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 al50	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 al51	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 al52	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 al53	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 al54	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 al55	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 al56	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 al57	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 al58	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 al59	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 al60	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 al61	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:

^apatients receiving surgery;

^bpatients receiving chemotherapy;

^cpatients receiving radiation;

^dpatients receiving surgery, chemotherapy, and radiation;

^epatients receiving surgery and chemotherapy;

^fpatients receiving chemotherapy and radiation;

^gpatients receiving hormone therapy;

^htreatment received not described;

ⁱeffect 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).