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Effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy: An experimental pilot study Woung-Ru Tang a,∗, Wan-Jung Chen a, Chih-Teng Yu b,c, Yue-Cune Chang d, Chuan-Mei Chen a, Chiu-Hua Wang a, Sien-Hung Yang e,f a
School of Nursing, College of Medicine, Chang Gung University, Taoyuan, Taiwan Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan c School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan d Department of Mathematics, Tamkang University, Taipei, Taiwan e Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan f School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan b
KEYWORDS Fatigue; Acupressure; Experimental study; Lung cancer
Summary Background: This study explored the effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy. Patients and methods: For this experimental study, 57 subjects were randomly assigned to three groups: acupressure with essential oils (n = 17), acupressure only (n = 24), and sham acupressure (n = 16). Acupoints were Hegu (LI4), Zusanli (ST36), and Sanyingjiao (SP6). All subjects received acupressure once every morning for 5 months, with each acupoint pressed for 1 min. Fatigue, functional status, anxiety, depression, and sleep quality were measured before initial chemotherapy (T0), on Day 1 of third chemotherapy (T1), and on Day 1 of sixth chemotherapy (T2). Outcome differences between groups were analyzed at T0, T1, and T2 by general estimating equations. Results: After controlling for baseline outcome values, age, and adherence to acupressure, subjects who received acupressure with essential oils and acupressure had significantly less fatigue in daily living activities and sleep better quality at T1 than subjects who received sham acupressure. Subjects who received acupressure with essential oils had significantly better sleep quality at T2 than the sham acupressure group. Subjects who received acupressure with or without essential oils had greater odds of better functional status at T1 than the sham group.
∗ Corresponding author at: School of Nursing, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Taoyuan, Taiwan. Tel.: +886 3 2118800 5331; fax: +886 3 2118433. E-mail address: [email protected] (W.-R. Tang).
http://dx.doi.org/10.1016/j.ctim.2014.05.006 0965-2299/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tang W-R, et al. Effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy: An experimental pilot study. Complement Ther Med (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.006
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W.-R. Tang et al. Conclusion: It is plausible that acupressure with or without essential oils helps lung cancer patients undergoing chemotherapy reduce cancer-related fatigue and increase activity level. Further study is wanted to test this hypothesis. © 2014 Elsevier Ltd. All rights reserved.
Introduction About 7.6 million people worldwide died from cancer in 2008, accounting for 13% of total mortality,1 with lung cancer as the top cause of cancer death.2,3 Lung cancer patients commonly experience fatigue; 70—96% of patients on chemotherapy and 65—100% of patients receiving radiotherapy report fatigue.4,5 Unfortunately, clinicians lack effective methods for treating fatigue.5 Cancer-related fatigue (CRF) is defined as subjectively perceived, persistent fatigue and exhaustion associated with cancer and its treatment.6 Most Chinese people with lung cancer use traditional Chinese medicine (TCM), e.g., Chinese herbal medicine, acupuncture, acupressure, and qigong therapy, combined with western medicine therapy.7,8 Indeed, combining Chinese and western medicine therapy is more effective on lung cancer patients than either treatment alone.9 TCM not only reinforces the effects of chemotherapy and avoids its side effects, but also enhances patients’ quality of life. In TCM, symptoms are believed to be caused by an imbalance between Ying and Yang, which influences the operation of qi, the energy of life, along meridians in the body to maintain health. When qi is blocked, illness will result in parts related to the meridians,10 which connect with the qi of organs at places called acupoints. The body has 365 important acupoints on 14 major meridians.11 Each acupoint is associated with a specific therapy. Acupressure and acupuncture therapy are based on the same theory and acupoints. Most studies on acupoint therapy have tested the clinical effectiveness of acupuncture. Since the 1970s over 500 randomized clinical trials (RCTs) have examined acupuncture, with a few studies on improving cancer patients’ symptoms by acupressure.12—16 Only two of them studied CRF.13,16 Acupressure has also been shown to control fatigue in patients with end-stage renal disease.17,18 A 1998 systematic review of 500 acupuncture-related RCTs concluded that ‘‘current quantity and quality of RCTs still cannot demonstrate the effectiveness of acupuncture.’’19,p.379 A similar conclusion was reached by four 2013 systematic reviews of TCM and CAM for controlling cancer symptoms.20—23 The findings were criticized for issues with research design, e.g., small sample size, imprecise definition of disease types, insufficient findings, and uncertain conditions of sample selection. Of the four recent systemic reviews, three investigated the effects of acupuncture,20—22 and one investigated the effect of all CAM modalities on CRF.23 No reviews investigated acupressure. Compared to acupuncture, acupressure is safe, convenient, and inexpensive; with a little training, it can be used by research personnel, medical care workers, family members and patients themselves.12,16,24 Acupressure achieves its effects by applying pressure to acupoints, thus releasing neurotransmitters that transmit signals along
neurons or activate the hypothalamic-pituitary-adrenal axis to regulate endocrine function.25,26 Another effect of acupressure is to release brain neurotransmitters, endorphins, and other neurochemicals to reduce symptoms of discomfort27—30 and alleviate stress.31 The effect of acupressure on CRF has only been examined in cancer survivors, after they had finished chemotherapy.13,16 Since CRF appears most serious during chemotherapy, immediately treating CRF will positively enhance cancer patients’ quality of life and treatment compliance. Therefore, our study was designed to examine the effect of acupressure on CRF in lung cancer patients receiving chemotherapy.
Methods Design For this experimental pilot study with repeated measures, lung cancer patients were recruited from pulmonary wards at a medical center in northern Taiwan from July 2008 to August 2010. This feasibility trial was implemented to help develop a future large trial.
Setting and subjects Lung cancer patients were included if they met these criteria: (1) receiving conventional chemotherapy, (2) no infection, injury and ulcers around the acupoints, (3) not taking antidepressants or suffering from a psychiatric disorder, (4) >18 years old, (5) never participated in acupressure and any fatigue-related intervention, and (6) willing to learn acupressure and apply it at home. Patients were excluded by these criteria: (1) pregnant, (2) lymphedema at acupressure points, (3) hemoglobin ≤ 9 g/dL, hematocrit < 30, (4) using steroids to treat fatigue, (5) moderate-to-severe heart failure or thyroid disorder, and (6) diagnosed with hepatitis and its acute exacerbation. Patients were screened by physicians in pulmonary wards, who referred possible subjects to a research assistant (RA) for assessment. Patients meeting the study criteria and willing to participate were enrolled. Those who agreed to participate were randomly allocated to three groups by flipping a coin twice. If the flipped coin landed heads two consecutive times, participants were randomized to receive essential oils and acupressure (group A); if the coin landed heads/tails one time, and tails/heads the second time, participants were randomized to receive only acupressure (group B); if the coin landed tails two consecutive times, participants were randomized to receive sham acupressure (group C).
Please cite this article in press as: Tang W-R, et al. Effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy: An experimental pilot study. Complement Ther Med (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.006
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Figure 1
3
Acupoint locations.
Interventions We chose three acupoints (Fig. 1), Hegu (LI4), Zusanli (ST36), and Sanyingjiao (SP6), which have been related to energy in the human body and were shown to alleviate fatigue in cancer patients.13 Sham acupressure was applied on the first metacarpal head, patella, and inner ankle (Fig. 1). These three locations have no acupoints, are not related to improving CRF, and are in the same dermatome region as our three acupoints, as suggested for experimental acupressure studies.32,33 Acupressure skills include pointing, pressing, kneading and pushing. Pointing is finding the acupoint. Pressing is applying enough pressure to release the flow of qi (Groups A and B only), which the patient experiences as a dull ache, tingling, and soreness.16 Kneading is rotating the finger around the acupoint to stimulate the curing effect. Pushing is pushing the thumb from the acupoint to the limb extremity to relax the patient’s muscles and enhance blood circulation.34 Acupressure was implemented by two RAs who were nursing graduate students. Both were trained in acupoint identification and acupressure skills by qualified TCM practitioners, who repeatedly confirmed accuracy of implementation. All participants received six cycles of traditional chemotherapy lasting about 5 months. During the first chemotherapy, participants were hospitalized for 4 days. On Day 1, an RA responsible for acupressure taught patients how to self-administer acupressure. Patients received a researcher-designed handbook (including a colored acupoint map and acupressure methods), and their learning effectiveness was confirmed by asking them to repeat what they were taught. On Days 2—4 and in subsequent hospitalizations for chemotherapy, one RA assisted patients in acupressure and confirmed their accuracy. Instruction was enhanced for older and less educated patients (approximately 20%) and repeated until patients could implement acupressure accurately. After discharge, patients self-administered acupressure once daily at home.
Participants started receiving the intervention on Day 1 of chemotherapy. Hence, the acupressure dosage was one application per day at the specified acupoints every morning for 5 months. As acupoints are symmetrically distributed, acupressure was applied on both sides of the body with each acupoint pressed in rotation for 1 min. Thus, participants spent 6 min doing acupressure. The acupoints and time of acupressure were based on two studies on acupressure therapy for CRF.13,16 In one study 10 acupoints were used, and each acupoint received acupressure for 3 min.16 In our study, we minimized the number of acupoints and acupressure time because middle-aged and elderly people in Taiwan are less well educated than their western counterparts. After discussion with a senior clinical TCM practitioner, we adopted the approach of the second study,13 i.e., three acupoints and 1 min of acupressure per acupoint. Group A received acupressure with essential oils. This 5% essential oil compound containing extracts of fir needle, Scotch pine, tea tree, sandalwood, peppermint, and cinnamon leaf was approved by the Therapeutic Goods Administration of Australia as effective in reducing physical and psychological fatigue and improving immunity.35 Two drops of essential oils were used for acupressure every time: one drop for the three acupoints on one side of the body, and one drop for three acupoints on the other side.
Measures Fatigue, functional status, anxiety and depression, and sleep quality were assessed by validated Chinese versions of the Tang Fatigue Rating Scale (TFRS),36 Eastern Cooperative Oncology Group Performance Status Rating (ECOG-PSR),37,38 Hospital Anxiety and Depression Scale (HADS),39,40 and Pittsburgh Sleep Quality Index (PSQI),41 respectively. Tang fatigue rating scale The 37-item TFRS has three subscales: physical functions (15 items), psychological aspects (12 items), and daily
Please cite this article in press as: Tang W-R, et al. Effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy: An experimental pilot study. Complement Ther Med (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.006
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living activities (10 items).36 Items are rated on a 1—10 point scale; higher scores indicate higher fatigue levels. The TFRS had excellent internal consistency (Cronbach’s alphas = 0.96—0.97) in patients with chronic heart failure36 and lung cancer,42 as well as good convergent and construct validities.36,42 In this study, the TFRS had internal consistency (Cronbach’s alpha) of 0.97. Eastern cooperative oncology group performance status rating The ECOG-PSR has been widely used in Europe to measure cancer patients’ functional status.43 The single-item ECOGPSR is rated on a 5-point scale from 0 (fully active) to 4 (complete reliance on others for care). Higher scores (≥2) indicate poorer functional status.44 ECOG-PSR validity was demonstrated by high correlation with Karnofsky’s index of performance status (r = 0.87).43 Since the ECOG-PSR has only one item, its internal consistency reliability cannot be determined. Hospital anxiety and depression scale The 14-item HADS45 was used to measure anxiety and depression. Responses to items are rated on a 4-point scale from 0 (not at all) to 3 (definitely),46 with each subscale score ranging from 0 to 21 points. Higher scores indicate higher levels of anxiety/depression. The HADS showed very good reliability and validity in cancer patients.47 In this study, the anxiety and depression subscales had internal consistencies (Cronbach’s alphas) of 0.86 and 0.81, respectively.
Analysis Data were coded and entered into SPSS (v.18). Baseline differences among the three groups were compared by Fisher’s exact test and one-way ANOVA. Post hoc comparisons were made using Tukey’s HSD post hoc test. To compare group differences in outcome variables over the study period, we used the generalized estimating equation (GEE) method to account for within-subjects’ dependency due to repeated measurements and allow variation in case number at each time.51 Because the current GEE model does not offer information on the working correlate matrix for calculating effect size, we estimated sample size before the study to ensure that power was sufficient to verify research hypotheses. Sample size was estimated as described52 using repeated-measures ANOVA in G power 3.0.10, with power = 0.8, type 2 error ˛ = 0.05, and effect size 2 = 0.40 based on a similar study.13 The estimated sample size was 45 (15 per group).
Ethical considerations This study was approved by the Chang Gung Medical Center Institutional Review Board (97-2422B). After an RA fully informed participants, they signed consent. To protect participants’ privacy, all data were encoded. Patients were informed that participating or not would not affect their medical services at the medical center.
Results Pittsburgh sleep quality index The 19-item PSQI48 measures sleep quality and quantity in the past month. Items are rated on a 4-point scale from 0 to 3. For cancer populations, total scores >8 indicate poor sleep quality, and those ≤8 indicate good sleep quality.49,50 Acupressure daily log A researcher-designed acupressure daily log was used by subjects to record whether they implemented acupressure and to rate six items (fatigue, anxiety, depression, pain, activity status, and sleep quality) on visual analog scales. Log entries were used to assess subjects’ acupressure adherence.
Data collection Data were collected at three times: one day before participants received their first chemotherapy (T0), Day 1 of the third chemotherapy (T1), and Day 1 of the sixth chemotherapy (T2). To avoid bias, different personnel were responsible for randomization, for implementing/teaching acupressure, and for collecting data. To maintain a double-blind design, data collectors and patients were unaware of group assignment. However, personnel who implemented/taught acupressure had to know patients’ group assignment. Thirty minutes after acupressure was applied, the data collector collected questionnaire data on patient wards. Questionnaires were self-completed by literate patients. For illiterate patients, the researcher read each questionnaire item and recorded patients’ answers.
Subjects’ characteristics Among the 83 patients who met the study criteria, 26 refused to participate due to feeling too ill (n = 17), questionnaires too long (n = 7), or emotional distress (n = 2). The remaining 57 lung cancer patients were randomized to three groups: group A (n = 17) received acupressure with essential oils, group B (n = 24) received only acupressure, and group C (n = 16) received sham acupressure. Of the 57 subjects who started this study, 12 dropped out, leaving 45 subjects who completed data collection (Fig. 2). For participants’ baseline characteristics, see Table 1. Most participants were diagnosed with Stage IV non-small cell lung cancer. Subjects’ characteristics did not differ significantly among groups except for age, which was treated as a confounding variable and controlled in GEE analysis of follow-up data. Dropouts and completers did not differ significantly in demographic and disease severity data (p > 0.05).
Baseline fatigue, psychological status, and sleep quality Baseline scores for fatigue, psychological status, and sleep quality did not differ significantly by ANOVA across the three groups (p > 0.05, Table 2), suggesting that the major outcome variables were homogeneous across groups before intervention. However, these outcome measures had quite large SDs, possibly contributing to outcomes not differing
Please cite this article in press as: Tang W-R, et al. Effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy: An experimental pilot study. Complement Ther Med (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.006
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Effects of acupressure on cancer-related fatigue
5 Eligible patients (N=83)
Refused to participate (n=26) Reasons: Too ill to participate (n=17) Questionnaires too long (n=7) Emotional distress (n=2)
Participants (n=57) Randomization Group A (n=17) Acupressure/oils
Group B (n=24) Acupressure only
Group C (n=16) Sham acupressure
Non-completers (n=2)
Non-completers (n=8)
Non-completers (n=2)
Reasons:
Reasons:
Reasons:
Death (n=1) Treatment change
Death (n=4) Treatment change
Death (n=1) Refused to continue study (n=1)
(n=1)
(n=3) Transfer to other hospital (n=1)
Included in analysis
Included in analysis
Included in analysis
(n=17) (15 completed study)
(n=24) (16 completed study)
(n=16) (14 completed study)
Figure 2
T0
T1
T2
CONSORT diagram.
significantly among groups. Thus, baseline values of outcome measures were controlled in GEE analyses.
Effects of acupressure on fatigue levels across chemotherapy cycles Adherence rates to acupressure (number of times acupressure was performed/number of times acupressure should have been performed) differed significantly for groups A, B, and C (93.0, 91.9, and 77.3%, respectively, p < 0.001). Hence, age, baseline outcome values, and adherence to acupressure were controlled in GEE analyses, and differences among participants’ fatigue levels (TFRS total and subscale scores) were compared by group and time. The results of GEE multiple linear regression models (with AR(1) as the working correlation matrix) are shown in Table 3. The adjusted total TFRS scores of group A changed less from T0 to T1 and T2 than group C by 21.90 (p = 0.44) and 20.74 (p = 0.57), respectively, but these differences were not significant (Table 3). Likewise, the adjusted total TFRS
scores of group B changed less from T0 to T1 and T2 than group C by 27.65 (p = 0.26) and 17.66 (p = 0.59), respectively, but not significantly. However, among the adjusted TFRS subscale scores, only subscale scores for fatigue in daily activity of groups A and B at T1 were significantly lower than those of group C by 25.15 (p = 0.02) and 20.03 (p = 0.04), respectively. The three groups’ adjusted fatigue subscale scores for daily activity at T2 and for physical and psychological dimensions at T1 and T2 did not differ significantly.
Effects of acupressure on sleep quality across chemotherapy cycles For group A at T1, the adjusted PSQI score changed significantly less than that of group C by 3.00 (p = 0.048). For group B at T2, the mean PSQI changed significantly less than that of group C by 2.25 (p = 0.040). At other times the sleep quality of groups A and B improved, but not significantly more than that of group C (Table 3).
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W.-R. Tang et al. Table 1
Baseline demographic and treatment characteristics by group (n = 57).
Variable
Age (years), mean ± SD Gender Male Female Education ≤Sixth grade Junior high or high school ≥College Marital status Single Married Divorced Widow/Widower Type of lung cancer NSCLC SCLC Cancer stage I II III IV Chemotherapy Gemcitabine Gemcitabine + Cisplatin + Taxotere Gemcitabine + Cisplatin + Navelbine Gemcitabine + Cisplatin Gemcitabine + Cisplatin + Taxol Other Hb (g/dl), mean ± SD Hct (%), mean ± SD ECOG-PSR 0 1 2 3
Group A, n = 17
Group B, n = 24
Group C, n = 16
p
n (%)
n (%)
n (%)
53.9 ± 9.8
54.8 ± 9.5
66.1 ± 8.0
90%3 ), who were the majority in previous studies.13,16 Lung cancer patients also have more severe distressful symptoms (e.g., fatigue, pain and difficulty breathing, and insomnia) than other cancer patients.62,63 Hence, lung cancer patients need an intervention they can practice at home. Our study shows that acupressure is a safe and simple intervention that can be applied even by late stage lung cancer patients undergoing chemotherapy.
Please cite this article in press as: Tang W-R, et al. Effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy: An experimental pilot study. Complement Ther Med (2014), http://dx.doi.org/10.1016/j.ctim.2014.05.006
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Effects of acupressure on lung cancer patients’ physical function (ECOG-PSR score).
Variable
Estimate
Standard error
95% CI for ORb
Exp(B)
p
ECOG-PSR Group × Timea Group A × T2 Group A × T1 Group B × T2 Group B × T1
−2.65 −4.55 −1.05 −2.18
1.85 1.66 1.08 1.05
(0.00, (0.00, (0.04, (0.02,
0.071 0.011 0.351 0.113
0.153 0.007 0.332 0.037
2.68) 0.29) 2.92) 0.88)
ECOG-PSR: Eastern Cooperative Oncology Group Performance Status Rating. a Group × Time: Interaction between group and time. b 95% CI for OR: 95% confidence interval for odds ratio, adjusted for the effects of baseline outcome values, age, and adherence to acupressure.
Furthermore, our results show that acupressure reduces fatigue related to daily activity and improves sleep quality of lung cancer patients. If our preliminary results can be validated in large-scale RCTs, the use of acupressure can be promoted in pre-chemotherapy interventions on patients with lung cancer, thus reducing CRF during chemotherapy.
Conflict of interest
Study limitations and future directions
This work was supported by the National Science Council in Taiwan (grant no. NMRPD180821). Special thanks to all the lung cancer patients who participated in this research. The time spent with you will be a treasured experience in our lives.
Despite its contributions, this study had some limitations. First, this pilot study had a small sample (N = 57) and lacked enough power to detect the effectiveness of acupressure on CRF. More rigorous investigation of this topic requires multi-center studies with larger samples. Second, our sample comprised only lung cancer patients under chemotherapy, limiting inference about the findings to all cancer cases or patients receiving other therapies (e.g., surgery or radiotherapy). Thus, future studies should recruit subjects with different cancer diagnoses and different treatments to increase generalizability. Third, data were only collected 30 minutes after acupressure was done; thus, the response duration is unknown. In future studies, fatigue should be assessed before and after acupressure. Fourth, despite our efforts to maintain a double-blind study, subjects who received essential oils may have guessed their group status. This problem may be avoided in future studies by adding another sham-acupressure group with essential oils, thus more rigorously testing the effectiveness of acupressure with essential oils.
Relevance to clinical practice Few studies have examined the effectiveness of acupressure on cancer patients, underlining the need for more studies to determine the effects of relevant factors, e.g., duration of acupressure intervention, pressure technique, dosage, and number of acupoints. Although we did not find a significant benefit of acupressure on total fatigue, we found beneficial effects on fatigue related to daily living activities and sleep quality in lung cancer patients undergoing chemotherapy. It is plausible that acupressure with or without essential oils helps lung cancer patients undergoing chemotherapy reduce cancer-related fatigue and increase activity level. Further study is wanted to test this hypothesis.
The authors have declared no conflicts of interest.
Acknowledgments
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W.-R. Tang et al. 31. Andersson S. Physiological mechanism in acupuncture. J Chin Med 1996;7:73—81. 32. Chen ML, Lin LC, Wu SC, Lin JG. The effectiveness of acupressure in improving the quality of sleep of institutionalized residents. J Gerontol 1999;54:M389—94. 33. Lang T, Hager H, Funovits V, Barker R, Steinlechner B, Hoerauf K, et al. Prehospital analgesia with acupressure at the Baihui and Hegu points in patients with radial fractures: a prospective, randomized, double-blind trial. Am J Emerg Med 2007;25: 887—93. 34. Chan P. Finger acupressure. New York: Ballantine Books; 1995. 35. Essential Therapeutics. About Essential Therapeutics; 2006 http://www.essentialtherapeutics.com.au/about.htm [accessed 11.05.12]. 36. Tang WR, Yu CY, Yeh SJ. Fatigue and its related factors in patients with chronic heart failure. J Clin Nurs 2010;19:69—78. 37. Hu WY, Dai YT, Berry D, Chiu TY. Psychometric testing of the translated McGill Quality of Life Questionnaire-Taiwan version in patients with terminal cancer. J Formosan Med 2003;102:97—104. 38. Ng T, Chew L, Yap CW. A clinical decision support tool to predict survival in cancer patients beyond 120 days after palliative chemotherapy. J Palliat Med 2012;15:863—9. 39. Chen ML, Chang HK, Yeh CH. Anxiety and depression in Taiwanese cancer patients with and without pain. J Adv Nurs 2000;32:944—51. 40. Chen PY, See LC, Wang CH. The impact of pain on the anxiety and depression of cancer patients. J Formosan Med 1999;3:373—82. 41. Wang RC, Wang SJ, Chang YC, Lin CC. Mood state and quality of sleep in cancer pain patients: a comparison to chronic daily headache. J Pain Symptom Manage 2007;33:32—9. 42. Chou TL. Change of fatigue level of lung cancer patients under chemotherapy, its relationship with cytokines, and the effectiveness of the intervention measure of the energy conservation physical activity disposal: a longitudinal study. Taoyuan: Chang Gung University; 2008 (Doctoral thesis). 43. Buccheri G, Ferrigno D, Tamburini M. Karnofsky and ECOG performance status scoring in lung cancer: a prospective, longitudinal study of 536 patients from a single institution. Eur J Cancer 1996;32A:1135—41. 44. Goodwin L, Lee W, Price A, Rayner L, Monroe B, Sykes N, et al. Predictors of non-remission of depression in a palliative care population. Palliat Med 2012;26:683—95. 45. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiat Scand 1983;67:361—70. 46. Snaith RP. The hospital anxiety and depression scale. Health Qual Life Outcomes 2003;1:29. 47. Wang GL, Hsu SH, Feng AC, Chiu CY, Shen JF, Lin YJ, et al. The HADS and the DT for screening psychosocial distress of cancer patients in Taiwan. Psycho-Oncol 2011;20:639—46. 48. Buysse DJ, Reynolds 3rd CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193—213. 49. Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh Sleep Quality Index. J Psychosom Res 1998;45:5—13. 50. Mystakidou K, Parpa E, Tsilika E, Pathiaki M, Patiraki E, Galanos A, et al. Sleep quality in advanced cancer patients. J Psychosom Res 2007;62:527—33. 51. Fitzmaurice GM, Laird NM, Ware JH. Applied longitudinal analysis. New York: Wiley; 2004. 52. Cohen J. A power primer. Psycho Bull 1992;112:155—9. 53. Kohara H, Miyauchi T, Suehiro Y, Ueoka H, Takeyama H, Morita T. Combined modality treatment of aromatherapy, footsoak, and reflexology relieves fatigue in patients with cancer. J Palliat Med 2004;7:791—6. 54. Umezu T, Sakata A, Ito H. Ambulation-promoting effect of peppermint oil and identification of its active constituents. Pharmacol Biochem Behave 2001;69:383—90.
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11 59. Lin ZG. New color acupuncture school. Taipei: Jyin; 2009. 60. Miaskowski C, Dodd M, Lee K. Symptom clusters: the new frontier in symptom management research. J Natl Cancer Inst Monographs 2004:17—21. 61. Dantzer R, Meagher MW, Cleeland CS. Translational approaches to treatment-induced symptoms in cancer patients. Nat Rev Clin Oncol 2012;9:414—26. 62. Cooley ME. Symptoms in adults with lung cancer. A systematic research review. J Pain Symptom Manage 2000;19:137—53. 63. Tanaka K, Akechi T, Okuyama T, Nishiwaki Y, Uchitomi Y. Impact of dyspnea, pain, and fatigue on daily life activities in ambulatory patients with advanced lung cancer. J Pain Symptom Manage 2002;23:417—23.
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Effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy: An experimental pilot study Woung-Ru Tang a,∗, Wan-Jung Chen a, Chih-Teng Yu b,c, Yue-Cune Chang d, Chuan-Mei Chen a, Chiu-Hua Wang a, Sien-Hung Yang e,f a
School of Nursing, College of Medicine, Chang Gung University, Taoyuan, Taiwan Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan c School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan d Department of Mathematics, Tamkang University, Taipei, Taiwan e Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan f School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan b
KEYWORDS Fatigue; Acupressure; Experimental study; Lung cancer
Summary Background: This study explored the effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy. Patients and methods: For this experimental study, 57 subjects were randomly assigned to three groups: acupressure with essential oils (n = 17), acupressure only (n = 24), and sham acupressure (n = 16). Acupoints were Hegu (LI4), Zusanli (ST36), and Sanyingjiao (SP6). All subjects received acupressure once every morning for 5 months, with each acupoint pressed for 1 min. Fatigue, functional status, anxiety, depression, and sleep quality were measured before initial chemotherapy (T0), on Day 1 of third chemotherapy (T1), and on Day 1 of sixth chemotherapy (T2). Outcome differences between groups were analyzed at T0, T1, and T2 by general estimating equations. Results: After controlling for baseline outcome values, age, and adherence to acupressure, subjects who received acupressure with essential oils and acupressure had significantly less fatigue in daily living activities and sleep better quality at T1 than subjects who received sham acupressure. Subjects who received acupressure with essential oils had significantly better sleep quality at T2 than the sham acupressure group. Subjects who received acupressure with or without essential oils had greater odds of better functional status at T1 than the sham group.
∗ Corresponding author at: School of Nursing, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Taoyuan, Taiwan. Tel.: +886 3 2118800 5331; fax: +886 3 2118433. E-mail address: [email protected] (W.-R. Tang).
http://dx.doi.org/10.1016/j.ctim.2014.05.006 0965-2299/© 2014 Elsevier Ltd. All rights reserved.
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W.-R. Tang et al. Conclusion: It is plausible that acupressure with or without essential oils helps lung cancer patients undergoing chemotherapy reduce cancer-related fatigue and increase activity level. Further study is wanted to test this hypothesis. © 2014 Elsevier Ltd. All rights reserved.
Introduction About 7.6 million people worldwide died from cancer in 2008, accounting for 13% of total mortality,1 with lung cancer as the top cause of cancer death.2,3 Lung cancer patients commonly experience fatigue; 70—96% of patients on chemotherapy and 65—100% of patients receiving radiotherapy report fatigue.4,5 Unfortunately, clinicians lack effective methods for treating fatigue.5 Cancer-related fatigue (CRF) is defined as subjectively perceived, persistent fatigue and exhaustion associated with cancer and its treatment.6 Most Chinese people with lung cancer use traditional Chinese medicine (TCM), e.g., Chinese herbal medicine, acupuncture, acupressure, and qigong therapy, combined with western medicine therapy.7,8 Indeed, combining Chinese and western medicine therapy is more effective on lung cancer patients than either treatment alone.9 TCM not only reinforces the effects of chemotherapy and avoids its side effects, but also enhances patients’ quality of life. In TCM, symptoms are believed to be caused by an imbalance between Ying and Yang, which influences the operation of qi, the energy of life, along meridians in the body to maintain health. When qi is blocked, illness will result in parts related to the meridians,10 which connect with the qi of organs at places called acupoints. The body has 365 important acupoints on 14 major meridians.11 Each acupoint is associated with a specific therapy. Acupressure and acupuncture therapy are based on the same theory and acupoints. Most studies on acupoint therapy have tested the clinical effectiveness of acupuncture. Since the 1970s over 500 randomized clinical trials (RCTs) have examined acupuncture, with a few studies on improving cancer patients’ symptoms by acupressure.12—16 Only two of them studied CRF.13,16 Acupressure has also been shown to control fatigue in patients with end-stage renal disease.17,18 A 1998 systematic review of 500 acupuncture-related RCTs concluded that ‘‘current quantity and quality of RCTs still cannot demonstrate the effectiveness of acupuncture.’’19,p.379 A similar conclusion was reached by four 2013 systematic reviews of TCM and CAM for controlling cancer symptoms.20—23 The findings were criticized for issues with research design, e.g., small sample size, imprecise definition of disease types, insufficient findings, and uncertain conditions of sample selection. Of the four recent systemic reviews, three investigated the effects of acupuncture,20—22 and one investigated the effect of all CAM modalities on CRF.23 No reviews investigated acupressure. Compared to acupuncture, acupressure is safe, convenient, and inexpensive; with a little training, it can be used by research personnel, medical care workers, family members and patients themselves.12,16,24 Acupressure achieves its effects by applying pressure to acupoints, thus releasing neurotransmitters that transmit signals along
neurons or activate the hypothalamic-pituitary-adrenal axis to regulate endocrine function.25,26 Another effect of acupressure is to release brain neurotransmitters, endorphins, and other neurochemicals to reduce symptoms of discomfort27—30 and alleviate stress.31 The effect of acupressure on CRF has only been examined in cancer survivors, after they had finished chemotherapy.13,16 Since CRF appears most serious during chemotherapy, immediately treating CRF will positively enhance cancer patients’ quality of life and treatment compliance. Therefore, our study was designed to examine the effect of acupressure on CRF in lung cancer patients receiving chemotherapy.
Methods Design For this experimental pilot study with repeated measures, lung cancer patients were recruited from pulmonary wards at a medical center in northern Taiwan from July 2008 to August 2010. This feasibility trial was implemented to help develop a future large trial.
Setting and subjects Lung cancer patients were included if they met these criteria: (1) receiving conventional chemotherapy, (2) no infection, injury and ulcers around the acupoints, (3) not taking antidepressants or suffering from a psychiatric disorder, (4) >18 years old, (5) never participated in acupressure and any fatigue-related intervention, and (6) willing to learn acupressure and apply it at home. Patients were excluded by these criteria: (1) pregnant, (2) lymphedema at acupressure points, (3) hemoglobin ≤ 9 g/dL, hematocrit < 30, (4) using steroids to treat fatigue, (5) moderate-to-severe heart failure or thyroid disorder, and (6) diagnosed with hepatitis and its acute exacerbation. Patients were screened by physicians in pulmonary wards, who referred possible subjects to a research assistant (RA) for assessment. Patients meeting the study criteria and willing to participate were enrolled. Those who agreed to participate were randomly allocated to three groups by flipping a coin twice. If the flipped coin landed heads two consecutive times, participants were randomized to receive essential oils and acupressure (group A); if the coin landed heads/tails one time, and tails/heads the second time, participants were randomized to receive only acupressure (group B); if the coin landed tails two consecutive times, participants were randomized to receive sham acupressure (group C).
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Figure 1
3
Acupoint locations.
Interventions We chose three acupoints (Fig. 1), Hegu (LI4), Zusanli (ST36), and Sanyingjiao (SP6), which have been related to energy in the human body and were shown to alleviate fatigue in cancer patients.13 Sham acupressure was applied on the first metacarpal head, patella, and inner ankle (Fig. 1). These three locations have no acupoints, are not related to improving CRF, and are in the same dermatome region as our three acupoints, as suggested for experimental acupressure studies.32,33 Acupressure skills include pointing, pressing, kneading and pushing. Pointing is finding the acupoint. Pressing is applying enough pressure to release the flow of qi (Groups A and B only), which the patient experiences as a dull ache, tingling, and soreness.16 Kneading is rotating the finger around the acupoint to stimulate the curing effect. Pushing is pushing the thumb from the acupoint to the limb extremity to relax the patient’s muscles and enhance blood circulation.34 Acupressure was implemented by two RAs who were nursing graduate students. Both were trained in acupoint identification and acupressure skills by qualified TCM practitioners, who repeatedly confirmed accuracy of implementation. All participants received six cycles of traditional chemotherapy lasting about 5 months. During the first chemotherapy, participants were hospitalized for 4 days. On Day 1, an RA responsible for acupressure taught patients how to self-administer acupressure. Patients received a researcher-designed handbook (including a colored acupoint map and acupressure methods), and their learning effectiveness was confirmed by asking them to repeat what they were taught. On Days 2—4 and in subsequent hospitalizations for chemotherapy, one RA assisted patients in acupressure and confirmed their accuracy. Instruction was enhanced for older and less educated patients (approximately 20%) and repeated until patients could implement acupressure accurately. After discharge, patients self-administered acupressure once daily at home.
Participants started receiving the intervention on Day 1 of chemotherapy. Hence, the acupressure dosage was one application per day at the specified acupoints every morning for 5 months. As acupoints are symmetrically distributed, acupressure was applied on both sides of the body with each acupoint pressed in rotation for 1 min. Thus, participants spent 6 min doing acupressure. The acupoints and time of acupressure were based on two studies on acupressure therapy for CRF.13,16 In one study 10 acupoints were used, and each acupoint received acupressure for 3 min.16 In our study, we minimized the number of acupoints and acupressure time because middle-aged and elderly people in Taiwan are less well educated than their western counterparts. After discussion with a senior clinical TCM practitioner, we adopted the approach of the second study,13 i.e., three acupoints and 1 min of acupressure per acupoint. Group A received acupressure with essential oils. This 5% essential oil compound containing extracts of fir needle, Scotch pine, tea tree, sandalwood, peppermint, and cinnamon leaf was approved by the Therapeutic Goods Administration of Australia as effective in reducing physical and psychological fatigue and improving immunity.35 Two drops of essential oils were used for acupressure every time: one drop for the three acupoints on one side of the body, and one drop for three acupoints on the other side.
Measures Fatigue, functional status, anxiety and depression, and sleep quality were assessed by validated Chinese versions of the Tang Fatigue Rating Scale (TFRS),36 Eastern Cooperative Oncology Group Performance Status Rating (ECOG-PSR),37,38 Hospital Anxiety and Depression Scale (HADS),39,40 and Pittsburgh Sleep Quality Index (PSQI),41 respectively. Tang fatigue rating scale The 37-item TFRS has three subscales: physical functions (15 items), psychological aspects (12 items), and daily
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living activities (10 items).36 Items are rated on a 1—10 point scale; higher scores indicate higher fatigue levels. The TFRS had excellent internal consistency (Cronbach’s alphas = 0.96—0.97) in patients with chronic heart failure36 and lung cancer,42 as well as good convergent and construct validities.36,42 In this study, the TFRS had internal consistency (Cronbach’s alpha) of 0.97. Eastern cooperative oncology group performance status rating The ECOG-PSR has been widely used in Europe to measure cancer patients’ functional status.43 The single-item ECOGPSR is rated on a 5-point scale from 0 (fully active) to 4 (complete reliance on others for care). Higher scores (≥2) indicate poorer functional status.44 ECOG-PSR validity was demonstrated by high correlation with Karnofsky’s index of performance status (r = 0.87).43 Since the ECOG-PSR has only one item, its internal consistency reliability cannot be determined. Hospital anxiety and depression scale The 14-item HADS45 was used to measure anxiety and depression. Responses to items are rated on a 4-point scale from 0 (not at all) to 3 (definitely),46 with each subscale score ranging from 0 to 21 points. Higher scores indicate higher levels of anxiety/depression. The HADS showed very good reliability and validity in cancer patients.47 In this study, the anxiety and depression subscales had internal consistencies (Cronbach’s alphas) of 0.86 and 0.81, respectively.
Analysis Data were coded and entered into SPSS (v.18). Baseline differences among the three groups were compared by Fisher’s exact test and one-way ANOVA. Post hoc comparisons were made using Tukey’s HSD post hoc test. To compare group differences in outcome variables over the study period, we used the generalized estimating equation (GEE) method to account for within-subjects’ dependency due to repeated measurements and allow variation in case number at each time.51 Because the current GEE model does not offer information on the working correlate matrix for calculating effect size, we estimated sample size before the study to ensure that power was sufficient to verify research hypotheses. Sample size was estimated as described52 using repeated-measures ANOVA in G power 3.0.10, with power = 0.8, type 2 error ˛ = 0.05, and effect size 2 = 0.40 based on a similar study.13 The estimated sample size was 45 (15 per group).
Ethical considerations This study was approved by the Chang Gung Medical Center Institutional Review Board (97-2422B). After an RA fully informed participants, they signed consent. To protect participants’ privacy, all data were encoded. Patients were informed that participating or not would not affect their medical services at the medical center.
Results Pittsburgh sleep quality index The 19-item PSQI48 measures sleep quality and quantity in the past month. Items are rated on a 4-point scale from 0 to 3. For cancer populations, total scores >8 indicate poor sleep quality, and those ≤8 indicate good sleep quality.49,50 Acupressure daily log A researcher-designed acupressure daily log was used by subjects to record whether they implemented acupressure and to rate six items (fatigue, anxiety, depression, pain, activity status, and sleep quality) on visual analog scales. Log entries were used to assess subjects’ acupressure adherence.
Data collection Data were collected at three times: one day before participants received their first chemotherapy (T0), Day 1 of the third chemotherapy (T1), and Day 1 of the sixth chemotherapy (T2). To avoid bias, different personnel were responsible for randomization, for implementing/teaching acupressure, and for collecting data. To maintain a double-blind design, data collectors and patients were unaware of group assignment. However, personnel who implemented/taught acupressure had to know patients’ group assignment. Thirty minutes after acupressure was applied, the data collector collected questionnaire data on patient wards. Questionnaires were self-completed by literate patients. For illiterate patients, the researcher read each questionnaire item and recorded patients’ answers.
Subjects’ characteristics Among the 83 patients who met the study criteria, 26 refused to participate due to feeling too ill (n = 17), questionnaires too long (n = 7), or emotional distress (n = 2). The remaining 57 lung cancer patients were randomized to three groups: group A (n = 17) received acupressure with essential oils, group B (n = 24) received only acupressure, and group C (n = 16) received sham acupressure. Of the 57 subjects who started this study, 12 dropped out, leaving 45 subjects who completed data collection (Fig. 2). For participants’ baseline characteristics, see Table 1. Most participants were diagnosed with Stage IV non-small cell lung cancer. Subjects’ characteristics did not differ significantly among groups except for age, which was treated as a confounding variable and controlled in GEE analysis of follow-up data. Dropouts and completers did not differ significantly in demographic and disease severity data (p > 0.05).
Baseline fatigue, psychological status, and sleep quality Baseline scores for fatigue, psychological status, and sleep quality did not differ significantly by ANOVA across the three groups (p > 0.05, Table 2), suggesting that the major outcome variables were homogeneous across groups before intervention. However, these outcome measures had quite large SDs, possibly contributing to outcomes not differing
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5 Eligible patients (N=83)
Refused to participate (n=26) Reasons: Too ill to participate (n=17) Questionnaires too long (n=7) Emotional distress (n=2)
Participants (n=57) Randomization Group A (n=17) Acupressure/oils
Group B (n=24) Acupressure only
Group C (n=16) Sham acupressure
Non-completers (n=2)
Non-completers (n=8)
Non-completers (n=2)
Reasons:
Reasons:
Reasons:
Death (n=1) Treatment change
Death (n=4) Treatment change
Death (n=1) Refused to continue study (n=1)
(n=1)
(n=3) Transfer to other hospital (n=1)
Included in analysis
Included in analysis
Included in analysis
(n=17) (15 completed study)
(n=24) (16 completed study)
(n=16) (14 completed study)
Figure 2
T0
T1
T2
CONSORT diagram.
significantly among groups. Thus, baseline values of outcome measures were controlled in GEE analyses.
Effects of acupressure on fatigue levels across chemotherapy cycles Adherence rates to acupressure (number of times acupressure was performed/number of times acupressure should have been performed) differed significantly for groups A, B, and C (93.0, 91.9, and 77.3%, respectively, p < 0.001). Hence, age, baseline outcome values, and adherence to acupressure were controlled in GEE analyses, and differences among participants’ fatigue levels (TFRS total and subscale scores) were compared by group and time. The results of GEE multiple linear regression models (with AR(1) as the working correlation matrix) are shown in Table 3. The adjusted total TFRS scores of group A changed less from T0 to T1 and T2 than group C by 21.90 (p = 0.44) and 20.74 (p = 0.57), respectively, but these differences were not significant (Table 3). Likewise, the adjusted total TFRS
scores of group B changed less from T0 to T1 and T2 than group C by 27.65 (p = 0.26) and 17.66 (p = 0.59), respectively, but not significantly. However, among the adjusted TFRS subscale scores, only subscale scores for fatigue in daily activity of groups A and B at T1 were significantly lower than those of group C by 25.15 (p = 0.02) and 20.03 (p = 0.04), respectively. The three groups’ adjusted fatigue subscale scores for daily activity at T2 and for physical and psychological dimensions at T1 and T2 did not differ significantly.
Effects of acupressure on sleep quality across chemotherapy cycles For group A at T1, the adjusted PSQI score changed significantly less than that of group C by 3.00 (p = 0.048). For group B at T2, the mean PSQI changed significantly less than that of group C by 2.25 (p = 0.040). At other times the sleep quality of groups A and B improved, but not significantly more than that of group C (Table 3).
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W.-R. Tang et al. Table 1
Baseline demographic and treatment characteristics by group (n = 57).
Variable
Age (years), mean ± SD Gender Male Female Education ≤Sixth grade Junior high or high school ≥College Marital status Single Married Divorced Widow/Widower Type of lung cancer NSCLC SCLC Cancer stage I II III IV Chemotherapy Gemcitabine Gemcitabine + Cisplatin + Taxotere Gemcitabine + Cisplatin + Navelbine Gemcitabine + Cisplatin Gemcitabine + Cisplatin + Taxol Other Hb (g/dl), mean ± SD Hct (%), mean ± SD ECOG-PSR 0 1 2 3
Group A, n = 17
Group B, n = 24
Group C, n = 16
p
n (%)
n (%)
n (%)
53.9 ± 9.8
54.8 ± 9.5
66.1 ± 8.0
90%3 ), who were the majority in previous studies.13,16 Lung cancer patients also have more severe distressful symptoms (e.g., fatigue, pain and difficulty breathing, and insomnia) than other cancer patients.62,63 Hence, lung cancer patients need an intervention they can practice at home. Our study shows that acupressure is a safe and simple intervention that can be applied even by late stage lung cancer patients undergoing chemotherapy.
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Effects of acupressure on lung cancer patients’ physical function (ECOG-PSR score).
Variable
Estimate
Standard error
95% CI for ORb
Exp(B)
p
ECOG-PSR Group × Timea Group A × T2 Group A × T1 Group B × T2 Group B × T1
−2.65 −4.55 −1.05 −2.18
1.85 1.66 1.08 1.05
(0.00, (0.00, (0.04, (0.02,
0.071 0.011 0.351 0.113
0.153 0.007 0.332 0.037
2.68) 0.29) 2.92) 0.88)
ECOG-PSR: Eastern Cooperative Oncology Group Performance Status Rating. a Group × Time: Interaction between group and time. b 95% CI for OR: 95% confidence interval for odds ratio, adjusted for the effects of baseline outcome values, age, and adherence to acupressure.
Furthermore, our results show that acupressure reduces fatigue related to daily activity and improves sleep quality of lung cancer patients. If our preliminary results can be validated in large-scale RCTs, the use of acupressure can be promoted in pre-chemotherapy interventions on patients with lung cancer, thus reducing CRF during chemotherapy.
Conflict of interest
Study limitations and future directions
This work was supported by the National Science Council in Taiwan (grant no. NMRPD180821). Special thanks to all the lung cancer patients who participated in this research. The time spent with you will be a treasured experience in our lives.
Despite its contributions, this study had some limitations. First, this pilot study had a small sample (N = 57) and lacked enough power to detect the effectiveness of acupressure on CRF. More rigorous investigation of this topic requires multi-center studies with larger samples. Second, our sample comprised only lung cancer patients under chemotherapy, limiting inference about the findings to all cancer cases or patients receiving other therapies (e.g., surgery or radiotherapy). Thus, future studies should recruit subjects with different cancer diagnoses and different treatments to increase generalizability. Third, data were only collected 30 minutes after acupressure was done; thus, the response duration is unknown. In future studies, fatigue should be assessed before and after acupressure. Fourth, despite our efforts to maintain a double-blind study, subjects who received essential oils may have guessed their group status. This problem may be avoided in future studies by adding another sham-acupressure group with essential oils, thus more rigorously testing the effectiveness of acupressure with essential oils.
Relevance to clinical practice Few studies have examined the effectiveness of acupressure on cancer patients, underlining the need for more studies to determine the effects of relevant factors, e.g., duration of acupressure intervention, pressure technique, dosage, and number of acupoints. Although we did not find a significant benefit of acupressure on total fatigue, we found beneficial effects on fatigue related to daily living activities and sleep quality in lung cancer patients undergoing chemotherapy. It is plausible that acupressure with or without essential oils helps lung cancer patients undergoing chemotherapy reduce cancer-related fatigue and increase activity level. Further study is wanted to test this hypothesis.
The authors have declared no conflicts of interest.
Acknowledgments
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