Transcript Acupuncture for radiation-induced xerostomia: a clinical trial

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
A Phase III Prospective Randomized Trial of
Acupuncture for Treatment of Radiation-Induced
Xerostomia in Patients with Head and Neck Cancer
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Primary Objective:
To determine whether or not acupuncture can
symptomatically improve severe xerostomia (grade 2 or 3)
due to head/neck radiotherapy.
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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
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Over 35,000 new cases of oral cavity and pharyngeal
cancers were diagnosed in the United States in 2009.1
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Over 7600 deaths
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Approximately 80% of patients develop xerostomia
after only a few weeks of treatment.2
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Radiation-induced xerostomia becomes chronic in
almost 70% of patients.2
1
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
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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
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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
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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
Current treatment
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Rarely spontaneously improves by itself
Current treatment:
pilocarpine, amifostine
saliva substitutes
IMRT – still results in xerostomia
palliative for symptom relief
Low success rate or low acceptance
Acupuncture
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Traditional Chinese Medicine Theory
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Excess vs Deficiency Heat Syndrome
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Yin Deficiency Syndrome
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Lung
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Stomach
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Kidney
Proposed Putative Mechanisms
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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
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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.
2.
3.
4.
5.
Johnstone P, et al, Cancer 2002; 94:1151.
Rydholm M, Strang P. J Palliat Care 1999; 15:20.
Blom M, et al, Oral Oncology, Eur J Cancer 1996; 32B:182.
Andersen S, Machin D. Oral Oncol 1997; 33:146.
Blom M. Lundeberg T. Oral Dis 2000; 6:15
Our Preliminary Studies
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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)
40
35
30
(0.0004)
25
20
Baseline
(0.0001)
Week 2
Week 4
Week 8
Clinical Significance:
XI Scores
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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 Care
Prevention Trial
SYMPTOMS
<0.0001
Acupuncture
<0.0001
Control
Control (S)
<0.0001
50
6
<0.0001
0.0001
40
Acupuncture (S)
7
0.003
30
0.059
20
10
Stimulated Saliva Weight (g)
Xerostomia Questionnaire
60
SALIVA FLOW
5
4
3
0.014
0.005
0.003
2
0.025
0.002
1
0
0
1
2
3
4
5
6
7
8
9
10
11
0
0
Week
1
2
3
4
5
6
7
8
9
10
Week
15
11
Acupuncture vs Standard Care
Prevention
SYMPTOMS
SALIVA FLOW
Acupuncture
Acupuncture (S)
7
Control
Control (S)
Stimulated Saliva Weight (g)
Xerostomia Questionnaire
60
50
40
<0.00061
30
20
10
0
0
5
10
15
20
Week
25
30
35
40
6
5
4
3
2
0.002
1
0
0
5
10
15
20
25
30
35
40
Week
16
Placebo Controlled PreventionTrial
17
Development of Xerostomia
Main Study
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)
Placebo Study
Acupunture
%
Control
%
7 weeks
25.0
87.5
0.006 0.29 (0.10, 0.79)
11 weeks
12.5
75.0
0.02
p
RR (95% CI)
0.17 (0.03, 1.07)
18
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3 groups
CCOP Study Design
(Treatment)
1) Standard Oral Hygiene
2) Standard Oral Hygiene + True acupuncture twice
weekly for 4 weeks
3) Standard Oral Hygiene + Sham acupuncture twice
weekly for 4 weeks
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Follow-up
If PR or NR, follow-up at 8 and 12 weeks
If MR, continue assigned treatment twice weekly for
4 weeks
Eligibility
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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
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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
Dry mouth/salivary
gland
(xerostomia)
Short name: Dry
mouth
1
Symptomatic (dry or
thick
saliva) without
significant
dietary alteration;
unstimulated saliva
flow
>0.2 ml/min
2
Symptomatic and
significant oral intake
alteration (e.g.,
copious
water, other
lubricants,
diet limited to purees
and/or soft, moist
foods);
unstimulated saliva
0.1 to 0.2 ml/min
3
Symptoms leading to
inability to adequately
aliment orally; IV
fluids,
tube feedings, or TPN
indicated;
unstimulated
saliva <0.1 ml/min
True Acupuncture Treatment
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Body points
CV 24, Lu7, K6, LI1-prime
Gb32 (placebo needle)
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Ear points
Shenmen, Point zero,
Salivary Gland 2-prime
Sham Acupuncture Treatment
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Body points
Sham 1 chin; Sham 2,3
BUE; Sham 4-BLE; 1
penetraing needle at
Gb32 right knee
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Ear points
3 points on the ear helix that
are not electrodermally
active
Measures
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Subjective
• Xerostomia Questionnaire (XQ)
• MDASI-HN
• FACT-G
• Acupuncture Expectancy Scale (AES)
Patient Response
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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
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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
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Training of acupuncturists
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1 day training + materials
Patient Recruitment
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Anticipate 150 enrolled
Resources
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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:
Investigators
The University of Texas
M. D. Anderson Cancer Center
Community Clinical Oncology
Program Research Base
1515 Holcombe Blvd, Unit 241
Houston, Tx 77030-0276
713-563-0276
713-563-2957 fax
[email protected]
Joseph Chiang, MD-Chair
Mark Chambers, DMD-Co Chair
Lorenzo Cohen, PhD
M. Kay Garcia, LAc, DrPH
David Rosenthal, MD
Lynn Palmer, PhD