Stiles Program In Integrative Oncology - Cancer Alternatives - UCLA
Stiles Program In Integrative Oncology - Cancer Alternatives - UCLA
Stiles Program In Integrative Oncology - Cancer Alternatives - UCLA
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<strong>Stiles</strong> <strong>Program</strong> in<br />
<strong>In</strong>tegrative <strong>Oncology</strong><br />
Herbal and Natural Products<br />
for <strong>Cancer</strong> Prevention and<br />
Therapy<br />
Richard J. Pietras, PhD, MD<br />
Jonsson Comprehensive <strong>Cancer</strong><br />
Center, <strong>UCLA</strong>
Herbs and Natural<br />
Products in <strong>Cancer</strong><br />
• <strong>Cancer</strong> facts<br />
• What is complementary therapy?<br />
• Unproven and proven therapies<br />
• Natural products in development and in<br />
clinical trials for cancer treatment<br />
• Herbal and natural approaches to cancer<br />
prevention<br />
• What you can do to stop cancer
CANCER, The 36 Years War<br />
Jemal, A. et al. CA <strong>Cancer</strong> J Clin 2003<br />
National <strong>Cancer</strong> Act<br />
for “War on <strong>Cancer</strong>”<br />
passed in 1971<br />
Each day, 1,500 Americans die from cancer (559,650 /year)<br />
About 40% men and 33% women at lifetime risk for cancer
The Bad News:<br />
The <strong>Cancer</strong> Epidemic<br />
- 10 million cancer cases, 6 million deaths / year worldwide<br />
- 1,300,000 cases of cancer per year in US<br />
The Good News:<br />
- Currently, more than 10 million survivors of cancer<br />
- US cancer death rates are falling by ~ 2.1% per year<br />
- 40-60% of cancers may be avoided or prevented by :<br />
a) personal changes in behavior (diet, lifestyle, habits)<br />
b) environmental interventions<br />
c) vaccines for papillomavirus,hepatitis B, H. pylori
<strong>Cancer</strong> <strong>In</strong>cidence in Men and Women
Annual <strong>Cancer</strong> Death Rates, 1930-2003<br />
Since 1971, comprehensive research helped to raise 5-year survival for<br />
breast, prostate and colon cancers, but lung cancer is only 15%<br />
Jemal, A. et al. CA <strong>Cancer</strong> J Clin 2007;57:43-66; Morosini D. CURE 2007; 6: 80
normal cell<br />
How do tumors form and<br />
Heredity Endocrine<br />
progress?<br />
metastasis<br />
Chemicals Nutrition Gene changes<br />
Radiation <strong>In</strong>flammation<br />
Viruses<br />
stem/progenitor cell<br />
preneoplastic malignant<br />
metastasis<br />
INITIATION PROMOTION PROGRESSION
<strong>Cancer</strong> progression : early detection &<br />
treatment is best chance for CURE<br />
PROGRESSION<br />
PROMOTION<br />
INITIATION<br />
DEATH<br />
CURE CURE
Current <strong>Cancer</strong> Therapy<br />
• Surgery<br />
• Chemotherapy<br />
• Radiation Therapy<br />
• Biologic Therapy<br />
• Complementary Therapy<br />
• Preventive Therapy
History of Complementary<br />
Medicine<br />
Hippocrates<br />
Father of<br />
modern<br />
western<br />
medicine and<br />
herbal<br />
practitioner<br />
460-370 BC
History of Complementary Medicine<br />
Ancient Mesopotamia 3000 BC Sumerian Empire used plant<br />
medicines for fever, stroke, lung and liver disease<br />
Traditional Chinese Medicine 2900-2600 BC ‘Neiching’ and<br />
yin-yang philosophy. Combines diet, >1800 herbs, and acupuncture<br />
to enhance, restore health<br />
Ayurvedic Medicine 800 BC- 1000 AD <strong>In</strong>dian healing system<br />
with diet, herbs, exercise, meditation, massage, light<br />
Greek Medicine 500 BC Hippocrates emphasized treating the<br />
patient, not just the disease, with diet as main treatment and<br />
herbs when diet alone not adequate<br />
Aztec, Mayan, <strong>In</strong>ca and Native American Medicine in the<br />
Americas. Medicinal herbs, minerals and natural products
Complementary<br />
Medicines<br />
WHO estimates that 80% of world<br />
population relies on plant-based<br />
medicines for primary healthcare<br />
75% of all pharmaceuticals were<br />
discovered by examining use of<br />
plants in traditional medicine
Hope or Hype?<br />
Alternative medicine is edging into the<br />
mainstream, with Californians in the lead.<br />
Debate rages about its effectiveness and<br />
scientific oversight<br />
ALTERNATIVE MEDICINE<br />
The $22-Billion Experiment<br />
Los Angeles Times (2005)
Complementary and Alternative Therapies<br />
Complementary Medicine - complement traditional western,<br />
evidence-based medicine :<br />
• meditation to reduce stress<br />
• acupuncture for relief of pain and nausea<br />
Alternative Medicine – therapeutic approaches taken in place<br />
of western medicine and often based on anecdotal reports,<br />
uncontrolled trials or traditional use suggesting lack of harm<br />
<strong>In</strong>tegrative Medicine - combination of traditional western (or<br />
allopathic) medicine & complementary medical approaches<br />
Complementary and Alternative Medicine (CAM) - acronym<br />
to describe study or use of complementary and alternative<br />
approaches<br />
American <strong>Cancer</strong> Society Guide to Complementary and Alternative <strong>Cancer</strong> Methods
Alternative Therapies<br />
Disproven in Clinical Trials<br />
Laetrile: cancer due to deficiency vitamin B17 (no such<br />
vitamin); median survival 4.8 mo in advanced cancer pts<br />
Livingston-Wheeler: cancer due to progenitor cryptocides<br />
bacteria (but bacteria does not exist)<br />
DiBella Multitherapy: cancer asstd with growth hormone<br />
Antineoplaston: NCI trial in glioblastoma, TTP 29 days and<br />
all patients died before study closed<br />
High-Dose Vitamin C: No change in colorectal cancer<br />
survival
Proven Antitumor Therapies<br />
Derived from Natural Sources<br />
Podophyllum peltatum, P. hexandrum:<br />
etoposide<br />
Catharanthus roseus (Madagascar periwinkle):<br />
vincristine<br />
vinblastine<br />
Taxus brevifolia (Pacific Yew tree):<br />
taxol (paclitaxel)<br />
taxotere (docetaxel)
Complementary Therapies with<br />
Potential Benefit in <strong>Cancer</strong> Prevention<br />
or Therapy: Ongoing Clinical Trials<br />
Saw Palmetto: BPH, prostate cancer?<br />
Lycopene: prostate cancer<br />
Beta-Glucans: lymphoma,<br />
activate complement<br />
receptor-3 to promote antitumor immunity<br />
Squalamine: non-small cell lung cancer, ovarian cancer<br />
Scutelleria: prostate, breast, lung cancers<br />
Green tea: breast cancer, prostate cancer, oral cancers
Proven Antitumor Therapies<br />
Derived from Natural Sources<br />
Of 92 antitumor drugs approved 1983-1994, 62 (67%) were<br />
of natural origin: based on natural cmpd:<br />
Actinomycin D Vincristine aminoglutethemide<br />
Asparaginase Epirubicin cytosine arabinoside<br />
Bleomycin Estramustine floxuridine<br />
Daunomycin Etoposide fluorouracil<br />
Doxorubicin Idarubicin goserelin acetate<br />
Mithramycin Irinotecan methotrexate<br />
Paclitaxel Megestrol mitoxantrone<br />
Streptozocin Vinorelbine tamoxifen<br />
Vinblastine Leuprolide faslodex
Trends in use of complementary medicine<br />
• 42% Americans use some form of complementary therapy<br />
• 629 million visits to alternative practitioners > primary care<br />
visits<br />
• 50-70% of breast cancer patients use some form of<br />
complementary therapy<br />
30% dietary therapy (megavitamins, supplements)<br />
24% spiritual healing<br />
21% herbal remedies<br />
15% physical methods (acupuncture, massage)<br />
10% psychological methods
Why Do People Use<br />
Complementary Therapy?<br />
• “Safer” and “more natural”<br />
•“Holistic”<br />
• “My complementary practitioner spends<br />
more time and treats me as a whole<br />
person”<br />
• Symptom relief (pain, nausea)
The Communication Gap<br />
• Don’t ask, don’t tell. Patients not talking to<br />
physicians about their use of CAM.<br />
• Only 54% of breast cancer patients seeing a<br />
CAM practitioner told their MD (“The doctor<br />
never asked”)<br />
• 94% cancer patients discussed their biomedical<br />
treatments with their CAM providers<br />
Herb-Drug <strong>In</strong>teractions : On review by<br />
pharmacologists, more than 12% of herbal<br />
treatments could interfere with conventional<br />
cancer therapies
Federal Drug Law<br />
1906 Pure Food and Drug Act : truthful labeling (TR)<br />
1938 Food, Drug and Cosmetic Act : safety testing<br />
1962 Food, Drug and Cosmetic Act : prove drug efficacy;<br />
stringent guidelines for testing (preclinical toxicity, efficacy,<br />
controlled clinical trials)(JFK) - thalidomide and phocomelia<br />
1994 Dietary Supplement Health and Education Act :<br />
allows OTC sale of herbals and food supplements for<br />
general health maintenance without FDA review; no proof<br />
of safety or efficacy required; burden of safety placed on<br />
FDA to remove products with compelling evidence of harm<br />
2004 FDA bans dietary supplements with ephedra
New Federal Drug Laws<br />
2007 FDA Amendments Act - new FDA post-market<br />
surveillance (adverse effects, advertising) and<br />
enforcement powers to regulate prescription<br />
drugs, but specifically does not alter regulation<br />
of supplements under DSHE Act or adverse<br />
event reporting under prior federal law<br />
2007 FDA sets new rules to regulate what’s in a<br />
supplement (purity) and to report adverse<br />
effects, but manufacturers still not required to<br />
show product safety or efficacy, rules that are<br />
strict requirements for prescription drugs
Dietary Supplements, Adverse<br />
Events, and Efficacy<br />
FDA overload: 4,000 unregulated products in 1994<br />
when DSHEA passed, but more than 29,000 now<br />
<strong>In</strong> 2001, FDA had 500 reports of adverse events due<br />
to supplements; and 19,468 at poison-control centers<br />
FDA, California Dept of Health and Japanese Health<br />
Ministry find 10%-32% of Chinese herbal products<br />
contain undeclared drugs or heavy metals (lead,<br />
mercury or arsenic)<br />
Randomized control trial evidence of clinical efficacy<br />
exists for < 30 herbs
Herbal Therapies<br />
• Herbal supplements not standardized for safety<br />
or efficacy; purity standards not mandated til 2010<br />
-“Standardized” ginseng has defined % ginsenosides, but<br />
more than 30 ginsenosides may contribute to biologic<br />
effect; different suppliers provide different amounts<br />
• “Natural” not necessarily beneficial<br />
-Drug effects (PC-SPES reduces PSA prostate CA but<br />
decreases libido, breast enlarge, nausea, diarrhea,<br />
thromboembolism)<br />
-Unknown drug interactions
Potential Adulterants and<br />
Contaminants in Herbal Preparations<br />
Drugs warfarin, anti-inflammatory, corticosteroids,<br />
benzodiazepines, sildenafil, diethylstilbestrol<br />
Toxic metals lead, cadmium, mercury, arsenic<br />
Pesticides chlorinated pesticide, organic phosphate, triazin<br />
herbicide, fungicide, carbamate insecticides<br />
Microbes Staphylococcus aureus, E. coli, salmonella,<br />
shigella, Pseudomonas aeruginosa<br />
Toxins aflatoxin, bacterial endotoxins<br />
Botanicals digitalis, rauwolfia, belladonna alkaloids<br />
Wood (2002) NEJM 347 : 2046
Specific risks of complementary<br />
therapies in cancer patients<br />
Tumor CAM Chemorx Concern<br />
NHL echinacea Rituximab stimulates targeted B-cells<br />
breast yam hormonal estrogenic effects<br />
milk thistle Taxol reduces taxol metabolism<br />
kava chemorx hepatotoxicity<br />
prost cod liver oil antithrombotic<br />
ovary laetrile contains cyanide<br />
any milk thistle adriamycin reduces drug metabolism<br />
NOTE: refer to Memorial Sloan-Kettering <strong>Cancer</strong> Center <strong>In</strong>tegrative Medicine<br />
website for listing of 60 other herbal/natural products with known health risks
Potential Systemic Adverse<br />
Effects of Herbal Remedies<br />
Cardiotoxicity leigongteng, mahuang, licorice root,<br />
colchicine-rich herbs, cardioactiveglycoside-rich<br />
herbs<br />
Hepatotoxicity mahuang, kava rhizome, chaparral,<br />
herbs rich in anthranoids, podophyllotoxin,<br />
pyrrolizidine alkaloids<br />
Renal toxicity chinese yew, impila root, jering fruit,<br />
pennyroyal oil and certain essential<br />
oils, star fruit<br />
Neurotoxicity mahuang, kava rhizome, nux<br />
vomica, aconite root tuber, star fruit
Buyer Beware:<br />
Consumers Can’t Trust That<br />
• Plant was accurately identified<br />
• Potency will be the same bottle-to-<br />
bottle<br />
• Herb is pure (until 2010)<br />
• Herb is safe (until 2010)<br />
• Herb is effective
Advice for Patients Taking Herbs<br />
• Purchase only products labeled with name and<br />
part of herb, batch or lot #, expiration date, name<br />
and address of manufacturer<br />
• Choose manufacturer in business for a while or<br />
herbal products of major pharmaceutical firms<br />
• Use multiple herbs with caution<br />
• Talk with your practitioner and pharmacist about<br />
possible herb-drug interactions<br />
• Stop herbs before elective surgeries<br />
• Learn as much as you can
How to Find a<br />
Quality Product<br />
• Use information from independent<br />
testing laboratories, such as<br />
ConsumerLab.com<br />
• Look for a “seal of approval”, such as<br />
USP, NSF<br />
• Look for products that have been<br />
tested in clinical trials
Learn As Much As You Can<br />
Many websites offer info on CAM, but select public sites that review<br />
published work. Be wary of sites reporting only testimonial or anecdotal<br />
evidence from former users or promote only a particular product<br />
Authoritative public websites:<br />
• M. D. Anderson <strong>Cancer</strong> Center (www.mdanderson.org/cimer)<br />
• American <strong>Cancer</strong> Society (www.cancer.org)<br />
• NCCAM ( http://nccam.nih.gov)<br />
• NCI data query (www.cancer.gov/cancerinfo/PDQ/cancerdatabase)<br />
• MSKCC (www.mskcc.org/about herbs)<br />
• <strong>Stiles</strong> <strong>Program</strong> (www.canceralternatives.mednet.ucla.edu)<br />
• <strong>UCLA</strong> Collaborative Centers for <strong>In</strong>tegrative Medicine<br />
• Medline, PubMed and NaturalStandard.com<br />
Books: Evidence-Based Herbal Medicine by Rothblatt & Ziment<br />
ACS Guide to Complementary and Alternative <strong>Cancer</strong> Methods<br />
Mary Hardy, MD: Simms/Mann-<strong>UCLA</strong> Center for <strong>In</strong>tegrative <strong>Oncology</strong><br />
Ka Kit Hui, MD: <strong>UCLA</strong> Center for East-West Medicine
How to assess CAM research findings<br />
Replication: Do not change your lifestyle because of<br />
one study. Wait for other studies to confirm.<br />
Size of Effect: Look for doubling or halving of effect,<br />
but also look at absolute risk (rare vs common risk)<br />
Size of study: studies with 10,000 subjects more<br />
reliable than those with 50<br />
Randomized, controlled trials : generally more reliable<br />
than observational studies<br />
Statistical Significance and Consistent Findings:<br />
trends not sufficient; more precise results better.
Recommendations for patients with cancer*<br />
1. Discuss use of CAM with your doctor<br />
2. Ask your doctor for guidance on CAM advantages/disadvantages<br />
3. Check dietary supplements, esp. herbals, for side effects and interactions<br />
with other drugs. If likely to interact with chemotherapy, do<br />
not use concurrently during chemo or radiation, or before surgery<br />
4. <strong>In</strong> patients who do not respond to or decline antitumor therapy, it<br />
is recommended to use botanical agents in a clinical trial setting<br />
5. Consider acupuncture for poorly-controlled chemo-induced<br />
nausea, vomiting or pain and for neuropathy or xerostomia<br />
6. If anxiety or pain, massage by oncology-trained massage therapist<br />
may be part of a multimodality approach, but deep, intense manipulation<br />
not advised near cancer lesions or distorted postop areas<br />
7. <strong>In</strong> those with bleeding tendency, acupuncture or massage should<br />
be done only by qualified practitioners and used cautiously<br />
8. Consider mind-body methods as another approach to reduce<br />
anxiety, mood disturbances, chronic pain<br />
*Based on Cassileth et al. Chest, 2007
Lobby for New Regulatory<br />
Safeguards in Federal DHSEA<br />
1. Register with FDA address, contact names of those<br />
manufacturing dietary supplements for sale in US<br />
2. Show evidence of good manufacturing practices to<br />
prevent adulteration, standardize products (2010)<br />
3. Premarketing FDA approval to show that products<br />
have no risk of injury with recommended use<br />
4. Manufacturers report all adverse events (2010)<br />
5. Labels to list all constituents and inform about on<br />
adverse effects, including herb-drug interactions
Evidence-Based Research:<br />
Approaches to Discovery of<br />
New Therapies<br />
• Surveys<br />
• Observational cohort studies<br />
• Case-Control Studies<br />
• Laboratory/Pre-clinical Models<br />
• Prospective Trials (phase I/II)<br />
• Controlled randomized trials (Phase III)
Strategies for Botanical<br />
Phase I/II<br />
safety and<br />
efficacy<br />
studies<br />
Randomized,<br />
Controlled<br />
Phase III Trials<br />
Drug Discovery<br />
Herbs or regimens<br />
used historically for<br />
specific indications<br />
Laboratory<br />
studies of herbal<br />
extracts<br />
HPLC or other<br />
compound<br />
isolation strategy<br />
Modified from Tripathy (2004)
Use of scientific principles to develop<br />
antitumor medicines from plants<br />
• Estimated 287,000 higher terrestrial plants, with less<br />
than 10% investigated for medical application<br />
• Ethnobotanical data important for drug leads<br />
• Rational target-based drug discovery for screening<br />
using data from DNA microarrays, proteomics,<br />
molecular signal transduction<br />
• Evaluation of purity, safety, interactions<br />
• Natural products as templates for new drug discovery
Natural Products in<br />
Testing for <strong>Cancer</strong><br />
Prevention and Treatment<br />
• Squalamine for lung and ovarian cancer<br />
• Scutellaria for breast, prostate and lung<br />
cancers<br />
• Tanacetum parthenium to enhance antitumor<br />
antibody therapy<br />
• Natural foods in the diet to promote survival<br />
in patients with cancers
Lung <strong>Cancer</strong> in US Women<br />
A Contemporary Epidemic<br />
Age-adjusted death rates for lung cancer and breast cancer among women,<br />
US, 1930-1997 (Patel et al. JAMA 291 : 1763, 2004)
Lung <strong>Cancer</strong> Statistics<br />
• 214,000 people will be diagnosed with lung<br />
cancer in 2007<br />
• Majority of lung cancers, 60%, diagnosed in<br />
non-smokers (former- or never-smokers)<br />
• 10-15% of lung cancers, about 25,000,<br />
occur in never-smokers (e.g., Dana Reeves)<br />
• Most of the never-smokers (2/3) are women
Therapy for Advanced Lung<br />
<strong>Cancer</strong><br />
• Modest improvement in past 20 years<br />
• Response rates to combination cytotoxic<br />
chemotherapies about 20-25%<br />
• Median survival 8-10 months<br />
• Need for development of rationally designed<br />
therapeutics, possibly targeting tumor<br />
and tumor-associated cells<br />
Schiller et al. 2007
As in the legend of William Tell,<br />
it’s important to aim for the<br />
right target…<br />
estrogen<br />
and growth<br />
factor signaling<br />
in lung tumors
Activated estrogen receptor-α is<br />
present in NSCLC tumor specimens<br />
N<br />
Anti-phospho S167<br />
S118<br />
ER-alpha Serine phosphorylation<br />
S167<br />
Anti-phospho S118<br />
A/B C D E F C<br />
Estrogen receptor alpha: substrate for kinase signaling
Lung tumor microarray: aromatase and survival<br />
Low Aromatase<br />
High Aromatase<br />
Survival probability in postmenopausal women with Stage<br />
I/II NSCLC and tumor aromatase expression (P
Ongoing studies and trials of<br />
biologic antitumor therapies in<br />
lung cancer<br />
• Antagonists of estrogen receptor<br />
(fulvestrant)<br />
• <strong>In</strong>hibitors of aromatase, a protein<br />
that synthesizes estrogen in tumors<br />
(anastrazole, exemestane, grape<br />
seed extract)
Another<br />
critical target :<br />
tumorassociated<br />
angiogenesis<br />
Avastin<br />
Squalamine
SQUALAMINE<br />
Blocks blood vessel<br />
growth in tumors<br />
Starves tumors<br />
+<br />
H N 3<br />
+<br />
N<br />
H<br />
2<br />
+<br />
N<br />
H<br />
2<br />
C<br />
H 3<br />
H<br />
H C 3<br />
H3C OH<br />
O<br />
O<br />
O<br />
S O<br />
CH 3<br />
CH 3<br />
• Natural steroid, now synthesized in laboratory<br />
• Orphan drug designation by FDA
Squalamine blocks vascular<br />
growth factor (VEGF)-induced<br />
reorganization and growth of<br />
tumor-associated endothelial cells<br />
CON SQ VEGF VEGF + SQ<br />
pFAK (Focal Adhesion Kinase) / F-actin (phalloidin)
Squalamine Blocks Growth of<br />
Human Non-Small Cell Lung Tumor<br />
Tumor Volume (cubic mm)<br />
600<br />
500<br />
400<br />
300<br />
200<br />
100<br />
0<br />
CONTROL<br />
0 10 20 30 40 50 60 70<br />
Treatment Days<br />
SQUALAMINE<br />
World Congress-Gynecologic <strong>Oncology</strong>, 2003
Phase I/IIA study of<br />
squalamine in lung cancer<br />
• Stage IIIB/IV chemo-naïve non-small cell lung cancer: squalamine (5day<br />
CI) + paclitaxel (225 mg/m2) + carboplatin (AUC 6) Q 21 days<br />
• 45 pts enrolled (18 phase I, 27 phase IIA)<br />
• Little to no squalamine-related toxicity and no drug interactions<br />
• 43 evaluable for response : 28% PR, 19% stable disease based on ITT<br />
• Clinical benefit 47%<br />
• Median survival = 10 months; 1-year survival = 40%<br />
• 40% completed full 6-cycle regimen as planned<br />
• More frequent dosing of squalamine showing improved RR in new<br />
phase II trials underway
Antitumor Activity of Squalamine<br />
CA-125 LEVEL<br />
in Human Ovarian <strong>Cancer</strong><br />
4000<br />
3000<br />
2000<br />
1000<br />
0<br />
0 50 100 150 200 250<br />
Days after treatment<br />
Phase II clinical trials in patients with advanced<br />
platinum-refractory or-resistant malignancy<br />
Proc. ASCO (2003)
Herbals from Traditional Chinese<br />
Medicine (TCM) for Breast <strong>Cancer</strong><br />
• Centuries-long Tradition of Use and Experience<br />
• Based on Written Texts and Documentation<br />
• Some Conformity and Reproducibility in Practice<br />
• Licensed Profession in Many States and in Wide<br />
Use by Patients<br />
• Of note, China has now launched a "Plan for<br />
Modernization of Chinese Medicine". Natural<br />
products from TCM will be investigated for<br />
development of molecular target-guided therapies<br />
and individualized treatments.
Preparation of Extracts from Chinese<br />
Herbs for Preclinical Testing<br />
More than 120 herbs<br />
reported to have<br />
breast selectivity in<br />
TCM practice<br />
Preparation of selected<br />
herbal extracts (<strong>UCLA</strong>’s<br />
CDSRB)<br />
Campbell et al. (2002)
Herb Scutellaria blocks MAPK<br />
activation by growth factors and<br />
estrogen in breast cancer cells<br />
CON GF GF/HE<br />
Mitogen-activated Protein<br />
kinase (MAPK)<br />
Growth Factor (GF)<br />
Scutellaria (HE)
Scutellaria Stops Breast <strong>Cancer</strong> Cell<br />
Growth<br />
100<br />
Cell proliferation (% control)<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
MCF-7/HER-2<br />
MCF-7 Parent<br />
0<br />
0 10 20 30 40 50 60 70 80 90 100<br />
Herbal extract (mcg/ml)
Phase I clinical trial in patients with advanced<br />
breast cancer to test Scutellaria barbata extract<br />
Clinical trial recruited patients with advanced and heavily<br />
pretreated breast cancer to evaluate BZL101, aqueous<br />
extract from Scutellaria barbata<br />
Rationale: BZL 101 induces apoptosis (cell death) in<br />
human breast cancer cells in the laboratory<br />
Results: BZL101 was found to be safe, with a favorable<br />
toxicity profile (low-grade nausea, diarrhea, headache)<br />
BZL101 showed evidence of clinical activity. Of 16<br />
patients evaluable for response, 4 had stable disease >90<br />
days (25%) and 3/16 had SD for >180 days (19%). Five<br />
patients had tumor regression, but no CR or PR<br />
Rugo H, Tripathy D et al. (2007). Breast <strong>Cancer</strong> Res Treat.
Sampling of Complementary Therapy Data<br />
• Chen S et al. (2006) - Enrolling patients in a City of Hope Phase I trial to<br />
assess efficacy of different concentrations of grape seed extract on<br />
estrogen suppression in women at risk for breast cancer, as phytochemicals<br />
(procyanidin B dimers) in grape seeds inhibit aromatase<br />
• Seeram et al. (2006) - <strong>UCLA</strong> phase II clinical trial with pomegranate<br />
extracts show reduced PSA in men after treatment for prostate cancer<br />
• Neto (2007) - Evidence for protective effects of cranberries and blueberries<br />
against cancer<br />
• Sartippour et al. (2006) - Green tea extracts may enhance activity of<br />
tamoxifen in ER+ breast cancer cells<br />
• ASCO Meetings (2007) - Ginseng may reduce cancer fatigue; flaxseed<br />
may slow growth prostate cancer<br />
• ASCO Meetings (2007) - Modafinil, treatment for narcolepsy, may help<br />
reduce symptoms of memory decline and fatigue after chemotherapy<br />
• NCCAM Breast <strong>Cancer</strong> Trials (2007) - Pycnogenol for treatment of<br />
lymphedema of the arm in breast cancer survivors<br />
• See NCCAM and OCCAM websites for listings of ongoing clinical trials
Dietary influence on survival<br />
after ovarian cancer<br />
609 women with new diagnosis ovarian cancer<br />
followed for 7 years after diagnosis and treatment<br />
Those who ate most vegetables and vitamin E-rich<br />
foods in year before diagnosis most likely to survive<br />
5 years after diagnosis<br />
Nutrients via supplements had less effect<br />
Cruciferous vegetables (cabbage, cauliflower,<br />
broccoli) had greatest benefit<br />
Nagle et al. <strong>In</strong>t J <strong>Cancer</strong> 106 : 264, 2003
Vegetable Consumption Improves<br />
Survival of <strong>Cancer</strong> Patients<br />
High > 5.6<br />
Med 3.9-5.6<br />
Low < 3.9<br />
<strong>In</strong>t. J. <strong>Cancer</strong> 106<br />
: 264 (03)
<strong>In</strong>tensive lifestyle changes affect<br />
progression of prostate cancer<br />
Men with low-grade prostate cancer who chose not to have RT, surgery or<br />
hormonal rx assigned to experimental (lifestyle changes) or control groups<br />
RESULTS: No experimental pts, but 6 control pts required conventional<br />
therapies due to increased PSA and/or disease progression on MRI.<br />
PSA down 4%<br />
in experimental;<br />
up 6% in control<br />
(p = 0.016).<br />
Changes in PSA associate with degree of<br />
change in diet & lifestyle (P=0.005)<br />
Ornish D et al. (2005). J Urol. 174 : 1065
- Nutrition, lifestyle and colorectal cancer incidence: a<br />
prospective investigation of 10,998 vegetarians and<br />
non-vegetarians in the UK<br />
<strong>In</strong> a cohort of 10,998 men and women, 95 incident cases of<br />
colorectal cancer were recorded after 17 years. Risk increased in<br />
association with smoking, alcohol, and white bread consumption,<br />
and decreased with frequent consumption of fruit. The relative risk<br />
in vegetarians compared with nonvegetarians was 0.85 (95% CI)<br />
[see British Journal of <strong>Cancer</strong>, 2004]<br />
-Western diet increases recurrence, mortality risk in<br />
patients with colon cancer<br />
<strong>In</strong> a prospective observational study of patients with stage III colon<br />
cancer s/p adjuvant chemotherapy, patients were followed 5 years<br />
and classified as prudent diet (high in fruits, vegetables, poultry,<br />
fish) versus western diet (high in meat, fat, refined grain, desserts).<br />
The western diet associated with higher risk for tumor recurrence<br />
and reduced survival. [see Meyerhardt et al. JAMA, 2007]
The <strong>Cancer</strong><br />
Process<br />
<strong>In</strong>fluence of<br />
food, nutrition,<br />
obesity and<br />
physical activity<br />
on the cancer<br />
process<br />
(AICR/WCRF)
Body Fat linked to 6 types of cancers<br />
AICR/WCRF recommendations to prevent cancer<br />
Limit red meat and alcohol, avoid processed meats and maintain normal<br />
range of body weight. <strong>In</strong>creased body fat, esp. in abdominal area, alters<br />
hormones and growth factors that influence cancer development. Excess<br />
fat linked to cancers of esophagus, pancreas, colon & rectum, kidney,<br />
endometrium, and breast in postmenopausal women.<br />
• Be physically active at least 30 min each day<br />
• Avoid fast foods, sugary sodas, processed foods low in fiber/high in<br />
fat, processed meats (hot dogs, bacon, ham)<br />
• Eat more fruits and vegetables<br />
• Limit red meat to 11-18 oz. per week; every additional 1.7 oz. per day<br />
increases cancer risk by 15%<br />
• Get necessary vitamins and minerals from nourishing foods rather<br />
than dietary supplements<br />
Report at www.dietandcancerreport.org<br />
See, also: www.sciencereview.silentspring.org
US Dept. Agriculture data collected<br />
from 1998-2002<br />
- 28% Americans get only 2 servings of fruit per day<br />
- 32% get 3 servings vegetables<br />
- 90% do not get recommended daily intake of 5-a-Day<br />
- 52% of overall vegetable consumption by Americans comes<br />
from lettuce, potatoes, canned tomatoes – fast foods<br />
- Studies of diet often contradictory due to bias of tainted<br />
memory, diet effects early in life, genetic differences,<br />
cooking variations (fat-soluble tomato lycopenes best enter<br />
the bloodstream after cooking, while the water-soluble<br />
glucosinolates in broccoli become anti-carcinogenic in the<br />
body but are reduced by cooking
Check to see if you<br />
are normal weight,<br />
overweight, or<br />
underweight?<br />
BMI = wt (kg)/ht (m) 2<br />
Person 1.7 m (~5’6”) tall<br />
and 68 kg (~150 lb)<br />
BMI = 23.5<br />
Recent data suggest<br />
increased waist-hip ratio<br />
or waist circumference<br />
may be better cancer<br />
risk indicators (Larsson<br />
et al. 2007)
Chemoprevention <strong>In</strong>itiatives<br />
People eating 5 servings/day friuts & veggies have<br />
1/2 risk of developing cancer of those who eat < 2<br />
servings/ day<br />
NCI identified 35 plant-based foods with cancerpreventive<br />
activity : garlic, soybean, ginger, onion,<br />
tumeric, tomatoe and cruciferous vegetables<br />
NCI “Five-A-Day for Better Health” <strong>Program</strong> –<br />
encourages eating fruits & veg 5 servings/day<br />
European Prospective <strong>In</strong>vestigation of <strong>Cancer</strong> &<br />
Nutrition (EPIC) - enrolled 520,000 subjects to<br />
identify dietary determinants of cancer
Micronutrients and<br />
Phytochemicals<br />
Antioxidant vitamins in dark, leafy green vegetables<br />
and yellow/orange fruits and vegetables may reduce<br />
cancer risk, especially the dietary ‘ACE’ vitamins<br />
(caution : excessive amounts promote some cancer)<br />
About 1,000 non-nutritive phytochemicals have<br />
cancer-preventive activity, and more than 100<br />
phytochemicals are in one serving of vegetables<br />
More than 400 potential agents now under study,<br />
and NCI sponsored more than 70 Phase I-III trials<br />
last year
Recommendations<br />
Maintain a HEALTHY BODY WEIGHT<br />
DO NOT SMOKE<br />
Obtain most your nutrients and phytochemicals from foods<br />
rather than supplements<br />
Eat in moderation from a variety of food groups, especially<br />
fruits and vegetables (>5 per day)<br />
Favor dishes with multi-plant based ingredients: salads,<br />
soups; add leafy greens to sandwiches<br />
Most food additives now come from China, the world’s major<br />
supplier of food flavorings, preservatives and vitamins ($2.5<br />
billion exports in 2006). Buy with caution as China has limited<br />
oversight of manufacturing, and toxic pesticide residues may<br />
remain in many products.
The Promise of New<br />
Antitumor Products<br />
Valuable plants and<br />
natural products may be<br />
lost before their medical<br />
use can be discovered
Deforestation and the loss of species
Threatened Species in 2006<br />
Group Number known Threatened<br />
Mammal 4,842 1,130<br />
Fish 28,100 750<br />
Molluscs 70,000 967<br />
Plants 287,655 6,774<br />
Harvard biologist E. O. Wilson recently estimated<br />
that scientists have discovered only about 10% of all<br />
the species of life that currently exist on the earth
“Silent Spring” in the Los Angeles Basin<br />
Agri-chemicals<br />
Agri chemicals<br />
Pesticides<br />
Organophosphates<br />
MTBE<br />
PCBs Asbestos<br />
Mercury<br />
DDT<br />
Dioxin<br />
Chromium 6<br />
SMOG
A Toxic Landscape<br />
Dozens of toxic chemicals are found indoors in American homes<br />
Study of 120 residential homes in Massachusetts showed 67<br />
carcinogenic chemicals in nail polish, hair-spray, some detergents,<br />
household cleaners, pesticides<br />
DDT, banned in US 30 years ago, was found in dust of 65% of homes<br />
Human exposure to DDT was assessed in blood collected from 1959-<br />
1967 from 129 women who gave birth. Women in the top 1/3 of blood<br />
DDT levels were 5-times as likely to get breast cancer as women with<br />
the lowest DDT levels<br />
<strong>In</strong> California, 36 million lbs of 7 different fumigants were used on farms<br />
in 2005. Fumigants, with some suspected to be carcinogens, used on<br />
grape, strawberry, almond, carrot, lettuce, potato crops<br />
Environmental Science & Technol, 2003<br />
Environmental Health Perspectives, 2007
216 common chemicals linked to breast cancer<br />
People are exposed to many of the following inductrial solvents, dyes,<br />
pesticides, gasoline and diesel exhaust, cosmetic ingredients, and<br />
hormone-like agents :<br />
1,4-dioxane (detergents, soaps)<br />
1,3-butadiene (vehicle exhaust)<br />
acrylamide (fried foods)<br />
benzene (vehicle exhaust)<br />
perfluorooctanoic acid (Teflon)<br />
styrene (carpets, adhesives)<br />
vinyl chloride (vinyl)<br />
toluene diisocyanate (furnishings, bedding)<br />
polychlorinated biphenyls , PCB’s (electrical transformers)<br />
Atrazine (herbicide)<br />
Bisphenol A (polycarbonate plastic in baby bottles, food packaging,<br />
juice and ketchup bottles, dental sealants)(recycling symbol 7)<br />
<strong>Cancer</strong>, 2007
Support <strong>Cancer</strong> Research :<br />
It Saves Lives<br />
National <strong>Cancer</strong> <strong>In</strong>stitute budget proposed for 2008:<br />
~$5.5 billion (0.2% of federal spending)<br />
US Congress agreed to an increase of 2.67% above<br />
2007 levels for the 2008 National <strong>Cancer</strong> <strong>In</strong>stitute<br />
budget, but the President issued a veto of the bill<br />
because he objected to increased funding<br />
California <strong>Cancer</strong> Research <strong>Program</strong> budget for 2008:<br />
$ 0 (applications closed)
Health and cancer care for all?<br />
• War on cancer may be undone by lack of adequate insurance for<br />
Americans. Some are unemployed; others receive no benefits from<br />
employers, can’t afford costly premiums or are uninsurable due to<br />
existing conditions. <strong>In</strong> 2006, 47 million Americans were uninsured and<br />
millions more are under-insured (American <strong>Cancer</strong> Society)<br />
• Failings of our health system may contribute to cancer suffering and<br />
death. <strong>In</strong> 2006, 1/3 of patients diagnosed with cancer were financially<br />
distressed, and 100,000 went bankrupt due to cancer care expenses.<br />
• Of women with breast cancer, proportion with advanced-stage cancer<br />
at diagnosis was 8% for privately-insured and 18% for uninsured.<br />
Those with no or limited insurance less likely to obtain preventive<br />
services and seek timely medical care (Halpern et al. <strong>Cancer</strong> 2007)<br />
• Patients who miss prescribed drug doses have increased risk of death<br />
• <strong>In</strong> spite of major advances in cancer prevention and treatment, it is not<br />
enough if people cannot get access to the care that they need to fight<br />
cancer (see cancer.org)
Acknowledgements<br />
• <strong>Stiles</strong> Fund JCCC/<strong>UCLA</strong><br />
Dr. Michael Tobias Diana Marquez<br />
Jane Morrison Hsiao-Wang Chen<br />
Cary Freeny<br />
• California BCRP Rebecca Rausch<br />
• National <strong>Cancer</strong> <strong>In</strong>stitute David Heber<br />
• National Lung <strong>Cancer</strong> Steve Dubinett<br />
Partnership Judith Gasson<br />
• DOD Ovarian <strong>Cancer</strong> Lonnie Zeltzer<br />
Research <strong>Program</strong> Dennis Slamon
END of presentation