Randomization and blinding
All research procedures were approved by the Institutional Review Board (IRB) of Fudan University Shanghai Cancer Center, Shanghai, China (IRB approval number: 1301118-8-1303), and investigations were conducted in accordance with the Consolidated Standards of Reporting Trials statement  and the 2010 Standards for Reporting Interventions in Clinical Trials of Acupuncture . The study protocol was registered on ClinicalTrials.gov (Identifier: NCT01895010).
We included all patients at least 18 years old, with primary or metastatic liver cancer and planned to receive cisplatin-based TACE. None of them was receiving other acupuncture therapy. The skin of acupoint site receiving electrical acupoint stimulation must be intact and without visible evidence of injury and can tolerate mild discomfort following electrical stimulation. Exclusion criteria were as follows: (1) combined use of other venous chemotherapy within 5 days after TACE; (2) other confounding factors that may cause nausea and vomiting (such as intestinal obstruction, anorexia, and so on); (3) installing pacemaker; (4) cognitive dysfunction, unable to finish Scale; or (5) TEAS treatment within the past year regardless of indication.
Patients enrolled in this study were assigned into an active-acupuncture group or a placebo-acupuncture group, using covariate-adaptive randomization (or minimization) at a ratio of 1:1. This randomization was used to avoid covariate imbalances resulting from simple randomization, owing to the fact that this was a small study . The study was designed as single-blind, in which the random codes and corresponding treatment measures were known only by the acupuncturist (F.J.). Patients, nurses, researchers, and the principal investigators were unaware of the randomization scheme. Patients who did not receive electrical acupoint stimulation were not told during assignment about the potential responses of the control and electro-acupuncture procedures.
This study was conducted in the Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. All patients received TACE with cisplatin for primary or metastatic liver cancer between January 2012 and December 2014. Investigators explained the research to the patients in detail and answered questions, and patients were informed about the study design, including the use of active and placebo acupuncture, as well as the possible adverse effects of anti-emetic drugs (constipation, headache, and dizziness) and acupuncture treatment (uncomfortable feelings of the skin). Patients were enrolled in the study if they met all the inclusion criteria and did not fall under any exclusion criteria. Enrolled patients were required to maintain close contact with the researchers.
To treat liver lesions, all patients underwent one TACE treatment with cisplatin (60 mg) as the main drug. The TACE procedure took 0.5–1.0 h. The chemotherapy regimen did not include steroids. Before the TACE procedure, all patients received the 5-HT3 receptor antagonist palonosetron hydrochloride (0.25 mg, intravenous injection) to prevent vomiting. Then, the patients received the randomized intervention: active or placebo acupuncture. On the first day, patients in the active-acupuncture group received the first electrical stimulation 1–2 h before TACE and another stimulation just after TACE. Acupuncture was continued twice daily for 5 consecutive days, for a total of 6 days.
Patients were asked to adopt a comfortable sitting or supine position. The acupoints were wiped with a moist cotton swab and then connected to the anode and cathode of the electrical stimulation generator (Yao Yang Kang Da Company, Shanghai, China) through an electrode patch placed on the skin surface. Continuous waveform mode was selected, and then the electric current produced continuous stimulation on the acupoints. Stimulation frequency was set at 4 Hz , and the default value was set as 10 mA, which was twice the sensory threshold (5 mA). The intensity was adjusted every 10 min to keep the patients comfortable, and its actual value ranged from 7 to 15 mA . Each acupuncture treatment took 30 min.
Acupoints included were as follows. (i) Neiguan (P6): located 6 cm above the transverse crease of the wrist and between the palmaris longus tendon and the tendon of flexor carpi radialis; (ii) Zusanli (ST36): located below the knee, on the anterior tibialis muscle, along the stomach meridian; and (iii) Hegu (LI4): located on the dorsum of the hand, between the first and second metacarpal bones, approximately in the middle of the second metacarpal bone on the radial side.
In the placebo-acupuncture group, the electrodes were placed on the same acupoints and treated for the same duration as in the active-acupuncture group, but the intensity of electric stimulation was 0 mA. During treatment sessions, patients were allowed to watch the operation of the electrical stimulator and view the entire procedure. They could watch the doctor set the acupoint stimulation equipment at 4 Hz and press the start button. Therefore, all patients thought they received real electro-acupuncture.
Chemotherapy, palonosetron, and additional anti-emetics were given by an independent staff physician, who was blinded to the acupuncture treatment. As prescribed by the staff physician, the following rescue anti-emetics were administered: palonosetron (0.25 mg), metoclopramide (10 mg), and steroids (5 mg).
Every day, patients were required to fill out nausea and vomiting diary records to document the severity and frequency of nausea and vomiting. Visual analogue score (VAS) of anorexia is a secondary clinical outcome that measures appetite improvement. VAS ranges from 0 (normal appetite) to 10 (no food intake possible) . In addition, the M. D. Anderson Symptom Inventory (MDASI)  was used to assess the effect of CINV on a patient’s QoL. Adverse events were recorded during treatment and at follow-up visits. Some events, such as constipation, headache, and dizziness, could be related to the anti-emetic drugs. Other events, such as tingling, pain, or redness where the electrode contacted the skin, could be related to acupuncture treatment.
Statistical analysis was performed by a statistician from the Department of Statistics, Fudan University Shanghai Cancer Center who was blinded to treatment allocation. Data analysis of baseline characteristics was based on the intention-to-treat population, which included all randomly assigned patients. Baseline demographic and clinical variables of the two groups were compared using Student’s t test (continuous variables) or the Chi square test (categorical variables). Efficacy analyses were based on observed patients who completed both baseline and endpoint evaluation. To determine clinical response, the primary outcome variable was analyzed using the Chi square test. Secondary outcome variables, including anorexia VAS and MDASI score, were analyzed in the form of a descriptive comparison using Student’s t test. For adverse events, we compared the occurrence rates using Fisher’s exact test. P values less than 0.05 (two-sided) were considered statistically significant. All analyses were performed using SPSS 22.0 software (SPSS Inc., Chicago, IL, USA).