Objectives The present study examined the impact of a patient-tailored complementary/integrative medicine (CIM) programme on sleep quality in patients undergoing chemotherapy for breast and gynaecological cancer.
Methods Study participants received standard supportive care, with or without weekly CIM treatments. Disturbed sleep quality was defined as a score of ≥4 on the Edmonton Symptom Assessment Scale (ESAS) or a score of ≥3 on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Adherence to integrative care was defined as attending ≥4 CIM treatments, with ≤30 days between each session.
Results Of 388 eligible patients, 264 (68%) reported disturbed sleep quality. Baseline-to-follow up assessment (at 6 weeks) was optimal for 104 patients in the treatment group and for 76 controls, with 75 of treated patients found to be adherent to the CIM intervention. Sleep-related ESAS scores improved more significantly in treated patients (p=0.008), as did sleep-related concerns on EORTC (treatment group, p=0.026).
Conclusions A patient-tailored CIM programme may improve sleep quality and related concerns among patients with breast and gynaecological cancer undergoing chemotherapy. Further research is needed to better understand the impact of CIM on sleep quality in this patient population.
Trial registration number NCT01860365.
- complementary/integrative medicine (CIM)
- breast cancer
- gynecological cancer
- sleep disorders
- integrative oncology.
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- complementary/integrative medicine (CIM)
- breast cancer
- gynecological cancer
- sleep disorders
- integrative oncology.
More than a third of patients with cancer report sleep-related concerns following the initial cycle of chemotherapy,1 and at least 20% use sleep-related medications prior to adjuvant treatment.2 3 Disturbed sleep quality includes difficulty falling asleep, short sleep duration and poor sleep quality, and can negatively impact quality of life (QOL), increasing fatigue, depression and vasomotor symptoms.4 Chronic sleep-related concerns can be further exacerbated during chemotherapy,5 as a result of emotional distress (eg, persistent thoughts, concerns and anxiety),6 disease progression,7 pain8 and high doses of glucocorticoid medication.9 Pharmacological therapies are of limited efficacy and can have significant adverse effects. It has been shown that patients with ovarian cancer using sleep and pain-relief medications reported worse quality of sleep.10 Conversely, cognitive behavioural therapies can improve sleep quality and fatigue in cancer survivors.11
Complementary/integrative medicine (CIM) is popular among patients with cancer, and many patients are using these therapies during chemotherapy.12 Randomised controlled trials have shown that CIM can improve sleep quality in patients with breast cancer practising yoga during adjuvant radiotherapy,13 guided imagery training before chemotherapy,14 Tibetan yoga during treatment of lymphoma,15 and yoga among cancer survivors, in addition to standard care.16 In a cohort of male patients with prostate cancer undergoing radiotherapy, qigong and tai chi exercises significantly increased sleep duration, although this effect did not persist over time.17 In breast cancer survivors with insomnia, tai chi led to a greater reduction in cellular inflammatory responses than cognitive behavioural therapy, and in expression of genes encoding proinflammatory mediators.18 Nutritional supplements have also been found to improve sleep quality (eg, melatonin in breast cancer survivors,19 Viscum album/mistletoe in pancreatic cancer20), as have acupuncture,21 massage therapy22 and self-administered acupressure.23 Non-randomised pragmatic studies have suggested that CIM may improve sleep quality and QOL-related concerns. Despite the positive findings of this research, the heterogeneity of the study population and treatments precludes reaching any conclusions from their findings.24 25
The present study set out to examine the impact of a patient-tailored CIM programme, provided within a supportive care service in a conventional oncology setting, on sleep quality and QOL-related outcomes in patients with breast and gynaecological cancer undergoing chemotherapy for localised or advanced disease. The hypothesis of the present study was that sleep-related concerns among patients undergoing chemotherapy have multifaceted aetiologies, reflecting a wide biopsychospiritual spectrum. It is thus probable that a patient-tailored CIM approach may better meet patients’ sleep-related symptoms, in that it addresses a more complex ‘picture’ than conventional treatments. The present study set out to evaluate the effectiveness of an individualised integrative medicine approach, focusing on patients’ sleep-related concerns, as opposed to examining a specific effect of a single CIM treatment modality on this outcome.
Study design and setting
The study was prospective, controlled and non-randomised and took place at the Lin and Zebulon medical centres of the Haifa and Western Galilee District, Clalit Healthcare Services, Israel.26 The integrative oncology programme (IOP) at these centres offers patients undergoing chemotherapy a wide range of CIM modalities. Treatments are provided by a multidisciplinary team of medical (physicians and nurses), paramedical (social workers, occupational therapists, nutritionist) and non-medical CIM practitioners trained in integrative supportive oncology care.
Study recruitment took place from May 2013 to May 2016. Patients aged ≥18 years undergoing chemotherapy (neoadjuvant, adjuvant or palliative) for breast or gynaecological (ovarian, endometrial or cervical) cancer were eligible. Patients’ oncology Health Care Practitioners (HCPs) (oncologist, nurse-oncologist or social worker) referred them to integrative physicians (IPs are physicians dually trained in supportive cancer care and complementary medicine) via the study nurse, who informed potential recruits about the IOP service throughout the study period. This was done in order to minimise the potential for a selection bias created by a lack of awareness about the service, or the absence of an oncology HCP referral. The referral required at least one chemotherapy or cancer-related indication, including disturbed sleep quality and related concerns. After receiving an in-depth explanation of the study protocol and signing of an informed consent form, participants were scheduled for an initial consultation with the study IP.
Recruited patients attending the IP consultation were designated as the treatment group, and those not attending as controls. Treated patients were divided according to their adherence to integrative care (AIC) programme, defined as attending ≥4 CIM treatments with ≤30 days between each session. Both treatment and control groups received standard conventional supportive care, including medications for disturbed sleep quality and related concerns. Psycho-oncology interventions were also provided as part of the supportive care service.
CIM treatment regimen
The IP consultation lasts approximately 1 hour, concluding with the design of a comprehensive CIM treatment programme. Recommendations are based on the research findings regarding the effectiveness and safety of treatments; the indications listed in the oncology HCP referral, and HCP input during the study period; and patients’ expectations from the integrative programme. Weekly CIM treatments include guidance on herbal and dietary supplements; acupuncture and other manual and movement modalities (eg, acupressure, reflexology, Feldenkrais method); and mind–body–spirit therapies (eg, guided imagery, music therapy, spiritual care). CIM treatment regimens are adapted throughout, addressing changes in patient symptoms during chemotherapy. Treatment regimens are planned for at least 6 weeks’ duration.
Patients who were identified during the IP consultation as suffering from disturbances in sleep quality and related concerns were provided with a patient-tailored, CIM treatment programme. CIM treatments included specific insomnia-related interventions, such as guided imagery exercises and acupuncture (eg, acupoint Heart 7 for insomnia). Throughout the study period the CIM interventions which focused on improving sleep quality were adjusted, in accordance with the patients’ expectations and their willingness to experience treatments, which may or may not concur with their health belief model.
Assessment of sleep quality and related concerns
Baseline sleep quality and related concerns, as well as other QOL-related outcomes, were assessed at baseline by the IP for patients in the treatment arm and by the study nurse for controls, with repeat assessment at 6-week and 12-week visits. Study outcomes were measured using the Edmonton Symptom Assessment Scale (ESAS)27 28 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).29 The sleep-related question in ESAS asks patients to score their ‘sleep quality’ (the ninth scale), ranging from 0 (lowest severity) to 10 (greatest severity). The EORTC study tool asks patients the question ‘have you had trouble sleeping?", with scores ranging from 0 (lowest severity) to 100 (greatest severity).
Patients reporting disturbed sleep quality and related concerns were further questioned about specific sleep-related parameters. These included time to sleep initiation, number of early and/or multiple awakenings, sleepiness during the day and understanding of what led to these sleep-related concerns. Patients were considered to have disturbed sleep quality or related concerns if they fulfilled one or more of the following criteria: (1) ESAS score ≥4 for sleep-related outcomes and (2) a score of ≥3 on EORTC for insomnia. The decision to set the ESAS score for sleep at ≥4 was done with the goal of identifying patients with moderate-to-severe insomnia.30 An EORTC score of ≥3 was used in accordance with area under the receiver operating characteristic curve ≥0.70.31 The impact of the CIM treatments on sleep was assessed using the ESAS and EORTC sleep-related scores, which were established as the study’s primary outcome variables, between baseline and the 6-week follow-up assessment. Both questionnaires were employed in the study since they ask different questions when addressing QOL-related concerns and do so using different time frames: the ESAS asking patients about the last 24-hour period the EORTC about the last 7-day period. The use of both tools in parallel thus increases the likelihood of identifying and assessing QOL-related outcomes, including disturbances in sleep quality. The use (and dosage) of medications used for sleep and anxiety-related concerns was extracted from patients’ electronic medical file and at baseline and follow-up IP visits.
Optimality of assessment between baseline and 6 weeks
Optimality of assessment between baseline and 6 weeks was necessary in order to ensure a similar time interval between chemotherapy and follow-up assessments. This approach prevents the need to correct for changes in symptom severity, which may have been caused by shortened or lengthened spans of time between the first day of chemotherapy and the day of the study assessment visit. The timing of the baseline and 6-week assessments was kept to consistent intervals from the administration of chemotherapy, as assessed by two independent investigators. For adjuvant or neoadjuvant chemotherapy, assessment was considered optimal if it took place within a similar interval of time between the administration of chemotherapy and the assessment (≤72-hour difference), at both baseline and 6-week assessments, provided that the chemotherapy regimen was the same. For patients undergoing palliative treatment, assessment was considered to be optimal if either no chemotherapy was given or if IP assessments took place with an interval ≤1 week difference between chemotherapy and assessments at baseline and 6 weeks.
The sample size was calculated using the OpenEpi program (Microsoft). It was determined that in order to assess the impact of the CIM treatments, at least 80 patients would be needed in each arm of the study. This would allow an alpha error of 0.05 and beta error of 0.2 (power 80%) to detect a difference of 20% decrease (or difference) in ESAS 11-point scales. Data were collated and evaluated using the SPSS V. 21 software program. Fisher’s exact test was used to detect differences in the prevalence of categorical variables and demographic data between both groups. A t-test was used to determine differences in continuous variables when normality was assumed, and a Mann-Whitney U test for abnormal distribution. p Values of <0.05 were considered statistically significant. A repeated measure analysis was conducted to determine changes in ESAS scores. Paired test repeated measure was conducted to determine changes in ESAS and EORTC scores in the treatment versus control groups, at baseline and 6-week assessments.
The study protocol was approved by the Ethics Review Board (Helsinki Committee) at the Carmel Medical Center in Haifa, Israel, and registered at ClinicalTrials.gov (NCT01860365). Participation was voluntary, and no payment or other incentive was offered as an incentive. Participation in the study was open to patients of any gender, ethnicity or religious persuasion.
Description of the study groups
A total of 388 patients undergoing chemotherapy for breast or gynaecological cancer were identified, of whom 224 expressed an interest in undergoing an IP consultation (figure 1).Of these, 152 reported disturbed sleep quality and related concerns, and were designated to the treatment arm of the study. The remaining 72 either did not attend the consultation (n=63) or did not fulfil the criteria for disturbed sleep quality and related concerns. The reasons given for not attending the IP consultation were as follows: scepticism regarding the effectiveness of CIM (n=14), logistical difficulties related to the scheduled visit (9), geographical constraints (4), other reasons (10) or no reason given (26). Of the 152 treated patients 133 were assessed at 6 weeks, with baseline-to-6-week assessment considered as optimal for 104. In this group, 75 were shown to be adherent to the CIM programme (AIC group) and 29 non-adherent (non-AIC group).
Of the 164 controls, 112 reported disturbed sleep quality and related concerns. The remaining 52 were excluded, either because they did not report disturbed sleep quality (n=42) or because they declined to fill in the initial assessment questionnaires (n=10). At 6 weeks, 100 of the controls were seen by the study nurse, with 76 considered to have been optimally assessed.
Baseline characteristics of study groups
The demographic, cancer and oncology treatment-related characteristics of the treatment and control groups are presented in table 1. Demographic parameters (age, country of birth, occupation, religion, religiosity, distance of residence from research centres) were similar in both groups, although the treatment arm had higher levels of income (p=0.02) and education (p=0.0003), and listed Hebrew as their primary language (p=0.004). Both groups had similar rates of cancer recurrence, evidence of metastasis and oncology treatment setting (adjuvant/neoadjuvant vs palliative chemotherapy). However, the treatment group had more cases of gynaecological cancer (vs breast cancer) when compared with controls (p=0.04), reported higher rates of both previous cancer (p<0.0001) and non-cancer-related use of complementary medicine (p=0.034), and expressed a belief in a connection between the body and soul (p=0.021). Both groups had similar levels of belief in the effectiveness of complementary medicine, although the treatment arm attributed a lower risk to these therapies than did controls (p=0.038).
CIM intervention modalities
Of the 104 patients in the treatment group, 94 (90.4%) had been treated with acupuncture. Other CIM modalities that had been administered during the study period included touch/movement therapies (78, 75%), mind–body therapies (70, 67.3%) and herbal/nutritional interventions (67, 64.4%). The majority of patients (93, 89.4%) had been treated with at least two of the above therapies in parallel.
Impact of CIM on ESAS outcomes
ESAS scores (24 hours) for both study arms are presented in table 2. Baseline scores for sleep quality scores were similar for both groups, as were other outcomes. Between-group analysis indicated a significantly greater improvement in the treatment group for sleep-related ESAS scores (p=0.008), anxiety (p=0.004) and feeling of well-being (p=0.007), with a trend for a greater improvement in drowsiness (p=0.07) (figure 2). Within-group analysis found that only treated patients showed a reduction in pain, fatigue, nausea, depression and drowsiness scales.
Impact of CIM on EORTC QLQ-C30 outcomes
Baseline and 6-week follow-up EORTC QLQ-C30 scores (for the previous 7 days) are presented in table 3. Both groups had similar baseline scores, with between-group analysis showing a greater improvement in QOL-related outcomes in the treatment group for cognitive function (p=0.003), fatigue (p=0.03) and appetite loss (p=0.046). Within-group analysis detected a greater improvement in EORTC scales for only the treatment group for insomnia (p=0.026) and nausea/vomiting (p=0.02).
Impact of CIM in adherent versus non-adherent treatment groups
Patients in the AIC and non-AIC subgroups had similar demographic, cancer and oncology treatment-related parameters (table 1). However, the AIC subgroup reported higher rates of prior cancer-related complementary medicine use (p=0.007) and tended more to perceive these treatments as effective as non-AIC (p=0.002).
AIC and non-AIC treatment subgroups reported similar ESAS sleep-related scores at baseline, as well as most ESAS parameters (figure 2). Between-group analysis indicated a greater improvement for ESAS scores in the adherent group regarding anxiety (p=0.046) and appetite (p=0.012). Within-group analysis showed a significant improvement in ESAS scores among adherent patients (and not in non-AIC) for pain (p<0.001), fatigue (p=0.03), nausea (p=0.006), depression (p<0.001), anxiety (p<0.001) drowsiness (p=0.005) and sleep quality (p<0.001). Both subgroups of patients in the treatment arm had similar baseline EORTC QLQ-C30 scores. Between-group analysis found a greater improvement in the AIC group for global health status/QOL(p=0.024), and for physical (p=0.003), role (p=0.002), emotional (p=0.036) and social functioning (p=0.006), as well as fatigue (p=0.002), nausea and vomiting (p=0.032), and appetite (p=0.005). A trend was observed favouring the AIC group for insomnia (p=0.064). Within-group analysis indicated improvement in only the AIC group for insomnia (p=0.01), global health status/QOL (p=0.006), emotional functioning (p=0.006), fatigue (p=0.004), nausea and vomiting (p=0.001) and appetite (0.003).
Impact of CIM on medication use
Baseline assessment showed similar rates of sleep-related drug use in the two groups (p=0.32). No significant differences were found between the two groups regarding the type of medication being used, and both between-group and within-group analysis found no differences regarding changes in medication use from baseline to 6-week assessment (p=0.27).
The present study examined the impact of a patient-tailored CIM programme on disturbed sleep quality and related concerns among female patients with breast and gynaecological cancer undergoing chemotherapy. Patients in the treatment arm of the study were shown to have a more significant improvement in sleep quality outcomes, as shown with the ESAS tool. Within-group analysis showed a better response in the treatment group for baseline to 6-week EORTC scales, a finding that was not apparent in the between-group analysis. The use of medications for either sleep-related concerns or anxiety was similar in both groups, from baseline to the 6-week follow-up. ESAS and EORTC sleep-related parameters were better in the AIC subgroup, a finding that was significant in within-group analysis and borderline in between-group analysis.
QOL outcomes unrelated to sleep were found to improve more significantly in the treatment group, with significantly greater reduction in levels of anxiety and improved feeling of well-being on ESAS. Reduced anxiety was also found to be greater in the adherent (AIC) treatment subgroup. The treatment group also showed greater improvement in cognitive functioning, fatigue and appetite loss on EORTC. Within-group analysis indicated an improvement in the treatment group for pain, fatigue, nausea, depression and drowsiness on ESAS, and nausea and vomiting and emotional functioning on EORTC. Controls did not show any improvement in these outcomes, in either study tool.
The improvement in sleep-related outcomes observed in the treatment group may have resulted from either specific effects of CIM treatments and/or indirect effects of CIM on outcomes such as pain and anxiety. Previous studies have found a correlation between anxiety levels and sleep quality, although the impact of an intervention reducing the former on the latter remains to be shown.32 And while pain may play a direct role in impairing sleep quality, the aetiological relationship between cancer-related fatigue and sleep needs to be better understood.33 Future studies will need to explore the correlation between the impact of CIM on sleep-related concerns and potential mediators such as anxiety, fatigue and pain.
The study setting and methodology described offer an innovative approach towards understanding the impact of CIM on supportive cancer care. The use of a pragmatic format enables the researcher to focus on patients with a significant impairment in sleep quality and related concerns at baseline, as well as other QOL-related concerns. This differs greatly from other CIM-related research, which has focused almost exclusively on sleep quality as a specific and isolated concern. The use of a pragmatic approach is more reflective of the ‘real-world’ clinical setting in which CIM is being used to help reduce the symptom load during chemotherapy. Prior research using the pragmatic approach has also examined the impact of CIM on sleep quality and related concerns, although this is the first in which this outcome was examined among patients reporting significant impairment in QOL as a result.34
There are several limitations that need to be addressed in future research. The first is the potential selection bias, which may have resulted from the need for a referral from an oncology HCP to the IP consultation. While both study groups had nearly identical baseline demographic and cancer-related parameters, the rates of prior complementary medicine use in general and for cancer-related concerns were higher in the treatment group, who also expressed a greater belief in the mind–body connection and in the safety of CIM. High rates of complementary medicine use have been found in earlier pragmatic studies of CIM, and have been associated more with female patients, as well as those with higher levels of education and income.35 It is also possible (and even probable) that the study population does not adequately reflect other targeted patient populations, especially since there was a higher prevalence of patients with breast cancer (vs gynaecological) in the control group. While both study centres treat patients with breast cancer, only the centre in which CIM treatments are provided also treats patients with gynaecological cancer.
Other study limitations include methodological design lacking randomisation and considering control group as patients who did not attend the CIM consultation. The non-randomised design was meant to reflect real-life clinical practice where patients’ decision-making and the modelling of a patient-tailored treatment programme are essential. In contrast to an explanatory, randomised and controlled design, we did not attempt to explore the effectiveness of specific CIM modalities in relieving sleep-related issues, but rather to study a whole patient-centred system approach in which CIM is integrated within supportive cancer care. Thus, while designating those patients who did not attend the CIM consultation as a control group may have reflected their health belief model, it also respected their willingness to experience the CIM consultation and treatments, which were available to them throughout the study period. Nevertheless, the self-selecting sample bias created should be recognised as a potential study limitation, limiting the generalisability of the findings. In addition to the above, while the use of strict criteria for optimal assessment used to compare the changes in QOL-related parameters, from baseline to 6 weeks, may have limited the study sample size, it was necessary to maximise the quality and accuracy of the data assessment.
Another study limitation is the use of QOL-based subjective patient-reported outcome (PRO) measures as a primary outcome, and not an objective parameter. In our study, general PRO tools were used, as opposed to sleep-specific tools such as the Pittsburgh Sleep Quality Index (PSQI)36 or Epworth Sleepiness Scale (ESS) questionnaires.37 The ESAS and EORTC questionnaires were used in order to explore the impact of CIM on sleep quality and related concerns within the context of the spectrum of QOL-related outcomes, which is more pragmatic and reflective of the supportive care setting. Future research should include tools such as the PSQI and ESS, with ESAS and EORTC as a means for screening patients suffering from sleep-related concerns.
In summary, the present study found that a patient-centred CIM intervention led to improved quality of sleep and related concerns. This effect was significantly greater in the treatment arm of the study, more so among patients found to be adherent to the integrative care programme (AIC subgroup). Further research is needed in order to better understand the impact of CIM on sleep quality and related concerns among patients undergoing chemotherapy. Objective measures of sleep quality should be used, in addition to patient-reported outcome measures. There is also a need to establish CIM treatment protocols for sleep-related issues, addressing related QOL-related issues such as anxiety, pain and fatigue. The findings of the present study should encourage such research, within a patient-centred and directed integrative supportive care setting.
We would like to thank Ms Ronit Leiba for her assistance in statistical analysis.
Contributors HK, NS, SBM, ISS and EB-A contributed to the planning, conduct and reporting of the work described in this article. EB-A, HK and NS are responsible for conception and design, acquisition of data, analysis and interpretation of data.
Competing interests The authors state that there are neither actual nor potential conflicts of interest, including any financial, personal or other relationships with other people or organisations whatsoever.
Ethics approval Carmel Medical Center, Haifa, Israel.
Provenance and peer review Not commissioned; externally peer reviewed.