Are there efficacious treatments for treating the fatigue–sleep disturbance–depression symptom cluster in breast cancer patients? A Rapid Evidence Assessment of the Literature (REAL^©)

Figures & data

Figure 1 SIGN 50 checklist for RCT Study Design.

Note: Adapted from Scottish Intercollegiate Guidelines Network (SIGN). A Guideline Developer’s Handbook. Edinburgh: SIGN; 2001. (SIGN publication no. 50). [cited 24 June 2014]. Available from URL: http://www.sign.ac.uk.¹⁹ Adapted from Crawford C, Wallerstedt DB, Khorsan R, Clausen SS, Jonas WB, Walter JA. A systematic review of biopsychosocial training programs for the self-management of emotional stress: potential applications for the military. Evid Based Complement Alternat Med. 2013;747694. Epub 2013 Sep 23.⁷²
Abbreviations: RCT, randomized controlled trial; SIGN, Scottish Intercollegiate Guidelines Network.

Table 1 Characteristics and SIGN 50 score of included studies, grouped by population and treatment type, that address two cluster components (n=29)

Citation	Cluster	Population description	Description of intervention	Description of control	Intervention duration	Relevant outcomes assessed/results	Adverse events	Quality
Metastatic
Pharmacological
Bottomley et al^Citation21	Fatigue, sleep disturbance	275 patients with metastatic breast cancer patientsb with a median age of 53 years (C) and 52 years (T) (SD = ND)	Doxorubicin 60 mg/m^2 as an iv bolus plus paclitaxel 175 mg/m^2 as a 3-hr infusion Assessment time points: 2 wks pre-intervention, midpoint (cycles 2, 4, and 6) and EoT (3 mons after the last cycle, with a time window of 10 wks)	Doxorubicin 60 mg/m^2 plus cyclophosphamide 600 mg/m^2	Every 3 wks for a max of 6 cycles.	EORTC QLQ-C30 (Fatigue): No significant difference between arms (NS). Across time, fatigue ↑ in both arms by the 2nd assessment. Fatigue ↓ for C arm to levels comparable with baseline. Fatigue remained moderately clinically meaningful in T arm but NS. EORTC QLQ-C30 (Sleep Disturbance): No significant difference between arms or across time (NS).	More headaches, feeling unwell, dry mouth, and food tasting unusual in both groups	+
Svensson et al^Citation22	Fatigue, sleep disturbance	287 female metastatic breast cancer patientsb (≤ Stage II) (mean age = ND)	ET (epirubicin plus paclitaxel): Epirubicin 75 mg/m^2 by iv infusion Assessment time points: baseline, 2 mons, and 9 mons	TEX (epirubicin plus paclitaxel plus capecitabine): Epirubicin 75 mg/m^2 by iv infusion Both groups were offered 2nd line treatment with oral capecitabine when the disease progressed	ET: 30-min infusion followed by a 3-hr infusion with paclitaxel 175 mg/m^2 TEX: 30-min infusion followed by a 3-hr infusion with paclitaxel 155 mg/m^2. 2× daily for 14 days; both treatments Oral capecitabine 825 mg/m^2 given repeated every 3 wks for 9 mons.	EORTC QLQ-C30 (Fatigue): The ET arm scored clinically ↓ than TEX on fatigue at the 2 mons assessment but NS. EORTC QLQ-C30 (Sleep Disturbance): A small clinical difference was found for insomnia in favor of the TEX at the 2 and 9 mons assessments but NS.	Yes but ND	+
Hakamies-Blomqvist et al^Citation23	Fatigue, sleep disturbance	283 female metastatic breast cancer patientsd with a mean age of 52.13 years (T) and 52.16 (C)	Docetaxel 100 mg/m^2 Assessment time points: baseline and before each treatment (cycles 2–6)	MF: sequential methotrexate and 5-fluorouracil at 200 mg/m^2 and 600 mg/m^2, respectively	TD: Every 3 wks until treatment cycle 6 MF: Given at days 1 and 8 every 3 wks until treatment cycle 6	EORTC QLQ-C30 (Fatigue)i: At EoT, TD suffered ↑ fatigue compared to MF (P=0.04). EORTC QLQ-C30 (Sleep Disturbance)i: At EoT, the TD suffered ↑ from insomnia compared to MF (P=0.04).	Yes but ND	−
Diel et al^Citation24	Fatigue, sleep disturbance	466 female breast cancer patientsd (Stage = ND) with a mean age of 54.5±11.5 (C), 55.3±10.9 (2MGIBT) and 56.1±11.4 (6MGIBT) years	2MGIBT: Ibandronate 2 mg by iv bolus injection 6MGIBT: Ibandronate 6 mg by iv infusion Assessment time points: baseline day before each study visit (Visits 2–5, 8, 11, 14, 17, 20, 23, 26)	Placebo	2MGIBT: iv over 1–2 hr at 3–4 wkly intervals limited to a max of 24 treatments for 96 wks 6MGIBT: iv over 1–2 hr at 3–4 wkly intervals limited to a max of 24 treatments for 96 wks	EORTC QLC-C30 (Fatigue)i: For 6MGIBT, fatigue had ↓ significantly (P<0.05) at the EoT compared with placebo. EORTC QLC-C30 (Sleep Disturbance): Insomnia ↓ in the 6MGIBT compared with placebo, but NS.	Disease progression, bone pain, and spontaneous bone fracture-	−
Geels et al^Citation25	Depression, sleep disturbance	300 female breast cancer patientsb (Stage and mean age = ND)	Doxorubicin 40 mg by iv Assessment time points: baseline and every 3 wks (1st day of each new cycle)	Doxorubicin 60 mg by iv	ID40: 40 mg/m^2 (day 1) plus iv vinorelbine 20 mg/m^2 (days 1 and 8) at every 3 wks ID60: 60 mg/m^2 day 1 at every 3 wks	EORTC QLQ-C30 (Depression)i: 60.3% patients showed ↓ depression scores, 26.3% were stable and 13.4% worsened. A positive relationship between likelihood of improvement and objective tumor response (P=0.046). EORTC QLQ-C30 (Sleep Disturbance): Clinical ↓ in sleep disturbance but no significant difference between arms or across time (NS). CRF (Insomnia): Clinical ↓ in insomnia but no significant difference between arms or across time (NS).	ND	−
Psychosocial
Bordeleau et al^Citation26	Fatigue, sleep disturbance	215 female metastatic breast cancer patientsd with a mean age of 49.4±8.4 (T) and 51.5±10.0 (C) years	Supportive-expressive therapy (SET): Supportive-expressive therapy receiving UC plus educational materials about breast cancer and its treatment, relaxation, and nutrition. Assessment time points: baseline, 4 mons, 8 mons, and FU (12 mons)	UC plus educational materials about treatment, relaxation, and nutrition at every 6 mons	SET: wkly 90-min therapist-led support group + participated in 2-day workshops every 9–12 mons and received monthly reviews of videotapes of randomly selected sessions.	EORTC QLC-C30 (Fatigue)i: A significant across-time deterioration (time effect) in fatigue regardless of study arm (P=0.003).(br)EORTC QLC-C30 (Sleep Disturbance): There were no significant differences across-time (NS).	ND	+
Williams and Schreier^Citation27	Fatigue, sleep disturbance	71 breast cancer patientsb (≤ Stage 4) with a mean age of 50.39 (T) and 50.42 (C) years, (SD = ND)	Audiotape on self-care behaviors and SE (SCB): 20-min audiotape that consisted of education about exercise and relaxation to manage anxiety, fatigue, and sleep problems Assessment time points: 1-mon, 3 mons	Received the standard education and care given to all patients during CHT	The subjects were instructed to listen to the audiotape 12–24 hr before the start of CHT cycles and as often as desired during the course of their treatment.	SCD (Fatigue): There were no significant differences between SCB and control in severity of SE for fatigue (NS). Higher percentage in the control arm than in the SECA arm reported fatigue. The fatigue severity ratings significantly ↑ from the 1st SCD to the 2nd SCD for both arms. Overall fatigue remained a troublesome SE during the study. SCD (Sleep Disturbance): There were no significant differences between the arms in severity of SEs for sleep disturbance (NS). More women in control than in the SCB arm reported difficulty in sleeping whereas the severity significantly increased between the 1st SCD and the 2nd SCD for both arms but NS.	ND	+
Low et al^Citation28	Depression sleep, disturbance	62 female breast cancer patientsh (Stage IV) with a mean age of 53.8±10.3 years	Emotional writing (EMO): Participants wrote at home about cancer-related emotions Assessment time points: baseline, 3 mons	Control Writing Condition (CTL): Writing facts about diagnosis and treatment	4 × 20 min sessions for 3 wks	CES-D (Depression): No differences between arms or across time (NS). PSQI (Sleep Disturbance): No differences between arms or across time (NS).	ND	+
Multi-modal lifestyle
Targ and Levine^Citation29	Fatigue, depression	181 female breast cancer patientsf (≤ Stage IV) with a mean age of 49±8.6 (T) and 47±8.8 (C) years	CAM program (CAM): Intensive lifestyle change and group support program with an emphasis on psychospiritual issues, and inner process Assessment time points: pre-test, post-test	Standard Program (SP): 1.5 hrs/wk unstructured psycho-educational support group led by a psychologist with emphasis on coping with real life issues	2/wk for 2.5 hrs each time; each wk included 1 hr health series; 90 mins of dance/movement program; experiential work; and 90 min discussion group led by a licensed clinical social for a total of 12 wks.	POMS (Depression)i: Both the CAM arm (P<0.004) and control (P<0.02) showed a significant ↓ in depression at EoT. POMS (Fatigue): No significant difference between arms or across time (NS).	ND	+
Non-metastatic
Medical procedures
Bonnema et al^Citation30	Depression, sleep disturbance	139 female breast cancera patients (≤ Stage II) with a mean age = ND	Short hospital stay: Evaluating the medical and psychosocial effects of short hospital stays after surgery for breast cancer Assessment time points: Baseline, 1-mon after surgery EoT (4 mons); During outpatient visits	Long Hospital Stay: Effects of long hospital stay after surgery for breast cancer	At admission, patients were given a daily diary, to be used for 1 mon, and a wkly diary to be used for the next 3 mons for a total 4 mons. The length of hospital stay was recorded.	VDBP (Sleep Disturbance): No differences between arms at EoT (NS). VDBP (Depression): No differences between arms at EoT (NS).	None	+
Behavioral
Courneya et al^Citation31	Fatigue, depression	242 breast cancer patientsb (≤ Stages IIIA) with a mean age of 49.2 years, (SD = ND)	Aerobic exercise (AET): Exercise on a cycle ergometer, treadmill, or elliptical Resistance exercise (RET): Exercise performing two sets of 8–12 reps included leg extension, leg curl, leg press, calf raises, chest press, seated row, triceps extension, biceps curls, and modified curl-ups Assessment Time Points: baseline (1–2 wks after starting CHT), midpoint (middle of CHT), EoT (3–4 wks after CHT), and FU (6 mons)	UC: Offered a 1-mon exercise program after post intervention assessment	AET: 3×/wk for ∼4 wks: duration began at 15 min for wks 1–3. It ↑ by 5 min every 3 wks until the duration reached 45 min at wk 18. RET: 3×/wk: performing 2 sets of 8–12 reps of 9 different exercises. Resistance was ↑ by 10% when participants completed more than 12 reps at wk 18.	FACT-A (Fatigue): No differences between AET, RET and UC arms (NS). However, for AET adherence (P=0.002) had greater mean changes at EoT compared to UC. CES-D (Depression): No differences between AET, RET and UC arms (NS). However, for adherence to AET (P=0.003) and RET (P=0.019) had greater mean changes at EoT compared to UC; no differences between arms at FU (NS). Effect Size: 0.30	Lightheaded, hypotensive, moderately nauseous (n=1), experienced dizziness, weakness and mild diarrhea (n=1)	+
Wang et al^Citation32	Fatigue, sleep disturbance	72 Taiwanese breast cancer patientsd (≤ Stage II) with a mean age of 48.40±10.15 years (T) and 52.30±8.84 years (C)	BSET-based: Home-based self-efficacy related exercise (walking) program Assessment Time Points: baseline (24 hrs prior to the surgery), 24 hrs prior to the day of the one cycle of CHT (2–3 wks after surgery), day of expected nadir (7–10 days after CHT), and EoT (6 wks)	UC	Low to moderate intensity exercise per wk, and at least 30 mins per session or the accumulation of 10-min sessions to reach 30 mins for 6 wks.	FACIT-F (Fatigue)i: Fatigue ↓ in the BSET arm with significant differences between arms at time-3 (P=0.001) and at EoT (P=0.001). PSQI (Sleep Disturbance)i: BSET had significantly ↓ sleep disturbances than those in control over the intervention period (P=0.006).	Anemia and dizziness with dyspnea (n=2)	+
Mock et al^Citation33	Fatigue, depression	52 female breast cancer patientsd (≤ Stage III) with a mean age of 47.14±11.72 years (LW) and 48.64±10.69 (HW) years	Low walk (LW): <90 min of walking/wk + adjuvant CT or RT after breast cancer surgery High walk (HW): >90 min of walking/wk + adjuvant CT or RT after breast cancer surgery. Assessment time points: baseline, 6 wks of RT, and EoT (during 4–6 mons of adjuvant CHT)	UC	6 wks of RT and 4–6 mons of CT. Most exercise prescriptions began at 10–15 mins per session and 5–6 sessions per wk. Subjects were advanced to 30 mins per session, 5–6 daily sessions per wk.	POMS (Fatigue)i: HW had significantly ↓ fatigue at EoT compared to LW (P=0.001). POMS (Depression)i: HW had significantly ↓ depression at EoT compared to LW (P=0.03). Diary (Fatigue)i: Mean fatigue on the daily diaries was significantly ↓ for the HW compared to LW (P=0.001). CHT was significantly ↑ than RT (P=0.01). PFS (Fatigue Total Score)i: HW had ↓ total fatigue at EoT compared to LW but not NS.	ND	−
CAM
Listing et al^Citation34	Fatigue, depression	34 female breast cancer patientsd (≤ Stage II) with a mean age of 59.2±12.1 (T) and 59.9±11.5 (C) years	Classical massage (CM): Swedish techniques while subjects were in prone position Assessment time points: baseline, 5 wks; and FU (11 wks)	No treatment: wait list	30 min/day for 5 wks plus FU.	BSF (Tiredness)i: No differences between arms at EoT (NS); CM had ↓ levels of tiredness compared to control at FU (P<0.01). BSF (Anxious Depression)i: CM had ↓ levels of anxious depression compared to control at EoT (P=0.03); no differences between arms at FU (NS).	Higher level of back pain (n=1), increase in blood pressure (n=1)	++
Listing et al^Citation35	Fatigue, depression	115 female breast cancer patientsb (≤ Stage II) with a mean age of 57.6±10.8 years (T) and 61.4±10.9 years (C)	Classical massage: Standardized Swedish techniques on back, neck and head Assessment time points: baseline (T1), EoT (5-wks;T2), and FU (11 wks;T3)	UC: waiting list	2 × 30 min/wk for 5 wks plus FU.	BSF (Anxious Depression): Anxious depressions between arms were NS. BFS (Tiredness): Tiredness between arms was NS. GBB (Fatigue): Fatigue was ↓ at the EoT between arms but was NS. This positive effect was sustained over time and achieved significance compared with control at FU (P=0.048). Effect Size: 0.3	ND	−
da Costa et al^Citation36	Fatigue, depression	36 breast cancer patientsc (≤ Stage II) with a mean age of 59 (A) and 57 (B) years, (SD = ND)	Guarana A: Guarana extract daily; before beginning 14th RT, group switched to placebo for remainder of study Guarana B: Received placebo; before beginning 14th RT, group switched guarana daily for remainder of study Assessment time points: Beginning of RT, midpoint of RT, (before the 14th RT session), and EoT (last session of RT or 28th session)	Placebo: crossover	75 mg of guarana extract daily for last session of RT or 28th session.	CFS (Fatigue): Fatigue between all arms was NS. MDA BFI (Fatigue): Fatigue between all arms was NS. BDI-II (Depression): Depression between all arms was NS.	None	−
Psychosocial
Berger et al^Citation37	Fatigue, sleep disturbance	219 female breast cancer patientse (≤ Stage IIIA) with a mean age of 52.13 years (T) and 52.16 (C), (SD = ND)	Behavioral therapy (BT): Individualized sleep promotion plan (ISPPr): Modified stimulus control, modified sleep restriction, relaxation therapy, and sleep hygiene Assessment time points: Baseline (2 days prior CT), during the 7 days after each treatment, and FU (30 days after the last treatment)	HEC: Healthy Eating Control received healthy eating information and attention	Prior to the initial CT, BT participants developed an ISPP plan that was regularly reinforced and revised for 30 days after the last CT, compared with scores prior to the initial treatment. HEC group participants received equal time and attention at each home visit.	PFS (Fatigue)i: Fatigue in both arms changed over time, with ↑ during the treatments and ↓ after treatments ended (P=0.001). The fatigue pattern was similar between the BT and HEC arms (NS). PSQI (Sleep)i: Significant changes in sleep quality in the arms over time (P=0.003). A group by time interaction was found (P=0.04). Sleep quality ↑ significantly in BT arm, but sleep of the HEC arm was more disturbed at treatment 4 and remained more disturbed at FU. Diary (Sleep): Significant ↓ number of awakenings (P=0.032), ↓ WASO-M (P=0.027), and ↑ sleep efficiency P=0.001) in the BT arm over time. But sleep efficiency favoring BT was significant between arms (P=0.075). Effect size: 0.17	ND	+
Cohen and Fried^Citation38	Fatigue, sleep disturbance	154 female early-stage breast cancer patientsd (≤ Stage II) with a mean age of 55.9±10.4 (CBT), 51.8±11.6 (RGI), and 52.9±11.8 (C) years	Cognitive behavior (CBT): cognitive and behavioral strategies Relaxation and guided imagery (RGI): systematic learning of deep RGI plus deep breathing and autogenic relaxation Assessment time points: preintervention, EoT (3 mons), and FU (4 mons)	UC	9 × 90 min sessions/wk for 3 mons plus FU	FSI (Fatigue symptoms): Mean of fatigue symptoms ↓ in both intervention arms (P<0.001) but only the reduction in the RGI arm from pre-to-post intervention appeared significant. Fatigue remained significantly ↓ in the RGI arm than in CB and UC, (P<0.01). Effect Size =0.20 MSQ (Sleep difficulties): Mean of sleep difficulties ↓ in both intervention arms (P<0.001), but only the reduction in the RGI arm from pre-to-post intervention appeared significant. Sleep difficulties remained significantly ↓ in the RGI arm than in CB and UC (P<0.001). Effect Size: 0.10	ND	−
Badger et al^Citation39	Fatigue, depression	48 female breast cancer patientsf (≤ Stage III) with a mean age of 53.04±8.72 (T) and 54.71±10.34 (C) years	Telephone interpersonal counseling (TIPC): telephone calls from a nurse counselor; sessions focused on issues such as cancer education, interpersonal role disputes, social support, awareness, management of depressive symptoms, and role transitions Assessment time points: baseline, post-intervention (wk 6), and FU (wk 10)	Usual Care Attentional Control Group (UC): calls from nurse counselor and 3 calls for partner plus resource list	6 wkly sessions for 6 wks plus FU	CES-D (Depression): No difference between arms or across time (NS). PANAS (Negative Affect): No difference between arms or across time (NS). MFI (Fatigue)i: No significant main effect existed for time. However, a trend was found in the time by group interaction that indicate a ↓ for TIPC arm but not for those in control but NS (P=0.09).	ND	+
Sandgren et al^Citation40	Fatigue, depression	62 female breast cancer patientsd (≤ Stage II) with a mean age of 51.23±12.5 years	Telephone therapy: therapy included providing support, teaching coping skills, managing anxiety and stress, and helping to solve patient-generated problems (eg, interpersonal problems, problems returning to work) Assessment time points: baseline, 4 mons, 10 mons	No treatment	1/wk for 4 wks and then every other wk for 10 mons; phone sessions lasted up to 30 mins	POMS (Fatigue): No difference between arms or across time (NS). POMS (Depression): No difference between arms or across time (NS).	ND	+
Dolbeault et al^Citation41	Fatigue, depression	203 breast cancer patientsb with a mean age of 54.5±9.3 (T) and 51.6±9.6 (C) years	Psychoeducationally structured model (PSM): Based on CBT principles, exercises were initiations combined with general medical information and peer exchanges on defined themes; 8–12 participants, led by 2 psychologists or psychiatrists Assessment time points: 1-wk pre-intervention, EoT (8 wks), and FU (1-wk pre-deferred intervention)	Wait list	8 × 2 hr sessions/wk for 8 wks pus FU	POMS (Depression)i: PSM had ↓ levels of depression compared to control (P<0.05); depression scores ↓ over time in both arms (P<0.05). POMS (Fatigue)i: Greater ↓ of fatigue in the PSM arm compared to control (P<0.01). EORTC QLQ-C30 (Fatigue)i: Greater ↓ of fatigue in the PSM arm compared to control (P<0.01). POMS Global (Negative Affect)i: A greater reduction of negative effects were observed in the TG compared with the CG arm but NS.	ND	+
Multimodal lifestyle
Lindemalm et al^Citation42	Fatigue, depression	41 female low-stage breast cancer patientsd with a mean age of 56.5 (T) and 66 years (C), (Stage and SD = ND)	Support group program CT-RT: Support team + adjuvant-combined CT and RT Support Group Program RT: Support team + adjuvant RT only Assessment time points: Pre-intervention, and FU (2 mons, 6 mons, 12 mons)	UC	From Sunday to Saturday on a residential basis followed by 4-days and FU (2 mons after initial visit)	NFQ (Fatigue)^q: No difference between arms (NS); both arms showed significant ↓ of total fatigue (P=0.01) and physical fatigue (P=0.015) over time compared to control. HADS (Depression)^q: No differences between arms or across time (NS).	ND	−
Mixed
Pharmacological
Roscoe et al^Citation43	Fatigue, depression	122 female breast cancer patientsb (Stage = ND) with a mean age of 52.2±9.3 (T) and 52.2±10.2 (C) years	Paroxetine: 20 mg Assessment time points: Cycle 1–4 of CHT	Placebo	Daily starting 7 days after 1st on-study treatment (1st cycle of CHT) and stopping 7 days after 4th on-study treatment (4th cycle of CHT)	CES-D (Depression)i: Paroxetine had greater effective than control in ↓ depression across all CHT cycles (P<0.001); paroxetine arm (P<0.01) showed a significant ↓ in depression between treatments 1 and 4 while control showed no significant differences (NS). POMS-DD (Depression)i: Paroxetine (P<0.01) and control (P=0.03) both showed significant ↑ in depression between treatments 1 and 4 POMS-FI (Fatigue): There were no significant differences between arms at any time point (NS). FSCL (Fatigue): There were no significant differences between arms at any time point (NS). MAF (Fatigue): There were no significant differences between arms at any time point (NS).	Nausea and headache	+
Psychosocial
Thornton et al^Citation44	Fatigue, depression	45 female breast cancer patientsd (Stage II, III) with a mean age of 50±11.6 (C) and 50±8.6 (T) years	Psychological intervention: conducted in groups of 8–12 patients led by two psychologists; Assessment time points: baseline, 4 mons, 8 mons, 12 mons	No treatment	Two sessions over 12 mons consisting of 4 mons of 1.5 hr sessions (intensive phase) followed by 8 monthly sessions (maintenance phase)	CES-D (Depression)i: Depression symptoms ↓ faster over time for psychological arm when compared to control (P<0.04). POMS (Depression)i: Depression ↓ faster over time for psychological arm when compared to control (P=0.02). POMS (Fatigue)i: The psychological arm showed greater ↓ in fatigue over time when compared to control (P=0.048)	ND	+
Sandgren and McCaul^Citation49	Fatigue, depression	235 female breast cancer patientsd (≤ Stage III) with a mean age of 54.5±11.8 years	Cancer health education (CHE): Structured curriculum presented by the nurse with time for brief discussion and questions. Emotional expression therapy (EET): Same number of calls from the same nurses; nurses instructed patients to feel free to explore their emotions and the things that are on their mind Assessment time points: pre-intervention, and FU: approx 5-mons	UC	Both interventions: 5 × 30 min phone calls/wk, plus 6th FU call at 3 mons	POMS (Fatigue): No differences between the CHE, EET, and control arms (NS); pooled analyses show no differences across time (NS). POMS (Depression)i: No differences between the CHE, EET, and control arms (NS), pooled analyses show an improvement in depressed scores over time (P<0.01).	ND	+
Sandgren and McCaul^Citation45	Fatigue, sleep disturbance	237 female breast cancer patientsd (≤ Stage III) with a mean age of 54.4 years, (SD = ND)	Health education group (HET): topics included: 1) understanding breast cancer, 2) managing post-surgical changes, 3) understanding treatment, 4) managing treatment side effects and fatigue, 5) healthy lifestyle, and 6) FU review. Emotional expression therapy (EET): nurse instructed patients to describe their thoughts and feelings about breast cancer, and any emotional issues about breast cancer Assessment time points: pre-test, 6 mons, 13 mons	No treatment: not restricted from participating in community support groups, receiving mental health care or using standard clinic nurse helpline	Both interventions: 5 × 30 min phone calls/wk, plus 6th FU call at 3 mons. Seven oncology nurses delivered both interventions for a total 13 mons	POMS (Depression)i: No differences between the HET, EET and control arms (NS), combined group scores show a decrease in depression over time (P<0.03). POMS (Fatigue)i: No differences between the HET, EET and control arms (NS), combined group scores show a ↓ in fatigue over time (P<0.03).	ND	+
Survivors
CAM
Jain et al^Citation46	Fatigue, depression	76 breast cancer survivors (≤ Stage IIIA) with a mean age of 52 (BH), 52 (MH) and 19 (C) years, (SD = ND)	Biofield healing (BH): practitioner practices hands-on healing with standard hand positions for 45–60 min (energy chelation technique) Mock healing (MH): delivered by practitioners who were skeptical scientists trained to use the identical hand placements as biofield healing practitioners Assessment time points: pre-intervention, post-session 2, midpoint, post-session 6, and EoT (4 wks)	Waitlist	Two sessions/wk × 4 wks	MFI (Fatigue)i: Both the BH (P<0.0005) and MH (P=0.02) arms had a greater ↓ in fatigue symptoms than the control. There were no significant changes in fatigue for control (NS). Effect size: Biofield healing vs Control (d=1.04), Mock healing versus control (d=0.68) CES-D (Depression): There were no significant interactions (NS).	None	++
Behavioral
Lee et al^Citation47	Fatigue, depression	50 breast cancer survivors with a mean age of 47.5±5.1 (SSEP), 45.6±7.0 (GEP) and 47.6±9.2 (C) years	Both training interventions: include stretching and strengthening Scapula-oriented shoulder exercise program (SSEP): Adopted from scapular mobilization exercises for shoulder dyskinesis and kinetic chain-based shoulder rehabilitation. Participants were asked to do exercises from simple motions to advanced strengthening. General Exercise Program (GEP): regular exercise program for shoulder and whole body Assessment time points: 1 and 4 wks after the EoT for 8-wks	UC: A leaflet guiding self-care including general shoulder range of motion exercise after surgery was provided as a UC	Gradually with an interval of 2 wks for a total 8 wks	EORTC QLQ-C30 (Fatigue)i: No differences between SSEP, GEP and control arms (NS); fatigue scores of GEP arm ↓ at FU (P=0.027); no differences over time were seen in the SSEP (NS) or control (NS). BDI (Depression): No significant differences between arms or across time (NS).	Shoulder discomfort (scapula-oriented exercise group)	++
Multimodal lifestyle
Kim et al^Citation48	Fatigue, depression	45 female breast cancer (≤ Stage III) survivors with a mean age of 44.6±9.9 (T) and 47.1±7.3 (C) years	Simultaneous stage-matched exercise and diet (SSED): Stage-matched telephone counseling complimented with a workbook, individualized prescription for regular moderate exercise, a balanced diet program, exercise and diet prescriptions Assessment time points: baseline and wk 12	ND	Delivered wkly during 30 min telephone counseling session for 12 wks	BFI (Fatigue)i: SSED arm had greater ↓ in fatigue levels compared to control (P=0.001). HADS (Depression)i: SSED arm had greater ↓ on depression scores compared to control (P=0.035).	ND	+

Notes: 31% of the studies did not have sufficient statistical power and 41% of studies did not report a power calculation:

a patients receiving surgery;

b patients receiving chemotherapy;

c patients receiving radiation;

d patients receiving surgery, chemotherapy, and radiation;

e patients receiving surgery and chemotherapy;

f patients receiving chemotherapy and radiation;

g patients receiving hormone therapy;

h treatment received not described;

i effect size not reported.

Abbreviations: 95% CI, 95% Confidence Interval; BDI, Beck Depression Inventory; BFI, Brief Fatigue Inventory; BSF, Berlin Mood Questionnaire; C, control Group; CBT, Cognitive Behavioral Therapy; CES-D, Center for Epidemiological Studies-Depression Scale; CFS, Chalder Fatigue Scale; CHT, chemotherapy; CRF, Case Report Form; EORTC QLC-C30, European Organization for Research and Treatment of Cancer Health Related Quality of Life Questionnaire; EoT, end of treatment; FACIT-F, Functional Assessment of Chronic Illness Therapy; FACT-A, Functional Assessment of Cancer Therapy-Anemia; FSCL, Fatigue Symptom Checklist; FSI, Fatigue Symptom Inventory; FU, follow-up; GBB, Geissen Complaints Inventory; GHQ, General Health Questionnaire; HADS, Hospital Anxiety Depression Score; HDRS, Hamilton Depression Rating Scale; hr, hour; HSCL-25, Hopkins Symptom Checklist-25; iv, intravenous; ISI, Insomnia Severity Index; MAF, Multidimensional Assessment of Fatigue; Max, maximum; MD, mean difference; MDA BFI, Anderson Brief Fatigue Inventory; MFI, Multidimensional Fatigue Inventory; Min, minutes; Mon(s), month(s); MSQ, Mini Sleep Questionnaire; NCI-CTC, National Cancer Institute Common Toxicity Criteria; ND, not described; NFQ, Norwegian Fatigue Questionnaire; NS, not significant; PANAS, Positive and Negative Affect Scale; PFS, Piper Revised Fatigue Scale; POMS-DD, Monopolar Profile of Mood States; POMS, Profile of Mood States; PSQI, Pittsburgh Sleep Quality Index; QOL, quality of life; RT, radiation therapy; reps, repetitions; SAS, Self-rating Anxiety Scale; SCD, Self Care Diary; SD, standard deviation; SE, side effect; T, treatment group; SIGN, Scottish Intercollegiate Guidelines Network; UC, usual care; VDBP, van den Borne and Pruyn; wk(s), week(s); wkly, weekly.

Table 2 Characteristics and SIGN 50 score of included studies, grouped by population and treatment type, that address three cluster components (n=12)

Citation	Population description	Description of intervention	Description of control	Intervention duration	Relevant outcomes assessed/results	Adverse events	Quality
Metastatic
Psychosocial
Savard et al^Citation50	45 depressed female breast cancer patientsd (≤ Stage IV) with a mean age of 51.4±8.05 (T) and 51.66±8.62 (C) years	CBT: Strategies meant for treating depression including coping strategies identified Assessment time points: pre-treatment, EoT (8 wks), and FU: 3 mons, 6 mons	Wait list: Waited a minimum of 8 wks before receiving CBT	CBT: 8 × 60–90 min sessions; plus 3 booster sessions administered every 3 wks following treatment during which psychologists reviewed the difficulties the patient had experienced since the last session and the strategies used/could have been used to cope with them	HDRS (Depression): Depression ↓ over time in the CBT arm (P<0.0001) but not in the control (NS); combined scores across both arms ↓ from pre to Eot (P<0.0001) and from EoT to FU (P<0.01). Effect size: Treatment (d=−1.811), Control (d=−0.544) BDI (Depression): No differences between arms (NS); combined scores across both arms ↓ from pre to EoT (P<0.0001) but not from EoT to FU (NS). Effect size: Treatment (d=1.859), Control (d=0.84) HADS (Depression): No differences between arms (NS); combined scores across both arms ↓ from pre to EoT (P<0.0001) but not from EoT to FU (NS). Effect size: Treatment (d=−1.82), control (d=−1.30) MFI (Fatigue): No differences between arms and across time (NS); combined scores across both arms ↓ from pre to EoT (P<0.01) but not from EoT to FU (NS). Effect size: Treatment (d=−0.940), control (d=−0.736) ISI (Insomnia): No differences between arms and across time (NS); combined scores across both arms ↓ from pre to EoT (P<0.01) but not from EoT to FU (NS). Effect Size: Treatment (d=0.958), control (d=−0.089)	ND	+
Non-metastatic
Medical procedures
Prescott et al^Citation51	255 breast cancer (≤ Stage III) patientsc with a mean age of 72.3±5.0 (T) and 72.8±5.2 (C) years	RT: Standard treatment of postoperative breast irradiation Assessment time points: baseline, 2 wks, 9 mons, 15 mons	No RT treatment	Standard treatment of postoperative breast irradiation for 15 mons total	EORTC QLQ-C30 (Insomnia)i: Mean levels of insomnia tended to ↑ slightly in the control arm, whereas insomnia levels were ↓ in the RT arm. The treatment difference is statistically significant (P=0.01) which remained consistent throughout FU. HADS (Depression)i: There is evidence of ↑ depression scores over time (P=0.04), but there is no evidence of a treatment effect. Although the ↑ in mean depression scores is significant, the absolute change is small. EORTC QLQ-C30 (Fatigue): There was no evidence of a time, treatment, or time by treatment effect (NS).	Skin rashes, angioedema, taste changes, jaundice and liver damage	+
Groenvold et al^Citation52	303 premenopausal breast cancer patientsd with a mean age of 45.0 (CHT) and 44.4 (ovarian ablation) years (Stage and SD = ND)	CHT: Intravenous cyclophosphamide, methotrexate, fluouracil Assessment Time points: 1 mon, 3 mons, 5 mons, 9 mons, 15 mons, 24 mons	Ovarian ablation (OA): Pelvic irradiation or surgical oophorectomy	CHT: Nine cycles given every 3 wks for 2 years Ovarian Ablation: Pelvic irradiation with a total dose of 15 Gy given as 5 daily fractions or surgical oophorectomy for 2 years	EORTC QLQ-C30 (Fatigue)i: CHT had ↑ levels of fatigue compared to the OA arm at 3 mons (P<0.001) and 5 mons (P<0.001) but not at other time points (NS). EORTC QLQ-C30 (Sleep)i: CHT had ↑ levels of sleep disturbances at 1 mon (P<0.05) and 5 mons (P<0.001) but not at other time points (NS). HADS (Depression)i: CHT had ↑ levels of depression at 3 mons (P<0.05) and 5 mons (P<0.01) but not at other time points (NS).	ND	−
CAM
de Oliveira Campos et al^Citation53	75 breast cancer patientsb (≤ Stage III) with a mean age of 50.2±11.95 (Placebo-guarana group) and 51.76±9.73 (Guarana-placebo group) years	Guarana: Standardized dried extract from P cupana; cornstarch; guarana preparation had a pH of 4.83 (10% solution in water), a water content of 3.9%, a concentration of 1.7% tannins, and 6.46% caffeine Assessment time points: Day 1, Day 21, Day 49	Crossover: Placebo capsules	Guarana 50 mg by mouth 2× daily or placebo for 21 days. After a 7-day washout period, patients were crossed over to the opposite experimental arm for 49 days total	CFS (Fatigue)i: Guarana arm had ↓ fatigue compared to placebo on day 21 (P<0.01) but not on day 49 (NS). PSQI (Sleep Disturbance)i: Guarana group had ↓ sleep disturbances compared to placebo on day 49 (P=0.05) but not day 21 (NS). BFI (Fatigue)i: Guarana arm had ↓ global fatigue compared to placebo on days 21 and 49 (P<0.01). HADS (Depression): No significant difference on depression between arms (NS). FACIT-F (Fatigue Global Scores)i: The average of fatigue scores ↓ from baseline to EoT for the patients receiving guarana for both arms (ie, received guarana first and the group that switched to guarana after receiving placebo) (NS).	Insomnia, palpitations, nausea, anxiety	++
Behavioral
Payne et al^Citation54	20 female breast cancer patientsg receiving hormonal therapy with a mean age of 64.7±6.3 years	Exercise: Moderate walking Assessment time points: baseline, 2 wks, 12 wks and EoT (14 wks)	UC: Standard interaction with nurses, physicians and staff	4 × 20 min of moderate walking each wk for 14 wks total	PFS(Fatigue)i: Fatigue levels between arms and across time were NS. PSQI (Sleep Disturbance)^q: PSQI scores in the exercise arm ↓ significantly over time (P=0.007). PSQI (Actual Wake Time)i: After 12 wks, actual wake time was shorter in the exercise arm compared to control (P=0.002). PSQI (Actual Sleep Time)i: After 12 wks, actual sleep time was shorter in the exercise arm compared to control (P=0.005). PSQI (Movement During Sleep)i: After 12 wks, exercise showed less movement during sleep compared to control (P=0.002). PSQI (Sleep Efficiency): No differences between arms (NS). CES-D (Depression): No difference between arms or over time (NS).	ND	−
Mock et al^Citation55	50 women with early stage breast cancerc (≤ stage II) with a mean age of 49 years, 48.09±5.42 years (T) and 50.29±8.47 (C)	Exercise: Individualized, home-based walking program Assessment time points: baseline (before or during the first days of radiation therapy), end of 3-wks and end of radiation therapy (about 6 wks)	UC	Self-paced, progressive program, with 20–30 min brisk walk increments followed by 5-min slow walk for 6 wks total	SAS (Fatigue)i: Fatigue levels significantly ↓ between arms and across time (P=0.018). SAS (Sleep Disturbance)^q: Sleep disturbance ↓ significantly between arms and across time (P=0.027). PFS (Fatigue)i: Fatigue ↓ significantly between arms and across time (P=0.001). SAS (Depression): Depression between arms and across time were NS.	None	−
Mixed
Pharmacological
van Dam et al^Citation56	104 female breast cancer patientsd (≤ Stage III) with a mean age of 45.5±6.2 (CTC), 48.1±6.8 (FEV) and 46.1±5.2 (C) years	CTC: High-risk breast cancer who were treated with high-dose CHT plus tamoxifen FEV: High-risk breast cancer who were treated with standard-dose CHT plus tamoxifen Assessment time points: ND	No treatment	In both the CTC and the FEV arms, the patients were treated with tamoxifen (40 mg periorally once/day) for 2 years	EORTC QLQ-C30 (Fatigue)i: CTC reported being ↑ fatigued than patients in the control (P=0.025). EORTC QLQ-C30 (Sleep Disturbance): No significant difference between arms or across time (NS). HSCL-25 (Depression)i: CTC had significantly elevated scores on the depression subscale in comparison with the patients in the control (P=0.041).	ND	+
Psychosocial
Arving et al^Citation57	179 breast cancer patientsd (≤ Stage N0) with a mean age of 55 years, (SD = ND)	Psychosocial support with nurse (INS): Carried out by two oncology nurses specially trained in psychosocial support including lectures covering knowledge and skills to assess and treat common psychosocial problems in cancer patients. Psychosocial support with psychologist (IPS): Delivered by two psychologists with theoretical knowledge about cancer diseases and treatment, and had experience of counseling Assessment time points: baseline, 1-mon, 3 mons, 6 mons	UC: regular contact with patient’s oncologist and medical staff	Participants met for 4 × 3 hr wkly lessons. Between meetings, they met to train assessment and techniques. FU discussions were held at termination and 5 mons later	EORTC QLQ-C30 (Insomnia)i: Both intervention arms improved significantly more than the UC arm regarding insomnia (P<0.01). There were significant differences between arms with INS having the greatest ↓ in insomnia, followed by IPS and UC arm (P<0.05). EORTC QLQ-C30 (Fatigue): No differences in fatigue between INS, IPS and control arms (NS). HADS (Depression): No differences in depression between INS, IPS and control arms (NS); no differences across time (NS).	ND	+
Savard et al^Citation58	58 female breast cancer patientsd (≤ Stage III) with a mean age of 54.81±7.01 (T) and 53.37±7.72 (C) years	CBT: Combined approach combining behavioral and educational strategies Assessment time points: baseline, EoT (8 wks), and FU: 3 mons, 6 mons, 12 mons	Wait List: waited a minimum of 8 wks before receiving CBT	Participants met for 8 × 90 min wkly sessions offered in groups of 4–6 patients for 8 wks total; FU carried out 3, 6, and 12 mons after the treatment	ISI, Sleep Diary, Insomnia Interview Schedule (Insomnia)i: CBT arm showed great improvement compared to control on total sleep time (P<0.001), sleep onset latency (P<0.05), wake after sleep onset (P<0.001), and ISI (P<0.05); pooled analyses show a significant improvement from pre to EoT on all sleep variables (P<0.01); improvements were maintained from EoT to FU for all variables except total sleep time (P<0.05) and ISI (filled out by significant other; P<0.05) which showed further improvement. HADS (Depression)i: Depression ↓ over time only in the CBT arm (P<0.01); pooled analyses showed a significant improvement in depression scores from pre to EoT (P<0.001); improvements were maintained from EoT to FU (NS). MFI (Fatigue)i: No differences between arms (NS); pooled analyses showed a significant improvement in fatigue scores from pre to EoT (P<0.001); improvements were maintained from EoT to FU (NS).	ND	+
Survivors
Pharmacological
Fahlen et al^Citation59	75 female breast cancer survivorsg with a mean age of 57.0±5.6 years	Menopausal hormone therapy (HT): Estradiol 2 mg and progestogen Assessment time points: baseline, 6 mons, 12 mons	No HT	Estradiol in combinations with different progestogens for 1 year	HADS (Depression)i: No significant results between arms (NS); depression ↓ for all women across time (P<0.001). EORTC QLQ-C30 (Fatigue)i: No significant results between arms (NS); fatigue ↓ for all women across time (P<0.05). EORTC QLQ-C30 (Insomnia)i: Insomnia ↓ more and at a faster rate in the HT arm than the control (P<0.001); insomnia scores ↓ for all women across time (P<0.01).	ND	−
Carpenter et al^Citation60	70 breast cancer survivorsg (Stage = ND) with a mean age of 50.5±8.7 years	Low dose: Venlafaxine High dose: Additional dose of venlafaxine Assessment Time points: baseline, wkly for 14 wks, and FU: 1 mon, 6 mons, 12 mons	Placebo: Crossover	Low dose: 37.5 mg of venlafaxine daily for 6 wks High dose: 1 wk of 37.5 mg of venlafaxine daily plus 4 wks of 75 mg of venlafaxine daily plus 1 wk of 37.5 mg of venlafaxine daily	Negative affect index (Negative Affect): No significant differences between treatment and placebo (NS), with minimal effect size for low (0.06) and high dose (0.02) treatments, POMS (fatigue): No significant differences between treatment and placebo (NS), with minimal effect sizes for low (0.03) and high (−0.03) dose treatments, PSQI (Sleep Quality): No significant differences between treatment and placebo (NS), but notable effect sizes for low (0.29) and high (0.22) dose treatments.	Hypertension	+
CAM
Carson et al^Citation61	37 female breast cancer survivors (≤ Stage IIB) with a mean age of 53.9±9.0 (T) and 54.9±6.2 (C) years	Yoga awareness (YA): Group classes led by a certified yoga teacher; each class included gentle stretching poses, breathing techniques, meditation, study of pertinent topics, group discussion; participants encouraged to spend time practicing yoga at home with the aid of CD recording and illustrated handbooks Assessment time points: baseline, EoT (2 mons), and FU: 3 mons	Wait list: Participants invited to participate in yoga after 3 mons assessment	YA: 8 × 120 min/wk group classes for 8 wks total – gentle stretching poses (40 min) – breathing techniques (10 min) – meditation (25 min) – study of pertinent topics (20 min) – group discussion (25 min)	Daily diary (Fatigue)i: YA arm showed greater ↓ in fatigue compared to the control at EoT (P<0.01) and FU (P<0.01). Daily diary (Negative Mood)i: No differences in negative mood between arms at EoT (NS) but YA showed greater improvement compared to control at FU (P<0.001). Daily diary (Sleep Disturbance)i: YA showed greater ↓ in sleep disturbance compared to control at EoT (P<0.01) but not at FU (NS).	ND	+

Notes: 33% of studies did not have sufficient statistical power, and 33% of studies did not report a power calculation:

a patients receiving surgery;

b patients receiving chemotherapy;

c patients receiving radiation;

d patients receiving surgery, chemotherapy, and radiation;

e patients receiving surgery and chemotherapy;

f patients receiving chemotherapy and radiation;

g patients receiving hormone therapy;

h treatment received not described;

i effect size not reported; ***Negative affect index was calculated as the combination of standardized scores on four questionnaires: the POMS-Short Form total mood disturbance score (excluding fatigue), the negative affect subscale of the PANAS, the CES-D, and the Ham-D.

Abbreviations: 95% CI, 95% Confidence Interval; BFI, Brief Fatigue Inventory; BSF, Berlin Mood Questionnaire; C, control group; CBT, Cognitive Behavioral Therapy; BDI, Beck Depression Inventory; CES-D, Center for Epidemiological Studies-Depression Scale; CFS, Chalder Fatigue Scale; CHT, chemotherapy; CRF, Case Report Form; EORTC QLC-C30, European Organization for Research and Treatment of Cancer Health Related Quality of Life Questionnaire; EoT, end of treatment; FACIT-F, Functional Assessment of Chronic Illness Therapy; FACT-A, Functional Assessment of Cancer Therapy-Anemia; FSCL, Fatigue Symptom Checklist; FSI, Fatigue Symptom Inventory; FU, follow-up; GBB, Geissen Complaints Inventory; GHQ, General Health Questionnaire; HADS, Hospital Anxiety Depression Score; HDRS, Hamilton Depression Rating Scale; HR, hour; HSCL-25, Hopkins Symptom Checklist-25; ISI, Insomnia Severity Index; MAF, Multidimensional Assessment of Fatigue; MD, mean difference; MDA BFI, Anderson Brief Fatigue Inventory; MFI, Multidimensional Fatigue Inventory; Min, minutes; Mon(s), month(s); MSQ, Mini Sleep Questionnaire; NCI-CTC, National Cancer Institute Common Toxicity Criteria; ND, not described; NFQ, Norwegian Fatigue Questionnaire; NS, not significant; PANAS, Positive and Negative Affect Scale; PFS, Piper Revised Fatigue Scale; POMS-DD, Monopolar Profile of Mood States; POMS, Profile of Mood States; PSQI, Pittsburgh Sleep Quality Index; QOL, quality of life; RT, radiation therapy; reps, repetitions; SAS, Self-rating Anxiety Scale; SCD, Self Care Diary; SD, standard deviation; SE, side effect; SIGN, Scottish Intercollegiate Guidelines Network; T, treatment group; UC, usual care; VDBP, van den Borne and Pruyn; Wk(s), week(s).

Figure 2 Flow chart.

Abbreviations: CAM, complementary/alternative medicine; RCT, randomized controlled trial.

Table 3 GRADE analysis: quality of the overall literature pool by population/intervention type for studies assessing three cluster components

Condition	Number of participants of completed (number studies)	Confidence in estimate of effect GRADE	Magnitude of estimate of effect GRADE	Safety GRADE	GRADE recommendation	Comments
Metastatic (n=1)
Psychosocial*	–	–	–	–	–	–
Non-metastatic (n=5)
Behavioral	70 (2)	C	ND	0	No recommendation	Some promise for sleep, mixed for fatigue, neither statistically significant on depression. Both poor quality (−, −) studies and under-powered.
Pharmacological	558 (2)	B	ND	0	Weak recommendation in favor	Promising for sleep, mixed for fatigue, and neither statistically significant for depression. Mixed quality studies (+, −).
CAM*	–	–	–	–	–	–
Mixed (n=3)
Psychosocial	237 (2)	B	ND	0	Weak recommendation in favor	Promising for sleep, mixed for depression and not statistically significant for fatigue. Adequate quality studies (+,+).
Pharmacological*	–	–	–	–	–	–
Survivors (n=3)
Pharmacological	145 (2)	B	ND	0	No recommendation	Promising for sleep, no evidence for depression or fatigue. Mixed quality studies (+,−).
CAM*	–	–	–	–	–	–

Notes:

* Due to the small number of studies in these categories, four studies^35,40,42,43 were not assessed via the GRADE; There are four major domains that comprise the core of the modified GRADE methodology: (1) confidence in the estimate of the effect was categorized into the following groups using pre-defined criteria: A) High: further research is very unlikely to change confidence in the estimate of effect; several high quality RCTs with consistent results or in special cases, or one large, high quality, multi-center RCT; B) Moderate: further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate; one high quality RCT or several RCTs with some limitations; C) Low: further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate; one or more RCTs with severe limitations; D) Very Low: any estimate of effect is very uncertain; expert opinion, no direct research evidence or one or more RCTs with severe limitations. (2) magnitude of the effect was categorized into five levels of none (<0.2), small (0.2–0.5), moderate (0.5–0.8), large (>0.8), or not described (authors did not describe or report effect size for this review’s outcomes of interest due to the lack of author reporting). (3) safety grade is dependent on the frequency and severity of adverse events and interactions. Safety was categorized into one of the following grades: +2, appears safe with infrequent adverse events and interactions; +1, appears relatively safe but with frequent but not serious adverse events and interactions; 0, safety not well understood or conflicting; −1, appears to have safety concerns that include infrequent but serious adverse events and/or interactions or; −2, has serious safety concerns that include frequent and serious adverse events and/or interactions. (4) strength of the recommendation can be determined using the following categories and criteria: strong recommendation in favor of or against – very certain that benefits do, or do not, outweigh risks and burdens; no recommendation – no recommendations can be made or; weak recommendation in favor of or against – benefits and risks and burdens are finely balanced, or appreciable uncertainty exists about the magnitude of benefits and risks.

Abbreviations: CAM, complementary/alternative medicine; GRADE, Grading of Recommendation Assessment, Development and Evaluation; RCT, randomized controlled trial.

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