1. A Phase III Prospective Randomized Trial of Acupuncture for Treatment of Radiation-Induced Xerostomia in Patients with Head and Neck Cancer CCOP Investigators’ Meeting March 4, 2011 M. Kay Garcia, LAc, DrPH M. D. Anderson Cancer Center Integrative Medicine

2. A Phase III Prospective Randomized Trial of Acupuncture for Treatment of Radiation-Induced Xerostomia in Patients with Head and Neck Cancer Primary Objective: Primary Objective: To determine whether or not acupuncture can symptomatically improve severe xerostomia (grade 2 or 3) due to head/neck radiotherapy. Secondary Objective: Secondary Objective: To explore the duration of response (up to a maximum of 12 weeks) in the subgroup of patients who report a response to the acupuncture intervention. To explore the duration of response (up to a maximum of 12 weeks) in the subgroup of patients who report a response to the acupuncture intervention.

3. Significance Over 35,000 new cases of oral cavity and pharyngeal cancers were diagnosed in the United States in 2009. 1 Over 35,000 new cases of oral cavity and pharyngeal cancers were diagnosed in the United States in 2009. 1 Over 7600 deaths 1 Over 7600 deaths 1 Approximately 80% of patients develop xerostomia after only a few weeks of treatment. 2 Approximately 80% of patients develop xerostomia after only a few weeks of treatment. 2 Radiation-induced xerostomia becomes chronic in almost 70% of patients. 2 Radiation-induced xerostomia becomes chronic in almost 70% of patients. 2 1. Jemal A, et al, CA Cancer J Clin 2009;59(4):225. 2. Emami B, et al, Int J Radiat Oncol Biol Phys 1991; 21:109.

4. Xerostomia Radiation clearly damages salivary tissue Radiation clearly damages salivary tissue Damage at doses <50Gy may be partially reversible Damage at doses <50Gy may be partially reversible No evidence of reversibility at higher doses No evidence of reversibility at higher doses Reduced salivary flow typically begins during the first few days of treatment Reduced salivary flow typically begins during the first few days of treatment 80% decrease noted at 6 weeks 80% decrease noted at 6 weeks Other quantitative changes Other quantitative changes decrease in salivary pH, increase in viscosity, reduction of salivary constituents (immunoglobulins, buffering capacity, small organic molecules)

5. Salivary Flow Significant variation between individuals Significant variation between individuals Subjective sensation of dryness does not correlate well with measured flow rates Subjective sensation of dryness does not correlate well with measured flow rates FDA currently recognizes the subjective response as the primary benefit FDA currently recognizes the subjective response as the primary benefit 1. Screebny L, et al, Int Dent J 1992; 42:287. 2. Fox PC. J Dent Res 1987; 66: 689.

6. Common Symptoms Xerostomia (dry mouth) can impart a profound impact on QOL for patients and lead to: Xerostomia (dry mouth) can impart a profound impact on QOL for patients and lead to: taste aberrations loss of appetite dysphagia & odynophagia difficulty speaking difficulty sleeping irreversible nutritional deficits

7. Current treatment Rarely spontaneously improves by itself Rarely spontaneously improves by itself Current treatment: Current treatment: pilocarpine, amifostine saliva substitutes IMRT – still results in xerostomia palliative for symptom relief Low success rate or low acceptance

8. Acupuncture Traditional Chinese Medicine Theory Traditional Chinese Medicine Theory Excess vs Deficiency Heat Syndrome Excess vs Deficiency Heat Syndrome Yin Deficiency Syndrome Yin Deficiency Syndrome Lung Lung Stomach Stomach Kidney Kidney

9. Proposed Putative Mechanisms Increase in local blood flux Increase in local blood flux Increased production of neuropeptides such as calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) Increased production of neuropeptides such as calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) 1. Dawidson I, et al, Neuropeptides 1999; 33: 244. 2. Dawidson I, et al, Neuropeptides 1998; 32: 543. 3. Blom M, et al, J Oral Rehabil 1993; 20: 541.

10. Previous Studies of Acupuncture for Xerostomia Studies conducted by different investigators in the U.S. and Europe Studies conducted by different investigators in the U.S. and Europe Different points and techniques Different points and techniques Similar results Similar results -- improvement with 5-10 treatments -- improvement with 5-10 treatments -- benefits documented up to 3 years after treatment after treatment 1. Johnstone P, et al, Cancer 2002; 94:1151. 2. Rydholm M, Strang P. J Palliat Care 1999; 15:20. 3. Blom M, et al, Oral Oncology, Eur J Cancer 1996; 32B:182. 4. Andersen S, Machin D. Oral Oncol 1997; 33:146. 5. Blom M. Lundeberg T. Oral Dis 2000; 6:15

12. Our Preliminary Studies Single-arm pilot (MDACC treatment) Single-arm pilot (MDACC treatment) 2-arm acu vs standard care (MDACC/Fudan, prevention) 2-arm acu vs standard care (MDACC/Fudan, prevention) 2-arm true acupuncture vs sham (MDACC/ Fudan, prevention) 2-arm true acupuncture vs sham (MDACC/ Fudan, prevention)

13. Single Arm Pilot (MDACC) Mean XI Scores Mean XI Scores (high score = increased severity) (0.0004) (0.0001)

14. Clinical Significance: XI Scores Partial response (PR) = difference > 6 points from baseline or 30% of starting score if baseline 6 points from baseline or 30% of starting score if baseline <20 Minor response (MR) = difference < 6 points but at least 3 points from baseline after 4 weeks of acupuncture Minor response (MR) = difference < 6 points but at least 3 points from baseline after 4 weeks of acupuncture No response (NR) = absence of PR or MR No response (NR) = absence of PR or MR Expected response rate = 40% Expected response rate = 40% Actual response rate = 44% at week 4 and 56% at week 8 Actual response rate = 44% at week 4 and 56% at week 8

15. Acupuncture vs Standard Care Prevention Trial 15 SYMPTOMSSALIVA FLOW

16. Acupuncture vs Standard Care Prevention 16 SYMPTOMSSALIVA FLOW

17. 17 Placebo Controlled PreventionTrial

18. 18 Development of Xerostomia Main Study Placebo Study

19. CCOP Study Design (Treatment) 3 groups 3 groups 1) Standard Oral Hygiene 2) Standard Oral Hygiene + True acupuncture twice weekly for 4 weeks weekly for 4 weeks 3) Standard Oral Hygiene + Sham acupuncture twice weekly for 4 weeks weekly for 4 weeks Follow-up Follow-up If PR or NR, follow-up at 8 and 12 weeks If MR, continue assigned treatment twice weekly for 4 weeks

20. Eligibility Inclusion Criteria Inclusion Criteria  Head/neck cancer  Received bilateral RT & developed xero of at least grade 2 or 3  Completed RT at least 9 months prior  Acupuncture naïve  Chemo during or subsequent to RT is allowed (& expected)  No hx of xero prior to RT  No active infection Exclusion Criteria Exclusion Criteria  Patients on or planned to receive another xero treatment agent (all other xero tx stopped at least 14 days prior to enrollment)  Previous acupuncture  Local infection  Hx of xero prior to head/neck RT

21. True Acupuncture Treatment Body points Body points CV 24, Lu7, K6, LI1-prime CV 24, Lu7, K6, LI1-prime Gb32 (placebo needle) Gb32 (placebo needle) Ear points Ear points Shenmen, Point zero, Shenmen, Point zero, Salivary Gland 2-prime Salivary Gland 2-prime

22. Sham Acupuncture Treatment Body points Body points Sham 1 chin; Sham 2,3 BUE; Sham 4-BLE; 1 penetraing needle at Gb32 right knee Sham 1 chin; Sham 2,3 BUE; Sham 4-BLE; 1 penetraing needle at Gb32 right knee Ear points Ear points 3 points on the ear helix that are not electrodermally active 3 points on the ear helix that are not electrodermally active

23. Measures Subjective Subjective Xerostomia Questionnaire (XQ)Xerostomia Questionnaire (XQ) MDASI-HNMDASI-HN FACT-GFACT-G Acupuncture Expectancy Scale (AES)Acupuncture Expectancy Scale (AES)

24. Patient Response XQ scores at baseline and 4 weeks after beginning treatment XQ scores at baseline and 4 weeks after beginning treatment No response=xero worsens or no decrease in XQ from baselineNo response=xero worsens or no decrease in XQ from baseline Minor response = 10-19 point decreaseMinor response = 10-19 point decrease Partial response =20 points or more decrease from baselinePartial response =20 points or more decrease from baseline Complete response = XQ score of 10Complete response = XQ score of 10 Duration determined by XQ at 8 and 12 weeks Duration determined by XQ at 8 and 12 weeks At week 4, patients will be asked which group they think they were assigned At week 4, patients will be asked which group they think they were assigned

25. Training & Accrual Training of acupuncturists Training of acupuncturists 1 day training + materials 1 day training + materials Patient Recruitment Patient Recruitment Anticipate 150 enrolled Anticipate 150 enrolled

26. Resources National Institutes of Health (NIH). National Center for Complementary and Alternative Medicine (NCCAM). [Online]. http://www.nccam.nih.gov http://www.nccam.nih.gov National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM) [Online]. http://www.nccaom.org/om_first.htm http://www.nccaom.org/om_first.htm http://www.mdanderson.org/cimer

27. Thank you! Coordinating Center: The University of Texas M. D. Anderson Cancer Center Community Clinical Oncology Program Research Base Program Research Base 1515 Holcombe Blvd, Unit 241 Houston, Tx 77030-0276 713-563-0276 713-563-2957 fax mdaccop@mdanderson.orgInvestigators Joseph Chiang, MD-Chair Mark Chambers, DMD-Co Chair Lorenzo Cohen, PhD M. Kay Garcia, LAc, DrPH David Rosenthal, MD Lynn Palmer, PhD