TREATMENT INTERACTIONS & TODAY’S MYELOMA PATIENT

1. TREATMENT INTERACTIONS &TODAY’S MYELOMA PATIENT Timothy Tyler, Pharm.D., FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center

2. Objectives • Understand at a basic level, the complexity of current treatments for Multiple Myeloma • Review major interactions and cautions with standard and complementary treatments • Review specific oral supplements of concern • Focus on appropriate sources of information • Have Fun (that’s okay – really!)

3. Comprehensive Cancer CenterDesert Regional Medical Center

4. Comprehensive Cancer Center • Established in 1990 – 21st year of operation • Part of 5 cancer center chain (CA / FL / NY / NJ) • DRMC-CCC began a CAM team in 1999 • Presented 6 month study at ISOPP VII (Prague) • CAM team established weekly meetings 2000 • Team is composed of a Physician, Physiologist, Pharmacist, Dietician, Social Worker • Patient satisfaction survey results demonstrate ongoing satisfaction with service CAM = Complementary & Alternative Medicine

5. The Desert Experience • 108 cancer patients from a single physician surveyed from 1/99 through 6/99 • Brief patient interview with a questionnaire • Overall 85% prevalence rate in CAM usage • About 50% of which was multivitamins or multivitamin w/ mineral supplement • Information not volunteered prior to survey CAM = Complementary & Alternative Medicine

6. The Desert Experience • 85% used at least one form of CAM (includes multivitamin, +/- mineral combination) • 52% of those using CAM take only a multi-vitamin, +/- mineral combination • 29% used herbal preparations • 13% used food derivatives/supplements • 9% used (other) complementary therapies CAM = Complementary & Alternative Medicine

7. Possibly Unrealistic Goals … According to the late Varro Tyler, Ph.D., Sc.D. and professor emeritus of pharmacognosy at the School of Pharmacy at Purdue University, people do set somewhat unrealistic treatment goals. If people do set unrealistic goals for themselves as it pertains to herbal products, many time they verge on “paraherbalisim – the belief in the superiority of anything natural and organic”. The most dangerous misconception that this concept brings is that natural substances cannot cause harm. Tyler warns that “some highly toxic substances are derived from plants.” Foreman J. The Boston Globe 3/17/97

8. Traditional Oriental Medicine (TOM) • “Traditional” medical in such places such as: China, Japan, Cambodia, Korea, and Vietnam • Basic principles: • Five elements of wood, fire, earth, metal, and water. • Tao = “the way”, significance of change & process • Yin & Yang = 2 opposing forces that drive change • Ch’i = invisible universal energy force that is believed to flow through all living organisms. • Acupuncture = opens the meridians and/or directing the flow of ch’i to promote health • Combines diet, acupuncture, meditation, physical exercise, healing exercise, herbal medicine, and massage to promote health.

9. Acupuncture • NIH supports efficacy in the control of: • Chemotherapy-related nausea & vomiting • Palliation of chronic pain • Studies suggest that it is reasonable to accept the use of acupuncture in conjunction with a standard antiemetic to control chemotherapy-related nausea and cancer-related pain. NIH = National Institute of Health

10. Acupuncture • Caution should be exercised in patients with: • A compromised immune system • Affected limb of someone who has a lymph node dissection (impaired lymphatic drainage) • Avoid insertion of needles in patients who are: • Thrombocytopenic (low platelet counts) • Using anticoagulant therapy (warfarin, aspirin, etc)

11. Manual Healing Methods • Touch and manipulation, used for hundreds of years in the medical profession • Hippocrates discussed the benefits of therapeutic touch with students • Three types: • Massage • Bodywork • Chiropractic • Use with extreme caution with bone pain and bone disease – particularly with Multiple Myeloma

12. Massage • Involves manipulation of soft tissues • Benefits may include: •  stress aches & pain • Improved circulation • Lymph movement & motility • Enhanced digestion & intestinal function • General relaxation 

13. Massage Studies Results … • Inconclusive for relief from cancer-related pain • Evidence does not indicate promotion of tumor metastasis at this time • 1 trial showed that massage reduced nausea in patients undergoing autologous (self) BMT • 2 trials found manual lymph drainage to be effective with compression bandaging or sleeves in patients with arm lymphedema after surgery for breast cancer BMT = Bone Marrow Transplant

14. Massage • Studies have shown that massage can be helpful in treating pain, anxiety, depression, and lethargy • Concerns: • Patients who are prone to bleed, thrombocytopenic or receiving anticoagulation therapy • Deep abdominal massage has been associated with internal bleeding • Avoid over stents or other prosthetic devices • Multiple Myeloma patients have greater fracture risk

15. IV CHEMOTHERAPY Bortezomib (Velcade) Carmustine (BCNU) Cyclophosphamide (Cytoxan) Doxorubicin, Lipo. (Doxil) Melphalan (Alkeran) Vincristine (Oncovin) ORAL CHEMOTHERAPY Dexamethasone (Decadron) Lenadiomide (Revlamid) Melphalan (Alkeran) Prednisone (Deltasone) Thalidomide (Thalamid) Agents Used in Multiple Myeloma SUPPORTIVE CARE • Pamidronate (Aredia) • Zolendronic Acid (Zometa) NOTE = Agents Listed are FDA-Approved (excluding compendia) for the treatment of Multiple Myeloma

16. Antioxidants vs. Chemotherapy To date, no definitive studies in humans have demonstrated long term effects of combining oral antioxidants and chemotherapy. There is sufficient cause for concern regarding potential interactions and it should be possible to predict obvious interactions and suggest where caution should be exercised. Improving short-term tolerance should not come at the expense of decreased effectiveness. Oncology – July 1999

17. Bortezomib + Green Tea = Bust • Green tea contains powerful polyphenols such as epigallocatechin gallate (EGCG) • Preliminary research in vitro and in vivo shows green tea polyphenols interact with Bortezomib (Velcade) and other proteasome inhibitors. • The result is blocking the proteasome inhibitory effects such that cell death is not induced in multiple myeloma or glioblastoma cancer cell lines. • Patients taking boronic acid-based proteasome inhibitors like Bortezomib (Velcade) should not take green tea. Source = Natural Medicines Database

18. St. John’s Wort = No Way Jose • St. John's Wort induces liver enzymes thus making it problematic and somewhat patient variable • Drugs that might be affected include Chemotherapy agents Etoposide, Paclitaxel, Vinblastine, Vincristine. • In addition, pain medications, steroids, antiemetics, antidepressants, OTC acid blockers and numerous others are impacted • Interaction Rating = Major (Do not take) • Severity = High • Occurrence = Probable • Level of Evidence = B Source = Natural Medicines Database

19. Cyclophosphamide + Astragalus = ? • Be cautious with taking Cyclophosphamide (Cytoxan) + Astragalus in combination • Some evidence suggests astragalus might reduce immunosuppression caused by Cyclophosphamide • Astragalus seems to stimulate immune function so theoretically, taking Astragalus might decrease the effects of immunosuppressive therapy such as steroids and chemotherapy like Cyclophosphamide • The problem stems from when the treating clinician does not know the patient is taking an immunomodulator • In addition to Astragalus, Alfalfa, Ashwagandha, Cat’s Claw, Echinacea and about 38 other immunostimulants should be used only after gaining approval from your doctor Source = Natural Medicines Database

20. Chemotherapy + Alpha Lipoic Acid • Theoretically, use of Alpha Lipoic Acid (ALA) might decrease the effectiveness of chemotherapy. • Preliminary evidence from an unpublished study suggests antioxidants may decrease the effectiveness of chemotherapy • Natural Medicines Database listed this for Bortezomib, Carmustine, Doxorubicin, Cyclophosphamide, Melphalan, Vincristine Source = Natural Medicines Database

21. Chemotherapy + Enzyme CoQ10 • Theoretically, taking Coenzyme Q-10 supplements might prevent cardiotoxicity induced by Doxorubicin & Cyclophosphamide • But there is also concern that coenzyme Q-10 might lower effectiveness of doxorubicin by protecting tumor cells from chemotherapeutic agents that work by inducing oxidative stress • Similar concerns exists for the alkylating agents such as Cyclophosphamide and radiation therapy Source = Natural Medicines Database

22. Vitamin C and The Big ‘C’ • Dr. Linus Pauling advocated in the 1970’s • 3 trials to date using 10,000 mg daily • No difference in patient survival has been seen • Therapy with mega doses are not benign Oncolink Website 3/17/2000

23. Vitamin C and The Big ‘C’ • The use of antioxidants like Vitamin C during chemotherapy remains controversial • There's concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals • Mechanisms other than the antioxidant effects of vitamin C might be involved. This might include prevention of the damaging to the cell powerhouse (mitochondria) caused by many chemotherapy drugs, which is involved in regulating cell death • In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells • More evidence is needed to determine what effects vitamin C has on chemotherapy. Advise patients to consult their oncologist before using vitamin C supplements, especially in high doses. Source = Natural Medicines Database

24. Chemotherapy + Vitamin E • The use of antioxidants like vitamin E during chemotherapy remains controversial. • There's concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as Cyclophosphamide, Carmustine, and Doxorubicin • However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells • More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy • Natural Medicines Database advises patients to consult their oncologist before using vitamin E supplements, particularly when considering high doses especially with bleeding risks or surgery Source = Natural Medicines Database

25. Acceptable CAM Treatments • Nutrition – Fluid, Protein, Fat, MVI (RDA) • Variety of fish (Omega 3 FA) • 2-3 servings/day Soy in form of food • 1-2 tablespoonfuls daily ground Flaxseed • Certain herbal products – consulted & supervised • Acupuncture for N/V and pain • Massage for anxiety and pain (Physician willing) • Moderate exercise (Physician willing) • Psychological and mind-body therapies Source = Comprehensive Cancer Center CAM Team

26. Top 12 Notes on Medicinal Herbs • Doctors should be asking you about your use of herbs/supplements • If they don't – volunteer the information especially when on treatment • Natural does not mean safe (strychnine is natural) • Lack of standardization: contents and efficacy may vary with brands • Lack of quality control/regulation: contamination • Do not use more than the recommended dose • Herbals generally should not be used for more than several weeks • Infants, children, and elderly should use with professional guidance • Medicinal herbs should not be taken during pregnancy and lactation • Avoid herbals that are known to have toxic/adverse side effects • Accurate diagnosis and discussion of proven treatments are essential • Stop all herbs at least 10 days prior to surgery

27. CAM or SHAM? • Many have adopted a “whatever works” philosophy of medicine • There are products that have documented aid • There are products with documented harm • There are products we don’t know much about

28. Web Surfing: Watch Four Red Flags • One study suggests to avoid sites with one or more of the following red flags: • Online purchase of described product is available. • Treatment description includes patient testimonials. • The treatment is described as a “cancer cure.” • The treatment is described as “having no side effects.” • The authors also point out that the absence of red flags isn’t necessarily a guarantee of scientific accuracy.

29. Created by congressional mandate in 1992 to “facilitate the evaluation of alternative medical treatment modalities”. Originally called the Office of Alternative Medicine, it was renamed the National Center for Complementary and Alternative Medicine in 1998. It is a division of the National Institute of Health, which is under the auspices of the Department of Health and Human Services. http://nccam.nih.gov

30. Reasons People with Cancer Choose CAM • Making Choices • What is Complementary and Alternative Medicine • Types of Complementary and Alternative Medicine • Talk with Your Doctor Before You Use CAM • Natural Does Not Mean Safe! • Choose Practitioners with Care • Getting Information from Trusted Sources • Resources

31. Questions to ask about a Web site: • Who runs and pays for the site? • Does it list any credentials? • Does it represent an organization that is well-known & respected? • What is the purpose of the site, and who is it for? • Is the site selling or promoting something? • Where does the information come from? • Is the information based on facts or only on someone's feelings / opinions? • How is the information chosen? • Is there a review board or is the content reviewed by experts? • How current is the information? • Does the site tell when it was last updated? • How does the site choose which other sites to link you to?

32. Elements of good information: • Also Known As (AKA) • Scientific Names (geekius herbifora) • People Use This For (you’d be amazed) • Safety Profile (MANDATORY): • Likely Safe • Likely Unsafe • Definitely Unsafe

33. More good Elements: • Effectiveness: • Likely Effective for… • Likely Ineffective for… • Unknown efficacy ? • Mechanism of Action • Adverse Reactions • Dosage and Administration • References

34. Nothing Exists in a Vacuum • Interactions with Herbs & Supplements • Interactions with Drugs • Interactions with Foods • Interactions with Lab Tests • Interactions with Diseases or Conditions • Interactions with pocketbook!!!

35. Good CAM/Drug Information Until there is a cure … There is the IMF