PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Elder care, palliative care

Societies in the United States and Europe continue to have different recommendations regarding the use of ESAs during cancer treatment; for QoL in palliative settings, the harmful effects of ESAs should be balanced against potential benefits. There is no evidence to support their use in managing cancer-related fatigue.

Greater than 90% of the studies were funded by pharmaceutical companies.

For patients receiving palliative care, there may be a role for ESAs in reducing transfusion use; there does not appear to be any role for ESAs in managing cancer-related fatigue.

A psychoeducational intervention was offered between three weeks and four months postsurgery for malignant melanoma to groups of 8 to 10 patients. The intervention was organized into six sessions lasting approximately 2.5 hours each and was performed over a six-week period. The intervention consisted of health education about malignant melanoma and follow-up routines, the importance of limiting sun exposure, stress awareness, and stress management (relaxation and guided imagery). Patients were given a workbook and a CD with relaxation and imagery exercises. Psychological support was provided via the presence of a group therapist throughout all sessions and through peer support in the group setting.

• In total, 262 patients with T1-4, N1a-2a, M0 malignant melanoma were recruited between 3 and 12 weeks postsurgery.
• No follow-up data on these patients were available.
• There were no significant differences between the treatment and control groups relative to any demographic or medical variables.
• The majority of the patients in both groups were married and between ages 40 and 60 years.

• Multisite
• Outpatient oncology clinics in eastern Denmark

Patients were undergoing the long-term follow-up phase of care.

The study was a randomized, controlled trial with a usual care control group. Fatigue was evaluated at baseline prior to the intervention and at 6 and 12 months postintervention.

Profile of Mood States (POMS)

Controlling for baseline levels of fatigue, there was a statistically significant effect of the intervention on fatigue six months postintervention. This effect was not sustained at 12-month follow-up. Sixteen patients dropped out of the intervention before it started or after one session. All patients who dropped out cited that they dropped out due to the time or the distance involved or that they felt no need for support.

• The study lacked an attentional control group.
• Sixteen patients dropped out of the intervention.
• The direction of the bias on the intervention effect on fatigue (i.e., overestimation of the effect versus underestimation of the effect) created by these drop-outs was not examined/reported.
• Professional training was required to deliver the intervention.

Efficiencies of treatment were achieved through the group intervention modality.

To test the effects of a group cognitive behavioral therapy (CBT) intervention on psychosocial symptoms in women with breast cancer

One to two weeks after surgery, women who agreed to participate were randomly assigned to a psychosocial intervention or a usual-care control group. The intervention consisted of 12 hours of education over a two-week period. Education provided information about treatment modalities, side effects, social rights, healthful diet, stress management, cognitive reframing, and sexuality issues. The intervention then involved meetings of eight women. Each group met weekly, in a 2.5-hour session, for eight weeks. In the sessions, the women shared experiences to reveal negative thinking and integrate the elements of cognitive therapy. Follow-up was up at 1, 6, and 12 months.

• The sample consisted of 176 women with breast cancer.
• In the intervention group, 61% were older than age 50; in the control group, 76% were older than age 50. Mean age and range were not stated.
• The majority of patients had received treatment with chemotherapy plus radiation therapy plus hormonal therapy.
• 74% of the women were married or cohabiting.

• Single site
• Outpatient setting
• Denmark

 Randomized controlled trial

• Profile of Mood States questionnaire
• Mental Adjustment to Cancer Scale
• EORT Quality of Life questionnaire
• Barrett-Lennard Relationship Inventory

At no time in the study did differences exist between groups in regard to mood disturbances, quality of life, or marital relationships.

The psychosocial intervention, consisting of cognitive behavioral techniques, had no effect on depression, anxiety, quality of life, or marital relationship.

• The study included baseline sample and group differences.
• The study presents risk of bias because it did not include blinding or an appropriate attentional control condition.
• Patients in the control group were older than patients in the intervention group. 
• The study does not make clear whether women were actively receiving adjuvant treatment during the study.

The CBT intervention tested had no observable effect on depression or anxiety in women with breast cancer.

To investigate the effects of modafinil on fatigue, depression, cognitive impairment, and health-related quality of life in patients with primary brain tumors

The intervention consisted of subjects receiving modafinil versus a placebo over six weeks. The week 1 dosage was 100 mg twice daily and the weeks 2–6 dosages were 200 mg twice daily. The cross-over occurred after the completion of week 6; thus, subjects who initially received the placebo followed the same dosing schedule over the next six weeks while those who had taken modafinil previously were given a placebo. Neuropsychological assessments and self-report measures were completed at baseline, six weeks, and 12 weeks.

• N = 37  
• AVERAGE AGE = 48.16 years (SD = 12.02 years)
• MALES: 37.8%, FEMALES: 62.8%
• KEY DISEASE CHARACTERISTICS: Gliomas and meningiomas with stable tumor status for six months
• OTHER KEY SAMPLE CHARACTERISTICS: Subjects had to score > 27 on the Checklist Individual Strength Test indicating the presence of fatigue. Exclusions include psychiatric disease or depressive disorders and medication interactions with modafinil.  

• SITE: Multi-site    
• SETTING TYPE: Outpatient    
• LOCATION: VU University Medical Center (Amsterdam), Academic Medical Center (Amsterdam), and Medical Center Haaglanden (Hague)

PHASE OF CARE: Multiple phases of care

Randomized, controlled, double-blinded clinical trial using a cross-over design. Measurements were performed at baseline, six weeks, and 12 weeks.

• Rey Auditory Verbal Learning Test (RAVLT)
• Memory Comparison Test
• Stroop Color and Word Test (Stroop)
• Letter Digit Substitution Test
• Concept Shifting Test (CST)
• Categorical Word Fluency Test
• Checklist Individual Strength (CIS)
• Center for Epidemiologic Studies Depression Scale (CES-D)
• Medical Outcomes Study Short-Form Health Survey (MOS SF-36)
• Medical Outcomes Study Subjective Cognitive Functioning Scale (MOS)

The CIS severity and reduced motivation scores for fatigue were lower after treatment with both modafinil (p = 0.01, p = 0.021) and placebo arms (p < 0.001, p = 0.027), but there was no difference in scores between trial arms. Significant improvements in working memory (p = 0.04, p = 0.043), information-processing (p = 0.036, p = 0.04), and attention (p = 0.015, p = 0.013) were found after treatment with modafinil and the placebo, respectively. There were no differences in scores between trial arms. Health-related quality of life measured by the physical component summary of the SF-36 was significantly improved for both modafinil (p = 0.001) and placebo arms (p = 0.008). There were no differences in depressive symptoms following modafinil or placebo.

The results indicate that there were no significant differences observed in fatigue, cognitive functioning, health-related quality of life, and mood between modafinil and a placebo. These findings may be related to the study design, duration of treatment, low study accrual, subject withdrawals, and lack of longitudinal follow-up.

• Small sample (< 100)
• Subject withdrawals ≥ 10%

Findings do not support the use of modafinil to improve fatigue, cognitive functioning, mood, and health-related quality of life in patients with brain tumors.

To determine factors that impact health-related quality of life (HRQOL) and mastery of caregivers of patients with high-grade glioma, and to investigate if a structured intervention consisting of psycho-education and cognitive behavioral therapy (CBT) leads to an improvement in the mental component of HRQOL and mastery of caregivers

Caregiver dyads randomly were assigned to the intervention group or care as usual group. The intervention group consisted of six one-hour sessions with a psychologist for CBT and psycho-education regarding disease-specific symptoms. Participants completed questionnaires concerning their perception of the patients' HRQOL, neurologic functioning, cognitive functioning, their own HRQOL perceptions, and feelings of caregiver mastery at baseline (prior to randomization) and every two months thereafter until eight months later, five times total.

• N = 56 caregiver dyads  
• MEAN AGE = 50 years
• MALES: Intervention group = 26%, control group = 48%; FEMALES: Intervention group = 74%, control group = 52%
• KEY DISEASE CHARACTERISTICS: High-grade glioma stage III/IV
• OTHER KEY SAMPLE CHARACTERISTICS: Participants were informal caregivers (defined as a spouse or significant other providing at least 21 hours of care per week); aged 18 years or older; 57% were receiving active treatment during the study 

• SITE: Multi-site    
• SETTING TYPE: Outpatient  
•  LOCATION: VU University Medical Center (Amsterdam)/Academic Medical Center (Amsterdam), and Medical Center Haaglanden (Netherlands)

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Palliative care

• Randomized, controlled trial

• MOS 36-item short form survey (SF-36)
• Caregiver mastery scale
• MOS Cognitive Functioning Scale
• Brain cancer module

Caregivers' HRQOL and caregiver mastery were associated with patient-related factors at baseline. A positive correlation was found between a positive mental functioning (MCS) of the patient and a positive MCS of the caregiver. Feelings of mastery in the intervention group increased over time, while feelings of mastery in the control group showed the opposite pattern. Those who received the intervention maintained a more stable level of mental functioning and showed modest improvement in feelings of mastery in comparison to the control group. Patients' HRQOL and neurologic functioning were found to be related to HRQOL and feelings of mastery of the informal caregiver at baseline. The intervention helped caregivers in maintaining a stable level of HRQOL and improved feelings of mastery over an eight-month period.

The findings from this RCT suggest that informal caregivers can benefit from a psychological CBT intervention because it is a helpful tool in maintaining a stable level of mental functioning and caregiver mastery.

• Small sample (less than 100)
• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Findings not generalizable as a result of high attrition
• Intervention expensive, impractical, or training needs—significant time/burden for the caregiver (burdensome)
• Subject withdrawals 10% or greater
• Other limitations/explanation: Approximately 24% died prior to study conclusion

Future nursing practice should focus on offering supportive interventions to patients with high-grade glioma and their informal caregivers. Further research should continue to look at the effects of a psychological intervention on HRQOL and feelings of mastery of informal caregivers of the high-grade glioma patient population. Findings suggest that CBT interventions can be of benefit to caregivers.

Evaluate the efficacy of venlaxafine and clonidine for hot flashes in patients with breast cancer

Patients were randomly assigned to receive 75 mg venlafaxine,  0.1 mg clonidine, or placebo daily.  Subjects were stratified by age, duration of hot flashes, concurrent endocrine therapy, and previous chemotherapy.   Patients were treated for 12 weeks.  Hot flash scores at week 12 were compared among the three groups.

N  80 AGE   Median = 49, range 28-71

MALES (%)          FEMALES (%)100%

KEY DISEASE CHARACTERISTICS 31% had age related symptoms, and 99% were post menopausal after breast cancer treatment.  52% received endocrine treatment
 

SITE  Multi-site  SETTING TYPE  Outpatient  LOCATION Netherlands

PHASE OF CARE Late effects and survivorship

 Double blind placebo controlled RCT

• Daily diary of frequency and severity of hot flashes - mild, moderate, severe categorization and calculation of daily hot flash scores
• Groningen Sleep Quality Index
• Hospital Anxiety and Depression Score
• Sexual Activity Questionnaire
   

Hot flash scores were lower in the clonidine group than the placebo group at week 12 ( p = .03), and lower in the venlaxafine group than placebo, though not statistically significant ( p = .07).  Over the 12-week period, reduction in the venlaxafine group was 41% ( P<.001), 26% in the clonidine group ( p=.045), and 29% in the placebo group (p<.001).  Those on venlaxafine tended to have some loss of appetite ( p = .003) as well as symptoms of nausea.  Sleep and sexual function were not different between the two treatment groups.  At week 12, anxiety and depression scores were higher in the venlafaxine than the clonidine group. (p = .03).  Significantly lower hot flash scores began in the venlafaxine group compared to placebo in weeks 1-4 (p =.01), and in the clonidine group, lower scores began compared to placebo in weeks 5-8 ( p = .04)

Both venlafaxine and clonidine were slightly more effective than placebo in reducing hot flash symptoms in this group of patients. However, over the 12 weeks, all study groups showed significant reduction in symptoms.

• Questionable protocol fidelity
• Other limitations/*explanation  Authors state that the final sample was underpowered.  It is noted that not all patients were compliant with the medications, but is not clearly stated how compliant they were or were not.  No information is given regarding any missing diary data, and reliability of diary and self-report of severity of hot flashes is not clear.  Follow up period was relatively short, so longer term efficacy is not clear.

Findings suggest that venlafaxine and clonidine may be of benefit in reducing hot flash symptoms in women with breast cancer. However, further research is needed for support, because placebo group also showed reduction in hot flashes. Some patients did have side effects from these medications; patients should be monitored for nausea, changes in appetite, anxiety, and depression if these medications are used.

To evaluate the effectiveness and safety of aprepitant related to the incidence and severity of chemotherapy-induced nausea and vomiting (CINV) when added to a standard antiemetic regimen for highly or moderately emetogenic chemotherapy in pediatric patients

Both male and female patients received a standard antiemetic regimen of ondansetron 0.45 mg/kg and dexamethasone 7 mg/². In addition, they also received oral (solution or capsule) aprepitant with weight-based dosing based on the facility’s dosing table. Issues related to quality of life, such as severity of nausea, frequency of vomiting, appetite, and effect on activities of daily living (ADLs) were assessed using a survey. Since there are few studies using aprepitant in young patients weighing < 40 kg, the safety and tolerability of aprepitant in this population was the focus of this study.

• N = 11 patients (20 encounters)  
• MEAN AGE = 9.55 (4.85) years (range = 12 months–17 years)
• MALES: Not identified, FEMALES: Not identified
• KEY DISEASE CHARACTERISTICS: Confirmed malignancy
• OTHER KEY SAMPLE CHARACTERISTICS: Patients received a cycle of highly or moderately emetogenic chemotherapy.

• SITE: Single-site  
• SETTING TYPE: Not specified  
• LOCATION: Not indicated

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics 

Prospective, observational study

A patient survey was created by the investigators using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) grading system v4.0 and a 4-point Likert scale. It was completed at baseline, every day in which chemotherapy was administered, and for five days after the completion of chemotherapy. The survey evaluated the occurrence and severity of nausea, vomiting, appetite, and affect on ADLs during the phases of acute (0–24 hours), delayed (1–5 days), and overall phase (acute and delayed) after chemotherapy. The survey was administered by a study investigator or sent home with the patient’s caregiver. Complete response (CR) was defined as no nausea, vomiting, or no use of rescue drugs during the acute phase.

A total of 7 out of 16 (38.9%) CRs were achieved. No vomiting was reported in the overall (acute and delayed) phase in 16 out of 18 encounters (88.9%). In 5 out of 17 encounters (29.4%), no nausea was experienced in the overall phase. There was no interference in ADLs in 47.1% and no interference with appetite in 10 out of 18 (55.6%) patients. Rescue medications were not required in the acute phase for 7 out of 11 patients. There were no directly attributable adverse effects related to the systemic absorption of aprepitant, and it was found to be well-tolerated in this pediatric study population.

Oral aprepitant administration was found to be safe in patients as young as 12 months in moderate and highly emetogenic chemotherapy. During the study period, complete responses (no nausea, vomiting, or use of rescue drugs) were experienced in 33.3% of patients.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Risk of bias (sample characteristics)
• Selective outcomes reporting
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Findings not generalizable
• Other limitations/explanation: The range of ages from 12 months to 17 years in a small sample makes it difficult to come to valid conclusions about the results. No tool was used to measure the safety of aprepitant in this population.

In the study population, weight-based dosing of oral aprepitant was well-tolerated and did not cause any systemic adverse reactions.

To examine fatigue levels in patients supported by a mistletoe preparation compared to patients who did not receive mistletoe

Data were extracted from the medical records of patients from the time of diagnosis or surgery (visit 1), during postoperative chemotherapy or chemoradiotherapy (visit 2), and at the end of postoperative therapy (visit 3). Patient complains related to fatigue and symptoms of inflammation were noted by the physician via interview. The results of patients allocated to mistletoe therapy were compared to those of the control patients. Mistletoe was provided as an injectable extract preparation that was given subcutaneously at a total average dose of 16–20 mg per week.

• N = 324  
• AGE = Not provided
• MALES: Not provided, FEMALES: Not provided
• KEY DISEASE CHARACTERISTICS: All patients had colorectal cancer and were receiving 5-fluorouracil-based chemotherapy.

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: Germany

• PHASE OF CARE: Active antitumor treatment

Retrospective, observational cohort study

Specific measurements were not described. Signs of inflammation and cancer-related fatigue were apparently coded by physicians as “yes” or “no” to indicate the presence of clinical signs.

There was a significantly increased odds ratio of suffering with fatigue among patients in the control group at visits 2 and 3 (p < 0.001). However, by visit 2, 85% of those in the mistletoe group had dropped out, and by visit 3, only 16 patients remained in the mistletoe group. The results regarding inflammation were not described.

This report provides insufficient evidence regarding the effects of mistletoe therapy on cancer-related fatigue.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: The study design, lack of clear objective methods to measure outcomes, and extremely high drop-out rate limit the usefulness of the findings reported. The actual dosages, timing, and duration of mistletoe therapy were not described.

This study does not provide any strong evidence regarding the efficacy of mistletoe extract for the management of cancer-related fatigue, and it does not provide evidence regarding the impact of this therapy on inflammatory markers. Inflammation is a suggested mechanism that may influence fatigue in patients with cancer, and mistletoe extract has been proposed as an intervention to reduce inflammation. Well-designed studies examining the potential effects of mistletoe extract in these areas are needed.

To evaluate the safety and efficacy of micafungin for antifungal prophylaxis in pediatric patients at high risk for fungal infection

Children who were intolerant to polyenes and axoles or in whom theses were otherwise contraindicated were given 3–4 mg/kg micafungin twice weekly. Micafungin was begun when the patient could not take other antifungals and was continued until hematopoetic recovery after chemotherapy or until 100 days after HCT. Trough concentrations were determined from blood drawn prior to micafungin infusion, and peak levels were obtained 30 minutes after the end of the infusion.

• N = 21
• MEDIAN AGE = 9 years
• AGE RANGE = 0.2–16 years
• MALES: 66.6%, FEMALES: 33.4%
• KEY DISEASE CHARACTERISTICS: All relapse, Non-Hodgkin lymphoma, AML, or undergoing allogeneic HCT

• SITE: Single site  
• SETTING TYPE: Multiple settings  
• LOCATION: Germany

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Pediatrics

• Observational retrospective

• IFD defined according to European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG)
• Peak and trough micafungin concentrations

There was no premature discontinuation of micafungin due to related adverse events. Proven or probably invasive fungal infection did not occur in any patients.

Findings suggest that intermittent micafungin for antifungal prophylaxis can be safe and effective in high-risk pediatric patients. Additonal larger studies are needed to confirm these results.

• Small sample (less than 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 

There are a number of limitations to the use of oral triazoles for routine antifungal prophylaxis, and micfungin has been used for prevention and treatment of candida infections in children. This study showed that a larger dose, delivered intermittently, may be a safe and effective alternative for antifungal prophylaxis in high-risk children with cancer. The ability to not have to provide infusions daily can be an attractive and convenient alternative to daily treatment. This study has several important limitations, so additional well-designed research to confirm these findings in larger samples is needed.

To compare the efficacy and tolerability of the granisetron transdermal delivery system (GTDS) to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV)

Patients were randomized to oral (2 mg per day for 3–5 days) or transdermal (one GTDS patch over 7 days) granisetron before receiving multiday chemotherapy. Patients received placebo capsules or capsules according to group assignment. Corticosteroids and rescue medications were given at the discretion of the investigator. Patients were followed for 14 days after chemotherapy.

• The study consisted of 582 participants.
• The mean age of participants in the GTDS group was 54 years (SD = 13 years). The mean age of participants in the oral granisetron group was 55 years (SD = 14 years).
• In the GTDS group, 52% of patients were female and 48% were male. In the oral granisetron group, 51% were female and 49% were male.
• Diagnoses were not provided.
• Patients were receiving the first cycle of a new multiday moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) regimen.

The study was conducted at multiple sites in Europe, the United States, Mexico, and India.

This was a randomized, double-blind, controlled trial.

Patients recorded the following in diaries daily.

• Vomiting, presence and severity, on a five-point scale ranging from 1 = none and 5 = very severe.
• Nausea, presence and severity, on a four-point scale ranging from 1 = none and 4 = severe.

Complete control (CC) was defined as no vomiting or retching, no more than mild nausea, and no use of rescue medication from the first administration until 24 hours after the last administration of chemotherapy.

• GTDS was not inferior to oral granisetron in CC.
• The percentage of patients achieving complete response (CR) or total control (TC) was not significantly different.
• Time to failure and time to treatment CC failure were similar.
• In patients receiving three- and five-day chemotherapy regimens, CC and CR were similar between the GTDS and oral granisetron groups.
• The GTDS group reported more constipation, and the oral granisetron group reported more headaches.
• In the experimental group, 65% of patients achieved CR with oral graniestron, and, in the control group, 60% of patients achieved CR with oral granisetron.

The GTDS provided effective, well-tolerated control of CINV associated with moderately or highly emetogenic, multiday chemotherapy.

• Diagnoses were not reported.
• No information was provided or subgroup analysis done on the use of dexamethasone or rescue medications.
• No differentiation or analysis was provided regarding acute versus delayed nausea or between those receiving MEC or HEC.
• No neurokinin 1 (NK1) receptor antagonists were used.

GTDS could be an option for CINV from multiday chemotherapy regimens. Further research to determine the role of this approach within an overall antiemetic regimen is warranted.