Integrative Oncology

Integrative Oncology

Comprehensive Care of the Patient with Cancer

Philip Trabulsy M.D.Assistant Professor UVM COM

UVM Program In Integrative HealthHematology Oncology Rounds UVM

September 18, 2012

Integrative Medicine and Health

“It is more important to know what sort of person has a disease than to know what sort of disease a person has.”

Hippocrates/Sir William Osler

“The good physician treats the disease; the great physician treats the patient who has the disease.”

Sir William Osler, To his students

Integrative Medicine

What It’s NotAlternative Medicine• Typically promoted as a substitute for conventional

care• Not been scientifically proven• Scientific foundation lacking• Some therapies disproved by scientific analysis• Generally not taught in Medical Schools• Not covered by third-party payors

NIH, NCCAM 2002

Integrative MedicineWhat it is

Integrative medicine combines biomedical care with appropriate complementary therapies, to heal and preserve the health of the patient’s body, mind, and spirit.It emphasizes the individual’s capacity for self-healing and offers an approach to care that is personalized, collaborative, and comprehensive. This approach is interdisciplinary and utilizes the skills of other health care disciplines and professionals through referral and consultation. Consortium of Academic Health Centers for Integrative Medicine

RelationshipsResearch suggests that our presence as medical or mental health clinicians, the way we bring ourselves fully into connection with those for whom we care, is one of the most crucial factors supporting how people heal- how they respond to our therapeutic efforts.

Dan Siegel: The Mindful Therapist, 2010

“ Care more for the individual patient than for the special features of the disease… The kindly word, the cheerful greeting, the sympathetic look – these the patient understands”

Sir William Osler

Integrative Therapies( Complementary and Alternative Medicine)

“ a group of diverse medical and health care systems, practices, and products that are not presently considered part of conventional medicine”

• Biologically based : dietary, nutreuceutical, herbal, homeopathy

• Mind-body : Hypnosis, guided imagery, meditation, expressive arts: ie music therapy

• Manual therapy : Massage, chiropractic, osteopathic, physical therapy

• Energy therapies : Reiki, Healing/Therapeutic Touch, QiGong, Reflexology

• Traditional medical systems : TCM, Ayurvedic

National Center for Complementary and Alternative Medicine( NCCAM)

Why Integrative Oncology?

• CAM use in adult oncology patients: 25-90%

• CAM use in pediatric oncology patients: 31-84%

• High risk women in genetic testing program: rate of 53% CAM use

• Hospitalized cancer patients supplement use of 73% in previous 30 days

• High rates of 68% in oncology pts, with 80% dietary use during radiation therapy

Yates et al, Support Care Cancer 2005

Kelley KM, Eur. J Cancer 2004

Vapiwala et al, Cancer J 2006

Why Integrative Oncology? Predictors of CAM use n= 676, 302 non-ca volunteer, 219 ca pt., 156 professionals

-prevalence CAM use: 29%, 31%, and 39% - female gender, 30-50yo (p <0.001)

- High school or higher education, private insurance, higher income (p<0.001)

- No assoc. with ca. stageReasons for use: Non-Users- 51% family , friends - 50% lack info- 31% own choice, 9% media - 21% no interest- 4% MD recommend - 12% no belief- 61% immune support - 4.7% never needed it- 27% well-being - 1.7% too expensive- 6% prevent ca - 1.3% happy conventional

Chang et al. BMC Cancer 2011, 11:196

Why Integrative Oncology?Communication Gaps– CAM users : 30 % openly reported to MD– 8/149 MD’s asked about CAM use

Provider perspective• 17% encourage continue, 4% stop use, 60% neither Patient perspective• 37% encouraged continue, 16% stop use, 47% neither• 35% MD did not ask, 4% not understand, 6%

disapproveKnowledge• 59% faculty report lack knowledge base• 78% faculty report not up to date on recent evidence • > 50% would welcome further education

Why Integrative Oncology?

Patient Perspectives– Locus of control - CAM is”safe,non-toxic”– Empowerment - Loss faith in traditional– Immune support – Symptom management– Fear – Decrease stress– Shouldering the hope

Richardson MA, et al., 2000 J Clin Oncol, 18: 2505

Disclosure of CAM use to the Oncologist

• 57% disclosure by cancer patients• Majority of disclosures are incomplete (1 CAM)• Prayer and relaxation most commonly reported• Dietary supplement use reported 20-30%• 85% Oncologists felt lack knowledge to recommend CAM• 84% Oncologists concern for drug-interactions

Barriers

– Physicians indifference or opposition

– Did not think it important or that it was CAM

– Providers rarely asked

– Patient’s anticipation of a negative response from their physician

– Just asking directed question about CAM increased disclosure from 7%-43%

Hyodo et al, Cancer, 2003;97(11):2861-85

Pathways Study• 1000 women AJCC stage I/II BC, prospective cohort– 98% CAM use prior to Dx.– >20% weekly green tea, omega-3fa , prayer, religion– 86% use CAM post-diagnosis

• 47% botanicals• 47% other”natural’ products• 28% special diets• 64% mind-body healing• 27% manual, energy treatments

“CAM use before and after Dx is common. Emphasis on need to discuss CAM use with all BC patients”

Greenlee et al., Breast Cancer Res Treat. 2009 Oct;117(3)

Don’t Ask, Don’t Tell Optimizing Chemotherapy: Concomitant Medication Lists M H Hanigan B Ldela Cruz SS Shord P J Medina J Fazili and D M Thompson Clinical Pharmacology & Therapeutics (2011) 89 1, 114–119.

Lifestyle and Cancer

• For the 12 common cancers about 35% of the cases in the U.S. are preventable through a healthy diet, being physically active and maintaining a healthy weight. 37% for the UK., 30% for Brazil and 27% for China.

• This translates to 340,000 preventable cases of cancer in the USA

– AICR 2009 Policy Report, GLOBOCAN 2008

Weight GuidelinesMaintain healthy weight through life

Weight Guidelines

Weight Guidelines

•Balance caloric intake with physical activity•Avoid excessive weight gain throughout lifecycle•Achieve and maintain a healthy weight if currently overweight

Cancer Obesity Theory

Obesity-Associated Malignancies% Annual U.S. Ca Excess Body Fat

TYPE % Cases

• Breast 17 33,000• Esophagus 35 5,800• Pancreas 28 11,900• Gallbladder 21 2000• Colorectal 9 13,200• Endometrial 49 20,700• Kidney 24 13,900

AICR/WCRF “Policy and Action for Cancer Prevention” report 2009

September: National Gynecologic Cancer Awareness Month

• Endometrial Cancer– 47,000 cases/yr. in U.S. 8000 deaths– 33,000 preventable• Stay lean• Avoid abdominal fat• Active every day

» Ferav Jet al., GLOBOCAN 2008, Cancer Incidence and Mortality: AIRC

Insulin Like Growth Factor-I• Evidence implicates IGF-I signaling in development

and progression of many cancers, including breast– High IGF-I levels predict increased risk– Antiestrogens reduce IGF-I levels– IGF-IR hyperactive and overexpressed– IGF-IR targeted in therapies

• IGF-I caused gene expression changes in breast ca. assoc. cell proliferation, metabolism and DNA repair

Creighton et al., JCO, 2008

Exercise and Cancer Survival• 50% decreased risk cancer-specific mortality with 9-15 MET

hrs./wk. Nurses Health Study

(Holmes et al. 2005)

• 49% risk reduction of recurrence/death at 3 years. Study: 832 pts. Stage III colon ca. Adjuvant chemo + physical therapy

• 61% reduction death. 573 nurses, stage I-III colorectal ca, 18 METs/wk

Meyerhardt JCO August 2006

Supplement Debate

“ There is strong evidence that a diet rich in vegetables, fruit, and other plant-based foods may reduce the risk of cancer, but there is no evidence that supplements can reduce cancer risk… and some evidence that indicates that high-dose supplements can increase cancer risk “

Selenium and Vitamin E(SELECT) Study, Alpha-Tocopherol, B-Carotene Study (ATBC), Women’s Antioxidant Cardiovascular (WACS)

Supplement Research Difficulties

• Concentrated intake of a single form vs. combined forms natural foods

• Higher exposure than through normal food• Lack of other healthy dietary components ( poor habits)• Recommendations

– Use in those with micronutrient deficiencies– Observe appropriate doses– If high dose mimic natural form of supplement: ie. Vit E as mixed

tocopherols, Vitamin A in mixed caratenoids vs. B-caraotene or Vit A palmitate

– Aim to meet needs through diet alone WCRF/AICR

The Antioxidant Debate

Disadvantages

• Antioxidants interfere with mechanism of cytotoxic chemo or radiotherapy

• Use of antioxidants causes diminished treatment effect and protection of tumor

Advantages

• Oxidation supports malignant proliferation• Oxidation may diminish therapeutic benefit of

chemo/radiation• Antioxidants improve Rx efficacy and protect from toxicity of

treatments

Antioxidant Advice• Depends on goal of treatment

If Cure, proceed with caution• Delay antioxidants until end of Rx• Discontinue day before, of, after chemo• Avoid during radiotherapy unless for specific toxicity ameliroation

If Palliation, encourage use for protection of normal tissue, optimization of QOL

Abrams D. Integrative Oncology 2006

→ Antioxidant radiation and chemoprotectants (mesna, amifostine) reportedly do not interfere with anti-tumor effects of Rx

Vitamin D3 ( Cholecalciferol)

• Long recognized as involved in bone health, now felt to be linked to:– Depression/Schizophrenia– Pain syndromes – Insulin resistance– Infections (URI/Tb)– Impaired immunity– Macular degeneration – Pre-eclampsia

Vitamin D3 ( Cholecalciferol)• Cancer Modulation– Promotes apoptosis– Suppresses malignant cell proliferation– Inhibits effects prostaglandins– Suppresses production cytokines– Decrease expression aromatase > reduces estrogen– Inhibits new tumor vascular growth and inhibits

metastases

– Krishnan AV,Feldman D. Mechanisms of Anti-cancer and Anti-Inflammatory Actions of Vitamin D. Annual review of pharmacology and toxicology Jan. 2010

Vitamin D3 ( Cholecalciferol)• Epidemiologic studies have shown that low Vit D levels are

assoc. with increased prevalence of breast, colorectal, prostate, and pancreas.

• A recent meta-analysis of 35 studies showed that a 10ng/ml increase in25(OH)D was assoc. with 15% risk reduction in colorectal ca, but not for prostate or breast.

• Breast cancer research showed inverse assoc. of Vit D level when checked post-diagnosis but not in prospective studies

• One study actually found adverse effects of Vit D for certain cancers ( > 80nmol) stressing need to examine the health status, life stage, adiposity, estrogen exposure, and nutritional status of the population in question

Toner et al.; The Vitamin D and Cancer Conundrum:Aiming at a Moving Target, J Amer Dietic Assoc, NCI, NIH

VITamin D and OmegA-3 TriaLVITAL Study

• Randomized, double-blind, placebo controlled multi-center trial in 20,000 participants, 5 year study, began 2010

• Women > 65, men> 60 w/o hx cancer, CVD, CVD

• One or both, or placebo• Endpoints cancer, cardiovascular events,

cognitive function, diabetes, fractures

Herb-Drug Interactions: Cytochrome P450, CYP3A4

Anticancer Agents• Camptothecins• Cyclophosphamide• EGFR-TK inhibitors• Taxanes• Vinca alkaloids

Herbal Products• CYP3A induction

– St. John’s Wort– Echinacea– Grape seed– Kava– Garlic– Ginseng – valerian

• CYP3A inhibition– Ginkgo

Herb-Drug Interactions

• Anticoagulant effects– Feverfew– Garlic– Ginger– Ginkgo– Dong guai

• Phytoestrogen effects– Red clover– Dong guai– Licorice

Potential Benefits of Dietary Supplement UseDuring Conventional Therapy

• Immune ModulatorsMedicinal mushroom ( PSK)– Solid tumors, mostly animal studies, some human– RCT 207 pt., Stage II,III colorectal ca. 3gm/day PSK

• 5yr disease free survival and regional metastases significantly reduced in treatment group.

– 8 RCT’s 8009 gastric ca. pt’s: PSK 3gms/day• pt’s> increased survival p<.018, increase disease free survival

– Study 30 advanced lung ca. pt’s. > no change survival

Ohwada S. et al.,Br J Cancer 2004;90(5 Oba K. et al., Cancer Immunol Immunother 2007;56(6) Gao Y. et al.,J Med Food 2005;8(2)


• Immune Modulation Avemar

– Methoxy-substituted benzoquinone shown immunomodulatory and anti-tumor activity in animal and human clinical trials

– Triggers apoptosis by regulating Poly( ADP-ribose) polymerase without harm normal cellc

– Non-random advanced adult colorectal ca.pt’s (n=104) +conventional Rx

– After 6mos. Fewer recurrences (3% vs 17%), new mets (8% vs 23%), death (12% vs 32%) all p< .01

• RCT Stage III melanoma (n=42) receive decarbazine chemo – increase time-to-relapse (9 vs 4 mos.), without change in relapse rate,

and with increase no. free of disease at 1 yr (55% vs 38%)

Boros LG et al., Ann NY Acad Science 2005;1051:529-42 Jakob F et al.,Br J Cancer 2003;89(3) Demidov L et al., 18th UICC Inter CA Congress.Oslo, 2002


Stomatitis/MucositisGlutamine– Positive results reported in a number of adult and pediatric

studies with oral glutmamine as swish and swallow. Both chemotherapy and radiation induced mucositis. No untoward chemo effects

• One large phase III trial using 5-FU chemo did not show benefit

Cerchietti LC et al., Int J Radiat Oncol Biol Phys 2006 Okuno SH et al., et al., Am J Clin Oncol 1999


Peripheral Neuropathy• Glutamine

– Wang et al. small RCT (n=86) 15gm 2x/day– Significantly lower incidence Grade 3-4 neuropathy after 4 cycles (5%

vs 18% p=0.05)– After 6 cycles (12% vs 32%; p=0.04)– Need for oxaliplatin dose reduction lower in treatment arm– No between-group difference in response to chemo or survival

• Results promising, but need for larger RCT

Wang WS et al., Oral glutamine is effective for preventing oxaliplatin induced neuropathy in colorectal cancer patients. Oncologist 2007;12(3)


Melatonin• Recent meta-analysis of 8 RCT’s ( n=761) Solid tumor

cancers– Melatonin sig. improved complete and partial remission

(16.5% vs 32.6%; p< 0.00001)– ↑1-year survival (28.4% vs 52.2%;p=0.001)– Dramatic ↓radio-chemo side-effects ( p< 0.001)– Consistent across all cancers. – No serious adverse events– Dosage studied: 20mg/day, target dose slowly over 1-3

weeks

Wang YM et al., Cancer Chemother Pharmacol. 2012 May:69(5)

Complementary Cancer CareMassage Therapy

• Numerous observational studies demonstrate reduction anxiety, pain, fatigue, and stress

• Most common forms used in oncology include Swedish massage, therapeutic massage, acupressure, and reflexology

• East Carolina School of Nursing (2000)– 23 inpatients with breast/lung ca– foot reflexology 15 min. vs usual care– Significant reduction anxiety scores and 1 in 3 of pain measures

Cochrane review meta-analysis prior 2002. 8 RCT, n=357 Anxiety decrease 8, pain 1/3, nausea 2/3

Massage TherapyMechanism of Action Theories

• Gate theory of pain• Parasympathetic activity• Endorphins, serotonin,?enkephalins• Blood flow• Lymphatic flow• Interpersonal attention


• 87 hospitalized cancer patients randomized to foot massage or an appropriate control– VAS scale: treatment > control for” immediate” pain

and anxiety ( p<0.03) Grealish L et al. Cancer Nurs 2000:23

• RCT comparing acupuncture + massage for post-operative cancer patients– N=94 Ac+massage, n=48 usual care– Intervention 1.4 pts. 0-10 scale vs 0.6 control (p=.038)

Depressive mood: intervention 0.4 (1-5 scale), control =/-0 (p=0.003)

Mehling et al. J Pain Symptom Manag 2007:33


• Largest uncontrolled study at Sloan Kettering Cancer Center. 1290 cancer pts. Symptom score decreased 50%.– Both in/outpatients, self-reported pre/post survey 48hrs

RC multi-center trial - Massage vs simple touch– N=380 (90% hospice, mod/severe pain)– 30 min massage or ST over two weeks– Both improved pain and mood– Massage superior immediate pain and mood– Effects not sustained for pain, QoL, analgesic use

• Kutner JS et al. Ann Intern Med 2008

Massage Therapy

• Systematic review of all RCT’s of non-cancer subacute and chronic back pain– Massage therapy demonstrated significant

improvements in pain, Qol, function, and possibly a reduction in cost of care

Evidence-Based Practice Guidelines for Integrative Oncology• Recommend use for anxiety, pain by oncology- trained

massage therapist. Grade 1C

Supportive Cancer CareEnergy Therapies

• eg. Healing Touch, Therapeutic Touch, Reiki, Qi gong

• Prospective study massage, healing touch, or “caring presence” during chemotherapy– N=230, 44% stage III, 4/wk x 45 min– Credentialed nurses– MT,HT significant decrease HR( 7bm), SBP, pain– HT significantly reduced distress, fatigue ( Profile of Mood )– MT significant decrease NSAID use– Drawback of high drop out 29%

Post-White J et al. 2003 Integrative Cancer Therapies, 2(4)

Supportive Cancer CareEnergy Therapies

• Single-blind randomized trial, HT vs. Mock– Gyn / breast ca. pts. undergoing Radiation Rx– N=78, 62 completed– Pts. Separated by screen from practitioner

• Results– HT higher overall scores for QoL( SF-36), mental health, emotional

functioning, health transition– Mock Rx did show similar increases in physical functioning and health

transition, not QoL– Drawback: statistical analysis was different between groups

Cook CAL et al., 2004 Alternative Therapies, 10 (3)

Supportive Cancer CareAcupuncture

• Strong evidence supports the use of acupuncture for post-op pain, chronic pain, OA knee, and headache Berman BM et al. 2004 Ann Intern Med

• Acupuncture also shown to suppress N/V related to surgery, pregnancy, and motion sickness

Ming JL et al., J Adv Nurs 2002 (39) Strietberger K et al. Anaesthesia 2004 (59)


Cancer related pain: • Randomized, blinded, controlled trial auricular acupuncture– N=90, true acup., sham acup., acupressure– Pain intensity decrease true >sham, pressure by

36% at two months ( p<0.001)– Majority >60% with neuropathic pain

Alimi D et al., J Clin Oncol 2003(21)


Cancer related pain - Pilot study acupuncture treatment for arthralgias

related to aromatase inhibitor therapy

– N=21 post-menopausal women with breast ca.– Randomized to acupuncture 2x/wk x 6wks– Full body + auricular acupuncture+ local points– Results: worst pain (5.3 to 3.3,p=0.01), pain severity ( 3.7 to 2.5

p=0.02),functional interference (3.1 to 1.7, p=0.02), phys.well-being FACT-G ( 19.9 to 23.4 p=0.03)and WOMAC (80.9 to 47.4, p=0.04)

Crew KD et al., J Cancer Surviv 2007(1)


Chemotherapy-induced N/V• Randomized controlled trial true electroacupuncture, minimal needling w/ mock electroacupuncture or antiemetics alone

– N=104 breast cancer patients receive high emetogenic chemotherapy. Acup Rx 1x/day x 5 days

– Results: significant decrease # episodes emesis in electroacupuncture group sig. less than the other 2 groups ( # episodes 5, 10, 15 respectively ; p<0.001) minimal needling< pharm alone

– Differences among groups not significant at 9 days

Shen J et al., JAMA 2000 (284)


Other reported benefits:

Equal to venlafaxine in relief hot flashes ( RCT) Walker EM et al J Clin Oncol 2010 (4)

• 30% improvement in radiation-induced xerostomia ( case series)

Johnstone et al., Cancer 2002 (26)

• Effective in hot flashes in men undergoing ADT for prostate cancer ( case control study)

Beer et al., Urology 2010

• Safe in children with cancer related thrombocytopenia (retrospective study)

Ladas et al., Support Care Cancer

Supportive Cancer CareMind-Body Medicine

• Guided imagery• Hypnosis• Breath work• Mindfulness therapies• Biofeedback• Music therapy, expressive arts• Cognitive therapies• Yoga, Tai Chi, movement therapies

Mind-Body ApproachHypnosis Before Breast Cancer Surgery

• N=200 pts. randomized to a)15 min hypnosis before surgery or b) empathic listening (attention control). Staff blind ( surgeon, anesthesia, nursing, research)

• Hypnosis group– Less anesthesia; same post-op meds– Less pain intensity, pain unpleasantness, nausea,

discomfort, fatigue, emotional upset– Cost savings: $770 per pt. ( 10.5 min less in surgery)

• 100 cases annual $77,271 savings ? Hire hypnotherapist Montgomery GH et al., J Nat Canc Inst 2007 ( 99)

Recommended Web-Sites

• NCI/CAM www.cancer.gov/cam/health

• Memorial Sloan Kettering Cancer Center www.mskcc.org• U of T MD. Anderson Cancer Center www.mdanderson.org• Cochrane Review Organization www.cochrane.org• Natural Standard www.naturalstandard.com• Natural Medicines Database www.naturaldatabase.com• American Botanical Council www.herbalgram.org

http://www.cancer.gov/cam/health

http://www.mskcc.org/

http://www.mdanderson.org/

http://www.cochrane.org/

http://www.naturaldatabase.com/

Insights• Integrative practitioner can assist oncology teams

navigation across the bridge between conventional and complementary worlds.

• Non- judgemental communication needs to exist between practitioner-patient to enhance honesty, openness, and trust.

• A number of complementary therapies have a reasonable evidence-base.

• Education (faculty and resident) and use of reputable resources will help in supporting the clinical-decision making process.

Evidenced-Based Clinical Practice Guidelines for Integrative Oncology:

Complementary Therapies and Botanicals

• Practice recommendations based on strength of the evidence and the risks/benefits ratio

• Grading system modeled from the American College of Chest Physicians Task Force on Grading– Recommendations: strong ( grade 1),weak (grade 2) Quality

of evidence high (grade A), moderate ( grade B ), low( grade C )

Journal of the Society for Integrative Oncology Vol 7, No. 3, 2009

“Two roads diverged in a wood, and I— I took the one less traveled by, And that has made all the difference”

Robert Frost, New England Wisdom

“ The role of the physician is to Cure sometimes,

Heal often, Support always “

Ambroise Pare

Health & Medicine

Integrative Oncology