STUDY PURPOSE: To review the published evidence on non-pharmacologic interventions for fatigue in men with prostate cancer

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: PubMed, PsycINFO, CINAHL, Cochrane Central Trials Register and Embase, PsychExtra, SIGLE, Australian New Zealand Clinical Trials Registry, ClinicalTrials.gov, World Health Organisation International Clinical Trials Registry Platform, EU Clinical Trials Register, MedNar, and reference lists of articles included in review

KEYWORDS: key concepts of prostate cancer, fatigue, non-pharmacological and nursing management, and various interventions; detailed search for PubMed included as appendix

INCLUSION CRITERIA: Adult men older than 18 years with prostate cancer at any stage of treatment; non-pharmacologic interventions including exercise, exercise with diet and lifestyle modification, education, and cognitive behavioral therapy; comparison to other non-pharmacologic interventions or usual care; experimental studies; fatigue as primary outcome of interest using existing validated tools to measure

EXCLUSION CRITERIA: Not stated

TOTAL REFERENCES RETRIEVED = 1,480

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two independent reviewers appraised studies; validity assessed with Johanna Briggs Institute Critical Appraisal Checklist for Randomised and Pseudo-Randomised Studies

• FINAL NUMBER STUDIES INCLUDED = 8
• SAMPLE RANGE ACROSS STUDIES: 21–240
• TOTAL PATIENTS INCLUDED IN REVIEW = 600
• KEY SAMPLE CHARACTERISTICS: Undergoing treatment for prostate cancer or completed treatment within past 12 months; age range 46–86 years

PHASE OF CARE: Multiple phases of care     

APPLICATIONS: Elder care

All studies were of high methodologic quality. Four out of five studies measuring physical activity found statistically significant fatigue reduction; the other study showed a trend toward fatigue reduction. Two studies concluded that cognitive behavioral therapy was effective in managing cancer-related fatigue. Two studies looking at education had mixed results. Brief nursing education was not significant in reducing fatigue, but intensive prostate-specific education was significant.

This report supports physical activity for managing cancer-related fatigue. Cognitive behavioral therapy and intensive focused education are also likely to be effective.

• Only eight studies included
• Variety in delivery of interventions and measurement of fatigue

Nurses should continue to recommend physical activity for management of cancer-related fatigue. Cognitive behavioral therapy and intensive education may be considered.

To compare a meditative movement practice, Qigong/Tai Chi Easy (QG/TCE), with sham Qigong (SQG), testing the effects of the meditation/breath aspects of QG/TCE on breast cancer survivors’ persistent fatigue and other symptoms

Hour-long sessions held twice weekly taught breast cancer survivors QE/TCE or SQG for 12 weeks measuring the effect on fatigue, depression, and sleep. Participants were asked to practice at home at least 30 minutes per day.

• N = 87  
• AGE RANGE = 40–75 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Stages 0–III; the majority of participants were educated at the level of at least some college and were at higher income levels. 90% were white and non-Latino.

• SITE: Single-site    
• SETTING TYPE: Outpatient    
• LOCATION: Mayo Clinic Cancer Center, Scottsdale, AZ

• PHASE OF CARE: Late effects and survivorship

This was a double-blinded, randomized, controlled trial. Fatigue was the primary outcome and sleep quality and depression were secondary outcomes.

• Fatigue Symptom Inventory (FSI)
• The Pittsburgh Sleep Quality Index (PSQI)
• Beck Depression Inventory (BDI)

Fatigue decreased in the QG/TCE group compared to the SQG group at postintervention and at the three-month follow-up (p = .024). However, fatigue declined significantly in both groups. Depression and sleep quality did not demonstrate improvement in the QG/TCE group compared to the SQG group at the post-intervention and at the three-month follow-up.

QG/TCE showed significant improvement over time compared to SQG for fatigue. Both groups showed improvement for fatigue, depression, and sleep dysfunction

• Small sample (< 100)
• Findings not generalizable
• Subject withdrawals ≥ 10%
• Other limitations/explanation: Blinding of the session instructors is identified as a limitation. The instructors could have unintentionally made a difference in the delivery of the interventions and outcomes. There is a concern that the contrast between the two interventions may have not been enough. The sham intervention is not described fully. There was a greater than 15% drop-out rate with no intent to treat analysis.

Low-intensity exercise may be beneficial in reducing a number of symptoms and improving the well-being of cancer survivors. This study demonstrates that QG/TCE’s focus on meditative movement with a focus on breath appears to have an advantage for improving breast cancer survivors' persistent fatigue. A larger sample and longer intervention time is needed.

To evaluate the effects of a structured, in-person, group multidisciplinary approach on several domains of quality of life (QOL) for patients with advanced cancer and their caregivers

The four-week intervention, tested previously in eight sessions, included six 90-minute sessions. Patients were invited to all six sessions, and caregivers were invited to four. Structured sessions targeted emotional, cognitive, physical, spiritual, and social domains of QOL. Every session opened with 15 minutes of physical therapy and closed with 15 minutes of relaxation therapy. Weekly topics included strategies to deal with health behavior and mood changes, radiation and chemotherapy effects, spirituality, social needs, record keeping, coping, exercise, quality of life, spiritual dimensions of disease, and communication with healthcare and support teams. Healthcare providers with diverse roles delivered the intervention. Ten brief telephone counseling sessions over a period of 20 weeks followed the four-week intervention. Patient/caregiver dyads were evaluated at baseline, four weeks postintervention, 27 weeks postintervention, and 52 weeks postintervention.

• N = 131  
• AGE = Not stated
• MALES: Not stated, FEMALES: Not stated
• KEY DISEASE CHARACTERISTICS: Caregivers and patients with newly diagnosed (within past 12 months) advanced cancer receiving radiation therapy.  
• OTHER KEY SAMPLE CHARACTERISTICS: In total, 88% of caregivers were married, 75% were spouses, 62% were employed, and 66% or more had some college education.

• SITE: Single site    
• SETTING TYPE: Outpatient    
• LOCATION: Suburban cancer center in Minnesota

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Palliative care 

Randomized, controlled trial

• Caregiver Quality of Life Index–Cancer (CQQOL)
• Linear Analog Self-Assessment (LASA)
• Profile of Mood States (POMS)

At four weeks postintervention, statistically significant differences in favor of the intervention arm were found for the LASA spiritual well-being domain (p = 0.0.048), the POMS vigor and activity subscale (p = 0.02), the POMS fatigue and inertia subscale (p = 0.02), the POMS total score (p = 0.02), and the CQOLC adaptation domain (p = 0.02). Durability was found at 27 weeks only for improvements in the POMS fatigue and inertia subscale (p = 0.01). At 27 weeks postintervention, the intervention group showed improvement over the standard care group in the CQOLC disruptiveness domain (p = 0.049) and the CQOLC financial concerns domain (p = 0.02). Although levels of significance did not appear, study results were similar at 52 weeks.

Although caregivers showed improvements in a few specific QOL domains assessed in this study, this comprehensive multidisciplinary intervention did not affect overall ​caregiver QOL. Continued study to identify and evaluate specific, tailored interventions focused on improving cancer caregiver QOL is needed.

• Baseline sample/group differences of import
• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Findings not generalizable
• Subject withdrawals ≥ 10% 
• Other limitations/explanation: The results at 52 weeks postintervention were not provided. Limited information was listed about caregiver demographics, which may have influenced study findings.  Recruitment methods and phone call intervention specifics did not appear to interpret study findings. There was a lack of information on the usefulness of intervention for improving caregiver QOL.  

Continued research focused on dyadic (patient/caregiver) versus individualized caregiver interventions may offer insight into optimal ways to meet caregiver QOL needs. Conceptually defined and structured mixed methods approaches (qualitative and quantitative) could define components of tailored interventions to minimize caregiver burden and emotional distress that affect caregiver well-being.

To quantify the overall effect of antidepressants in the treatment of depressive symptoms in patients with cancer

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: PubMed and Cochrane library

KEYWORDS: Depressive or depression and cancer

INCLUSION CRITERIA: Double-blind randomized trials, presence of depression or depressive symptoms in patients with cancer determined by diagnostic criteria or depression rating scale, primary outcome was reduction in severity of depressive symptoms, published between 1980–2010

EXCLUSION CRITERIA: Not specified

TOTAL REFERENCES RETRIEVED: N = 5,959

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Cochrane collaboration tool for risk of bias

• N (studies) = 9
• SAMPLE RANGE ACROSS STUDIES: 35–177
• TOTAL PATIENTS INCLUDED IN REVIEW: 722

Six trials compared antidepressants to placebo. In head-to-head comparison trials, fluoxetine was not superior to desipramine, no difference was seen between paroxetine and amitryptiline, and mirtazapine had a greater effect than imipramine. Overall effect size in meta-analysis was RR = 1.56 (95% CI 1.07 = 2.28, p = .021) in favor of antidepressants. Only three studies reported the number of patients with side effects, and many studies had a lot of missing data and high dropout rates or low samples.

Findings suggest that antidepressants are beneficial for depression and depressive symptoms in patients with cancer. However, the strength of this finding is limited due to limitations in studies included in this meta-analysis.

A low volume of studies was included. Average risk of study bias was unclear. Differing depression scales and criteria for depression response were used across studies. Most studies had small sample sizes for analysis. Study duration ranged from five weeks to six months.

This analysis provides some support for effectiveness of antidepressants in treatment of depression and depressive symptoms in patients with cancer. Nurses need to be aware of adverse side effects of antidepressants that may make other symptoms worse, such as nausea and cognitive impairment. Most studies reviewed did not analyze antidepressant side effects, so the real tolerability of antidepressants in patients with cancer is not clear. Patients may benefit from antidepressants but need to be monitored for side effects of this treatment.

The purpose of the study was to establish efficacy for the use of fluroquinolones in reducing the occurrence of fever in pediatric patients undergoing chemotherapy.

Patients were randomly assigned to receive 10 mg/kg per day of ciprofloxacine orally or placebo twice daily within five days after beginning chemotherapy. Young children who could not take pills were given a liquid form. Axillary temperatures were to be taken every eight hours. Outpatients were seen weekly for evaluation.

• 95 total patients
• Patients were aged 3 months to 18 years
• Patients had acute lymphoblactic leukemia and lymphoma

A single-site inpatient setting.

• The phase of care was active antitumor treatment
• The application was in pediatrics

The study was a prospective, double-blind, randomized, placebo-controlled trial.

• Bacterial isolation tests for infection sites and rectal swabs.
• Infections classified as microbiologically documented, clinically documented, or fever of unknown origin.

The median duration (IQR) of prophylaxis was longer in the ciprofloxacin group than in the placebo group (18 days [5–30] versus 10 days [3–15], p = 0.031). The number of patients who continued the intervention after discharge from the hospital also was higher in the ciprofloxacin group than in the placebo group (18/45 (40%) versus 10/50). In 71 patients with neutropenia, a lower proportion developed fever in the ciprofloxacin group than in the placebo group (17/34 [50%] versus 27/37 [73%]; absolute difference in risk, -23%; 95% CI [-45%, -0.9%]; p = 0.046). In subgroup analysis of patients with ALL, again the proportion of patients who developed fever was significantly lower in the ciprofloxacin group than in the placebo group (13/24 [54.2%] versus 24/30 [80%],  absolute difference in risk, -25.8%; 95% CI [-50.4%, -1.3%]; p = 0.042).

Ciprofloxacin can prevent fever in neutropenic patients with ALL during the induction phase of chemotherapy with good tolerance and no serious side effects.

The small sample (less than 100) was a limitation.

Ciprofloxacin was associated with lower incidence of fever in pediatric patients with neutropenia, and was not associated with significant side effects. There was no difference among patients who did not develop neutropenia. Patients with previous use of flouroquinolones as treatment may be  at risk of colonization with flouroquinolone-resistant bacteria, so empiric use in the setting of no neutropenia is not necessarily recommended.  Potential adverse effects of flouroquinolone use in children has been identified as a potential concern. This study provides some evidence in this area. Further research of appropriate prophylaxis in pediatric patients with cancer who are at high risk for infection is needed.

Palifermin was administered at 60 mcg/kg per day for three consecutive days before the initiation of conditioning therapy and again after graft infusion.

A group of 30 patients who had been treated with palifermin and undergone allogeneic hematopoietic stem-cell transplantation (HSCT) were retrospectively compared to a control group of 30 consecutive untreated patients receiving myeloablative conditioning.

• Median age of patients was 38 years old, with a range was 18–59 years.
• Patients had the following diagnoses.
  • Acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) (n = 40)
  • Acute lymphocytic leukemia (ALL) (n = 14)
  • Chronic myelogenous leukemia (CML) (n = 5)
  • Chronic myelomonocytic (CMML) (n = 1)
• Patients received allogeneic HSCT after CY/TBI or chemotherapy solely.
• No growth factors were given.

The study was conducted from May 2005 to December 2006 in Austria and Germany.

The study was conducted within a compassionate use program.

The World Health Organization (WHO) Oral Toxicity Scale was used.

• Incidence of grade 2–4 WHO oral toxicity was 60% in the palifermin group and 86% in the control group (p = 0.04).
• Grade 3–4 oral toxicity was present in 37% of the palifermin group and 53% of the control group (p = 0.19).
• Mean duration of oral mucositis (OM) was 6 versus 12 days (p = 0.003) in favor of palifermin. 
• Severity of OM was significantly reduced in the study group at 1.73 versus 2.47 (p = 0.03).
• Palifermin was associated with significantly decreased use of opioids. The median cumulative dose  was 150 versus 378 morphine equivalents (p = 0.04). However, the difference in median time of use was not significant at 6 versus 7 (p = NS).
• Total parenteral nutrition (TPN) use was lower in the palifermin group at 26 versus 15 days (p = 0.002). 
• No significant difference was found in incidence and duration of febrile neutropenia, with the palifermin group at 4 days versus 3 days in the control group (p = NS).
• Hematopoietic recovery was not influenced.
• No significant difference was found in graft-versus-host disease (GVHD).

• The authors declared no funding or financial support by company.
• An historical control group was used.
• The sample size was small.
• No discussion of added costs was included.

To synthesize findings from intervention studies for sleep disturbance in patients with cancer and their caregivers.

Databases searched were PubMed, CINAHL, and PsycINFO.

Search keywords were sleep, sleep disturbance, insomnia, intervention, cancer, oncology, and caregivers.

Studies dated through 2010 that evaluated sleep disturbance/sleep quality as the primary or secondary outcome were included.

• The total number of references retrieved was not stated.
• The method of study evaluation was described for the type of intervention, mode of delivery, dose, and duration but not for study quality.
• There were only two studies that affected caregivers.

• The final number of studies included was 49 (47 targeting patients and 2 targeting caregivers). 
• Thirteen studies were included in the meta-analysis (total of 1,202 patients with cancer). 
• The total sample across all studies was 3,205 patients.
• The sample range across studies was 9 to 276 patients (including patients with cancer).
• Patients had various cancer types, phases of treatment, and stages of disease. 
• Women with breast cancer were studied most commonly.

Intervention groupings analyzed via meta-analysis included cognitive-behavioral therapy (CBT), education, exercise, and complementary and alternative therapies. Effect sizes appeared to be slightly over 1.0 for CBT, close to 0 for education, slightly over 1.0 for exercise, and slightly over 0 for complementary and alternative therapies. Specific effect sizes were only shown graphically, and actual data were not presented. No separate analysis of caregiver effects could be determined. Modes of delivery of interventions varied widely across studies.

Findings suggest at least moderate effects of CBT and exercise for improvement in sleep disturbances for patients with cancer. No substantial effects of exercise and education were demonstrated.

The review was limited by the lack of any data regarding heterogeneity in the meta-analysis, variability of interventions, and modes of delivery to enable any firm conclusions.

Insufficient evidence was provided to draw any conclusions regarding intervention effects for caregivers.

To perform an integrative review of four electronic databases to determine the effectiveness of complementary and alternative medical (CAM) interventions, either alone or as an adjunct to pharmacologic therapy, in alleviating procedure-related pain, anxiety, and distress in children and adolescents with cancer

Databases searched were MEDLINE, CINAHL, PsycINFO, and Cochrane Database.

Search keywords were procedure, pain, anxiety, distress, childhood cancer, pediatric oncology, CAM, and complementary therapies.

Studies were included in the review if

• The studies were case reports or reports of a clinical series or reports of clinical trials that included at least one CAM intervention aimed at reducing procedure-related pain, anxiety, or distress
• The studies reported on a CAM intervention in one of the following: bone marrow aspiration or biopsy, lumbar puncture, injection, venipuncture for the purpose of blood sampling or starting an IV, or percutaneous access (excluding surgical procedure) to an implanted vascular device
• The sample included at least some children and adolescents (that is, young people between the ages of 2 and 18 years) with cancer
• The studies were published in English

Excluded from the review were studies that reported on surgical procedures (except percutaneous access to an implanted vascular device) and on the anxiety and distress of a parent.

• Investigators retrieved a total of 195 references.
• Reviewers read each paper and extracted information, including names of authors, publication year, study design, medical procedure performed, CAM modalities studied, description of study sample, level of evidence, and summary of  results.
• Results were analyzed for themes.

• Thirty-two studies—two meta-analyses, 18 experimental studies, 9 quasi-experimental studies, one nonexperimental study, and two case studies—were included in the review.
• The total sample size was 1,760, with a range across studies of 3–514 participants.
• Eleven studies included children with leukemia only; 13 included children with various cancer diagnoses other than leukemia; and 8 included children with a range of pediatric illnesses, including cancer.
• Seven studies reported on children younger than 10 years, 3 studies reported on older children (10–17 years), and 22 studies included both age groups.

• Phase of care: diagnostic
• Clinical applications: pediatrics, procedure-related

Results suggest that mind-body intervention may be effective, alone or as an adjunct to pharmacologic interventions, in managing procedure-related pain, anxiety, and distress in pediatric patients with cancer. In this population the three most commonly studied mind-body modalities were distraction, hypnosis, and imagery.

Although multiple studies demonstrated the value of CAM interventions, many of the studies were small and incorporated multiple CAM therapies as a single intervention. These types of interventions may be useful, particularly when used in combination with pharmacologic agents, but further research is needed to identify which interventions were valuable.

To investigate whether the addition of a neutral, supersaturated, calcium phosphate (CP) mouth rinse benefits the severity and duration of acute mucositis in patients with head and neck cancer treated with (chemo)radiation

Patients in group A were instructed to use caphosol mouth rinse twice daily with 15 ml solution for one minute plus standard care. Patients in group B were instructed to use standard care consisting of gargling with 15 ml of “magic mouth wash” (hydrocortisone, lidocaine, nystatin, propylene glycol, sodium carboxymethylcellulose, aqua admixture) up to six times per day, swallowing one time out of two. Two experienced physicians conducted visual inspection of the oral cavity and visualized oropharyns weekly until two to seven weeks after completion or until mucositis grade 1 or 0.

• N = 58
• MALES: 84.4%, FEMALES: 15.5%
• Patients had all histological subtypes of head and neck cancer.
• Patients were receiving curative radiation (intensity-modulated radiation therapy of 60–72 Gy over six to seven weeks), primary or postoperative oral mucosa or part of oral mucosa in radiation field, concurrent chemotherapy consisting of 100mg/m² cisplatin at weeks one and four, and induction chemotherapy with docetaxel, cisplatin, fluorouracil, or epidermal growth factor receptor monoclonal antibody.
• Patients were excluded from the study if they had received prior head and neck cancer radiation therapy.

• Single site
• Outpatient radiotherapy department at the University Hospital of Leuven, Belgium

PHASE OF CARE: Active antitumor treatment

• Single center
• Prospective randomized controlled (no placebo) study

• The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3 (NCI CTCAE 3.0)
• Oral pain was scored with a visual analog scale.

No significant differences were found in grade, time of onset, or duration of peak mucositis between groups. Fewer patients in the study arm experienced grade 3 or higher mucositis (59% versus 71%). Mean time to development  of mucositis was 28.6 days in the study group versus 28.7 days in the control group (p = .96). Duration of mucositis was 22.7 days in the study group versus 24.6 days in the control group (p = .62). No significant reduction in the need for analgesics was found.

An oral solution of neutral CP mouth rinse does not reduce frequency, duration, or severity of oral mucositis or pain in patients treated with (chemo)radiation for head and neck cancer. No evidence supports its standard use.

• Small sample (< 100)
• Key sample group differences that could influence results
• Other limitations include the heterogeneity of the patient population and treatment sample and no assessment of patient characteristics that could influence mucositis (poor oral health, alteration salivary production, alcohol use, or existing mucosal damage).

Mucosal damage continues to be an important and debilitating side effect that warrants continued research.

• Six studies looking at the incidence of bone pain associated with GCSFs in cancer patients evaluating diagnosis, dosing, and incidence
• Five studies looking at incidence of bone pain associated with GCSFs in healthy people evaluating dose and incidence
• Three studies involving elderly patients with lymphoma who received GCSFs evaluating chemotherapy regimens with or without GCSFs and incidence
• Six studies evaluating the prevention and treatment of bone pain with GCSFs in varying forms of interventions with a maximum of two studies looking at opioids, one with no reported relief of pain

There was no real difference between pegfilgrastim and daily GCSFs in terms of incidence of bone pain, and most patients will benefit from the use of NSAIDs to control pain. The authors suggest that patients who do not respond to NSAIDs should consider second-line treatment with antihistamines. The study cites a series of four patients and one case study in which this was effective.

Only one study was cited that evaluated the efficacy of antihistamines in relieving or decreasing bone pain associated with GCSFs from 2005. Main evidence is case reports only.

More studies are needed to evaluate the efficacy of antihistamines versus NSAIDs or acetaminophen in relieving bone pain.