Acupuncture for Fatigue in Breast Cancer Survivors: a Study Protocol for a Pragmatic, Mixed-method, Randomised Controlled Trial

Introduction Breast cancer is the most common tumour type in women worldwide. The success of the treatment of breast cancer have improved hence the prevalence of survivors have increased (American Cancer Society). However, experienced side effects from the cancer itself or from cancer treatments is substantial. Anti-cancer treatment can have a number of side-effects including nausea, fatigue, vomiting, anorexia and alopecia (1 - 3). However, some side effects such as cancer-related fatigue (CRF) are very persistent. CRF is a common adverse effect of cancer and cancer therapy, and effects the quality of life of the patients (4). The definition of CRF from the National Comprehensive Cancer Network (NCCN) is that it is "a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness, related to cancer or cancer treatment, that is not proportional to recent activity and interferes with usual functioning" (5). It is important to point out that CRF is a form of fatigue that are different from normal fatigue which everyone can experience every now and then. The symptoms of CRF is under-reported by patients and underestimated and undertreated by clinicians, despite the prevalence and negative impact of CRF (6). It is recommended to patients that they are screened for CRF after completion of primary treatment and that they are offered specific information and strategies for management of the fatigue (7). Getting CRF as a side-effect after cancer treatment can have a major impact in their life.

In Norway on average 3090 women are diagnosed with breast cancer each year, giving a incidence rate per 100 000 persons of 121,0. In 2014, 3348 patients were diagnosed with breast cancer. The prevalence of fatigue is high in breast cancer survivors (BCS), with some studies reporting as many as 50% of the patients experiencing this (8). In a meta-analysis involving 12327 BCS, concluded that approximately one in four BCS suffers from severe fatigue (9). Several different treatments have been recommended for CRF such as exercise, psychosocial intervention, pharmacological interventions and mind-body interventions (4). From several randomized trials mind-body interventions such as yoga and acupuncture has been shown to relieve fatigue in cancer survivors (7). These studies, have however not focused solely on BCS but included other cancer types as well (10). Acupuncture has been shown to have an effect on CRF (10,11). A recent meta-analysis on CRF and acupuncture is positive (12) In Norway BCS are offered treatment such as cognitive behaviour therapy, exercise, relaxation techniques, yoga and nutritional coaching for their CRF. The use of acupuncture in the treatment of chemotherapeutic induced nausea is well established in Norway (13), also a Norwegian study on acupuncture on hot flashes in breast cancer patients has been published (14). The patients are found to be positive to acupuncture (15,16). In US acupuncture seems to have found its place in several hospitals which offers integrative medicine care to cancer patients (10).

Methodological approach A pragmatic, randomised controlled trial At the moment the study group, behind this present application, is running a pilot study on fatigue in breast cancer survivors with acupuncture as the intervention. This pilot study has been approved by the Regional Committee for Medical and Health Research Ethics (REK sør-øst A; reference 2017/2197). The purpose of conducting this pilot study is to examine the feasibility of our approach that is intended to be used in the planned larger randomised controlled study. Hence the design and methodological approach of the study in question wil be equal to the ongoing pilot study. By doing this the investigators can evaluate the feasibility of recruitment, randomization, collaboration, assessment procedures, and implementation of acupuncture. This will help us also to identify, revisions, if any, needed in the design of the larger, pragmatic randomised trial.

The intention with the pragmatic, RCT is to test acupuncture as a complete treatment package, i.e. including the therapeutic relationship and expectation, and address the important question of the overall effect of acupuncture-care, which is highly relevant to breast cancer survivors experiencing CRF. This question concerning the overall effect of acupuncture is also of importance for their health care providers and health authorities in general. As such a pragmatic trial will help users choose between options for care, and ''explanatory'' to describe trials that test causal research hypotheses (i.e., that a given intervention causes a particular benefit).Further, a pragmatic trials are primarily designed to determine the effects of an intervention under the usual conditions in which it will be applied, whereas explanatory trials are primarily designed to determine the effects of an intervention under ideal circumstances.

Baseline assessment includes sociodemographic data, medical and gynaecological history, previous experience with acupuncture, which other self-provided and therapist-provided interventions they have used earlier to relieve fatigue, current use of drugs and dietary supplements, level of physical activity, smoking status and level of alcohol consumption.