Epidemiology of complementary and alternative medicine therapy use in allogeneic hematopoietic stem cell transplant survivorship patients in Australia

Abstract In addition to prescribed conventional medicines, many allogeneic hematopoietic stem cell transplant (HSCT) survivors also use complementary and alternative medical therapies (CAM), however, the frequency and types of CAMs used by allogeneic HSCT survivors remain unclear. Study participants were adults who had undergone an allogeneic HSCT between 1st January 2000 and 31st December 2012. Participants completed a 402‐item questionnaire regarding the use of CAM, medical complications, specialist referrals, medications and therapies, infections, vaccinations, cancer screening, lifestyle, and occupational issues and relationship status following stem cell transplantation. A total of 1475 allogeneic HSCT were performed in the study period. Of the 669 recipients known to be alive at study sampling, 583 were contactable and were sent study packs. Of 432 participants who returned the completed survey (66% of total eligible, 76% of those contacted), 239 (54.1%) HSCT survivors used at least one form of CAM. These included dietary modification (13.6%), vitamin therapy (30%), spiritual or mind–body therapy (17.2%), herbal supplements (13.5%), manipulative and body‐based therapies (26%), Chinese medicine (3.5%), reiki (3%), and homeopathy (3%). These results definitively demonstrate that a large proportion of HSCT survivors are using one or more form of CAM therapy. Given the potential benefits demonstrated by small studies of specific CAM therapies in this patient group, as well as clearly documented therapies with no benefit or even toxicity, this result shows there is a large unmet need for additional studies to ascertain efficacy and safety of CAM therapies in this growing population.


Introduction
Worldwide, 90,000 [1] allogeneic HSCTs were performed between 2001 and 2011, with 4369 [2] of these procedures occurring in Australia. With improvements in donor selection, conditioning therapies, and supportive care, 35-80% of HSCT recipients can now be expected to become longterm survivors and be cured of their underlying disease [3]. While HSCT provides a clear benefit for many patients with malignant and nonmalignant disease, it is also associated with significant morbidity and mortality [4].

Epidemiology of complementary and alternative medicine therapy use in allogeneic hematopoietic stem cell transplant survivorship patients in Australia
In recent years, there has been growing literature on the long-term (or late) psychosocial and medical complications experienced by HSCT survivors. The impact of these is profound with HSCT survivors experiencing a 30% lower life expectancy than a matched population cohort [4]. While many survivors rate their quality of life highly at 2 years posttransplant, many HSCT recipients experience considerable difficulty coping with the short-, medium-, and long-term physical and psychological sequelae of HSCT and with the uncertainties of their prognosis. Given the extent and impact of late complications of HSCT, ongoing long-term follow-up and multidisciplinary care of HSCT recipients is essential [5].
In addition to prescribed conventional medicines, many HSCT survivors also use complementary and alternative medical therapies (CAM). However, the prevalence and extent of the usage of CAMs in this patient group remains unclear. A review published in 1998 found the prevalence of CAM use among cancer patients ranges from 7% to 64% of patients sampled in 26 studies conducted worldwide [6]. This is consistent with CAM use in the general population, estimated at 40% in Australia, Canada, Europe, New Zealand, and the United States [7].
Studies in the United States have reported that the most common complementary practices and products used by individuals with cancer are vitamin/mineral supplements, prayer for self, intercessory prayer, chiropractic/ osteopathic manipulation, and herbal therapies [8]. To date, no studies have reported CAM usage by HSCT patients.
Despite the lack of literature on the epidemiology of CAM use in HSCT patients, there have been a number of small trials, including randomized controlled studies showing a potential benefit for some CAM therapies such as mind and body interventions, although the majority of CAM treatments show inconclusive mixed results [9]. The authors of a recent literature review of these known studies of CAMs in HSCT proposed that a current barrier to the use and research in CAM therapy is the recognition and acceptance of CAM use in this population and that epidemiologic estimates were required [9]. The aim of this study was to describe the frequency and types of CAM used by HSCT survivors, with the intention of enhancing recognition of CAM use.

Patients and procedures
Study participants were eligible if they were >18 years of age and had undergone an allogeneic HSCT between 1st January 2000 and 31st December 2012 in New South Wales (NSW) (NSW is Australia's most populous state -with a population of ~7.5 million [10]), and could read and write English. Potential participants were identified from the transplant databases of all allogeneic transplant centers in NSW, with names and phone numbers provided to the research team. Consenting participants were given the option to self-complete the questionnaire or to complete it via a phone interview with one of the researchers. A second round of telephone calls was made to consenting participants who had not returned the survey within a month. The study protocol was approved by the Northern Sydney Coast Human Research Ethics Committee (NSLHD Reference: 1207-217M).

Instruments
The Sydney Post HSCT Study survey (SPBS) was developed by the research team. Item construction was informed by a review of the literature and discussions with patients attending HSCT long-term follow-up clinics. It consisted of 402 questions, including questions relating to the use of CAMs, specifically: Nutrition and Dietary approaches, Herbal supplements, Vitamin therapies, Mind-Body therapies (e.g., Meditation), Manipulative and Body therapies (e.g., Acupuncture), Traditional medicine (e.g., Traditional Chinese Medicine), Energy medicine (e.g., Reiki), and Homeopathy. Other relevant domains included demographic data, medical complications, specialist referrals, tests and assessments, medications and therapies, infections, vaccinations, cancer screening, close personal contacts, lifestyle, occupation, and relationship status following stem cell transplantation. The questionnaire used tick box response, short answer questions, and 5-step Likert scales measuring attitudes and other factors, and takes approximately 1 h to complete. The questionnaire was piloted in clinic and phone interviews to assess face and content validity and to check for comprehension of the survey questions.
An additional one page HSCT clinical data form (The Sydney Post HSCT Clinical Data Form) was used to collect information from the transplant database including date of transplant, date of diagnosis, stage at transplant, transplant conditioning, Graft-versus-Host Disease (GvHD) prophylaxis, stem cell source, and donor type.

Measures
Participants were classified as CAM users if they used at least one therapy in any of the CAM categories. CAM use was correlated with demographics, medical complications, posttransplant medical therapies, treatments and clinical variables, relationship status, and social determinants including income and occupational status. The relationship of CAM use was further explored against a range of survey instruments that measured quality of life

Statistical considerations
Categorical responses were summarized using frequencies and percentages. Parametric continuous variables were summarized using means and standard deviations, and nonparametric variables using medians and interquartile ranges. The Pearson's X 2 test or Fishers Exact tests were used for comparative analysis of dichotomous categorical variables. Two sample comparisons of means and medians were determined using the independent t test and Wilcoxon Rank Sum tests, respectively; greater than two sample comparisons of means and medians were determined using one-way analysis of Variance (ANOVA) and Kruskal-Wallis tests, respectively. A two-tailed P < 0.05 was used as the level of statistical significance.

Study subjects
A total of 1475 Allogeneic HSCT were performed in the study period. Of the 669 recipients known to be alive at study sampling, 583 were contactable and were sent study packs. A total of 432 (66% of total eligible, 76% of those contacted) returned the completed survey. Three percent declined participation.
Characteristics of CAM users are shown in Table 3. There was no age difference between CAM users and nonusers. Women (P = 0.019), people living in a major city (P = 0.017), those with a university education (P = 0.001), and those with bone disease (P = 0.029) were significantly more likely to use at least one CAM. When comparing pretransplant diagnosis, type of conditioning or time from transplant, cGvHD, diabetes, cardiovascular risk, thyroid problems, anxiety, and depression, no difference in CAM use was seen.
Additionally, patients taking antibacterial, antiviral, or antifungal treatment were significantly less likely to use CAMs (P = 0.041), whereas patients taking other prescription drugs, including immunosuppressant, cardiovascular, hormone replacement, or psychotropic medications, were no more or less likely to use CAMs. Patients who routinely saw a Psychologist (P = 0.024) or Physiotherapist (P = 0.010) were more likely to use CAMs, as were those who did regular exercise (P = 0.049). There was no   Diagnosis, comorbidities (diabetes mellitus, cardiovascular disease), bone disease, and posttransplant cancer diagnosis were not significantly associated with dietary modification. Those using dietary modification were significantly more likely to be further out from their transplant date (median 6.6 years compared to 5.0 years [P = 0.04]) and reported significantly higher FACT-BMT scores (Median 109, IQR 99-121), indicative of better quality of life.

Herbal therapy
Herbal therapies were uncommonly used by HSCT survivors, with the most common therapies including Ginseng . Patients were significantly less likely to take herbal supplements the more prescription medications they took (P = 0.004). There was no significant relationship between FACT-BMT and patient's use of herbs.

Discussion
In this survey of 583 allogeneic Australian HSCT survivors, over half (54.2%) used at least one CAM. The most common CAM therapies used were vitamin therapies (27.3%) and manipulative body-based therapies (26.0%), with survivors also using mind-body therapies (17.2%), dietary modification (13.6%), and herbal supplementation (13.5%). This usage is consistent with internationally reported CAM usage in cancer patients [6,11]. The types of CAM therapies used by HSCT survivors in our study are similar to those used by cancer patients, with vitamins, manipulative body-based therapies, and herbal supplementation used more often than other CAMs. Few participants (3.1%) reported using homeopathy compared to other studies in cancer patients, which report usage up to 10% [12]. This may reflect low rates of homeopathy usage in Australia compared to the United States, and/or the results of recent efforts by the Australian NHMRC (National Health and Medical Research Council) which released an advisory noting the absence of evidence for homeopathy and calling for restrictions on education and health insurance subsidies of homeopathy [13]. At the same time it is of some concern that only half of responders reported taking calcium (47.8%) and vitamin D supplements (56.7%), given that these have shown to be beneficial in this high-risk patient group [14].
As has been documented in other studies of CAM use, both in the general population and in cancer patients [6,11,12], we found a higher proportion of CAM usage by women (across all CAM subgroups), those with a university education and people living in a major city (which may be due to a lack of access to CAM in remote regions and smaller towns). We did not see any correlation between CAM usage and cGVHD or patient age. Although a cohort study using a questionnaire risks selection bias, with such a large response rate (76%) of our patient cohort of all contactable HSCT survivors over a 13-year period, we believe selection bias is minimal and this is an accurate proportion of CAM usage.
Given the number of HSCT survivors taking CAM therapies, it is important to be aware of the potential harms CAM therapies may have, including interactions with conventional allogeneic therapies, particularly immunosuppressants and antifungals, as well as risks of