electro-acupuncture versus sham electro-acupuncture versus ......the acupuncture service in the day...
TRANSCRIPT
Electro-acupuncture versus Sham Electro-acupuncture
versus Standard Care for Acute and Delayed
Chemotherapy-Induced Nausea and Vomiting—A
Feasibility Pilot Study and Acupuncture Service Evaluation
in the Day Oncology Unit
Christopher Graham McKeon
A thesis submitted in fulfilment of the requirements for the
degree of Master of Science (Honours) Health Science
National Institute for Complementary Medicine,
School of Science and Health, University of Western Sydney
June, 2014
ii
Declaration
I, Christopher Graham McKeon declare that this thesis, submitted in fulfilment of the
requirements of the award of Master of Science (Honours), in the National Institute
for Complementary Medicine, School of Science and Health, University of Western
Sydney, is wholly my work unless otherwise referenced or acknowledged. This
document has not been submitted, either wholly or in part, to any other educational
institution.
Signature: Date: 15th June 2014
iii
Acknowledgments
I wish to give my love and thanks to my lovely wife Danielle and two beautiful boys
Hamish and Callum, who have given me great support and tolerance as I have strived
to complete this research and particular to the boys and their lost afternoons playing
cricket and rugby because Dad was too busy writing. This thesis is dedicated to my
family who has been with me throughout this long journey.
To my supervisors, Professor Caroline Smith, Professor Esther Chang and Professor
Janet Hardy I thank you for your help, encouragement, patience and support during
this project. Particular thanks go to Caroline for her extreme patience, as I was
developing my academic writing skills. You collectively have helped me grow as a
person and a researcher, so I thank you. I would like to acknowledge and thank Elite
Editing, who edited my thesis, and editorial intervention was restricted to Standards
D and E of the Australian Standards for Editing Practice.
My thanks go to the Australian Acupuncture and Chinese Medicine Association and
the Mater Foundation for the funding to conduct the trial. My gratitude also goes to
the Mater Foundation and the Smiling for Smiddy Foundation for the funds to set up
the acupuncture service in the day oncology unit in the Mater Adult Hospital, being
the first one in Australia where the patients do not pay was an honour and pleasure.
To all my colleagues in the Mater day oncology unit, doctors, nurses, allied health
and administration staff thank you for the support and help to conduct this trial and
service evaluation I could not done it without your help.
And finally but definitely thank you to the wonderful patients who agreed to
participate and utilise the service.
iv
Contents
Declaration .................................................................................................................. ii Acknowledgments ..................................................................................................... iii Contents ..................................................................................................................... iv List of Figures .......................................................................................................... viii List of Tables ............................................................................................................. ix List of Abbreviations ................................................................................................. x Abstract ...................................................................................................................... xi Chapter 1: Cancer Treatment Side Effects and Complementary Medicines ....... 1
1.1 Introduction ........................................................................................................ 1 1.2 Background ........................................................................................................ 2 1.3 Cancer ................................................................................................................ 2 1.4 Management of Cancer ...................................................................................... 3
1.4.1 Surgery ........................................................................................................ 3 1.4.2 Radiotherapy ............................................................................................... 4 1.4.3 Chemotherapy ............................................................................................. 4
1.5 Chemotherapy Adverse Effects .......................................................................... 6 1.6 Chemotherapy-Induced Nausea and Vomiting .................................................. 7
1.6.1 Mechanism of Chemotherapy-Induced Nausea and Vomiting ................... 9 1.6.2 Evidence-Based Research and Practice in Relation to Chemotherapy-
Induced Nausea and Vomiting ................................................................... 9 1.6.3 Use of Anti-Emetics in the Treatment of Chemotherapy-Induced
Nausea and Vomiting ............................................................................... 10 1.6.4 Treatment of Chemotherapy-Induced Nausea and Vomiting Using
Non-Pharmacological Interventions ......................................................... 11 1.7 Use of Complementary Medicine (Including Acupuncture) in Cancer Care ... 15 1.8 History and Definition of Acupuncture ............................................................ 16 1.9 The Practice of Acupuncture ............................................................................ 16 1.10 Rationales and Style of Acupuncture ............................................................. 17 1.11 Integrative Medicine ...................................................................................... 17 1.12 History of Integrative Oncology .................................................................... 18 1.13 Conclusion...................................................................................................... 21
Chapter 2: A Systematic Review of Acupuncture and/or Acupressure for Chemotherapy-Induced Nausea and Vomiting ..................................................... 22
2.1 Introduction ...................................................................................................... 22 2.2 Background ...................................................................................................... 22 2.3 Methods ............................................................................................................ 23
2.3.1 Type of Studies ......................................................................................... 23 2.3.2 Participants ................................................................................................ 23 2.3.3 Type of Intervention to be Included .......................................................... 24 2.3.4 Types of Outcome Measures ..................................................................... 24 2.3.5 Search Strategy ......................................................................................... 24
2.4 Methods of the Review .................................................................................... 25 2.4.1 Study Selection ......................................................................................... 25 2.4.2 Data Extraction ......................................................................................... 25
v
2.4.3 Assessment of Risk of Bias ....................................................................... 25 2.4.4 Measures of Treatment Effect ................................................................... 26
2.5 Systematic Review ........................................................................................... 26 2.6 Randomised Controlled Trials ......................................................................... 27
2.6.1 Excluded Studies ....................................................................................... 29 2.6.2 Excluded Reviews ..................................................................................... 29
2.7 Characteristics of the Studies ........................................................................... 29 2.8 Description of the Interventions ....................................................................... 30 2.9 Outcome Measures ........................................................................................... 31 2.10 Assessment of Risk of Bias in Acupuncture Trials ........................................ 31
2.10.1 Selection Bias .......................................................................................... 35 2.10.2 Attrition Bias ........................................................................................... 35 2.10.3 Performance Bias .................................................................................... 36 2.10.4 Measurement Bias ................................................................................... 36
2.11 Assessment of the Risk of Bias Acupressure Trials ....................................... 36 2.11.1 Selection Bias .......................................................................................... 36 2.11.2 Attrition Bias ........................................................................................... 37 2.11.3 Performance Bias .................................................................................... 37 2.11.4 Measurement Bias ................................................................................... 37
2.12 Meta-Analysis ................................................................................................ 37 2.12.1 Acupuncture plus Medication v. Medication Only ................................. 37
2.12.1.1 Frequency of Vomiting ..................................................................... 37 2.12.1.2 Dose of Rescue Medication .............................................................. 38
2.12.2 Acupuncture plus Medications v. Sham Acupuncture plus Medications .............................................................................................. 38
2.12.2.1 Frequency of Vomiting ..................................................................... 38 2.12.2.2 Frequency of Nausea........................................................................ 38 2.12.2.3 Dose of Rescue Medication .............................................................. 38 2.12.2.4 Helpfulness of Acupuncture ............................................................. 38
2.12.3 Acupressure plus Medication v. Medication Only .................................. 38 2.12.3.1 Frequency of Vomiting ..................................................................... 38 2.12.3.2 Frequency of Nausea........................................................................ 39
2.12.4 Acupressure plus Medication v. Sham Acupressure plus Medication .... 39 2.12.4.1 Frequency of Vomiting ..................................................................... 39 2.12.4.2 Frequency of Nausea........................................................................ 39 2.12.4.3 Use of Rescue Medication ................................................................ 39
2.13 Discussion ...................................................................................................... 40 2.14 Agreements and Disagreements with Other Studies or Reviews ................... 43 2.15 Clinical Commentary ..................................................................................... 43 2.16 Conclusion...................................................................................................... 43
Chapter 3: Methodology .......................................................................................... 45 3.1 Methods ............................................................................................................ 45
3.1.1 Research Questions ................................................................................... 45 3.2 Study Design .................................................................................................... 46
3.2.1 Study Design Rationale ............................................................................. 46 3.3 Methodological Issues to Consider for Acupuncture Research ....................... 47 3.4 Study Participants............................................................................................. 48 3.5 Recruitment Strategy ........................................................................................ 48 3.6 Randomisation.................................................................................................. 49 3.7 Blinding ............................................................................................................ 50
vi
3.8 Treatments and Study Schedule and Intervention ............................................ 50 3.8.1 Treatment as Usual .................................................................................... 50 3.8.2 Electro-Acupuncture ................................................................................. 50 3.8.3 Control Arm: Sham Electro-Acupuncture ................................................ 52
3.9 Outcome Measures and Data Collection .......................................................... 53 3.9.1 Feasibility Endpoints ................................................................................. 53 3.9.2 Secondary Endpoints ................................................................................. 53 3.9.3 Data Collection ......................................................................................... 53
3.10 Data Collection Instruments ........................................................................... 54 3.10.1 Functional Living Index Emesis (FLIE) ................................................. 54 3.10.2 Patient Diary ........................................................................................... 55 3.10.3 Toxicity ................................................................................................... 55 3.10.4 Practitioner Therapeutic Interaction ........................................................ 57 3.10.5 Expectations ............................................................................................ 57
3.11 Sample Size .................................................................................................... 58 3.12 Data Analysis ................................................................................................. 58 3.13 Acupuncture Service Evaluation .................................................................... 59 3.14 Research Questions ........................................................................................ 60 3.15 Study Design .................................................................................................. 60 3.16 Study Participants........................................................................................... 60
3.16.1 Inclusion Criteria ..................................................................................... 61 3.16.2 Exclusion Criteria ................................................................................... 61
3.17 Ethics .............................................................................................................. 61 3.18 Study Administration ..................................................................................... 62 3.19 Acupuncture Service ...................................................................................... 62 3.20 Sampling ........................................................................................................ 63 3.21 Study Endpoints ............................................................................................. 63 3.22 Data Collection ............................................................................................... 63 3.23 Data Collection Instruments ........................................................................... 64 3.24 Safety.............................................................................................................. 64 3.25 Quality of Life and Wellbeing ....................................................................... 66 3.26 Data Analysis ................................................................................................. 67
Chapter 4: Pilot Study and Service Evaluation Results ....................................... 68 4.1 Results from the Pilot Randomised Controlled Trial of Electro-
Acupuncture for Chemotherapy-Induced Nausea And Vomiting .................... 68 4.2 Recruitment to the Trial ................................................................................... 69
4.2.1 Consort Statement ..................................................................................... 69 4.3 Demographics .................................................................................................. 71
4.3.1 Age ............................................................................................................ 71 4.3.2 Sex ............................................................................................................. 71 4.3.3 Diagnosis ................................................................................................... 71 4.3.4 Emetogenic Rating .................................................................................... 71 4.3.5 Compliance with Treatment Schedule Day 3 ........................................... 73 4.3.6 Loss and Drop Out From the Trial ............................................................ 73 4.3.7 Completion Rates of Outcome Measures .................................................. 73 4.3.8 Integrity of Blinding in the Study ............................................................. 75
4.4 Secondary Study Endpoints ............................................................................. 76 4.4.1 Functional Living Index Emesis Changes over Time and between
Groups ...................................................................................................... 76 4.4.2 Symptom: Vomiting Changes over Time and Between Groups ............... 78
vii
4.4.3 Symptoms of Nausea Changes over Time and Between Groups .............. 79 4.4.4 Use of Rescue Anti-Emetics ..................................................................... 79 4.4.5 Toxicity of Intervention ............................................................................ 80 4.4.6 Identification of a Washout Period During a Second Cycle of
Chemotherapy ........................................................................................... 82 4.4.7 The Influence of Participant Expectations of Benefit on Treatment
Outcomes .................................................................................................. 82 4.4.8 Effect of the Practitioner Therapeutic Encounter ..................................... 85
4.5 Results from the Acupuncture Service Evaluation .......................................... 86 4.6 Demographics of Participants .......................................................................... 86
4.6.1 Sex ............................................................................................................. 86 4.6.2 Age ............................................................................................................ 87 4.6.3 Diagnosis ................................................................................................... 87
4.7 Participant’s Feedback on Service and Complementary and Alternative Medicine Use .................................................................................................... 87
4.8 Participants’ Perception of Benefit from the Service ....................................... 88 4.9 Adverse Events ................................................................................................. 89 4.10 Measure Yourself Concern and Wellness Concerns and Problems ............... 90 4.11 Measure Yourself Concern and Wellness Pre- and Post-Test Results ........... 91 4.12 Measure Yourself Concern and Wellness Concerns Qualitative Analysis .... 92 4.13 Measure Yourself Concern and Wellness: Other Concerns Affecting
Your Health ...................................................................................................... 94 4.14 Measure Yourself Concern and Wellness: Important Aspects of the
Service as Identified by Participants ................................................................ 94 4.15 How We Might Improve the Service ............................................................. 95 4.16 Other Feedback Provided by Respondent Comments .................................... 96 4.17 Discussion of Results ..................................................................................... 96 4.18 Discussion of Results Acupuncture Service Evaluation .............................. 102 4.19 Concluding Comments ................................................................................. 104
Chapter 5: Discussion ............................................................................................ 105 5.1 Systematic Review of Acupuncture to Reduce Chemotherapy-Induced
Nausea and Vomiting Key Findings............................................................... 105 5.2 Key Findings from the Feasibility Study ....................................................... 106 5.3 Key Findings from Acupuncture Service Evaluation. ................................... 108 5.4 Methodological Discussion ............................................................................ 108 5.5 Strengths of the Trial ...................................................................................... 109 5.6 Study Limitations ........................................................................................... 111 5.7 Future Research .............................................................................................. 113 5.8 Clinical Implications ...................................................................................... 115 5.9 Implications for Education ............................................................................. 116 5.10 Conclusion.................................................................................................... 117
References ............................................................................................................... 118 Appendices .............................................................................................................. 134
viii
List of Figures Figure 2.1: Results from Search Strategy .................................................................. 28
Figure 4.1: Consort Diagram...................................................................................... 70
Figure 3.1 Sham Points Location ............................................................................. 209
ix
List of Tables Table 1.1: Cancers Treated by Chemotherapy ............................................................. 5
Table 1.2: Emetogenicity of Chemotherapy Agents .................................................... 8
Table 1.3: Summary of Non-Pharmacological Intervention Trials ............................ 12
Table 2.1: Assessment of Bias ................................................................................... 32
Table 4.1: Demographics of Trial Participants .......................................................... 72
Table 4.2: Outcome Measures Completion Rates ...................................................... 74
Table 4.3: Blinding Integrity of Allocation................................................................ 75
Table 4.4: FLIE Outcomes by Study Group .............................................................. 77
Table 4.5: Vomiting by Study Group over Cycle 1 and 2 ......................................... 78
Table 4.6: Nausea by Study Group over Cycle 1 and 2 ............................................. 79
Table 4.7: Adverse Events over the Trial Period ....................................................... 80
Table 4.8: Expectations of Study Participants by Group ........................................... 84
Table 4.9: Therapeutic Encounter by Treatment Group ............................................ 85
Table 4.10: Demographics of Study Participants ....................................................... 87
Table 4.11: Participants’ Feedback about the Service ............................................... 88
Table 4.12: Participant’s Expectations of Benefit from Acupuncture ....................... 89
Table 4.13: AEs Of Patients Using the Acupuncture Service .................................... 90
Table 4.14: Symptoms/Concerns Identified by Participants in MYCaW .................. 91
Table 4.15: Participant Symptoms Concerns Measured at Baseline and at the End
of Acupuncture .......................................................................................... 92
Table 4.16: Qualitative Analysis of Concerns into Super Categories ........................ 93
Table 4.17: Other Concerns Affecting Health Categorised into Super Categories.... 94
Table 4.18: Qualitative Analysis of Important Aspects of the Service ...................... 95
x
List of Abbreviations
ADL Activities Of Daily Living
AE Adverse Events
ANZCTR Australian New Zealand Clinical Trials Registry
CAM Complementary And Alternative Medicine
CI Confidence Interval
CINV Chemotherapy-Induced Nausea And Vomiting
CMF Cyclophosphamide, Methotrexate And Fluorouracil
CNS Central Nervous System
EA Electro-Acupuncture
EBP Evidence-Based Practice
EERW Enriched Enrolment With Randomised Withdrawal
FLIE Functional Living Index Emesis
HRQOL Health-Related Quality-Of-Life
INVR Index Of Nausea, Vomiting And Retching
IQR Interquartile Range
JBI Joanna Briggs Institute
MD Mean Difference
MYCaW Measure Yourself Concern And Wellness
MYMOP Measure Yourself Medical Outcome Profile
NIDL No Or Minimal Impact On Daily Life
NRS Number Rating Scale
QoL Quality Of Life
RCT Randomised Controlled Trial
STRICTA Standards For Reporting Interventions In Controlled Trials Of
Acupuncture
TCM Traditional Chinese Medicine
TNM Tumour, Nodes And Metastasis
UK United Kingdom
xi
Abstract
The purpose of this study was to examine: the feasibility of conducting an efficacy
trial of electro-acupuncture (EA) for chemotherapy-induced nausea and vomiting
(CINV); the role of an acupuncture service in the day oncology unit on patients’
wellbeing; and evaluate participants’ perceptions of the service. CINV is managed by
new state-of-the-art anti-emetics; however, 30 per cent of patients continue to
experience CINV. These symptoms have a significant impact on their quality of life.
A Cochrane Systematic Review 2006, identified the need for further study with
acupuncture for CINV, particularly EA. Offering complementary medicine as
supportive care for cancer patients who are undergoing conventional treatment is an
emerging field; there is a need to establish a research basis for the benefits and risks,
particularly from a patient-centred perspective.1-4
Patients attending for their first cycle of chemotherapy were randomised to one of
three arms: EA plus standard care; sham EA plus standard care; or standard care
alone. Treatment arms received acupuncture on the first day of chemotherapy, ten
minutes prior to chemotherapy, and for total 30 minutes, returning in two days for
another treatment. Acupuncture points used ST36, PC6, LV3 and LI4 bilaterally. The
primary outcome was feasibility, time to recruit, percentage of follow up treatment,
blinding effectiveness, and secondary endpoints with change in ‘Functional Living
Index Emesis’ (FLIE) scores between Day one, four and seven, and nausea and
vomiting scores. The sample size was 60 participants. An intention to treat analysis
using the Kruskal-Wallis test (for non-parametric data) was done on the FLIE,
nausea and vomiting scores.
Patients using the acupuncture service were asked to participate in the evaluation.
The evaluation was a pre- and post-test observational study, using the tool, MYCaW
(Measure Yourself Concern and Wellness); a researcher developed the questionnaire.
Questionnaires and MYCaW were completed prior to, and redone in four to six
weeks after, at least two treatments.
xii
Sixty patients were recruited from 153, screened from April 2009 to May 2011.
Feasibility was shown with some changes to recruitment timeframes, inclusion
criteria and outcome measures for objectivity. The incidence of CINV was low in the
first cycle chemotherapy and the number recruited was not large enough to show
significant benefit. The change in the Functional Living Index Emesis (FLIE) score
Day 1 to 7: standard care -1.02 (19.4), sham acupuncture -1.05 (21.6) and true
acupuncture -3.36 (20.8) (median (interquartile range) p= 0.589), with no significant
difference between groups.
One-hundred-and-twelve patients were recruited from October 2011 to October
2012. Evaluation of the acupuncture service identified a positive response from
patients in relation to the benefit, helpfulness and usefulness of the service. The
majority of patients (73%) found the service worthwhile and would have liked the
service to continue. The pre- and post-test observational tool, Measure Yourself
Concerns and Wellness (MYCaW) showed a clinical and statistical significant
improvement of patients’ symptoms or concerns scores, 1.75 (p= <.0001) and 1.46
(p= <.0001) for concern one and two.
This thesis will show it is possible to conduct a randomised controlled trial (RCT)
and identify the sample size needed to conduct a fully powered trial, to examine if
EA has a greater benefit than standard treatment. Overall, patients’ perspectives of
the integrated service were positive, and they reported benefits from receiving
acupuncture.
1
Chapter 1: Cancer Treatment Side Effects and
Complementary Medicines
1.1 Introduction
Cancer is the leading cause of death in Australia. One in two males and one-in-four
females will be diagnosed with cancer by the age of 85.5 The vast majority of people
are touched by cancer in some way: through having a loved one, close relative or
perhaps a friend diagnosed with cancer. Cancer treatments involving chemotherapy,
radiotherapy or surgery all have side effects that impact on a patient’s quality of life
(QoL) and sense of wellbeing. Side effects can occur during treatment, but some
continue after active treatment has ceased, sometimes for months or even
permanently. While some side effects are easily treated through pharmacological
methods, others have no treatment and patients are turning to complementary
therapies for symptom relief and a sense of hope, improved wellbeing and control.6
Patients want to use treatments they perceive as ‘more natural’, ‘less toxic’ and ‘not
more medication’.
One of chemotherapy’s most feared side effects is nausea and vomiting. Control of
this symptom has dramatically improved with new anti-emetics, but some patients
still experience chemotherapy-induced nausea and vomiting (CINV), and there is a
need for non-pharmacological approaches and for further research into these
approaches.7 Acupuncture is one non-pharmacological approach, into which some
research has been done; in fact, a systematic review8 identified areas for further
research. This thesis looks at the use of acupuncture for CINV, and addresses some
issues surrounding its use; for example, using more than one acupuncture point and
modern anti-emetics. The thesis will also look at acupuncture in an integrative
oncology setting, and patients’ perceived benefit in relation to side effects and
symptoms of treatment for cancer.
2
1.2 Background
The first section of this chapter covers an introduction to cancer, its epidemiology,
and management through surgery, radiation and chemotherapy; an introduction to
chemotherapy adverse events, the mechanism of CINV, evidence-based practice
(EBP) and systematic reviews; it finishes with current pharmacological and non-
pharmacological treatment of CINV. This is followed by a definition of acupuncture,
its practice, treatment styles and rationales. In the second part of this chapter,
integrative medicine and integrative oncology will be defined, and the application of
acupuncture in this setting and an overview of research presented.
1.3 Cancer
Cancer is a major cause of death worldwide. The global burden of cancer has more
than doubled in the past 30 years. Estimates from the year 2002 reported 10.9 million
new cancer cases per year, 6.7 million deaths and 24.6 million people living with
cancer.9 Recent data from 2008 indicates an increasing incidence, with more than 12
million new cancer diagnoses, seven million deaths from cancer, and 25 million
individuals living with a cancer diagnosis.10
A report from the Australian Institute of Health and Welfare (AIHW)5 indicates that
114, 137 people were diagnosed with cancer in 2009. The report estimates that, for
2012, the age-standardised rate will be 474 (per 100, 000 of population). Incidence
rates for men will be 557 per 100, 000, while for females the rate is predicted to be
404 per 100,000. Cancer deaths were 39, 000, or a rate of 182 per 100, 000 people.
Incident rates were 234 per 100, 000 for men and 144 per 100,000 for women.5
Deaths in 2010 were expected to be greater than 43, 000. It is estimated the incidence
of new cancer diagnoses will rise to 120, 700 in 2012.5
With current treatments, the survival rates for cancer in the Western world have
greatly improved over the past 20 years; more people are now living with a cancer
diagnosis than ever before. Despite increased survival, there can be a significant
3
impact on QoL, a cost to individuals and their families, and to society more widely.
Survival rates may disregard the person’s quality of life, which can be affected by
treatment or the cancer—or a combination of both—anywhere along a continuum
ranging from minimal to severe. Adverse effects can include respiratory problems,
peripheral neuropathy, pain, diarrhoea, anorexia, fatigue and poor mobility. The
burden of cancer on society includes the drain on health budgets and resources, and
the years of what could otherwise be a productive life lost to cancer, as well as the
personal stress and suffering endured by the person and their family. In 1990, it was
estimated the costs associated with cancer were $US 96 billion.11 In 2000, Australian
costs associated with cancer—both directly and indirectly—were estimated at $AUS
61 billion.5
1.4 Management of Cancer
The main modalities of cancer treatments are surgery, radiotherapy and
chemotherapy. Modern treatments for cancer are delivered through a
multidisciplinary team and involve treatment and input from one or more of the
above modalities, as well as involvement of other allied health professionals.
1.4.1 Surgery
Surgery is used for screening and prevention, diagnosis, staging, treatment,
rehabilitation, cancer emergencies and palliative care.10 Surgery’s role in screening
and prevention relates to its use in conditions treatable by removing the malignancy;
it is also used for the removal of precancerous lesions or normal organs that have an
elevated risk of developing into cancers. The primary aim of the surgeon is to obtain
tissue samples for diagnosis and staging, an important process that identifies the
extent of the disease and helps to define treatment and outcomes. The most common
staging system is the tumour, nodes and metastasis (TNM) staging system; this is
used for nearly all tumours.12 Surgical palliation is designed to relieve symptoms and
improve quality of life for patients beyond cure.10
4
1.4.2 Radiotherapy
Radiotherapy has become an integral part of the management of many tumours. This
treatment approach has been developed since the late nineteenth century, with the
discovery of a method to generate X-rays. Progress since that time has resulted in
high-energy radiation, causing less skin reaction and more accurate delivery of
radiation dose to the cancer. This has led to less viable tissue being radiated during
treatment.10 Radiotherapy is used in 50 per cent of new cases. It is used for both
curative and palliative treatments.13
Cancers of the nasopharynx, paranasal sinuses, hypopharynx, oropharynx, larynx,
unknown primary of head and neck, and central nervous system have recommended
radiotherapy utilisation rates from 90 to 100 per cent. Breast, lung, oesophageal,
salivary gland and oral cavity cancers have optimal utilisation rates of greater than
74 per cent.13
Side effects from radiotherapy can be divided into two categories: acute and chronic
or delayed. Acute side effects include: skin reactions, such as erythema and
desquamation of the exposed skin and mucosa; fatigue; and pain at the radiation site.
Chronic or delayed side effects can include: ulceration, fistulas, severe fibrosis and
strictures, xerostomia (dry mouth), osteonecrosis and secondary malignancies.
1.4.3 Chemotherapy
Chemotherapy is an important treatment when the cancer has metastasized from the
initial site to distant sites in the body, through the blood or lymphatic systems. The
effectiveness of radiotherapy and surgery is limited when this occurs. The aim of
chemotherapy is to stop the cell cycle in one or more of the phases of cell division,
causing cell death. Normal cells, which can replicate, do so by a process called
‘mitosis’.10 Mitosis occurs in five distinct phases: these are called the G0, G1, G2, S
and M phases.14
Some chemotherapy agents target the DNA or DNA replication to induce cell death
or slow progression. Most standard types of chemotherapy kill both normal and
5
malignant cells, the theory being that normal tissue has a better ability to repair
minor damage than malignant cells. Two major classes of chemotherapy agents can
be defined as either ‘cell cycle phase-specific’ or ‘cell cycle phase-nonspecific’
agents.
Currently, many cancers are treated primarily by chemotherapy; it is also used as
adjuvant therapy (see Table 1.1). Although combined therapy is not always a cure for
advanced cancer, it does improve progression-free survival, with reduced incidence
of local and systemic recurrence and overall length of survival.15
Table 1.1: Cancers Treated by Chemotherapy
Advanced cancers treated primarily by
chemotherapy
Cancers treated as adjuvant by
chemotherapy after surgery
Bladder cancer Anaplastic astrocytoma
Cervical cancer Breast cancer
Colorectal cancer Colorectal cancer
Oesophageal cancer Cervical cancer
Gastric cancer Gastric cancer
Head and neck cancer Head and neck cancer
Nasopharyngeal Pancreatic cancer
Non-small cell lung cancer Melanoma
Ovarian cancer Non-small cell lung cancer
Pancreatic cancer Osteogenic sarcoma
Prostate cancer Ovarian cancer
Adapted from Devita and Chu.15
6
Treatment advances in chemotherapy continue to look for novel ways of treating
cancer. A recent development is the use of monoclonal antibodies that enhance the
effects of chemotherapy. The adverse effect profiles of these agents are markedly
less than traditional chemotherapy agents. These agents are presently not used as a
single agent; they are instead used in combination with standard chemotherapy
regimes, with their attendant inherent adverse effects. Chemotherapy is in transition,
however, as treatment approaches increasingly embody the age of ‘targeted
therapy’.15 Further development will look at targeting specific biological functions of
the tumour cell and blocking these to induce cell death, as the tumour reaches a
critical size it proactively produces hormones and chemicals to block cell apoptosis
or cell death. Other methods will involve targeting the cancer cells so that the body’s
natural defences can identify and kill the cancer cells.
1.5 Chemotherapy Adverse Effects
Drugs or interventions may have adverse effects (AEs) or unwanted side effects,16
and are therefore used only when the benefits of treatment outweigh the risk of
adverse effects. The range of chemotherapy adverse effects is extensive, and these
often result in a period of poor quality of life. Some adverse or unwanted side effects
can be acute coinciding with the administration of chemotherapy, while other
adverse effects such as fatigue may last beyond completion of treatment.17 The
particular adverse effects experienced by the patient may depend on the individual
treatment protocol and the agents administered in the regime. Taking into
consideration all the chemotherapy agents used, the 13 most common adverse effects
arising from treatment are peripheral neuropathy, anaemia, alopecia, nausea and
vomiting, constipation, diarrhoea, fatigue, neutropenia, thrombocytopenia, mucositis
and stomatitis, myalgia and arthralgia, and rash.17-20
A survey of 814 patients receiving chemotherapy and/or radiotherapy reported that
84 per cent experienced at least one AE from treatment.21 The most commonly
reported AE during treatment was fatigue (88%), followed by pain (48%), nausea
and vomiting (48%), anxiety (46%) and insomnia (45%).21
7
1.6 Chemotherapy-Induced Nausea and Vomiting
Nausea and vomiting is one of the most distressing and debilitating AEs identified by
patients receiving chemotherapy treatment,22, 23 and continues to be a major concern
for patients, despite new and improved anti-emetic therapy.24-26 Patients have also
identified it as the most fearful aspect of chemotherapy.27, 28 Nausea is defined as an
unpleasant feeling in the throat or stomach, which may or may not lead to expulsion
of stomach contents; vomiting is motor reflex resulting in the expulsion of stomach
contents.29 CINV can be defined as either ‘acute’ (occurring within the 24 hours
immediately post-treatment) or ‘delayed’ (occurring from 24–120 hours post-
treatment). This delineation in definition is due to the identification of these as two
different clinical syndromes, with acute CINV being mostly serotonin-related and
delayed CINV being in part substance p-related.30 The other type of CINV is
classified as ‘anticipatory’, and is believed to be a conditioned reflex resulting from
poor prior control of emesis.30
The prevalence of acute and delayed CINV is approximately 40 to 60 per cent and 40
to 80 per cent, respectively.22 The incidence of CINV is influenced by several
factors, including age and sex, with women and younger people having a higher risk
of developing CINV. Previous history of motion sickness or morning sickness, or a
patient belief that nausea and vomiting will be severe, has been associated with a
higher incidence of CINV. A history of high alcohol intake, by contrast, has been
shown to decrease the risk of CINV.31 The dose of chemotherapy and individual
emetogenic rating of the agent can increase the risk of CINV.31 Chemotherapy agents
are divided into high, moderate, low and minimal, according to their emetogenicity;
this categorisation was decided by an expert panel conference32 (see Table 1.2.).
8
Table 1.2: Emetogenicity of Chemotherapy Agents
Emetic risk (estimated incidence without prophylaxis)
High (>90%) Moderate (30–90%) Low (10–20%) Minimal (<10%)
Cisplatin
Mechlorethamine
Strptozotocin
Cyclophosphamide
>1500 mg/m2
Carmustine
Dacarbazine
Oxaliplatin
Cytarabine >1
gm/m2
Carboplatin
Ifosfamide
Cyclophosphamide
<1500mg/m2
Doxorubicin
Danorubicin
Epirubicin
Idarubicin
Irinotecan
Paclitaxel
Docetaxel
Mitoxantrone
Topotecan
Etoposide
Pemetrexed
Methotrexate
Mitomycin
Gemcitabine
Cytarabine <100
mg/m2
5-Fluorouracil
Bortezomib
Cetuximab
Trastuzum
Bleomycin
Busulfan
2-Chloro-
deoxyadenosine
Fludarabine
Vinblastine
Vincristine
Vinorelbine
Bevacizumab
9
1.6.1 Mechanism of Chemotherapy-Induced Nausea and Vomiting
Vomiting is the body’s defence mechanism to eliminate ingested toxins. It may or
may not be preceded by an unpleasant sensation: nausea. Although the exact
mechanisms are not yet fully understood, the central nervous system plays an
important role in the physiology of nausea and vomiting, receiving the emetic stimuli
from various areas and sending signals to induce vomiting. The mechanism of CINV
is considered to arise from three main areas: two central to the brain (the area
postrema and the nucleus tractus solitarius), and the abdominal vagal afferents (in the
small intestine). CINV is mainly thought to come from the abdominal vagal afferents
located in the intestinal mucosa of the small intestine.
Chemotherapy elicits a damage or inflammatory response in the intestinal mucosa,
which then sends input to the dorsal vagal complex, comprising the nucleus tractus
solitarius (which is the main area) and the area postrema. The chemotherapy agent
may also directly stimulate the area postrema; at this site: the blood–brain barrier is
relatively permeable. Neurotransmitter receptors play an important role in the emetic
response and are present in the dorsal vagal complex. These include neurokinin-1, 5-
HT3 and dopamine-2 receptors, which bind respectively to substance P, 5-HT3 and
dopamine.31 Understanding this process led to the development of a class of 5-HT3
receptor antagonists, containing ondansetron in the early 1990s. This led to greater
control of CINV than previously achievable. These 5-HT3 antagonists are more
effective against acute CINV, and are minimally to moderately effective in treating
delayed CINV. Their effect is increased when combined with a corticosteroid,
normally dexamethasone.32
1.6.2 Evidence-Based Research and Practice in Relation to Chemotherapy-
Induced Nausea and Vomiting
The emphasis on Evidenced-Based Practice (EBP) has grown over the past decade.
EBP uses the latest research to guide how a particular intervention or treatment is
implemented. This trend has occurred in human services generally, and in specific
professions, such as medicine, psychiatry, psychology, social work, chiropractic and
nursing, along with others.33, 34 Sackett et al. state 35: ‘Evidence-based medicine
10
involves integrating clinical expertise with the best available clinical evidence
derived from systematic research’. The authors emphasise patient values as an
equally important element. Treatment is a combination of best external evidence with
individual clinical expertise and patients’ choice.35, 36
1.6.3 Use of Anti-Emetics in the Treatment of Chemotherapy-Induced Nausea
and Vomiting
A number of professional oncology groups have developed evidence-based treatment
guidelines that have involved comprehensive literature reviews, examining: the
validity, reliability and reproducibility of studies; clinical applicability and
flexibility; and clarity.31, 37 However, these guidelines are underutilised and
consequently, control of CINV remains less than optimal for many patients.37
The latest anti-emetic used in chemotherapy is aprepitant. Aprepitant is a neurokinin-
1-receptor antagonist, which has increased efficacy in acute and delayed CINV than
previously seen with the standard treatment of a 5-HT3 antagonist and a
corticosteroid (usually dexamethasone). In a recent systematic review of 17 trials of
aprepitant for moderate and highly emetogenic chemotherapy, the meta-analysis
showed complete response rates (i.e., no vomiting and no rescue medication) for 72
per cent of participants, compared with 54 per cent in control arms of ondansetron
and dexamethasone alone.38 Nevertheless, despite advances in anti-emetic therapy,
there still remain those who experience some form of CINV. The newer anti-emetics
have resulted in better control of acute symptoms and vomiting overall, but the most
common adverse effect experienced by patients is delayed nausea. Both nurses and
doctors underestimate CINV when gauged against patient responses about the
adverse effects they experience.39
Uncontrolled nausea and vomiting has a detrimental effect on a patient’s QoL and
functional ability, many are unable to carry out normal daily activities. CINV can
also lead to increased use of hospital resources 40 through emergency admissions for
rehydration and doctor reviews. In extreme cases, another consequence of
uncontrolled CINV can be possible early cessation of treatment by the patient, due to
the severity of symptoms.
11
1.6.4 Treatment of Chemotherapy-Induced Nausea and Vomiting Using Non-
Pharmacological Interventions
Non-pharmacological interventions for treating CINV are designed as adjuvant
treatments, not replacements for standard treatment. They aim to assist with
symptom management and to improve quality of life.37 Non-pharmacological
interventions in general are under-researched and lack sufficient evidence to make
recommendations for clinical practice.7, 37 Yet, despite the limitations of research,
some interventions have been evaluated as likely to be effective. These interventions
are supported by evidence at a lower level than is required to recommend for EBP.7
The interventions identified as likely to be effective are: guided imagery, music
therapy, progressive muscle relaxation, psycho-educational support and information,
and acupuncture and acupressure (Table 1.3).
12
Tab
le 1
.3: S
umm
ary
of N
on-P
harm
acol
ogic
al In
terv
entio
n T
rial
s
Mod
ality
St
udie
s N
umbe
r of
parti
cipa
nts
Stud
y de
sign
Fi
ndin
gs
Cog
nitiv
e di
stra
ctio
n V
aste
rling
41
60
Thre
e in
divi
dual
sess
ions
with
ther
apis
t bef
ore
each
chem
othe
rapy
sess
ion,
follo
wed
by p
atie
nt se
lf-di
rect
ed
dist
ract
ion
on c
ompu
ter
Seve
rity
of n
ause
a w
as
sign
ifica
ntly
low
er a
t firs
t and
four
th tr
eatm
ent
Zelte
r42
54
One
pre
-inte
rven
tion
with
ther
apis
t and
afte
r
chem
othe
rapy
Inci
denc
e of
ant
icip
ator
y na
usea
and
vom
iting
was
sign
ifica
ntly
redu
ced
Exer
cise
M
ock43
14
W
alki
ng e
xerc
ise,
incr
emen
tal
four
or f
ive
times
per
wee
k an
d
supp
ort g
roup
fortn
ight
ly. O
ver
4–6
mon
ths o
f che
mot
hera
py
Seve
rity
of n
ause
a w
as
sign
ifica
ntly
low
er a
t mid
poin
t
in tr
eatm
ent p
roto
col
Win
ning
ham
44
42
Ten-
wee
k ex
erci
se p
rogr
amm
e
with
exe
rcis
e su
perv
isor
, thr
ee
times
per
wee
k
Seve
rity
of n
ause
a w
as
sign
ifica
ntly
low
er a
t 10-
wee
k
post
-test
follo
w u
p
Hyp
nosi
s Ze
lter42
54
One
pre
-inte
rven
tion
sess
ion
with
ther
apis
t and
afte
r
chem
othe
rapy
sess
ion
Inci
denc
e of
ant
icip
ator
y na
usea
and
vom
iting
was
sign
ifica
ntly
redu
ced
13
Jack
now
45
20
Two
or th
ree
sess
ions
with
ther
apis
t in
first
cou
rse
of
chem
othe
rapy
, to
lear
n se
lf-
hypn
osis
tech
niqu
es
Inci
denc
e of
ant
icip
ator
y na
usea
was
sign
ifica
ntly
redu
ced
at 1
–2
mon
ths a
fter d
iagn
osis
Cot
anch
46
12
One
sess
ion
with
nur
se th
erap
ist
prio
r to
chem
othe
rapy
sess
ion,
to le
arn
indi
vidu
alis
ed se
lf-
hypn
osis
Seve
rity
and
inci
denc
e of
naus
ea a
nd v
omiti
ng
sign
ifica
ntly
dec
reas
ed a
t fol
low
up (2
4 ho
urs)
Mus
ic
Ezzo
ne47
33
Li
sten
ing
to 4
5-m
inut
e pa
tient
-
sele
cted
mus
ic o
n po
rtabl
e C
D
play
er a
t 6, 9
and
12
hour
s pos
t-
chem
othe
rapy
star
ting,
ove
r tw
o
cons
ecut
ive
days
Seve
rity
and
inci
denc
e of
naus
ea a
nd v
omiti
ng
sign
ifica
ntly
dec
reas
ed fo
r
inte
rven
tion
patie
nts a
t 8 a
nd 1
6
hour
s fol
low
up
Rel
axat
ion
Lueb
bert48
74
2 M
eta-
anal
ysis
of 1
5 st
udie
s St
atis
tical
ly si
gnifi
cant
redu
ctio
n in
nau
sea,
but
not
in
vom
iting
Syst
emat
ic
dese
nsiti
satio
n
Mor
row
49
72
1. T
wo
1-ho
ur se
ssio
ns w
ith
clin
ical
psy
chol
ogis
t bet
wee
n
third
and
four
th c
ycle
s. Le
arne
d
syst
emat
ic d
esen
sitis
atio
n
Seve
rity
and
inci
denc
e of
antic
ipat
ory
and
post
-trea
tmen
t
naus
ea a
nd v
omiti
ng
sign
ifica
ntly
dec
reas
ed a
t fou
rth
14
tech
niqu
es
2. T
wo
1-ho
ur se
ssio
ns w
ith
clin
ical
onc
olog
ist o
r nur
se–
sam
e te
chni
que
and
fifth
cyc
le fo
llow
-ups
for
both
inte
rven
tion
grou
ps
com
pare
d w
ith c
ontro
l; no
diff
eren
ce b
etw
een
psyc
holo
gist
and
clin
ical
staf
f
Mor
row
50
92
Two
1-ho
ur se
ssio
ns w
ith
ther
apis
t bet
wee
n fo
urth
and
fifth
cyc
les.
Lear
ned
syst
emat
ic
dese
nsiti
satio
n te
chni
ques
Seve
rity
of a
ntic
ipat
ory
naus
ea
and
post
-trea
tmen
t nau
sea
sign
ifica
ntly
low
er a
t tw
o- to
four
--w
eek
follo
w u
p
Psyc
ho-e
duca
tiona
l
supp
ort a
nd
info
rmat
ion
Dev
ine51
53
26
Met
a-an
alys
is o
f 98
stud
ies
Show
ed a
sign
ifica
nt re
duct
ion
in n
ause
a, a
lthou
gh in
thei
r
revi
ew L
otfi-
Jam
et a
l ide
ntifi
ed
only
two
stud
ies,
whi
ch w
as
desc
ribed
as i
ncon
clus
ive
15
1.7 Use of Complementary Medicine (Including Acupuncture) in
Cancer Care
Interest in and use of complementary and alternative medicine (CAM) has increased
in the general population, and this trend has also been reflected among patient groups
living with cancer. In Australia, the general population’s use of CAM grew from
48.5% to 52.5% in from 1996 to 2002.52-54 A more recent study in 2005, examining
use of acupuncture, chiropractic and osteopathy in Australia, showed that, in the
preceding 12 months, one-in-four people had used at least one of these three
therapies.55
Use of CAM in cancer patients is high, due in part to the nature of the disease and
patients’ desire to use anything that may help prolong their lives. Other reasons for
use include boosting the immune system and alleviating the side effects of cancer
treatment.6 Studies have shown that usage rates vary from 50 to 75 per cent.56 A
systematic review of 21 studies showed that 31.4% of adult cancer patients used
CAM.57 Australian studies have shown similar results, with one recent study of
patients suffering cancer identifying that 30 per cent of patients had used CAM
during their treatment. With this increased use comes the need for research to help
benefit both clinicians and patients in making informed decisions about using
CAM.58
Cancer patients have used acupuncture to treat both various symptoms relating to
their cancer, and side effects arising from the treatment of that cancer. Surveys
conducted in respective clinical populations and numerous studies researching its
effectiveness have examined the use of acupuncture.17, 52, 58-65 Symptoms researched
include pain, xerostomia (dry mouth), peripheral neuropathy, fatigue, vasomotor
symptoms (hot flushes), post-operation recovery, insomnia, anxiety, and nausea and
vomiting.66-75
16
1.8 History and Definition of Acupuncture
Acupuncture, as defined by a Traditional Chinese medicine (TCM) rationale, literally
means ‘to puncture with a needle’.76 Acupuncture involves the insertion of thin, solid
needles into specific anatomical points in the body, called ‘acupuncture points’ or
‘acu-points’. Stimulation of these acupoints by needling has an effect on the patient’s
clinical condition or health status.77 TCM is a system based on observing the natural
world and its forces, and how these interact and manifest within the human body in
wellness and illness; acupuncture is one modality. Acupuncture, in its broad sense,
includes traditional body needling, moxibustion, EA, laser acupuncture, microsystem
acupuncture (such as ear (auricular), face, hand and scalp acupuncture), and
acupressure.76
Many scholars believe that acupuncture originally developed in China over the last
few centuries (BCE), although the exact historical origin of acupuncture continues to
be debated. It is commonly accepted that the first evidence of an organised and
documented system was in the Huang Di Nei Jing, or Inner Classic of the Yellow
Emperor.77 This work, dated as originating in the Han Dynasty, around 200 to
100BCE, its first part consists of Su Wen (Simple Questions), while the second part is
Ling Shu (The Spiritual Pivot). The Huang Di Nei Jing is a discussion between the
legendary ‘Yellow Emperor’ and his chief physician. Several key texts were
produced in the following centuries. These include the Nan Jing (Classic of Difficult
Issues, first or second century CE), Zhen Jiu Jia Yi Jing (A Classic of Acupuncture
and Moxibustion, third century CE) and Zhen Jiu Da Cheng (Great Compendium of
Acupuncture and Moxibustion, 1601CE), among many others.77, 78
1.9 The Practice of Acupuncture
Acupuncture was originally practised in China. Over the centuries, patterns of
Chinese migration and foreign trade with countries including Japan, Korea, France
and Britain have helped spread the practice, to the point that styles named after
regions have developed. Acupuncture is now practised throughout the world,
especially since the 1970s.77
17
Acupuncture is usually practised in dedicated stand-alone clinics, with one or more
practitioners, or as part of a multidisciplinary complementary therapy clinic that
includes practitioners experienced in naturopathy, homeopathy, remedial massage
and other modalities, depending on the practice. Acupuncture can also be practised
as part of an integrative medicine clinic; one where general practitioners or medical
doctors work as a team with complementary therapists to treat patients. This can be
established as a separate clinic or attached to a hospital.1, 79-81 Many practitioners use
acupuncture as part of their repertoire in treating patients, including medical doctors
and physiotherapists.
1.10 Rationales and Style of Acupuncture
Numerous styles of acupuncture have developed over time. These include: Japanese;
Korean; French (also known as auricular); British (or five elements); and Western
(more commonly known as medical acupuncture).77 Each style is characterised by
differences in theory and rationale for its particular use, but all include the common
principles of yin–yang balance, and regulation of the qi within a meridian network.77
Medical acupuncture has developed on an understanding of anatomy and physiology,
and an increasing body of clinical trial data. Other systems formed in relation to
treating the whole body through a specific area, such as the scalp, ear or hand.77
1.11 Integrative Medicine
Integrative medicine is the use of complementary therapies, with the best practice of
conventional treatment, for treating patients with chronic health conditions. Rakel
and Weil describe the term ‘integrative medicine’ as follows:
Integrative medicine involves using the best possible treatments from both CAM and allopathic medicine based on the patient’s individual needs and condition. This selection should be based on good science and neither rejects conventional medicine nor uncritically accepts alternative practices. It integrates successes from both worlds and is tailored to the patient’s needs, by using the safest, least invasive, most cost-effective approach while incorporating a holistic understanding of the individual.82
CAM can be categorised into five groups: biological-based (herbal remedies,
vitamins, dietary supplements); mind–body techniques (meditation, guided imagery,
18
expressive arts (such as music, art, dance therapy)); manipulative and body-based
(massage, reflexology, exercise); energy therapies (magnetic field therapy, reiki,
healing touch, qigong); and ancient medical systems (TCM, Ayurvedic medicine,
acupuncture).70
An extension of the integrative medicine movement is the evolving speciality of
‘integrative oncology’, the term for the specificity of integrative medicine for
patients receiving cancer treatment, rather than for other general or specific
conditions.
1.12 History of Integrative Oncology
Studies highlight several drivers that may have influenced the development of
integrative medicine. First, CAM provides patients with control, a sense of hope,
symptom control and improved quality of life; second, there has been an increase in
scientific evidence supporting the benefit of different modalities concerning patient
treatment management.83, 84 The use of CAM may also be influenced by an
individual’s desire for a more holistic approach to their care and journey through
diagnosis, treatment and survivorship. There has also been a societal shift in the way
in which complementary therapies are perceived; this has resulted in greater
acceptance of CAM. As stated previously, up to 75 per cent of cancer patients use
complementary therapies alongside conventional cancer treatment.56
Patients experience many physical and emotional symptoms as a result of
undergoing treatment for cancer. Seely et al. (2012) state:
The goals of the integrative oncology are to reduce the side effects of conventional treatment, to improve cancer symptoms, to enhance emotional health, to improve quality of life and sometimes to enhance the effect of conventional treatments.”4 Core principles of integrative oncology are individualised treatment and care; treating the whole patient and not just the cancer; being dynamic by changing directions over time depending on the individual patient’s journey; and developing a respectful patient–practitioner therapeutic alliance.2
19
Integrative cancer centres in Germany, the United Kingdom (UK) and the United
States of America (USA) were established in the late 1990s. Centres include MD
Anderson Cancer Center, Memorial Sloan-Kettering Cancer Center, Johns Hopkins
University, Dana-Farber Cancer Institute, Penny Brohn Cancer Care and Germany’s
Tumor Biology Center. Common integrative services provided include: massage;
mindfulness; meditation and relaxation techniques; music, art and/or dance therapy;
acupuncture; yoga; reiki; diet and supplements.
A recent review of integrative oncology programmes4 identified 29 integrative
oncology programmes, supported by 53 articles. This review included only
programmes that had published articles, and the authors reported that the number of
integrative services was much greater than those reported in the review. The
programmes included in the review were unique with regard to structure and
operational model. The majority of the articles were descriptive (n=44, 83%),
reporting on the integrative service itself, such as the funding, history, location and
population. A small number described research (17%), with five evaluating the
service; three were qualitative studies and two were observational studies. Almost
half (n=24) of the articles were published in the past five years, suggesting this is a
new and emerging area. Twelve of these programmes were located in the USA, ten
in the UK, three in Canada and two in Germany. Twelve programmes offered
complementary and conventional treatment in the same location, with eight of the
remaining programmes offering CAM services in collaboration with a conventional
oncology centre. A number of complementary therapies was usually offered, with
mind–body medicine (meditation, visualisation, relaxation), massage, nutritional
education and acupuncture being identified as the most common.4 The two most
common reasons for offering a particular therapy were that it was based on clinical
evidence (n=12) and in response to patient demand (n=10). The goals of all
programmes were quite similar, offering ‘whole person’, ‘patient-centred’,
‘collaborative’, ‘empowerment’, and ‘evidence-based’ treatment. The varied models
of care and therapies suggest there is no gold standard when it comes to an
integrative oncology model of care.
20
The review4 identified that 20 of the 29 programmes maintained an active research or
evaluation programme, and 16 conducted both forms of research and evaluation.
Sixteen programs used patient outcomes to evaluate the programme, and some
qualitative research was conducted. Outcomes assessed include quality of life, cancer
and cancer treatment–related symptoms, wellbeing, survival, and patient-identified
concerns and benefits. The evaluation of integrative services is important to ensure
benefit from the patients’ perspective, ensuring they have good outcomes in the
movement towards patient-centred care, with funding bodies for ensuring value or
cost-effectiveness, and informed policy makers who are aware of potential future
changes.85-87
As integrative oncology is an emerging model of care, there is also a need for further
research to evaluate both individual complementary therapies and integrative cancer
care as a whole. A recent article identifying future research directions for integrative
medicine proposes that determining the efficacy of individual modalities is not a
preferred research question, but that instead, future questions need to assess the
effectiveness of CAM modalities in a way that reflects the individualistic, synergistic
and holistic approach of complementary medicines,2 and that they also need to focus
on measurements that assess patients’ quality of life (QoL).87, 88
A recent evaluation of an integrated support programme highlights this approach.88 A
service based at three privately funded community settings in the UK was evaluated
by use of Measure Yourself Concerns and Wellness (MYCaW). This individualised
outcome measure has been designed for evaluating complementary therapies in
cancer support care89, and was included as part of the evaluation. Patients completed
MYCaW following their first CAM session and after receiving six hours of
individual therapies. Patients nominated psychological and emotional concerns
(48%), with physical being (23%), wellbeing (17%) and hospital cancer treatment
concerns (11%); the post-evaluation found highly statistically significant
improvement in the mean scores of concerns one and two.
This approach highlights the benefit of using a patient-centred tool. Doing this aligns
with complementary therapy treatments being individualised to the patient, and with
the premise behind integrative oncology clinics. The approach assessed change in the
21
patients’ concerns after treatment, and qualitative data provided answers to questions
about what symptoms were important to the patients, what benefits they perceived
from the service and what was important about the service. This method has been
supported as an effective way to expand the research knowledge base.2, 90 There is a
need to replicate the study in an Australian population, using a similar design and
methodology.
1.13 Conclusion
CINV continues to be a common symptom experienced by patients, one that is not
well managed. The current research highlights important clinical effectiveness gaps,
and there is a need to use modalities other than pharmaceuticals to improve CINV
control. Acupuncture is one modality currently and increasingly used in ‘integrative
oncology’. It is important to continue examining the evidence base for this emerging
therapy. An important part of any new programme or service is the evaluation of its
benefits and patient perspectives. The following chapter will describe a systematic
review examining the effect of acupuncture and acupressure on CINV.
22
Chapter 2: A Systematic Review of Acupuncture and/or
Acupressure for Chemotherapy-Induced Nausea and
Vomiting
2.1 Introduction
The aim of this chapter is to review the clinical evidence for the effectiveness and
efficacy of acupuncture and acupressure, in the treatment of CINV. The systematic
review in the first section presents background information about CINV, and control
with current anti-emetics and the effect on a patient’s QoL. The use of non-
pharmacological treatment is discussed. The second section details the search
methodology for identifying RCTs and systematic reviews, with meta-analysis for
acupuncture and/or acupressure for CINV. The third section reports the results of the
search, and the subsequent meta-analysis of the trials identified for inclusion. The
final section examines the results and discusses the implications for clinical practice
and further research directions.
2.2 Background
Nausea and vomiting rate highly as feared, distressing and debilitating adverse
effects identified by patients receiving chemotherapy, 22, 23 and continue to be a
major concern for patients, despite new and improved anti-emetic therapy.24-26
Overall, the prevalence of acute and delayed CINV is 40 to 60 per cent (range, 12%–
82%) and 40 to 80 per cent (range, 19%–84%) respectively.22 CINV is influenced by
several factors, including age, sex, history of motion or morning sickness, alcohol
intake and the emetogenic rating of chemotherapy agents.31
Current medical management involves the use of 5-HT3 receptor antagonists
combined with dexamethasone, a corticosteroid. Newly developed anti-emetics, such
as aprepitant, a neurokinin-1-receptor antagonist, have increased the efficacy in acute
and delayed CINV, compared to standard treatment with 5-HT3 antagonists and a
23
corticosteroid (usually dexamethasone). In a recent systematic review of 17 trials of
aprepitant for moderate and highly emetogenic chemotherapy, the meta-analysis
showed complete response rates (no vomiting and no rescue medication) for 72 per
cent of participants, compared with 54 per cent in control arms of ondansetron and
dexamethasone alone.38
Reviews on the control of CINV identified that non-pharmacological methods are a
useful addition to standard treatment with anti-emetics. 17 A growing number of
studies have shown benefits from EA for CINV. Although acupuncture for CINV has
been investigated previously, there remains a need for further high quality research. 91-100 Since the publication of a systematic review in 2006, 8 evaluating acupoint
stimulation for CINV, several clinical trials have been published. These trials have
been updated in a published systematic review summarising the findings in this
chapter101(Appendix One).
The aim of this review is to update the evidence examining the role of acupuncture
and acupressure for the management of CINV.
2.3 Methods 2.3.1 Type of Studies
Systematic reviews and RCTs, including parallel and crossover designs, were
included. In the crossover trials, data from the first phase only was analysed as the
sufficiency of the washout period was unknown. Quasi-experimental trials were
excluded.
2.3.2 Participants
Adults and children (aged 6–18 years old), receiving chemotherapy for any cancer,
were included.
24
2.3.3 Type of Intervention to be Included
Acupuncture involving stimulation using manual acupuncture, EA and acupressure
(pressure applied to acupuncture points) were included. Styles of acupuncture
practiced included TCM, medical, auricular and Japanese. Stimulations using laser
acupuncture and point injection, transcutaneous electric nerve stimulation were
excluded.
Control groups included: placebo acupuncture, defined as non-penetrating needles at
the same acupuncture points or non-acupuncture points, minimal invasive needling
or sham acupuncture with no or little stimulation with a non-acupuncture point; EA
inert position and no electrical stimulation; and placebo acupressure defined as
acupressure at non-acupuncture points or an acupressure band with no button. Other
control groups included standard care, including pharmacological interventions or
other active intervention.
2.3.4 Types of Outcome Measures
Frequency/severity of acute or delayed CINV, as measured by numbered rating
scales, visual analogue scales, Rhodes Nausea scale, vomiting, retching tool and
Morrow assessment of nausea and emesis tool. Other measures included QoL, use of
rescue medications and/or breakthrough anti-emetics.
2.3.5 Search Strategy
The following databases were searched: AMED, MEDLINE, CINAHL, PUBMED,
Cochrane Controlled Trials Registry, and Science Direct. The search was undertaken
from inception of database to December 2012. Reference lists were reviewed for any
possible missed trials.
The search strategy was limited to RCTs, reviews and systematic reviews only.
Terms used included: acupuncture, acup*, electroacup*, electro-acup*, acupuncture
therapy, TCM, nausea, vomiting, cytotoxic, antineoplastic, chemotherapy, sham
acupuncture and MESH headings.
25
Only English language texts were considered. Unpublished data was included in the
analysis if obtainable.
2.4 Methods of the Review 2.4.1 Study Selection
Chris McKeon performed the literature search and reviewed the citation list. Two
reviewers (Chris McKeon and Caroline Smith) independently reviewed all articles
for study inclusion or exclusion and any disagreement not resolved by discussion
was referred to the third reviewer (Janet Hardy) for resolution.
2.4.2 Data Extraction
Following an assessment of study eligibility, two reviewers extracted the data.
For each trial, data were extracted on the treatment, including the number of
treatments, the number of needles used, the style of point selection and the time of
needle retention. For the acupressure studies, data were collated on the duration of
acupressure stimulation, type of stimulation and the number of times points were
stimulated. The following characteristics of the trial were documented: the number of
participants, details of control arms, study setting and the country of the trial.
The authors were contacted to obtain additional information for unclear reporting or
for primary data.
2.4.3 Assessment of Risk of Bias
To assess the risk of bias for clinical trials, a modified ten-point scale developed by
Joanna Briggs Institute (JBI)102 was used. The scale assessed bias in relation to:
1. randomisation
2. control
3. blinding
4. attrition: dropouts and withdrawals.
26
The quality of systematic reviews were assessed using the Critical Appraisal Skills
Programme103 (CASP) tool, adapted from Oxman.104 The researcher undertook an
assessment of the quality of acupuncture or acupressure in each included study. The
acupuncture assessment reviewed the following components: a description of the
dose of acupuncture, the duration of stimulation, any rationalisation behind point
selection, number of needles used, number of treatments and if any needle sensation
was reported, such as ‘de qi’.
2.4.4 Measures of Treatment Effect
Data entry and statistical analysis was performed using Review Manager105 software.
A statistical summary of the data was undertaken, with continuous data expressed as
mean difference (MD) with 95 per cent confidence intervals (CIs), with no missing
scores being input.
2.5 Systematic Review
The results from the literature search showed only one systematic review was
identified. This was the Cochrane systematic review, published in 2006.8
The Cochrane systematic review8 was of a high methodological quality:
• The review asked a clearly focused question in relation to the population;
interventions and outcomes considered and included RCTs only.
• The method of the review clearly stated the databases used, follow up of
references and the limitations of not looking for unpublished studies or non-
English language studies.
• A clearly defined strategy was used for assessing the quality of the included
studies, looking at anti-emetic regimes, acupuncture point stimulation
procedures and assessing the methodological quality of the studies.
• The meta-analysis of the data was displayed clearly as relative risks (RR) and
standardised mean difference (MD) and 95 per cent confidence intervals
(CIs), for each study.
27
• The authors identified heterogeneity in some trials in their analysis.
• The population treated was varied, enabling generalisation of study findings.
• The review clearly identified the implications for practice, concluding the
practice was safe, with minimal side effects, and identifying a need for
further research.
The Cochrane review identified a total of 1,247 participants from a total of 11 RCTs.
Four were acupuncture or EA trials, three used a form of acupressure and the
remaining four trials used non-invasive electro-stimulation. The review identified
some benefit from acupuncture point stimulation (manual and EA, acupressure and
non-invasive electro-stimulation) on acute vomiting (RR = 0.82; 95% CI 0.69 to
0.99; P = 0.04), but not acute or delayed nausea severity. Acupressure appeared to
have a protective effect on acute nausea, reducing mean and worst acute nausea
scores (MD = -0.19; 95% CI -0.37 to -0.01; P = 0.04), when used in conjunction with
state-of-the-art anti-emetic therapy. Acupuncture reduced the proportion of patients
experiencing acute vomiting, but the EA trials did not use state-of-the-art anti-
emetics (RR = 0.74%; 95% CI 0.58 to 0.94; P = 0.01).
2.6 Randomised Controlled Trials
The results of the search identified trials included in the Cochrane systematic review
(total of seven), along with new trials published since 2005 (see Figure 2.1). In total,
there were 19 trials identified for eligibility in this review; this included the seven
trials from the Cochrane review. Twelve trials were included and seven trials were
excluded.
Included trials were: Dibble106, Dibble107, Dundee93; Dundee92, Gottschling94,
Jones108, Melchart97, Molassiotis73, Reindl98, Roscoe109, Shen99 and Streitberger100.
Seven trials were included in the acupuncture group,92-94, 97-100 and six for the
acupressure group.73, 97, 106-109 One trial97 was included in both the acupuncture and
acupressure interventions, compared to standard treatment. A description of the trials
is presented in Appendix Two.
28
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097 For more information, visit www.prisma-statement.org
Figure 2.1: Results from Search Strategy
Records identified through database searching
(n = 73)
Scre
enin
g In
clud
ed
Elig
ibili
ty
Iden
tific
atio
n
Additional records identified through other sources
(n = 0)
Records after duplicates removed (n = 57)
Records screened (n = 57)
Records excluded ( )
Full-text articles assessed for eligibility
(n = 19)
Full-text articles excluded, (n = 7)
1 not RCT 1 transcutaneous stimulation band 1 herbal formula
2 exploratory analysis of previous
trials 2 insufficient data
Studies included in quantitative synthesis
(meta-analysis) (n = 12)
29
2.6.1 Excluded Studies
Eight trials were excluded (see Appendix Three). Three were excluded due to
insufficient data availability or inability to contact the author.110-112 One trial was not
a RCT.91 One trial used transcutaneous stimulation bands,113 one trial was not
acupressure or acupuncture, but used a herbal formula.114 Two trials reported on
exploratory analysis of data from previous trial.115, 116
2.6.2 Excluded Reviews
Six reviews were excluded (see Appendix Four). Two reviews83, 117 were excluded as
they encompassed all symptoms of cancer treatment and were descriptive reviews.
One systematic review addressed only breast cancer patients,68 with no meta-
analysis; another examined all types of nausea and vomiting.118 One publication was
excluded because it was a narrative review of acupressure only.119 One review was
excluded due to a focus on moxibustion for symptom control in cancer patients.120
2.7 Characteristics of the Studies
Four acupuncture trials were conducted in Germany, two in Northern Ireland and one
in the USA (see Appendix Two). Four trials were single centre only, and three were
conducted in a multicentre format. Five trials were undertaken in an inpatient setting,
one in an outpatient setting and one in an inpatient and outpatient setting.
Four acupressure studies were conducted in the USA, one in Germany and one in the
UK. Two trials were single centre only and four trials were conducted in multi-
centres. Three trials were conducted in an inpatient setting and three in an outpatient
and inpatient setting.
Sample sizes ranged from 10 to 739 participants, with five trials73, 99, 100, 107, 109 using
samples greater than 50 participants; the majority had less than 30. Acupuncture trial
30
sample sizes ranged from 10 to 104, and acupressure trials from 18 to 739
participants, three trials97, 106, 108 had less than 30 participants.
2.8 Description of the Interventions
The acupuncture intervention varied between trials. There was significant variation
in the point selection, frequency of treatments and total number of treatments. The
majority of trials (five of seven) used a formula approach to point selection, and
point selection using only one or two points, (Pericardium 6 Neiguan and/or Stomach
36 Zusanli).
In the acupressure trials, only one trial106 used two points, they were Pericardium 6
and Stomach 36; all other trials stimulated one point only, Pericardium 6.
In the acupressure trials, only one trial106 used two points they were Pericardium 6
Neiguan and Stomach 36 Zusanli; all other trials stimulated one point only,
Pericardium 6 Neiguan.
The duration of needling varied from 20 to 40 minutes in one trial,94 with four trials 97-100 reporting a needling duration of 20 minutes. Two trials92, 93 did not report on the
duration of stimulation. The number of treatment sessions varied from one to ten,
with three trials93, 94, 99 having five to six treatments. One trial98 reported
administering eight to ten sessions, one trial100 reported two sessions and two trials92,
97 reported one session only.
Acupressure stimulation method was either by digital pressure106, 107 or acupressure
bands 73, 97, 108, 109. Acupressure stimulation varied from three minutes106, 107, to 72
hours97 to five days,109 with one trial108 not clearly stating the duration. The number
of sessions varied greatly from one session,73, 97, 109 to a minimum of 28 sessions;106,
107 one trial108 did not clearly state the number.
31
2.9 Outcome Measures
In the acupuncture trials, the inclusion of primary outcome measures varied between
trials. Two trials92, 93 measured acute vomiting on a four-point scale (‘very good’ (no
sickness), ‘some benefit’ (marked reduction in sickness), ‘no change’ (no benefit)
and ‘worse’ (worse than before)); two trials measured rescue anti-emetic use,94, 98
two assessed the number of vomits99, 100 and one measured nausea only.97 Inclusion
of secondary outcome measures also varied between trials. Three trials94, 98, 100
measured number of vomits, two trials98, 100 measured nausea intensity, two trials97, 99
measured rescue anti-emetic use, one trial99 measured vomiting free days, one trial97
frequency and duration of nausea and vomiting and one trial100 perception of benefit.
Acupressure primary outcomes varied between the trials. Two trials measured nausea
scores,97, 106 two assessed nausea and vomiting scores,107, 109 one used the Morrow
scale108 and one the Rhodes Nausea, Vomiting and Retching scale.73 Secondary
outcomes measured included nausea intensity (three trials),73, 106, 107 expectations of
benefit (two trials),108, 109 and anxiety states (two trials).73, 107.One trial each measured
satisfaction with treatment,108 QoL109 and a chemotherapy problem checklist.106
2.10 Assessment of Risk of Bias in Acupuncture Trials
Five trials were assessed at a low-to-moderate risk of bias.97-100 Only one trial was at
a low risk of bias on all domains,100 four trials94, 97-99 were at moderate risk of bias,
and the remaining two trials93, 94 were at a high risk of bias. (Table 2.1). The three
trials published after the Cochrane review8 scored seven-to-eight out-of-ten using the
JBI assessment tool,102 indicating a low-to-moderate risk of bias.
32
T
able
2.1
: Ass
essm
ent o
f Bia
s
Crite
ria
Acup
unct
ure
artic
les
Dun
dee
1987
Dun
dee
1988
Shen
2000
Stre
itber
ger
2003
Mel
char
t
2006
Rei
ndl
2006
Got
tsch
ling
2008
Ass
ignm
ent t
o gr
oups
trul
y ra
ndom
U
ncle
ar
Unc
lear
Y
es
Yes
Y
es
Yes
Y
es
Wer
e pa
rtici
pant
s blin
ded
to
treat
men
t allo
catio
n?
Yes
N
o N
o Y
es
Yes
N
o N
o
Was
allo
catio
n to
trea
tmen
t gro
ups
conc
eale
d fr
om th
e al
loca
tor?
Unc
lear
U
ncle
ar
Yes
Y
es
Yes
Y
es
Yes
Wer
e th
e ou
tcom
es o
f peo
ple
who
with
drew
des
crib
ed a
nd in
clud
ed in
the
anal
ysis
?
No
Unc
lear
Y
es
Yes
N
o Y
es
Yes
Wer
e th
ose
asse
ssin
g th
e ou
tcom
es
blin
d to
the
treat
men
t allo
catio
n?
No
Yes
Y
es
Yes
Y
es
No
Unc
lear
Wer
e co
ntro
l and
trea
tmen
t gro
ups
com
para
ble
at e
ntry
?
Unc
lear
U
ncle
ar
No
Yes
U
ncle
ar
Yes
U
ncle
ar
Wer
e gr
oups
trea
ted
iden
tical
ly o
ther
than
for t
he n
amed
inte
rven
tions
?
Unc
lear
U
ncle
ar
Yes
Y
es
Yes
Y
es
Yes
33
Wer
e ou
tcom
es m
easu
red
in th
e
sam
e w
ay fo
r all
grou
ps?
Yes
Y
es
Yes
Y
es
Yes
Y
es
Yes
Wer
e ou
tcom
es m
easu
red
in a
relia
ble
way
?
Yes
U
ncle
ar
Yes
Y
es
Yes
Y
es
Yes
Was
app
ropr
iate
stat
istic
al a
naly
sis
used
?
Yes
U
ncle
ar
Yes
Y
es
Yes
Y
es
Yes
Scor
e ou
t of 1
0
4 2
8 10
8
8 7
Crite
ria
Acup
ress
ure
artic
les
Dib
ble
2000
Ros
coe
2003
Mel
char
t
2006
Dib
ble
2007
Mol
assi
otis
2007
Jone
s
2008
Ass
ignm
ent t
o gr
oups
trul
y
rand
om
Yes
Y
es
Yes
Y
es
Yes
Y
es
Wer
e pa
rtici
pant
s blin
ded
to
treat
men
t allo
catio
n?
No
Unc
lear
Y
es
Yes
N
o Y
es
Was
allo
catio
n to
trea
tmen
t gro
ups
conc
eale
d fr
om th
e al
loca
tor?
Unc
lear
U
ncle
ar
Yes
U
ncle
ar
Yes
U
ncle
ar
34
Wer
e th
e ou
tcom
es o
f peo
ple
who
with
drew
des
crib
ed a
nd in
clud
ed
in th
e an
alys
is?
Yes
N
o N
o N
o N
o N
o
Wer
e th
ose
asse
ssin
g th
e ou
tcom
es
blin
d to
the
treat
men
t allo
catio
n?
Unc
lear
U
ncle
ar
Yes
Y
es
Unc
lear
Y
es
Wer
e co
ntro
l and
trea
tmen
t gro
ups
com
para
ble
at e
ntry
?
Yes
U
ncle
ar
Unc
lear
Y
es
Yes
Y
es
Wer
e gr
oups
trea
ted
iden
tical
ly
othe
r tha
n fo
r the
nam
ed
inte
rven
tions
?
Yes
Y
es
Yes
Y
es
Yes
Y
es
Wer
e ou
tcom
es m
easu
red
in th
e
sam
e w
ay fo
r all
grou
ps?
Yes
Y
es
Yes
Y
es
Yes
Y
es
Wer
e ou
tcom
es m
easu
red
in a
relia
ble
way
?
Yes
Y
es
Yes
Y
es
Yes
Y
es
Was
app
ropr
iate
stat
istic
al a
naly
sis
used
?
Yes
U
ncle
ar
Yes
Y
es
Yes
U
ncle
ar
Scor
e ou
t of 1
0 7
4 8
8 7
7
35
2.10.1 Selection Bias
Three trials94, 97, 99 reported the method of generating a randomisation sequence to the
treatment or control arms, and were assessed as low risk. Two trials94, 97 used a
computer program and one trial 99 used a table to generate randomisation. Four
trials92, 93, 98, 100 did not state how the randomisation sequence was generated, and
were assessed as risk unclear. Two trials92, 93 were published prior to the CONSORT
statement outlining the reporting of RCTs.
Five trials94, 97-100 identified the randomisation allocation as concealed from the
allocator, ensuring a low risk of bias. Three trials94, 98, 100 also concealed the
allocation by using phone randomisation, while two trials97, 99 used sealed opaque
envelopes. Again the two older trials92, 93 did not identify if this occurred, and were
rated as unclear risk of bias.
Three trials92, 98, 100 reported the control and treatment groups as comparable at entry,
and were assessed with a low risk of selection bias. One trial did not report patient
characteristics, and it was unclear if there was bias.93 Two trials94, 97 used crossover
designs; the risk of bias was assessed as low. One trial99 was assessed at a low risk of
bias, as there was no difference in groups at entry in relation to ethnicity, emesis with
prior chemotherapy and alcohol use.
2.10.2 Attrition Bias
Four trials94, 98-100 had no withdrawals and were assessed as a low risk of bias. Two
early trials92, 93 did not detail reasons for withdrawal and were assessed as having an
unclear risk of bias. The remaining trial97 reported a 25 per cent loss due to
withdrawals, but did not include them in the analysis, and was assessed at a low-to-
moderate risk of attrition bias.
36
2.10.3 Performance Bias
Four trials addressed performance bias in relation to blinding of outcome assessors.93,
97, 99, 100 Two trials92, 98 did not conceal the allocation from the assessors, and were
identified as moderate-to-high risk of bias. The remaining trial94 was unclear.
2.10.4 Measurement Bias
Six trials93, 94, 97-100 used the same outcome measure for both groups and used reliable
measures, ensuring a low risk of bias. The remaining trial92 did not clearly state how
the outcome measurements were reliably assessed.
2.11 Assessment of the Risk of Bias Acupressure Trials
Five trials73, 97, 106-108 were assessed at a low risk of bias, and the remaining trial109
was assessed at a high risk of bias. The four trials published after the Cochrane
review8 only scored seven-to-eight out-of-ten in the assessment tool of JBI,102 giving
them a low-to-moderate risk of bias.
2.11.1 Selection Bias
Two trials were assessed at a low risk of bias. One trial97 was assessed as a low risk
of bias because of a stated randomisation sequence generation by computer. Another
trial,73 using computer generation, had simple random selection and was at low risk
of bias. The remaining trials106-109 were categorised as unclear risk of bias.
Four trials73, 106-108 reported that control and treatment groups were comparable at
entry and were assessed as low risk. One trial97 used a crossover design trial and was
assessed as an unclear risk of bias. The other trial109 was assessed as unclear.
37
2.11.2 Attrition Bias
Only one trial106 reported withdrawals and was assessed at a low risk of bias. The
remaining trials73, 97, 107-109 identified the withdrawals. However, they did not include
withdrawals in the analysis and were assessed at a low-to-moderate risk of bias.
Levels of withdrawal were: Dibble106 eight per cent; Jones108 14 per cent; Melchart97
25 per cent; Molassiotis73 34 per cent and Roscoe109 34 per cent.
2.11.3 Performance Bias
Three trials97, 107, 108 reported that outcome assessment was blind to group allocation.
Three trials73, 106, 109 were assessed as unclear.
Two trials73, 97 ensured the allocation of treatment was concealed from the allocator,
with staff collecting the information blind to group allocation; these were assessed at
a low risk of bias. The remaining trials106-109 were assessed as unclear.
2.11.4 Measurement Bias
All six trials73, 97, 106-109 measured outcomes the same way for both groups, and used
reliable measures. They were assessed at low risk of bias.
2.12 Meta-Analysis 2.12.1 Acupuncture plus Medication v. Medication Only
2.12.1.1 Frequency of Vomiting
The frequency of vomits was reported in two trials (see Appendix Five).94, 99A
reduction in vomiting frequency was shown in the acupuncture plus medication
group, (MD -7.40, 95% CI -9.07 to - 5.72, 94 participants).
38
2.12.1.2 Dose of Rescue Medication
The dose of rescue medication was reported in one trial,94 and showed a reduction in
the dose of rescue medication in the acupuncture plus medication group (MD -5.52,
95% CI -7.45 to -3.58, 23 participants).
2.12.2 Acupuncture plus Medications v. Sham Acupuncture plus Medications
2.12.2.1 Frequency of Vomiting
The frequency of vomits was reported in three trials,93, 97, 100 showing no difference
between groups (MD 0.70, 95% CI 0.38 to 1.29, 138 participants).
2.12.2.2 Frequency of Nausea
The frequency of nausea was reported in two trials,97, 100 and showed no difference
between groups (MD 1.01, 95% CI 0.67 to 1.50, 128 participants).
2.12.2.3 Dose of Rescue Medication
The dose of rescue medication was reported in two trials. 97, 100 There was no
difference between groups (MD 1.03, 95% CI 0.64 and 1.67, 128 participants).
2.12.2.4 Helpfulness of Acupuncture
The helpfulness of acupuncture was reported in one trial.100 There was no difference
between groups (MD 1.11, 95% CI 0.71 and 1.74, 80 participants).
2.12.3 Acupressure plus Medication v. Medication Only
2.12.3.1 Frequency of Vomiting
Frequency of vomiting was reported in one trial.73 No difference was found between
groups (MD 0.13, 95% CI -1.46 and 1.20, 94 participants).
39
2.12.3.2 Frequency of Nausea
Frequency of nausea was reported in three trials.73, 106, 109 There was a decrease in the
frequency of nausea in the acupressure plus medication group (MD -0.32, 95% CI -
0.59 to 0.06, 510 participants).
2.12.4 Acupressure plus Medication v. Sham Acupressure plus Medication
2.12.4.1 Frequency of Vomiting
Frequency of vomits was reported in one trial.97 There was no difference between
groups (MD 1.24, 95% CI 0.34 and 4.43, 48 participants).
2.12.4.2 Frequency of Nausea
Frequency of nausea was reported in one trial.97 There was no difference between
groups (MD -0.10, 95% CI -5.52 to 5.02, 48 participants).
2.12.4.3 Use of Rescue Medication
The dose of rescue medication was reported in one trial.97 There was no difference
between groups (MD 1.03, 95% CI 0.64 and 1.67, 48 participants).
40
2.13 Discussion
Twelve trials were included in the review: seven acupuncture and six acupressure
trials. The trials included a total of 1,381 participants: 1,133 in acupressure studies
and 275 in acupuncture studies. One trial97 was included in both acupuncture and
acupressure analysis.
The meta-analysis showed a reduction in the frequency of acute chemotherapy-
induced nausea in the acupressure plus medication group, compared with the
medication only group (MD -0.10, 95% CI 0.34 to 4.43). In addition, there was a
reduction in frequency of vomiting (MD -7.40, 95% CI -9.07 to -3.58), and a
reduction in the dose of rescue medication (MD -5.52, 95% CI -7.45 to -3.58) in the
acupuncture plus medication group versus medication only. Overall, the number of
trials included in the meta-analysis was quite small due to unavailability of data from
articles and/or the authors, limiting the conclusions drawn.
The limitations of the primary studies relate to whether an adequate dose of
acupuncture or acupressure was administered. Treatment frequency also varied
between studies; some trials treated daily and others weekly or once only. The actual
dose of acupuncture required is an area of research that has not been fully evaluated.
It has been suggested that a minimum of six treatments is needed to constitute
adequate treatment.121 Only two acupuncture trials94, 98 had greater than six
treatments, though one trial99 had five treatments. Of the acupressure trials, three97,
106, 107 had six or more treatments, with one trial108 unclear. Five from seven
acupuncture trials used a formula for point selection using just one or two points.
Two points may not give an adequate dosing of acupuncture for symptoms. As with
TCM and conventional medicine, a majority of conditions are multi-factorial and not
caused by one imbalance or factor, leading to inadequate treatment with only one or
two points. Two acupuncture trials used a flexible point selection process, with TCM
practitioners selecting points based on TCM principles and investigating the
acupuncture treatment, rather than acupuncture stimulation of a particular point or set
of points. In these instances, researchers reported the most common points that were
used in the intervention; this treatment may help guide further research and guide
41
practitioners in clinical practice. The use of sham controls within acupuncture
remains controversial, as some studies indicate physiological activity with many of
the techniques of sham acupuncture.122-124 In addition, ethical concerns have been
raised about the use of a sham control in the evaluations of acupuncture in cancer
care.125, 126
The most recent acupuncture trials are beginning to reflect modern practice by using
more than one or two points, and in the use of individualised treatments, rather than a
formula of points. Research is moving away from investigating the effects of a
specific acupuncture point to investigating acupuncture as a ‘whole person’
intervention, including the specific and non-specific effects of acupuncture treatment
and the acupuncturist.127-129 In these instances, researchers reported the most
common points used in the intervention. This may help guide both further research
and practitioners in their clinical practice, but heterogeneity will make it difficult to
compare studies.
The methodology of recently published acupuncture studies has not greatly improved
from the trials identified in the Cochrane review;8 with the trials only scoring seven-
to-eight out-of-ten for the JBI assessment tool.102 In addition, the reporting of trials
has not progressed, despite the publishing of the Standards for Reporting
Interventions in Controlled Trials of Acupuncture (STRICTA)130 guidelines: with
improved reporting, a more accurate assessment of bias risk can be obtained. The
studies remain small, with most being pilot studies. This is common and a major
weakness. There has been a tendency to use crossover designs for the most recent
trials. The issue raised by this design is that the washout period for acupuncture or
acupressure treatment has not been clearly identified through research. However,
using this design may ensure better recruitment and retention of participants. Overall,
few studies remain at a low risk of bias.
The quality of the trials in relation to risk of bias was only fair: this could and should
be improved. Four of the seven acupuncture trials94, 97-99 had a low-to-moderate risk
of bias; only one100 had a low risk of bias. Five of the six73, 97, 106-108 acupressure trials
had a low-to-moderate risk of bias. Bias in the other trial98 was assessed as moderate-
to-high, as it did not clearly state many criteria. There was a slight improvement in
42
addressing bias in the acupuncture and acupressure trials following the Cochrane
review.
Selection bias in the acupuncture trials was addressed well by three trials,94, 97, 99
ensuring effective randomisation. An allocator was blinded to the treatment group
and control and treatment group were comparable, ensuring a low risk of bias. The
remaining trials were assessed as being at risk of bias unclear, due to incomplete
reporting of the randomisation method. Only both Dundee trials92, 93 failed to identify
clearly if allocators were blinded to treatment group allocation. In the acupressure
trials, two trials73, 97 were assessed at a low risk of bias due to effective
randomisation, with the allocator blinded and comparable groups at entry. The
remaining trials stated they randomised patients but not how, and did not clearly state
if the allocator was blinded.
Five of the 13 trials94, 98-100, 106 had a low risk of bias, with six trials having low-to-
moderate bias due to withdrawals being identified but not included in the analysis.
Two trials92, 93 had a high level of bias; both were early work done by Dundee, prior
to the established criteria for reporting bias.
The sample sizes for the majority of studies remain small, with most being pilot
studies. No power analysis or sample size calculations were undertaken to examine
statistical significant benefit.
Characteristics of the participants in these trials varied. Some recent acupuncture
trials included children with cancer. This is a patient group not often seen by
practitioners, but it is relevant to the growing number of practitioners who work in
integrative oncology clinics. There were also trials that included patients with more
than one cancer type. This mixed patient group is more representative of what
acupuncture practitioners would treat in their clinics. Therefore, the findings relating
to the patients seen in trials99,73,107 only treating women with breast cancer are less
relevant to practitioners in their clinic.
43
2.14 Agreements and Disagreements with Other Studies or Reviews
One other systematic review of acupuncture has been published in the literature.8
This review included 11 trials, and one other form of acupoint stimulation, non-
invasive electro-stimulation, which was excluded from this review. This review
found some benefit with respect to acute nausea for acupressure (MD -0.32, 95% CI
-0.59 to -0.06, 510 participants) and there was evidence of a decrease in frequency of
vomiting (MD -7.40, 95% CI -9.07 to - 5.72, 94 participants) and dosage of rescue
medication (MD -5.52, 95% CI -7.45 to -3.58, 23 participants) in those receiving
acupuncture. This review concurs with previous findings,8 suggesting a clinical
effect from acupuncture point stimulation on CINV.
2.15 Clinical Commentary
There is some evidence to support the use of the two major points Pericardium 6
Neiguan and/ or Stomach 36 Zusanli, for acute CINV, although there is less evidence
for delayed CINV. These points are commonly used in clinical practice and are also
used often in treating nausea and vomiting arising from other causes, including post-
operative and pregnancy-induced nausea and vomiting.131, 132 There is less evidence
for the use of other points, such as Conception Vessel 12 Zhongwan and Large
Intestine 4 Hegu, which needs more high quality research before recommended for
use. Acupressure on Pericardium 6 Neiguan and Stomach 36 Zusanli, has shown
some benefit for acute chemotherapy-induced nausea. The research is not conclusive,
but as the intervention is inexpensive, low risk and easy for patients to learn and
perform, this could be included for patients experiencing CINV.119
2.16 Conclusion
Overall, the methodological quality of trials has not improved greatly since the
Cochrane review, although there has been no worsening of quality. There remains a
need for further research with a fully powered study examining the effect of
acupuncture on delayed and acute nausea. Acupuncture appears to reduce
chemotherapy-induced vomiting and decrease use of rescue medications.
44
Acupressure appears to have a benefit for reduction in severity of acute
chemotherapy-induced nausea.
There is a need to conduct further research with trials using appropriate sample sizes
and adequate power. Future research needs to ensure that when designing trials,
outcome measures are both clinically relevant and patient centred to reflect what is
important for the patient.133-135 Further trials should also allow the treating
acupuncturist to have the flexibility to decide the appropriate acupuncture treatment,
thus ensuring trials have clinical relevance and help to direct practice.127, 128 There is
support for moving the focus from efficacy to effectiveness studies, where the design
more closely reflects practice. The adoption of broad trial inclusion and exclusion
criteria will also ensure the findings of the study are able to be generalised and
representative of the usual care situation.129, 136 This will ensure research is more
reflective of what occurs in clinical practice.
The following chapter describes the methodology for a pilot RCT, and the
implementation and evaluation of an integrative acupuncture oncology service at the
Mater Hospital in Brisbane.
45
Chapter 3: Methodology
The overall aim of this study was to examine the role of acupuncture in an integrated
cancer care setting of a public hospital day oncology unit. The research objectives
examined: the (i) feasibility of conducting an efficacy trial of acupuncture for CINV,
and (ii) the role of an acupuncture service in the day oncology unit on patient’s
wellbeing. This chapter describes the methodology used for: (i) the pilot feasibility
RCT of EA versus sham EA versus no acupuncture for acute and delayed CINV; and
(ii) an evaluation of the acupuncture service for cancer patients using a validated
patient-reported outcome measure.
3.1 Methods 3.1.1 Research Questions
The primary research question examined if it was feasible to conduct a RCT of EA
versus sham EA versus no acupuncture for CINV at a day oncology unit.
Feasibility questions examined:
1. Timeframe to recruit 60 participants for the trial.
2. Number of participants willing to return for further intervention on Day 3.
3. Number of dropouts from the trial to be expected and the reasons for drop
out.
4. Suitability of the outcome measures used for the trial.
5. If integrity of blinding was maintained at the end of intervention.
Secondary questions:
1. Were there group differences between Functional Living Index Emesis FLIE
scores and changes of scores between groups at Day 1, 4 and 7?
2. Were there differences between nausea scores on Day 1, 2 and 4?
3. What number of breakthrough anti-emetics was used?
4. What number of participants reported side effects from treatment?
46
5. Was the presence of any washout period during the second cycle detected?
6. What influence do participants’ expectations of benefit have on
effectiveness?
7. Did the practitioner therapeutic encounter introduce bias?
3.2 Study Design
A pilot randomised, controlled, three-arm single-blinded trial of EA or sham EA
versus treatment as usual.
3.2.1 Study Design Rationale
The main reasons for conducting a pilot or feasibility study can be categorised into
several broad classifications, which are process, resources, management and
scientific.137-140 The rationale behind this study was to identify if it was possible to
conduct a trial in a busy day oncology unit environment; what resources and
management systems would be required and if the scientific process was sound and
obtained the necessary data to help obtain funding for a definitive trial.
The other rationale of this study drew on the findings from the Cochrane review by
Ezzo et al.8 The review recommended that further research consider: (i) the use of
more than one acupuncture point; (ii) the use of EA as an adjunct to modern anti-
emetics; and (iii) examination of the role of EA on delayed nausea and vomiting.
The study also evaluated the duration of any treatment or sham effect on symptoms
of CINV to identify the potential washout period from the study interventions. To do
this, further data was collected from the EA and sham group during the participants’
second cycle of chemotherapy.
The inclusion of three study groups allowed examination of the adjunctive effect
from EA, compared with treatment as usual in controlling CINV, and secondly
would determine if the effects of EA were greater than sham EA. This design may
allow some methodological concerns of previous acupuncture research to be
addressed.
47
3.3 Methodological Issues to Consider for Acupuncture Research
Acupuncture has been described as a complex, multi-component intervention. The
effects of acupuncture can be attributed to the specific effects from needling, specific
non-needling components based in acupuncture theory, such as palpation, and non-
specific effects including the therapeutic relationship and other contextual factors.
The specific effects of acupuncture include needling components, needle depth, point
stimulation, location of acupuncture point. Non-specific components that are generic
and not specific to acupuncture (include the therapeutic interaction with the
practitioner, therapeutic setting diagnosis and belief and expectations of the
practitioner and patient) are common to all interventions, such as belief and
expectancy, therapeutic setting, time and attention.128, 136, 141
The placebo non-specific effects are variables that researchers frequently try to
control when using sham acupuncture in efficacy studies of acupuncture. Sham
acupuncture may involve the use of needles inserted at non-acupuncture points,
superficially with no needle stimulation (no de qi), or non-penetrating needles.142-145
A sham treatment may also include attempts to control for the therapeutic
relationship, active listening and touch. Concentrating on one element of the
complex intervention, for instance, looking at the specific effects of acupuncture
points and needling using sham controlled trials, not the whole intervention,
minimises the effect size from the specific non-needling aspects of acupuncture.128,
136, 141
Some studies comparing sham with true acupuncture demonstrate no difference in
effect. One explanation of this may be that sham acupuncture is not an inert placebo,
but instead has a physiological effect.123, 135, 146, 147 The non-specific effect from
placebo and sham controls can vary widely between individual patients; in sham
controls the non-specific effects may be larger than for inert placebo
interventions.128, 148-150 To account for these effects, a control arm usual has been
included in this trial.
48
3.4 Study Participants
The inclusion criteria were:
• Patients with cancer admitted to the haematology/oncology day unit for their
first cycle of moderate-to-highly emetogenic chemotherapy (see Appendix
Six), aged 18 years and older, receiving moderate-to-highly emetogenic
chemotherapy, not on consecutive days.
• Chemotherapy naïve.
• Diagnosis of solid tumours (non-haematological malignant disease).
• A good understanding of English and cognitive ability, allowing for fully
informed written consent and to complete all trial questionnaires.
Exclusion criteria were:
• A history of acute, chronic or sub-acute ileus.
• Thrombocytopenia (defined as platelet count <100 x 109/l).
• Previous use of acupuncture for nausea and vomiting.
• Pre-existing nausea or vomiting from another medical condition.
• Participation in any other trial, including those of new chemotherapy
regimens.
• Concurrent treatment of chemotherapy and radiotherapy.
• Uncontrolled central nervous system (CNS) involvement by tumour.
• Needle phobias.
• Insufficient understanding of the trial and its requirements.
3.5 Recruitment Strategy
The setting for the study was the day oncology outpatients unit, at a public hospital
in Brisbane, Queensland. The unit had two part-time oncology and two full-time
consultant/s; they referred patients to the trial. The unit at the time of the trial treated
approximately 550 new patients per year, with 7, 000 occasions of service per year.
No promotion or information was disseminated directly to the patients or the
community for recruitment. Presentations to the cancer services divisional research
49
meeting were given on a monthly basis, prior to commencement of the trial and
regular reports were given during the course of recruitment to the study. Information
regarding the trial was given to nursing staff as an in-service, prior to
commencement of the study. Referral of potential study participants was from the
oncology consultants, or from a hospital research officer, who identified patients
attending the oncology day unit for their first cycle of moderate or highly emetogenic
chemotherapy.
Following consent by the treating oncologist, potential participants were given the
trial information sheet while waiting in the chemotherapy waiting room or prior to
attending the unit (if possible) by the research nurse. A screening log was
maintained. This was used to confirm patient eligibility, to collect data relating to
whether or not the patient consented to the trial, the reason for declining the trial if
this information was volunteered, and reasons for exclusion.
Those patients who met the eligibility criteria and were willing to consent to the trial
(Appendix Seven) were randomised to one of the three arms following written
informed consent had been obtained.
Mater Health Services Human Research Ethics Committee approved the study,
approval number 1276A. Trial registered with ANZCTR (Australian New Zealand
Clinical Trials Registry) number ACTRN12609001054202. Funding was generously
supplied by the Mater Foundation, South Brisbane and the Smiling for Smiddy
Foundation.
3.6 Randomisation
Randomisation was conducted through the Mater Research Support Centre, within
the Mater Research Institute adjacent to the hospital. A computer randomisation
program generated the randomisation sequence. Randomisation was stratified
according to the emetogenic rating of the chemotherapy. Sealed envelopes,
numbered consecutively according to patient entry number, containing the
randomised treatment allocations were kept on the day unit. The study investigator
50
(CM) opened the envelopes in numbered sequence and delivered the treatment as
specified (i.e., EA, sham EA, treatment as usual). Each arm of the study had an equal
number of participants.
3.7 Blinding
A research assistant, who was blind to the treatment allocation, collected the data
from the patient. An independent data manager, who was blind to treatment
allocation, entered information from the trial diaries into a database. The study
statistician was blind to treatment allocation. Patients were blind to treatment
allocation for the EA and sham groups only.
3.8 Treatments and Study Schedule and Intervention 3.8.1 Treatment as Usual
All patients received standard anti-emetic therapy, as appropriate for the particular
chemotherapy they received, according to CHARM, TM 151 the computerised
chemotherapy/anti-emetic protocol system used at Mater Health Services. This
system has been developed and updated according to best international practice. 152
All patients received rescue anti-emetics according to protocol if required. Standard
anti-emetic therapy at the time was ondansetron 8mg intravenously (IV) on Day 1,
8mg orally twice a day for Days 2 and 3, dexamethasone 8mg IV Day 1 and 8mg
orally daily for Days 2 and 3 for moderate emetogenic chemotherapy. Highly
emetogenic chemotherapy used the same regime plus aprepitant 125mg orally Day 1
and 80mg orally on Day 2 and 3. Rescue antiemetics were metoclopramide 10mg
orally four times a day when necessary.
3.8.2 Electro-Acupuncture
All acupuncture was given by the researcher, who is a trained acupuncturist with an
Advanced Diploma of Acupuncture, a member of Australian Acupuncture and
Chinese Medicine Association and has six years of clinical practice.
51
EA was selected as the method of stimulating acupuncture points, following review
of evidence from earlier trials, 92, 93 suggested marked benefits for reducing CINV.
Mayor 153 suggests that the continuous stimulation offered by EA provides greater
benefit over time following a treatment, compared to manual acupuncture, and that
this mode of stimulation is less labour intensive for the acupuncturist 153 and less of a
burden on the patient. It allows the nurse to focus on the administration of
chemotherapy and to answer any questions the patients may have.
EA was applied using a newly purchased SDZ-III Electronic Acupuncture Treatment
Instrument 6 channel, which was safety tested by Mater Health Services Biomedical
Department.
EA has the same risks of adverse events as acupuncture relating to needling pain,
bruising, fainting, local skin irritation, pain, exacerbation of symptoms and
pneumothorax, which are negligible when delivered by a qualified practitioner.154, 155
Specific AEs to EA include spasm, peripheral nerve irritation, cardiac conduction
block and electrical burn. The specific adverse events were reported in a review that
identified that the risks of these are very low with EA, when used by a qualified
practitioner. 156
Four acupuncture points were used: ST36 Zusanli, PC6 Neiguan, LR3 Taichong and
LI4 Hegu. The points were chosen based on evidence from previous trials and TCM
textbooks,157, 158used as a standardised protocol. PC6 has been widely investigated as
the major point for nausea and vomiting from different causes, such as pregnancy,
post-operative and chemotherapy-induced.118, 131, 159, 160 ST36 is the other point
commonly used for CINV.91, 94, 98 ST36 is one of the main points in treating any
stomach disorder or pattern.157 Li 157 has identified LR3 and LI4 as useful for nausea;
these two points in combination treat spasms within the whole body and have a
calming effect.158 LI4 is a point that ‘quiets the spirit’ and promotes down-bearing of
qi and is used to harmonise rebellious qi. 158, 161 LR3 influences the liver. According
to TCM, it reduces the effect chemotherapy has on the liver and its interaction with
digestion.157
52
Standard EA, using the points at ST36, PC6, LR3 and LI4, were applied using sterile
surgical stainless steel 0.20mm x 30mm acupuncture needles (Sensei brand made in
China, for Acuneeds Australia) to ST36, PC6, LV3, LI4 bilaterally, a total of eight
needles. Once inserted, the needle was manipulated using a thrusting, twirling
movement until a de qi sensation was achieved and the patient felt soreness, fullness,
heaviness or local area dissention. The depth of needle insertion varied between
patient and points, and was inserted to a depth of 0.2 to 1.5 cm. The negative pole
was attached to PC6 and the positive pole to ST36, to form one circuit; the negative
to LI4 and positive to LR3, and the procedure was undertaken bilaterally. The
frequency of stimulation was 10Hz and intensity of stimulation was adjusted
according to patient’s tolerance (maximum 10 mA). Stimulation commenced ten
minutes prior to chemotherapy and continued for total of 30 minutes on the first
cycle (Day 1). Patients were invited to return to the day unit for a second course of
EA on Day 3, when treatment was repeated as per Day 1.
3.8.3 Control Arm: Sham Electro-Acupuncture
The acupuncturist used points adjacent to the true acupuncture point and off-channel,
but considered far enough away to negate any anti-emetic effect. Each point was
defined by the corresponding acupuncture points and measurements, for instance, 1
cun lateral to PC6, midpoint between ST36 and GB34, 1 cun medial to LI4, 1cun
lateral to LR3. 1 cun is equal to the width of the patients’ knuckle of their thumb, and
is a standard acupuncture measurement (see Figure 3.1).
Sham EA was applied using sterile surgical stainless steel 0.20mm x 30mm
acupuncture needles (Sensei brand, made in China) to points bilaterally. The needles
were inserted superficially 0.2 to 0.5cm depth, the needle was not manipulated, nor
the de qi sensation obtained. The circuit was set up the same as in the treatment arm.
A non-functioning EA machine was used. The machine was made non-functioning
by turning the amplitude up on an unconnected channel, giving the appearance and
noise when completed of the actual machine giving a treatment. Sham stimulation
was given in a similar manner as the real EA treatment (Day 1). Patients were invited
to return to the day unit for a second course of sham EA on Day 3, treatment was
repeated as per day 1.
53
Patients in the ‘treatment as usual group’ received standard anti-emetic medication
treatment without acupuncture (Day 1). Patients allocated to this group were offered
acupuncture on their second cycle if they requested it, as an incentive to participate.
3.9 Outcome Measures and Data Collection 3.9.1 Feasibility Endpoints
1) Time to recruit sufficient numbers for the trial.
2) Number of patients returning for further intervention on Day 3.
3) Number of dropouts from the trial.
4) Outcome measures sensitive to change.
5) 80% of participants blind to their group allocation at the end of the trial
intervention.
3.9.2 Secondary Endpoints
1. FLIE at days 7, 4 and 1. (See 3.10.1)
2. Number of vomits at days 1 to 6.
3. Nausea score at days 1 to 6.
4. Proportion using anti-emetics over seven days.
5. Proportion of patients reporting side effects.
6. Performance bias assessed from the therapeutic encounter.
7. Patient expectations.
8. FLIE, nausea and vomiting scores in Cycle 2.
3.9.3 Data Collection
To maintain integrity of blinding the research, a nurse was responsible for co-
ordinating data collection or interviewing patients to collect data on entering the trial:
• Baseline demographic characteristics were collected on Day 1.This included
employment status, occupation, education level, race, marital status, date of
birth, age, gender, height, weight, chemotherapy protocol, emetogenic rating,
54
diagnosis, anti-emetic regime, concurrent medication and patient expectation
of benefit. (Appendix Eight).
• FLIE was collected on day 1 prior to chemotherapy starting and on day 4 and
day 7. The research nurse helped the patients complete the form on day 1; the
patient completed it independently thereafter. (Appendix Nine). All patients
in the treatment arms completed the daily diary and FLIE scores in Cycle 2 of
their chemotherapy in the same manner as Cycle 1.
• A daily diary between days 1 to 7 was completed by study participants
assessing symptoms of nausea and vomiting over the previous 24 hours.
Participants were advised to complete the diary at approximately the same
time each night. (Appendix Ten).
An adverse event form was completed on Days 1, 3 and 7 (Appendix 11). Any
adverse event was reported according to standard procedure for research in the Mater
Adult Hospital. The patient’s consultant was contacted and informed, an entry was
made in the patient’s medical record, including any subsequent treatment and follow
up. The Mater Health Services Ethics Committee was contacted and supplied with
the necessary information on the appropriate adverse event notification form if
greater than a grade three in severity. A questionnaire was given to participants to
obtain their views on expectancy and perception of their group allocation on Day 3
(Appendix 12). Patient perception of acupuncture effectiveness was completed by
the research nurse on Day 7 (Appendix 13). See Appendix 14 for the outcome
assessment diagram.
3.10 Data Collection Instruments 3.10.1 Functional Living Index Emesis (FLIE)
The FLIE is a validated nausea- and vomiting-specific patient reported outcome
instrument that rates nausea and number of vomits and the impact of CINV on QoL).
QoL and the effects of CINV have been identified as directly affecting the health
care decisions and continuation of treatment by patients.23, 24, 162, 163 FLIE is
composed of two domains (vomiting and nausea), with nine identical items in each
domain.162 Participants rate the severity of their nausea and vomiting over the
55
preceding three days on a seven-point scale anchored by 1 (‘a great deal’) and 7 (‘not
at all’). It is self-completed by the patient, with instruction from the research nurse
when completing for the first time. The first item in each domain asks the participant
to rate how much nausea and vomiting has been experienced during the previous
three days. The remaining eight items cover different sections influencing the
patient’s quality of daily life (i.e., ‘recreation or leisure activities’, ‘make meal/do
tasks’, ‘ability to enjoy meal’, ‘enjoy drinking fluids’, ‘see family/ friends’, ‘daily
functioning’, ‘personal hardship’, ‘hardship on others’).
The FLIE score is determined by summing the responses to the 18 questions on a
seven-point analogue scale. Therefore, the range of total scores possible is between
seven (worst response on each scale) and 126 (best responses on each scale).
Therefore, a higher score corresponds to a higher QoL, or less impact of CINV on
daily life. No or minimal impact on daily life (NIDL) was defined as an average
FLIE item score of more than six on the seven-point continuous visual analogue
scale, or a total FLIE score of more than 108.24, 162, 163 This indicates the patient may
be experiencing a small amount of nausea or vomiting, but that there is no or
minimal impact on their QoL.
3.10.2 Patient Diary
Patients were given a diary to record their symptoms of CINV daily. Nausea was
assessed according to a numerical rating scale (NRS). Participants recorded the
number of vomits, and use of rescue emetic medications for six days post-
chemotherapy, including the day of chemotherapy. Patients in the EA and sham EA
arms completed the diary on their second cycle of chemotherapy, without the
interventions, to assess any lasting effects.
3.10.3 Toxicity
At the time of designing this study, there were no validated tools for assessing the
side effects of acupuncture. Although Witt et al.155 recently published a observational
study of 229, 230 patients and reported adverse events, categorising them in relation
to the severity: ‘common’, ‘uncommon’, ‘rare’ and ‘very rare’, with relevant
56
occurrence ratios and categories: ‘pain’, ‘bleeding/haematoma’, ‘inflammation’,
‘vegetative symptoms’, ‘nerve irritation/injuries’ and ‘other’. However, for this study
the side effects reported by Melchart et al.164 and White154 were used to identify
adverse events occurring in the trial:
• needling pain
• bleeding
• haematoma
• fainting
• local skin irritation
• exacerbation of symptoms
• pneumothorax (this side effect will not be assessed, even though it can be
very severe, as no needling is done in the thoracic region).
These side effects were assessed using modified questions adapted from the National
Cancer Institute Toxicity Scale,165 ranging from ‘none’ to ‘severe’, with a grading
number of 0 to 5. It is widely accepted throughout the oncology research community
as the standard grading scale for adverse events.166 Grades 1 to 5 refer to the severity,
with a unique clinical description for each adverse event based on the general
guideline of:
Grade 1: mild, asymptomatic or mild symptoms; clinical or diagnostic
observations only; interventions not indicated.
Grade 2: moderate; minimal, local or non-invasive intervention indicated;
limiting age-appropriate activities of daily living (ADL).
Grade 3: severe or medically significant but not immediately life-threatening;
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting
ADL.
Grade 4: life-threatening consequences; urgent intervention indicated.
Grade 5: death related to adverse event.
(Not all grades are appropriate for all AEs measured.)
All patients were asked to complete at baseline and on exit (Day 7), and post-
treatment on Day 1 and 3 for treatment arms.
57
3.10.4 Practitioner Therapeutic Interaction
Some practitioners may give extra or less attention to sham acupuncture patients,
knowing they are not getting true acupuncture. If the two groups were treated
differently this might introduce performance bias. Observation of the interaction, and
scoring against a checklist designed to measure the therapeutic interaction between
the practitioner and patient, was used to examine evidence of performance bias. The
checklist was developed using the Therapists Features Scale.167, 168 This scale
includes statements and observations on the timing of the interaction, explanation of
treatment, side effects and adherence to a script (Appendix 15). Other statements
include ‘building rapport’, ‘develops sense of trust and confidence’, ‘amount of
talking’, ‘body language’, ‘tone of voice’, ‘empathetic, warm and friendly’,
‘confident’, ‘use of humour’, ‘sincere’, ‘respectful’, ‘rewarding/encouraging’.
To examine performance bias, the research nurse observed the interaction between
the study acupuncturist and participants in both the EA and sham EA group.
Observations occurred for approximately 20 minutes, from when CM first
approached the patient to explain what the intervention was, until he left. The five
patients from each group were selected randomly by a computer randomisation
program, generating the randomisation sequence. Sealed envelopes, numbered
consecutively according to patient entry number, were kept on the day unit and
contained the randomised treatment allocations, and if they were to have the
therapeutic interaction observed or not.
3.10.5 Expectations
Participant expectations of benefit, generally and personally from acupuncture
treatment, were assessed from responses to two questions:
I. How effective do you consider acupuncture in general? With the patient
responding to one of the following answers: ‘Very effective’, ‘Effective’,
‘Slightly effective’, ‘Not effective’ or ‘Don’t know’.
II. What do you personally expect from the acupuncture treatment? With the
patient responding to one of the following answers: ‘Complete’, ‘Clear
58
improvement’, ‘Slight improvement’, ‘No improvement’ or ‘Don’t know’
(see Appendix Eight).
3.11 Sample Size
A sample size calculation was performed, based on the primary outcome of the FLIE
score at Day 7. Assuming that the score for the control, sham EA and EA arms
would be 100, 105 and 110 respectively, with a standard deviation of 14, type I error
of 0.05 and power of 80 per cent, after including 20 per cent attrition, a total of 141
participants was required.
Funding for this study allowed for recruitment of 60 patients (20 to each arm of the
trial). It was anticipated that this study size would not be powered to detect
differences between study groups, but would allow assessment of feasibility and data
to confirm the treatment effect and power for the design of future research.
3.12 Data Analysis
Sample characteristics and baseline data were summarised using means and standard
deviations (MD & SD) for continuous data and frequencies for nominal data. The
FLIE score over different days was investigated graphically to determine if there
were any trends on the nausea and vomiting scores. Analyses were undertaken
separately for the FLIE scores on three days (Days 1, 3 and 7), and then an analysis
of the change in FLIE score between Days 1 and 4, 1 and 7 was also calculated. The
number of vomits over the course of the study was explored using bivariate analysis
with cross-tabulation. Sub-group analyses by the emetogenic rating of the
chemotherapy agent were also conducted on FLIE scores on the three days (Days 1,
3 and 7), and then an analysis of the change in FLIE score between Days 1 and 4, 1
and 7.
The analysis of the FLIE score for the three different arms was completed using a
Kruskal-Wallis test (for non-parametric data). This was determined if there was a
difference between at least two of the three groups, and if a difference existed, post-
hoc tests determined which groups were significantly different from each other. The
59
NRS scale for nausea was analysed using a Kruskal-Wallis test, comparing the
change between scores on Day 1 and Day 2 and Day 1 and Day 4 for the groups. The
number of vomits was analysed using a Kruskal-Wallis test, comparing the change
between scores on Day 1 and Day 2 and Day 1 and Day 4 for the groups.
3.13 Acupuncture Service Evaluation
Funding to provide a complementary therapies service was obtained from the
Smiling for Smiddy Foundation in 2009. The service offered complementary
therapies to patients undergoing chemotherapy at the day oncology unit, Mater
Adults Hospital, South Brisbane. The composition of services was influenced by a
review of what was offered in other integrative clinics, predominately in the USA
and UK. The author undertook a review of the integrative medicine literature. The
results and recommendations were presented at a cancer services departmental
meeting with the results from a survey of 100 patients regarding what services they
would use if available and for finalisation of the decision. Services identified were
massage, acupuncture, information on herbs and supplements, art therapy and music
therapy. Trained volunteers offered hand and feet massage, a computer with access
to a subscription natural therapies database was situated in the waiting room, the
acupuncture service and art therapy services were commenced.
As part of the funding agreement, an evaluation of the acupuncture service was
undertaken. The service commenced in October 2010, and the evaluation covered the
period from the 1 October 2011 to 31 October 2012. Evaluation of the service was
the primary objective of the second study.
60
3.14 Research Questions
The following questions were examined:
a) Do patients using the acupuncture service find it beneficial, helpful and
useful?
b) What symptoms do patients present for treatment by the acupuncture service?
c) Are there any unacceptable risks of harm from the service?
d) Are there clinically significant improvements in patient concerns/symptoms?
3.15 Study Design
A pre and post-test observational study was undertaken to examine participants’
perspectives and experiences on the acupuncture service. To evaluate this service and
to ensure the total patient experience was captured, both qualitative and quantitative
outcomes were assessed.
The methodological approach used in this study included a questionnaire collecting
data on participants’ perceived benefits of treatment, their views on the service and
areas for improvement, and an assessment of QoL and wellbeing.
3.16 Study Participants
Participants were patients receiving chemotherapy for malignant disease (oncological
or haematological) at the day oncology unit at the Mater Adult Hospital Brisbane and
who requested access to, or were referred to the acupuncture service for treatment of
their symptoms including pain, nausea and vomiting, fatigue, peripheral neuropathy,
insomnia, hot flushes, diarrhoea, constipation, anxiety, stress and sense of wellbeing.
The oncology/haematology outpatients unit is located in a public hospital in
Brisbane, Queensland. The unit had two full-time and two part-time oncology
consultants and two full-time haematologists, who referred patients to the service and
trial. At the time the unit treated approximately 1, 000 new patients per year, with
61
11, 000 occasions of service per year. The unit consisted of five rooms with four
chairs and one bed in each room.
3.16.1 Inclusion Criteria
The inclusion criterion was as follows:
• patients receiving chemotherapy or chemotherapy and radiotherapy at the day
oncology unit
• patients having a malignant disease
• a good understanding of English
• cognitive ability allowing for fully informed written consent and to complete
all trial questionnaires
• clearance required if participating in any other trial, including those of new
chemotherapy regimens.
3.16.2 Exclusion Criteria
Exclusion criterion was as follows:
• thrombocytopenia (defined as platelet count less than 100 x 109/l)
• neutropenia (defined as neutrophil count less than 1 x 109/l)
• participation in any other trial, including those of new chemotherapy
regimens with no clearance
• treatment of radiotherapy only
• chemotherapy for medical conditions other than oncology or haematology
• insufficient understanding of the service and its requirements.
3.17 Ethics
Patients interested in using the acupuncture service were required to give written
consent. The information and consent form provided detailed information on
contraindications to acupuncture; these included platelet count less than 100 x 109/l,
neutrophil count less than 1 x 109/l, no needling of affected limb following lymph
node resection and active infection. Documented cautions included areas of reduced
sensation, diabetes, heart disease and anti-coagulant therapy. These patients that
62
were not excluded, but extra precaution was taken with needling techniques and
point selection (Appendix 16). The Mater Human Ethics Committee and Health
Information Service at Mater Health Services gave approval for the evaluation of the
service, (reference number 1276A).
3.18 Study Administration
Patients accessing the service for the first time were informed that the service would
be evaluated. Posters in the day oncology unit and the consultant clinics advertised
the service. Education sessions were given to staff via in-service on the unit and the
divisional research meeting. The patient information and research consent form for
the evaluation was given to patients by the research nurse or the acupuncturist
(Appendix 17). After consent was obtained, the patient was also required to read and
sign a consent form for the acupuncture (Appendix 16). Additional information about
the commencement of treatment, and what to expect from treatment was also
provided to the patient.
3.19 Acupuncture Service
Conditions for which acupuncture was offered were pain, nausea and vomiting,
fatigue, peripheral neuropathy, insomnia, hot flushes, diarrhoea, constipation,
anxiety, stress and sense of wellbeing. Patients could have up to two treatments per
week while undergoing chemotherapy. Patients received acupuncture while receiving
chemotherapy at the day oncology unit in the treatment chairs. As a result, the
majority of the treatments included the selection of acupuncture points on the arms,
legs and abdomen, with only a few patients having treatment on their back. Needles
were retained for 30 minutes, and then removed. The acupuncturists prescribed the
acupuncture points using a TCM framework. Patients could select to receive the
acupuncture while having their chemotherapy or after. Treatment times were co-
ordinated with the nurses caring for the patients and available chairs, space and time.
Some treatments were conducted after a patient’s chemotherapy, in a spare chair, due
to unit workflow pressures. Treatment and any adverse events were documented in
the hospital’s electronic ordering system, CHARMTM. 151
63
The acupuncturist, a registered nurse with over 20 years experience, held an
Advanced Diploma of Acupuncture obtained in 2003, and had over six years clinical
experience, is a member of the Australian Acupuncture and Chinese Medicine
Association and has been a Registered Acupuncturist with the Chinese Medicine
Board of Australia since July 2012.
3.20 Sampling
Sampling was by non-probability or convenience sampling. All participants
attending the service during a 12-month period were invited to participate in the
acupuncture service. With historical data from the previous 12 months of service, the
expected numbers were predicted to be approximately 100. The actual number
sample size was 112 participants.
3.21 Study Endpoints
The primary endpoints of the study were the proportion of patients reporting a
benefit, help or perception of usefulness from the acupuncture service.
Other endpoints included: proportion of patients reporting adverse effects, changes in
wellbeing, and a description of the characteristic of patients using the service.
3.22 Data Collection
Baseline data collection was completed face-to-face with study participants. To help
with completion rates, a research nurse was available to assist with any questions or
issues.
The timing of the post-test was at four to eight weeks following the first acupuncture
treatment, (after receiving two to four treatments). This varied, depending on
patient’s appointments and availability of research staff, as the acupuncturist never
collected or administered the post-test.
64
3.23 Data Collection Instruments
Data questionnaires included questions about previous acupuncture use for any
condition, symptoms to be treated, benefit expected from treatment, use of
medication to treat symptoms, referral source and the first part of MYCaW
(Appendix 18).
Assessing patients’ views on the service was undertaken by a self-completion of a
researcher-designed questionnaire, devised by the author in consultation with co-
supervisors. Patients noting ‘marked improvement’, ‘some improvement’, ‘slight
improvement’, ‘no improvement’, ‘slight worsening’, ‘some worsening’, ‘marked
worsening’ or ‘don’t know’, rated the benefit of the service. Helpfulness and
usefulness were assessed by the questions ‘do you think the acupuncture service is a
worthwhile addition?’ and ‘would you like the service to continue?’, and if yes, ‘how
might it be improved?’ (Appendix 19)
3.24 Safety
The adverse events form addressed the most common and severe side effects of
acupuncture;154, 155 the form was completed in four to six weeks, at the same time as
the questionnaire (Appendix 20). The side effects were assessed using modified
questions adapted from the National Cancer Institute Toxicity Scale,165 ranging from
‘none’ to ‘severe’, with a grading number of 0 to 5. It is widely accepted throughout
the oncology research community as the standard grading scale for adverse events.165
Grades 1 to 5 refer to the severity, with a unique clinical description for each adverse
event based on the general guideline of:
Grade 1: mild, asymptomatic or mild symptoms; clinical or diagnostic
observations only; interventions not indicated.
Grade 2: moderate, minimal, local or non-invasive intervention indicated,
limiting age-appropriate ADL.
Grade 3: severe or medically significant but not immediately life threatening;
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting
ADL.
65
Grade 4: life-threatening consequences; urgent intervention indicated.
Grade 5: death related to adverse event.
(Not all grades are appropriate for all adverse events measured. The AEs included
needling pain, pain, bruising/haematoma, fainting, local skin irritation,
dizziness/light-headedness and pneumothorax.)
66
3.25 Quality of Life and Wellbeing
The MYCaW questionnaire was used to assess wellbeing. The MYCaW instrument
is an individualised questionnaire designed to evaluate complementary therapies in
cancer support care.89 MYCaW is adapted from the validated MYMOP (Measure
Yourself Medical Outcome Profile) questionnaire; it was developed with repeated
adaptation, piloting and monitoring, and has demonstrated good face validity and
content validity. However, formal validation of the construct and concurrent validity
of MYCaW is yet to be carried out.88, 89 This tool has recently been used in the
evaluation of complementary therapies to cancer patients in a UK centre,88 showing
the relevance, ease of use and suitability to the population targeted in this project.
The tool allows the patient to identify one or two major concerns or problems that
are affecting them the most and what they want to have treated. This makes the tool
patient centred, as they decide which symptoms or problems most affect them. After
identifying one or two problems, the patient then rates it on a seven-point Likert
scale, with 0 = ‘not bothering me at all’ and 6 = ‘bothers me greatly’. The third
question also asks the patient to rate their general feeling of wellbeing on the same
scale, with 0 = ‘as good as it could be’ and 6 = ‘as bad as it could be’. The scoring is
done by circling one number only, with no part or half scores allowed. The patient
completes a second score after four to six weeks, the timeframe being decided by the
researchers. This timeframe was chosen as most patients would have had at least two
cycles of chemotherapy, and at least two treatments. When completing the second
phase, the patient is aware of the concern/s they originally identified in the baseline
questionnaire, but not the original scores. Patients were asked to take the MYCaW
home to complete and return via a reply-paid envelope.
The second part of the instrument includes the same questions as the first phase,
relating to the patient’s identified concerns/symptoms and their sense of wellbeing.
Descriptive text data is obtained from open questions asked in the second part. This
includes questions about other things affecting health, what have been the most
important aspects of their time with the service, and also provides an opportunity for
patients to comment on any further items that have not been included.
67
3.26 Data Analysis
Descriptive statistics were used to summarise patient demographics and MYCaW
results. MYCaW two concerns scores were presented as median and SD, the change
in scores as a mean and 95 per cent CI and p-value of ≤ 0.05. Analysis was
completed on the pre- and post- score from the participants’ one or two listed
concerns/symptoms, to see if it was statistically and clinically significant. All
statistical analysis was conducted using SPSS for Windows version 15.169
Responses to the open-ended questions and the two concerns patients listed were
categorised using super categories, as defined by Polley et al.,170 who developed
these categories after analysing 782 patients responses from three cancer services in
the UK that offered complementary therapies. The two concerns that patients
identified were allocated into super categories as defined by Polley:170 psychological
and emotional concerns, physical concerns, hospital cancer treatment concerns and
concerns about wellbeing. The super categories were further delineated (see
Appendix 21). The open-ended question relating to ‘Other things affecting your
health’ had the super categories of: awareness of wellbeing, receiving
complementary therapies, major life events, social support, work situation, health
issues and other. The final question had 11 categories: support and understanding
received, individual and group therapies, access to therapies, confidence in the
therapists, care and kindness, being with other visitors, relaxation and time for self,
the environment/atmosphere, appreciation of the centre and its resources, negative
feedback and non-specific. The responses were all coded by CM and discussed with
the principal supervisor.
68
Chapter 4: Pilot Study and Service Evaluation Results
This chapter presents the results from: (i) the pilot feasibility RCT of EA versus
sham EA versus no acupuncture for acute and delayed CINV; and (ii) an evaluation
of the acupuncture service for cancer patients using a validated patient-reported
outcome measure.
4.1 Results from the Pilot Randomised Controlled Trial of Electro-
Acupuncture for Chemotherapy-Induced Nausea And Vomiting
The trial aimed to examine the feasibility of conducting this trial and examined the
following research questions to determine the following:
1. Timeframe to recruit 60 participants for the trial.
2. Number of participants willing to return for further intervention on Day 3.
3. Number of dropouts from the trial to be expected and the reasons for drop
out.
4. Suitability of the outcome measures used for the trial.
5. If the integrity of blinding was maintained at end of intervention.
Secondary questions examined:
1. Were there group differences between FLIE scores and changes of scores
between groups at Day 1, 4 and 7?
2. Were there differences between nausea scores on Day 1, 2 and 4?
3. What was the number of breakthrough anti-emetics used?
4. What number of participants reported side effects from treatment?
5. Was the presence of any washout period during the second cycle detected?
6. What influence do participant’s expectations of benefit have on
effectiveness?
7. Did the practitioner therapeutic encounter introduce bias?
69
4.2 Recruitment to the Trial 4.2.1 Consort Statement
A total of 153 patients were approached and presented with information about the
study. (Figure 4.1). Sixty participants were recruited to the trial. Of the 93
participants not enrolled, 18 subjects were excluded. Nine subjects were needle
phobic or disliked needles, three subjects had previous chemotherapy, three subjects
had no or little English comprehension; three subjects each had CNS involvement,
previous acupuncture use and previous nausea from a medical condition. Thirty-
seven declined participation; ten were too busy, three reported feeling too anxious
about chemotherapy, and four did not want to receive sham EA. One person declined
for each of the following reasons: varicose veins in needle site, unable to return on
Day 3 if in a treatment group, severe bruising, poor previous acupuncture experience,
no nausea, previous trial experience with no benefit. Fourteen people gave no reason
for declining participation in the study. Thirty-eight subjects were not recruited due
to the acupuncturist being unavailable or unable to obtain consultant consent in time.
Sixty participants were randomised to the three groups: 21 to true EA, 19 to sham
EA and 20 to no acupuncture. The screening of participants was originally planned to
be undertaken by the cancer care coordinator, but due to workload this was
supplemented by the research nurse and acupuncturist scanning the treatment lists in
the hospital chemotherapy administration and booking system. These changes lead to
an increase in the number of participants approached. The referrals by consultants
were less than anticipated, possibly due to time constraints.
Recruitment of 60 participants required 25 months, April 2009 to May 2011. Initial
estimates of six to 12 months to recruit participants to the trial were overly
optimistic. Recruitment was hindered initially by the acupuncturist only being
available for two days per week; this was increased to four days per week at the latter
stage of the trial.
70
Adapted from Consort Statement171
Figure 4.1: Consort Diagram
71
4.3 Demographics 4.3.1 Age
The age range for the participants of the pilot study was 27 to 77 years old, with a
median age of 57.5 and interquartile range (IQR) of 15. Patient age was similar
across the three groups (Table 4.1).
4.3.2 Sex
The majority of participants were female (88%, n=53) reflecting predominance of
breast cancer. The proportion of females in the respective groups was: the no
acupuncture group 80 per cent (n=16), sham EA group 95 per cent (n=18), and in the
true EA group 90 per cent (n=19).
4.3.3 Diagnosis
Overall, breast cancer, 62 per cent (n=37), was most common diagnosis of study
participants, followed by colorectal cancer, 18 per cent (n=11), gynaecological
cancers (including ovary, cervix and uterus) 12 per cent (n=7), and other cancers
eight per cent (n=5). Cancer diagnosis was evenly spread across the three groups.
Given the low numbers of male participants, the high percentage of breast cancer
was not unexpected in this study population.
4.3.4 Emetogenic Rating
The chemotherapy emetogenic rating was evenly distributed between moderate and
high emetogenic chemotherapy. Overall, there were 47 per cent (n=28) participants
on moderate emetogenic and 53 per cent (n=32) on highly emetogenic chemotherapy
regimens. The emetogenic potential of the chemotherapy received was evenly spread
across the three groups. The ratio of high-to-moderate emetogenic being even was
not expected.
72
Table 4.1: Demographics of Trial Participants
No
acupuncture
% n
Sham EA
% n
True EA
% n
Total
% n
Sex
Male
20.0 (4) 5.0 (1) 10.0 (2) 12.0 (7)
Female
80.0 (16) 95.0 (18) 90.0 (19) 88.0 (53)
Age
Median
(IQR)*
62 (15) 54 (19) 58 (10) 57.5 (15)
Range
35-73 27-77 35-70 27-77
Diagnosis
Breast
55.0 (11) 63.0 (12) 66.0 (14) 62.0 (37)
Colorectal
25.0 (5) 11.0 (2) 19.0 (4) 18.0 (11)
Gynae-
cological
10.0 (2) 11.0 (2) 15.0 (3) 12.0 (7)
Other
10.0 (2) 15.0 (3) 0.0 (0) 8.0 (5)
Emetogenic rating
Moderate
45.0 (9) 47.0 (9) 47.0 (10) 47.0 (28)
High
55.0 (11) 53.0 (10) 53.0 (11) 53.0 (32)
* IQR = interquartile range
73
4.3.5 Compliance with Treatment Schedule Day 3
The 40 participants randomised to EA and sham EA agreed to return for follow up
treatment on Day 3 (Figure 4.1). Thirty-three returned for their second treatment.
Seventeen per cent declined treatment, one participant was hospitalised with sepsis
unrelated to the intervention and the remaining six participants refused due to
distance and/or difficulty getting into the hospital.
4.3.6 Loss and Drop Out From the Trial
Eleven participants (18%) dropped out of the trial (Figure 4.1). Eight participants in
the no acupuncture control group were lost, with one from the sham EA group and
two from true EA group excluded from analysis. One participant did not receive the
intervention due to hospitalisation after the first treatment (for neutropenic sepsis).
4.3.7 Completion Rates of Outcome Measures
When calculating the initial sample size of 165 prior to obtaining funding, the
attrition rate was estimated at 20 per cent. High completion rates for the FLIE,
nausea and vomiting scores for cycle one were achieved, with missing data and
dropouts less than 20 per cent (Table 4.2). However, missing data was problematic
for some study outcomes. Some outcome measures had close to 50 per cent missing
or incomplete data, particularly relating to the outcome measurement planned during
the second cycle. Only 21 participants were eligible for data collection in the second
cycle, of which only 11 completed the data for the FLIE, ten for nausea score change
on Day 2, nine for nausea score change on Day 4, nine for vomiting score change on
Day 2 and eight for vomiting score change on Day 4. Twenty-one participants were
given the FLIE tool to complete on Days 1, 4 and 7, along with a nausea and
vomiting diary to complete daily to Day 7. Of the 21 participants, ten participants
either did not return the forms or they were returned uncompleted.
74
Table 4.2: Outcome Measures Completion Rates
Outcome measures
Valid Missing Not
collected
Acupuncture benefit 17 1 42
Pre-Treatment benefit 40 0 20
Personal experience 39 1 20
Cycle 1
Day 1 FLIE score 53 7 0
Day 4 FLIE score 51 9 0
Day 7 FLIE score 51 9 0
Day 4 change FLIE score 49 11 0
Day 7 change FLIE score 49 11 0
Day 1 nausea score 53 7 0
Day 2 nausea score 51 9 0
Day 4 nausea score 51 9 0
Day 2 change nausea
score
51 9 0
Day 4 change nausea
score
51 9 0
Day 1 vomiting score 53 7 0
Day 2 vomiting score 49 11 0
Day 4 vomiting score 49 11 0
Day 2 change vomiting
score
49 11 0
Day 4 change vomiting
score
49 11 0
Cycle 2
Day 1 FLIE score 11 10 39
Day 4 FLIE score 11 10 39
Day 7 FLIE score 11 10 39
Day 4 change FLIE score 10 11 39
Day 7 change FLIE score 10 11 39
75
Day 1 nausea score 11 10 39
Day 2 nausea score 11 10 39
Day 4 nausea score 11 10 39
Day 2 change nausea
score
10 11 39
Day 4 change nausea
score
9 12 39
Day 1 vomiting score 10 11 39
Day 2 vomiting score 10 11 39
Day 4 vomiting score 10 11 39
Day 2 change vomiting
score
9 12 39
Day 4 change vomiting
score
8 13 39
4.3.8 Integrity of Blinding in the Study
We set a threshold to achieve 100 per cent of study participants remaining blinded to
group allocation at the end of their participation in the trial. Overall, 71 per cent of
participants were blind to group allocation (Table 4.3). Fifty-eight per cent of
participants (14 participants) were unsure which group they were allocated to, and of
the remaining 42 per cent (10 participants) that answered this question, three were
incorrect in their response and the other seven guessed correctly their allocation.
Participants were not unblinded during the trial, allocation was concealed throughout
the trial, but participants could request this information after the trial was complete
no participants did so.
Table 4.3: Blinding Integrity of Allocation
Number Percentage p-value
Unsure 14 58.3
Incorrect 3 12.5 0.485
Correct 7 29.2
76
4.4 Secondary Study Endpoints 4.4.1 Functional Living Index Emesis Changes over Time and between Groups
The FLIE scores were presented as median and IQR, as the data were not normally
distributed (Table 4.4). In cycle one of chemotherapy, at baseline there were no
significant differences between groups p=0.097. The maximum score for the FLIE
was 126; this indicates that the level of pre-chemotherapy nausea and vomiting was
very low.
The FLIE scores on Day 4 declined with no significant difference between groups
p=0.688. The FLIE scores on Day 7 increased marginally with no significant
differences identified between groups p=0.948. These findings suggest for this
sample of participants in cycle one of chemotherapy, that CINV had no significant
impact on their QoL. A score below 108 is seen as having a clinically significant
impact on QoL, due to nausea and vomiting.
In cycle two of chemotherapy, the change in FLIE scores over time between Days 1
and 4, and between Day 1 to 7 in each group was not significant: (p=0.852) and
(p=0.589). The negative change indicates the participant’s score on the day in
question was worse than baseline; this finding was not unexpected, due to
chemotherapy side effects having a negative impact on QoL, due to CINV. The
negative impact identified in this outcome must be viewed with caution, and no real
statement can be made due to the small number of participants.
77
Table 4.4: FLIE Outcomes by Study Group
Variable No
acupuncture
median
IQR
Sham EA
median
IQR
True EA
median
IQR
p-value
Kurskal
Wallis
test
Cycle 1 N= 12 N= 18 N= 19
FLIE Day 1 124.2 (3.0) 125.8 (3.9) 126 (1.6) 0.097
FLIE Day 4 117.9 (21.0) 121.6
(29.4)
122.5 (15.8) 0.688
FLIE Day 7 121.8 (22.2) 122.9
(29.1)
121.2 (22.5) 0.948
FLIE Change Day 1
& 7
-1.0 (19.4) -1.1 (21.6) -3.4 (20.8) 0.589
FLIE Change Day 1
& 4
-2.0 (20.4) -0.54 (21.1) -2.8 (13.6) 0.852
Cycle 2 N= 5 N= 5
FLIE Day 1 NA 123.9
(18.2)
126.0 (1.1) 0.156
FLIE Day 4 NA 123.3
(45.1)
123.6 (16.0) 0.459
FLIE Day 7 NA 106.0
(28.1)
124.1 (21.8) 0.249
FLIE Change Day 1
& 7
NA 8.6 (48.3) -1.9 (17.0) 0.221
FLIE Change Day 1
& 4
NA -1.3 (45.0) -2.4 (15.1) 0.530
78
4.4.2 Symptom: Vomiting Changes over Time and Between Groups
No statistical difference in vomiting scores between groups was found between Day
1 and 2 (p=0.723), and Day 1 and 4, (p=0.774) (see Table 4.5). These scores suggest
that vomiting was not a problem experienced by this sample of participants in Cycle
1 over the two time periods measured, and there was good control from standard
anti-emetic therapy. In Cycle 2, similarly no difference was found between groups
between Day 1 and 2 (p=0.723), and between Day 1 and 4 (p=0.774). This data again
indicates that during the second cycle, vomiting was not a significant problem
experienced by these study participants when measured at these time periods.
Table 4.5: Vomiting by Study Group over Cycle 1 and 2
Vomiting score No
acupuncture
median IQR
Sham EA
median IQR
True EA
median IQR
p-value
Kurskal
Wallis
test
Cycle 1 N=10 N=14 N=16
Difference Day 1 &
4
.00 (0.25) .00 (.00) constant 0.774
Difference Day 1 &
2
.00 (.00) .00 (.00) constant 0.723
Cycle 2 N=6 N=3
Difference Day 1 &
4
NA constant .00 0.197
Difference Day 1 &
2
NA .00 (0.5) .00 0.157
79
4.4.3 Symptoms of Nausea Changes over Time and Between Groups
The nausea scores indicate that overall, the sample experienced no or minimal
nausea (Table 4.6). There was little change in nausea over time and between groups,
no difference in nausea scores was found between Days 1 and 2 and between groups
(p=0.813). There was also no difference in nausea scores between Day 1 and 4
between groups (p=0.859). In Cycle 2, no change in nausea scores was found
between groups over Day 1 and 2 (p=0.337) and between Day 1 and 4 (p=0.421).
Table 4.6: Nausea by Study Group over Cycle 1 and 2
Nausea score
No
acupuncture
median
IQR
Sham EA
median
IQR
True EA
median
IQR
p-value
Kurskal
Wallis
test
Cycle 1 N=11 N=15 N=15
Difference Day 1
& 4
0.0 (19.0) 0.5 (9.0) 0.0 (3.8) 0.859
Difference Day 1
& 2
0.0 (24.0) 0.0 (23.0) 0.0 (2.0) 0.813
Cycle 2 N= 6 N= 4
Difference Day 1
& 4
NA .00 (26.0) .0 0.421
Difference Day 1
& 2
NA .00 (0.5) .0 0.337
4.4.4 Use of Rescue Anti-Emetics
Collection of rescue antiemetic use was incomplete. Collection of data was not
undertaken for the first 30 study patients recruited to the trial, due to a missed
document in the protocol. This was not identified until an internal review; for the
remaining study participants, this data was missing for 22. This was mainly due to
time and budget constraints. The low rate of return was due to the data collection
opportunity being missed by the research nurse and researcher. Data was only
80
available from eight participants; four reported using rescue medication and four did
not report using rescue medication. All four participants used metoclopramide and
not prochlorperazine as rescue anti-emetics. One participant used one to two tablets a
day, one used two tablets, one used three tablets and one used four tablets a day. The
data available was too small to undertake any analysis.
4.4.5 Toxicity of Intervention
Overall, 11 per cent of patients experienced an adverse event; the majority of these
(19) were mild, four were moderate, with one report of severe needling pain (Table
4.7). No participant discontinued because of needling pain. There were six reports of
localised bruising, three of localised skin irritation and 12 reports of exacerbation of
CINV, with the majority being mild.
Table 4.7: Adverse Events over the Trial Period
Symptom
None
n %
Mild
n %
Moderate
n %
Severe
n %
Disabling
n %
Missing
n %
Not
collected
n %
Needling pain
Day 1 18 30.0 12
20.0
3 5.0 1 1.7 0 11 18.3 15
25.0
Day 3 12 20.0 7 11.6 1 1.7 0 0 24 40.0 16
26.7
Day 7 11 18.3 0 0 0 0 31 51.7 18
30.0
Bruising
Day 1 32 53.3 2 3.4 0 0 0 11 18.3 15
25.0
Day 3 17 28.3 3 5.0 0 0 0 24 40.0 16
26.7
Day 7 10 16.6 1 1.7 0 0 0 31 51.7 18
30.0
81
Fainting
Day 1 33 55.0 0 n/a n/a n/a 12 20.0 15
25.0
Day 3 20 33.3 0 n/a n/a n/a 24 40.0 16
26.7
Day 7 11 18.3 0 n/a n/a n/a 31 51.7 18
30.0
Local skin irritation
Day 1 31 51.7 3 5.0 0 0 0 11 18.3 15
25.0
Day 3 19 31.6 0 0 0 0 25 41.7 16
26.7
Day 7 10 16.7 0 0 0 0 32 53.3 18
30.0
Exacerbation of nausea
Day 1 34 56.7 0 0 0 0 11 18.3 15
25.0
Day 3 16 26.6 3 5.0 1 1.7 0 0 24 40.0 16
26.7
Day 7 6 10.0 5 8.3 0 0 0 31 51.7 18
30.0
Exacerbation of vomiting
Day 1 34 56.7 0 0 0 0 11 18.3 15
25.0
Day 3 19 31.6 0 1 1.7 0 0 24 40.0 16
26.7
Day 7 9 15.0 2 3.3 0 0 0 31 51.7 18
30.0
82
4.4.6 Identification of a Washout Period During a Second Cycle of
Chemotherapy
The washout period is sufficient, if at the end of one acupuncture treatment episode
relating to Cycle 1 of chemotherapy and the commencement of a second cycle of
chemotherapy, there were no statistical difference in baseline scores between sham
EA and true EA groups.
In this study, the washout period was between two and three weeks in duration,
depending on the participant’s particular chemotherapy regime. These results are
shown in Table 4.4 for FLIE scores, Table 4.5 for vomiting scores and Table 4.6 for
nausea scores. There was no evidence of an effect being carried over from the true
EA group compared to the sham EA group.
4.4.7 The Influence of Participant Expectations of Benefit on Treatment
Outcomes
Participants’ views about the belief of benefit from acupuncture using a numerical
rating scale were collected from the first 18 participants (Table 4.8). Views about the
belief of acupuncture were compared to the change in the FLIE score on Day 4 and
Day 1 using Spearman’s coefficient = 0.237, p=0.701. Acupuncture belief of
perceived benefit was compared to the change of FLIE score at Day 7 and Day 1
using Spearman’s coefficient = 0.789, p=0.112. The data showed no statistical
correlation between belief and benefit.
Participants rated their expectation of pre-treatment effect in response to two
questions. Participants were asked how effective they consider acupuncture was in
general and secondly, what they personally expected from the acupuncture treatment.
The pre-treatment effect for acupuncture in general was compared to the change of
FLIE score at Day 4 and Day 1, using Spearman’s coefficient (= -0.056, p = 0.751).
This data showed no statistical correlation between expectation and benefit.
Participants’ views of the pre-treatment effect for acupuncture in general were
compared to the change of FLIE score at Day 7 and Day 1 using Spearman’s
83
coefficient = -0.044, p = 0.806, with data showing no statistical correlation between
expectation and benefit.
Participants’ views of expectation were compared to the change of FLIE score at
Day 4 and Day 1 using Spearman’s coefficient = -0.001, p = 0.996, with data
showing no statistical correlation between expectation and benefit. Participants’
views of expectation were compared to the change of FLIE score at Day 7 and Day 1
using Spearman’s coefficient = 0.055, p = 0.762, with data showing no statistical
correlation between expectation and benefit. Participants’ expectations of benefit did
not positively influence the outcomes measured; however, this does consider that the
sample size did not allow any definitive conclusion to be made.
84
Table 4.8: Expectations of Study Participants by Group
Expectations
No acupuncture Sham EA True EA p-value Kurskal
Wallis Baseline
acupuncture benefit+
n= 17
62.80
14.73
67.17
23.99
60.33
27.67
0.772
Acupuncture benefit
compared to FLIE
change Day 4 **
n= 17
1.00
-0.429
p= 0.397
0.237
p= 0.701
0.237
p=
0.701
Acupuncture benefit
compared to FLIE
change Day 7 **
n= 17
1.00
0.872
p= 0.872
0.789
p= 0.112
0.789
p=
0.112
Pre-treatment effect*
n = 40
2.00 (2) 5.00 (3) 2.00 (3) 0.301
Personal
expectation* n= 39
2.00 (2) 2.00 (1) 2.00 (1) 0.420
Pre-treatment effect
compared to FLIE
change Day 4**
-0.300
p = 0.470
-0.252
p = 0.430
0.352
p = 0.217
-0.056
p =
0.751
Pre-treatment effect
compared to FLIE
change Day 7**
-0.109
p = 0.797
-0.435
p = 0.157
0.651
p = 0.012
-0.044
p =
0.806
Personal expectation
compared to FLIE
change Day 4**
-0.347
p = 0.445
-0.200
p = 0.533
0.385
p = 0.174
-0.001
p =
0.996
Personal expectation
compared to FLIE
change Day 7**
0.077
p = 0.869
-0.267
p = 0.402
0.806
p = 0.000
0.055
p =
0.762 + Mean and SD *Results shown as median and (IQRs) + collected on first 18 patients only ** Spearman’s coefficient
85
4.4.8 Effect of the Practitioner Therapeutic Encounter
A total of ten participants, randomly selected from the sham EA and true EA groups
and their practitioner therapeutic encounter, were scored by the research nurse (Table
4.9). We found no difference in the rating of the practitioner therapeutic encounter
between the two groups. These results suggest that the practitioner, when treating
each group, introduced no bias.
Table 4.9: Therapeutic Encounter by Treatment Group
Group Checklist score
mean and SD
Sham EA
N=5
4.5 (0.15)
True EA
N=5
4.4 (0.19)
86
4.5 Results from the Acupuncture Service Evaluation
The evaluation of the acupuncture service used a pre- and post-test observational
study and examined the following research questions:
• Do study participants using the service find it beneficial, helpful and useful?
• What symptoms do participants present for treatment?
• Were there any unacceptable risks of harm?
Were there clinically significant improvements in participants’ concerns/symptoms?
The acupuncture service was evaluated over a 13-month period (1 October 2011 to
31 October 2012). Over this time, 120 new patients were approached to participate in
the evaluation. Eight patients declined participation and their reasons included: four
patients not having sufficient English comprehension to participate in the study; two
patients were unable to make the time commitment; one patient had only two
treatments; no reason was given by one patient.
The 112 participants in the evaluation received a total of 1, 186 acupuncture
treatments during the period of evaluation. Of the 112 participants, 81 completed all
requirements for the evaluation. Thirty-one participants did not complete the survey
and evaluation. The reasons included: 15 patients completed their chemotherapy and
were lost to follow up; two moved to another treatment facility; three only completed
two treatments and did not think they could respond; 13 did not return the survey and
no reason was given.
4.6 Demographics of Participants 4.6.1 Sex
The majority of participants were women, 88 per cent (n=99), and 12 per cent (n=13)
were male. This sex ratio of participants was similar to the sex ratio reported in the
pilot trial (Table 4.10). However, this was not consistent with the sex ratio seen in
the outpatients unit, where the ratio was closer to one male to three female patients,
not the 1:9 ratio of participants in the service evaluation.
87
4.6.2 Age
The age range of patients using this service was between 17 to 87 years. The mean
age was 54 (SD 12.6 years). The mean age was similar to that found in the RCT.
4.6.3 Diagnosis
The most common cancer diagnosis of patients was breast (40%), followed by
gynaecological (33%), (including cancer of the uterus, cervix, ovary and vagina),
colorectal (11%) and others (16%), which included brain, testis, bladder, lung and
haematological. The combined percentage of female cancers (breast and
gynaecological) was 73 per cent.
Table 4.10: Demographics of Study Participants
Characteristic n %
Sex
Male 13 (11.0)
Female 99 (89.0)
Age
Mean (SD) 54.2 (12.7)
Range 17 - 87
Diagnosis
Breast 45 (40.0)
Gynaecological 37 (33.0)
Colorectal 12 (11.0)
Other 18 (16.0)
4.7 Participant’s Feedback on Service and Complementary and
Alternative Medicine Use
Of the 83 participants who responded to the questions asking for feedback on the
service, 99 per cent thought the acupuncture service was a worthwhile addition to
their usual care, and would like the service to continue (Table 4.11). Interestingly, of
88
the 82 responders, only 16 had used CAMs in the last 12 months, and 19 had used
acupuncture in the previous 12 months. It was unclear if some participants who
answered had used acupuncture in the previous 12 months and included treatments
from the acupuncture service as part of their answer.
Table 4.11: Participants’ Feedback about the Service
Questions Yes
n %
No
n %
Missing
n %
Total
n %
Do you think the acupuncture
service is a worthwhile
addition?
82 73.2 1 0.9 29 25.9 112 100
Would you like the service to
continue?
82 73.2 1 0.9 29 25.9 112 100
Have you used cam in the last
12 months?
16 14.3 66
58.9
30 26.8 112 100
Have you had acupuncture for
symptoms in the last 12
months?
19 16.9 63
56.3
30 26.8 112 100
4.8 Participants’ Perception of Benefit from the Service
The majority of participants expected an improvement with their symptoms, with
54.5% expecting a slight or some improvement and no participant expecting no
change or worsening (Table 4.12). The results from the 80 participants who
completed this section suggest the majority of participants had at least slight
improvement of their symptoms, with 50.9% of participants experiencing some or
marked improvement. Many participants reported they received a marked
improvement compared to the number that expected an improvement. Five patients
had no improvement in any symptom, which was greater than expected.
89
Table 4.12: Participant’s Expectations of Benefit from Acupuncture
What benefit did
you expect?
What benefit did you
receive?
n % n %
Marked improvement 14 12.5 27 24.1
Some improvement 43 38.4 30 26.8
Slight improvement 18 16.1 14 12.5
No improvement 0 0 5 4.4
Slight worsening 0 0 0 0
Some worsening 0 0 0 0
Marked worsening 0 0 0 0
Don’t know 5 4.4 2 1.7
Not collected/missing 32 28.6 34 30.5
4.9 Adverse Events
Overall, the majority of patients experienced no AEs (Table 4.13). However, 40 per
cent reported pain from needling, and 20 per cent reported bruising. Participants
reported two severe adverse events from acupuncture, with one was reported as
disabling needling pain being the most severe on the scale used, (‘none’, ‘mild’,
‘moderate’, ‘severe’ and ‘disabling’; see Appendix 11). No participant required
hospitalisation or further care and the majority of AE were minor and transient in
nature. The other severe AE, was one reported case of pneumothorax, identified by
the participant, who also stated that the symptoms were mild. Due to the seriousness
of the event, it was followed up for clarification. The patient had a pleural effusion as
a result of the disease process, which was being treated the next day by a medical
procedure and the patient mistakenly thought this was the same as a pneumothorax.
90
Table 4.13: AEs Of Patients Using the Acupuncture Service
Symptom None Mild Moderate Severe Disabling
Needling pain 45 28 2 1 0
Pain 63 10 1 1 1
Bruising 61 14 1
Fainting 76 0
Local skin
irritation
70 5 1 0
Dizziness 70 4 2 0 0
Pneumothorax 75 1 0 0 0
4.10 Measure Yourself Concern and Wellness Concerns and
Problems
The most common symptom for which acupuncture was given was pain; this was
followed by fatigue and nausea (Table 4.14). Although the majority of symptoms
presented here were physical, acupuncture was also used to treat emotional
symptoms, including anxiety and stress. The frequency of symptoms treated was a
reflection of the multiple symptom burden experienced by patients. Not all
participants identified a second concern or problem to be treated.
91
Table 4.14: Symptoms/Concerns Identified by Participants in MYCaW
Symptoms
treated
Concern 1
n %
Concern 2
n %
Total
n %
Pain 27 13.0 22 10.6 49 23.6
Fatigue 15 7.2 30 14.4 45 21.6
Nausea 24 11.5 15 7.2 39 18.7
Peripheral
neuropathy
22 10.6 7 3.4 29 14.0
Anxiety/stress/
mood problems
8 3.9 5 2.4 13 6.3
Insomnia 4 1.9 6 2.9 10 4.8
Hot flushes 3 1.4 4 1.9 7 3.3
Other 7 3.4 9 4.3 16 7.7
Total 110 52.9 98 47.1 208 100
4.11 Measure Yourself Concern and Wellness Pre- and Post-Test
Results
Concerns 1 and 2 were the symptoms patients initially identified as their primary
symptom for treatment using acupuncture. The concerns or symptoms were collated
and analysed together (Table 4.15). A change of 0.7 – 1 is seen as being a clinically
significant change in symptoms, when using the seven-point Likert scale.172, 173 The
change in both symptoms, Concern 1 and 2, was shown to be moderate-to-highly
clinically significant, showing a marked improvement in the participant’s concern or
symptoms over time. There was an improvement in the participant’s sense of
wellbeing, but this was not statistically significant.
92
Table 4.15: Participant Symptoms Concerns Measured at Baseline and at the
End of Acupuncture
Pre-score
mean (SD)
Post score
mean (SD)
Change over
time
mean (95%CI)
p-value
Concern 1 4.60 (1.22)
n=106
2.73 (1.54)
n=85
1.86
(1.46-2.26)
n=85
<.0001
Concern 2
4.12 (1.43)
n=92
2.66 (1.49)
n=71
1.46
(1.03-1.89)
n=71
<.0001
Wellbeing
2.73 (1.27)
n=106
2.39 (1.34)
n=85
0.34
(-0.004-0.68)
n=85
0.053
4.12 Measure Yourself Concern and Wellness Concerns Qualitative
Analysis
Using the super categories designed by Polley et al.,170 data were re-categorised into
three categories: psychological and emotional, physical and hospital cancer treatment
concerns (Table 4.16). Physical concerns were the most frequently reported patient-
reported concern (one) (45%), followed by cancer treatment concerns (44%). For
patient-reported concern (two) the most frequent concern were physical (59%),
hospital cancer treatments (29%) and psychological and emotional concerns (11%).
The most common psychological and emotional concern was sleep disturbances,
followed by fear and anxiety. The super category physical concerns included three
symptoms of pain, aches and low energy levels, which accounted for almost 90 per
cent of the super category physical concerns. The super category hospital cancer
treatment concerns included side effects from chemotherapy. There were no
responses coded to the fourth super category, concerns and wellbeing.
93
Table 4.16: Qualitative Analysis of Concerns into Super Categories
Super category Concern 1
N = 108
n %
Concern 2
N = 98
n %
Total concerns
n %
S1 Psychological and
emotional concerns
12 11.2 11 11.3 23 11.1
S2 Physical concerns
49 45.4 58 59.2 107 51.7
S3 Hospital cancer
treatment concerns
48 44.4 29 29.5 77 37.2
Breakdown of super category
S1 Psychological and emotional concerns
Emotional problems 1 1 2
Fear and anxiety 2 4 6
Sleep problems 5 6 11
Stress and tension 4 0 4
S2 Physical concerns
Arm problems 1 0 1
Hot flushes and night
sweats
3 4 7
Pains/aches 27 21 48
Physical problems 4 2 6
Poor energy levels 14 31 44
S3 Hospital cancer treatment concerns
Side effects of
chemotherapy
48 29 77
See Appendix 21 for all categories.
94
4.13 Measure Yourself Concern and Wellness: Other Concerns
Affecting Your Health
Thirty-six participants identified other concerns that affected their life (Table 4.17).
Over half of the responses were in the super category of health issues (33.3%), or
awareness of wellbeing (22.2%). The next most common was major life events
(13.9%). Each of the super categories were identified as either positive or negative
responses.170 The number of positive and negative responses were collated, giving a
total of 33 responses. This identified ten positive response and 23 negative responses,
excluding responses in the ‘other’ category.
Table 4.17: Other Concerns Affecting Health Categorised into Super Categories
Super category n %
1. Awareness of wellbeing 8 22.2
2. Receiving complementary therapies 2 5.5
3. Major life events 5 13.9
4. Social support 4 11.1
5. Work situation 2 5.5
6. Health issues 12 33.3
7. Other 3 8.3
Total 36
4.14 Measure Yourself Concern and Wellness: Important Aspects of
the Service as Identified by Participants
Participants were asked to identify important aspects of the service using the 11
categories as devised by Polley et al.170 (See Table 4.18) These categories were
further categorised as positive or negative; categories one to nine were identified as
positive, category ten as negative and category 11 was not categorised as a positive
or negative response.
95
Table 4.18: Qualitative Analysis of Important Aspects of the Service
Category n %
1. Support and understanding received 29 37.1
2. Individual and group therapies 0 0
3. Access to therapies 10 12.8
4. Confidence in the therapist 21 26.9
5. Care and kindness 9 11.6
6. Being with other visitors 0 0
7. Relaxation and time for self 1 1.3
8. The environment/atmosphere 0 0
9. Appreciation of the centre and its
resources
1 1.3
10. Negative feedback 5 6.4
11. Non-specific 2 2.6
Total 78
Sixty-one participants responded with 78 responses coded. Overall, the response to
the service was positive. The most common response was support and understanding
received (37.1%), and confidence in the therapist (26.9%). There were only five
responses that were negative, and they were all relating to the failure of acupuncture
to treat their concern or problem.
4.15 How We Might Improve the Service
Participants were asked how the service could be improved. Most frequently,
participants indicated that the service was good and that no improvement was needed
(n=16). Other responses indicating improvements to the service were few; these
included the need to advertise the service better, particularly when first meeting with
staff (n=7), sharing acupuncture expertise with a trainee acupuncturist or
acupuncturists in regional areas. The remaining received only one comment: these
were ‘more time to make sure the treatment is available’, ‘being offered for bone
pain caused by anti-hormonal treatments’ and ‘being able to book appointments after
chemotherapy was completed for a specific time’.
96
4.16 Other Feedback Provided by Respondent Comments
Eighteen participants provided additional comments. Five responses were provided
relating to the practitioner and his expertise, his personality being suited for the job
and thanking him. Three responses identified the symptom that acupuncture helped,
two responses wanted more information about the symptoms acupuncture can treat
being made available to patients, and the two responses given in support of
continuing the service.
4.17 Discussion of Results
In this section the main findings from this chapter will be discussed. In Chapter Five,
the findings from the trial and service evaluation will be discussed in relation to the
main aim of the thesis, methodological strengths and weaknesses, implications for
research, practice and education policy.
The aims of this study were to examine the feasibility of conducting an efficacy trial
of EA for CINV, and the role of an acupuncture service in the day oncology unit on
patients’ wellbeing, evaluating participants’ perceptions of the service.
We found it was feasible to conduct a RCT in the day oncology unit at the Mater
Hospital, although important changes to recruitment strategies and methodology
were highlighted for future research. In this study, we found the incidence of CINV
between Days 1 to 7, after one cycle of chemotherapy was not as high as anticipated.
This is contrary to literature suggesting the incidence of CINV reported at 25 per
cent, even following the latest anti-emetic guidelines.29, 38, 174 The very low incidence
of CINV identified in this trial influenced the preliminary assessment of EA to
determine if symptoms were responsive to the intervention. The second cycle
incidence of CINV was also lower than expected, though the IQR was larger in cycle
two, indicating a greater variance in experiences of CINV for participants.
The FLIE scores at baseline were high in all groups, indicating CINV had no impact
on patients’ QoL. This finding was not unexpected, with measurement occurring
97
prior to the onset of chemotherapy treatment. High pre-chemotherapy scores were
similar to other studies that used FLIE to measure CINV.23, 163, 175 However, this
score may be different for subsequent cycles. The FLIE scores on Day 4 and 7 were
also high in all groups, which further suggested that CINV did not affect the
participants’ QoL. There was a trend towards a lower score on Day 4 for participants
in the no acupuncture group. This was not statistical significant, possibly due to the
study being under-powered. These higher scores on the FLIE resulted in minimal
changes when comparing Day 7 and 4 to baseline. The data indicated scores were
worse on Days 7 and 4, suggesting CINV affected QoL, although this did not reach
statistical significance.
However, overall the high scores suggest that CINV was not a clinically relevant
problem faced by the study participants after one course of chemotherapy. There
were also minimal episodes of vomiting reported in any group at any time period.
This may have been influenced by the inclusion criteria of only accepting
chemotherapy naïve patients. Previous research has shown that CINV can worsen
with subsequent cycles.31 Previous acupuncture trials97, 98, 176 have reported higher
levels of CINV than encountered in this trial, though one trial also reported low
levels of nausea.97
Although the overall sample experienced minimal CINV, there were some
participants that experienced clinically significant CINV (16%). Clinically
significant nausea is measured as greater than 30mm on a NRS.177 It is possible that
these findings may be explained by patients being assessed during one cycle of
chemotherapy. The majority of common side effects from chemotherapy are
accumulative in nature, and therefore subsequent cycles may produce higher levels.28
One other Australian study176 reported higher levels of CINV, with 21 per cent
experiencing vomiting and 86 per cent experiencing nausea for participants in the
true EA arm, and 31 per cent experiencing vomiting and 75 per cent experiencing
nausea in the sham EA arm. The difference in this study was that the researchers
examined three cycles of chemotherapy, and the sample was a homogenous group of
females with breast cancer having highly emetogenic chemotherapy, compared to
our sample that included patients having moderate and highly emetogenic
chemotherapy.
98
Overall, we determined it was feasible to conduct a three-arm RCT to examine the
effect of EA on CINV. Recruitment was hindered by the researcher being
unavailable at times to perform the acupuncture. It would however be feasible in the
day oncology unit with increased availability and funding to provide a fulltime
acupuncturist. The problem of recruitment due to a lack of dedicated acupuncturists
in CINV trials has been identified in previous trials as affecting recruitment.94, 97, 98
This issue did not have as much influence on our trial when compared to others. For
example, one trial94 recruited 23 participants after screening 86 patients in almost
five years. This was exacerbated by patients being recruited in other trials and hence
being excluded. In this trial, we recruited 60 participants from 153 patients screened
in just over two years. Overall, the study identified a need to make changes to
recruitment strategies, research staff and identifying patients that are experiencing
CINV.
The total number of patients approached during the period was 153, resulting in 60
participants, a recruitment percentage of 40 per cent. This was an acceptable yield
for recruitment. Other data suggests 33 per cent of Australians with cancer want to
be in cancer clinical trials, even though overall recruitment rates are only one to two
per cent of all cancer incidences.178-180 This high rate of recruitment may be due to
the fact we were treating CINV, a feared side effect of chemotherapy, resulting in
more patients interested in looking at novel approaches to symptom management.
The other possible reason for interest in this trial was the investigation of
acupuncture as a complementary medicine, which may be perceived as beneficial,
instead of a drug with side effects. This treatment modality is becoming more
accepted by the general population.6, 181, 182 There were 37 potential participants
missed due to the acupuncturist being unavailable. Increasing resources to improve
acupuncturist availability would help increase the recruitment percentage to a higher
level of 50 per cent.
Compliance with the treatment schedule was high, with over 80 per cent of
participants returning for treatment on Day 3. Study participant compliance was
greater than anticipated due to the heavy symptom burden cancer treatment may have
on patients, and the need to return to the hospital for unrelated treatment. This may
99
be influenced by the participants having had only one cycle and not being
overburdened by repetitive cycles of chemotherapy and visits to the hospital, hence
adversely affecting their QoL. In a study23 examining CINV effects on QoL, using
the FLIE tool, data showed an increasing effect on baseline scores at Day 1 between
consecutive cycles, indicating that subsequent cycles of chemotherapy negatively
affected patients’ QoL. This is supported by other studies,23, 175, 183 which show that
QoL is affected by an increasing number of cycles.
The median age of study participants was 57.5 years, with an IQR 15. This was as
expected with cancer generally a disease of old age.5 This median age is similar to
that represented in other acupuncture studies for CINV.97, 100, 176 There was little
statistical difference between the groups. The high participation of women in the trial
did not reflect the gender-patient ratio of the unit. The trial had a larger percentage of
females (88%) to males (12%) than s normally seen: females (70%) to males (30%).
This may be due to more females using CAMs than males, and being more likely to
enrol in a study using a CAM, but the Mater has a high percentage of breast and
gynaecological patients in treatment at any one time.
The emetogenic rating was evenly distributed between moderate and high
emetogenic chemotherapy, which was unexpected. Based on clinical experience, it
was expected there would be more moderate than high ratings, closer to a 65 to 35
split. This may have been influenced by the over representation of women and breast
cancer diagnoses in the trial. The majority of first line chemotherapy protocols for
breast cancer, such as AC protocol (doxorubicin and cyclophosphamide) and FEC
(Fluorouracil (5FU), epirubicin and cyclophosphamide) are highly emetogenic: this
resulted in the increase of highly emetogenic chemotherapy.
Blinding of the study participants did not meet the study threshold. This suggests that
there may have been some awareness of the group allocation of participants. This
may have influenced behavioural change and participation in the trial, or their
reporting of clinical outcomes. At no stage during the trial were participants
informed of their allocation group, participants in the no acupuncture arm obviously
were aware of the allocation. Blinding of acupuncture participants can be a challenge
due to increasing exposure of acupuncture use and awareness among the general
100
population. However, it was unclear how naïve this clinical population was towards
acupuncture. A previous study55 in Australia identified 9.2% of the sample of the
general population had seen an acupuncturist in the last 12 months. To ensure
blinding of participants to sham and true acupuncture, studies have addressed this in
different ways. Some studies have achieved blinding by not informing participants
that they will be receiving sham EA, but they will be experimenting with two
different styles of acupuncture. This method raises an ethical issue around informed
consent. In this study, participants were advised prior to enrolment that they might
receive sham EA. The information provided to participants about the study design
may have affected recruitment numbers, as four patients did not participate for this
reason. The 29 per cent of participants who were not blind may have spent more time
considering whether they were receiving sham or true EA.
The incidence of adverse events was low, and the majority of reported events were
mild and transitory. In this study 11 per cent of patients experienced an adverse
event, with the most common being mild needling pain. Nausea and vomiting
accounted for 12 (38%) adverse event reports. A possible explanation was that when
participants completed the adverse event form they may have scored their nausea and
vomiting as they experienced it at the time, and not as an actual exacerbation of the
symptom following acupuncture treatment. However, it would be difficult to decide
if any exacerbation was from the acupuncture or chemotherapy.
The percentage of adverse events is higher than reported by other studies reporting
on acupuncture for CINV: Melchart et al.97 with five events; Gottschling et al.94 with
three participants not continuing due to pain; and Beith et al.176 reporting no adverse
events. This pilot study collected data on adverse events at three different
timeframes; this may have resulted in greater incidence and/or reporting. Other
acupuncture studies did not clearly state if the information was collected on more
than one occasion, the inference is that it was only collected once. Overall, the
methods and tools used in these studies were under-reported.94, 97, 176 In general
practice, Witt et al.155 studied 229, 230 patients who received, on average, ten
treatments. They identified that 8.6% of all patients experienced at least one adverse
event. This study identified the majority of adverse events (AEs) were minor and
101
transient. Overall, our study confirmed that acupuncture was a relatively safe
intervention when administered to a population receiving chemotherapy.
The study did not identify any statistical difference between true EA and sham EA
groups in the second cycle, indicating no lasting benefit from true EA, and that the
time of two to three weeks was a sufficient washout period. The washout period from
acupuncture has not been clearly identified in the literature. Acupuncture studies94,
184, 185 with crossover design have used periods varying from one to three weeks, the
rationale for choosing this timeframe has not been well justified. Only one of the
studies94 addressed CINV and the washout period was at least two weeks. Two other
studies97, 98 with crossover design for CINV did not clearly identify the timeframe.
The time period for an examination of a wash out period in this study considered the
time between chemotherapy cycles. This was dependent upon the participant’s
chemotherapy protocol. For example, participants with colorectal and gynaecological
cancer had two weeks and breast cancer participants had three weeks between cycles.
The finding that there was no significant difference between the true EA and sham
EA groups, suggests that there was no follow over effect from the acupuncture, and
that the washout period of two to three weeks was sufficient time.
We found no evidence that a participant’s view of a perceived benefit affected the
actual benefit or treatment effectiveness received. Patient expectations of benefit
have been shown to have an influence on actual effectiveness of treatments, in
particular in pain studies, where the high expectation can lead to greater benefit
through activation of pain areas in the brain and is thought to be a part of the placebo
effect,186-188 though nothing in the literature specifically for CINV. Our findings may
be due to the low levels of CINV experienced by study participants, and the small
sample size not powered to detect a treatment effect.
The study found no difference in the practitioner therapeutic encounter between true
EA and sham EA groups as assessed. This encounter was assessed to ensure that the
practitioner introduced no performance bias by treating the two groups differently.
This is important aspect of acupuncture research design as it is difficult to perform
double-blinded acupuncture trials due to being unable to blind effectively the
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acupuncturist and researchers need to be aware of not introducing performance bias
and ensure that both groups are treated the same.123, 136, 144, 146, 189, 190
4.18 Discussion of Results Acupuncture Service Evaluation
Complementary medicine for supportive care for cancer patients while undergoing
conventional treatment is an emerging field. With any new and emerging field there
is the need to establish a basis in the research of the benefits and risks particularly
from a patient-centred perspective.1-4 Overall the patient’s perspective of the
integrated service was positive and that patients reported benefits from receiving
acupuncture, although there was some evidence of minimal AEs.
Evaluation of the acupuncture service identified a positive response from patients in
relation to the benefit, the helpfulness and usefulness of the service. The majority of
patients (73%) found the service worthwhile and would like the service to continue.
Our findings concur with other evaluations of acupuncture and complementary
medicine services.191-194 These evaluations have reported positive responses between
75 to 95% assessing the helpfulness, improvement of QoL, or satisfaction with the
service and effectiveness in treating the participants concern or symptom. An
evaluation of an anthroposophic health care service in Sweden191 found the
satisfaction score was 95%, this contrasted to data they presented from a earlier study
using the same tool for patient satisfaction with a satisfaction score of 73% relating
to conventional treatment. Demmer et al.192 assessed the response of participants in a
hospice service that offered complementary therapies and found that 43% of patients
thought the service was helpful when compared to other services in the hospice and
43% thought it was very helpful. QoL improved in 58 per cent of patients, and 17 per
cent reported significantly greater changes to their QoL. In a recent study194 of an
acupuncture service in a radiation oncology unit in Cornwall, UK, 80 per cent had
some improvement of their symptoms, 95 per cent of participants were satisfied or
very satisfied with the treatment and 95 per cent thought it should continue.
Although the majority of the Mater participants reported a benefit, the high level of
missing data may have influenced our findings. Though the overall high percentage
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of positive responses from participants in these services give weight to the benefit
they provide. As identified by Salmon,194 these studies with broad inclusion criteria
reflect clinical practice and acupuncture is unlikely to be given without conventional
treatment such as radiation, chemotherapy and pharmacological treatments and make
it difficult to evaluate efficacy of acupuncture, but does identify that an acupuncture
service gives benefit to patients.
Pain and fatigue combined represented almost half the symptoms treated in the
clinic. In a survey21 conducted in 2008 in the USA, fatigue was reported as the most
common side effect experienced by patients undergoing chemotherapy followed by
pain, nausea and vomiting and anxiety. The symptoms treated in the evaluation of
the service reflect those symptoms commonly experienced in relation to cancer
treatment but are also frequently not well managed. The findings of benefit in this
evaluation may also reflect the research evidence that many of these symptoms can
benefit from these integrative services.83, 176, 195-205
Overall, this study confirmed that acupuncture was a relatively safe intervention in
the setting of a complementary therapy service and not only in a clinical trial.154, 155
In this study 13 per cent of patients experienced an adverse event; the most common
being mild needling pain. The majority of AEs was mild (85%) and was transitory.
The higher percentage of AEs in both the study and the evaluation presented here
may be due to the population being cancer patients who have an increased risk of
bruising due to thrombocytopenia and higher incidence of sensitivity to pain and
interventions due to the number of interventions than the general population.
The evaluation of wellbeing using the MYCaW pre and post-test found a positive
improvement on both self-reported patient concerns. The improvement was both
clinically and statistically significant, with the change in concern one being highly
clinically significant and concern two being moderately clinically significant. We
also found a trend towards increased wellbeing score was tending towards being
statistically significant at p=0.053. The change of scores for participant’s
concerns/symptoms was similar to that from the initial study validating the tool89 and
subsequent studies.88, 206 Two studies88, 207 found a statistically significant
improvement in the wellbeing of the participants and both trials were approaching
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the level of clinically significant, identified as a change of 0.7,172, 173 having a change
of 0.67 and 0.64 respectively. The other study206 had a p-value = 0.16, which was not
close to being statistically significant unlike this current trial, but did find a
statistically significant improvement in another QoL tool, (EuroQol (EQ-5D)208, 209
which measured general wellbeing (p-value = 0.01). This variance in results from use
of the same tool may indicate that using MYCaW to measure wellness in participants
in a cancer care centre is not the best tool, and suggests there is no gold standard tool
for measuring QoL but that a pragmatic approach is taken to use a tool appropriate
for the population, setting and aims.210 Participants were continuing with
chemotherapy treatment, which is known to affect QoL17, 21, 28 and may have
impacted on the improvement of the participant’s wellbeing.
The MYCaW also included an open-ended question about aspects in the participant’s
life that was also affecting their health. The super categories relating to “other things
affecting your health”, when scored as either positive or negative. In this trial the
overall score was negative 23 to 10 positive. This proportion is different from that
reported from a cancer care centre in the UK,88 which was positive overall. The
difference maybe due to the fact the UK centre was provided by a charity not in a
public hospital setting and the centre only treated breast cancer patients.
Furthermore, the patients were actively looking for complementary therapies to help
them. The UK centre data collection occurred over a timeframe between three to 12
months that has also been shown to impact on recall.211
4.19 Concluding Comments
To conclude, it is feasible to conduct a true EA/sham EA/no acupuncture RCT on the
day oncology unit, although no definitive conclusions can be drawn on clinical
endpoints due to the small sample size and the low level of CINV symptoms
experienced by all study participants. The evaluation of the acupuncture service
appears to be beneficial to patients; it improved common symptoms but not their
wellbeing, and was found to be a relatively safe intervention with only minor AEs.
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Chapter 5: Discussion
The overall aim of this study was to examine the role of acupuncture in an integrated
cancer care setting at the Mater public hospital day oncology unit. The research
objectives were to: (i) review the clinical evidence of effectiveness and efficacy for
acupuncture and acupressure for the treatment of CINV; (ii) examine the feasibility
of conducting an efficacy trial of EA for chemotherapy induced nausea and vomiting
and (iii) examine the role of an acupuncture service in the day oncology unit on
patient’s wellbeing and personal views of benefit, helpfulness and usefulness of the
service. To achieve this aim a systematic review of acupuncture and/or acupressure
for CINV, a feasibility pilot RCT, and an evaluation of the Mater acupuncture
service was undertaken.
The findings from this body of work have shown that acupuncture may benefit
symptom management, when offered in the setting of a day oncology unit. The thesis
findings have shown:
1) A benefit with reducing CINV from conducting a systematic review of the
evidence of acupuncture for the treatment of CINV.
2) The feasibility of conducting a RCT in this setting, and methodological
considerations when planning future acupuncture research for acupuncture
for CINV, including enriched enrolment, not chemotherapy naïve and Delphi
process for acupuncture treatment.
3) That an acupuncture service does have a benefit in treating patients concerns
and problems they identified was most important to them to have treatment
for.
5.1 Systematic Review of Acupuncture to Reduce Chemotherapy-
Induced Nausea and Vomiting Key Findings
The systematic review of acupuncture and/or acupressure for CINV identified five
new trials since the Cochrane systematic review was published in 20068. Nineteen
trials in total were identified and 12 trials were included in this review.
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The findings from this review indicated that acupuncture appears to reduce
chemotherapy-induced vomiting and decrease the use of rescue medications.
Acupressure appeared to have a benefit with reducing the severity of acute
chemotherapy-induced nausea. There was evidence to support the use of the two
major points Pericardium 6 Neiguan and/ or Stomach 36 Zusanli, for the treatment of
acute CINV; this effect was not shown with delayed CINV, particularly the
application of acupressure on these points Pericardium 6 Neiguan and Stomach 36
Zusanli. Overall, the methodological quality of trials has not improved greatly since
the Cochrane review in 2006.8 There were only a few trials that were rated as having
minimal to low level of bias. Findings from this review suggest that there is
insufficient evidence about the effectiveness of acupuncture to treat delayed CINV,
in particular delayed nausea.
5.2 Key Findings from the Feasibility Study
The findings clearly identified that it was possible to conduct an efficacy trial of EA
for CINV. We found it was feasible to recruit and implement the study on a busy
oncology day unit. However, recruitment was slower than planned. Patients were
willing to return for extra treatment, the attrition rate was acceptable, and the
outcome measures were suitable when using the daily diary. The change in NRS
scale as the primary outcome measure and FLIE as secondary outcome was
acceptable, and we also found the integrity of the blinding to be maintained. The
results showed it was possible to conduct a future trial with some changes to
methodology, recruitment targets and resource availability.
A surprising finding was the high scores reported by study participants in response to
the FLIE tool for CINV and QoL. This finding indicated that overall CINV was not a
burdensome symptom experienced by these participants in this study. As previously
discussed in Chapter Four this was not indicative of the literature reporting on the
prevalence of CINV. Studies describe CINV incidence from the UK, USA and
Europe as between 10 to 30 per cent.23, 27, 29, 38, 212 The low level of CINV found in
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this study may reflect improved use of and the availability of certain anti-emetic
drugs and regimens to patients with moderate or highly emetogenic chemotherapy.
The results from both the nausea and vomiting participant diaries reinforce the low
level of CINV experienced by this sample. There were minimal episodes of vomiting
in any group at any time. This is supported by the literature; vomiting caused by
chemotherapy is better controlled than nausea and is not the issue it once was.23, 27, 29,
38, 212 The main area that needs control in relation to CINV remains delayed nausea.
Doctors and nurses underestimate delayed CINV compared to patients.25, 39, 213 This
is further compounded by the issue of accuracy from patient recall. Delayed self-
reporting also affects the severity of symptoms reported, with patients reporting
lower levels in recall, compared to real time.39, 211 This can occur when patients are
reporting at the next review to their doctor or consultant prior to chemotherapy. The
nausea scores did not reflect the literature in relation to delayed nausea; overall, the
nausea scores were low during the whole period.
The washout period, being the time that any benefit from acupuncture becomes non-
existent, has not been clearly identified in previous studies. Previous studies94, 184, 185
with crossover designs have used washout periods varying from one to three weeks.
The washout period in this study was between two and three weeks, depending on
the participants’ protocol. All participants with colorectal or gynaecological cancer
had a two week washout period, and breast cancer participants had a three week
washout period. This study found no significant difference between the true
acupuncture and sham acupuncture groups, indicating that the washout period of two
to three weeks was sufficient time to negate any follow over effect from the
acupuncture. However, this statement needs some qualification: firstly the sample
size was small and there was a risk of type two error, as a positive affirmation of the
null hypothesis may be shown as a negative. Secondly, the overall low level of CINV
may mean that any benefit from acupuncture is not large enough to carry over and be
detected.
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5.3 Key Findings from Acupuncture Service Evaluation.
Many patients undergoing treatment for their cancer are treated with chemotherapy,
which has extensive and sometimes serious side effects. These side effects can
adversely affect the patient’s QoL while undergoing treatment. Oncology supportive
care aims to minimise the adverse effects from treatment, and supportive care is an
important and integral part to standard cancer care in the modern world.214
Supportive cancer care, including complementary therapies in care, uses the term
‘integrative oncology’ and is an emerging field. As any newly emerging field it
needs more research to support the benefits and risks, particularly from a patient-
centred perspective. Public health administrators need to become a more integral part
of supportive care.1-4, 85-87
The key finding from the service evaluation was the value patients placed on this
service, and the data supporting a significant improvement to their wellbeing.
Patients reported the service was beneficial, helpful and useful. Establishing safety
was a key outcome from this evaluation. We found some minimal AEs reported from
acupuncture, and the majority of these were minor. Benefits to the symptoms patients
experienced was also identified, these included: pain, fatigue, nausea and peripheral
neuropathy, with these accounting for 78 per cent of all symptoms treated.
5.4 Methodological Discussion
The main methodological objectives examined by the feasibility study were to
ascertain: the suitability and sensitivity of outcome measures and tools, trial
procedures and protocols; assessing randomisation and blinding; time and resource
allocation and data management problems.139, 215 These components will be
discussed in the context of study strengths and limitations.
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5.5 Strengths of the Trial
This is the one of the few studies to evaluate EA and delayed CINV, and this
preliminary study contributes important data to examining the evidence base of
acupuncture, and undertaking a study in an Australian setting, in particular the
treatment of CINV.176 The use of four points for a trial in CINV was a novel
approach. Most previous research used only one or two acupuncture points, the
majority using Pericardium 6 only. The consensus by an expert group, for the
development of a tool in 2011 to assess acupuncture protocols in trials, identified
preference for a minimum of six needles per treatment, unless justified from the
treating paradigm.216 This tool was developed after the trial commenced and included
the practicalities of administering the treatment while patients were receiving
chemotherapy; the use of four points remains a strength.
The choice of two treatments was aimed at treating delayed CINV. The proportion of
participants returning for their second treatment was high, and greater than
anticipated due to the symptom burden on these patients. Seven participants refused
to participate in the second treatment due to travel or work commitments. This was
an important finding affecting feasibility demonstration regarding the trial, also
ensuring the optimal dose of acupuncture treatment was delivered, as set out in the
design of this trial, and targeting delayed CINV.
The process of seeking informed consent from participants considering participation
in this trial involved clear explicit statements that they would possibly receive sham
acupuncture or no acupuncture. Discussions in the acupuncture literature have
regarded the transparency of explaining sham acupuncture. Previous acupuncture
trials addressing CINV97, 99 informed patients they were receiving two different types
of acupuncture; this has been identified as a possible ethical issue in acupuncture
studies.124, 217
Unlike some studies which only include one type of medication protocol91, 99 of high
emetogenic chemotherapy, or studies including highly emetogenic protocols,94, 98, 100,
176 this study contributes data to the small body of research97 that includes patients
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using both moderate and highly emetogenic regimens. The advantage of using the
broader inclusion criteria is that the study population better reflects clinical practice,
as seen in the day oncology unit and in private acupuncture practice. This mixed
patient group suggests the results are more readily generalised than if only one
particular patient group was used.91, 94, 98-100, 176
The trial design was successful with reducing potential sources of biases affecting
the results and their interpretation. The trial was successful in achieving a good level
of blinding, with no differences detected between groups. Seventy-one per cent of
patients could not guess their group allocation, reducing the effect of performance
bias. The level of participant blinding to group allocation may have been affected by
the fact that participants were not screened for being acupuncture naïve, just
chemotherapy naïve. The level of blinding may have also been enhanced due to the
use of EA. EA has been shown to successfully maintain blinding by using minimal
stimulation and connection of the micro-stimulator, without any current being
administered. There was also little evidence of performance bias relating to study
personnel. The practitioner interaction was assessed through observation of the
practitioner-participant interaction, who found no notable difference in interaction by
the practitioner. Patients were randomised to one of the three groups by an
independent person via a computer randomisation program. This generated the
randomisation sequence and treatment allocations were hidden by simple sealed
consecutively numbered envelopes. These measures help reduced selection bias to
minimal levels, ensuring any result was not influenced by the researcher assigning
patients to particular arms.
The inaccuracy due to delayed reporting of CINV, which has been identified as a
measurement bias in this area of research,211 was overcome in this study by using a
daily diary that patients completed, reviewing the last 24 hours or the previous three
days.
Previous research has shown that expectation can influence participants’ response to
acupuncture treatment.116, 186 In this study, there was no relation between expected
benefit and actual benefit, though the small sample size and low levels of CINV need
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to be taken into account. In this study any benefit from the acupuncture treatment
was not influenced by expectation.
The evaluation of the acupuncture service identified that patients thought it was a
beneficial and helpful service. The excellent response from a large number of
participants responding to the evaluation was a key strength of this study, with 93 per
cent of patients approached agreeing to participate.
This was the first evaluation of an integrated acupuncture service in the Australian
population to our knowledge. No other service existed at this time within Australian
healthcare offering acupuncture to public cancer patients in the day oncology unit
free-of-charge. Our findings add important observational data to the evaluation of
integrated services in UK and USA.
The patient’s perspective is an important consideration in evaluating health care
services. There is the call for more evaluation, research and care to be more patient-
centric, and involve patients more in their care, including evaluation of that care.218-
220 The use of an evaluation tool designed to obtain service benefits from a patient’s
perspective, such as the MYCaW and the researcher-designed survey, were
appropriate to providing evidence of clinical change.
5.6 Study Limitations
A primary limitation of the trial relates to the acupuncture treatment protocol being
designed and administered by a sole practitioner. This reflects only one practitioners’
experience and skill influencing the design of the treatment protocol, addressing
point selection, stimulation method, duration of treatment and dosage. Acupuncture
styles and treatment protocols vary widely between different practitioners, and there
is no large evidence base to assist with designing treatment protocols. A recent
approach to developing clinical protocols to ensure they reflect actual clinical
practice is to use a group consensus technique, such as the Delphi process.216, 221-223
Another limitation was the overall low levels of CINV in all groups: it was difficult
to determine if there was any indication of an effect from EA. This was an important
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finding from the feasibility study. An increase in the acupuncturists’ available hours
may also lead to increased recruitment and fewer potential recruits being missed.
This may have introduced a selection bias due to the days patients were recruited
early in the trial, as only patients being seen on Tuesday and Thursdays were initially
recruited. Obtaining consent from the consultants to recruit their patients was also
problematic and resulted in slower recruitment. The difficulty was obtaining
consultant consent prior to approaching potential participants in a busy clinical
setting.
There was a bias in the favour of female participants (88%) and breast and
gynaecological diagnosis, which may mean the results cannot be generalised to the
wider oncology setting. The under-representation of men may have arisen due to
men not being as open to using complementary therapies as the female population, or
they were being stoic (as is expected and observed from the older generations).224, 225
Some male participants where encouraged by a wife or partners to participate in the
trial, as identified by the researcher nurse and researcher. Another factor contributing
to the low study uptake by men with prostate cancer was these patients were not
generally seen in the outpatient clinic, with treatment for prostate cancer involving
surgery or medication, particularly first line. Why this uptake by male participants
was so low was difficult to ascertain. Numerous studies of CAM usage by cancer
patients identify the ratio as being approximately 1:1.56, 58, 59, 61 This imbalance has
not been seen in other cancer trials, in fact a review of participation in cancer clinical
trials226 identified a bias towards male participants and this is the same for other trials
for heart disease, statins and pain.227, 228 This is supported in the literature, where a
review of complementary therapy use of chiropractic, acupuncture and osteopathy in
the general population in Australia identified that the female:male ratio to be almost
1:1, with only osteopathy having a greater female:male ratio.55 The equal ratio of
female:male also corresponds with a survey of Western Australian cancer patients
using CM in 2008.58
The following section reflects on the limitations of the service evaluation. A
limitation of the outcome instrument MYCaW in relation to the benefits seen in the
participants’ specific concerns was not particular to the acupuncture service. This
was an evaluation of the whole service related to the participants concerns, as we did
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not control for any other treatments they may have received. There may be some
benefit as the majority of common symptoms experienced by patients undergoing
treatment have a cumulative effect and worsen during course of their treatment.21, 28,
229 To explore this, future research needs to look at controlling for standard care
received by the patients with a RCT.
Patients were self-selecting to have the intervention and may have held an
expectation of benefit that could have influenced results. This is a limitation of all
studies that are not randomly controlled, as only patients who want the treatment
were evaluated, which gives a biased view of the benefits involved. Follow up for the
evaluation was conducted at four to six weeks; there is support in the literature for
longer follow up particularly in the area of complementary therapies.
5.7 Future Research
There is a need to conduct further research of EA for CINV. Based on the findings of
this study, recommendations for research would include:
1. Future studies must be appropriately powered. Using data from this feasibility
trial a future study would require a sample size of 171 participants. The
sample size calculation is based on the primary outcome of the change of
‘worst’ nausea score between Day 4 and Day 1. It is anticipated that patients
would have a score of 0 or 1 on Day 1, that the control arm will have a 2-
point change in ‘worst’ nausea score (shown in previous studies to be
clinically significant177, 230, 231), the sham acupuncture a 1-point change and
the acupuncture arm approximately no change. The expected standard
deviation of the change in nausea scores is 2.8, based on NRS data from
patient diaries in the pilot study and information from the literature.177, 231
Using these assumptions, along with a type 1 error of 0.05 and 80 per cent
power, 39 participants in each group are required for a total of 117 patients.
Using a drop out rate of approximately 20 per cent, 49 patients per group are
required. To account for the possibility of non-parametric data and therefore a
loss of power, a correction of 1.157 is used to give a total number of 57 per
group, of 171 patients total. Realistic recruitment timeframe would need to be
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three years and be a multicentre trial with a full-time trial nurse, acupuncturist
and part-time data manager, to help with recruitment, data collection and
particularly data follow up.
2. A future study might use of the NRS tool for primary outcome measurement
tool objective assessment and use the FLIE or other tools that are specific for
measuring the cancer patient’s QoL. Examples of possible tools include: the
European Organisation Research and Treatment of Cancer—QoL
Questionnaire (EORTC QLQ-C30), the Functional Assessment of Cancer
Therapy (FACT/FACIT) and the SF-36 Health Survey.210, 232
3. Pragmatic designed trials that are well designed addressing effective
randomisation and blinding. Future research needs to ensure that outcome
measures are both clinically relevant and patient centred, and reflect what is
important for the patient.133-135 Further trials should be pragmatic in design,
allowing the treating acupuncturist flexibility to decide the appropriate
acupuncture treatment to ensure the trials have clinical relevance and help
direct practice.127, 128 There is support for moving the focus from efficacy to
effectiveness studies, where the design is closer to what is reflected in
practice. The adoption of broad trial inclusion and exclusion criteria will also
ensure the findings of the study are more readily generalised and
representative of the usual care situation.129, 136 This will help the research to
reflect what occurs in clinical practice. Even though all trials were conducted
in the cancer care setting, practitioners in private practice do treat cancer
patients for symptom control; this will help guide their practice as well.
4. Identify why females are more drawn to complementary medicine services
than males in the particular setting of complementary therapy services,
compared to the general population and develop recruitment strategies to help
address the imbalance in future studies and clinical practice.
5. Target participants with CINV. This could also be addressed by recruiting
patients from Cycle 2 onwards to ensure the intervention targets patients
experiencing of CINV,24, 31 and using an enriched enrolment recruitment
strategy. This strategy has been used predominately for pain studies, but as an
enriched enrolment randomised withdrawal clinical trial design. In these trials
there are two phases, phase one is enrichment phase, where all participants
are given the drug, the second phase is a double blind randomised
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withdrawal, where only the responders are randomised to the drug or
placebo.233, 234 In this setting, the enrichment will be the identification of
potential participants who experienced CINV in their previous cycle.
Participants could be given information at first cycle of chemotherapy and
then assessed prior to second cycle of chemotherapy; if they experienced
CINV they would be consented and randomised. Patients that were not first
cycle would be approached prior to their next chemotherapy to consent and
be randomised if they were identified as suffering CINV. This would include
patients that were experiencing CINV to see if they would benefit with the
addition of acupuncture to improve control of CINV. These changes would
address the issue of the low level of CINV in the participant group. This will
target patients without complete control of their CINV with standard anti-
emetic therapy and who would potentially benefit more from acupuncture. It
would definitively identify if acupuncture is beneficial in the clinical setting.
The evidence base of complementary therapies in supportive care needs more
research. Future recommendations derived from this study include:
1. Evaluation designs using a matched controlled outcomes study, by using
cancer databases to match participants in an integrative service with cancer
patients with same demographics, cancer diagnosis, staging and treatment
from the databases.86 To evaluate the impact of CM on the patient’s survival
outcomes.
2. Do integrative oncology clinics have a cost saving or contribute an added cost
to patient care? This is an area under-researched in supportive cancer care.
5.8 Clinical Implications
The systematic review identified that the use of the two major points Pericardium 6
Neiguan and/ or Stomach 36 Zusanli, for acute CINV has some evidence of benefit.
Less evidence exists for reducing symptoms for patients with delayed CINV. These
points are commonly used in clinical practice and are also well used for treating
nausea and vomiting arising from other causes, including post-operative and
pregnancy-induced nausea and vomiting, which reinforces their broad application in
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clinical practice for treating nausea and vomiting.131, 132 The review also identified
that acupressure at Pericardium 6 Neiguan, even though the evidence is not
conclusive, is inexpensive, low risk and easy for patients to learn and perform. This
could be included for patients experiencing CINV.119
Results from the service evaluation highlight the benefit to patients receiving
acupuncture for symptom control in the clinical setting of a day oncology unit. The
number of actual acupuncture services available in hospitals is very low, but many
patients see complementary therapists privately while undergoing chemotherapy.
The evaluation identified that acupuncture from a qualified acupuncturist is relatively
safe with clinically and statistically significant benefits for symptom control. In
Australia, the new regulation of acupuncturists under the government initiative, the
National Registration and Accreditation Scheme, ensures professional standards are
maintained and the safety of the public is protected; this addresses the issue of
patients seeking a qualified acupuncturist to help with symptom control. Practitioners
will be able to offer supportive cancer care as a result of the increasing knowledge
base of the benefits acupuncture has for patients undergoing chemotherapy
treatments. Symptoms that may have some benefit from acupuncture include fatigue,
nausea and vomiting, insomnia, hot flushes, pain, peripheral neuropathy and anxiety.
5.9 Implications for Education
With the emerging field of integrative oncology, and the inclusion of complementary
therapy in to cancer care units in Australia, for example the Chris O’Brien Lifehouse
in Sydney, Olivia Newton John Cancer and Wellness Centre at Austin Hospital,
Melbourne and the Mater Cancer Care Centre Survivorship and Wellbeing Centre,
educational implications follow. The implications for education administrators and
institutions particularly in the pre-registration area are twofold:
1. Educating pre-registration acupuncture students in the practical knowledge of
treating patients undergoing chemotherapy and radiotherapy including
cautions, contraindications and treatment protocols.
2. Effective communication skills for pre-registration acupuncture students may
help so they feel confident communicating with healthcare professionals.
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This effective communication will convey and educated the other health
practitioners what acupuncturists do and what we can offer to the patients.
For the practitioners who have completed study and are already in practice and wish
to expand their skills, courses and seminars need to be presented so the individual
and profession has the necessary knowledge base and skills to address the new roles.
5.10 Conclusion
This thesis follows evidence from a Cochrane systematic review that acupuncture
has benefit in treating acute CINV, although more research is needed to identify if
there is any benefit for delayed CINV. The review also found the need to improve
the design, to reduce bias and reporting of the trials, in particular addressing both
CONSORT 171 and STRICTA guidelines.
The feasibility trial showed it was possible to conduct a trial in a busy day oncology
unit, with some changes to methodology to overcome low incidence of CINV in the
population, the outcome measures and better resources to ensure data collection and
follow up. This provides information to guide the planning and design of future
research
The acupuncture service evaluation was positive, with a large majority of
participants finding the service beneficial and wanting the service to continue. The
result was positive in both a clinically and statistically significant improvement of
participant’s concerns using the MYCaW tool. Overall, this thesis has identified that
acupuncture may benefit patients in the support cancer care setting, helping with
symptom control, but further research is needed.
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134
Appendices
Appendix One Systematic Review Article
McKeon C, Smith CA, Hardy J & Chang E. Acupuncture and Acupressure for
Chemotherapy-Induced Nausea and Vomiting: A Systematic Review. AUST J
Acupunct Chin Med 2013;8(1):2–27.
Background: Control of CINV has improved with advances in anti-emetics, such as
NK1 antagonists. Despite these advances, patients still experience these symptoms,
and expert panels encourage additional methods to reduce these symptoms.
Objectives: The objective was to assess the effectiveness of acupuncture and
acupressure on acute and delayed CINV in cancer patients. Search strategy: The
following databases were searched: AMED, MEDLINE, CINAHL, PubMed,
Cochrane Controlled Trials Registry, and Science Direct. The search was undertaken
from the inception of the database to January 2012. Selection criteria: RCTs and
systematic reviews of acupoint stimulation by needles, electrical stimulation or
acupressure (excluding laser, point injection and non-invasive electro-stimulation)
and assessing CINV, or both. Data collection and analysis: Data was provided by
publications of original trials and pooled. Standardised MDs with confidence
incidences were calculated. Main results: seven trials were pooled for acupuncture
and six for acupressure. Acupuncture reduced the frequency of acute vomiting ([MD]
-7.40, 95% CI ([CI] -9.07 to -5.72), but did not reduce acute nausea severity or
frequency compared to control. Delayed symptoms for acupuncture were not
reported. Acupuncture showed a reduction in the dose of rescue medication (MD -
5.52, 95% CI -7.45 to -3.58). Acupressure showed a decrease in frequency of nausea
(MD -0.32, 95% CI -0.59 to 0.06) but not acute vomiting or delayed symptoms. All
trials used state-of-the-art combination anti-emetics, except for the early EA trials.
Authors’ conclusions: Acupuncture has demonstrated some benefit for
chemotherapy-induced acute vomiting by reducing the frequency of vomiting and
reducing the use of rescue medication, while acupressure has shown a decrease in the
frequency of nausea. Further trials of acupuncture and acupressure for CINV in
135
patients with refractory symptoms are needed before recommendations for clinical
practice can be made. Future trials must be sufficiently powered, as this remains a
major flaw with the majority of studies to date.
Link to article
http://ajacm.com.au/Portals/0/AJACMFiles/PDFs/Vol 8 Iss 1/AJACM Vol 8 Iss
1_CanAcupunctureReduceCINV.pdf
13
6
App
endi
x Tw
o C
hara
cter
istic
of S
tudi
es
D
ibbl
e 10
6
Met
hods
D
esig
n: P
aral
lel–
acup
ress
ure
plus
med
icat
ion
v. m
edic
atio
n on
ly
Dur
atio
n: O
ne c
ycle
21–
28 d
ays
Parti
cipa
nts
Setti
ng: O
utpa
tient
onc
olog
y cl
inic
teac
hing
hos
pita
l and
priv
ate
outp
atie
nt o
ncol
ogy
prac
tice,
USA
Mea
n ag
e (+
/-SD
or r
ange
): 49
.5yr
(SD
= 6
.0)
Men
/wom
en (n
/n):
0/18
Rec
ruitm
ent m
etho
d: re
sear
ch a
ssis
tant
s app
roac
hed
patie
nts o
r by
thei
r phy
sici
ans
Incl
usio
n cr
iteria
: re
ceiv
ing
CM
F (c
yclo
phos
pham
ide,
met
hotre
xate
and
flu
orou
raci
l) or
a r
egim
en c
onta
inin
g
doxo
rubi
cin,
nau
sea
from
pre
viou
s cyc
le o
r firs
t cyc
le o
f che
mot
hera
py, a
bilit
y to
com
mun
icat
e in
Eng
lish
Excl
usio
n cr
iteria
: non
e st
ated
Inte
rven
tions
In
terv
entio
n gr
oup:
acu
pres
sure
Num
ber a
lloca
ted
to a
cupr
essu
re =
9
Poin
ts st
imul
ated
: PC
6 an
d ST
36
Tota
l len
gth
of tr
eatm
ent p
erio
d: 2
1 to
28
days
, one
cyc
le o
f che
mot
hera
py
Num
ber o
f ses
sion
s: d
aily
and
whe
n ne
cess
ary
min
imum
of 2
1
Num
ber o
f poi
nts u
sed:
2 p
oint
s
Dur
atio
n: m
axim
um 3
min
utes
or u
ntil
poin
t "re
leas
ed"
Met
hod
of st
imul
atio
n: d
igita
l acu
pres
sure
Con
trol g
roup
: sta
ndar
d ca
re
13
7
Num
ber a
lloca
ted
to c
ontro
l = 9
Tota
l len
gth
of tr
eatm
ent p
erio
d: 2
1 to
28
days
Out
com
es
Nau
sea–
daily
sco
re f
rom
nau
sea
expe
rienc
e su
bsca
le f
rom
the
Ind
ex o
f na
usea
, vom
iting
and
ret
chin
g (I
NV
R)
and
daily
inte
nsity
scal
e
Rep
orte
d as
p-v
alue
s and
mea
n w
ith S
D.
Attr
ition
bia
s D
ropo
uts/
with
draw
als:
no
drop
outs
or w
ithdr
awal
s
Sele
ctio
n bi
as
Unc
lear
, st
ated
ran
dom
but
not
met
hod,
unc
lear
if
allo
catio
n of
tre
atm
ent
was
con
ceal
ed f
rom
allo
cato
r an
d bo
th
grou
ps w
ere
com
para
ble
at e
ntry
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? N
ot a
pplic
able
Parti
cipa
nts n
ot b
linde
d, u
ncle
ar if
ass
esso
rs w
e bl
inde
d
Mea
sure
men
t
bias
Low
risk
bia
s, bo
th g
roup
s tre
ated
sam
e, p
-val
ue a
naly
sis r
epor
ted
DIB
BLE
107
Met
hods
D
esig
n: P
aral
lel–
acup
ress
ure
plus
med
icat
ion
v. s
ham
acu
pres
sure
plu
s m
edic
atio
n v.
med
icat
ion
only
. Dur
atio
n: 2
1 to
28 d
ays
Parti
cipa
nts
Setti
ng: m
ultic
entre
tota
l 19
setti
ngs t
hrou
ghou
t USA
in c
linic
al o
ncol
ogy
cent
res
Mea
n ag
e (+
/-SD
or r
ange
): 49
.3 (S
D =
9.4
)
Men
/wom
en (n
/n):
0/16
0
Rec
ruitm
ent m
etho
d: n
ot st
ated
Incl
usio
n cr
iteria
: wom
en re
ceiv
ing
cycl
opho
spha
mid
e w
ith o
r w
ithou
t 5-F
U, d
oxor
ubic
in w
ith p
aclit
axel
or d
ocet
axel
,
13
8
or 5
-FU
, epi
rubi
cin
and
cycl
opho
spha
mid
e fo
r bre
ast c
ance
r, ha
d m
oder
ate
naus
ea o
n pr
evio
us c
hem
othe
rapy
cyc
le (p
er
MA
NE
scal
e)
Excl
usio
n cr
iteria
: see
ing
acup
unct
uris
t, un
able
to c
omm
unic
ate
in E
nglis
h
Inte
rven
tions
In
terv
entio
n gr
oup:
acu
pres
sure
to P
C6
Num
ber a
lloca
ted
to a
cupr
essu
re =
53
Styl
e of
acu
pres
sure
: sel
f acu
pres
sure
Poin
ts st
imul
ated
: PC
6
Tota
l len
gth
of tr
eatm
ent p
erio
d: 2
1 to
28
days
, dep
endi
ng o
n ch
emot
hera
py c
ycle
Num
ber o
f ses
sion
s: m
inim
um o
f one
dai
ly
Num
ber o
f poi
nts u
sed:
one
Dur
atio
n: 3
min
utes
eac
h po
int
Met
hod
of st
imul
atio
n: d
igita
l
Con
trol s
ham
gro
up: a
cupr
essu
re to
SI3
N a
lloca
ted
to c
ontro
l: 53
Styl
e of
acu
pres
sure
: sel
f acu
pres
sure
Poin
ts st
imul
ated
: PC
6
Tota
l len
gth
of tr
eatm
ent p
erio
d: 2
1 or
28
days
dep
endi
ng o
n ch
emot
hera
py c
ycle
Num
ber o
f ses
sion
s: m
inim
um o
f one
dai
ly
Num
ber o
f poi
nts u
sed:
one
Dur
atio
n: 3
min
utes
eac
h po
int
Met
hod
of st
imul
atio
n: d
igita
l
13
9
Con
trol g
roup
: sta
ndar
d tre
atm
ent
Num
ber a
lloca
ted
to c
ontro
l = 5
4
Tota
l len
gth
of tr
eatm
ent p
erio
d: 2
1 to
28
days
Out
com
es
Acu
te n
ause
a an
d vo
miti
ng D
ay 1
Del
ayed
em
esis
Day
s 2 to
11
Del
ayed
nau
sea
Day
s 2 to
11
Sele
ctio
n bi
as
Yes
par
ticip
ant’s
allo
catio
n co
ncea
led
Ran
dom
ised
to g
roup
, met
hod
not s
tate
d so
unc
lear
and
bot
h gr
oups
wer
e co
mpa
rabl
e at
ent
ry
Attr
ition
bia
s D
ropo
uts/
with
draw
als:
yes
(13
with
drew
reas
ons n
ot st
ated
) not
incl
uded
in a
naly
sis
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? Y
es
Parti
cipa
nts b
linde
d to
gro
up, n
ot c
lear
if o
utco
me
asse
ssor
s whe
re b
linde
d, re
sear
ch a
ssis
tant
s blin
ded
to a
ctiv
e po
int
Mea
sure
men
t
bias
Type
of a
naly
sis r
epor
ted–
mea
n SD
, con
sist
ent b
oth
grou
ps
Dun
dee93
Met
hods
D
esig
n: c
ross
over
with
in c
ycle
–acu
punc
ture
plu
s med
icat
ion
v. sh
am a
cupu
nctu
re p
lus m
edic
atio
n
Dur
atio
n: 3
day
s
Parti
cipa
nts
Setti
ng: i
npat
ient
, Bel
fast
, Nor
ther
n Ir
elan
d
Mea
n ag
e (+
/-SD
or r
ange
): no
t pro
vide
d
Men
/wom
en (n
/n):
10/0
Rec
ruitm
ent m
etho
d: u
ncle
ar
14
0
Incl
usio
n cr
iteria
: pre
viou
s sev
ere
sick
ness
afte
r tre
atm
ent d
espi
te m
etoc
lopr
amid
e
Excl
usio
n cr
iteria
: non
e id
entif
ied
Inte
rven
tions
In
terv
entio
n gr
oup:
ant
i-em
etic
s and
EA
to P
C6
Num
ber a
lloca
ted
to a
cupu
nctu
re =
10
Styl
e of
acu
punc
ture
: TC
M
Poin
t sel
ectio
n: fo
rmul
a
Poin
ts st
imul
ated
: PC
6
Tota
l len
gth
of tr
eatm
ent p
erio
d: 3
day
s
Num
ber o
f ses
sion
s: 5
or 6
Num
ber o
f poi
nts u
sed:
one
Inse
rtion
dep
th: n
ot st
ated
Was
Deq
i rep
orte
dly
soug
ht: Y
es
Dur
atio
n: n
ot st
ated
Met
hod
of st
imul
atio
n: D
C st
imul
ator
freq
uenc
y 10
Hz,
pul
se w
idth
0.2
5 m
s
Con
trol g
roup
: ant
i-em
etic
s and
sham
EA
to p
oint
nea
r rig
ht e
lbow
Num
ber a
lloca
ted
to sh
am a
cupu
nctu
re =
10
Tota
l len
gth
of tr
eatm
ent p
erio
d: 3
day
s
Num
ber o
f ses
sion
s: m
axim
um o
ne sh
am tr
eatm
ent i
n 3
days
Num
ber o
f poi
nts u
sed:
one
Inse
rtion
dep
th: n
ot st
ated
Was
de
qi re
porte
dly
soug
ht: n
ot st
ated
14
1
Dur
atio
n: n
ot st
ated
Met
hod
of st
imul
atio
n: E
A w
as a
pplie
d vi
a D
C st
imul
ator
(10
Hz,
pul
se w
idth
0.2
5 m
s).
Out
com
es
Acu
te v
omiti
ng
Out
com
e m
easu
red
by 4
poi
nt s
cale
–ver
y go
od (n
o si
ckne
ss),
som
e be
nefit
(mar
ked
redu
ctio
n in
sic
knes
s), n
o ch
ange
(no
bene
fit) a
nd w
orse
(wor
se th
an b
efor
e)
Sign
ifica
nt le
ss si
ckne
ss fo
r PC
6 th
an sh
am (p
<0.0
01)
Con
trol f
rom
pre
viou
s st
udy
show
ed 5
2 of
54
patie
nts
on c
ispl
atin
who
had
dis
tress
ing
sym
ptom
s af
ter f
irst t
reat
men
t
had
just
as s
ever
e th
e su
bseq
uent
trea
tmen
t
Sele
ctio
n bi
as
Stat
ed th
at p
atie
nts
wer
e un
awar
e of
allo
catio
n. R
ando
m s
elec
tion
but m
etho
ds n
ot c
lear
. Unc
lear
if a
lloca
tor b
linde
d
to tr
eatm
ent g
roup
allo
catio
n an
d un
sure
if b
oth
grou
ps w
ere
com
para
ble
at e
ntry
Attr
ition
bia
s N
o dr
opou
ts o
r with
draw
als,
low
risk
of b
ias
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? N
o
Parti
cipa
nts
wer
e bl
inde
d, u
ncle
ar if
out
com
e as
sess
ors
blin
ded,
Obs
erve
rs n
ot a
lway
s bl
inde
d as
pat
ient
con
veye
d si
te
of a
cupu
nctu
re
Mea
sure
men
t
bias
Type
of a
naly
sis r
epor
ted:
p-v
alue
sam
e fo
r bot
h gr
oups
Not
es
Did
not
iden
tify
time
of st
imul
atio
n.
Dro
p re
ason
s not
iden
tifie
d.
Early
stud
y, n
ot u
sing
new
er a
nti-e
met
ics
14
2
Dun
dee92
Met
hods
D
esig
n: P
aral
lel–
acup
unct
ure
v. m
edic
atio
n on
ly
Dur
atio
n: 5
min
utes
Parti
cipa
nts
Setti
ng: o
utpa
tient
s clin
ic, B
elfa
st, N
orth
ern
Irela
nd
Mea
n ag
e (+
/-SD
or r
ange
): no
t sta
ted
Men
/Wom
en (n
/n):
not s
tate
d 20
tota
l
Rec
ruitm
ent m
etho
d: n
ot st
ated
Incl
usio
n cr
iteria
: firs
t cyc
le c
hem
othe
rapy
Excl
usio
n cr
iteria
: non
e st
ated
Inte
rven
tions
In
terv
entio
n gr
oup:
ant
i-em
etic
s and
EA
to P
C6
Num
ber a
lloca
ted
to a
cupu
nctu
re =
10
Styl
e of
acu
punc
ture
: TC
M
Poin
t sel
ectio
n: fo
rmul
a
Poin
ts st
imul
ated
: PC
6
Tota
l len
gth
of tr
eatm
ent p
erio
d: o
ne
Out
com
es
Acu
te v
omiti
ng m
easu
red
at 8
–10h
r pos
t che
mot
hera
py a
dmin
istra
tion
Scal
e be
ing
mod
erat
e or
slig
ht -
thou
gh im
prov
emen
t not
stat
istic
ally
sign
ifica
nt
Sele
ctio
n bi
as
Unc
lear
–ran
dom
ised
from
pre
viou
sly
prep
ared
list
–uns
ure
who
and
how
list
was
gen
erat
ed n
or if
allo
catio
n to
gro
up
conc
eale
d fr
om th
e al
loca
tor a
nd u
nsur
e if
both
gro
ups w
ere
com
para
ble
at e
ntry
Attr
ition
bia
s N
o dr
opou
ts o
r with
draw
als,
low
risk
of b
ias
14
3
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? N
ot a
pplic
able
Blin
ding
: pat
ient
s not
blin
ded,
obs
erve
r was
blin
ded.
Mea
sure
men
t
bias
Not
cle
arly
stat
ed if
out
com
e m
easu
re c
arrie
d ou
t in
relia
ble
way
Not
es
Old
er st
udy,
not
usi
ng m
oder
n an
ti-em
etic
s
Got
tsch
ling94
Met
hods
D
esig
n: c
ross
over
–acu
punc
ture
plu
s med
iatio
n v.
med
icat
ion
only
Dur
atio
n: v
arie
d fr
om 4
–5 d
ays
depe
ndin
g on
che
mot
hera
py t
reat
men
t. O
ffer
ed f
irst
day
then
pre
cedi
ng d
ays
depe
ndin
g on
pat
ient
s’ d
ecis
ion.
Tw
o cy
cles
wer
e ob
serv
ed, o
ne w
ith a
cupu
nctu
re o
ne w
ithou
t. To
tal t
ime
4 w
eeks
.
Parti
cipa
nts
Setti
ng: 5
pae
diat
ric in
patie
nt se
tting
s, G
erm
any
Mea
n ag
e (+
/-SD
or r
ange
): 13
.6 +
/- 2.
9
Men
/wom
en (n
/n):
(10/
13)
Rec
ruitm
ent m
etho
d: n
ot c
lear
ly st
ated
Incl
usio
n cr
iteria
: re
ceiv
ing
3 id
entic
al c
ours
es o
f hi
ghly
em
etog
enic
che
mot
hera
py (
rela
ting
to t
ype
amou
nt o
f
antin
eopl
astic
age
nts)
for s
olid
tum
ours
.
Excl
usio
n cr
iteria
: pat
ient
s w
ith fu
ll co
ntro
l of C
INV
with
out t
he n
eed
for r
escu
e m
edic
atio
ns in
firs
t cyc
le, a
ge u
nder
6 an
d ov
er 1
8 ye
ars,
cere
bral
met
asta
sis
Inte
rven
tions
In
terv
entio
n gr
oup:
sta
ndar
d an
ti-em
etic
s an
d ac
upun
ctur
e D
ay 1
prio
r to
che
mot
hera
py a
nd f
ollo
win
g 4
or 5
day
s
depe
ndin
g on
pat
ient
s req
uest
Num
ber a
lloca
ted
to a
cupu
nctu
re =
23
14
4
Styl
e of
acu
punc
ture
: TC
M
Poin
t sel
ectio
n: fl
exib
le, p
ract
ition
er d
ecis
ion
base
d on
TC
M p
rinci
ples
Poin
ts st
imul
ated
: mos
t com
mon
ly u
sed
poin
ts, P
C6,
ST3
6, C
V12
and
LI4
.
Tota
l len
gth
of tr
eatm
ent p
erio
d: 4
wee
ks in
clud
ing
was
hout
per
iod
of tw
o w
eeks
bet
wee
n cy
cles
Num
ber o
f ses
sion
s: m
axim
um o
f 6
Num
ber o
f poi
nts u
sed:
not
stat
ed, s
tate
d co
uld
be u
nila
tera
l or b
ilate
ral
Inse
rtion
dep
th: n
ot st
ated
Was
de
qi re
porte
dly
soug
ht: y
es
Dur
atio
n: 2
0 - 4
0 m
ins
Met
hod
of st
imul
atio
n: M
anua
l acu
punc
ture
Con
trol g
roup
: Sta
ndar
d an
ti-em
etic
s onl
y
Num
ber a
lloca
ted
to c
ontro
l = 2
3
Tota
l len
gth
of tr
eatm
ent p
erio
d: 4
wee
ks in
tota
l, co
ntro
l was
one
cyc
le e
ither
4 o
r 5 d
ays.
Out
com
es
Prim
ary
outc
ome–
anti-
emet
ic re
scue
med
icat
ion
use,
obt
aine
d fr
om c
hart
docu
men
tatio
n
Seco
ndar
y ou
tcom
e–nu
mbe
r of e
piso
des o
f ret
chin
g an
d vo
miti
ng, o
btai
ned
from
cha
rt do
cum
enta
tion
Sele
ctio
n bi
as
Patie
nt r
ando
mis
ed b
y co
mpu
ter
gene
ratio
n se
quen
cer
and
notif
ied
by p
hone
. Allo
catio
n of
trea
tmen
t was
con
ceal
ed
from
allo
cato
r and
bot
h gr
oups
wer
e co
mpa
rabl
e at
ent
ry
Attr
ition
bia
s N
o dr
opou
ts o
r with
draw
als,
low
risk
of b
ias
Perf
orm
ance
bias
Atte
mpt
to
conf
irm p
atie
nt b
lindi
ng f
or s
ham
con
trol?
Not
app
licab
le P
artic
ipan
ts n
ot b
linde
d du
e to
stu
dy d
esig
n.
Unc
lear
if o
utco
me
asse
ssor
s blin
ded.
Mea
sure
men
t Ty
pe o
f ana
lysi
s re
porte
d: p
erio
d ef
fect
s bo
th m
ean
and
stan
dard
err
or a
nd tr
eatm
ent e
ffec
ts a
nd tr
eatm
ent e
ffec
t bei
ng
14
5
bias
eq
ual i
n bo
th p
erio
ds
Not
es
Patie
nts a
lso
docu
men
ted
thei
r sub
ject
ive
expe
rienc
e of
acu
punc
ture
in a
shor
t ope
n-fo
rm e
ssay
Jone
s108
Met
hods
D
esig
n: C
ross
over
–acu
pres
sure
plu
s med
icat
ion
v. sh
am a
cupr
essu
re p
lus m
edic
atio
n v.
med
icat
ion
only
Dur
atio
n: 1
–5 d
ays f
or e
ach
cycl
e an
d to
tal 3
cyc
les
Parti
cipa
nts
Setti
ng: C
hild
ren’
s inp
atie
nt h
ospi
tal U
S.
Mea
n ag
e (+
/-SD
or r
ange
): 5–
19 (
two
sequ
ence
11.
7 +/
- 4.2
and
12.
5 +/
- 3.6
Men
/wom
en (n
/n):
9/9
Rec
ruitm
ent m
etho
d: n
ot st
ated
Incl
usio
n cr
iteria
: pa
tient
s re
ceiv
ing
chem
othe
rapy
tha
t in
clud
ed o
ne o
f th
e fo
llow
ing:
an
alky
latin
g ag
ent,
an
antit
umor
ant
ibio
tic o
r hig
h do
se c
ytar
abin
e
Excl
usio
n cr
iteria
: not
rece
ivin
g 3
cycl
es o
f che
mot
hera
py, o
ver 7
yea
rs o
ld a
nd d
id n
ot a
ssen
t or n
ot E
nglis
h sp
eaki
ng
Inte
rven
tions
In
terv
entio
n gr
oup:
acu
pres
sure
wris
t ban
d
Num
ber a
lloca
ted
to a
cupr
essu
re =
18
Poin
t sel
ectio
n: fo
rmul
a
Poin
ts st
imul
ated
: PC
6
Tota
l len
gth
of tr
eatm
ent p
erio
d: ti
me
of c
hem
othe
rapy
trea
tmen
t, no
t cle
arly
stat
ed a
s var
ied.
Num
ber o
f ses
sion
s: o
ne se
ssio
n
Num
ber o
f poi
nts u
sed:
One
14
6
Dur
atio
n: n
ot c
lear
, cou
ld b
e ho
urs t
o da
ys.
Met
hod
of st
imul
atio
n: se
a-ba
nds,
elas
tic w
rist b
and
with
pla
stic
but
ton
Con
trol g
roup
1: s
ham
acu
pres
sure
wris
t ban
d
Num
ber a
lloca
ted
to c
ontro
l = 1
8
Tota
l len
gth
of tr
eatm
ent p
erio
d: u
ncle
ar, c
ould
be
hour
s to
days
Met
hod
of st
imul
atio
n: se
a-ba
nds,
elas
tic w
rist b
and
with
no
plas
tic b
utto
n
Con
trol g
roup
2: n
o ac
upre
ssur
e
N a
lloca
ted
to c
ontro
l: 18
Tota
l len
gth
of tr
eatm
ent p
erio
d: u
ncle
ar
Out
com
es
Mod
ified
Mor
row
with
que
stio
ns w
ritte
n in
age
app
ropr
iate
. Nau
sea
mea
sure
d w
ith 1
1-po
int
Like
rt sc
ale.
Pre
viou
s
know
ledg
e an
d ex
perie
nce
with
acu
punc
ture
/acu
pres
sure
, ex
pect
atio
ns o
f na
usea
pre
vent
ion,
epi
sode
s of
em
esis
,
degr
ee o
f na
usea
at
vario
us t
ime
poin
ts, s
ide
effe
ct, s
atis
fact
ion
and
perc
eive
d di
ffer
ence
s ac
upre
ssur
e an
d pl
aceb
o
band
s.
Sele
ctio
n bi
as
Patie
nt r
ando
mis
ed,
met
hod
uncl
ear
and
uncl
ear
if al
loca
tion
of t
reat
men
t w
as c
once
aled
fro
m a
lloca
tor
and
both
grou
ps w
ere
com
para
ble
at e
ntry
Attr
ition
bia
s D
ropo
uts/
with
draw
als:
yes
(1 d
ied,
1 in
com
plet
e da
ta a
nd 1
cha
nged
che
mot
hera
py) b
ut n
ot in
clud
ed in
ana
lysi
s
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? N
ot a
pplic
able
Parti
cipa
nts w
ere
blin
ded,
unc
lear
if th
e ou
tcom
e as
sess
ors w
ere
blin
ded
Mea
sure
men
t
bias
Type
of a
naly
sis r
epor
ted:
mea
n an
d SD
and
con
sist
ent i
n bo
th g
roup
s
14
7
Mel
char
t 97
Met
hods
D
esig
n: C
ross
over
–acu
punc
ture
plu
s ac
upre
ssur
e pl
us m
edic
atio
n v.
sha
m a
cupu
nctu
re p
lus
sham
acu
pres
sure
plu
s
med
icat
ion
Dur
atio
n: tw
o cy
cles
of c
hem
othe
rapy
, not
cle
arly
stat
ed.
Parti
cipa
nts
Setti
ng: 1
hos
pita
l, M
unic
h, G
erm
any
Mea
n ag
e (+
/-SD
or r
ange
): 57
(17-
72)
Men
/wom
en (n
/n):
18/9
Rec
ruitm
ent m
etho
d: n
ot st
ated
Incl
usio
n cr
iteria
: sc
hedu
led
for
mod
erat
ely
or h
ighl
y em
etog
enic
che
mot
hera
py r
egim
es, s
tand
ard
anti-
emet
ics
and
addi
tiona
l med
icat
ion
for t
wo
chem
othe
rapy
cyc
le a
nd a
ges b
etw
een
18 -
75
Excl
usio
n cr
iteria
: ant
icip
ator
y na
usea
and
vom
iting
, che
mot
hera
py w
ithin
last
3 m
onth
s, ce
rebr
al m
etas
tase
s, ch
roni
c
ileus
or s
ub-il
eus,
lym
phed
ema
of a
rms
Inte
rven
tions
In
terv
entio
n gr
oup:
ant
i-em
etic
s and
acu
punc
ture
follo
wed
by
acup
ress
ure
band
s
Num
ber a
lloca
ted
to a
cupu
nctu
re =
10
Styl
e of
acu
punc
ture
: TC
M
Poin
t sel
ectio
n: fo
rmul
a
Poin
ts st
imul
ated
: PC
6
Tota
l len
gth
of tr
eatm
ent p
erio
d: 7
day
s for
eac
h cy
cle
tota
l 2 c
ycle
s
Num
ber o
f ses
sion
s: o
ne
Num
ber o
f poi
nts u
sed:
one
Inse
rtion
dep
th: 0
.5–1
cm
14
8
Was
Deq
i rep
orte
dly
soug
ht: y
es
Dur
atio
n: 2
0 m
ins a
cupu
nctu
re, 7
2hrs
acu
pres
sure
ban
ds a
nd fu
rther
4 d
ays i
f nee
ded
Met
hod
of st
imul
atio
n: m
anua
l and
acu
pres
sure
ban
d
Con
trol g
roup
: ant
i-em
etic
s and
sham
acu
punc
ture
and
acu
pres
sure
ban
ds
Num
ber a
lloca
ted
to a
cupu
nctu
re =
11
Poin
ts st
imul
ated
: sha
m p
oint
loca
ted
3-4c
m p
roxi
mal
to w
rist c
reas
e; in
serti
on o
f nee
dle
unde
r the
radi
us
Tota
l len
gth
of tr
eatm
ent p
erio
d: 7
day
s for
eac
h cy
cle,
tota
l 2 c
ycle
s
Num
ber o
f ses
sion
s: o
ne
Num
ber o
f poi
nts u
sed:
one
Inse
rtion
dep
th: 0
.5cm
Was
Deq
i rep
orte
dly
soug
ht: N
ot so
ught
, nee
dle
not m
anip
ulat
ed
Dur
atio
n: 2
0 m
ins f
or a
cupu
nctu
re fo
llow
ed b
y 72
hrs w
ith a
cupr
essu
re b
and
Met
hod
of st
imul
atio
n: m
anua
l sha
m a
cupu
nctu
re a
nd sh
am a
cupr
essu
re b
and
Out
com
es
Nau
sea
and
vom
iting
, ant
i-em
etic
resc
ue m
edic
atio
n
Dai
ly d
iary
com
plet
ed f
or 7
day
s, (in
tens
ity s
cale
0-6
) do
cum
entin
g fr
eque
ncy
and
dura
tion
of n
ause
a an
d vo
miti
ng
and
use
of a
dditi
onal
ant
i-em
etic
med
icat
ion.
Sho
rtene
d ve
rsio
n of
the
MA
NE
(Mor
row
Ass
essm
ent o
f N
ause
a an
d
Vom
iting
).
Mai
n ou
tcom
e w
as th
e in
tra-in
divi
dual
diff
eren
ce o
f the
nau
sea
scor
e (s
um o
f int
ensi
ty ra
ting
for
naus
ea in
the
diar
y
rang
e 0–
48) b
etw
een
acup
unct
ure
and
sham
acu
punc
ture
Seco
ndar
y ou
tcom
e m
easu
res w
here
No
naus
ea a
t all
14
9
No
vom
iting
Com
plet
e co
ntro
l (no
vom
iting
and
nau
sea
scor
e <9
)
Hou
rs w
ith n
ause
a
Num
ber o
f vom
iting
epi
sode
s
Use
of r
escu
e m
edic
atio
n
Acu
punc
ture
/acu
pres
sure
hel
ped
a lo
t
Pref
eren
ce
Adv
erse
eff
ects
Sele
ctio
n bi
as
Parti
cipa
nts
rand
omis
ed w
ith c
ompu
ter r
ando
m g
ener
atio
n an
d co
ncea
led
enve
lope
s an
d al
loca
tor b
linde
d to
allo
catio
n
of tr
eatm
ent g
roup
and
unc
lear
if b
oth
grou
ps w
ere
com
para
ble
at e
ntry
Attr
ition
bia
s D
ropo
uts/
with
draw
als:
yes
(3
chan
ge c
hem
othe
rapy
/dea
th,
1 tim
e pr
oble
ms,
1 in
effe
ctiv
e an
d 1
no d
ata)
but
not
incl
uded
in a
naly
sis
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? N
ot a
pplic
able
Ass
esso
rs o
f out
com
es b
linde
d to
allo
catio
n - n
ursi
ng st
aff a
nd o
ncol
ogis
t wer
e bl
inde
d to
allo
catio
n ar
m
Mea
sure
men
t
bias
Type
of a
naly
sis r
epor
ted:
rela
tive
risks
or M
D
15
0
Mol
assi
otis
73
Met
hods
D
esig
n: P
aral
lel–
acup
ress
ure
plus
med
icat
ion
v. m
edic
atio
n on
ly
Dur
atio
n: 5
day
s
Parti
cipa
nts
Setti
ng: t
wo
cent
res i
n th
e U
K, o
ne c
ance
r cen
tre a
t gen
eral
hos
pita
l and
one
a sp
ecia
list c
ance
r hos
pita
l
Mea
n ag
e (+
/-SD
or r
ange
): 51
(+/-
12.2
)
Men
/wom
en (n
/n):
0/54
Rec
ruitm
ent m
etho
d: n
ot st
ated
Incl
usio
n cr
iteria
: di
agno
sis
brea
st c
ance
r, ch
emot
hera
py n
aïve
, re
ceiv
ing
Dox
orub
icin
and
Cyc
loph
osph
amid
e or
equi
vale
nt E
piru
bici
n pr
otoc
ols
Excl
usio
n cr
iteria
: pa
lliat
ive
chem
othe
rapy
, le
ss t
han
3 m
onth
s to
liv
e, m
etas
tatic
dis
ease
, su
ffer
ed f
rom
bow
el
obst
ruct
ion,
hav
ing
conc
urre
nt ra
diot
hera
py o
r had
lym
phoe
dem
a of
the
arm
s.
Inte
rven
tions
In
terv
entio
n gr
oup:
acu
pres
sure
ban
ds
Num
ber a
lloca
ted
to a
cupr
essu
re =
17
Poin
t sel
ectio
n: fo
rmul
a
Poin
ts st
imul
ated
: Per
icar
dium
6
Tota
l len
gth
of tr
eatm
ent p
erio
d: 5
day
s
Num
ber o
f ses
sion
s: o
ne
Num
ber o
f poi
nts u
sed:
one
Dur
atio
n: 5
day
s
Met
hod
of st
imul
atio
n: se
a-ba
nd w
rist b
ands
Con
trol g
roup
: no
acup
ress
ure
15
1
Num
ber a
lloca
ted
to c
ontro
l = 1
9
Tota
l len
gth
of tr
eatm
ent p
erio
d: 5
day
s
Out
com
es
Rev
ised
Rho
des I
NV
R, n
umbe
r of t
imes
wris
tban
d st
ud w
as p
ress
ed, a
nti-e
met
ic u
se
Attr
ition
bia
s D
ropo
uts/
with
draw
als:
yes
(18
not c
ompe
ted
stud
y re
ason
s no
t sta
ted,
6 c
ontro
l gro
up a
nd 1
2 ex
perim
enta
l gro
up) n
ot
incl
uded
in a
naly
sis
Sele
ctio
n bi
as
Patie
nt e
ffec
tivel
y ra
ndom
ised
, allo
catio
n of
gro
up c
once
aled
from
allo
cato
r and
bot
h gr
oups
com
para
ble
at e
ntry
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? N
ot a
pplic
able
Parti
cipa
nts n
ot b
linde
d, u
ncle
ar if
out
com
e as
sess
ors w
here
blin
ded
Mea
sure
men
t
bias
Type
of a
naly
sis r
epor
ted:
p v
alue
, util
ised
on
both
gro
ups
Rei
ndl 98
Met
hods
D
esig
n: C
ross
over
–acu
punc
ture
plu
s med
icat
ion
v. m
edic
atio
n on
ly
Dur
atio
n: to
tal o
f 3 c
ycle
s tim
e no
t spe
cifie
d.
Parti
cipa
nts
Setti
ng: 4
inpa
tient
pae
diat
ric c
entre
s, G
erm
any
Mea
n ag
e (+
/-SD
or r
ange
): 15
.2 (1
0.0-
16.8
)
Men
/wom
en (n
/n):
4/7
Rec
ruitm
ent m
etho
d: n
ot st
ated
Incl
usio
n cr
iteria
: pa
tient
s ag
ed 6
–18y
ears
who
rec
eive
sev
eral
cou
rse
of h
ighl
y em
etog
enic
che
mot
hera
py t
reat
ing
Ewin
g’s s
arco
ma,
rhab
dom
yosa
rcom
a an
d os
teos
arco
ma
havi
ng 5
HT3
ant
agon
ists
as b
asic
ant
i-em
etic
med
icat
ion
Excl
usio
n cr
iteria
: No
excl
usio
n cr
iteria
list
ed
15
2
Inte
rven
tions
In
terv
entio
n gr
oup:
Sta
ndar
d an
ti-em
etic
s and
acu
punc
ture
on
Day
1 p
rior t
o ch
emot
hera
py a
nd su
bseq
uent
4 o
r 5 d
ays
Num
ber a
lloca
ted
to a
cupu
nctu
re =
11
Styl
e of
acu
punc
ture
: TC
M
Poin
t sel
ectio
n: fl
exib
le, p
ract
ition
er d
ecis
ion
base
d on
TC
M p
rinci
ples
Poin
ts st
imul
ated
: mos
t com
mon
poi
nts u
sed
PC6,
ST3
6, C
V12
and
LI4
Tota
l len
gth
of tr
eatm
ent p
erio
d: T
hree
cyc
les w
ith th
ird c
ycle
not
eva
luat
ed
Num
ber o
f ses
sion
s: 4
or 5
dep
endi
ng o
n ch
emot
hera
py p
roto
col p
er se
ssio
n, to
tal o
f 8 o
r 10
Num
ber o
f poi
nts u
sed:
not
stat
ed, p
oint
s cou
ld b
e un
ilate
ral o
r bila
tera
l
Inse
rtion
dep
th: n
ot st
ated
Was
Deq
i rep
orte
dly
soug
ht: n
ot st
ated
Dur
atio
n: 2
0 m
ins
Met
hod
of st
imul
atio
n: m
anua
l stim
ulat
ion
Con
trol g
roup
: sta
ndar
d an
ti-em
etic
s alo
ne
Num
ber a
lloca
ted
to c
ontro
l = 1
1
Tota
l len
gth
of tr
eatm
ent p
erio
d: tw
o cy
cles
of c
hem
othe
rapy
Out
com
es
Res
cue
anti-
emet
ic u
se, e
piso
des o
f vom
iting
, nau
sea
and
wei
ght l
oss.
Res
cue
anti-
emet
ic u
se o
btai
ned
from
med
ical
cha
rt, re
porte
d as
mg/
day.
Vom
iting
epi
sode
s rec
orde
d as
a n
umbe
r per
day
for e
ach
cycl
e.
Wei
ght l
oss w
as re
cord
ed b
y kg
/cyc
le lo
st.
Nau
sea
scor
e us
ing
eval
uate
d to
ol (M
emor
ial S
ympt
om A
sses
smen
t Sca
le (M
SAS)
), co
ncer
ning
sen
satio
ns o
f nau
sea,
vom
iting
and
app
etite
.
15
3
Sele
ctio
n bi
as
Parti
cipa
nts
rand
omis
ed, m
etho
d un
clea
r, al
loca
tion
of tr
eatm
ent w
as c
once
aled
from
allo
cato
r an
d bo
th g
roup
s w
ere
com
para
ble
at e
ntry
Attr
ition
bia
s N
o dr
opou
ts o
r with
draw
als,
low
risk
of b
ias
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? N
ot a
pplic
able
Parti
cipa
nts n
ot b
linde
d to
trea
tmen
t gro
up d
ue to
tria
l des
ign,
unc
lear
if o
utco
me
asse
ssor
s whe
re b
linde
d
Mea
sure
men
t
bias
Type
of a
naly
sis r
epor
ted:
p v
alue
, con
sist
ent w
ith b
oth
grou
ps
Ros
coe
109
Met
hods
D
esig
n: P
aral
lel–
acup
ress
ure
plus
med
icat
ion
v. m
edic
atio
n on
ly
Dur
atio
n: 5
day
s
Parti
cipa
nts
Setti
ng: 1
7 C
ance
r Cen
tres i
n R
oche
ster
USA
Mea
n ag
e (+
/-SD
or r
ange
): N
ot re
porte
d
Men
/wom
en (n
/n):
55/6
45
Rec
ruitm
ent m
etho
d: n
ot c
lear
Incl
usio
n cr
iteria
: che
mot
hera
py n
aïve
, che
mot
hera
py c
onta
inin
g ci
spla
tin o
r dox
orub
icin
Excl
usio
n cr
iteria
: con
curr
ent r
adio
ther
apy
or in
terf
eron
, bow
el o
bstru
ctio
n, s
ympt
omat
ic b
rain
met
asta
ses
or c
ardi
ac
pace
mak
er.
Inte
rven
tions
In
terv
entio
n gr
oup:
acu
pres
sure
ban
d
Num
ber a
lloca
ted
to a
cupu
nctu
re =
231
(not
stat
ed)
Poin
ts st
imul
ated
: Per
icar
dium
6
15
4
Tota
l len
gth
of tr
eatm
ent p
erio
d: 5
day
s
Num
ber o
f ses
sion
s: o
ne
Num
ber o
f poi
nts u
sed:
one
Dur
atio
n: 5
day
s
Met
hod
of st
imul
atio
n: se
a-ba
nds a
cupr
essu
re b
ands
Con
trol g
roup
: no
treat
men
t
Num
ber a
lloca
ted
to c
ontro
l = 2
26
Tota
l len
gth
of tr
eatm
ent p
erio
d: 5
day
s
Out
com
es
Patie
nt re
port
diar
y de
velo
ped
by B
uris
h et
al a
nd C
arey
and
Bur
ish
mea
surin
g na
usea
and
em
esis
in 4
tim
e po
ints
eac
h
day.
Nau
sea
mea
sure
d on
7-p
oint
sca
le.
QoL
mea
sure
d by
FA
CT-
G (
Func
tiona
l A
sses
smen
t of
Can
cer
Ther
apy
–
Gen
eral
), ex
pect
ed e
ffic
acy
asse
ss o
n 5
poin
t sca
le.
Sele
ctio
n bi
as
Parti
cipa
nts
rand
omis
ed m
etho
d un
clea
r, un
clea
r if
allo
cato
r w
as b
linde
d to
gro
up a
lloca
tion,
unc
lear
if b
oth
grou
ps
wer
e co
mpa
rabl
e at
ent
ry
Attr
ition
bia
s D
ropo
uts/
with
draw
als:
yes
reas
ons n
ot st
ated
, not
util
ised
in a
naly
sis
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? N
ot a
pplic
able
Not
cle
ar if
out
com
e as
sess
ors b
linde
d to
gro
up
Mea
sure
men
t
bias
Type
of a
naly
sis r
epor
ted:
Mea
n an
d SD
, p-v
alue
, con
sist
ent w
ith b
oth
grou
ps
Shen
99
Met
hods
D
esig
n: P
aral
lel–
acup
unct
ure
plus
med
icat
ions
v. s
ham
acu
punc
ture
plu
s med
icat
ions
v. m
edic
atio
n on
ly
15
5
Que
stio
nnai
re a
t the
end
of D
ay 5
stud
y pe
riod
Dur
atio
n: 1
4 da
ys
Parti
cipa
nts
Setti
ng: 1
inpa
tient
hos
pita
l, U
SA
Mea
n ag
e (+
/-SD
or r
ange
): 45
.5(7
.4) E
A, 4
3.8(
8.0)
min
imal
nee
dlin
g an
d 48
.0(6
.8) p
harm
acot
hera
py o
nly
Men
/Wom
en (n
/n):
0/10
4
Rec
ruitm
ent m
etho
d: p
atie
nts a
ppro
ache
d at
clin
ics
Incl
usio
n cr
iteria
: fem
ale
patie
nts
18 -
62
year
s of
age
, bre
ast c
ance
r, re
ceiv
ing
mye
loab
lativ
e ch
emot
hera
py a
nd f
or
bone
mar
row
tran
spla
ntat
ion,
life
exp
ecta
ncy
at le
ast 6
mon
ths
Excl
usio
n cr
iteria
: pa
tient
s w
ith b
rain
met
asta
ses,
life
thre
aten
ing
conc
urre
nt n
on-m
alig
nant
con
ditio
ns,
activ
e
infe
ctio
ns, c
ardi
ac p
acem
aker
Inte
rven
tions
In
terv
entio
n gr
oup:
stan
dard
ant
i-em
etic
s and
EA
for t
otal
5 d
ays.
Num
ber a
lloca
ted
to a
cupu
nctu
re =
37
Styl
e of
acu
punc
ture
: TC
M
Poin
t sel
ectio
n: fo
rmul
a
Poin
ts st
imul
ated
: PC
6 an
d ST
36
Tota
l len
gth
of tr
eatm
ent p
erio
d: 5
day
s
Num
ber o
f ses
sion
s: 5
Num
ber o
f poi
nts u
sed:
2
Inse
rtion
dep
th: 1
to 1
.5 b
ody
inch
Was
Deq
i rep
orte
dly
soug
ht: Y
es
Dur
atio
n: 2
0 m
inut
es
15
6
Met
hod
of s
timul
atio
n: E
A -
2 to
10
Hz,
0.5
- 0.
7 m
s pu
lse
wid
th, u
nder
a v
aria
ble
DC
out
put w
ith s
quar
e w
avef
orm
bala
nced
alte
rnat
ing
pola
rity
of le
ss th
an 2
6 m
A m
axim
al v
olta
ge 1
5 V
Con
trol g
roup
1: s
tand
ard
anti-
emet
ics a
nd m
inim
al a
cupu
nctu
re fo
r tot
al 5
day
s
Num
ber a
lloca
ted
to a
cupu
nctu
re =
33
Poin
t sel
ectio
n: =
form
ula
Poin
ts st
imul
ated
: nea
r LU
7 an
d G
B34
Tota
l len
gth
of tr
eatm
ent p
erio
d: 5
day
s
Num
ber o
f ses
sion
s: 5
Num
ber o
f poi
nts u
sed:
2
Inse
rtion
dep
th: m
inim
al w
ith n
o st
imul
atio
n
Was
Deq
i rep
orte
dly
soug
ht: N
o
Dur
atio
n: 2
0
Met
hod
of st
imul
atio
n: e
lect
rost
imul
ator
was
con
nect
ed b
ut n
o cu
rren
t was
pas
sed
to th
e ne
edle
s
Con
trol g
roup
2: s
tand
ard
anti-
emet
ics
Num
ber a
lloca
ted
to a
cupu
nctu
re =
34
Tota
l len
gth
of tr
eatm
ent p
erio
d: 5
day
s
Out
com
es
Emes
is, e
mes
is fr
ee d
ays,
AEs
and
con
curr
ent a
nti-e
met
ic u
se
Emes
is m
easu
red
and
reco
rded
dai
ly b
y nu
rsin
g st
aff,
emes
is a
s de
fined
as
proj
ectio
n of
gas
tric
cont
ents
not
dry
retc
hing
.
Prop
ortio
n of
em
esis
free
day
s was
cal
cula
ted
Patie
nts i
dent
ified
any
AEs
they
thou
gh w
ere
attri
bute
d to
the
stud
y
15
7
Con
curr
ent a
nti-e
met
ic u
se w
as id
entif
ied
from
doc
umen
tatio
n.
All
staf
f wer
e un
awar
e of
pat
ient
s gro
up a
lloca
tion
Sele
ctio
n bi
as
Patie
nt e
ffec
tivel
y ra
ndom
ised
by
conc
eale
d en
velo
pe s
yste
m, a
lloca
tion
of g
roup
con
ceal
ed f
rom
allo
cato
r an
d bo
th
grou
ps w
ere
com
para
ble
at e
ntry
Attr
ition
bia
s N
o dr
opou
ts o
r with
draw
als,
low
risk
of b
ias
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng f
or s
ham
con
trol?
Yes
Par
ticip
ants
blin
ded.
Out
com
e as
sess
ors
wer
e bl
inde
d to
treat
men
t gro
up, n
ursi
ng st
aff a
nd o
ther
staf
f wer
e al
so b
linde
d to
pat
ient
allo
catio
n.
Mea
sure
men
t
bias
Type
of
anal
ysis
rep
orte
d: A
naly
sed
acco
rdin
g to
the
int
entio
n-to
-trea
t pr
inci
pal.
p va
lue
and
CIs
, co
nsis
tent
bot
h
grou
ps
Stre
itber
ger 10
0
Met
hods
D
esig
n: P
aral
lel–
acup
unct
ure
plus
med
icat
ion
v. sh
am a
cupu
nctu
re p
lus m
edic
atio
ns
Dur
atio
n: 2
day
s
Parti
cipa
nts
Setti
ng: O
ne h
ospi
tal H
aem
atol
ogy
and
Onc
olog
y un
it, H
eide
lber
g, G
erm
any
Mea
n ag
e (+
/-SD
or r
ange
): 54
.9 (9
.0) a
cupu
nctu
re a
nd 5
3.3(
9.3)
pla
cebo
gro
up
Men
/wom
en (n
/n):
41/3
9
Rec
ruitm
ent m
etho
d: n
ot c
lear
ly st
ated
Wer
e pe
ople
with
his
tory
of a
cupu
nctu
re tr
eatm
ent e
xclu
ded?
:Yes
, no
acup
unct
ure
for l
ast 6
mon
ths
Incl
usio
n cr
iteria
: 18
year
s or
old
er, p
atie
nts
rece
ivin
g hi
gh d
ose
chem
othe
rapy
and
aut
olog
ous
perip
hera
l blo
od s
tem
cell
trans
plan
tatio
ns
Excl
usio
n cr
iteria
: pat
ient
s su
ffer
ing
naus
ea a
nd v
omiti
ng la
st 2
4 ho
urs,
rece
ivin
g an
ti-em
etic
dru
gs 2
4 ho
urs
befo
re
15
8
chem
othe
rapy
, rec
eivi
ng b
enzo
diaz
epin
es (e
xcep
tion
for o
ne a
pplic
atio
n at
nig
ht),
had
rece
ived
an
anti-
emet
ic th
erap
y
befo
re t
he s
tart
of c
hem
othe
rapy
exc
eptio
n of
ste
roid
s if
part
of t
he c
hem
othe
rapy
tre
atm
ent
or a
phy
siol
ogic
al
supp
lem
ent
ther
apy,
ecz
emat
ous
skin
cha
nges
at
acup
unct
ure
poin
t PC
6, p
last
er a
llerg
y, o
pioi
d th
erap
y st
artin
g or
coag
ulop
athy
.
Inte
rven
tions
In
terv
entio
n gr
oup:
stan
dard
ant
i-em
etic
s and
acu
punc
ture
Num
ber a
lloca
ted
to a
cupu
nctu
re =
41
Styl
e of
acu
punc
ture
: TC
M
Poin
t sel
ectio
n: fo
rmul
a
Poin
ts st
imul
ated
: one
Tota
l len
gth
of tr
eatm
ent p
erio
d: 2
day
s
Num
ber o
f ses
sion
s: 2
Num
ber o
f poi
nts u
sed:
1
Inse
rtion
dep
th: N
ot st
ated
Was
Deq
i rep
orte
dly
soug
ht: Y
es
Dur
atio
n: 2
0 m
inut
es
Met
hod
of st
imul
atio
n: m
anua
l stim
ulat
ion,
initi
al d
e qi
sens
atio
n ob
tain
ed th
en le
ft in
situ
for 2
0 m
inut
es
Con
trol g
roup
: sta
ndar
d an
ti-em
etic
s and
pla
cebo
acu
punc
ture
Num
ber a
lloca
ted
to a
cupu
nctu
re =
39
Styl
e of
acu
punc
ture
: TC
M
Poin
t sel
ectio
n: fo
rmul
a
Poin
ts st
imul
ated
: PC
6
15
9
Tota
l len
gth
of tr
eatm
ent p
erio
d: 2
day
s
Num
ber o
f ses
sion
s: 2
Num
ber o
f poi
nts u
sed:
1
Inse
rtion
dep
th: Z
ero
Was
Deq
i rep
orte
dly
soug
ht: n
ot so
ught
Dur
atio
n: 2
0 m
inut
es
Met
hod
of st
imul
atio
n: u
se o
f Stre
itber
ger p
lace
bo n
eedl
e (b
lunt
ed, t
eles
copi
c pl
aceb
o ne
edle
)
Out
com
es
Vom
iting
, res
cue
med
icat
ions
, nau
sea,
side
eff
ects
of a
cupu
nctu
re, c
redi
bilit
y of
trea
tmen
t
Vom
iting
ass
esse
d by
num
ber
of p
atie
nts
who
had
one
epi
sode
of
vom
iting
in
the
even
ing
of e
ach
day
by u
se o
f
patie
nts d
iary
Use
of r
escu
e m
edic
atio
ns a
sses
sed
on fi
rst a
nd se
cond
day
Nau
sea
asse
ssed
by
4 po
int s
cale
(non
e =
0, m
ild =
1, m
oder
ate
= 2,
seve
re =
3)
Epis
odes
of v
omiti
ng a
nd re
tchi
ng
Sele
ctio
n bi
as
Parti
cipa
nts
rand
omis
ed b
ut m
etho
d un
clea
r, al
loca
tor
was
blin
ded
to t
reat
men
t gr
oups
and
bot
h gr
oups
wer
e
com
para
ble
at e
ntry
Attr
ition
bia
s N
o dr
opou
ts o
r with
draw
als,
low
risk
of b
ias
Perf
orm
ance
bias
Atte
mpt
to c
onfir
m p
atie
nt b
lindi
ng fo
r sha
m c
ontro
l? Y
es a
sses
sed
with
tool
dev
elop
ed b
y V
ince
nt
Out
com
e as
sess
ors w
here
blin
ded
to a
lloca
tion
and
patie
nts w
here
blin
ded
to tr
eatm
ent g
roup
Mea
sure
men
t
bias
Type
of a
naly
sis
repo
rted:
Ps
(t te
st fo
r con
tinuo
us v
aria
ble,
Fis
her's
exa
ct te
st fo
r cat
egor
ical
var
iabl
es),
cons
iste
nt fo
r
both
gro
ups
16
0
App
endi
x T
hree
Exc
lude
d St
udie
s
Excl
uded
stud
ies
Reas
ons f
or e
xclu
sion
Nog
a110
Stud
y in
vest
igat
ing
acup
ress
ure
for
cont
rol
of n
ause
a, v
omiti
ng a
nd r
etch
ing
durin
g bo
ne
mar
row
tran
spla
ntat
ion.
Exc
lude
d as
insu
ffic
ient
dat
a, a
bstra
ct f
rom
the
Am
eric
an S
ocie
ty o
f
Clin
ical
Onc
olog
y C
onfe
renc
e, a
utho
r con
tact
ed a
nd n
o re
spon
se.
Tolm
an-J
ager
111
Stud
y in
vest
igat
ing
acup
ress
ure
for
cont
rol
of n
ause
a, v
omiti
ng a
nd r
etch
ing
durin
g bo
ne
mar
row
tran
spla
ntat
ion.
Exc
lude
d as
insu
ffic
ient
dat
a, a
bstra
ct fr
om th
e U
nion
for I
nter
natio
nal
Can
cer C
ontro
l Con
fere
nce,
aut
hor c
onta
cted
and
no
resp
onse
.
Wul
ff 11
2
Stud
y in
vest
igat
ing
acup
ress
ure
for
naus
ea a
nd v
omiti
ng in
chi
ldre
n re
ceiv
ing
chem
othe
rapy
.
Excl
uded
as
insu
ffic
ient
dat
a, a
bstra
ct f
rom
the
Euro
pean
Con
gres
s fo
r In
tegr
ativ
e M
edic
ine,
auth
or c
onta
cted
and
no
resp
onse
.
Cho
o91
Stud
y in
vest
igat
ing
EA f
or r
efra
ctor
y ac
ute
emes
is i
nduc
ed b
y ch
emot
hera
py.
Excl
uded
, as
sam
ple
was
not
rand
omly
sele
cted
.
Ros
coe
113
Stud
y in
vest
igat
ing
acus
timul
atio
n ba
nds
on c
hem
othe
rapy
rel
ated
nau
sea
in b
reas
t ca
ncer
patie
nts.
Excl
uded
, as a
cust
imul
atio
n ba
nd n
ot in
clud
ed in
the
sear
ch c
riter
ia
16
1
Li11
4
Stud
y in
vest
igat
ing
Hai
shen
gsu
for
non-
smal
l ce
ll lu
ng c
ance
r an
d ch
emot
hera
py i
nduc
ed
naus
ea o
r vom
iting
. Exc
lude
d as
her
bal f
orm
ulat
ion
not a
cupo
int s
timul
atio
n.
Lee11
5
Stud
y in
vest
igat
ing
the
rela
tions
hip
of c
hem
othe
rapy
ind
uced
nau
sea
to t
he f
requ
ency
of
Peric
ardi
um 6
, dig
ital a
cupr
essu
re. E
xclu
ded
as e
xplo
rato
ry a
naly
sis o
f pre
viou
s tria
l.
Ros
coe11
6
Stud
y in
vest
igat
ing
incr
easi
ng e
xpec
tatio
n of
eff
icac
y of
acu
pres
sure
ban
ds w
ould
enh
ance
thei
r eff
ectiv
enes
s in
CIN
V. E
xclu
ded
as e
xplo
rato
ry a
naly
sis o
f pre
viou
s tria
l.
16
2
App
endi
x Fo
ur E
xclu
ded
Rev
iew
s
Excl
uded
revi
ews
Reas
ons f
or e
xclu
sion
Cap
odic
e117
A r
evie
w o
f ac
upun
ctur
e in
the
onc
olog
ical
set
ting,
with
a c
linic
al u
pdat
e. E
xclu
ded
as
cove
red
all s
ympt
oms a
cupu
nctu
re c
ould
be
used
for a
nd w
as d
escr
iptiv
e re
view
.
Saga
r83
A re
view
of a
cupu
nctu
re a
s an
evid
ence
d ba
sed
optio
n fo
r sym
ptom
con
trol i
n ca
ncer
pat
ient
s.
Excl
uded
as c
over
ed a
ll sy
mpt
oms a
cupu
nctu
re c
ould
be
used
for a
nd w
as d
escr
iptiv
e re
view
.
Cha
o68
A re
view
of t
he e
ffic
acy
of a
cupo
int s
timul
atio
n fo
r the
man
agem
ent o
f the
rapy
-rel
ated
AEs
in
brea
st c
ance
r. Ex
clud
ed a
s no
met
a-an
alys
is a
nd o
nly
look
ed a
t bre
ast c
ance
r pat
ient
s
Stre
itber
ger11
8 A
rev
iew
of
acup
unct
ure
for
naus
ea a
nd v
omiti
ng,
an u
pdat
e of
clin
ical
and
exp
erim
enta
l
stud
ies.
Excl
uded
as r
evie
w in
clud
ed a
ll ca
uses
of n
ause
a an
d vo
miti
ng.
Lee11
9
A r
evie
w o
f ac
upre
ssur
e st
udie
s fo
r C
INV
con
trol.
Excl
uded
as
narr
ativ
e re
view
of
acup
ress
ure
stud
ies.
163
Appendix Five
Meta Analysis Forest Plots
1.1 Frequency of Vomiting
Study or
Subgroup
Experimental Control Mean difference
Mean SD Total Mean SD Total Weight % IV, Fixed, 95% CI
Gottschling 2008 3.83 2.41 12 11.36 2.56 11 67.5 -7.53 [-9.57, -5.49]
Shen 2000 6.23 4.16 37 13.41 7.77 34 23.5 -7.12 [-10.06, -4.18]
Total (95% CI) 49 45 100.00 -7.40 [-9.07, -5.72]
Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.82); 12 = 0%Test for overall effect: Z = 8.66 (P < 0.00001)
Mean difference
IV, Fixed, 95% CI
–100 –50 0 50 100Favours experimental Favours control
1: ACUPUNCTURE + MEDICATION VS MEDICATION ONLY
1.2 Dose of Rescue Medication
Study or
Subgroup
Experimental Control Std. Mean difference
Mean SD Total Mean SD Total Weight % IV, Fixed, 95% CI
Gottschling 2008 13.47 6.07 12 48.95 6.34 11 100.00 -5.52 [-7.45, -3.58]
Total (95% CI) 12 11 100.00 -5.52 [-7.45, -3.58]
Heterogeneity: Not applicableTest for overall effect: Z = 5.59 (P < 0.00001)
Std. Mean difference
IV, Fixed, 95% CI
–100 –50 0 50 100Favours experimental Favours control
2.1 Frequency of Vomiting
Study or
Subgroup
Acupuncture
plus Meds Control Risk Ratio
Events Total Events Total Weight % M–H, Fixed, 95%
Dundee 1987 2 7 3 3 26.2 0.36 [0.12, 1.06]
Melchart 2006 7 24 6 24 33.6 1.17 [0.46, 2.96]
Streitberger 2003 4 41 7 39 40.2 0.54 [0.17, 1.71]
Total (95% CI) 72 66 100.00 0.70 [0.38, 1.29]
Total events 13 16
Heterogeneity: Chi2 = 2.81, df = 2 (P = 0.25); 12 = 29%Test for overall effect: Z = 1.13 (P = 0.26)
Risk Ratio
M–H, Fixed, 95% CI
0.01 0.1 1 10 100Favours experimental Favours control
2: ACUPUNCTURE PLUS MEDICATIONS VS SHAM PLUS MEDICATIONS
164
2.2 Frequency of Nausea
Study or Subgroup
Acupuncture
plus Meds Sham plus meds Risk Ratio
Events Total Events Total Weight % M–H, Fixed, 95%
Melchart 2006 10 24 12 24 43.8 0.83 [0.45, 1.55]
Streitberger 2003 18 41 15 39 56.2 1.14 [0.67, 1.93]
Total (95% CI) 65 63 100.00 1.01 [0.67, 1.50]
Total events 28 27
2: ACUPUNCTURE PLUS MEDICATIONS VS SHAM PLUS MEDICATIONS CONT.
Risk Ratio
M–H, Fixed, 95% CI
0.01 0.1 1 10 100Favours experimental Favours control
Heterogeneity: Chi2 = 0.58, df = 1 (P = 0.45); 12 = 0%Test for overall effect: Z = 0.03 (P = 0.98)
2.3 Use of Rescue Medications
Study or Subgroup
Experimental Control Risk Ratio
Events Total Events Total Weight % M–H, Fixed, 95%
Melchart 2006 12 24 12 24 59.4 1.00 [0.57, 1.76]
Streitberger 2003 9 41 8 39 40.6 1.07 [0.46, 2.49]
Total (95% CI) 65 63 100.00 1.03 [0.64, 1.67]
Total events 21 20
Risk Ratio
M–H, Fixed, 95% CI
0.01 0.1 1 10 100Favours experimental Favours control
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.89); 12 = 0%Test for overall effect: Z = 0.11 (P = 0.91)
2.4 Helpfulness of Acupuncture
Study or Subgroup
Acupuncture
plus Meds Sham plus Meds Risk Ratio
Events Total Events Total Weight % M–H, Fixed, 95%
Streitberger 2003 21 24 12 24 59.4 1.00 [0.57, 1.76]
Total (95% CI) 65 63 100.00 1.03 [0.64, 1.67]
Total events 21 20
Risk Ratio
M–H, Fixed, 95% CI
0.01 0.1 1 10 100Favours experimental Favours control
Heterogeneity: Not applicableTest for overall effect: Z = 0.45 (P = 0.65)
165
3: ACUPRESSURE PLUS MEDICATIONS VS MEDICATIONS ONLY
4: ACUPRESSURE PLUS MEDICATION VS SHAM ACUPRESSURE PLUS MEDICATION
3.1 Frequency of Vomiting
Study or
Subgroup
Experimental Control Mean difference
Mean SD Total Mean SD Total Weight % IV, Fixed, 95% CI
Molassiotis 2006 0.53 2.1 17 0.66 1.94 19 100.0 -0.13 [-1.46, -1.20]
Total (95% CI) 17 19 100.00 -0.13 [-1.46, -1.20]
Heterogeneity: Not applicableTest for overall effect: Z = 0.19 (P = 0.85)
Mean difference
IV, Fixed, 95% CI
–10 –5 0 5 10Favours experimental Favours control
3.2 Frequency of Nausea
Study or
Subgroup
Experimental Control Mean difference
Mean SD Total Mean SD Total Weight % IV, Fixed, 95% CI
Dibble 2000 2.83 1.6 8 3 0.58 9 5.1 -0.17 [-1.34, -1.00]
Molassiotis 2006 0.66 1.6 17 2.16 2.4 19 4.0 -1.50 [-2.82, -0.18]
Roscoe 2003 1.99 1.47 231 2.27 1.55 226 90.9 -0.28 [-0.56, -0.00
Total (95% CI) 256 254 100.00 -0.32 [-0.59, -0.06]
Mean difference
IV, Fixed, 95% CI
–10 –5 0 5 10Favours experimental Favours control
Heterogeneity: Chi2 = 3.21, df = 2 (P = 0.20); 12 = 38%Test for overall effect: Z = 2.40 (P = 0.02)
4.1 Frequency of Vomiting
Study or
Subgroup
Experimental Control Odds Ratio
Events Total Events Total Weight % M–H, Fixed, 95% CI
Melchart 2006 7 24 6 24 100.00 1.24 [0.34, 4.43]
Total (95% CI) 24 24 100.00 1.24 [0.34, 4.43]
Total events 7 6
Odds Ratio
M–H, Fixed, 95% CI
0.01 0.1 1 10 100Favours experimental Favours controlHeterogeneity: Not applicable
Test for overall effect: Z = 0.32 (P = 0.75)
166
4: ACUPRESSURE PLUS MEDICATION VS SHAM ACUPRESSURE PLUS MEDICATION CONT.
4.3 Use of Rescue Medication
Study or Subgroup
Experimental Control Odds Ratio
Events Total Events Total Weight % M–H, Fixed, 95% CI
Melchart 2006 12 24 12 24 100.00 1.00 [0.32, 3.10]
Total (95% CI) 24 24 100.00 1.00 [0.32, 3.10]
Total events 12 12
Odds Ratio
M–H, Fixed, 95% CI
0.01 0.1 1 10 100Favours experimental Favours controlHeterogeneity: Not applicable
Test for overall effect: Z = 0.00 (P = 1.00)
4.2 Frequency of Nausea
Study or Subgroup
Experimental Control Mean difference
Mean SD Total Mean SD Total Weight % IV, Fixed, 95% CI
Melchart 2006 6.2 9 24 6.3 9.1 24 100.00 -0.10 [-5.22, 5.02]
Total (95% CI) 24 24 100.00 -0.10 [-5.22, 5.02]
Heterogeneity: Not applicableTest for overall effect: Z = 0.04 (P = 0.97)
Mean difference
IV, Fixed, 95% CI
–100 –50 0 50 100Favours experimental Favours control
167
APPENDIX Six
Emetic risk
(estimated incidence
without
prophylaxis)
High (>90%) Moderate (30-90%)
Agent of emesis Cisplatin
Mechlorethamine
Strptozotocin
Cyclophosphamide >1500
mg/m2
Carmustine
Dacarbazine
Oxaliplatin
Cytarabine >1 gm/m2
Carboplatin
Ifosfamide
Cyclophosphamide
<1500mg/m2
Doxorubicin
Danorubicin
Epirubicin
Idarubicin
Irinotecan Adapted by Roila et al. 2010. Guideline update for MASCC and ESMO in the prevention of chemotherapy and radiotherapy-induced nausea and vomiting.32
168
APPENDIX Seven
PATIENT INFORMATION AND CONSENT FORM
Protocol Title: A Randomised trial of electroacupuncture versus sham acupuncture and no acupuncture for the control of acute and delayed chemotherapy induced nausea and vomiting – pilot feasibility study
Principle Investigator:
Co-Investigators:
Chris McKeon RN/Acupuncturist
Prof. Janet Hardy
Kerry Reed RN
Study Nurse: Ms Helen Anderson
Address: Day Oncology Unit Mater Adult Hospital Raymond Terrace South Brisbane, QLD, 4101
Telephone Number: 07 3163 5689 or 07 3163 3884
Your doctor has asked if you would be willing to take part in this study. The purpose of this form is to explain the study. Please ask the study doctor or the study staff to explain any words or information that you do not clearly understand. You may take home an unsigned copy of this participant information and consent form to think about or discuss with family or friends before making a decision about whether or not you want to take part in this study.
If you agree to take part in this research study, be sure all your questions are answered before signing the consent form. You will be given a signed copy of this form to keep.
169
Purpose of the study
The purpose of this study is to try and reduce the incidence of chemotherapy induced nausea and vomiting (CINV) in medical oncology patients by looking at acupuncture as an additional method of control. Chemotherapy induced nausea and vomiting remains a major concern for some patients despite the new and improved anti-sickness drugs (antiemetics) now available. Chemotherapy is one of the most important tools in the fight against cancer. The development of new and better antiemetic therapy, has led to a marked improvement in CINV and hence a patient’s quality of life. However, there still remain those who experience some form of nausea and vomiting.
The study is to determine whether electroacupuncture is beneficial in helping to prevent the incidence of CINV when delivered in conjunction with standard antiemetic therapy. The interview is to obtain information from you in regards to your experiences, perceptions and beliefs about the acupuncture intervention in relation to the trial
Description of the study and procedure You are about to have your first course of chemotherapy. If you agree to enter this study, you will be allocated randomly (by chance) to one of three groups. One-third of patients will receive true electroacupuncture, one-third will receive sham electroacupuncture (not using true acupuncture points) and one-third will act as a control arm and will receive standard care with no acupuncture. All patients will receive standard antiemetic (anti nausea) medications and breakthrough anti-sickness medications. Those patients having acupuncture arms will receive eight needles in total, two in each hand and two in each leg, and will be connected to a micro-stimulator that will deliver a very small current. The treatment will commence 10 minutes before chemotherapy starts and continue for a total of 30 minutes. For those receiving acupuncture, the treatment can be repeated on day 3 if you are prepared to come back to the hospital. Parking costs will be covered for the visit on day 3 if you agree to a further session of acupuncture. The acupuncture is only being given during the first course of chemotherapy. Your oncologist has been informed that we will be asking you to enter this study. It will not effect your treatment in any way. Patients in the treatment arm may be approached to participate in an interview about the treatment and their experiences. The participation is voluntary and you will be asked to give written consent for interview to be recorded. It is expected the interview would last approximately 40 minutes. You will be asked to keep a diary of nausea and vomiting episodes, completing it once a day in the evening and to fill out a questionnaire about any nausea or vomiting you might have had at the start of the study (day 1), and on the mornings of day 4 and day 7. Patients in the treatment or acupuncture arms will be asked to complete the diary and questionnaires on the second cycle of chemotherapy as well as the first.
170
Patients in the control or standard treatment arm (i.e. no acupuncture); will be offered acupuncture treatment for their next cycle if they request it. Adverse side effects from acupuncture are extremely rare. Side effects of acupuncture include needling pain, bleeding, bleeding or bruising at the needle site, fainting, local skin irritation, exacerbation of symptoms and pneumothorax, majority of side effects are temporary and self correct with removal of the needle. Serious adverse effects are extremely rare. For the period of the treatment movement will be limited due to position of needles and the micro-stimulator. Potential Benefits The potential benefit is that you may not experience chemotherapy induced nausea and vomiting, but this cannot be guaranteed. Even with anti-sickness drugs and electroacupuncture, you may still experience some nausea and vomiting. Confidentiality
All records containing personal information will remain confidential and no information which could lead to identification of any individual will be released. All patient documents produced during the study will contain unique numbers to identify the patients. Your name will not appear in any materials produced from this study. However, direct access to your medical records may be required by the Mater Health Services Human Research Ethics Committee for the purposes of auditing.
All records will be stored for 15 years
Serious effects or injury
We do not expect you to suffer any serious effects or injury from the treatment or from participating in this study. However, in the event of serious illness or injury resulting from the treatment or from your participation please contact your study doctor immediately. If you think you have an injury/illness that is related to the study, you should immediately notify Professor Hardy, or one of the staff members working on the study. The investigator and the study staff may be reached at:
Principal Investigator Chris McKeon 0411080888
Study nurse Helen Anderson 07 3163 5689
Version 1. 6, 1 September 2010 If you are unable to contact any of the above study staff on the telephone numbers provided, please ring the Mater Health Services switchboard on 07 3163 8111 and ask to page or connect you with the preferred study team member or Professor Janet Hardy.
171
If you have a study-related injury/illness, the investigator and the study staff will make sure that you receive necessary treatment. This research has been approved by the Mater Health Services Human Research Ethics Committee, which is responsible for ensuring that the rights of human patients are protected at this institution, have given approval this study to be conducted at the Mater Adult Hospital.
If you have any complaints about any aspect of the project, the way it is being conducted or any questions about your rights as a research participant; please be advised that you may contact the Research Ethics Coordinator on (07) 3163 1585. The Ethics Research Coordinator may contact the Patient Representative or Hospital Ethicist at its discretion. Before deciding to take part you should discuss this matter with your family, a friend or your local doctor, if you feel this would help you make a decision.
Voluntary participation
Participation in any research project is voluntary. If you do not wish to take part you are not obliged to. If you decide to take part and later change your mind, you are free to withdraw from the project at any stage. If you do choose to leave the study, you should return to your doctor in order that the appropriate assessments can be completed and suitable care provided. Your decision whether to take part or not to take part, or to take part and then withdraw, will not affect your routine treatment, your relationship with those treating you or your relationship with The Mater Adult Hospital. Your doctor may also withdraw you from the study if he or she feels it appropriate to do so for any reason.
Investigators Qualifications and Experience
Chris McKeon is a trained acupuncturist with an Advance Diploma of Acupuncture, member of Australian Acupuncture and Chinese Medicine Association, member number 1921 and has five years of clinical practise. Chris is a registered nurse with almost 20 years of experience mainly in cancer nursing and intensive care.
When the study is completed, the results will be widely distributed.
If during the course of this study, you have questions concerning the nature of the research or your rights as a participant, you should contact: Investigator Chris McKeon RN Site Mater Health Services Hospital name Mater Adult Hospital Street address Raymond Terrace, Suburb and post code South Brisbane Contact phone number 0411080888
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THANK YOU FOR CONSIDERING THIS STUDY.
PATIENT CONSENT FORM
Protocol Title: A Randomised trial of electroacupuncture versus sham acupuncture and no acupuncture for the control of acute and delayed chemotherapy induced nausea and vomiting – pilot feasibility study
Principle Investigator: Co-Investigators:
Chris McKeon RN/Acupuncturist Prof. Janet Hardy Kerry Reed RN Prof. Caroline Smith Prof. Esther Chang
Study Nurse: Ms Helen Anderson
Address: Day Oncology Unit Mater Adult Hospital Raymond Terrace South Brisbane, QLD, 4101
Telephone Number: 07 3163 5689 or 07 3163 3884
Study Nurse: Ms Helen Anderson
Address: Day Oncology Unit Mater Adult Hospital Raymond Terrace South Brisbane, QLD, 4101
Telephone Number: 07 3163 5689 or 07 3163 3884
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I have: Read and understood the information sheet; Had any questions or queries answered to my satisfaction; Been informed of the possible risks or side effects of the tests or
procedures being conducted; Understood that the project is for the purpose of research and not for
treatment; Been informed that the confidentiality of the information will be maintained
and safeguarded; Given permission for access to my medical records, for the purpose of
this research; Given permission for medical practitioners, other health professionals,
hospitals or laboratories outside this hospital, to release information concerning my disease and treatment which is needed for this trial and understand that such information will remain confidential;
• Been assured that I am free to withdraw at any time without comment or penalty; and
• Agreed to participate in the project. Signatures:
Participant
Signature Date
Print name Witness
Signature Date
Print name
Investigator
Signature
Date
Print name
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Appendix Eight
ELECTROACUPUNCTURE STUDY FOR CINV
Participant Number Date ________________ ______________
DEMOGRAPHICS Which of the following best describes your current employment status?
□ working full time (permanent or contract) □ working part time (permanent or contract) □ unemployed □ home duties □ student □ permanently unable to work/ill □ casual: full time □ casual part time □ other
If usually working (full or part time), what is your usual occupation? Job position……………………….. Industry…………………………….
Did you finish high-school?
Yes 1 No 2 NA 3
Have you completed any tertiary education? Yes 1 No 2 If yes Qualification from a TAFE or similar 3
University degree 4 Race 1 Caucasian 5 Maori 2 Asian 6 Unknown 3 Aboriginal/TSI 7 Other – specify 4 Polynesian ……………………
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Which of the following best describes your current situation? Single 1 Married 2
Defacto 3 Separated but not divorced 4
Divorced 5 Other 6 (please specify)…………
Date of Birth: ___/___/___
Age:_____yrs
Gender: M or F
Height: ________cms
Weight: _____kg
Chemotherapy Protocol: ___________
Emetogenic Rating: _________
Diagnosis: ____________
Antiemetic regime: __________
Pre treatment How effective do you consider acupuncture in general?
□ Very effective □ Effective □ Slightly effective □ Not effective □ Don’t know
What do you personally expect from the acupuncture treatment? □ Complete □ Clear improvement □ Slight improvement □ No improvement □ Don’t know
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Appendix Nine
177
178
179
180
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Appendix Ten DAILY DIARY FOR NAUSEA AND VOMITING IN THE ELECTROACUPUNCTURE STUDY Patient Identification Number ____________ Please fill out the daily diary in the evening, marking the line on the scale as a vertically line and write the number of times that you have vomited. If you haven’t vomited please just put in a zero. We are after your responses not that of your family or friends. Vomiting is defined as the expulsion of stomach contents through the mouth. Retching is non-productive attempt at vomiting. An episode of vomit includes numerous small expulsions in a short time frame, which is 20 minutes for this trial. Day 1 – day of chemotherapy 0 1 2 3 4 5 6 7 8 9 10 No Nausea Severe Nausea Number of vomits last 24 hours. ____ Day 2 0 1 2 3 4 5 6 7 8 9 10 No Nausea Severe Nausea Number of vomits last 24 hours. ____ Day 3 0 1 2 3 4 5 6 7 8 9 10 No Nausea Severe Nausea Number of vomits last 24 hours. ____ Day 4 0 1 2 3 4 5 6 7 8 9 10 No Nausea Severe Nausea Number of vomits last 24 hours. ____
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Day 5 0 1 2 3 4 5 6 7 8 9 10 No Nausea Severe Nausea Number of vomits last 24 hours. ____ Day 6 0 1 2 3 4 5 6 7 8 9 10 No Nausea Severe Nausea Number of vomits last 24 hours. ____ Day 7 0 1 2 3 4 5 6 7 8 9 10 No Nausea Severe Nausea Number of vomits last 24 hours. ____ Thank you.
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Appendix 11 Adverse Event Assessment Form – Electroacupuncture Study for CINV. Participant Number: Date: ________________ ____________
Needling Pain None
Mild
Moderate
Severe
Disabling
0 1 2 3 4 Bruising/ Haematoma None Localised or in dependent
area
Generalised
0 1 2
Fainting Absent Present 0 1 Local Skin Irritation None pain or itching or
erythema pain or swelling, with inflammation or phlebitis
ulceration or necrosis that is severe or prolonged, or requiring surgery.
0 1 2 3 Exacerbation of Symptoms Nausea None able to eat oral intake
significantly decreased
no significant intake, requiring IV fluids
0 1 2 3 Vomiting None 1 episode in
24 hours over pre-treatment
2-5 episodes in 24 hours over pre-treatment
>= 6 episodes in 24 hours over pre-treatment or need IV fluids
Requiring parenteral nutrition; or physiologic consequences requiring intensive care; hemodynamic collapse
0 1 2 3 4
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APPENDIX 12 Post treatment Day 3 Assessment How confident do you feel that this treatment will alleviate your nausea and vomiting?
0 1 2 3 4 5 6 No Confidence Total Confidence How confident would you be in recommending this treatment to a friend in similar circumstances?
0 1 2 3 4 5 6 No Confidence Total Confidence How logical does this treatment seem to you?
0 1 2 3 4 5 6 No Logic Completely Logical How successful do you thinks this treatment would be in alleviating other complaints?
0 1 2 3 4 5 6 Not Successful Completely Successful Patient Blinding Which treatment arm do you believe you are in? □ True acupuncture arm □ Sham acupuncture arm □ Unsure which arm.
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Appendix 13 Date________________ Study ID_____________
Study Cessation – Electroacupuncture
How effective do you consider the acupuncture to have been? ¨ Very effective ¨ Effective ¨ Slightly effective ¨ Not effective ¨ Don’t know ¨ Not applicable (patient in standard arm) Checklist ¨ Adverse event assessment ¨ Concomitant medications ¨ Rescue anti emetic medications ¨ Patient diary collected or date arranged for collection
18
6
App
endi
x 14
O
utco
me
Ass
essm
ent D
iagr
am
Com
plet
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by
rese
arch
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e
Com
plet
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by
parti
cipa
nt
Cyc
le
1 Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Cyc
le 2
Day
1
Inte
rven
tion
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ps o
nly
Day
2
Day
3
Day
4
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5
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6
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Dem
ogra
phic
s
*
*
Dai
ly
Dia
ry
Nau
sea/
vom
iting
scor
e
Follo
wed
up b
y *
* *
* *
* *
* *
* *
* *
* *
FLIE
Fo
llow
ed
up b
y *
*
*
* *
*
*
Adv
erse
ev
ent
form
Follo
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y *
*
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Patie
nt
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Follo
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*
Stud
y ce
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ion
form
–
how
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as
acup
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ure
*
*
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Appendix 15 PRACTITIONER INTERACTION CHECKLIST Study ID ____________ Date ____________ Practitioner develops rapport with participant 1 2 3 4 5 6 7 Never Rarely Occasionally Sometimes Often Very Often Always Allows patient to ask questions 1 2 3 4 5 6 7 Never Rarely Occasionally Sometimes Often Very Often Always Practitioner explanation of the therapy method 1 2 3 4 5 6 7 Never Rarely Occasionally Sometimes Often Very Often Always Practitioner develops sense of trust and confidence 1 2 3 4 5 6 7 Never Rarely Occasionally Sometimes Often Very Often Always Practitioner explanation of the side effects of the therapy
1 2 3 4 5 6 7 Never Rarely Occasionally Sometimes Often Very Often Always Amount of talking N/A 1 2 3 4 5 Somewhat Sufficient Too Much
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Open interested body language N/A 1 2 3 4 5 Somewhat Sufficient Too Much Warm tone of voice N/A 1 2 3 4 5 Somewhat Sufficient Too Much Empathetic N/A 1 2 3 4 5 Somewhat Sufficient Too Much Warm and friendly N/A 1 2 3 4 5 Somewhat Sufficient Too Much Confident N/A 1 2 3 4 5 Somewhat Sufficient Too Much Appropriate use of humour N/A 1 2 3 4 5 Somewhat Sufficient Too Much Sincere/genuine N/A 1 2 3 4 5 Somewhat Sufficient Too Much Respectful to clients N/A 1 2 3 4 5 Somewhat Sufficient Too Much Rewarding/encouraging N/A 1 2 3 4 5 Somewhat Sufficient Too Much
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Adherence to script N/A 1 2 3 4 5 Somewhat Sufficient Too Much SCRIPT
• Insert 8 needles in total, 2 each arm and leg • Treatment will start 10 minutes before your chemotherapy and last a
total of 30 minutes • If initial insertion is painful advise me as will reinsert • You may or may not feel a dull, strong, heavy or electric sensation if
you do let me know • When I turn on the micro stimulator you may or may not have a
twitching or tingling sensation at some of the needle sites
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Appendix 16
ACUPUNCTURE PATIENT INFORMATION CONSENT FORM CANCER SERVICES
What and Why?
• Acupuncture is a form of treatment where very fine acupuncture needles are inserted into the tissues (penetrating the skin).
• Acupuncture can assist some people with nausea and vomiting, pain, fatigue, anxiety, xerostomia (dry mouth), peripheral neuropathy, hot flushes, feelings of wellbeing and insomnia.
Precautions & Contraindications: Your clinician will assess whether extra care needs to be taken or whether you should not have acupuncture.
Potential risks/side effects of acupuncture include:
1. Minor (<1 per 100) These include but not limited to: • bruising or bleeding • discomfort or pain
2. Rare (<1 per 1000) • fainting • nausea • exacerbation of symptoms being treated. • alteration of energy levels. This may be either high or low levels of energy
3. Very rare (<1 per 10,000) • pneumothorax (collapsed lung) if needling around the chest. • infections
Technique
• You will be positioned comfortably and the selected points will be cleaned with an alcohol swab.
• Sterile needles (single use) will be then be inserted. This may feel sharp. • The needles will be manipulated (twisted or slightly raised and lowered) until
a sensation is felt. This sensation varies for different people and different points, but typically may be a feeling of heaviness, warmth, fullness, aching or numbness. Needles may be further manipulated during the treatment.
• Needles will be removed after approximately 30 minutes. Cautions after the Treatment:
• Fatigue and Drowsiness. If you are going to be driving ensure you are not feeling drowsy or fatigued. If you do experience this – have a snack or hot drink and rest until you feel safe to drive.
• Discomfort and minor bruising. It is normal for some people to experience mild discomfort – particularly after the first treatment or two. Very minor bruising or bleeding may occur. An ice pack can assist recovery (10-15 minutes)
• Pneumothorax (Punctured/collapsed lung). This is extremely unlikely. However if you do experience increasing shortness of breath following acupuncture over the shoulders or trunk, please contact your therapist directly or attend to the nearest hospital emergency department.
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Precautions & Contraindications Form for Acupuncture (Health professional to complete with patient prior to acupuncture. Any concerns to be discussed with the consultant in charge) Please indicate whether you have any of the following conditions: CONDITIONS PLEASE TICK THERAPIST COMMENT Blood clotting disease (eg haemophilia) If yes – what type ____________
□ Yes □ No Controlled with medications?
Anticoagulants – blood thinners If yes – what type____________
□ Yes □ No INR – level stable?
Platelets count < 50 x 109/l □ Yes □ No If yes, acupuncture is contraindicated
Neutrophil count < 1.00 x 109/l
□ Yes □ No If yes, acupuncture is contraindicated
Artificial Implants (eg pacemaker, heart valves, joint replacement) Type ____________________
□ Yes □ No
Recent Infection? If yes where? ________
□ Yes □ No Antibiotics?
Mastectomy or Axillary clearance? □ Yes □ No Which side? Diabetes (If yes note the type) Unstable/uncontrolled Controlled with insulin Controlled with diet and/or medications
□ Yes □ No □ Yes □ No
Cardiac (Heart) conditions. Heart failure/ Abnormal rhythm Other____________
□ Yes □ No Acute? Chronic? Controlled?
Immune diseases (eg Lupus, Rheumatoid Arthritis) If yes, disease type __________
□ Yes □ No Controlled? Acute flare up?
Epilepsy If yes – last seizure __________
□ Yes □ No Controlled?
Areas of numbness or reduced feeling? If yes where _______________
□ Yes □ No
Allergy to metals □ Yes □ No Stainless steel? Significant fatigue or drowsiness or history of fainting
□ Yes □ No
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As part of the service, we will ask you to complete an evaluation form, which is optional. If you agree we will give you more information and re-consent you for the evaluation. I ___________________________________________ (full name) consent to having acupuncture for my symptoms __________________________________________ ___________________________ (Please list). I have had the procedure explained to me including potential benefits and risks or side effects as detailed above. I have been given sufficient opportunity to ask any questions. Patient signature: ________________________ Date: _______________ Acupuncturist Name Signature: _______________________ Designation: ___________________
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APPENDIX 17
PATIENT INFORMATION AND CONSENT FORM FOR THE ACUPUNCTURE SERVICE EVALUATION
Protocol Title: Evaluation of the acupuncture service.
Principle Investigator:
Co-Investigators:
Chris McKeon, CN/Acupuncturist
Prof. Janet Hardy Peter Coxeter
Study Nurse: Ms Marina Luck
Address: Day Oncology Unit Mater Adult Hospital Raymond Terrace South Brisbane, QLD, 4101
Telephone Number: 07 3163 1952 or 07 3163 7805
You are invited to participate in this study. The purpose of this form is to explain the study. Please ask the study doctor or the study staff to explain any words or information that you do not clearly understand. You may take home an unsigned copy of this participant information and consent form to think about or discuss with family or friends before making a decision about whether or not you want to take part in this study.
If you agree to take part in this research study, be sure all your questions are answered before signing the consent form. You will be given a signed copy of this form to keep. Purpose of the project The purpose of this survey is to evaluate the acupuncture service within the Mater Adult Hospital. We will be asking you about your impressions, ideas and experiences of the acupuncture service. We will use this information in the planning of future services.
Description of the study and procedure You have asked for acupuncture to help with some health problem or symptoms. In order to evaluate the benefit of the acupuncture service, we are asking you to provide feed-back on the service. If you agree to participate, we will ask you to complete a survey asking about your experiences and expectations; we will ask you to complete a tool called MYCAW (Measure Yourself Concerns and Wellbeing). The study will include obtaining information from your medical record including but not limited to diagnosis, chemotherapy protocol and medical history. The survey will take about 5 to 10 minutes to complete. You will be asked to complete the survey 4 weeks from time
194
you first used the acupuncture service, if you don’t have an appointment at 4 weeks, your appointment which is close as possible to 4 weeks. We will ask you to complete the MYCAW before you have the acupuncture and when you complete the other part of the survey in approximately 4 weeks. Confidentiality All records containing personal information will remain confidential and no information which could lead to identification of any individual will be released. All patient documents produced during the study will contain unique numbers to identify the patients. Your name will not appear in any materials produced from this study. However, direct access to your medical records may be required by the Mater Health Services Human Research Ethics Committee for the purposes of auditing.
All records will be stored for 15 years If you have any concerns about the service or its evaluation, please contact one of the research staff listed below.
Principal Investigator Chris McKeon 07 3163 7805 or 0411080888
Study nurse Marina Luck 07 3163 1952
If you are unable to contact any of the above study staff on the telephone numbers provided, please ring the Mater Health Services switchboard on 07 3163 8111 and ask to page or connect you with the preferred study team member or Professor Janet Hardy. This survey has been approved by the Mater Health Services Human Research Ethics Committee, which is responsible for ensuring that the rights of human patients are protected at this institution, have given approval this study to be conducted at the Mater Adult Hospital.
If you have any complaints about any aspect of the project, the way it is being conducted or any questions about your rights as a research participant; please be advised that you may contact the Mater Research Ethics Coordinator on (07) 3163 1585. The Ethics Research Coordinator may contact the Patient Representative or Hospital Ethicist at its discretion. Before deciding to take part you should discuss this matter with your family, a friend or your local doctor, if you feel this would help you make a decision.
Voluntary participation
Participation in any research project is voluntary. If you do not wish to take part you are not obliged to. If you decide to take part and later change your mind, you are free to withdraw from the project at any stage. Your decision whether to take part or not to take part, or to take part and then withdraw, will not affect your routine treatment, your relationship with those treating you or your relationship with The Mater Adult Hospital. Your doctor may also withdraw you from the study if he or she feels it appropriate to do so for any reason.
Investigators Qualifications and Experience
Chris McKeon is a trained acupuncturist with an Advance Diploma of Acupuncture, member of Australian Acupuncture and Chinese Medicine Association, member
195
number 1921 and has five years of clinical practise. Chris is a clinical nurse with almost 20 years of experience mainly in cancer nursing and intensive care.
When the study is completed, the results will be widely distributed.
If during the course of this study, you have questions concerning the nature of the research or your rights as a participant, you should contact: Investigator Chris McKeon CN Site Mater Health Services Hospital name Mater Adult Hospital Street address Raymond Terrace, Suburb and post code South Brisbane Contact phone number 07 3163 7805 or 0411080888
THANK YOU FOR CONSIDERING THIS STUDY.
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PATIENT CONSENT FORM
Protocol Title: Evaluation of the acupuncture service.
Principle Investigator: Co-Investigators:
Chris McKeon CN/Acupuncturist
Prof. Janet Hardy
Peter Coxeter
Study Nurse: Ms Marina Luck
Address: Day Oncology Unit Mater Adult Hospital Raymond Terrace South Brisbane, QLD, 4101
Telephone Number: 07 3163 1952 or 07 3163 7805
I have: Read and understood the information sheet; Had any questions or queries answered to my satisfaction; Been informed of the possible risks or side effects of the tests or procedures
being conducted; Understood that the project is for the purpose of evaluating a service; Been informed that the confidentiality of the information will be maintained and
safeguarded; Given permission for access to my medical records, for the purpose of this
research; Given permission for medical practitioners, other health professionals, hospitals
or laboratories outside this hospital, to release information concerning my disease and treatment which is needed for this trial and understand that such information will remain confidential;
• Been assured that I am free to withdraw at any time without comment or penalty; and
• Agreed to participate in the project.
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Signatures:
Participant
Signature Date
Print name Witness
Signature Date
Print name
Investigator
Signature
Date
Print name
198
Appendix 18
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200
201
Appendix 19
ACUPUNCTURE SERVICE EVALUATION Participant Number Date ________________ ______________ Have you ever received acupuncture for treatment or management of any condition or related symptom/s before using the service at the hospital? □ No □ Yes Please give reason for having treatment and did the prior acupuncture help your symptom? ____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ What symptom/s do you want to be treated today with acupuncture? □ Fatigue □ Pain □ Nausea/Vomiting □ Peripheral Neuropathy □ Digestion problems. Please list___________________________________ □ Insomnia □ Anxiety/Stress/Mood problems. Please list __________________________ □ Other. Please list ______________________________________________ What benefit did you expect from this acupuncture treatment?
□ Marked improvement □ Some improvement □ Slight improvement □ No improvement □ Slight worsening □ Some worsening □ Marked worsening □ Don’t know
What benefit did you get from this acupuncture treatment?
□ Marked improvement □ Some improvement □ Slight improvement □ No improvement □ Slight worsening
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□ Some worsening □ Marked worsening □ Don’t know
If using medication to help with your symptom/s (eg pain relief, antinauseant medications), have you used
□ More medication □ Same amount □ Less medication □ Don’t know
How did you find out about the service?
◻Doctor
◻Nurse
◻Other health professional (e.g. physiotherapist, dietician)
◻Patient
◻Flyer
◻Other - Please list _____________________
Did you notice any side effects or problems immediately following the acupuncture or within the next few days? □ No □ Yes If yes, please inform the acupuncturist or a member of the research team
listed on the back of the information form and complete adverse event form. Do you think the Acupuncture Service is worthwhile addition to services currently
available to cancer patients during their treatment?
□ No □ Yes
Would you like the service to continue?
□ No □ Yes If yes, how might it be improved?
___________________________________________________________________
________
___________________________________________________________________
___________________________________________________________________
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___________________________________________________________________
___________________________________________________________________
________________________________
Is there anything else you would like to add, which is not covered above?
___________________________________________________________________
___________________________________________________________________
___________________________________________________________________
___________________________________________________________________
________________________________
Have you used any other Complementary or Alternative Medicines or Therapies (CAM) in the last 12 months? □ No □ Yes If yes, please list any CAM used in the last 12 months.
___________________________________________________________________
________
THANK YOU FOR COMPLETING THIS SURVEY
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APPENDIX 20
ADVERSE EVENT ASSESSMENT FORM – ACUPUNCTURE SERVICE
Did you experience any of the following adverse events after the acupuncture treatment? (Please circle one number only). We are looking at adverse events from the acupuncture treatment only, not from the chemotherapy. Even if no symptoms or adverse events please answer all questions. Participant Number: Date: ________________ ____________
Needling Pain
None
Mild
Moderate
Severe
Disabling
0 1 2 3 4
Pain
None
Mild
Moderate
Severe
Disabling
0 1 2 3 4
Bruising/ Haematoma
None Localised or in dependent area
Generalised
0 1 2
Fainting
Absent
Present
0 1
Local Skin Irritation
None Pain or itching or erythema
Pain or swelling, with inflammation or phlebitis
Ulceration or necrosis that is severe or prolonged, or requiring surgery.
0 1 2 3
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Dizziness/Lightheadedness None With head
movements only, not interfering with function
Interfering with function, but not interfering with normal activities
Interfering with normal activities
Disabling
0
1 2 3 4
Pneumothorax (Collapsed Lung) None Asymptomatic,
radiographic findings only
Symptomatic; intervention indicated (e.g. hospitalisation for observation, tube placement without sclerosis)
Sclerosis and/or operative intervention indicated
Life-threatening, causing haemodynamic instability (e.g. tension pneumothorax); ventilatory support indicated
Death
0 1 2 3 4 5
Other adverse event not listed above.
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Appendix 21
Coding for concerns
Super category (S)
Breakdown of super category
S1. Psychological
and Emotional
Concerns
a. Adapting and coping
b. Body image concerns
c. Confidence issues
d. Depression
e. Emotional problems
f. Family and relationships
g. Fear and anxiety
h. Psychological issues
i. Regaining balance and
normality
j. Sleep problems
k. Stress and tension
l. Support
m. The future
S2. Physical
Concerns
a. Arm problems
b. Hot flushes and night
sweats
c. Fertility
d. Pains/Aches
e. Physical problems
f. Poor energy levels
g. Recurrence and spread
S3. Hospital Cancer
(Medical)
Treatment
Concerns
a. Cancer treatment in general
b. Lymphoedema
c. Side effects of
chemotherapy
d. Side effects of hormonal
S4. Concerns about
Wellbeing
a. Exercise
b. General wellbeing and
mind/body connection
c. Healing
d. Information and guidance
on complementary therapies
e. Nutrition
f. Relaxation
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Coding for other events occurring
Super category (S) Breakdown of super category
S1. Awareness of Wellbeing a. Taking exercise
b. Improved awareness of own
wellbeing
c. Improved nutrition
d. Difficulties in maintaining change
S2. Receiving complementary therapies a. Benefit of therapies at the centre
b. Benefit of therapies outside of
the centre
S3. Major Life Events a. Positive change of environment
b. Negative change of environment
c. Bereavement
S4. Social Support a. Increased social support
b. General lack of support
c. Family problems
S5. Work Situation a. Changed work set up
b. Work problems
S6. Health Issues a. Cancer related and positive
b. Cancer related and negative
c. Non-cancer related
S7. Other
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Coding for experiences with service
Number Categories
1 Support and understanding received
2 Individual and group therapies
3 Access to therapies
4 Confidence in the therapists
5 Care and kindness
6 Being with other people with cancer
7 Relaxation and time for ones self
8 The environment and atmosphere
9 General appreciation of the centre and its
resources
10 Negative feedback
11 Other
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Figure 3.1 Sham Points Location
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211
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