Auricular acupressure for hot ashes in patients with prostate cancer: protocol for a pilot randomized controlled trial

26 Background : Hot flashes, characterized by intense heat sensation and diaphoresis, are 27 common side effects resulted from hormonotherapy in patients with prostate cancer. 28 Cumulated studies have revealed beneficial role of acupuncture as complementary and 29 alternative recipe for the management of hot flashes. However, little is known about the 30 auricular acupressure (AA), a micro-acupuncture technique whose therapeutic purpose is 31 similar with conventional acupuncture. Therefore, this current study aims to explore the 32 effects and determine the feasibility of AA for hot flashes in patients with prostate cancer. 33 Methods/Design : This proposed pilot study is a two-arm parallel, single-blinded, randomized 34 sham-controlled trial. A total of 72 participants of prostate cancer suffered with hot flashes 35 will be recruited and randomly allocated into two groups in a 1:1 ratio. Equal randomization 36 is conducted using a computer-generated random allocation sequence. Sheng Zhi Qi (TF2), 37 Nei Fen Mi (CO18), Shen Men (TF4), Shen (CO10) and Pi Zhi Xia (AT4) are selected as 38 experimental acupressure points, and five helix points (HX 8-12) are used as sham control 39 acupressure points. Participants in the experimental group and control group will receive AA 40 and sham-AA treatment, respectively. The duration of the treatment is 6 weeks with two 41 sessions per week, and the follow-up period is 12 weeks. The primary outcome is Hot Flash 42 Score (HFS). The secondary outcomes include Quality of Life (QoL), Pittsburgh Sleep 43 Quality Index (PSQI) and Hamilton Anxiety Scale (HAS). All outcomes measurement will be 44 conducted before and through treatment period as well as follow-up period. Safety 45 assessment will be carried out through treatment and follow-up period. 46 Discussion : This pilot study will for the first time advance our knowledge on feasibility of 47 AA in alleviating hot flashes in patients of prostate cancer and provide preliminary evidence 48 for a further full-scale trial. 49

Prostate cancer is one of the most common cancer types and the second leading cause of 54 cancer related death in men worldwide [1]. Hormonotherapy, carried out by surgical or 55 medical castration combined with antiandrogen, has been standard modality for the treatment 56 of locally advanced and metastatic prostate cancer [2,3]. Although this therapy can be quite 57 efficacious, it, concomitantly, is associated with a range of side effects [4][5][6]. One of the well-58 known and uncomfortable side effects is the experience of hot flashes, which occurs in 50% 59 to 80% of patients with advanced prostate cancer receiving hormonotherapy [7-9]. Hot 60 flashes, characterized by subjective sensations of heat or sweating, are often associated with 61 psychosomatic disorders and adversely affect the quality of life [10,11]. Given that the 62 hormonotherapy is usually lifelong for patients of advanced prostate cancer, manipulation of 63 potential hot flashes accompanied is urgently needed. 64 The pathophysiology of hot flashes is quite complex and has not been fully understood, 65 thus management of these symptoms remains challenging [12][13][14]. A variety of medical 66 options have been evaluated for alleviating hot flushes, including hormonal replacement 67 therapies (e.g., estrogen, progesterone analogs and cyproterone acetate), non-hormonal drug 68 treatments such as gabapentin, clonidine and selective serotonin reuptake inhibitors (e.g., 69 venlafaxine, paroxetine) [15][16][17]. Most of these treatments have been assessed mainly in post-70 menopausal women and particularly breast cancer patients undergoing hormonotherapy [ In the current study, we aim to perform a pilot, randomized and controlled trial (RCT) to 89 determine whether AA is effective and safe as compared to a sham-AA control for the 90 management of hot flashes in patients with prostate cancer. The results of this trial will form 91 an informative basis of feasibility and provide preliminary evidence guiding a further full-92 scale trial. 93 94

Design 96
This pilot study is a prospective, two-arm parallel, single-blinded, randomized, sham-97 controlled clinical trial, and the protocol is presented according to items recommendation of 98 SPIRIT 2013 Checklist (Additional file 1). Eligible patients will be randomly divided into the 99 AA experimental group and the sham-AA control group in a 1:1 allocation ratio. Equal 100 randomization will be conducted using a computer-generated random allocation sequence. 101 All participants will be required to sign the informed consent before proceeding into the trial. 102 The schematic flow chart of the study process is shown in Figure 1, and the participant 103 timeline with events schedule is provided in Figure 2. 2) Under treatment for hot flashes control by using gabapentin, venlafaxine, etc.; 127 3) Unable to receive AA treatment and known allergy constitution; 128 4) Those who with severe heart, brain, kidney, liver, infectious or mental disease; 129 5) Difficulties in cooperating with the researchers and filling out the study documents. 130 131

Withdrawal criteria 132
Participants will be withdrawn from this study in the following situations: 133 1) When a participant requests to withdraw from the study, for any reason, at any time; 134 2) When worsening disease or severe adverse events or reactions take place. 135 The data of these participants will be gathered and included in further analysis. 136 137

Randomization, allocation concealment and blinding 138
Eligible participants will be randomly assigned to either an experimental group 139 receiving AA intervention, or a control group receiving sham-AA intervention in a 1:1 ratio. 140 Equal randomization will be carried out using a computer-created random allocation 141 sequence through the method of stratified block randomization by the SAS 9.2 software (SAS 142 Institute Inc., Cary, NC, USA). The research coordinator will access for the treatment 143 allocation information for each eligible participant through an online system, which was 144 developed by the Key Unit of Methodology in Clinical Research, The Second Affiliated 145 Hospital of Guangzhou University of Chinese Medicine. The other personnel, including 146 clinical physicians, AA practitioners, and assessors, will not be authorized to apply for 147 randomization numbers. Treatment allocations will be blinded to participants, assessors and 148 statisticians, and will not be revealed until the trial is completed. In order to avoid the 149 influence of the Rosenthal and Hawthorne effects, the AA practitioners will be restricted to 150 communicate with the participants [28,29]. 151 152

Interventions 153
This trial includes a 6-week treatment period with two sessions per week, and a 12-week 154 post-treatment period with follow-up of every 3 weeks. AA and sham-AA will be conducted 155 in participants of experimental group and control group, respectively. The auricular points in 156 both groups are illustrated in Figure 3, and the locations of these points are listed in Table 1 AA manipulation will be delivered through pressure stimulation on auricular points 160 using Semen Vaccaria seeds (Wang-Bu-Liu-Xing). Briefly, after sterilization with 75% 161 alcohol, a 1.0cm × 1.0cm adhesive plaster with one bead imbedded will be attached and fixed 162 on the specific auricular points. The patients will be asked to press the auricular points by 163 themselves 4-6 times a day for a 3-minutes duration each time. The AA manipulation will be 164 conducted alternatively between the two ears every 2 days. The plaster with seeds will be 165 exchanged for a fresh set once a week 166 All participants will undergo laboratory tests, including evaluation of hematologic and 199 urinary routine tests, blood biochemical tests (renal and hepatic function) and 200 electrocardiograph, before the start of treatment and after 6 weeks of treatment. The 201 participants will be asked to report information about potential adverse events (AEs) such as 202 local skin irritation and discomfort, light tenderness or pain, and dizziness during AA 203 treatment [35]. In case of severe AEs, AA treatment will be discontinued immediately. All 204 AEs will be fully recorded on the AEs pages of the case report forms (CRFs). The researcher 205 will confirm the occurrence of AEs and record all details including the occurrence date, 206 duration, degree, and causal relationship with the treatment. Emergency medical assistance 207 will be provided if any serious AEs occurs, and all details will be noted. 208

Sample size estimation 210
This study aims to evaluate clinical trial feasibility and to investigate basic information 211 about the efficacy and safety of AA for the treatment of hot flashes in patients with prostate 212 cancer, rather than hypothesis testing. Therefore, the sample size was decided based on a 213 rationale for feasibility, which were unable to calculate the statistical power formally. In 214 reference of a previous similar study of acupuncture for the treatment of hot flashes in breast 215 cancer patients [36], the present research thus incorporated a sample size of 30 for each group. 216 Considering an estimated 15% dropout rate, a required sample size in each group was 217 estimated to 36. In total, 72 participants will be enrolled in this trial. 218 219 Data collection and management 220 All data will be recorded on the hard copy of CRFs. Data regarding the demographic 221 characteristics and the baseline assessment will be collected by the screeners when the 222 participants are recruited. Outcome measurements will be performed by assessors through the 223 treatment period and the follow-up period. Data of prescription and any AEs reported by 224 participants will be collected by clinicians. A research coordinator will perform quality 225 control of data collection and be responsible for data access. All data will be presented as means and standard deviations or number (percentage), and 238 all analyses will be based on the intention-to-treat principle. For the description of baseline 239 characteristics, the mean with standard deviation or range with the minimum and maximum 240 values for continuous data and frequency with percentage for dichotomous data will be 241 reported. Homogeneity between the two groups in terms of baseline characteristics will be 242 tested using the two-sample t test for continuous data and the chi square (χ2) test for 243 dichotomous data. Analysis of covariance (ANCOVA) or logistic regression will be used for 244 analysis and adjustment of baseline characteristic that differ significantly between the two 245 groups. Methodological benchmarks such as randomization, allocation concealment and blinding has 262 been robustly met in the protocol. The chosen primary outcome is change in frequency and 263 severity of hot flashes by HFS, which is known to be valid to treatment effects [33]. 264 There are several limitations in this pilot study. First of all, this pilot trial will include a 265 small sample size of participants and hypothesis testing will not be involved. For this reason, 266 the results of this trial are not capable to generate adequate data for assessing the efficacy and 267 safety of AA for the treatment of hot flashes. In addition, the treatment of hot flashes with 268 AA is not based on syndrome differentiation, which is the major concern in traditional 269 Chinese medicine. The selection of auricular points is standardized and put on every 270 participant, this may be convenient for better use of the treatment over different individuals. 271 Moreover, AA practitioner will not be blinded because of the nature of the intervention. In 272 order to avoid the influence of the Hawthorne and Rosenthal effects, the AA practitioners 273 will be restricted to communicate with the participants and will not be involved in assessing 274 outcomes or the data analysis.   Table 1 Locations of auricular acupoints used in the trial. 464 Figure 1 Schematic ow chart of the study process.