PURPOSE: To provide healthcare providers with evidence-based recommendations on the use of primary antifungal prophylaxis in children with cancer and undergoing hematopoietic stem cell transplantation (HSCT)

TYPES OF PATIENTS ADDRESSED: Allogeneic and autologous HSCT recipients, children with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), and pediatric patients with anticipated neutropenia for longer than seven days

RESOURCE TYPE: Evidence-based guideline 

PROCESS OF DEVELOPMENT: Literature search was done, and included studies were evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation system. Recommendations were established by a panel discussion. Guidelines then were externally reviewed by another interprofessional expert panel and provided to Canadian pediatric tertiary hospitals for stakeholder review.

DATABASES USED: MEDLINE, EMBASE, Cochrane Collaboration, proceedings of the American Society of Clinical Oncology and American Society of Hematology    

KEYWORDS: Not stated

INCLUSION CRITERIA: RCTs involving patients of any age with cancer or undergoing HSCT that compared antifungal agents with another antifungal agent, placebo, or no prophylaxis; no language exclusions

EXCLUSION CRITERIA: Trials involving nonsystemic antifungal treatment

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

Initially, 7,869 references were retrieved and screened. A final set of 47 studies were included.

The following are strong recommendations.

• Children one month to 19 years undergoing allogeneic HSCT should have fluconazole daily from the start of conditioning until engraftment (high-quality evidence).
• When fluconazole is contraindicated, echinocandin should be used as an alternative (moderate-quality evidence).
• Children undergoing autologous HSCT with anticipated neutropenia for longer than seven days should receive fluconazole daily from the start of conditioning until engraftment (moderate-quality evidence).
• Children with AML or MDS should receive fluconazole daily during chemotherapy-associated neutropenia (moderate-quality evidence).

Additional weak recommendations also are outlined in the guidelines.

Although these guidelines are aimed at pediatric patients, 17 studies included did not include children in the sample.

These evidence-based guidelines clearly recommend primary antifungal prophylaxis in at-risk children. Specific dosages recommended are identified in this reference.

To assess the likelihood of uncontrolled chemotherapy-induced nausea and vomiting (CINV) events following antiemetic prophylaxis with the 5-HT₃ receptor antagonist (RA) palonosetron plus aprepitant or fosaprepitant and dexamethasone versus any of the other 5-HT₃ RAs (granisetron, dolesetron, ondansetron) plus aprepitant or fosaprepitant and dexamethasone among single-day, highly emetogneic chemotherapy (HEC) cycles

This was a retrospective analysis of a healthcare claims database from January 2006 through June 2010 using data from International Classification of Diseases book 9 (ICD-9), Current Procedural Terminology (CPT), and pharmacy claims. Investigators evaluated two cohorts. The palonosetron cohort consisted of patients initiating antiemetic prophylaxis with palonosetron plus aprepitant or fosaprepitant and dexamethasone. The \"other 5-HT₃ cohort\" consisted of patients receiving any other 5-HT₃ RA plus aprepitant or fosaprepitant and dexamethasone.

• In all, 4,552 patients met the selection criteria; 3,574 for the palonosetron cohort and 978 for the other 5-HT₃ cohort. Mean age was 53 years.
• The sample was 23% male and 77% female.
• To be included in the study, patients could be diagnosed with any cancer but must have received treatment with a single-day, HEC regimen (defined as chemotherapy administrations with at least a 5-day gap between two consecutive administrations). Breast cancer was the predominant malignancy (n = 2,313, approximately 50%) followed by “multiple cancers” (n = 1,282, approximately 30%). All HEC-treated patients were required to have received a prophylactic antiemetic regimen that included a 5-HT₃ plus dexamethasone plus fosaprepitant or aprepitant regimen.
• In the database, the payer-type distribution was 80% commercial, 15% other, 3% Medicaid, and 1.7% Medicare Risk. All patients included in the database were eligible for medical and pharmacy benefits.

Patients were undergoing the active treatment phase of care.

This was a retrospective data analysis.

CINV was defined as at least one of the following during days 2–5 post chemotherapy: a diagnosis of nausea or vomiting (ICD-9 code); hydration procedure (CPT code); rescue medication use of any of the following: dexamethasone, diphenhydramine, olanzapine, promethazine, haloperidol, prochlorperazine, lorazepam, or metoclopramide; or antiemetic administration of palonosetron, ondansetron, granisetron, dolasetron and fosaprepitant/aprepitant by oral or IV routes.

A total of 8,018 cycles for the palonosetron cohort and 1,926 cycles for the other 5-HT₃-RA cohort were analyzed. Single-day HEC cycles received by the palonosetron cohort had a significantly lower unadjusted risk of an uncontrolled CINV event with a 17% lower risk for palonosetron-administered cycles versus 21% risk for other 5-HT₃ RAs (p = 0.0010). Results in the breast cancer and multiple cancer subgroups were consistent with those for the overall population.

This study suggests that all 5-HT₃ RAs may not be equivalent in preventing delayed CINV for patients receiving single-day HEC; however, the study design limits the strength of the evidence.  

• No appropriate control group was included.
• The study is limited in its design because retrospective database analysis does not allow for assessment of potential differences between cohorts in terms of patient history of CINV-predictive factors such as alcohol use and motion sickness.
• The study does not evaluate multiple-day regimens of HEC. 
• The data were taken from claims with the assumption that patients billed for antiemetic medications, prescriptions, or hydration experienced an “uncontrolled CINV event” and patients that did not have this same associated claim data did not have an uncontrolled CINV event. However, this does not reflect the practice styles of prescribers or patient reports. Some prescribers routinely give patients oral rescue antiemetic prescriptions and have them filled prior to the start of treatment. Additionally, patients may have had unreported or untreated CINV or may have taken prophylactic treatment without actually experiencing uncontrolled CINV. 
   

Nurses may want to consider substituting palonosetron as 5-HT₃ in antiemetic regimen for single day HEC.

To compare the incidence of chemotherapy-induced nausea and vomiting (CINV) among patients with cancer receiving low emetogenic chemotherapy (LEC) when given an antiemetic prophylaxis treatment of palonosetron versus other 5-HT₃ receptor antagonists. 

Using the Premier Perspective database, medical records were reviewed to identify patients with cancer who began LEC between the dates of 4/1/2007 and 3/31/2009. The medical records were then examined to determine the type of prophylactic antiemetic therapy prescribed and the patients were divided into two groups: patients prescribed palonosetron and patients prescribed other 5-HT₃ receptor antagonists (ondansetron, granisetron, or dolasetron). For the time period encompassing either the first eight cycles of chemotherapy or the first six months of treatment (whichever occurred first), the medical records were examined to determine the rate of acute and delayed CINV events, CINV-related rescue medications used, and CINV-related admissions that occurred during the study follow-up period. Acute events were defined as occurring on day one of a chemotherapy cycle, and delayed events were defined as occurring on days two through seven of a chemotherapy cycle. Outcomes were compared for those patients who were prescribed palonosetron as antiemetic prophylaxis versus those who were prescribed other 5-HT₃ receptor antagonists as antiemetic prophylaxis.

A total of 2,439 patients were included in the study.

Mean age was 66.3 years (SD = 12.6 years).

The sample was 54.2% male and 45.8% female.

Cancer diagnoses were lung, gynecological, head and neck, noncolon gastrointestinal, breast, urinary tract, and other or unknown.

All patients were beginning LEC and receiving palonosetron or other 5-HT₃ receptor antagonists as antiemetic prophylaxis.

This was a multisite, inpatient and outpatient review of data from more than 600 hospitals from across the United States.

Patients were undergoing the active treatment phase of care.

This was a nonexperimental, retrospective, longitudinal, observational study.

• Medical records were reviewed to identify any documented events of emesis, nausea, or volume depletion that occurred.
• Medical records were reviewed to identify any documented rescue medications used to treat established nausea or emesis.
• Medical records were reviewed to identify any documented hospitalizations due to nausea, emesis, volume depletion, dehydration, or hypovolemia.

Patients receiving palonosetron experienced significantly fewer CINV events (nausea, vomiting, volume depletion) (p < 0.0001), used significantly fewer antiemetic rescue medications (p < 0.0001), and were emergently/urgently admitted to the hospital significantly fewer times (p < 0.0001) than patients taking other 5-HT₃ antagonists.

Among patients with cancer receiving LEC, palonosetron may offer more relief from CINV compared to that offered by older-generation 5-HT₃ antagonists.

This was a retrospective study that compared palonosetron against a pool of other 5-HT₃ antagonists, with no random assignment to antiemetic medication. This makes it difficult to attribute the study results to the effects of the target “intervention” (palonosetron) and not to other factors.

Palonosetron is a newer 5-HT₃ antagonist with different receptor-binding characteristics and a longer half-life than older-generation 5-HT₃ antagonists. It may offer more relief from the effects of CINV compared to standard prophylactic emetic therapy. However, one important issue that was noted was that, with LEC, delayed nausea and vomiting was more of an issue than acute. Current guidelines suggest antiemetics that address only nausea and vomiting that occur in the acute phase. Palonosetron could replace older generation 5-HT₃ antagonists as standard prophylactic antiemetic therapy, but more research is needed.

To determine the safety and efficacy of palonosetron versus older 5-HT3 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving ​moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC)

• Acute phase = 0–24 hours after chemotherapy administration
• Delayed phase = > 24–120 hours after chemotherapy administration
• Overall phase = 0–120 hours after chemotherapy administration

• N = 2,962  
• MEAN AGE = 55 years
• MALES: 36%, FEMALES: 64%
• KEY DISEASE CHARACTERISTICS: All types of cancer

• SITE: Multi-site    
• SETTING TYPE: Outpatient    
• LOCATION: United States and Japan

• PHASE OF CARE: Active antitumor treatment

• Secondary analysis

• Complete response (CR): No emesis and no rescue medication in acute or delayed phase
• Complete control (CC): No emesis, no rescue medications, and no more than mild nausea during all phases
• Number of emetic episodes
• Number of nausea episodes
• Likert scale to measure nausea
• Adverse events, vital signs, laboratory tests, and ECG findings

CR rates were significantly higher for patients who received palonosetron during the delayed (p < 0.0001) and overall (p < 0.0001) phases. There was a greater likelihood for patients who received palonosetron to achieve a CR in the delayed (OR, 1.62 [1.40–1.88]) and overall (OR, 1.56 [1.34–1.81]) phases. CC rates were significantly higher in patients who received palonosetron in the delayed (p < 0.0001) and overall (p < 0.001) phases. No differences in CR or CC were seen between groups in the acute phase. There was a significant difference in the number of emetic episodes in patients who received palonosetron in the acute (p = 0.007), delayed (p < 0.0001), and overall (p < 0.0001) phases. Significant differences were seen in the severity of nausea in the delayed (p = 0.0002) and overall (p = 0.011) phases.

Palonosetron is more effective at achieving CR and CC for CINV in the delayed and overall phases when compared to older 5-HT3 receptor antagonists. Palonosetron is also more effective at reducing the severity of nausea experienced in the delayed and overall phases after chemotherapy. However, in the acute phase, palonosetron is not more effective at controlling CINV compared to older 5-HT3 receptor antagonists.

• Baseline sample/group differences of import
• Other limitations/explanation: Patients in Japanese study had lower body weights. The majority patients who received HEC were given steroids but some were not; some patients who received MEC received steroids but some did not.

For patients receiving MEC or HEC, the use of palonosetron rather than an older 5-HT3 receptor antagonist is more effective at controlling CINV in the delayed and overall phase after chemotherapy.

To assess rolapitant in combination with a serotonin receptor antagonist and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer after the administration of moderately emetogenic chemotherapy (MEC) or regimens containing an anthracycline and cyclophosphamide

Patients received either one oral dose of 180 mg rolapitant or a placebo 1–2 hours before chemotherapy on day 1. All patients received 2 mg granisetron plus 20 mg dexamethasone approximately 30 minutes prior to chemotherapy. Granisetron (2 mg) was also given once daily on days 2 and 3. Additional medications, such as dexamethasone for taxanes, were administered as needed and according to package instructions. Cycles were a minimum of 14 days, and patients received the same regimen (rolapitant or placebo) for up to five subsequent cycles during the study.

• N = 1,333
• AGE RANGE = 22–86 years (rolapitant group), 22–88 years (control group)
• MEDIAN AGE = 58 years (rolapitant group), 56 years (control group)
• MALES: 20% (rolapitant group), 20% (placebo group); FEMALES: 80% (rolapitant group), 80% (placebo group)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: No specific tumor type was recruited; however, the majority of patients had breast cancer or lung cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria required that patients be older than 18 years, have a Karnofsky score of 60 or better, have a life expectancy of four months or greater, and have adequate bone marrow, liver, and kidney functions. Patients with a history of receiving moderately or highly emetogenic chemotherapy or with a contraindication to any of the study drugs were excluded. Also, patients with histories of alcohol misuse, seizure disorders, or psychiatric conditions were excluded.

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: Data were collected from 170 study sites in 23 countries located in North, Central, and South Americas; Europe; Asia; and Africa.

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

• Global, multicenter, randomized, double-blind, active-controlled, phase-III trial

Efficacy was measured as a complete response (CR) or no emesis or use of rescue medications as reported in a daily patient journal for up to 120 hours post chemotherapy. Responses were stratified into acute (< 24 hours) and delayed (> 24 hours) phases. Also, the Functional Living Index-Emesis (FLIE) survey was used to measure the effect of nausea or vomiting on daily living. The FLIE uses a seven-point visual analog scale (VAS) on nine questions to assess patients on day 6 of cycle 1. Finally, safety variables (e.g., adverse reactions) were assessed and reported.

The findings showed that a significantly greater proportion of patients receiving rolapitant had CRs in the delayed phase than those who received the active control (95% CI [1.2, 2.0], p = 0.0002). No significance was found in the acute phase between patients receiving rolapitant and the control. Adverse events were similar between groups with the most frequent events being fatigue, constipation, and headache. In cycle 1, grade 3–4 neutropenia was 5% in the rolapitant group and 3% in the active control group.

The findings showed that rolapitant in combination with a 5-HT₃ and dexamethasone was well tolerated and showed superiority over active control for the prevention of CINV during the five-day (0–120 hour) at-risk period after the administration of MEC or drug regimens containing an anthracycline.

• Risk of bias (sample characteristics)
• Sample was disproportionately female.
• The authors referred to both a placebo control and an active control—control condition unclear.

Rolapitant in combination with a 5-HT₃ receptor antagonist and dexamethasone was well tolerated by this sample and demonstrated acceptable extended (0–120 hours) control of CINV associated with MEC regimens and regimens containing an anthracycline and cyclophosphamide.

Patients took methylphenidate 20 mg sustained release every morning and followed an aerobic exercise program for 15 to 30 minutes four days a week. Aerobic exercise is hypothesized to decrease fatigue by improving physical conditioning and mental concentration.

• Eight patients were included (compared with four patients who were unable to tolerate methylphenidate and were receiving exercise alone and 16 historic controls). 
• Most patients were Caucasian, college educated, worked full-time, and had stage III metastatic melanoma.
• Gender was not reported.
• All patients were newly diagnosed and being treated with interferon-alpha.
• Patients had undergone previous surgery but no other therapies.
• Only two patients exercised regularly prior to study entry.
• All patients received interferon-alpha at a dose of 5 million IU/m².
• Patients were excluded if they had uncontrolled hypertension; anxiety disorders; active central nervous system metastasis; or a history of glaucoma, motor tics, seizure disorders, or Tourette’s syndrome.

• Outpatient
• Large university cancer center

This was an open-label pilot study with comparison to historic controls.

• Schwartz Cancer Fatigue Scale (SCFS), completed at monthly intervals
• Functional status for 12-minute walk time
• Medical Outcomes Study (MOS) Short Form 36 (SF-36)
• Trail Making Test (TMT) Parts A and B

All patients adhered (as determined by patient diaries) to the exercise portion of the intervention over the four months of the study. Four of 12 patients were unable to adhere to methylphenidate:  three refused to continue on methylphenidate beyond the first 48 hours of the study (reasons for discontinuation included indigestion, mild nervousness, and unwillingness to take more pills), and one had methylphenidate discontinued by the investigators due to marked anxiety. Patients receiving exercise and methylphenidate or exercise alone experienced lower fatigue levels compared to historic controls. Patients who exercised and took methylphenidate reported the lowest levels of fatigue. The exercise-only group experienced a greater decline in cognitive function when compared with patients who exercised and took methylphenidate. Patients in the in exercise and methylphenidate group lost 8.1 kg, and those in the exercise-only group lost 8.2 kg.

• The study used an open-label design.
• The study lacked randomization.
• The study had a small sample size.
• The study failed to include a depression measure.

Special training or consultation may be required to prescribe an exercise program for patients with cancer. Cost is related to drug acquisition.

This study was conducted to examine the effect of exercise and methylphenidate (MPH) on fatigue, functional ability, and cognitive function in patients with melanoma. It also aimed to determine the percentage of patients who adhered to interferon-alfa, MPH, and exercise treatment.

The intervention group was given 20 mg of long-acting MPH every morning for four months and took part in at least 15–20 minutes of aerobic exercise four days per week. The duration and intensity of exercise gradually increased over the study's four months.

Assessments were completed prior to the first dose of interferon-alfa. Subsequent assessments of functional ability and cognition function (using Trail Making Test forms) and quality of life were repeated at one and four months after baseline. Subsequent assessments of fatigue scale, body weight, daily activity, and medication logs were submitted monthly.

• The total number of individuals involved in the study was 28.
• There were 12 participants and 16 historic controls. 
• The average age of the treatment group was 44, with a range of 20–64. Age information for the historic group was not provided.
• Gender information was not provided.
• 92% of the participants were Caucasian.
• The treatment group tended to have completed more years of formal education.
• Participants had newly diagnosed melanoma with surgical intervention, no prior treatment, and were actively undergoing treatment with interferon-alfa.

The study took place at a university-based cancer center.

This was a longitudinal pilot study with descriptive/exploratory design. It made use of a historic control group for comparison.

• The Trail Making Test (TMT) Parts A and B measured visual attention, motor speed, and cognitive flexibility.
• The Schwartz Cancer Fatigue Scale measured fatigue with 6 items. Scores range from 6–36, with higher scores indicating greater fatigue.
• The Medical Outcomes Study Short Form (SF-36) measured quality-of-life and global function with physical and mental health subscales. Scores range from 0–100, with higher scores indicating higher functioning.
• Adherence was measured with daily activity and medication logs.
• Body weight was measured to the nearest 0.1 kg and obtained monthly.

Functional ability increased an average of 6% for all participants and 9% for the treatment group. A percent change in a 12-minute walk was negatively related to TMT-A (p = 0.04) and TMT-B (p = 0.05), suggesting a relationship between higher exercise and improved cognitive functioning (indicated by lower scores on TMT). Taking MPH was correlated with improved TMT-B performance at 4 months (r = -0.85, p < 0.001). 

All participants' cognitive function scores were within normal ranges at baseline. Sixty-six percent of participants adhered to MPH at four months; all subjects continued to exercise at four months.

The combination of exercise and MPH has positive effects on cognitive function, functional ability, and fatigue over time. The authors suggest that MPH may have contributed to better exercise adherence.

• The study had a small sample size.
• One-third of the participants stopped taking MPH within the first week; for one participant, this was due to significant side effects related to anxiety.
• Two participants regularly exercised prior to enrollment, but the study did not address which group they were assigned to, potentially influencing outcomes.

• To evaluate the effectiveness of a group rehabilitation intervention in improving cognitive function in cancer survivors
• To explore the phenomenon of cognitive impairment and the relationship between objective and subjective measurements of cognition

The intervention, based on self-regulatory cognitive rehabilitation and cognitive behavioral principles, consisted of four weekly two-hour group sessions with between-session homework. Each session consisted of psycho-education, group discussion, and reinforcement of the content by skill development and application. Subject matter included overall information on cognition with specific information on memory, attention, and the impact of fatigue and emotions on cognition. Application exercises focused on goal setting, problem solving, relaxation, compensatory and enhancement strategies, and cognitive-behavioral strategies related to emotional adjustment, fatigue, sleep, and self-care.

All participants receiving the intervention were assessed at baseline, post-treatment (six weeks after the baseline assessment), and follow-up (three months after the second assessment). Study participants not receiving the intervention were assessed at similar time frames but only for the first two time periods.

• A total of 53 patients participated in the study. Their ages ranged from 34–84 years with a mean age of 58.3 years.
• The sample was 40% male and 60% female.
• Breast, colorectal, and prostate cancers accounted for 84.5% of the sample; the remaining 15.5% included ovarian, testicular, neck, and mixed cancers.
• All patients had undergone treatment with surgery, radiation, and/or chemotherapy and completed treatment a minimum of four months prior. Patients' education level ranged from 9–25 years with a mean level of 15.2 years.

• Single site
• Outpatient
• Australia

The clinical application is for late effects and survivorship.

The study consisted of a controlled trial with repeated measures.

• Objective Measurement: Repeatable Battery for Assessment of Neuropsychological Status (RBANS)
• Trail Making Test (TMT)
•  Subjective Measurement: Multiple Ability Self-Report Questionnaire (MASQ)
• The Functional Assessment of Cancer Therapy–Cognitive Scale (FACT-Cog volume 3)

In contrast to the cancer and community comparison groups, the intervention group had a significant improvement in immediate memory (p < 0.01), visuospatial skill (p < 0.001), language (p < 0.001), attention/concentration (p < 0.05), delayed memory (p < 0.001), and total cognitive score (p < 0.001) over the six-week time interval as measured by the RBANS. No change was found in either information processing speed as measured by the TMT-A or executive function as measured by the TMT-B. 

The intervention group was re-evaluated three months later; improvements remained, or were sustained, in immediate memory (p < 0.001), visuospatial skill (p < 0.001), delayed memory (p < 0.001), and total cognitive score (p < 0.001), but not in language or attention/concentration. At the final assessment, a significant improvement was also found on the TMT-A (p < 0.01). Although no change was found in self-report of cognitive function as measured by the MASQ, a significant improvement was found over time as measured by the FACT-Cog (p < 0.05).

Significant improvement was found in several cognitive domains for patients who received the group intervention. Many of these improvements were sustained three months after the completion of the intervention. The results of the subjective measures of cognitive function were mixed. This study found that a short group intervention may improve cognitive ability for cancer survivors over a limited period of time.

• The study was at risk for bias because no control group, random assignment, or appropiate attentional control condition existed.
• The intervention was expensive and impractical and required special training needs.

Further research is indicated, with larger sample sizes and longer follow-up, to determine whether group cognitive rehabilitation might be warranted to treat cognitive impairments. More detailed information regarding the intervention is needed to determine whether it could be facilitated by nurses rather than the clinical psychologists in the study.

To evaluate the safety and efficacy of combined prolonged-release (PR) oxycodone and PR naloxone for treatment of cancer-related pain in daily practice

Patients with severe chronic pain requiring strong analgesics entered a four-week observational period, during which they received PR oxycodone–PR naloxone. The physician determined dosage. Dose adjustments, comedication, rescue medication, and other treatments were also at the discretion of the physician. Follow-up visits occurred after the first week and at the end of the four-week observation. Data were gathered using interviewer-administered questionnaires.

• The sample was composed of 7,836 patients.
• Mean patient age was 65.8 years (SD = 13.6 years).
• Approximately 61% of patients were female and 39% were male.
• Of all patients, 17% had cancer; other diagnoses were musculoskeletal and nervous system disorders.
• Of all patients, 75% had been treated with opioids and 25% were opioid naive.
• Patients were treated by primary care physicians, anesthesiologists, and physicians with pain specialization.

• Multisite
• Outpatient
• Germany (6,496 sites)

Observational

• Brief Pain Inventory (BPI)
• Numeric pain rating scale, 0–100
• Bowel Function Index (BFI)
• Global rating scale (1 = very good, 5 = very bad)

• At baseline, the strongest pain score was 6.8 (SD = 1.8). That score declined to 3.9 (SD = 2.1) at the final follow-up visit (p < 0.001). A similar decline occurred in least, current, and mean pain intensity scores (p < 0.001).
• Rescue medication was prescribed to 11.5% of patients at the first visit and 9.5% at the first follow-up visit, one week later.
• Authors observed significant improvement in bowel function as measured by the BFI (p < 0.001). Improvement in bowel function was greater in those previously treated with opioids.
• Other symptoms associated with opioid use also declined.
• A total of 3,881 adverse events occurred in 1,566 patients (20% of patients).
• The most frequent adverse events were nausea, constipation, and diarrhea.
• Treatment with PR oxycodone–PR naloxone was discontinued in 1,157 patients (14.8%) because of adverse events or lack of efficacy.
• At the third follow-up visit, 54.5% of patients were receiving 10 mg-5 mg (PR oxycodone–PR naloxone) twice a day and 31.3% were receiving 20 mg-10 mg twice a day.

PR oxycodone–PR naloxone was associated with effective analgesia and reduction in symptoms of opioid-induced bowel dysfunction. This combination was associated with minimal adverse events.

• The study had risk of bias due to no appropriate control group.
• The design was observational, with a limited follow-up period.
• Authors did not discuss rescue medication or how rescue medications, medication changes, or other treatments may have affected results.
• A relatively small proportion of patients had cancer. Authors provided no subgroup analysis of different groups of patients.

The fixed combination of PR oxycodone–PR naloxone may be effective in managing chronic pain and cause few problems, such as constipation, which opioids typically cause.

Data were retrieved by investigators from the patients’ medical records at each of the study centers and were transferred to a standardized case report form (CRF). Data collected included patient demographics, characteristics of the tumor disease, treatments, signs, symptoms, side effects experienced by patients, and the course of the disease. For each symptom, a patient was included in the analysis if the symptom was present either at the beginning and/or the end of postoperative treatment, and if an assessment was available for both time points. The primary target criterion was the change in symptom score between the start and end of postoperative treatment.

• The sample was comprised of 689 women with primary breast cancer.
• The therapy group was comprised of 219 patents (mean age = 60 years [range 33–92]). The majority had stage IIa (26.5%).
• The control group was comprised of 470 patients (mean age = 64 years [range 35–90]). The majority had stage IIa (29.4%).
• Patients were excluded if they were taking any other complementary medication except standardized mistletoe extract, suffered from a relapse or developed metastasis at the beginning of the postoperative treatment, or if a secondary malignancy was detected.

The study included seven study centers randomly identified in Germany (hospitals and general or specialized practitioners).

Patients were undergoing the active treatment phase of care.

This was a controlled, epidemiologic, multicentric, retrolective, cohort study with parallel groups.

Data were collected on CRFs in which, prior to data collection, the data elements required for the study were identified and defined.

The mean change in fatigue symptom scores during the postoperative study period was significantly larger (beneficial) in the therapy group compared to the control group (p < 0.0001). The adjusted odds ratios for fatigue in treatment/control was 7.33. A multivariate analysis of the combined symptom score was calculated in accordance to Wei-Lachin and proved a significant superiority of the therapy group (p = 0.0001).