To assess effectiveness of methylphenidate versus placebo to reduce cancer-related fatigue and to analyze cytokine levels and symptoms of cognitive function

Patients were randomized to receive either methylphenidate 18 mg per day for two weeks followed by placebo for two weeks, or to receive placebo for the first two weeks followed by methylphenidate for three weeks. All completed a battery of tests at baseline and were asked to record fatigue level and interference with activities in a daily diary. Additional fatigue measurement occurred at week 1 and week 3. Bloodwork for cytokine levels was obtained at baseline, crossover, and the end of the study.

• N = 33
• MEAN AGE = 57 years (range 32–79 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: All had breast cancer; 74% had metastatic disease; 84% were currently on chemotherapy.
• OTHER KEY SAMPLE CHARACTERISTICS: 74% were white; 68% had more than high school education; 52% were working full-time or part-time.

• SITE: Single site
• SETTING TYPE: Outpatient    
• LOCATION: MD Anderson Cancer Center, Texas

PHASE OF CARE: Multiple phases of care

Double-blind, placebo-controlled crossover RCT

• Wechsler Adult Intelligence Scale (WAIS)
• Digit Span and Digit Symbol Tests
• Hopkins Verbal Learning Test
• Controlled Oral Word Association
• Trial Making Test Parts A and B
• Grooved Pegboard Test
• Brief Fatigue Inventory (BFI)
• Beck Depression Inventory II
• Brief Sleep Disturbance Scale
• Profile of Mood States (POMS)
• MD Anderson Symptom Inventory
• Work Productivity and Impairment Questionnaire (WPAI)
• Multiple inflammatory cytokine levels

There were no significant differences between treatment arms for fatigue by BFI scores or diaries. There was no carryover effect of methylphenidate, so data were pooled for analysis. There were no differences in symptom inventory results. The WAIS-III digit span test demonstrated improved cognitive processing speed in the treatment versus placebo condition (p = .01), and the subscale of confusion on POMS was lower with methylphenidate (p = .05). There was a significant correlation between BFI interference and activity level and the Hopkins Verbal Learning Test showing declining memory with higher levels of fatigue (p < .05).  Patients receiving methylphenidate missed fewer hours of work due to health (p = .03). There were no significant differences in or correlations with cytokine levels. There were no serious adverse events with methylphenidate.

This study did not show improvement in fatigue with methylphenidate. Findings suggest that some aspects of cognitive function are related to fatigue level.

• Small sample (< 100)
• Other limitations/explanation: The study was underpowered.

Findings do not show that methylphenidate improved fatigue symptoms, but it may have had some effect on missing work and some aspects of cognitive function. Further exploration of associations between fatigue and cognitive impairment associated with chemotherapy is warranted.

Zinc sulfate (50 mg zinc) capsules TID at 8 hr intervals. Began day 1 of radiation, during RT, and for 6 weeks after.

Oral hygiene for all patients: drink water, brush with soft brush after each meal and with mouth jellies, including fluoride. Patients were instructed to avoid alcoholic drinks, not smoke cigarettes, not drink liquids that were too hot or too cold, not eat excessive spiced or sour foods, and to not eat hard foods.
 

The study was comprised of 30 patients, 15 zinc, 12 placebo (3 excluded), age 18-71, with a median age of 54 years.

• Head and neck RT or chemo + RT
• Median rad dose 6400 cGy
• May 2001 – May 2002

Prospective, randomized placebo-controlled study

Assessed by two radiation MDs using RTOG morbidity scoring

13 of 15 zinc patients developed mucositis; however, no patientss developed grade 4 mucositis.
Gr 1 – 8 pts versus  0
Gr 2 – 5 pts versus 4
Gr 3 – 0 pts versus  8
Gr 4 – 0 pts versus 0

Greater severity p = 0.05

Mucositis developed later in the zinc group (p < 0.05) and  at a higher RT dose (p < 0.01)

At six weeks, only one patient in the zinc group had mucositis, while 10 of 12 patients in the placebo group had mucositis, p < 0.01.

Well tolerated
 

Local anesthetic solutions and analgesic agents were given to patients for pain.

Very small study

Need to ensure validity of MD evaluation and other agents used.
 

To evaluate the risk-benefit profile of the use of mirtazapine for the treatment of depression in patients with cancer

Patients were enrolled who presented for psychiatric evaluation and treatment of depression and met DSM-IV criteria for major depression (HAM-D-17 score > 18). Patients started a drug therapy of mirtazapine, 15 mg/day day orally; the dose was increased to 30 mg/day in the fourth week of therapy if patients were not responding and had no adverse effects. All patients continued receiving the minimum dose for 24 weeks, but the use of other medications was not controlled. Patients were assessed at the initial visit and at the end of weeks 4, 12, and 24. Adverse effects were noted during routine assessments.

• A total of 19 patients completed 24 weeks of follow-up and evaluation for treatment efficacy.
• The mean age was 55.47 (SD = 11.04; range = 22–69 years).
• 12 patients were female and 7 were male.
• Various types of cancer were represented, including breast, brain, gynecologic, liver, hematologic, and larynx/nasopharynx.
• The study states that most had advanced cancer, but stages were not reported.
• Most patients were receiving some form of cancer treatment (e.g., chemotherapy, radiation therapy, tamoxifen). Five patients were not receiving any cancer treatment during the study period.

• Unspecified but assumed to be outpatient
• Turkey

Active treatment

Open-label (no blinding) longitudinal study

• 17-item Hamilton Rating Scale for Depression (HAM-D-17)
• Clinical interview by psychiatrist
• Routine blood tests (heme panel and biochemistry) performed weekly during the first 12 weeks of therapy, then monthly

Clinical efficacy was defined as a greater than 50% reduction in HAM-D-17 scores (defined as a positive treatment response). Patients with HAM-D-17 scores of 8–18 were defined as partial responders. Patients with HAM-D-17 scores less than 8 and a period of at least two months without significant symptoms of depression met the criteria for remission. All patients obtained at least a 50% reduction in HAM-D-17 scores, which improved from baseline to one month and were maintained for the duration of the study (24 weeks) (p < 0.001). HAM-D-17 scores significantly decreased from baseline to one month (p < 0.001). The drug was well tolerated, and no one required discontinuation of therapy. Minimal adverse effects were reported, including mild to moderate hand tremor, fatigue, weight gain, and restless leg syndrome.

The study provides preliminary evidence that (open-label) the drug mirtazapine is safe, efficacious, and tolerated.

• The sample was small, containing fewer than 30 participants.
• The study was open-label, with no placebo control.
• The potential for selection bias existed.
• The findings could be confounded by the lack of control over the type of cancer therapy and the time lapse since cancer treatment.

This particular agent may have antiemetic effects, which may be desirable in this patient population, and it had a minimal side-effect profile. Future research should include a randomized, controlled trial examining mirtazapine versus selective serotonin reuptake inhibitors in this patient population.

• Databases searched were MEDLINE, Embase, Biosis, CISCOM, and Cochrane Library.
• Searched keywords were ginger, herbal remedy, nausea, and vomiting.

The review identified three studies on postoperative nausea, one for seasickness, one for morning sickness, and one for chemotherapy-induced nausea and vomiting (CINV). Studies were performed in the United States and in Denmark.

The total number of participants in the studies was 288 for postoperative nausea, 30 for morning sickness, 80 for seasickness, and 41 for CINV.

Clinical data was insufficient to draw a firm conclusion on the benefits of ginger for nausea and vomiting.

Although no adverse events were reported in these studies, ginger may have an adverse effect. A German monograph reported that ginger may be mutagenic in pregnancy.

Evaluate moderate intensity exercise programs for patients with breast cancer and their effect on several immune indicators as well as on fatigue, depression, and quality of life

Lab was obtained at week 0 and 12 and analyzed. Quality of life, fatigue, and depression were evaluated before and after the exercise program using tools mentioned. Patients were assigned to one of three groups. All were provided education. Group one did supervised exercise consisting of 45 minutes per day three times per week and brisk walking for 30 minutes per day three times per week. Group two did brisk walking for 30 minutes per day three times per week. Group three received education only. Patients wrote down their progress, and groups two and three were interviewed over the phone once a week. Arm circumference was measured to control for lymphedema at zero, one, two, and three months.

• N = 58
• AGE: 18–65 years
• MALES: 0%, FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer, completed surgery, radiation, chemotherapy, post-menopausal, had not smoked in past year, absence of physical condition that would hinder exercise, cognitive capacity
• OTHER KEY SAMPLE CHARACTERISTICS: Patient demographics, age at diagnosis, type of operation, time after diagnosis, axillary dissection, sentinel lymph node biopsy, operation side, number of chemotherapy cycles, number of radiation treatments, body mass index

• SITE: Single site    
• SETTING TYPE: Outpatient    
• LOCATION: Outpatient clinic for oncology and support unit of Ege University Tulay Aktas Oncology Hospital

PHASE OF CARE: Transition phase after active treatment

Prospective, randomized controlled study

• European Organisation for Research and Treatment of Cancer Quality of Life C30
• Brief Fatigue Inventory (BFI)
• Beck Depression Inventory (BDI)

Demographics were similar among the three groups. Exercise groups had a statistically significant decrease in some of the biomarkers, while the education group had a statistically significant increase in monocyte chemoattractant protein 1 levels. Functional score and global health score in both exercise groups increased.  Depression score was reduced in the supervised exercise group (p < .05). However, no significant differences were seen between groups after the intervention.

Significant changes in biomarkers were found at the end of 12 weeks, and improvements were seen in quality of life and depression in the supervised  and unsupervised exercise groups.

• Small sample (< 100)
• Findings not generalizable
• Intervention expensive, impractical, or training needs
• 12-week exercise program often is difficult for individuals
• Unclear if the home walking group adhered to the exercise program

Nurses encouraging patients with breast cancer to stay physically active and adopt a moderate exercise program is important to improve quality of life and help with symptoms of depression.

To determine the efficacy of royal jelly on oral mucositis in patients receiving chemotherapy and radiation

Patients were divided into two groups. All patients received benzydamine hydrochloride and nystatin rinses. In the experimental group, royal jelly was swished orally for 30 seconds and then swallowed twice per day for a total of 1 g per day. Patients could not eat or drink within 30 minutes of using the royal jelly. Both groups used the mouthwash protocol or mouthwash protocol plus royal jelly until mucositis was resolved. All participants and assessors were blinded to group. Oral mucosa was divided into five sites—labial mucosa, buccal mucosa, gingivae, tongue, and soft and hard palates—and the mucositis score was determined daily by a trained researcher for each site until no further evidence of mucositis existed.

• N = 103  
• AGE = 52.25 years
• MALES: 47%, FEMALES: 53%
• KEY DISEASE CHARACTERISTICS: Multiple types of cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Multiple stages of cancer, chemotherapy types, and chemotherapy cycles

• SITE: Single site    
• SETTING TYPE: Outpatient    
• LOCATION: Turkey

• PHASE OF CARE: Active antitumor treatment

• Prospective, randomized clinical trial

• World Health Organization criteria for mucositis

No statistical difference was seen in mucositis severity at the beginning of the study between the two groups. For grade 1 mucositis, the mean number of days to healing in the royal jelly group was 1.1 days, and in the control group it was 2.7 days (U = 64; p = 0.0001). For grade 2 mucositis, the mean number of days to healing in the control group was 5.8 days, and in the experimental group it was 3 days (U = 77; p = 0.0001). For grade 3 mucositis, those in the experimental group had a faster healing time than those in the control group (U = 59; p = 0.005).

The addition of royal jelly to a mouthwash protocol with benzydamine and nystatin rinses significantly decreased the healing time for grade 1, 2, and 3 oral mucositis.

• Risk of bias (no random assignment)
• Other limitations/explanation: Random assignment was not described in the study

Royal jelly should be considered as an additional intervention to promote the healing of oral mucositis caused by chemotherapy and radiation. Royal jelly, in addition to a mouthwash protocol consisting of a benzydamine and nystatin rinse, effectively reduced the number of days to complete healing of oral mucositis. The sample in this study included a wide variety of cancer types as well as a wide range of types of chemotherapy and number of chemotherapy cycles.

To evaluate the feasibility of a cognitive rehabilitation intervention for persistent post-treatment cognitive issues in survivors of breast cancer and to conduct a substudy to garner preliminary data related to the use of quantitative electroencephalography (qEEG) to assess changes in cognitive function

Five weekly, manualized, two-hour sessions were provided to five cohorts of four to nine participants. The last cohort participated in the qEEG substudy. Two difficulty levels of in-class cognitive training and three levels of homework exercises were designed to build skills in the targeted areas of attention, executive function, and memory. Participants were encouraged to do four 20-minute sessions of homework exercises per week and log their time. Participants received a training manual workbook, CDs for auditory exercises, answer keys, and a stopwatch. In-class education focused on a specified targeted area and instructions on coping strategies to minimize anxiety (such as deep breathing, relaxation, pacing, and countering negative thoughts). Goal attainment was discussed during the group sessions to facilitate setting individual short-term and long-term goals. Neurocognitive testing, self-report instruments, and the qEEG (substudy) were administered at baseline (T0), within one week (T1), and at two (T2), and four (T3) months after completing the intervention.

• N = 27 (8 in substudy)  
• MEDIAN AGE = 54.1 years (SD = 6.3 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer survivors within 18 months to five years after initial treatment completion who reported persistent cognitive issues that interfered with daily activities. Ongoing endocrine therapy and HER2-targeted adjuvant therapy were allowed. Inclusion requirements: 18–75 years old and stages 0–III breast cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: Participants primarily were Caucasian, married, and well-educated (mean 16.4 years of education). The majority received chemotherapy (89%), radiation (63%), or endocrine therapy (67%). Exclusion criteria included untreated depression, psychiatric disorders, and disorders of the central nervous system (CNS) (i.e., CNS cancer, CNS treatment with intrathecal chemotherapy, surgery, radiotherapy, traumatic brain injury, seizures, intellectual disabilities, substance abuse disorder).

• SITE: Single-site    
• SETTING TYPE: Outpatient    
• LOCATION: University of California, Los Angeles, United States

• PHASE OF CARE: Late effects and survivorship

Prospective trial

• CNS Vital Signs Computerized Testing Platform
  • Finger tapping dominant, finger tapping nondominant
  • Shifting attention test
  • Stroop reaction time
  • Continuous performance test
  • Symbol digit test
• Hopkins Verbal Learning Test, Revised (HVLT-R) (total recall, delayed recall)
• Brief Visuospatial Memory Test, Revised (BVMT-R)
• Trail Making Tests (TMT) A and B
• Paced Auditory Serial Addition Test (PASAT) Trial 1
• Judgment of Line Orientation (JLO) test
• Patient’s Assessment of Own Functioning Inventory (PAOFI)
• Beck Depression Inventory, Second Edition (BDI-II)
• Spielberger State-Trait Anxiety Inventory (STAI)
• Resting quantitative electroencephalography (qEEG)

PAOFI totals and memory complaint scores decreased between T0 and T1 (p = .031 and p = .009, respectively) and were maintained at T3 (p < .0001 in both). Decreases in high-level cognitive functions (PAOFI scale) were demonstrated at T3 (p = .005). Significant short- and long-term improvements were observed for the symbol digit, Stroop reaction time, and trail A tests (p < .05). Meaningful improvement by a reliable change index (RCI) occurred for 19% of patients (n = 5) between T0 and T1, and 30% of patients (n = 8) by T3. RCI improvement (in ≥ 2 of 16 tests) predominantly occurred for verbal learning and memory (HVLT-R), processing speed (symbol digit), and divided attention (shifting attention test). Absolute alpha power increase (qEEG) was associated with PAOFI improvements at T1 (p = .014). Change in alpha power correlated with change in PAOFI memory subscale at T1 (p = .021) and T2 (p = .004). Correlation also was noted with the PAOFI HLC subscale at T2 (p = .030) and T3 (p = .048).

This study's results demonstrated the feasibility of this cognitive rehabilitation intervention and preliminary evidence for the improvement of subjective and objective cognitive function. Larger randomized, controlled trials are necessary to further determine efficacy. Preliminary results supported the potential use of qEEG as a measure of change in cognitive function. An additional randomized, controlled trial is underway.

• Small sample (< 30)
• Risk of bias (no control group)
• Findings not generalizable
• Other limitations/explanation: Sample primarily was Caucasian, married, and well-educated. Results may not be generalizable to other demographics.

Cognitive rehabilitation interventions appear to be promising. Nurses should maintain an awareness of research results in this area and consider suggesting appropriate clinical trials to eligible survivors.

To determine the efficacy of a cognitive-behavioral intervention for treating insomnia in survivors of breast cancer.

Participants were assigned to either a multicomponent intervention with stimulus control, sleep restriction, and sleep education and hygiene or a control intervention with sleep education and hygiene. Participants attended four weekly treatment group sessions (the first session was two hours and the other three were one hour) followed by two weekly 15- to 30-minute individual telephone sessions. Outcomes measures were sleep-onset latency, wake-after-sleep onset, total sleep time, time in bed, sleep efficiency, and sleep quality.

• The study was comprised of 34 participants in the multicomponent intervention and 38 in the control group.
• Participants were women older than 18 years with a diagnosis of stage I, II, or III breast cancer and with insomnia of at least three months' duration.

The study was conducted in university and medical center classrooms.

Patients were undergoing the follow-up phase of care.

This was a randomized, controlled trial.

• Daily sleep diary
• Actiwatch®

After the intervention, based on daily sleep diaries, both groups improved in sleep-onset latency, wake-after-sleep onset, total sleep time, time in bed, sleep efficiency, and sleep quality. A between-group difference existed for time in bed. Wrist actigraph data showed significant pre- to postintervention changes for sleep-onset latency, wake-after-sleep onset, total sleep time, and time in bed. When compared to the control group, the multicomponent intervention group rated overall sleep as more improved.
 

A nonpharmacologic intervention is effective in the treatment of insomnia in survivors of breast cancer.

• The study used a selective sample:  the women were primarily white, well educated, and, on average, were diagnosed with cancer six years previously.
• Recruitment was via an advertisement and support groups; therefore, participants were more motivated to receive treatment.
• Space was required for group meetings.
• Actigraphs incurred a cost.
• The study required a Master’s level clinical nurse specialist in psychiatric-mental health nursing trained in the delivery of the intervention.

Participants were randomized to receive either benzydamine HCl oral rinse, containing 0.15% benzydamine oral rinse (1.5 mg/ml benzydamine) or placebo, which identical in appearance and taste consisting of the vehicle only (approximately 10% alcohol by volume, menthol, peppermint oil, clove oil, and other flavoring agents).

Patients were to rinse with 15 ml of solution for two minutes, 4–8 times daily, before and during radiation therapy (RT) and for two weeks after completion of RT. If burning or stinging occurred, dilution of the rinse with water at 1:1 or 1:2 was allowed.  

Patients were evaluated before RT, twice weekly during RT, at the end of RT, and 2–3 weeks after RT.

• The sample consisted of 172 patients, with 84 receiving benzydamine and 88 receiving placebo.
• Patients ranged in age from 18–80 years old.
• Patients had been diagnosed with head and neck cancer and were scheduled to receive at least 5000 cGy RT via megavoltage treatment. Patients were eligible if at least two oral sites were included in RT.
• Patients were excluded if they had Karnofsky performance status of less than 80%, known hypersensitivity to benzydamine or typical nonsterioidal anti-inflammatory drugs, had residual oral or pharyngeal mucositis from previous RT or chemotherapy, or were already on RT and had taken experimental drugs within 30 days of study start.

The study was conducted at 16 centers in North America (15 in the United States and 1 in Canada).

• Mucositis assessment involved evaluating 14 anatomic areas for erythema, pseudomembrane, and ulceration using a 4-point scale ranging from 0–3.
• Pain in the mouth or throat and pain during meals was assessed on a 7-point categorical self-rating scale ranging from 0–6.

Benzydamine produced a 26.3% reduction in mean mucositis area under the curve (AUC) compared with placebo for overall 0–5000 cGy (p = 0.009).

Pain also decreased as evidenced by a delay in use of concomitant systemic analgesics. Mouth pain showed a 25.8% reduction in AUC (p = 0.064) versus placebo, and throat pain showed a 22.5% reduction in AUC (p = 0.064).

Pain during meals was not effectively reduced.

Benzydamine was not effective in reducing more severe mucositis in patients receiving high, single, daily RT regimens of 220 cGy per day or more.

• The study is limited because of the small sample size.
• The intervention is not approved by the U.S. Food and Drug Administration.
• The decrease in pain was not statistically significant.

To determine the impact of repeated dosing with doxepin rinse over the course of one week in patients with oral mucositis

Patients were instructed to rinse the oral cavity for 1 minute with 5 mL doxepin suspension (5 mg/mL) and then spit it out. Patients were to continue using the rinse as needed, 3–6 times per day, for the following week until their second visit and assessment. Standard of care for mucositis also was used during this time. Subjects used diaries to record analgesic use and mouth rinses.

• The study reported on 9 patients, 3 women and 6 men, with a median age of 41 years.
• Patients were receiving radiation therapy, chemotherapy, hematopoietic stem cell transplantation (HSCT), or a combination of these for head and neck cancer.
• All patients had painful oral mucositis.

The study was conducted at a single site, outpatient setting in Canada.

This was a nonrandomized, unblinded, uncontrolled, open-label study.

• Data was compiled in Microsoft Excel. Statistical analysis was conducted using SAS 9.0 for Windows. Frequencies, medians, and ranges were used to report subject characteristics.
• Oral pain was graded using a visual analog scale (VAS) (0 = no pain, 10 = worst pain). Oral pain when eating and without function was graded prior to oral rinse and at 5 minutes, 15 minutes, 1 hours, 2 hours, 3 hours, and 4 hours following doxepin rinse.
• A VAS was used to report the taste of the rinse, discomfort, and fatigue.
• An Oral Mucositis Assessment Scale (OMAS) was used.
• Patients were asked to record in a diary estimates of their average pain up to four hours after using the rinse.

Statistically significant reductions in pain scores were reported for two hours following doxepin rinse during the initial visit (p < 0.05). Patients recalled that their pain significantly dropped within 5 minutes of rinsing over the week of repeated dosing (p < 0.05). At the follow-up visits, subjects reported statistically significant pain reduction 5 minutes after doxepin rinsing (p < 0.05). No changes were reported in systemic analgesics used during the study week despite the increasing severity of mucositis. No significant differences were found in mucositis scores over time.

Doxepin rinsing in addition to usual oral care produced reduced intensity of pain levels but no apparent difference in mucositis severity. No firm conclusions can be drawn from this extremely small sample.

• The sample size was small.
• Risk of bias exists because this was not a randomized, controlled, blinded study
• The standard care protocol, which also was used for oral care, was not described.

The doxepin rinse was well tolerated, and the results warrant a larger, randomized, controlled clinical trial.