1. S L I D E 0 Complementary, Alternative, and Integrative Medicine: Epidemiology and Relevance to Oncology Dr. Ather Ali, ND, MPH, MHS (c) Associate Research Scientist, Department of Pediatrics Integrative Medicine Specialist, Yale Stress Center Director, Integrative Medicine at Yale Atatürk Üniversitesi May 2014

2. S L I D E 1 Outline Reasons for seeking CAM/IM Risks of CAM therapies in oncology Research in CAM therapies Safety / efficacy balance Treatment guidelines Information Resources

3. S L I D E 2 Motivations for seeking CAM Same as other reasons for CAM/Integrative Medicine –Personal values –Sense of empowerment / participation in self-care –Concern about safety of conventional medicine –No resolution or improvement with conventional treatment –Desire for a “holistic” approach Cancer patients use CAM to –reduce adverse effects/organ toxicity –improve quality of life –protect and stimulate immunity –reduce risk of further cancers In most cases, patients are not disappointed/dissatisfied with conventional medicine

4. S L I D E 3 Cancer – CAM epidemiology in the United States 7-64% of cancer patients use some type of CAM (1) –Mean of 32% 68% of radiation therapy patients (2) –Majority are female and college-educated. –Of these, 58% discussed use with their physician 80% of breast cancer patients reported use of CAM (3) –Of these, 41% specifically to treat the cancer 1. Cancer. 1998 Aug 15;83(4):777-82. Review. 2. Am J Clin Oncol. 2006 Oct;29(5):468-73. 3. BMC Womens Health. 2007 Mar 30;7:4.

5. S L I D E 4 Cancer – CAM epidemiology CAM use increases after diagnosis High-risk women attending a genetic testing program were found to be using CAM at rates (53%) comparable to those reported in active treatment –especially in BRCA-1 + patients Radiation therapy –High rates (68%); especially dietary supplements (80%) Use of CAM often continues long after completion of conventional care Majority (53%) of patients using dietary supplements during recent chemotherapy did not seek advice from a medical provider Hematol Oncol Clin North Am. 2008 Aug;22(4):581-617.

6. S L I D E 5 Cancer – CAM risks When used as as a substitute for conventional treatment in 33 women with breast cancer –early death, higher rates of recurrence Every ‘‘natural cancer cure’’ examined so far has failed rigorous clinical trials –shark cartilage - no benefit –laetrile - ineffective and toxic (cyanide poisoning) Even for patients with advanced disease, most (88%) receive CAM care concurrently with conventional care –minority (8% in one study) who choose solely alternative cancer care Hematol Oncol Clin North Am. 2008 Aug;22(4):581-617.

7. S L I D E 6 Cancer – CAM risks (2) PC-SPES removed from the market in 2002 –found to contain warfarin, diethylstilbestrol, and other substances U.S. FDA – new rules regarding dietary supplement quality –DSHEA – Dietary Supplement Heatlh and Education Act (1994) –Current Good Manufacturing Practices –Structure/Function claims Hepatotoxictiy with some herbs –chaparral (Larrea tridentate), comfrey (Symphytum officinale), and kava (Piper methysticum) Hematol Oncol Clin North Am. 2008 Aug;22(4):581-617.

8. S L I D E 7 Natural product-Drug Interactions? 4% chemotherapy patients surveyed were using herbs (St. John’s wort and garlic) that may affect chemotherapy metabolism. In 318 chemotherapy patients using herbal remedies –11% took supplements in higher than recommended doses –potential interactions identified in 12% Herb with strongest risk of clinically significant interactions is St. John’s wort (Hypericum perforatum) –Can inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 Hematol Oncol Clin North Am. 2008 Aug;22(4):581-617.

9. S L I D E 8 Antioxidants? Potential for interactions and reduced efficacy Most concerns are theoretical –limited evidence for harm –mainly for vitamin E with head and neck cancer patients large amounts of pre-clinical data and limited human data to support antioxidant use –(intravenous / high-dose) Vitamin C – tumor response? –IMC experience and thought process –CoQ10 and vitamin E for doxirubicin-related cardiotoxicity Hematol Oncol Clin North Am. 2008 Aug;22(4):581-617.

10. S L I D E 9 Contemp Pediatr 2004;21:61-72. How to navigate inconclusive evidence

11. S L I D E 10 Promising Research - 1

12. S L I D E 11 Promising Research - 2

13. S L I D E 12 Promising Research - 3

14. S L I D E 13 Promising Research - 4

15. S L I D E 14 Society for Integrative Oncology Guidelines - Acupuncture Recommended for: –Poorly controlled pain –Clinically significant side effects such as neuropathy or xerostomia –Nausea/vomiting due to chemotherapy –Smoking cessation –Dsypnea, fatigue, chemotherapy induced neuropathy, or post- thoracotomy pain –Caution with patients with bleeding tendencies

16. S L I D E 15 Radiation and CAM - benefits Relaxation therapies–tension, depression, anger, fatigue (1) Acupuncture–xerostomia; can last up to 3 years (2) Acupuncture–fatigue (2) Probiotics–diarrhea (3) Glutamine–Decreased rates and severity of mucositis, neuropathy, and intestinal toxicity; decreased use of pain meds in stomatitis patients; improved nutrition in stomatitis patients; improved ADL in neuropathy patients Vitamin E / Zinc / Chamomile–improved stomatitis Calendula lotion–helpful for dermatitis Pomegranate juice–increased PSA doubling time 1.J Clin Psychol 1992;48:388–93 2.Journal of the Society for Integrative Oncology, Vol 5, No 2 (Spring), 2007: pp 65–84 3.Hematol Oncol Clin North Am. 2008 Aug;22(4):581-617, vii. Review.

17. S L I D E 16 Radiation and CAM - harms RCT of 540 patients with head and neck cancer undergoing radiation (1) –Subjects given antioxidants (400-IU α-tocopherol, 30-mg β-carotene) or placebo daily throughout radiation therapy and for 3 years afterwards. Acute side effects of radiation were significantly less in the antioxidant group Local recurrence higher in antioxidant group (OR 1.37; CI 0.93– 2.02). –After a median follow-up of 6.5 yr –all-cause mortality significantly higher in antioxidant group (HR 1.38; CI 1.03–1.85) (2) 1.J Clin Psychol 1992;48:388–93 2.Journal of the Society for Integrative Oncology, Vol 5, No 2 (Spring), 2007: pp 65–84

18. S L I D E 17 IMC Experience: Intravenous Vitamin C Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind RCTs of oral vitamin C therapy showed no benefit At concentrations above 1000 µmol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. Case reports (kidney, bladder, paraspinal) are intriguing. Patient demand vs. safety concerns (particularly renal) Created policy/procedure Input from pharmacy, medical oncology, legal, and experts in the field

19. S L I D E 18 Cancer – CAM resources http://www.cancer.gov/CAM/ http://nccam.nih.gov/health/cancer/ Abrams D and Weil A. Integrative Oncology. Oxford University Press, 2009. Society for Integrative Oncology: www.integrativeonc.org Integrative Medicine in Oncology: Hematol Oncol Clin N Am 24 (2008)

20. S L I D E 19 This work was supported by a grant from National Center for Complementary and Alternative Medicine National Institutes of Health U.S. Department of Health and Human Services www.nccam.nih.gov