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 population

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.

Data analysis

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.

Ethical considerations

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).

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Figure 1

Study algorithm. AIC, adherence to integrative care.

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.

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Figure 2

Sleep-related concerns change on ESAS and EORTC-QLQ-C30 scales. AIC, adherence to integrative care; EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; ESAS, Edmonton Symptom Assessment Scale.

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).