a phase iii prospective randomized trial of acupuncture for treatment of radiation-induced...
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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
mia
Que
stio
nnai
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 [email protected]
InvestigatorsJoseph Chiang, MD-ChairMark Chambers, DMD-Co ChairLorenzo Cohen, PhDM. Kay Garcia, LAc, DrPHDavid Rosenthal, MDLynn Palmer, PhD