A Phase III Prospective Randomized Trial of Acupuncture for Treatment of Radiation-Induced

Xerostomia in Patients with Head and Neck Cancer

CCOP Investigators’ MeetingMarch 4, 2011

M. Kay Garcia, LAc, DrPHM. D. Anderson Cancer Center

Integrative Medicine

A Phase III Prospective Randomized Trial of Acupuncture for Treatment of Radiation-Induced

Xerostomia in Patients with Head and Neck Cancer

Primary Objective:

To determine whether or not acupuncture can symptomatically improve severe xerostomia (grade 2 or 3) due to head/neck radiotherapy.

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.

Significance

Over 35,000 new cases of oral cavity and pharyngeal cancers were diagnosed in the United States in 2009.1

Over 7600 deaths 1

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

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.

Xerostomia Radiation clearly damages salivary tissue Damage at doses <50Gy may be partially

reversible No evidence of reversibility at higher doses Reduced salivary flow typically begins during the

first few days of treatment 80% decrease noted at 6 weeks Other quantitative changes

decrease in salivary pH, increase in viscosity,

reduction of salivary constituents (immunoglobulins, buffering capacity, small organic molecules)

Salivary Flow

Significant variation between individuals

Subjective sensation of dryness does not correlate well with measured flow rates

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.

Common Symptoms

Xerostomia (dry mouth) can impart a profound impact on QOL for patients and lead to:

taste aberrationsloss of appetitedysphagia & odynophagiadifficulty speakingdifficulty sleepingirreversible nutritional

deficits

Current treatment Rarely spontaneously improves by itself Current treatment:

pilocarpine, amifostinesaliva substitutesIMRT – still results in xerostomiapalliative for symptom relief

Low success rate or low acceptance

Acupuncture Traditional Chinese Medicine Theory

Excess vs Deficiency Heat Syndrome Yin Deficiency Syndrome

Lung Stomach Kidney

Proposed Putative Mechanisms

Increase in local blood flux

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.

Previous Studies of Acupuncture for Xerostomia

Studies conducted by different investigators in the U.S. and Europe

Different points and techniques Similar results

-- improvement with 5-10 treatments-- benefits documented up to 3 years

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

Our Preliminary Studies

Single-arm pilot (MDACC treatment) 2-arm acu vs standard care

(MDACC/Fudan, prevention) 2-arm true acupuncture vs sham

(MDACC/ Fudan, prevention)

Single Arm Pilot (MDACC) Mean XI Scores(high score = increased severity)

20

25

30

35

40

Baseline Week 2 Week 4 Week 8

(0.0004)

(0.0001)

Clinical Significance: XI Scores

Partial response (PR) = difference > 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

No response (NR) = absence of PR or MR Expected response rate = 40% Actual response rate = 44% at week 4 and

56% at week 8

Acupuncture vs Standard CarePrevention Trial

15

0

1

2

3

4

5

6

7

0 1 2 3 4 5 6 7 8 9 10 11

Week

Sti

mu

late

d S

aliv

a W

eig

ht

(g)

Acupuncture (S)

Control (S)

0.0140.005

0.0030.002

0.025

0

10

20

30

40

50

60

0 1 2 3 4 5 6 7 8 9 10 11

Week

Xer

osto

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Que

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re

Acupuncture

Control

0.059

0.003

0.0001

<0.0001

<0.0001<0.0001

<0.0001

SYMPTOMS SALIVA FLOW

Acupuncture vs Standard CarePrevention

16

0

1

2

3

4

5

6

7

0 5 10 15 20 25 30 35 40

Week

Sti

mu

late

d S

aliv

a W

eig

ht

(g)

Acupuncture (S)

Control (S)

0.002

0

10

20

30

40

50

60

0 5 10 15 20 25 30 35 40

Week

Xero

stom

ia Q

uest

ionn

aire

Acupuncture

Control

<0.00061

SYMPTOMS SALIVA FLOW

17

Placebo Controlled PreventionTrial

18

Acupunture Control% % p RR (95% CI)

7 weeks 25.0 87.5 0.006 0.29 (0.10, 0.79)

11 weeks 12.5 75.0 0.02 0.17 (0.03, 1.07)

Acupunture Control

% % p RR (95% CI)

7 weeks 89.7 97.8 0.12 0.92 (0.82, 1.03)

11 weeks 54.3 86.1 0.002 0.63 (0.45, 0.87)

6 months 24.1 63.6 0.002 0.38 (0.19, 0.76)

Development of XerostomiaMain Study

Placebo Study

CCOP Study Design(Treatment)

3 groups

1) Standard Oral Hygiene2) Standard Oral Hygiene + True acupuncture twice

weekly for 4 weeks3) Standard Oral Hygiene + Sham acupuncture twice

weekly for 4 weeks

Follow-upIf PR or NR, follow-up at 8 and 12 weeksIf MR, continue assigned treatment twice weekly for 4 weeks

Eligibility 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

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

Adverse Event 1 2 3 Dry mouth/salivary gland(xerostomia)Short name: Dry mouth

Symptomatic (dry or thicksaliva) without significantdietary alteration;unstimulated saliva flow>0.2 ml/min

Symptomatic andsignificant oral intakealteration (e.g., copiouswater, other lubricants,diet limited to pureesand/or soft, moist foods);unstimulated saliva0.1 to 0.2 ml/min

Symptoms leading toinability to adequatelyaliment orally; IV fluids,tube feedings, or TPNindicated; unstimulatedsaliva <0.1 ml/min

True Acupuncture Treatment

Body points CV 24, Lu7, K6, LI1-prime Gb32 (placebo needle)

Ear points Shenmen, Point zero, Salivary Gland 2-prime

Sham Acupuncture Treatment

Body points Sham 1 chin; Sham 2,3

BUE; Sham 4-BLE; 1 penetraing needle at Gb32 right knee

Ear points 3 points on the ear helix that

are not electrodermally active

Measures

Subjective• Xerostomia Questionnaire (XQ)• MDASI-HN• FACT-G• Acupuncture Expectancy Scale (AES)

Patient Response XQ scores at baseline and 4 weeks after

beginning treatment

• No response=xero worsens or no decrease in XQ from baseline

• Minor response = 10-19 point decrease• Partial response =20 points or more decrease from

baseline• Complete response = XQ score of 10

Duration determined by XQ at 8 and 12 weeks At week 4, patients will be asked which group

they think they were assigned

Training & Accrual

Training of acupuncturists 1 day training + materials

Patient Recruitment Anticipate 150 enrolled

Resources National Institutes of Health (NIH).

National Center for Complementary and Alternative Medicine (NCCAM). [Online]. http://www.nccam.nih.gov

National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM) [Online]. http://www.nccaom.org/om_first.htm

http://www.mdanderson.org/cimer

Thank you!Coordinating Center:The University of TexasM. D. Anderson Cancer CenterCommunity Clinical Oncology Program Research Base1515 Holcombe Blvd, Unit 241Houston, Tx 77030-0276713-563-0276713-563-2957 faxmdaccop@mdanderson.org

InvestigatorsJoseph Chiang, MD-ChairMark Chambers, DMD-Co ChairLorenzo Cohen, PhDM. Kay Garcia, LAc, DrPHDavid Rosenthal, MDLynn Palmer, PhD