
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survival
tumor size
Adv squamous cell CA mouth (human)
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mucositis
No change in survival (no interference)
Beta-Carotene
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Decreased efficacy of antimetabolites
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5-FU
Methotrexate
Increased efficacy of radiotherapy
Increased efficacy of some
chemotherapy
Alkylating (cyclophosphamide, ifosamide)
 Anthracycline (Adriamycin, bleomycin)
 Platinum-containing (cisplatin)
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Melatonin and
Chemotherapy
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100 people with metastatic Non-small cell
Lung cancer randomized to chemo alone vs.
chemo plus melatonin 20mg/day
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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
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RCT Glioblastoma
Radiation +/- melatonin 20mg
Increased 1 year survival in melatonin
group
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6/14 vs 1/14 still alive
Fewer side effects in melatonin group
Lissoni. Onc. 1996;53:43
N-acetylcysteine
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efficacy of anthracycline-type drugs in animal
studies
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Doxorubicin (Adriamycin)
Bleomycin
No known reduction of Adriamycin-associated
cardiotoxicity
No effect on alkylating agents
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Cyclophosphamide
hematuria associated with cyclophosphamide
efficacy of cisplatin vs bladder cancer cells in vitro
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But NAC is used to treat cisplatin-associated renal failure
Glutatione, Cisplatin
and Neurotoxicity
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Fear: Thiol-containing antioxidants
might interfere with platinum-containing
drugs
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N-acetylcysteine blunts efficacy of
cisplatin vs. bladder cancer cells in vitro
Glutatione is a thiol-containing
substance
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Glutathione does not interfere with
cisplatin
Glutathione, Cisplatin and
Neurotoxicity
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Glutathione found in Phase 3 clinical trials to
decrease adverse effects of cisplatin
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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
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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
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Some studies fail to replicate this
Bozzetti et al. Nutr. 1997;13:748
Tangeretin
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Flavanoid found in citrus fruit
efficacy of platinum drugs (cisplatin,
carboplatin)
efficacy of hormonal agent tamoxifen
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Bracke et al. J Natl Cancer Inst. 1999;91:354.
Green Tea
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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
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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.”
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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 combinedmodality 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
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One of the most common dose-limiting
complications of chemotherapy
Melatonin
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Improved WBC and platelet counts in NSCCLung
with etoposide and cisplatin
Astragalus
Cochrane Collaborative
 leukopenia, nausea, vomiting and overall side
effects of chemotherapy
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Chinese Medicine
and Radiation
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Fu-Zheng pattern (correct predisposing
patterns of deficiency and stagnation)
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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
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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.
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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
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Finish study SCCLung with chemo and
radiation +/- antioxidant supplement
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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
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Juice Plus is first supplement endorsed by the
Center for Advancement in Cancer Education
(CACE)
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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
curcmin, artemsia,
mistletoe, ginger
scutellaria,
resveratrol,
grapeseed extract,
green tea, gingko, ginger
squalamine, Vit D
artemsia
silymarin, glycine, mistletoe
curcumin
scutellaria
VEGFR
curcmin,
scutellaria,
cartilege,
silymarin,
green tea
EGCG, silymarin,
quercetin,
resveratrol, soy
isoflavones,
curcumin, EPA
Multifocal
Angiostatic
Therapy
Cu antagonists
bFGFR and TNF-1:
Growth
Factors
NFkB
COX-2
Cu antagonists
VEGF, AKs, bFGF, IL8, MMPs,
TNF-1, heparinases, collagenases
Silymarin,
Glycine, Ginger
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
Anti- NFkB: poria,
coriolus, ginger,
resveratrol, green tea,
artemsia, quercetin,
carnosol, panax ginseng,
silymarin, salicylates,
curcumin, picentannol,
basil, Cu antagonists
rosemary
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?