Primary antifungal prophylaxis with fluconazole, itraconazole, or an amphotericin B product were evaluated in neutropenic patients with hematologic malignancies.

Not described.

Thirty-eight randomized, controlled trials of primary antifungal prophylaxis and 13 historically controlled or uncontrolled trials of primary antifungal prophylaxis.

More than 9,000 neutropenic patients with hematologic malignancies.

Recommended antifungal prophylactic regimens for patients with hematologic malignancies and their level of evidence:

Conventional chemotherapy

• Fluconazole 50–400 mg every day by mouth (CI)
• Itraconazole oral suspension 5 mg/kg every day (BI)
• Amphotericin B desoxycholate 1.0 mg/kg every 48 hour by IV (CII)
• Amphotericin B desoxycholate 20 mg inhalation (CI)

Allogeneic transplantation

• Fluconazole 400 mg every day by mouth (AI)
• Fluconazole 50–200 mg every day by mouth (CI)
• Liposomal amphotericin B 1.0 mg/kg every day by IV (CI)

To examine peer-reviewed literature evaluating the surgical treatment of lymphedema

• Databases searched were MEDLINE, CINAHL, Cochrane Library, PapersFirst, ProceedingsFirst, Worldcat, PEDro, National Guidelines Clearing House, ACP Journal Club and Dare (2004–2010).
• Search keywords were not stated.
• Studies were included in the review if they were related to lymphedema and involved eight or more patients.
• Studies were excluded if they were not refereed articles.

• The total number of references retrieved was not stated.
• Studies were evaluated using an adapted checklist using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) scale. 

• The final number of studies was 19.
• Sample range across all studies was 9–1,800, with larger samples in retrospective descriptive studies
• Key sample characteristics were not provided.

Findings were grouped according to the type of procedure: excisional (8 studies, 4 involving liposuction), lymphatic reconstruction (8 studies of  lymphatic venous anastomosis [LVA]), and tissue transfer (4 studies involving lymph node transfer, stromal cell transplant, lymphatic tissue transplant, and lymph node transplant). Reduction in lymphedema volume was greatest after excisional procedures (91.1%). Lymphatic reconstruction was associated with 54.9% reduction, and tissue transfer with 47.6% reduction. Overall, surgical procedures did not appear to eliminate the need for compression therapy. Follow-up duration and methods of lymphedema measurement varied substantially across studies. Quality scores for studies ranged from 2–12 across all procedure types and tended to vary considerably within surgery type grouping as well. Studies were done in both upper and lower extremities, though most LVAs were done in lower extremities. The majority of studies did not comment on postoperative complications. Authors noted that a growing body of evidence supports the use of surgical procedures for prevention of lymphedema.

Evidence related to the effectiveness of various surgical procedures for lymphedema is somewhat limited, and the ability to generalize findings also is limited given the wide variation in study quality, sample sizes, measurement methods, and lack of long-term follow up information. Surgical procedures have not been shown to eliminate the need for ongoing conventional therapies for lymphedema.

This review is limited by a lack of full information on search results, with consort type of flow charting, lack of information about disease types, and patient characteristics.

Results of surgical procedures appear to show some promise for reducing lymphedema volumes. However, current evidence is too limited to generalize and more information is needed regarding postoperative complications or long-term results. Surgical intervention has not been shown to eliminate the need for ongoing conservative and conventional interventions as well.

To compare the effects of high and low weight load resistance exercise on lymphedema severity, symptoms, physical function and quality of life in women with breast cancer

Patients were randomly assigned to one of three groups: high load resistance exercise, low load resistance exercise, or a wait list usual care control group. Both exercise programs involved six exercises targeting the major upper body muscle groups. Intensity was moderate to high on the Borg scale. Sessions were done for 60 minutes once per week for three months and were supervised by an exercise physiologist. Patients chose whether or not to wear compression garments during exercise. Patients were instructed to maintain usual self care and activity.  Outcome measures were obtained at baseline and at three months post intervention.

• The study consisted of 60 patients with a mean age of 57 years.
• The sample was 100% female.
• Time since diagnosis ranged from an average of 5.9 years in the high load group to 9.5 years in control patients.
• The majority of patients (97%) had surgery. Overall, a mean of 15.4 lymph nodes were removed.
• The amount of patients who had received radiotherapy was 85%.
• Most patients had grade I or II lymphedema.

This was a single-site, outpatient study conducted in Australia.

This study has clinical applicability for late effects and survivorship.

This was a single-blind, randomized controlled trial.

The following measurement tools were used.

• Bioimpedance
• Dual energy x-ray absorption measurement
• Arm circumference measurement
• Disability of the arm, shoulder, and hand questionnaire (DASH)
• Brief Pain Inventory (modified)
• Functional Assessment of Chronic Illness-Breast cancer (FACT-B)
• European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) questionnaire
• Short Form Health Survey (SF-36)
• Hand dynamometry for grip strength
• Maximal muscle endurance testing

No lymphedema exacerbations or adverse events were reported. No differences across groups were found in change of swelling outcome measures or symptom severity. A nonsignificant trend toward greater improvement in grip strength was noted. Significant improvement was reported in upper body muscle endurance in both exercise groups compared to controls (p=.001). Physical functioning measurement showed significant improvement in both exercise groups compared to controls, in which the measure showed decline (p = 0.04). A fourth of the patients used compression garments during exercise.

Findings showed that women with breast cancer-related lymphedema can safely lift weight at both low and high relative load. Moderate- to high-intensity exercise may be beneficial to improve physical functioning.

• The sample size was small with fewer than 100 patients.
• A risk of bias exists because the study did not have an appropriate attentional control condition.

This study adds to the growing body of evidence that weight lifting and high or low load resistance exercise can be safe for patients with lymphedema. Of note, the evidence in this area includes only supervised weight lifting.

To examine the acute impact of upper-body resistance exercise on lymphedema symptoms in women with breast cancer-related lymphedema

After four sessions of exercise to familiarize patients with exercise routines over a two-week period, patients were instructed to perform five upper-body resistance exercises. Both low- and high-load exercises involved moderate to high intensity. Patients were to complete two sets of all exercises. High-load sessions involved lifting as much weight as possible for 6-8 repetitions. Low-load exercises involved lifting as much weight as possible for 15–20 repetitions. Load was prescribed and progressed individually. Patients were randomly assigned to which load condition was performed first, and then, after a 10–12 day washout period, crossed over to the other load condition. An exercise physiologist supervised all sessions.  Participants chose whether or not to wear compression garments during exercise. Study outcome measures were obtained prior to exercise, immediately after exercise, and at 24 and 72 hours after exercise. Patients were instructed to maintain usual self-care management and physical activities.

• The study reported on 17 patients.
• Mean age was 61.2 with a range of 52.1–70.3.
• The sample was 100% female.
• All patients had breast cancer-related clinical diagnosis of lymphedema. All had surgical treatment with an average of removal of 13 lymph nodes. Most of patients (88%) had received previous radiation therapy.
• Participants were generally overweight or obese.
• Average time since diagnosis was 5.4 years.
• Average arm circumference difference was 18.7% (SD = 11.9).

This was a single-site, outpatient study conducted in Australia.

This study has clinical applicability for late effects and survivorship.

The study used a randomized crossover design.

The following tools were used.

• Impedance spectorsopy
• Dual energy X-ray absorption
• Arm circumference measurements
• Brief Pain Inventory
• Visual analog scale (VAS) for pain, heaviness, and tightness

No significant differences were observed in lymphedema measures of affected arms across most time points in the study, and no differences were found between high- and low-load conditions. No significant changes were found in arm volume or circumference, and no differences were found between load conditions. No significant differences were found in severity of pain, heaviness, or tightness across all study time points.

Neither low- nor heavy-load resistance upper-body exercises had any acute impact on lymphedema symptoms.

• The sampel size was small with fewer than 30 patients.
• Use of compression garments during exercise varied. Other activities were not described. 
• This study only looked at short-term, acute effects; longer-term effects with ongoing resistance exercise are not known.

Findings showed that prescribed and supervised moderate- to high-intensity, upper-body exercise with low and high loads did not acutely exacerbate lymphedema. Traditional conservative guidelines have recommended avoidance of excessive upper-body exercise with resistance or weight to avoid exacerbation of lymphedema. Findings from this study suggest this may not be necessary. Of note, however, is that exercise done here was supervised and only examined immediate acute effects.  Long-term chronic response needs to be examined.

To determine if supervised exercise minimizes toxicity in patients receiving androgen deprivation therapy (ADT)

Patients were randomly assigned to usual care or a three-month exercise program. The program included aerobic and resistance exercise sessions two times per week in various exercise clinics. Sessions were conducted in groups and supervised by exercise physiologists. Sessions were 60 minutes in length involving moderate- to high-intensity aerobics. Study measures were obtained at baseline and after three months.

• N = 63
• MEAN AGE = 68.4 years
• MALES: 100%         
• KEY DISEASE CHARACTERISTICS: Prostate cancer receiving ADT

• SITE:  Multi-site
• SETTING TYPE:  Outpatient  
• LOCATION:  Australia

Randomized controlled trial

• Body composition measures
• 400 m walk test
• Static balance test
• Activities Specific Balance Confidence scale for falls self efficacy
• SF-36
• EORTC-QLQ-PR25
• FACIT Fatigue scale
• Brief Symptom Inventory (BSI) for anxiety and depression

Exercise participants attendance at sessions ranged from 14-24 sessions out of a possible 24 sessions. There was a non-significant trend for those in the exercise group to have less loss of lean body mass. Fatigue scores (SF-36) remained stable in the exercise group, whereas fatigue increased in the control group (p = 0.045). Depression remained stable in the exercise group and increased in the control group (p = 0.054). There was no difference between groups in anxiety.

Participation in a group-based, supervised, moderate- to high-intensity exercise program was associated with lower fatigue and improvement in some functional domains after three months when compared to usual care. No significant impact was noted on anxiety or depression.

• Small sample (less than 100)
• Risk of bias (no blinding)
• Measurement validity/reliability questionable
• Subject withdrawals 10% or greater
• Other limitations/explanation:  More patients in usual care withdrew and there is no clear ITT analysis. BSI measures were only for anxiety and depression.

The findings add to the body of evidence that exercise is beneficial for patients with cancer to reduce fatigue associated with cancer and cancer treatment.

To determine if voriconazole is a safe and effective antifungal prophylactic agent to be used for stem cell transplant (SCT) recipients.

All patients in the study received voriconazole prophylactically in one of two ways: either intravenously with maintenance doses of 4 mg/kg every 12 hours after receiving a loading dose of 6 mg/kg every 12 hours for two doses only or 200 mg of oral voriconazole every 12 hours after receiving a loading dose of 400 mg every 12 hours for two doses only. Loading doses were administered 48 hours after completion of conditioning chemotherapy for SCT and at least three days prior to SCT. Prophylactic voriconazole was to be continued up to 100 days posttransplant and could be continued for other specific medical conditions warranting additional coverage. The efficacy of prophylactic voriconazole was assessed during screening, baseline, and regular intervals during the study, which included posttransplant follow-ups.

• Forty-five adult patients (62% male, 38% female) were included.
• Age ranged from 22 to 72 years.
• Key disease characteristics were patients undergoing allogeneic SCT that included a conditioning regimen for any variety of hematological diseases.
• Patients had a proven or suspected history of invasive fungal infection in the prior 12 months.
   

• Multi-site  
• The study was conducted at 17 European healthcare sites, including locations in Belgium, France, Germany, Portugal, Spain, Sweden, Switzerland, and the United Kingdom.

Patients were undergoing the active treatment phase of care.

This study was a phase III, prospective, open-label, multicenter trial.

• Proportion of patients who developed a proven or probable invasive fungal infection between starting prophylaxis and the 12-month posttransplant follow-up evaluation 
• Proportion of patients who developed a proven or probable invasive fungal infection between the start of prophylaxis and the end of prophylaxis or the 6-month posttransplant follow-up evaluation 
• Time for a proven or probable invasive fungal infection to occur after initiation of prophylaxis
• Proportion of patients on prophylaxis who were free from a proven or probable invasive fungal infection 12 months posttransplant

Three of 42 patients who were given prophylactic voriconazole developed invasive fungal infections within six months of transplant (two were proven to be reoccurrences of old fungal infections and one was a probable new case).

In regard to the safety of voriconazole, the most common adverse events related to treatment included

• Hepatotoxicity in four patients
• Headache in three patients
• Visual hallucinations in three patients.

Other adverse events that were reported in the population were

• Mucosal inflammation
• Diarrhea
• Vomiting
• Pyrexia
• Headache
• Graft-versus-host disease
• Hypertension
• Febrile neutropenia
• Thrombocytopenia
• Abdominal pain
• Anemia
• Insomnia
• Nausea
• Rash.

Strictly based on this study, it appears as though voriconazole is safe and effective in the prevention of newly developing or reoccurring invasive fungal infection in patients undergoing SCT.

Small sample (<100)

Adherence to antifungal prophylactic regimens in SCT recipients is imperative to them achieving survival without developing invasive fungal disease. Study findings suggest that prophylaxis with antifungals for 100 days post SCT appears safe and may be of benefit in the prevention of invasive fungal infections in this population.

To review the efficacy and safety of modafinil for the treatment of cancer-related fatigue (CRF).

Databases searched were MEDLINE, International Pharmaceutical Abstracts, and Google Scholar (1950–November 2008).

Search keywords were modafinil, cancer, and fatigue.

Studies were included in the review if they were written in English.

No exclusion criteria were specified.

Articles were identified using the keywords, and publications were analyzed for significance. References from the identified articles were also reviewed for pertinence.

• Four studies were reviewed in detail, comprising a total of 805 patients.
• Two studies reported patients with breast cancer, one reported patients with cerebral tumors, and one reported that the diagnoses were unknown.

• One open-label trial demonstrated the effectiveness of 200 mg of modafinil daily, given for one month, in reducing fatigue and improving patient-reported global effectiveness.  Fifty-one percent of participants reported improvement in sleep and less daytime drowsiness.
• One open-label trial in women with breast cancer reported that 90% of participants reported improvement in fatigue with 200 mg of modafinil daily for one month.
• One randomized, dose-controlled trial was conducted in patients with cerebral tumors who had neurobehavioral dysfunction and/or fatigue posttreatment. Improvements in fatigue scores were seen eight weeks after baseline. Adverse effects included headache, insomnia, dizziness, dry mouth, depressed consciousness, and nausea.  The authors concluded that modafinil was effective in improving fatigue, with a low incidence of adverse reactions.
• One phase III, randomized, placebo-controlled, double-blind trial was conducted in 642 patients with cancer who reported fatigue while receiving chemotherapy. Those receiving modafinil had a significant decrease in fatigue levels compared with patients receiving placebo.

This review discussed the strengths and weaknesses of four relevant studies. The authors concluded that the preliminary findings demonstrated the benefits of modafinil use with minimal toxicity and that modafinil can be considered a treatment option for patients with CRF. Additional long-term placebo-controlled trials are needed in this area.

• Some of the evidence reviewed in this study was taken only from abstracts.
• The literature evaluated and selected were not clearly outlined.
•  No inclusion and exclusion criteria were specified other than language.

Databases searched were MEDLINE, CANCERLIT, Cochrane Central Register of Controlled Trials (CENTRAL), Dissertation Abstracts, PsycINFO, SPORTDiscus, HealthSTAR, Clinical Evidence, and CINAHL through 2002. The authors also searched the National Institutes of Health (NIH) database of funded studies from 1986 through 2002 and conducted hand searches of selected journals.

Thirty primary study reports (24 in the published literature and the remainder in unpublished dissertations and presentation papers) contained sufficient information to be included in the quantitative analysis. Thirteen studies were designed as single-group pre/post research; the remainder compared at least two groups of patients. Only one two-group study did not randomly assign patients to study arms. Comparisons groups were most often described as having received usual care. Outcomes were quality of life, physical functional ability, fatigue, symptoms other than fatigue, mood, body composition, and exercise behavior. 

Twenty-one of 30 studies tested supervised exercise interventions rather than home-based exercise. Supervised exercise was most often scheduled three times per week, and in 16 of the 21 studies of supervised exercise, the exercise program lasted longer than 10 weeks. Supervised exercise generally included aerobic activity (e.g., walking and cycling) and less often included resistance or flexibility exercise. Mixed types of aerobic exercise were used in several studies. The exercise intervention in most studies was of moderate intensity to achieve approximately 30% to 70% of maximum oxygen consumption.

• In 13 studies, the sample was comprised exclusively of women with breast cancer, and, in five other studies, women with breast cancer comprised more than half of the patients.
• Patients with other cancers were included less commonly, and few studies included patients with more advanced cancer, older patients, or minority patients.
• Sample sizes ranged from five to 155 patients.
• Age ranged from 31 to 71 years.

The effect size estimate for the outcome of fatigue in the two-group comparisons was small and not statistically significant (standardized mean difference [SMD] = 0.11). However, the effect size estimate for the outcome of fatigue in the single group comparisons of pre- and posttest was larger (SMD = 0.27) and remained statistically significant under both the assumption that there was no correlation between participants’ pre- and posttest scores and that pre- and posttest scores were strongly correlated (r = 0.80).

Effect sizes among only control group participants were very small but negative; this observation may lend some support to the validity of meta-analytic findings from single-group designs.

The small, nonsignificant effect size for exercise on the outcome of fatigue may have occurred due to heterogeneity in the exercise characteristics and intervention dose, varied samples, diverse measures of outcomes, and variable outcome assessment timing.

• Week 1: Breathing control and assessment
• Week 2: Review, relaxation, and anxiety management techniques
• Week 3: Review, energy conservation, goal setting, and lifestyle adaptation
• Week 4: Review and assessment
• Week 8: Review and re-assessment

This program was conducted for four years. The study was based on prior research conducted by Corner et al. (1996) and Bredin et al. (1999), also reported elsewhere in the table.

The study reported on a sample of 169 patients. All patients reported breathlessness as a symptom. Patients were referred from three sources to a physiotherapist-led breathlessness program for patients with intrathoracic malignancy. The three sources included an outpatient lung cancer clinic, the inpatient unit, or the community where they were referred by a specialist palliative care team. A screening questionnaire was used to identify the cause of breathlessness. If the cause was reversible, the patient received appropriate care. Only 14 of 169 completed the entire program.

The following tools were used at one, four, and eight weeks.

• Chronic Respiratory Disease Questionnaire
• Number counting
• VAS of breathlessness at worst and at best and distress related to breathlessness

Only 14 of 169 completed the entire program. The following are characteristics of the 14 who completed the program.

• Referred from the outpatient setting
• Had radical treatment
• Etiology of the breathlessness was either treatment-related or because of other causes but not from progression of disease.
• Median survival was 630 days

Of the 14 who completed the program, pre- and post-assessment scores showed modest improvement, but it was not statistically significant. The majority did not complete the program. One hundred thirty-one patients (85%) were seen at least once and anecdotally had subjective benefit. Of those who did not complete the program, some had progressive disease and were too ill to participate or died before being seen. Median survival was 95 days.

Patients with intra-thoracic cancer may benefit from a formal nonpharmacologic program. Patients who are frail and/or on palliative care may need a more flexible program.

One hundred fifty-five patients did not complete the program because of progressive disease and associated shorter survival. The small subset who did complete the program did not show significant improvement in dyspnea measures. Dropout rate was 82% versus 41% in the Corner study and 43% in the the Bredin study. Interventions in the three studies were similar. The difference in dropout rate for this study compared to Bredin and Corner’s studies is explained by the fact that the patients in this study were older and were recruited from the totality of patients with lung cancer presenting to the cancer center.

To assess current literature regarding the overall effectiveness of opioid therapy in cancer pain management

• Databases searched were PubMed, EMBASE, the Cochrane Collaboration, and ClinicalTrials.gov for the period 1996–June 2010. Investigators also searched bibliographies manually.
• Authors did not supply search keywords.
• Studies were included in the review if they were observational studies involving adults older than 18 years old who were being treated with any opiod for cancer-related pain.
• Authors did not supply exclusion criteria.

• The initial search retrieved 1,916 references. Investigators identified 53 observational studies for review. Of those 53, investigators analyzed 18.
• Investigators assessed the quality and validity of studies by using the Agency for Healthcare Research and Quality (AHRQ) criteria for assessing the quality of observational studies. Investigators graded studies by using the five levels of evidence developed by the United States Preventive Services Task Force.

• Seven studies met the criteria for methodology quality by achieving an evidence synthesis score equal to or greater than 50 (out of a possible score of 100) in regard to AHRQ criteria.
• The range of sample sizes was 55–589, with a total number of samples across studies of 1,619.
• All subjects had at least moderate to severe pain.

Studies involved a variety of opioid types and varied in terms of duration of follow-up, as the summaries that follow show.

• Transdermal opioid-delivery systems: Two large studies showed that transdermal opioids were effective and well tolerated. Authors conclude that transdermal fentanyl-buprenorphine shows promise. 
• Sustained-release oral opioids: Different types of formulations are available, and authors state that evidence shows them to be effective and safe. However, the review included only one study of sustained-release oral opiods, and data from this study showed poorer results at the end point than at the baseline.
• Breakthrough pain: Two studies showed oral preparations of fentanyl to be effective and well tolerated.
• Multimodal analgesic therapy: In one study, an nonsterioidal anti-inflammatory drug (NSAID) was added to a continuous morphine infusion. The addition of the NSAID improved analgesia.
• Intrathecal opioid administration: In one study, as a last resort, patients received an opioid via intrathecal route. Results showed long-term improvement over four years or until death. This study had a low AHRQ score.

This review identified evidence of moderate strength, from observational studies, regarding the effectiveness of opioids as a treatment for cancer pain. Authors strongly recommend opioids, by various routes, for the management of cancer-related pain.

Authors note that further evidence is needed in the areas of dose response and treatment for breakthrough pain.

Opioids by various routes remain the mainstay of cancer-pain management. Some evidence suggests that the addition of an NSAID can improve results and that use of fentanyl formulated for rapid onset and short duration is effective and well tolerated for breakthrough pain. Additional research in breakthrough pain is needed.