3.1 True SAS intervention protocol
The true SAS intervention protocol was developed through the following four procedures: 1) selecting appropriate SAS intervention and acupoints formula; 2) selecting appropriate SAS modality; 3) identifying appropriate SAS intensity and technique; and 4) identifying of appropriate SAS dosage. Table 1 summarises the contents of the true SAS intervention protocol, as well as relevant justifications and evidence source.
Table 1 Contents of the true SAS intervention protocol with relevant justifications and evidence
Contents
|
Details
|
Justifications
|
Sources of evidence
|
Acupoints formula
|
• Zusanli (ST36) • Sanyinjiao (SP6) • Taixi (KI3) • Hegu (LI4) • Neiguan (PC6) • Shenmen (HT7) • Baihui (GV20) • Qihai (CV6) • Guanyuan (CV4) • Yintang (EX-HN3) • Taichong (LR3)
|
• Demonstrated benefits in alleviating cancer-related symptoms of fatigue, sleep distress and depression
• Commonly utilised acupoints for alleviating cancer-related fatigue, sleep distress and depression in both clinical practice and research
|
• TCM theories: yin-yang theory, and zang-fu organs and meridians theory [43, 47,48]
• SAS practical standards: instructions of function and clinical usage of somatic acupoints [37,38]
• Systematic review evidence [28*]
|
SAS modality
|
• Somatic acupressure
|
• Commonly used SAS approach for cancer symptom management
• Superiority to invasive acupuncture regarding safety and convenience in facilitating self-management in the long run
|
• Systematic review evidence [28*, 29]
• Clinical research evidence [30-32]
|
SAS intensity and technique
|
• Intensity: achievement of “Deqi” sensation
• Technique: Survivors self-administrated manual acupressure using finger pressing
|
• “Deqi” sensation: a key indicator of the achievement of satisfactory therapeutic effects of SAS
• Acupressure via finger: a common approach of self-acupressure with demonstrated safety and convenience for self-practice
|
• Systematic review evidence [28*]
• SAS practical standards [30,49, 50]
|
SAS frequency, sessions and total duration
|
• A daily SAS for seven weeks, with each session lasting 36 min (2 min on each acupoint)
|
• Commonly used SAS dosage in both research and practice with demonstrated benefits for individual symptom alleviation, appropriate feasibility and acceptability
|
• Systematic review evidence [28*]
• SAS practical standards [51]
• Clinical research evidence [30]
|
SAS: Somatic acupoint stimulation; * The systematic review evidence was adopted from three systematic reviews that were conducted by our research team, with one published and two under review: (1) Wang, T., Tan, JY., Yao, LQ., et al. Effects of somatic acupoint stimulation on anxiety and depression in cancer patients: an updated quantitative synthesis of randomized controlled trials. Manuscript submitted for publication; (2) Tan, JY., Wang, T., Kirshbaum MN, et al., Somatic acupoint stimulation for cancer-related fatigue: A quantitative synthesis of randomized controlled trials. Manuscript submitted for publication). Only the published systematic review [28] was included in the reference list.
3.1.1 Selecting appropriate SAS intervention and acupoints formula
Neurophysiological theories particularly the inflammatory theory, and some TCM theories including the yin-yang theory and the zang-fu organs and meridians theory were used to describe the potential mechanism of SAS for FSDSC management in BCS. Inflammation has been regarded as the key biological pathway of FSDSC as the inflammatory cytokines can result in fatigue (the core symptom of the FSDSC) via the autonomic nervous system and/or the Hypothalamic-pituitary-adrenal axis [11,42]. An increase of inflammatory markers can also affect immune regulation and recovery via the cellular immune system [11]. Current evidence has demonstrated an important role of acupoint stimulation in decreasing the inflammatory cytokines and modulating the immune functions [43]. Such potential biological mechanisms of acupoint stimulation involving the regulation of inflammatory cytokines highlight its promising role for FSDSC management given that the development of cancer symptom is believed to be closely linked with the inflammatory responses induced by inflammatory cytokines [2].
The TCM believes that the main pathogeneses of FSDSC are the imbalance between yin and yang, and deficiencies of qi [44,45]. Imbalance between yin and yang can negatively affect the operation of qi and meridians and subsequently distort the normal zang-fu organ functions given that each major meridian is closely associated with specific zang-fu organs (heart, liver, spleen, lungs and kidney). Qi refers to the vital energy of the body, which can maintain blood circulation, warm body, and fights diseases [46]. Qi deficiency can significantly contribute to a range of deficiency syndromes in cancer patients including fatigue [46]. Acupoints are the areas where the qi of zang-fu organs and medians are transfused [43]. According to the yin-yang theory and the zang-fu organs and meridians theory, stimulating specific acupoints can promote the flow of qi of the body to maintain blood circulation, dredge the meridians, balance yin and yang, and regulate zang-fu functions [43, 47,48].
In accordance with the TCM theories and the relevant acupoint stimulation practice standards/handbooks regarding the indications, effects and roles of somatic acupoints [37,38], eleven acupoints were selected to use in the intervention protocol, which include Zusanli (ST36), Sanyinjiao (SP6), Taixi (KI3), Hegu (LI4), Neiguan (PC6), Shenmen (HT7), Baihui (GV20), Qihai (CV6), Guanyuan (CV4), Yintang (EX-HN3), and Taichong (LR3). Selection of these acupoints was also supported by our systematic reviews as the commonly utilised acupoints for alleviating the symptom of cancer-related fatigue, sleep distress and depression with demonstrated benefits for symptom improvement (details see Table 1). Two practice standards/handbooks of acupoints stimulation [37,38] were used to inform the accurate location of each acupoint included in the protocol. Details of the indications, effects and roles of each of the selected acupoints are listed in the Supplementary File.
3.1.2 Selecting appropriate SAS modality
Considering that the SAS has two modalities- somatic acupuncture and somatic acupressure, evidence from systematic review findings and clinical trials [28, 29-32] were adopted to support the selection of an appropriate SAS modality. Due to the popularity of somatic acupressure for symptom management in cancer population and its superiority to invasive somatic acupuncture regarding the risk-benefit balance, convenience, and safety [29-32], the non-invasive somatic acupressure was identified as an appropriate SAS modality. Comparing with somatic acupuncture which is administered by qualified practitioners and is an invasive method with potentially severe adverse effects, the non-invasive somatic acupressure can be a safe method for self-management of cancer symptoms long-term.
3.1.3 Identifying appropriate SAS intensity and technique
Deqi sensation as a key indicator of the achievement of satisfactory treatment effects of acupoint stimulation has been widely utilised in research and practice [28, 49]. Deqi usually refers to a local sensation of dull pain, aching, sore, numb, distended, heavy, electric, throbbing, and warmness [49]. In this study, the acupoints stimulation intensity was determined via using the indicator of deqi sensation. For the self-acupressure technique, practice standards of finger acupressure were adopted, which include the skills of pointing, pressing, and kneading. Pointing is the patients locating the acupoint [30,50]. Pressing is the patients using either thumb or index finger to press the point to evoke the deqi sensation [50]. Kneading is the patients rotating their thumb or index finger on the identified acupoint to achieve the therapeutic effects [50].
3.1.4 Identifying appropriate SAS dosage
The SAS dosage, including frequency, session and total duration, was determined based on the standards of acupressure [51], and research evidence from systematic reviews and high-quality clinical trials [28, 30]. The frequency of SAS treatment was commonly scheduled as daily, with acupressure performing on each acupoint for two to three minutes [51]. Considering that eleven acupoints were selected in this study and seven of which were bilateral acupoints, it was determined that each acupoint should be pressed for two minutes to minimize participants’ burden. For the total duration of SAS, clinical research has well documented that a minimal of four-week daily acupressure is required to achieve satisfactory effects and a seven-week daily acupressure to achieve maximum effects on cancer-related fatigue alleviation (the core symptom of FSDSC) [30]. Considering all the evidence mentioned above, the SAS dosage in this study was scheduled as a daily acupressure for seven weeks, with each acupoint been pressed for two minutes.
3.2 Protocol of the placebo SAS intervention
The placebo SAS intervention protocol was developed based on the evidence extracted from two comprehensive systematic reviews on placebo acupoint stimulation design [33, 34]. To promote the success of a satisfactory blind design in future RCT and to minimize the potential treatment effects of the placebo acupressure, non-acupoints located one to three cm away from the active acupoints utilised in the true intervention but away from the meridians [33] were selected as the placebo acupressure points. The number of the non-acupoints was same as that of the true SAS intervention.
3.2.1 Identifying appropriate placebo acupoints
A few placebo acupoints designs are commonly utilised in clinical research, which include non-acupoints, true acupoints (but irrelated to the targeted health problem), and the same acupoints as used in the true group with light or no stimulation [33,34]. Given that our future RCT will implement a blind design of participants between the true and placebo acupressure groups, true acupoints with light or no stimulation might not be an appropriate design to achieve a successful blind design, particularly for participants with previous experience of acupressure [33]. Meanwhile, research evidence has indicated that even light acupressure at the true points can evoke some therapeutic effects for symptom alleviation such as pain [52]. Irrelevant acupoints (to the targeted health condition) are another commonly adopted placebo acupoint stimulation approach. However, according to the “holism concept” of TCM, stimulation of any acupoint could lead to a comprehensive response of the human body and subsequently create some treatment effects, particularly when participants in true and placebo group receiving a same acupressure intensity [33,53]. Non-acupoints are defined as inactive points that located near the true acupoints but away from the meridians [33,34]. Non-acupoints have been the most commonly utilised placebo approach in acupoint stimulation studies as this method would theoretically avoid evoking any specific therapeutic effects generated from true acupoint stimulation. Non-acupoints located near true acupoints are also considered as an appropriate design for maintaining a successful blind design [33]. Given together, the non-acupoints approach was identified as the placebo SAS method in this study. The number of non-acupoints was same in the true intervention. All the selected non-acupoints were suited one to three cm away from the active acupoints used in the true intervention but away from the meridians [33].
3.2.2 Identifying appropriate placebo SAS intensity, technique, frequency, session and total duration
Using acupressure device has been recommended as an appropriate method to achieve satisfactory blind design, particularly when the devices in true and placebo group are identical [33]. However, many acupressure devices such as acupressure band are only applicable for acupoints located on arms and legs. Given that some of the selected acupoints in this study are on head and abdomen, it was unrealistic to use acupressure device on such acupoints. Finger acupressure on the non-acupoints was therefore applied for placebo intervention in this study.
Placebo acupressure using a same intensity as in the true acupressure intervention may secure a successful blind design. However, there are over 2000 extra-points currently identified in human body which are not linked with the meridians [53]. Therefore, it might be possible that some so-called non-acupoints are potentially active acupoints with specific treatment effects [53]. To minimize the potential therapeutic effects of placebo SAS intervention to the greatest extent, light acupressure on non-acupoints without evoking the deqi sensation was utilised in this study. Frequency, session and total duration of the placebo intervention were scheduled the same as the true intervention (a daily placebo acupressure for seven weeks, with each acupoint been lightly pressed for two minutes).
3.3 Content validity of the SAS intervention protocol
Seven experts in the field of oncology, TCM and/ or acupoint stimulation were recruited to evaluate the content validity of the proposed SAS intervention protocol. Basic information of the expert panel is shown in Table 2. Satisfactory I-CVI and S-CVI were achieved after one round of assessment. All the five items presented in the true and placebo SAS protocol were determined to be content valid (I-CVI ranged from 0.86 to 1.00 and S-CVI was 1.00). Details of the content validity assessment are presented in Table 3.
Table 2 Basic information of the expert panel (N=7)
Basic information of the expert panel
|
Percentage (%)
|
Working institution
|
|
• University
|
3 (42.9%)
|
• Hospital
|
4 (57.1%)
|
Age
|
|
• 30-40 years old
|
3 (42.9%)
|
• 40-50 years old
|
2 (28.5%)
|
• 50-60 years old
|
2 (28.5%)
|
Highest academic degree
|
|
• PhD or MD
|
4 (57.1%)
|
• Master’s degree
|
2 (28.5%)
|
• Bachelor’s degree
|
1 (14.3%)
|
Academic and professional title
|
|
• Full professor
|
3 (42.9%)
|
• Associate chief physician or associate consultant
|
4 (57.1%)
|
Years of professional experience
|
|
• 5-10 years
|
1 (14.3%)
|
• 11-15 years
|
2 (28.5%)
|
• 16-20 years
|
1 (14.3%)
|
• Over 20 years
|
3 (42.9%)
|
Table 3 Content validity assessment of the true and placebo SAS protocol (number of experts=7)
Item
|
Description of each item
|
Content validity assessment
|
CVI
|
No. of experts rating as “(4) very appropriate”
|
No. of experts rating as “(3) appropriate”
|
No. of experts rating as (3) or (4)
|
True SAS intervention protocol
|
1
|
Selection of acupoints formula
|
5
|
2
|
7
|
I-CVI 1.00
|
2
|
SAS modality
|
5
|
2
|
7
|
I-CVI 1.00
|
3
|
SAS intensity and technique
|
4
|
3
|
7
|
I-CVI 1.00
|
4
|
SAS frequency and sessions
|
3
|
4
|
7
|
I-CVI 1.00
|
5
|
SAS total duration
|
4
|
2
|
6
|
I-CVI 0.86
|
Scale level CVI
|
S-CVI 1.00
|
Placebo SAS intervention protocol
|
1
|
Selection of acupoints formula
|
5
|
1
|
6
|
I-CVI 0.86
|
2
|
SAS modality
|
6
|
1
|
7
|
I-CVI 1.00
|
3
|
SAS intensity and technique
|
6
|
1
|
7
|
I-CVI 1.00
|
4
|
SAS frequency and sessions
|
3
|
4
|
7
|
I-CVI 1.00
|
5
|
SAS total duration
|
4
|
2
|
6
|
I-CVI 0.86
|
Scale level CVI
|
S-CVI 1.00
|
* SAS: somatic acupoints stimulation; CVI: content validity index.