To determine whether methylphenidate is useful for the management of fatigue in Chinese patients with cancer in the palliative care setting

Oral methylphenidate 5 mg daily; reassessed at day 8 and day 29 (if patient was still in study)

• N = 24  
• MEAN AGE = 64 years (SD = 47–81 years)
• MALES: 80%, FEMALES: 20%
• KEY DISEASE CHARACTERISTICS: Mostly gastrointestinal and lung cancers; patients receiving palliative or hospice care
• OTHER KEY SAMPLE CHARACTERISTICS: Fatigue score of at least 4 on 0–10 scale

• SETTING TYPE: Outpatient palliative care clinic or inpatient hospice
• LOCATION: Hong Kong, China

• PHASE OF CARE: Palliative
• APPLICATIONS: Palliative care

Prospective study

• Brief Fatigue Inventory (BFI)

For patients < 65 years old, scores were significantly lower at day 8 than at baseline but not at day 29. There were no significant differences at day 29 or in patients > 65 years old. Ten out of 24 patients stopped methylphenidate before day 8, with eight of the withdraws due to side effects of medication.

This study demonstrated no clinically significant effect for methylphenidate on cancer-related fatigue.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Subject withdrawals ≥ 10%
• Other limitations/explanation: There were a large number of refusals to participate in approached patients.

Methylphenidate is not recommended for the management of cancer-related fatigue.

The study reported the effects of tibolone 2.5mg daily on climacteric symptoms, vaginal dryness, and health-related quality of life in breast cancer survivors.

Patients were randomized one-to-one to tibolone 2.5 mg by mouth daily or 1 placebo pill by mouth daily, with mean duration of treatment of 2.75 years.

The study enrolled 3098 women, with 1556 on tibolone and 1542 on placebo. Combined treatment and placebo groups mean age was 52.7 (SD=7.3), range = 28-75.
    

• KEY DISEASE CHARACTERISTICS:  Non-metastatic breast cancer T1-3, N0-2, M0
• INCLUSION CRITERIA: Postmenopausal, younger than age 75 and treated in past 5 years.  At entry to study 6.5%were taking aromatase inhibitors, 66.6% taking tamoxifen, 4.3% taking GnRH analogues, 16.7% post oophorectomy.  Race and ethnicity are not reported.

This was a multi-site, multi-national study conducted in at least eight countries: Austria, Belgium, Germany, Spain, France, United Kingdom, Italy, The Netherlands.
 

• PHASE OF CARE: Long term followup
• APPLICATIONS: Late effects & survivorship

The study was a multinational, multicenter, randomized, double-blind, parallel group, placebo-controlled trial.

Measurements and instruments included:

• Daily hot flash diary - frequency and severity - with calculated composite score    
• Climacteric symptoms form - hot flash frequency per day, change from baseline, maximum intensity of hot flashes, sweats, interference of flushes/sweats with normal life, palpitations, joint pain, vaginal dryness, incontinence
• Women’s Health Questionnaire - health-related quality of life,  subset of participants
   

Compared to placebo, tibolone resulted in a significantly greater reduction in:

1. Number of hot flashes per day at 12 and 104 weeks of treatment (p’s < 0.0001)weeks
2. Mean composite hot flash severity at week 12 (p < .0006)
3. Mean vaginal dryness score at week 104 (p < 0.0001)
4. WHQ scores in vasomotor, sexual and sleep at weeks 28, 52, 78, and 104 (p < .05)
5. WHQ scores of attraction at week 78 and mood at weeks 26, 52, and 78 (p’s < 0.05). 

There were interaction effects of tamoxifen and AI such that those using those therapies obtained less relief in hot flashes and climacteric symptoms with tibolone. 

Tibolone 2.5 mg orally daily was effective in alleviating menopausal symptoms in breast cancer survivors overall, but was less effective in tamoxifen users.

 A very small percentage of participants were on AIs or GnRH analogues at study entry.

Despite efficacy, the main trial report published in another journal indicated that tibolone increased the risk of breast cancer recurrence and is therefore contraindicated as a menopausal symptom therapy in breast cancer survivors.   Also, placebo effect was evident and persistent.

To investigate the effect of education and exercises on development and progression of lymphedema

Patients were informed about measures to prevent lymphedema and about exercises. They were given written material prepared by the investigators. No further specifics about the education or exercises is provided.

• The sample (N = 55) was comprised of 1.8% male and 98.2% female patients.
• All patients had breast cancer.
• Ninety-six percent of patients had modified radical mastectomy and 45% had adjuvant radiotherapy.

The study took place in an outpatient setting in Turkey.

The study used a prospective observational design.

Arm circumference was measured.

Authors compared the percent of patients with minimal to severe lymphedema between those who exercised and those who did not over a six-month period; however, only 10 patients were noted to not exercise and sample sizes used in analysis were extremely small per severity group. Some patients who had lymphedema at study entry were stated to have no lymphedema at week 6.

 Results are inconclusive given multiple limitations of the study.

• The study had a small sample size, with less than 100 participants.
• The study had risk of bias due to no blinding, no random assignment, and no control group.
• Measurement and methods are not well described, making the measurment validity and realiablity questionable.
• The study does not provide clear information about node dissection and radiotherapy in relation to lymphedema development, does not fully describe the intervention or any other standard care interventions (e.g., bandanging), and does not describe how severity of lymphedema was determined.
• There was only a single point at which arm circumference was measured, which is a questionable measurement method. 
• Time since surgery was highly varied with a range of 1–105 months.

Study findings are inconclusive regarding the effect of patient education and information to prevent or manage lymphedema in patients with breast cancer.  Findings provide minimal support for use of exercise because of study report limitations.

STUDY PURPOSE: To examine the effects of exercise on cancer-related lymphedema and associated symptoms, and to determine if wearing compression during exercise is needed for individuals with lymphedema

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 21 (exercise) and 4 (compression and exercise) studies met inclusion criteria.
• TOTAL PATIENTS INCLUDED IN REVIEW = Not clearly described
• SAMPLE RANGE ACROSS STUDIES: Exercise studies (unclearly reported): five studies (sample sizes < 15), nine studies (sample sizes 15–30), four studies (sample sizes 31–60), and three studies (sample sizes > 61); studies with compression and exercise: four studies (sample size range: 18–31)
• KEY SAMPLE CHARACTERISTICS: Women with unilateral breast cancer-related lymphedema, male and female participants with lower limb lymphedema

PHASE OF CARE: Late effects and survivorship
 
APPLICATIONS: Palliative care

Although exercise did not result in a worsening of lymphedema and associated symptoms of the affected limb, no statistically significant effect of exercise on lymphedema or related symptoms existed. Subgroup analyses for exercise mode (aerobic, resistance, mixed, and other) and intervention duration (> 12 weeks or 12 weeks) showed consistent results, that is, no effect on lymphedema or associated symptoms. Too few studies existed to conduct a meta-analysis for evaluating the effect of compression during regular exercise.

Exercise appeared to have no effect on lymphedema and associated symptoms in individuals with secondary limb lymphedema. However, the findings indicate that individuals with secondary limb lymphedema can safely perform exercise without experiencing a worsening of lymphedema or related symptoms. Insufficient evidence exists to support or disprove the current clinical recommendation to wear compression garments during regular exercise. In addition, injuries from exercises do occur, which were reported in several studies, yet the review did not mention the injuries.

• No quality evaluation
• Low sample sizes
• The majority of study samples had stable, mild, unilateral breast cancer-related lymphedema and were likely to be physically active before study participation.

Given the health benefits of exercise on the overall quality of life of survivors, the findings from this review and meta-analysis suggest that nurses can educate cancer survivors with limb lymphedema to conduct progressive/supervised regular exercise, which likely will not worsen lymphedema or associated symptoms. However, injury does occur with exercise, so reporting it is important, but the review did not mention potential injury with exercise.

To demonstrate improvement in constipation in individuals on prolonged-release (PR) oxycodone and PR naloxone compared with individuals receiving single-agent PR oxycodone.

Prerandomization comprised a run-in phase for conversion and titration of prestudy pain medication regimen to the PR oxycodone and bisacodyl laxative regimen. In the double-blind phase, patients were randomized to receive one of the following for 12 weeks: PR oxycodone/PR naloxone in a 2:1 ratio and PR oxycodone placebo, or PR oxycodone alone and PR oxycodone/PR naloxone placebo. All patients completing the double-blind phase were eligible to enter a 52-week extension phase and receive PR oxycodone/PR naloxone.

• The study reported on a sample of 277 patients aged 18 years or older.
• Patients had a documented history of the following:
  • Moderate-to-severe chronic noncancer pain (eg, musculoskeletal, neuropathic, visceral), needing 24-hour coverage with an oxycodone equivalent of 20 to 50 mg/day
  • Constipation caused or worsened by an opioid
  • Expectation of benefit from the World Health Organization (WHO) step III opioid therapy treatment for the duration of the study.

• Multi-site
• Outpatient
• 4 European countries

This was a randomized, double-blind, parallel-group, phase III study.

• Bowel Function Index (BFI)
• Patient Assessment of Opioid Induced Constipation (PACOI)
• Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM)
• Pain Intensity Scale
• Brief Pain Inventory (Short Form) (BPI-SF)

• At week 4, the mean BFI score for the PR oxycodone/PR naloxone group decreased by 26.9 points. In contrast, the mean BFI score for the PR oxycodone group decreased by 9.4 points. The difference between those scores was significantly in favor of the PR oxycodone/PR naloxone group (p < 0.0001).
• At week 4, the mean PACOI score in the PR oxycodone/PR naloxone group decreased to 6.4% compared to 9.4% in the PR oxycodone group, showing statistically significant improvement (p < 0.0001).
• During the first four weeks, significantly fewer patients in the PR oxycodone/PR naloxone group took bisacodyl compared with the PR oxycodone group (p < 0.0001).
• No statistically significant difference existed between the two groups for efficacy of pain control.
• Mean pain intensity scores remained stable throughout the study.
• Twelve patients (three in the PR oxycodone/PR naloxone group and 9 in the PR oxycodone group) experienced serious adverse events, including gastrointestinal bleeding, headache, and cerebrovascular accident.

PR oxycodone/PR naloxone demonstrated superiority in the management of constipation in patients with chronic noncancer pain without compromising analgesia.

The study only included patients with noncancer pain.

PR oxycodone/PR naloxone may be effective in the management of constipation without compromising pain control for patients with chronic pain. However, the study did not include patients with cancer or patients receiving doses of oxycodone equivalent higher than 50 mg/day. Additional studies are warranted with higher doses of opioids and the inclusion of patients with cancer.

STUDY PURPOSE: To evaluate the effectiveness of benzodiazepines in relieving dyspnea in individuals with advanced disease; in addition, to compare the effectiveness of different benzodiazepines and different dosages, routes of administration, side effects, as well as a comparison of effectiveness in various diseases

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED =  8 studies in qualitative synthesis and 7 studies in quantitative synthesis
• TOTAL PATIENTS INCLUDED IN REVIEW = 214 with advanced cancer and COPD
• SAMPLE RANGE ACROSS STUDIES: 5–101
• KEY SAMPLE CHARACTERISTICS: Adults suffering from dyspnea related to advanced malignant and nonmalignant diseases. Advanced diseases meeting inclusion criteria were cancer, COPD GOLD stage III or IV, HF NYHA class III or IV, MND, and IPF; however, all relevant studies included only individuals with cancer and COPD. The interventions included the use of any benzodiazepines at any dose, frequency, route, duration, or route.

PHASE OF CARE: Multiple phases of care
 
APPLICATIONS: Elder care, palliative care

There is currently insufficient evidence to recommend the use of benzodiazepines for the prevention or relief of dyspnea in individuals with cancer and COPD. The adverse effects of somnolence is more prevalent with benzodiazepines than placebo; however, somnolence is more prevalent when treating dyspnea with morphine compared to benzodiazepines. Results must be interpreted with caution because of limited quality and high heterogeneity in the studies evaluated.

• No quality evaluation
• High heterogeneity
• Low sample sizes
• Heterogeneity in the benzodiazepine group, disease group, control group, and others

Additional high quality studies are needed to fully evaluate the impact of benzodiazepines on dyspnea. Treatment of dyspnea with benzodiazepines does have side effects with potentially no benefit. Given uncertain benefits of treating dyspnea with benzodiazepines, interventions for management of dyspnea should include nonpharmacological approaches as first-line when appropriate. Assessment of response to benzodiazepines administered to treat dyspnea should include knowledge of potential benefits and potential burdens of the medication and their impact on overall quality of life; for example, drowsiness may be an acceptable side effect for some but not others.

The primary aim of the study was to determine the efficacy of benzodiazepines for the relief of breathlessness in patients with advanced disease. The secondary aim was to determine the efficacy of different benzodiazepines, different doses of benzodiazepines, different routes of benzodiazepines, adverse effects of benzodiazepines, and the efficacy in different groups for the relief of breathlessness .

Databases searched were the Cochrane Pain, Palliative, and Supportive Care Trials Register (September 2009), Cochrane Central Register of Controlled Trials (Central) in the Cochrane Library (September 2009), Cochrane Database of Systematic Reviews in the Cochrane Library (September 2009), Database of Abstracts or Reviews of Effectiveness (September 2009), MEDLINE (1950–2009), EMBASE (1980–1989 and 2009), CINAHL (1980–1989 and 2009), PsycINFO (1806–1809 and 2009), American College Physicians Journal Club (September 2009), Health Technology Assessment (September 2009), NHS Economic Evaluation Database (September 2009), Database of Halley Stewart Library (St Christopher’s Hospice) (September 2009), International Pharmaceutical Abstracts (1970–1979 and 2009), and Iowa Drug Information System (1966–1969 and 2009).

Search strategies for the 14 databases included variations of the following keywords: dyspnea, breathing, breathless, shortness of breath, breathing difficult, and breathing labour paired with benzodiazepine, anxiety agents, and a long list of specific benzodiazepine agents.

Randomized controlled trials and controlled clinical trials assessing the effect of benzodiazepines in relieving breathlessness in patients with advanced stages of cancer, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), motor neuron disease (MND), and idiopathic pulmonary fibrosis (IPF) were included.

Studies using all drugs in the pharmacologic class called benzodiazepines at any dose, frequency, duration, and through any route for the relief of breathlessness compared with placebo or active control were included.

Studies were excluded if they

• Were not controlled or randomized trials
• Included participants with acute or chronic asthma, pneumonia, or other potentially curable diseases.

A total of 1,309 references were reviewed initially from the databases, which were narrowed to 31 articles for closer evaluation. The final evaluable seven studies included seven randomized controlled trials, five crossovers, and two parallel designs, four with COPD and three with cancer. All studies were initially assessed for quality using the Review Manager (RevMan) and secondarily evaluated using “The Edwards Method Score,” and articles were graded for inclusion in data analysis or the meta-analysis if high quality. Two studies used alprazolam, one study used diazepam, two studies used midazolam with morphine, one study used lorazepam, and one study used clorazepare.

• Of the 200 participants analyzed, 52 had COPD and 148 had cancer.
• All studies were small, ranging from 5-29 participants, except for two studies (Navigante, 2006 with 101 participants and Naviagante, unpublished with 63 participants).
• Three studies had power calculations, but only two reached adequate numbers for power.
• Three studies included patients with cancer.
• Most stuides used the VAS or NRS scale for assessing breathlessness.
• Most studies measured breathlessness at rest, and three studies measured breathlessness with exercise.
• Anxiety was measured in two studies, depression in two studies, walking tests in three studies, and benzodiazepine adverse effects or attrition in all studies.

Only six of the seven studies were included in meta-analysis, and the other was included in general data. Other measured outcomes of the studies included anxiety, depression, adverse effects of benzodiazepines, functional exercise capacity, quality of life, and study attrition. Overall, the analysis (four studies) and meta-analysis (three studies) with 52/47 participants showed no significant effect of three different benzodiazepines in relief of breathlessness in patients with advanced COPD. The three studies of patients with cancer included in analysis included two with morphine control and one with placebo control. One morphine-controlled study showed no significant effect of midazolam as compared to morphine, and one showed a slightly better improvement of breathlessness in patients receiving midazolam. Although overall no effect of benzodiazepines could be demonstrated, this meta-analysis should be interpreted with caution given the hetereogeneity and design differences of these studies. Pooling of placebo-controlled and morphine-controlled data showed no significant effect of benzodiazepines on breathlessness at rest. Four of seven studies measured anxiety with different scales, and none demonstrated anxiety alterations from baseline or as compared to a control group. Three studies examined depression and did not show differences between the intervention and placebo groups.

When considering all studies, no enhanced effectiveness for management of breathlessness was noted with use of benzodiazepines either at rest or with breakthrough dyspnea for patients with COPD or cancer. When excluded studies with lesser research strength of evidence were compared with stronger evidence, these conclusions were affirmed.

Although overall no effect of benzodiazepines could be demonstrated, this meta-analysis should be interpreted with caution given the hetereogeneity and design differences of these studies.

The authors recommend larger studies with more participants, inclusion of more patients with other known etiologies of breathlessness (e.g., CHF, MND), treatment of breakthrough dyspnea, and use of benzodiazepines in patients with breathlessness during panic attacks.

• FINAL NUMBER STUDIES INCLUDED = 13 
• TOTAL PATIENTS INCLUDED IN REVIEW = 88
• SAMPLE RANGE ACROSS STUDIES: 1–35 patients
• KEY SAMPLE CHARACTERISTICS: Two randomized, controlled trials ([RCTs] one RCT only had a sample size of two patients), two nonrandomized before–after studies, and nine case studies; majority of patients were inpatients with lung cancer or chronic obstructive pulmonary disease and constant or episodic (four studies) breathlessness receiving fentanyl (oral, IV, or transdermal) 

PHASE OF CARE: Multiple phases of care 

APPLICATIONS: Elder care, palliative care

All studies reported the successful relief of breathlessness after fentanyl application, but the only RCT (N = 12) failed to demonstrate a statistically significant difference when fentanyl was compared to a placebo. The nature and incidence of fentanyl-related adverse events such as somnolence and dizziness were comparable to other opioids, and no respiratory depression was observed.

There is no conclusive evidence about use of fentanyl to relieve breathlessness because of the lack of sufficiently powered, controlled studies. The descriptive and quasi-experimental studies included in this review show promising results for the use of fentanyl for breathlessness. All studies reported an improvement in breathlessness, but a fully powered RCT to conclusively determine the effect of fentanyl on breathlessness is warranted.

The descriptive and quasi-experimental studies included were at-risk for bias because of the lack of a control. The doses of fentanyl varied considerably, which limits conclusions about the appropriate dose. Missing data included the time of response after the administration of fentanyl, which is important when comparing fentanyl to other opioids.

The clinical experience of fentanyl for breathlessness is promising. Considering emerging data, which suggests that breathless episodes often last less than 10 minutes, the current standard (immediate-release morphine) has a longer onset of action than the symptom episode duration. Fentanyl's time of onset still is unknown, but it may better match the characteristics of breathlessness episodes, which is clinically important.

To analyze the effect of different protocols of laser phototherapy (LPT) on the grade of mucositis and the degree of pain in patients undergoing radiation therapy

Patients were divided into three groups. One group was treated with low-dose laser therapy three times per week. Group 2 received combined high and low powered lasers used three times per week. The third group received low-level laser therapy (LLLT) once weekly. Oral mucositis and pain were assessed at the first visit and at each LPT visit.

• The study consisted of 39 patients whose ages ranged from 15–79 years.
• The sample was 38% female and 62% male.
• Patients had been diagnosed with head and neck cancer and were receiving radiation therapy, chemotherapy, or both.

This was a single-site study conducted at the Cancer Hospital of Mato-Grasso, Brazil.

This was a prospective clinical trial.

• A visual analog scale (VAS) was used to measure severity of oral pain.
• The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) for radiation-induced oral mucositis scale was used.

No differences were found between groups in overall grades of mucositis. Pain increased in the patients that received LPT weekly (p = 0.01), while pain severity remained about the same over time in other groups. Patients who received combined high and low power laser took significantly more time to heal (p = 0.04).

LPT using low power laser alone or in combination with high powered lasers when applied three times weekly maintained the mucositis grades at levels I and II and prevented increased pain. Combination low and high power laser treatment was associated with a longer time to healing mucositis.

• The sample size was small with fewer than 100 patients.
• No control group was included.

This study provides an initial look at differences in outcomes with LPT based on different dosages and types of LPT treatment. Further research in this area, as well as studies looking at timing differences in the phase of care, are necessary to determine the most effective use of this treatment modality.

To investigate the effects of Bryophyllum pinnatum (B pinnatum) on sleep quality in patients with cancer

B pinnatum is an herbal medicine previously found to improve sleep quality in pregnant women. Patients were included in the review of records if they were diagnosed with cancer and had been prescribed B pinnatum 50% (350 mg tablets at varying dosages) for at least 21 consecutive days for sleep-wake disturbance. The tablets contained 50% leaf-pressed juice on lactose, and dosages ranged from three to eight tablets per day. Study assessments were done at baseline and on day 22.

• N = 20
• MEAN AGE = 61 years (SD = 10.4 years)
• MALES: 15%, FEMALES: 85%
• KEY DISEASE CHARACTERISTICS: Various cancer types with the majority being breast cancer; average time since diagnosis was five years
• OTHER KEY SAMPLE CHARACTERISTICS: The majority of women were postmenopausal, and the duration of sleep problems was an average of two years. 65% of participants received previous therapy with mistletoe.

• SITE: Single-site  
• SETTING TYPE: Outpatient    
• LOCATION: Switzerland

• PHASE OF CARE: Late effects and survivorship
• APPLICATIONS: Palliative care

Retrospective, observational study

• Pittsburgh Sleep Quality Index (PSQI)

During treatment with B pinnatum, sleep quality improved from a mean PSQI score of 12.2 (SD = 3.62) to 9.1 (SD = 3.61) (p = 0.002). Improvement was seen in sleep latency and habitual sleep efficiency (p < 0.03). Patients receiving B pinnatum took fewer sleep medications. In most cases, patients took two tablets twice daily. There were very few minor side effects, and no severe adverse reactions were reported. One patient reported an improvement in hot flashes.

B pinnatum may be helpful in the management of sleep disturbances in patients with cancer.

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

The findings of this study suggest that B pinnatum may be helpful for patients with cancer who have insomnia; however, evidence is weak because of study design limitations and the small sample size. The positive findings seen here suggest that additional research on the use of B pinnatum is warranted.