The effect of digital acupressure on chemotherapy-induced nausea in Indonesian patients with stages III-IV breast cancer

Abstract

Patients with breast cancer are reported to experience nausea and vomiting during neoadjuvant chemotherapy. Both remain the most troubling side effects of chemotherapy, even in the era of new antiemetic agents. Hence, our study aims to investigate the clinical outcome of acupressure in the prevention of acute chemotherapy-induced nausea (CIN) by evaluating the frequency and severity of nausea. This study was a randomized controlled trial consisting of 42 breast cancer patients, divided equally into two groups (experimental (acupressure) and control groups). Digital acupressure was performed at pericardium 6 (P6 or Neiguan) and stomach 36 (ST36 or Zusanli) points. Assessment of nausea was conducted by examining the frequency of nausea and measuring nausea-related subscores from the simulator sickness questionnaire (SSQ) and visual analog scale (VAS) within one hour after chemotherapy. Our study indicated that patients in the experimental group had significantly lower frequency and less severe nausea than those in the control group. In conclusion, acupressure effectively decreased the frequency and severity of nausea in breast cancer patients undergoing neoadjuvant chemotherapy. Acupressure could be implemented as an adjunct intervention in addition to antiemetic therapy for the prevention of CIN in breast cancer patients.

1. Introduction

Breast cancer is one of the most frequently occurring malignant tumors among Indonesian women and has the highest mortality rate among Southeast Asian nations (18.6% per 100,000 population) [1]. More importantly, almost half of the patients with breast cancer in Indonesia had a delay in presentation and diagnosis, and thus the majority of patients are often at an advanced stage (stage III and IV) [2,3]. Chemotherapy is not only considered an adjuvant therapy but also a palliative treatment for breast cancer patients [4]. However, several side effects have been documented, and their severity may vary among patients. Nausea is the most prevalent side effect of chemotherapy experienced by breast cancer patients and is counted as a more distressing symptom than vomiting [5]. Patients with breast cancer often suffer from chemotherapy-induced nausea and vomiting (CINV) because chemotherapy for breast cancer contains highly emetogenic agents [6]. Notably, nearly half of patients receiving chemotherapy have been reported to experience CINV despite use of antiemetic medications [6,7]. This highlights the limitations of antiemetics for preventing CINV. While antiemetic drugs are the standard approach for managing CINV, different individuals may respond differently to these medications, and some may experience inadequate control of their symptoms. Hence, it is necessary to investigate other possible non-pharmacologic interventions as an additional therapy besides standard antiemetics for the management of CINV.

Acupressure has long been used in traditional Chinese medicine as one of the non-pharmacologic modalities to control nausea and vomiting. Two acupuncture points located at P6 and ST36 are closely associated with nausea and vomiting [8]. Although the exact mechanism for reducing nausea remains unclear, several studies suggest that acupressure stimulates a complex neuro-hormonal response with subsequent inhibition to the chemoreceptor trigger zone (CTZ) and vomiting center [9,10]. This is also supported by evidence regarding the efficacy of acupressure at the P6 point in suppressing treatment-related nausea [[4], [5], [6]].

Despite said reports on the implications of acupressure on CINV among various cancer patients, results still vary across studies [4,5,[11], [12], [13], [14], [15], [16]]. This may be attributed to various factors, including differences in patient characteristics/populations, variations in the type and dosage of chemotherapy administered, variations in acupressure techniques and protocols, and varying definitions and measures of CINV used across studies. Therefore, this study will help to gain a better understanding of the optimal utilization and effectiveness of acupressure as a complementary therapy for CINV in different cancer patient populations. The significance of this study lies in the fact that controlling and preventing CINV is crucial for cancer patients, as it greatly impacts their overall quality of life.

Moreover, due to its non-invasive nature and the ability of patients to self-administer the technique, acupressure is a more practical and accessible option for patients who may not have access to specialized acupuncture or electrostimulation services, or who prefer a self-care approach to manage their CINV symptoms. Therefore, our study aims to assess the effectiveness of acupressure in decreasing acute CIN by evaluating the frequency and severity of nausea in a homogeneous subset of patients with stage III–IV breast cancer receiving chemotherapy.

2. Patients and methods

2.1. Design and patients

The study was a randomized controlled trial with an allocation ratio of 1:1. Our pilot study indicated that the mean of nausea experienced within one hour after chemotherapy was 4.6 (standard deviation [SD] = 1.31) and 2.7 (SD = 0.48) in the control and experimental groups, respectively. Hence, at least 20 participants per arm would be required to achieve a 90% chance of obtaining a p-value <5%. A total of 42 participants were randomly assigned using a simple random technique into two equal groups (21 in each group, the control group received standard care of chemotherapy (including standard antiemetic treatment), whereas the experimental group received acupressure in addition to standard care). The duration of the trial was estimated at one year. The consort flow diagram is depicted in Fig. 1.

Fig. 1.

Consort flow diagram.

The population of the study consisted of all breast cancer patients undergoing chemotherapy at the Oncology clinic at Saiful Anwar General Hospital, Malang, between 2 January 2020 and 30 December 2020. Screening of patients was performed according to the hospital registration database and direct interviews before patients underwent chemotherapy. All patients received a premedication regimen, including rehydration with NaCl, injection of dexamethasone, ranitidine, and ondansetron prior to chemotherapy. Additionally, the physicians also prescribed antiemetic drugs to all patients for use at home after completing chemotherapy. Nonetheless, it should be noted that the usual treatment of nausea may vary among patients.

Patients were included if they fulfilled the following criteria: 1) women 30–50 years of age; 2) diagnosed with breast cancer stage III–IV; 3) undergoing the third, fourth, or fifth cycle of highly emetogenic neoadjuvant chemotherapy regimen (as per ASCO and MASCC classifications, either with the FAC (fluorouracil, adriamycin (doxorubicin), and cyclophosphamide) or FEC (fluorouracil, epirubicin, and cyclophosphamide) as outpatients at Oncology clinic Saiful Anwar General Hospital, Malang; 4); had more than mild levels of nausea and vomiting (more than 3 times in the first 24 h following chemotherapy administration) with the first and second cycle of chemotherapy; 5) had no problem in completing the study questionnaires and communicating in Indonesian; 6) willing to participate in the study.

2.2. Intervention

The acupressure treatments consisted of applying digital pressure at P6 and ST36 as previously described [11,17]. Briefly, for P6 points, digital pressure was applied on both forearms located approximately 5 cm proximal to the midpoint of the wrist (Fig. 2). For ST36 points, digital pressure was applied at 7.5 cm below the knee and 1.5 cm lateral of the tibia (Fig. 2). During the intervention, the thumb was used to apply pressure for 5 s and released for 1 s, the depth of pressure was defined as comfortable by the participants. Treatment was conducted for up to 10 min at each of the 2 acupoints on P6 and ST36 (a total of 20 min was required in one session) after patients completed their chemotherapy. Acupressure was performed by a certified nurse who had completed special training in the field of acupressure from Poliklinik Kesehatan RS. dr. Soepraoen, Malang, with over 12 years of experience practicing acupressure and acupuncture.

Fig. 2.

Diagram of P6 and ST36 acupoints location.

2.3. Outcome, data measurement, and collection

The primary outcome of this study was the frequency of acute CIN observed within one hour after chemotherapy. In addition, all participants filled out a baseline data questionnaire and assessed the severity of nausea as previously described [[18], [19], [20], [21]] using a nausea-related subscore quantified by the simulator sickness questionnaire (SSQ) and visual analog scale (VAS) after patients received acupressure treatment. Although both SSQ and VAS similarly evaluated nausea severity, SSQ tended to be more objective than VAS. SSQ consisted of seven questions, and their severity is rated from 0 (none) to 3 (severe), resulting in a maximum score of 21 (a total score of <6 = no nausea, 6 to < 12 = mild nausea, 13 to 18 = moderate nausea, and 18 to 21 = severe nausea). VAS consisted of a 10-scale representing nausea severity, where, 0 = no nausea, 1 to <4 = mild nausea, 4 to <7 = moderate nausea, and 7 to 10 = severe nausea.

2.4. Ethical considerations

The study was approved by the Ethics Committee of Saiful Anwar General Hospital, Malang (No. 400/225/K.3/302/2020). The patients were informed about the purpose of the study, the intervention procedures, and the contents of the questionnaires before they were implemented, and their written consent was obtained.

2.5. Statistical analysis

Data were analyzed using SPSS Statistics for Mac. Descriptive statistics were calculated to identify the demographic characteristics. Inferential statistics (chi-square test and t-test) were then performed to compare the outcomes between the groups. Regression analysis was performed to estimate the relationship between the intervention and the outcome.

3. Results and discussion

We achieved the planned sample size within a one-year timeframe, and no loss of follow-up was recorded (see Fig. 1). Forty-two patients consented and were randomized. All patients in both groups received standard antiemetic treatment prior to chemotherapy. The average age of patients in the experimental group was 54 ± 7.2 years, while the average age of patients in the control group was 54.5 ± 8.4 years. Characteristics of the included patients are depicted in Table 1, and no significant difference was observed between groups (p > 0.05).

Table 1.

Demographic of the included participants.

Variables	Experimental (n = 21)		Control (n = 21)		X2	p-value
	Number	%	Number	%
Age					1.037	0.595
≤ 40	0	0	1	5
40–50	14	67	13	62
> 50	7	33	7	33
Ethnicity					1.003	0.316
Javanese	16	76	13	62
Madurese	5	24	8	38
Educational level					1.128	0.569
Illiterate	4	19	7	33
Primary school	13	62	11	53
High school/college	4	19	3	14
Occupation					0.857	0.354
Unemployed	9	43	12	57
Occupied	12	57	9	43

The primary outcome of this study was the mean of acute nausea experience observed within one hour after chemotherapy. Our data indicated that the frequency of nausea in the experimental group was significantly lower than in the control group (2.05 ± 0.80 vs. 4.76 ± 1.42, p < 0.0001, Table 2). Additionally, the mean nausea-related subscore for patients in the experimental group (10.24 ± 1.89) was lower than those in the control group (12.81 ± 2.42) (p = 0.0004, Table 2). Similarly, nausea scores according to VAS were also lower in the experimental group (4.81 ± 1.03) than in the control group (6.14 ± 1.23) (p = 0.0005, Table 2). Severity based on nausea scores collected from SSQ and VAS indicated that patients treated with acupressure experienced less severe nausea than those in the control group (X² = 16.76, p = 0.0002 and X² = 13.20, p = 0.0014, respectively, Table 3). In corroboration, the estimated odds ratio of a higher (i.e., worse) nausea experience, SSQ, and VAS scores for acupressure compared with control were 0.06 (95% CI 0.01–0.46, p = 0.006), 0.56 (95% CI 0.38–0.82, p = 0.003), and 0.35 (95% CI 0.17–0.70, p = 0.003) (Table 4).

Table 2.

The primary outcome observed within one hour after chemotherapy.

Outcome	Experimental (n = 21)	Control (n = 21)	p-value
Frequency of nausea	2.05 ± 0.80	4.76 ± 1.42	<0.0001∗
Nausea-related subscore	10.24 ± 1.89	12.81 ± 2.42	0.0004∗
VAS for nausea	4.81 ± 1.03	6.14 ± 1.23	0.0005∗

Data presented as mean ± SD. VAS, visual analog scale. ∗p < 0.05.

Table 3.

Severity based on nausea scores collected from SSQ and VAS.

Nausea severity	Experimental (n = 21)		Control (n = 21)		X2	p-value
	Number	(%)	Number	(%)
SSQ
Mild	19	90.48	6	28.57	16.76	0.0002∗
Moderate	2	9.52	14	66.67
Severe	0	0	1	4.76
VAS
Mild	3	14.29	0	0	13.20	0.0014∗
Moderate	18	85.71	12	57.14
Severe	0	0	9	42.86

SSQ, simulator sickness questionnaire; VAS, visual analog scale. ∗p < 0.05.

Table 4.

Outcome and intervention interaction.

Effect	OR estimate	95% CI	p-value
Frequency nausea (acupressure vs. none)	0.06	0.01–0.46	0.006∗
Severity nausea (acupressure vs. none)
a) SSQ	0.56	0.38–0.82	0.003∗
b) VAS	0.35	0.17–0.70	0.003∗

CI, confidence interval; OR, odd ratio; SSQ, simulator sickness questionnaire; VAS, visual analog scale, ∗p < 0.05.

Our findings from the current study showed that acute chemotherapy-induced nausea (CIN) was significantly lower in the acupressure group than in the control group. We have also shown that patients receiving acupressure treatment had a lower ratio of worsening their nausea experience and severity compared to control arm. Notably, acupressure on P6 and ST36 points provides an immediate effect on relieving nausea (at least one hour after chemotherapy and before patients were discharged from the outpatient oncology clinic). Likewise, multiple studies have shown that auricular acupressure (AA) can effectively reduce the incidence and severity of acute CINV in patients with breast cancer [22,23]. Together, our study strengthens the previous notion [[4], [5], [6],[11], [12], [13], [14], [15], [16],[24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]] (15/20 studies show a positive impact of acupressure on reducing nausea in patients with cancer, listed in Table 5) that acupressure at P6 and/or ST36 are effective in reducing acute CIN for breast cancer patients. Despite a positive finding, it is important to note that several reports indicate that acupressure may not be effective in relieving CINV (Table 5) [4,13,24,29,32]. However, it is crucial to consider that these studies often recruited non-homogeneous subsets of participants who may have varied responses to acupressure treatments and thus influence the overall findings of the study.

Table 5.

Studies assessing the effect of acupressure at P6 and/or ST36 on CINV in adult patients with cancer.

Study	Cancer type	Acupressure point	Total sample size	Findings
Dibble et al., 2000	Breast cancer	P6 and ST36	17	The acupressure group exhibited reduced levels of nausea intensity and reported a lesser incidence of nausea
Dibble et al., 2007	Breast cancer	P6	160	The acupressure significantly reduce in the amount of vomiting and the intensity of nausea compared to controls
Genc and Tan, 2014	Breast cancer	P6	64	Reduction of the mean nausea, vomiting, retching, total, and anxiety score in patients treated with acupressure
Molassiotis et al., 2007	Breast cancer	P6	36	Acupressure prevents CINV in breast cancer patients
Peoples et al., 2019	Breast cancer	P6	242	Combination of acupressure with a relaxation recording are effective in reducing CIN
Roscoe et al., 2006	Breast cancer	P6	86	Acupressure significantly reduced the proportion of severe nausea than controls
Suh, 2012	Breast cancer	P6	120	Synergic effect of acupressure and counseling is effective in reducing CINV
Avc et al., 2016	AML	P6	90	Significant reduction on the number and severity of nausea-vomiting in those treated with acupressure
Byju et al., 2018	Various types of cancer	P6	40	Acupressure is effective in reducing nausea and vomiting among patients receiving chemotherapy
Gardani et al., 2006	Various types of cancer	P6	40	Acupressure is effective in the treatment of chemotherapy-induced vomiting
Gardani et al., 2007	Advanced neoplastic disease	P6	100	Acupressure is effective in the treatment of vomiting due to cancer chemotherapy
Genc et al., 2013	Various types of cancer	P6	120	Acupressure did not effective in preventing CINV
Melchart et al., 2006	Various types of cancer	P6	28	No significant reduction of CINV between experimental and control
Molassiotis et al., 2014	Various types of cancer	P6	372	No significant suppression of nausea experience between control and acupressure treated patients
Roscoe et al., 2003	Various types of cancer	P6	739	No significant differences in delayed nausea or vomiting between groups
Shen and Yang, 2017	Lung cancer	P6 and SP4	70	Experimental group had significantly less nausea and vomiting than the control group
Shin et al., 2004	Postoperative gastric cancer	P6	40	Acupressure is effective in controlling emesis
Taspinar and Sirin, 2010	Gynecologic cancer	P6	34	Significant reduction of mean score nausea, but not for the mean scores of vomiting and retching episodes
Kwon et al., 2016	Post operative thyroidectomy (Thyroid cancer)	P6	60	P6 acupressure had the short-term effect on relieving nausea but not vomiting and retching
Tsugita et al., 2021	Various types of cancer	P6 and ST36	12	No significant differences in nausea symptom before and after acupressure intervention

AML, acute myeloblastic leukemia; CINV, chemotherapy-induced nausea and vomiting; CIN, chemotherapy-induced nausea; grey shading indicates no significant effects identified in the study.

The molecular mechanism of acupressure in ameliorating CINV has not been identified. However, it is possible to speculate that acupressure may stimulate meridian energy and promote the recovery of gastrointestinal (GI) function [35]. Additionally, studies suggest that stimulating the P6 point may affect the level of beta-endorphins and transmission of 5-hydroxytryptamine in regulating gastric acid secretion and GI function, thus stopping nausea and vomiting [36,37]. Apart from the effectiveness of the current study, complementary medicine needs cultural acceptance in order to be effective. Interestingly, traditional medicine has been widely recognized and is practically implemented in Indonesia, particularly in remote areas. Therefore, the findings of this study highlight the importance of complementary medicine (i.e., acupressure) in preventing and alleviating patients' symptoms of CIN. Additionally, our results could be considered valuable since they add to the number of studies agreeing with the effectiveness of acupressure therapy in controlling CIN, which was also demonstrated in another country.

Despite our significant findings, our study has several limitations. Firstly, our sample is quite small. Secondly, our evaluation is relatively short. Thus, further research should replicate and expand the current study in order to examine the long-term effects of acupressure. Thirdly, the absence of a sham control group may make it challenging to eliminate the possibility of a placebo effect in the study [12,38]. Additionally, unidentified over-the-counter (OTC) antiemetic drugs that might be taken by the patients prior to chemotherapy may lessen the precision of this study.

4. Conclusion

In conclusion, the use of acupressure at specific points, such as P6 and ST36, can be considered a complementary approach in the management of acute CIN in patients with breast cancer.

Author contribution

Conceived the study: BW, ZU; Collected the data: BW, ZU; Performed the analysis: ZU; Wrote and revised the paper: ZU; Supervision: FH, AF, ZU. ZU is the main contributor to this article.

Funding

N/A.

Declaration of competing interest

None.