Integrative Care: What’s Safe During
and After Treatment
Aminah Keats, ND, FABNO
Director of Naturopathic Medicine
Cancer Treatment Centers of America
Philadelphia, PA
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© 2012 Rising Tide
What is Naturopathic Medicine?
Naturopathic Medicine is a distinctively natural
approach to health and healing that recognizes the
integrity of the whole person. It emphasizes the
treatment of disease through the stimulation,
enhancement, and support of the inherent healing
capacity of the person.
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Naturopathic Medical Education
• 5 accredited naturopathic medical schools
in the United States and 2 in Canada
• Pre-requisite pre-med undergraduate
degree
• 4 year graduate medical education
2 years basic sciences
2 years clinical sciences
• 2 sets of Board Exams
• Optional Residency
• Specialty training: Fellowship of the
Oncology Board of Naturopathic
Physicians
Naturopathic Medicine Modalities
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Nutritional Supplementation
Homeopathy
Botanical Medicine
Clinical Nutrition
Counseling
Hydrotherapy
Physical Medicine
Acupuncture
Minor surgery (certain states)
Intravenous and injection therapy (certain states)
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Patient Empowerment Team
© 2012 Rising Tide
Evaluating Natural Therapies:
Factors to Consider
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Drug-herb/nutrient interaction
Condition-herb/nutrient interaction
Published Evidence of Effectiveness
Complementary vs. Alternative treatment
Cost
Evaluating Natural Therapies:
Drug-herb/nutrient Interaction
• Certain supplements may effect the
pharmacokinetics of certain medications
-Decrease in effectiveness
i.e. St. John’s Wort and Taxol
-Increase in side effects
i.e. Folic acid and Xeloda
Evaluating Natural Therapies:
Condition-herb/nutrient Interaction
• Licorice root can potentially increase blood
pressure when large doses are taken over
extended periods
• Phytoestrogenic herbs are not advised in patients
with breast cancer due to theoretical concerns
i.e. Licorice, Red clover
Evaluating Natural Therapies:
Published Evidence of Effectiveness
Is there scientifically validated evidence of effectiveness?
Example: L-glutamine and oxaliplatin-induced peripheral
neuropathy
 86 pts with metastatic colorectal cancer received
oxaliplatin/5-FU/leucovorin on days 1, 8, and 15
 Pts were randomized to receive or not receive glutamine
 Lower percentage of grade 1-2 peripheral neuropathy was
observed in glutamine group after 2 cycles
 Lower incidence of grade 3-4 peripheral neuropathy was
noted in glutamine group after 4 cycles and 6 cycles
 Interference with activities of daily living was lower in
glutamine group
 Need for oxaliplatin dose reduction was lower in glutamine
group
 No difference in response to chemo or survival
Oncologist. 2007 Mar;12(3):312-9.
Evaluating Natural Therapies:
Complementary vs. Alternative treatment
• Complementary: Used in conjunction with
conventional treatment
• Alternative: Used instead of conventional
treatment
Evaluating Natural Therapies:
Cost
Consider cost vs. likely benefit
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Supporting research available?
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Do claims sound too good to be true?
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Is product primarily supported by testimonials?
Naturopathic Role in Integrative
Oncology
• Offer natural protocols that are
Individualized
– Symptom specific
– Treatment specific
– Tumor specific
• Enhance patient safety by screening
patients’ treatments for potential drug-herb
and drug-nutrient interactions
• Enhance the activity of conventional cancer
treatments
• Support the immune system
• Speed the healing process post-operatively
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Conventional Breast Cancer Care
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Chemotherapy
Targeted Therapy
Hormonal Therapy
Surgery
Radiation Therapy
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Chemotherapy
Doxorubicin and Cyclophosphamide
Doxorubicin = Adriamycin
– Anti-tumor antibiotic
– Metabolized through CYP450: 3A4
– Half Life 20–48 hours
Cyclophosphamide = Cytoxan
– Alkylating agent
– Metabolized through CYP450: 2B, 2C9, 2C8, 2C18,
2C19
– Half Life 3–12 hours
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Adriamycin Potential Adverse Effects
• Cardiac toxicity
– Irreversible and dose-dependent
– African-American women at highest risk for
cardiotoxicity
– Cardiomyopathy may occur at any time after
completion of Adriamycin therapy and should be
considered as a lifetime risk.
• Myelosuppression
• Nausea/Vomiting
• Mucositis/Stomatitis
• Photosensitivity
• Radiation recall
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Ginger and Nausea
• Ginger root powder was effective in reducing
severity of acute and delayed chemotherapyinduced nausea and vomiting as additional
therapy to ondensetron and dexamethasone in
patients receiving high emetogenic chemotherapy
Pediatr Blood Cancer. 2011 Feb;56(2):234-8. doi: 10.1002/pbc.22778.
Epub 2010 Sep 14
• Ginger preparations significantly reversed
cisplatin-induced delay in gastric emptying. The
reversal produced by the ginger acetone extract
was similar to that caused by the 5-HT3 receptor
antagonist ondansetron
J Ethnopharmacol. 1998 Aug;62(1):49-55.
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Nausea
• Acupressure applied to P6 acupuncture point with
wristbands may be effective in reducing
chemotherapy-related nausea and may decrease
the antiemetic use after chemotherapy
Eur J Oncol Nurs. 2010 Feb;14(1):49-54. Epub 2009 Sep 11.
• Acupuncture
• Stop nausea inhaler – contains essential oil of
Peppermint. May be effective in reducing postoperative nausea
J Perianesth Nurs. 2004 Feb;19(1):29-35.
• Homeopathy: Nux vomica, ipecac
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Coenzyme Q10 and Adriamycin
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Hypothesized that the increase in plasma CoQ10 observed in patients
undergoing adriamycin treatment was due to release of CoQ10 from
apoptotic or necrotic cardiac tissue. Clin Chim Acta. 2000 Dec;302(1-2):1-9.
Clinical trial designed to evaluate the usefulness of CoQ10 in the prevention
of side effects due to anthracycline agents (Adriamycin and Daunorubicin)
 79 patients treated with Adriamycin or Daunorubicin
 CoQ10 administered day before, day of and 2 days following chemo (40 pts)
 No significant differences in complete remission and mortality
 No significant differences in alopecia, fever, nausea and vomiting
 Incidences of diarrhea and stomatitis were significantly reduced
 EKG aggravation found in 20 of 40 patients given CoQ10 (50.0%) and in 18 of 25
receiving none (72.0%)
Gan To Kagaku Ryoho. 1984 Jul;11(7):1420-7.
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L-Carnitine
• L-carnitine interacts with cardiolipin, modifying
membrane permeability and protecting the
functions of the mitochondria. This mechanism
can be proposed to explain the protective effects
of L-carnitine against adriamycin-induced
cardiotoxicity.
» Drugs Exp Clin Res 2001;27(1):27-49 {in-vitro}
CoQ10 and L-carnitine
• The effect of the association of carnitine and
coenzyme Q10 on doxorubicin cardiotoxicity has
been investigated. The two drugs administered to
rats for two weeks have lower protective activity
when they are administered separately rather than
given in association (carnitine 200 mg/kg/day,
coenzyme Q10 10 mg/kg/day) for the acute toxic
effect of doxorubicin on perfused functioning
isolated hearts.
» Drugs Exp Clin Res. 1992;18(10):437-42 {in-vivo}
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Melatonin and Adriamycin
Combination of melatonin and adriamycin represents a potentially
useful regimen for the treatment of human neoplasms {animal and in
vitro}
• Reduced mortality rate
• Antitumor activity of adriamycin could be maintained using lower
doses of this drug in combination with melatonin
• Inhibited the growth of human breast cancer cells
• Combination of adriamycin and melatonin improved the antitumor
activity of adriamycin
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J Cardiovasc Pharmacol. 2005 Aug;46(2):200-10.
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Melatonin and Breast Cancer
3 anti-estrogenic mechanisms
• Down-regulating gonadal synthesis of steroids ->
decreasing their circulating levels
• Interaction with estrogen receptor
• Down-regulating the activity of some enzymes, i.e.
aromatase, involved in the synthesis of estrogens
from androgens
 J. Pineal Res. 2005; 38:217–222
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Cytoxan Potential Adverse Effects
• Hematologic toxicity (leukopenia, neutropenia, anemia,
thrombocytopenia, or pancytopenia) is one of the major and
dose-limiting adverse effects
• Anorexia, Nausea, Vomiting
• Acute cardiotoxicity
• Hemorrhagic cystitis with hematuria
• Hyperkalemia, hyperphosphatemia, hyperuricemia, and
hypocalcemia
• Fatigue
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Naturopathic Care for patients while on
Cytoxan
• L-carnitine
– Carnitine deficiency aggravates
cyclophosphamide-induced cardiotoxicity in rats
Chemotherapy. 2010;56(1):71-81.
• Slippery Elm
– Bladder protection
• Hydration
– Dilution of acrolein decreases tissue exposure
– Frequent urination decreases tissue exposure
and speeds elimination
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Adriamycin Cytoxan Interactions
• 3A4 inducers –
– Hypericum, Ginkgo
• 3A4 inhibitors –
– Piper meth., Hydrastis, Uncaria tomentosa, Trifolium pretense,
Matricaria chamomilla, Glycyrrhiza glabra/DGL, Echinacea,
Polygonum, Allicin, Harpagophytum procumbens, Schisandra
• 2C8 inhibitors
– Quercetin, Curcumin
• 2C19 inhibitors –
– Gingko, Valerian, Harpagophytum, Polygonum
• Caution with NAC and Glutathione - Enhances
Multidrug Resistance of Adriamycin
Taxol Potential Adverse Effects
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Peripheral neuropathy
Myalgia/Arthralgia
Stomatitis/Mucositis
Cardiac arrhythmia
Facial flushing
Hypersensitivity reaction
Myelosuppression
Alopecia
Fatigue
P450 Enzymes: CYP2C8, CYP3A4
Taxol half-life: 19 hours
Melatonin and Taxol
• Increased the efficacy of single-agent Taxol in
breast cancer, and significantly reduced the
frequency of thrombocytopenia, neurotoxicity,
cardio toxicity, stomatitis and asthenia.
 Eur J Cancer. 1999 Nov;35(12):1688-92
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Gastrointestinal Toxicity
Glutamine
• Study: Glutamine use with high dose Taxol
and Melphalan for BRCA patients
– Administered as swish & swallow, 24 G daily in
divided doses
– Patients in the glutamine group demonstrated
significantly fewer days of mucositis and a lower
maximum grade of mucositis
– Glutamine group had less oral ulceration and
bleeding, and were able to tolerate liquids sooner
than those in the non-glutamine group
Ann Pharmacother. 2000 Mar;34(3):300-3
Neurological Toxicity
Glutamine
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Study: Patients receiving Taxol given glutamine vs. no
intervention
– Glutamine: 10 G tid given for 4 days, 24 hours after
completion of chemo
– Statistically significant reduction in:
• severity of development of moderate to severe
dysesthesias and numbness in the fingers and toes
• degree and incidence of motor weakness
• deterioration in gait
• interference with activities of daily living
Clin Cancer Res. 2001 May;7(5):1192-7
Trastuzumab = Herceptin
HER2 positive refers to over expression of human
epidermal growth factor receptor 2 which leads to
uncontrolled growth.
Herceptin is a recombinant, humanized, monoclonal
antibody that targets HER-2 neu receptors on breast
cancer cells
Side effects:
• Dose-limiting cardiomyopathy
• Fever, chills, nausea, vomiting, diarrhea
• Hypokalemia
Naturopathic Considerations: CoQ10, L-carnitine
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Herceptin
• Causes a decrease in left ventricular
ejection fraction (LVEF) in a minority of
patients. Incidence is increased if
trastuzumab is given in conjunction with
paclitaxel or anthracyclines. It differs from
anthracycline cardiotoxicity in that it is not
cumulative dose-dependent and often
improves after withdrawal of treatment.
Re-treatment with trastuzumab is often
possible.
» Am J Cardiovasc Drugs. 2005;5(4):233-43.
Surgical Options
Lumpectomy
Involves removing the breast lump and surrounding margins. 70% of
stage I and II are treated with this method. When combined with
radiation it has the same overall survival as total mastectomy.
Mastectomy— Mastectomies are chosen for larger tumors, multicentric
disease, and by patient choice.
- Simple mastectomy involves removal of the entire breast tissue but
leaves the axillary lymph nodes and muscle intact.
– Modified radical mastectomy is the most common and involves
removing the entire breast and some of the axillary lymph nodes.
– Radical mastectomy involves removal of the pectoral muscles in
addition to all breast tissue and axillary lymph nodes.
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Surgery
Naturopathic Goals for supporting patients
through surgery:
– Decrease pain, inflammation, infection, and
adhesions.
– Provide precursors to connective tissue, DNA
and RNA repair (vitamin C, anti-inflammatory
herbs)
– All equal = SPEED HEALING PROCESS and
increase patient comfort
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After Surgery: Arnica 200C
Study: 60 patients were randomized to
receive either Arnica or placebo following
vascular surgery
– Arnica given once on the day before surgery, once just
prior to surgery and hourly after surgery on day of
surgery, followed by three times on days 2-14
– Beneficial effect of Arnica with regard to reduction of
hematoma and pain during the postoperative course
» Forsch Komplementarmed Klass Naturheilkd. 2003 Oct;10(5):242-7
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Support of Surgical Recovery
• Vitamin C
-Builds collagen
-Beneficial in wound healing
• Zinc
-Reduces healing time
-Immune support
• Vitamin A
-Activates
production of connective tissue
-Immune support
-Supports vascular growth to newly formed tissue
• Bromelain
-Reduces swelling, bruising, and pain after surgery and physical
injuries
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Naturopathic support with Surgery
Vitamin E
• Increased breaking strength and collagen content
of wounds were found in mice treated with Vitamin
E preparation
• Supplemental Vitamin E led to decreased
incidence and degree of peritoneal adhesions in
mice
>>Arch Surg. 1985 Aug;120(8):949-51.
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Blood-thinning supplements
Caution should be used with supplements that
posses blood-thinning potential
The following should be discontinued at least 5 days
prior to surgical procedures:
• Vitamin E, Fish oil, Gingko biloba, Ginger, Garlic,
St. John’s wort, Kava kava, Goldenseal, Valerian,
Feverfew, Bromelain, Curcumin
This is NOT an exhaustive list
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Radiation therapy
Adjuvant Therapy—Reduces rate of recurrence after breast
conservation therapy (lumpectomy, segmental mastectomy)
Timing—Typically delivered after chemotherapy
Typically 5 days/week x 5-6 weeks
IORT (Intraoperative Radiation Therapy)
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Radiation Therapy – Potential Adverse Effects
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Fatigue
Dermatitis
Myelosuppression
Desquamation of skin
Fat necrosis
Esophagitis
Respiratory distress
Pulmonary fibrosis
Reduced immunity
Vitamin deficiencies
Secondary cancers (leukemia, lymphoma, thyroid cancers)
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Naturopathic Recommendations concurrent with Chest
Radiation Therapy
Coconut Oil – apply to skin area daily. Make sure to
apply after radiation treatment
Calendula Cream – apply to skin area daily. Make
sure to apply after radiation treatment
Phase III randomized trial of Calendula officinalis compared with trolamine for
the prevention of acute dermatitis during irradiation for breast cancer. The
occurrence of acute dermatitis of grade 2 or higher was significantly lower
(41% v 63%; P <.001) with the use of calendula than with trolamine.
Moreover, patients receiving calendula had less frequent interruption of
radiotherapy and significantly reduced radiation-induced pain. J Clin Oncol.
2004 Apr 15;22(8):1447-5
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Curcumin
Curcumin as Chemosensitizer and Radiosensitizer
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Chemosensitization observed in cancers of the breast, colon,
pancreas, stomach, liver, blood, lung, prostate, bladder, cervix, ovary,
head and neck, and brain and in multiple myeloma, leukemia, and
lymphoma
Radiosensitization observed in glioma, neuroblastoma, cervical
carcinoma, epidermal carcinoma, prostate carcinoma, and colon
carcinoma.
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Mechanism of Action: Downregulates various growth regulatory pathways and
specific genetic targets, i.e. NF-κB, COX2, antiapoptotic proteins, growth factor
receptors, and multidrug-resistance proteins
Protective effect of normal organs such as liver, kidney, oral mucosa,
and heart from chemotherapy and radiotherapy-induced toxicity
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Mechanism of Action: Protective effects mediated through its ability to
induce the activation of NRF2 and induce the expression of antioxidant
enzymes
Nutr Cancer. 2010;62(7):919-30. doi: 10.1080/01635581.2010.509835.
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Radiation Contraindications
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Beta Carotene > 5000 IU
Vitamin E over 200 IU
N-acetyl-l-cysteine
Alpha-lipoic acid
Coenzyme Q10 >300 mg daily
Hormonal therapy
Hormonal therapy
– SERMS (Selective Estrogen Receptor Modulators): Nolvadex
(tamoxifen)
– Indications:
• ER/PR positive pre-menopausal node negative or positive women for 5 years
to prevent recurrence
• Post menopausal women with aromatase inhibitor resistance
• As a chemo-preventive agent in high risk populations
• With DCIS for 5 years to decrease risk of invasive disease
– Aromatase inhibitors – Aromasin (exemestane), Arimidex (anastrozole),
Femara (letrozole)
– Indications:
• ER/PR positive post-menopausal women node negative or positive for 5
years to prevent recurrence
• ER/PR positive women started on tamoxifen for 2-3 years and are now
menopausal can be switched to complete 5 years of adjuvant hormonal
therapy
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Tamoxifen
• Selective Estrogen Receptor Modulator that has
both antiestrogenic and estrogenic effects on
various tissues.
• Antiestrogenic effects in the breast.
• Estrogenic effects in bone and endometrium.
• With estrogenic effects can help prevent
osteoporosis however increases risk of
endometrial cancer.
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Tamoxifen
• Potential Side Effects
– Hot Flashes
– Amenorrhea, dysmenorrhea, menstrual irregularity,
oligomenorrhea, pruritus vulvae, vaginal bleeding,
vaginal discharge, and vaginal dryness
– Nausea
– thromboembolism such as a pulmonary embolism,
deep vein thrombosis, or stroke
– Endometrial cancer
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Naturopathic Treatments w/ Tamoxifen
Hot Flashes
• Black Cohosh: 50 breast cancer patients being
treated with Tamoxifen were given standardized
extract of back cohosh daily for 6 months. The
reduction of the total MRS II score under black
cohosh treatment from 17.6 to 13.6 was
statistically significant. Hot flashes, sweating,
sleep problems, and anxiety improved, whereas
urogenital and musculoskeletal complaints did not
change.
 Gynecol Endocrinol. 2011 Oct;27(10):844-8.
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Black Cohosh
• Decreased rates of recurrence of breast
cancer: 18,861 total patients followed, 1,102 had
received Black Cohosh. Over an observation time
of 3.6 years, Black Cohosh was associated with
prolonged disease-free survival. After 2 years
following initial diagnosis, 14% of the control group
had developed a recurrence, while the study group
reached this proportion after 6.5 years
» Int J Clin Pharmacol Ther. 2007 Mar;45(3):143-54
Hot Flashes/Night sweats
• Magnesium: Of 25 patients, 14 (56%) had a
>50% reduction in hot flash score. Doses
ranged from 400 – 800 mg of magnesium oxide
daily.
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Park H, Parker GL, Boardman CH, Morris MM, Smith TJ. A pilot phase II trial
of magnesium supplements to reduce menopausal hot flashes in breast
cancer patients. Support Care Cancer. 2011 Jan 27
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Hot Flashes/Night sweats
Hesperidin
• Flavanoid from citrus fruits
• Reduces vasomotor instability
• Study: 94 menopausal women. After 1 month of
treatment, 53% had no more hot flashes. Altern Med
Rev. 2003 Aug;8(3):284-302.
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Aromatase Inhibitors
• Potential Side Effects
– Women are at increased risk of osteoporosis and
bone fractures.
– Anxiety
– Insomnia
– Arthralgia
– Depression
– Fatigue
– Weight gain
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Naturopathic Considerations with Aromatase
Inhibitors
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Support Bone Health
– Calcium
– Magnesium
– Vitamin D
Arthralgia (More likely if patient has been on Taxane chemotherapy prior to use)
– Acupuncture
– Yoga
– Exercise
Hot Flashes
– Magnesium
– Black Cohosh
– Hesperidin
Insomnia
– Melatonin
– Cal/Mag
– Sleep hygiene
– Sedative herbs (Chamomile, Passionflower)
– L-theanine
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Green tea
In a group of Japanese women suffering from breast
tumors that had not yet metastasized, researchers
discovered that those who consumed 3 cups of
green tea a day had 57% fewer relapses than those
who only drank 1 cup a day
Cancer Lett. 2001 Jun 26;167(2):175-82.
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Vitamin D
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Vitamin D – Dosing based on 25(OH) D levels
– Ecologic studies have shown an inverse correlation between breast
cancer mortality and sun exposure and dietary vitamin D intake.
– In clinical studies an impaired vitamin D status is associated with a 2030% increased breast cancer incidence and 10-20% increased
mortality. Ugeskr Laeger. 2007 Apr 2;169(14):1299-302
– Breast cancer patients should be tested for vitamin D levels, since
vitamin D may be related to cancer incidence and to bone disease.
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings
Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 11082
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Sleep
• In a prospective study of 23,995 Japanese
women, short sleep duration was associated with
higher risk of breast cancer (143 cases).
• Women who slept </= 6 hr per day had a 62%
increased risk of developing breast cancer
compared to women who slept 7 h per day
Kakizaki M. et al. Br J Cancer. 2008
Case Study – SL
53 year old female diagnosed with carcinoma of the
left breast
• Abnormal mammogram involving left breast in
May 2005
• Underwent a biopsy of left breast mass in
February 2006
• Pathology confirmed invasive ductal carcinoma,
ER/PR positive, Her-2-neu negative disease
• Initiated chemotherapy with Adriamycin, Cytoxan,
Taxol
• PMH: Hypertension
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Case Study – SL
Naturopathic recommendations:
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Daily Vitamins - one capsule twice daily with meals.
EPA Fish Oils - one capsule tid with meals.
Melatonin 20 mg Q HS.
Carnitine 1000 mg twice daily with meals.
Co-Q-10, 200 mg daily with meals.
Glutamine 15 grams twice daily.
Encouraged to drink plenty of fluids with Cytoxan chemotherapy.
Complaints with chemotherapy: Insomnia, peripheral
neuropathy gastroesophogeal reflux
– Hot teas to decrease insomnia, i.e. lavender, chamomile,
passion flower
– Digestive enzymes and demulcent herbs to support digestion
– Vitamin B6 to reduce PNP
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Case Study – SL
Completed Chemotherapy
Initiated treatment with Hormonal therapy (Femara)
and RT
• Vitamin A – Immune support and radiopotentiation
• Hesperidin – To reduce hot flashes associated with
hormonal therapy
• Ground flaxseed – Good source of fiber, cancerfighting potential
• Calcium/Vitamin D supplementation to prevent
osteoporosis with Femara
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Conclusion
• Integrative therapies provide an increase in
Quality of Life during conventional cancer
treatment and decreased negative longterm effects of conventional treatment
Aminah Keats, ND, FABNO
Director of Naturopathic Medicine
Cancer Treatment Centers of America
Philadelphia
[email protected]
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