Efficacy of acupuncture in the prevention and treatment of chemotherapy-induced nausea and vomiting in patients with advanced cancer: a multi-center, single-blind, randomized, sham-controlled clinical research

Chemotherapy-induced nausea and vomiting (CINV) is one of the most common and debilitating side effects which exerts a detrimental influence on the quality of life (QOL) of cancer patients and reduces their compliance towards conventional therapies. CINV typically presents in two phases, the acute phase and the delayed phase [1]. Acute CINV occurs within 1–2 h of chemotherapy administration and can last for up to 24 h, while delayed CINV phase presents more than 24 h after chemotherapy until 120 h.

Nowadays, the development of prophylaxis for chemotherapy-induced emesis has dramatically relieved chemotherapy-induced emesis. Patients receiving highly emetogenic chemotherapy (HEC) are recommended with a four drug combination of a neurokinin 1 (NK₁) receptor antagonist, a serotonin (5-HT₃) receptor antagonist, dexamethasone, and olanzapine by the ASCO guideline [2]. A phase 3 trial reported this combination therapy achieved a complete response rate of 79% in the patients who were receiving the first circle of cisplatin-based chemotherapy [3]. However, this result was based on only a single circle of chemotherapy with cisplatin. Additionally, patients undergoing chemotherapy with anthracycline and cyclophosphamide had a more inadequate control of CINV in the acute phase than those who treated with cisplatin [4]. It could be speculated that the complete response rate of CINV by the standard antiemetic medications in clinical practice is lower than what is reported in the literature. Despite the advance in antiemetic therapy, practice patterns of antiemetic use revealed low adherence to those guidelines [5] due to unbalanced medical development, financial burdens, provider barriers, and patient factors in different countries and areas [6, 7]. Although emesis could be prevented well in most cases, nausea mainly occurring in delay-phase remains a significant challenge for cancer patients [4, 8, 9].

Efforts should be made to explore the economic and practical approaches for better symptom control of CINV. Integrative therapies, including acupressure and electroacupuncture, are recommended for clinical application with fewer side effects and high feasibility by ASCO guideline [10]. Acupuncture, as a component of traditional medicine systems, has been practiced in Asia for thousands of years and been well accepted worldwide. By stimulation on specific acupoints beneath the skin, acupuncture accommodates the flow of energy called qi throughout the body [11] and removes the blockages in meridians helping the body reestablishing homeostasis. Traditional Chinese acupuncture requires exerting manipulation on needles to present a sensation of de qi (a soreness, fullness, heaviness, or local area distension [12]).

It is reported by researchers from different countries with the optimized outcomes of acupuncture in controlling chemotherapy-induced emesis [12, 13]. Acupuncture could be considered as a supplementary therapy for relieving symptoms of CINV. Nevertheless, owing to the limitation of research quality, although acupuncture could be an appropriate adjunctive treatment for CINV, it still needs evidence of high-quality clinical researches according to a systematic review [14]. In our study, we performed a multi-center, single-blind, randomized, controlled trial to investigate the efficacy and safety of acupuncture in the prevention and treatment of chemotherapy-induced nausea and vomiting in patients with advanced cancer.

This study was a multi-center, single-blind, randomized, sham-controlled clinical trial designed to investigate the effect of acupuncture versus sham acupuncture on CINV symptoms in patients with advanced cancer. All research procedures were approved by the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University (ref: 2014BL-067). All patients included in this study provided written, informed consent. All investigations were conducted in accordance with the Consolidated Standards of Reporting Trials statement [15] and the 2010 Standards for Reporting Interventions in Clinical Trials of Acupuncture [16]. The study protocol was registered on ISRCTN and Clinical-Trials.gov (ISRCTN13287728; Clinical-Trials.gov: NCT02369107). This trial protocol is attached as Additional file 1.

Participants were eligible for inclusion if they were diagnosed with lung cancer, breast cancer, or gynecological cancer and scheduled to receive cisplatin, anthracycline, or taxane-based chemotherapy regimens. Patients were required to be aged 18 years or older and aged 75 years or younger. The Eastern Cooperative Oncology Group performance status was 0–2. The expected lifetime was longer than 6 months. On the other hand, patients were excluded from joining this trial under the following conditions: severe cardiac arrhythmia, serious hepatorenal abnormal function, immune system, or hematopoietic system diseases, pregnant or lactating women. Patients with intractable vomiting caused by malignant brain metastases, intracranial hypertension, digestive tract obstruction, severe liver or renal dysfunction, brain tumors, cerebrovascular diseases, or other reasons couldn’t take part in the research. Acupuncture is a minimally invasive therapy. Thus, patients diagnosed with coagulopathy, thrombocytopenia, or other bleeding disorders were not allowed to join. It was not suitable in our study in patients with lymphedema in selected treating areas, fear of acupuncture, or allergy to needles. Other exclusion standards included that diagnosis with depression, anxiety disorders, psychosis, sepsis, or bacteremia.

Randomization was done using permuted block randomization with a secure computer system. Randomly allocated information was sealed in opaque envelopes and delivered to each center. Random allocation was performed after eligible participants who consented in written form and complete baseline assessments. Statisticians generated the allocation sequence. Primary investigators who were responsible for enrollment, and acupuncturist who conducted treatment were aware of the allocation. Patients were not informed of the group allocation. Investigators in charge of participant interviews and stuff for statistical analysis were also blind to the assignment. Blinding will be applied to the outcome assessment.

Between March 2015 to July 2017, 158 eligible patients were enrolled from Beijing Shijitan Hospital, Beijing Friendship Hospital, Beijing Hospital of Traditional Chinese Medicine, and Guang’ Anmen Hospital. Guang’ Anmen Hospital was added as the fourth research center because the allocation progress was slower than we estimated.

In the 158 patients, 15 patients failed to meet the inclusion criteria, while seven declined to participate in this research. There were 136 patients joined in the study, while two patients withdrawn their signed informed consent before the assignment due to the changing of minds. Finally, 134 participants were randomly assigned into the true acupuncture group (n = 68) and the sham acupuncture group (n = 66). In the follow-up phase, nine patients (6.6%) withdrew from this trial (3 in the true acupuncture group and 6 in the sham acupuncture group). As for the reason of drop-out, six patients transferred to another hospital for a therapeutic reason, and three patients revoked the consent forms for personal willingness. In the process of data cleaning, 5 cases were eliminated for failing to meet the inclusion criteria (over the up-age limit). Finally, 120 patients (including 62 in the true acupuncture group and 58 in the sham acupuncture group) were included in data analysis (Fig. 1). Patient baseline characteristics are shown in Table 1.

A comparison of the CINV degree in complete response rate (CRR) between two groups is exhibited in Table 2a, b). Similar emetic CRR in the 21-day observation. Although since the day 3 the CRR for nausea and vomiting in the true acupuncture group was slightly higher than that of sham acupuncture group, there is no statistical difference between two groups excepting for the CRR of nausea on the last day of chemotherapy circle (83.9% to 67.2%, respectively, P = 0.033).

We evaluated the variation of nausea and vomiting degrees with CTCAE4.0 in both groups (Table 2c). Original nausea and vomiting degrees between groups showed no significant statistical difference. The nausea degree in the true acupuncture group increased in the first 2 days and reached a peak on day 2 by 0.355 points compared to baseline, and then decreased gradually till the end of the chemotherapy circle. There was a similar tendency in the nausea variation of the sham acupuncture group except that the value keeps increasing to day 3 by 0.621 points. The difference between the two groups had statistical significance since day 3 (0.306 vs. 0.621, P = 0.021) until the end of observation (Fig. 2). The rise in the true acupuncture group at the beginning of chemotherapy was lower than that in another group, which indicating true acupuncture relieve the severity of nausea during the delay CINV and follow-up periods.

During the observation, the nutritional conditions of patients were evaluated with the SNAQ scale (Table 3). The score of SNAQ decreased on day 7 and slightly rose after that. The true acupuncture group had a higher score compared to the sham acupuncture group in the follow-up duration, and the difference was significant on day 14 (21.82 vs.20.12, P = 0.003) and day 21 (22.39 vs. 20.43, P = 0.001). It depicted that patients receiving true acupuncture would have better nutritional status after chemotherapy.

While assessing the anxiety and depression of patients, no significant difference was found between two groups (Data were shown in Additional file 2: Table S2). All participants’ ECOG score ranged from 0 to 2.

Safety was evaluated in 125 participants who were randomly enrolled and received at least 3 days of study intervention (Data were shown in Additional file 2: Table S3). Two participants in the true acupuncture group and one in the sham acupuncture group were not evaluable who withdrew consents without any intervention. One participant in the true acupuncture group and 5 in the sham acupuncture group discontinued the treatment due to transferring to other hospitals for a therapeutic reason. During the observation, 4 patients reported headache in the true acupuncture group. Diarrhea (n = 2), constipation (n = 2), and headache (n = 4) were reported in the sham acupuncture group. One participant was evaluated with increased Urea nitrogen and Creatinine related to primary renal disease, while one in the sham acupuncture group with slightly ALT increased. No apparent adverse events related to acupuncture were observed. Patients who need an additional rescue for CINV were 17 (26.1%) and 20 (33.3%) in the true or sham acupuncture group, respectively (P = 0.435, data were not shown in the table).

We conducted a multi-center, single-blind, sham-controlled prospective clinical research to investigate the effect of acupuncture in preventing chemotherapy-induced nausea and vomiting. There is no noticeable improvement of true acupuncture in the complete response rate of CINV compared to the sham-control. However, TA indeed remarkedly alleviated the severities of nausea (day-3 to day-21) and emesis (day-7 to day-21) induced by chemotherapy. TA also contributed to nutritional status recovery since the day-14 after chemotherapy initiation.

Nowadays, CINV is less of a challenge for patients receiving chemotherapy owing to the development of antiemetic medications. We still need to pay special attention to the CINV occurred unreported by the data. The limitations of traditional antiemetic trials conclude evaluating outcomes only after the first circle of chemotherapy and mainly focusing on the cisplatin-based chemotherapy regimen. These designs are critical for the preciseness of researches, but also confine the application of the conclusions. Patients undergoing other drugs or multi-day chemotherapy regimens, or receiving multicycle treatments remain faced with a higher risk of CINV. Also, CINV is affected by several risk factors, such as a history of nausea/vomiting, female sex, the expectancy of CINV, younger age, anxiety, history of morning sickness, and low alcohol intake [22]. Antiemetic prophylaxis based on a risk model guide led to improved control effect of acute and delayed CINV [23]. Nevertheless, these factors are not much considered in clinical application. Compared to emesis, nausea is a more distressing symptom and less controlled [8]. More emphasis should be put on alleviating nausea to improve the QOL of cancer patients. It will promote the psychological and physical wellness of patients. Adjunctive measures require better management of CINV.

In our study, we didn’t find superior CRR in the TA group but observed that TA reduced the severities of CINV and augmented the score of nutritional status. The nausea degree increased by 0.306 in the TA group while 0.621 in the SA group (P = 0.021) on day 3. Although there was no significant improvement in vomiting in the 120 h after chemotherapy initiation, TA reduced the vomiting degree since day 7(0 vs.0.190, P = 0.033). These results are consistent with findings by other researchers [24, 25]. Acupuncture didn’t exhibit a promising effect in reducing the occurrence of CINV, which might due to acupuncture have less influence on preventing CINV from taking place than antiemetic drugs. The impact of acupuncture took a longer time to show up and mainly manifested in modulating gastrointestinal functions. The mechanisms related to electroacupuncture were analyzed with animal models. Electroacupuncture at Neiguan (PC 6) and Jianshi (PC 5) could reduce nausea and vomiting during chemotherapy, which was possibly associated with the deduction of 5-HT₃ and dopamine [26]. It was also confirmed that electro-acupuncture(EA) at Zhongwan (CV12) alleviated the cisplatin-induced anorexia in rats by reducing the levels of plasma monoamine neurotransmitters 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, dopamine, and norepinephrine; as well as upregulating the expression of ghrelin and neuropeptide Y [27]. In another rat model, EA at CV12 not only attenuated the cisplatin-induced increase in 5-HT but also suppressed neuronal activation marker c-Fos expression in the nucleus tractus solitarius (NTS) [28]. Acupuncture exhibits a positive effect on alleviating nausea and promoting the nutrition intake, which compensates for the deficiency of antiemetic medication. Our results also indicated that acupuncture functioned after a period of time of treatment in general cases. It might be an effective strategy to initiate acupuncture ahead of chemotherapy for patients with a high risk of CINV. What’s more, for the sake of widespread implementation, our research allocated patients with multiple types of advanced cancers receiving various regimens, multi-circle of chemotherapy. TA and SA groups were comparable with similar participant composition with each factor. However, it is not sufficient to draw a solid conclusion for which population is more suitable to receive acupuncture during chemotherapy. An enriched enrollment strategy was indicated for future studies.

To eliminate the impact of the subjective factor, patients in both groups received acupuncture treatment with the same frequency, needle-retained time, an interval of treatment to achieve effective masking. Investigators in charge of participant interviews were also blind to the assignment. Whereas, the principal investigator who was responsible for distributing tasks and acupuncturists were not blinded. We also applied blind evaluation in statistical analysis. All these measures contributed to addressing reliable conclusions.

This study has several strengths. The intervention was conducted by several acupuncturists undergoing rigorous standardized training to make sure the operational consistency in this trial. Patients were treated at multiple sites with different stages of cancer, different cycles of chemotherapy, which more like the situations in the real world and increased the generalizability of the findings. The observation not only for the CINV phase (5 days since chemotherapy administration) but also including the follow-up 16 days. It made it possible to evaluate the effect of acupuncture in the whole chemotherapy cycle.

This study also has several limitations. First, in the study design, waitlist control was in need to eliminate the influence of the physiological effect of sham acupuncture [29]. Second, some participants in the study withdrawing for different reasons might impact the evaluation of the effects of acupuncture. Third, enrollment progressed slower than expected due to the patients’ turnover in the hospitals, limiting the enthusiasm of patients for participating in a randomized clinical trial. Fourth, there may exist the possibility that rare patients were aware of their allocation due to possessing a good knowledge of Chinese Medicine.

Article Summary—Strengths and limitations of this study

In conclusion, the current study found the effect of acupuncture in preventing CINV occurring is relatively modest. Still, it was feasible and practical to apply acupuncture for alleviating chemotherapy-induced nausea and vomiting and improving nutritional status of patients with advanced cancer.