To test the hypothesis that aerobic exercise would be better than usual care for improving sleep quality, and to examine potential moderators of intervention effects

Patients were stratified by lymphoma type and whether the patient was receiving chemotherapy and then randomized to receive the exercise intervention or usual care. The intervention consisted of supervised aerobic sessions three days per week for 12 weeks. Prescriptions for unsupervised exercise were provided for patients who were unable or unwilling to attend supervised sessions, and these sessions were not counted in adherence evaluation. Usual care patients were asked to not change baseline exercise habits and were offered supervised exercise after final study assessments.

• N = 117
• AGE: 32.5% were younger than 50 years, and the rest were older than 50 years. No other age information is provided.
• MALES: 59%, FEMALES: 41%
• KEY DISEASE CHARACTERISTICS: All had non-Hodgkin lymphoma, 54.7% were off treatment, and 45.3% were in active treatment.  
• OTHER KEY SAMPLE CHARACTERISTICS: At baseline, 71.8% were not meeting recommended activity guidelines. At baseline, overall, 47% were poor sleepers. The prevalence of poor sleepers was higher in the intervention group (57.9% compared to 36.7%, p = .021).

• SITE: Not stated/unknown  
• SETTING TYPE: Outpatient  
• LOCATION: Canada

• PHASE OF CARE: Multiple phases of care

• RCT

• Pittsburgh Sleep Quality Index

Aerobic exercise resulted in a small (d = -0.19) but not significant improvement in global sleep quality. In the intervention group, the exercise program improved global sleep quality in patients receiving chemotherapy (p = .013), but not for those who were off therapy. Exercise improved global sleep quality in those who were poor sleepers at baseline (p = .007), but not in those who were good sleepers at baseline.  Analysis further showed that positive effects of exercise were seen in patients with shorter time since diagnosis, patients who were obese, and patients who had less aggressive disease.

Aerobic exercise did not significantly improve sleep quality in this study of patients with lymphoma. Exercise appeared to have some benefits for sleep quality in individuals who were in active treatment.

• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Key sample group differences that could influence results
• Other limitations/explanation: Findings showed that those with poor sleep quality had a greater effect with aerobic exercise, and, at baseline, more poor sleepers were in the intervention group. This suggests that actual effects may be even lower for exercise than shown here. No statement is provided of how many patients did not participate in the supervised exercise sessions and how this was handled in overall analysis of group differences.

Findings show that overall, participation in aerobic exercise does not improve overall sleep quality in patients with lymphoma. Some benefit may exist for patients during chemotherapy treatment and for individuals who have baseline poor sleep quality. For these types of patients, nurses should consider suggesting aerobic exercise or providing exercise prescriptions.

Patients were randomized to receive either 10 weeks of group psychotherapy and exercise (home-based, moderate intensity, 20 to 30 minutes, three to five times per week, and tailored across the intervention to promote progression toward the goal of achieving a heart rate during exercise of 65% to 75% of the estimated heart rate maximum) or group psychotherapy only. The group psychotherapy intervention consisted of stress management and relaxation training or expressive supportive therapy. Both group psychotherapy interventions had a psychoeducational focus. Patients in the group psychotherapy only arm received a personalized exercise plan after study completion. To control for possible contamination between the experimental conditions, groups of patients who had registered for a group psychotherapy program at a large cancer center, rather than individual patients, were randomized.

• The study included 96 patients (group psychotherapy and exercise group, n = 51; group psychotherapy only, n = 45).
• Mean age was 51.55 years (range 25–74).
• Of the patients, 84% were female, 50% had stage I or II disease, and 50% had stage III or IV disease.
• Most patients were Caucasian and had an annual income of $40,000 per year.
• All patients were screened for participation restrictions for a moderate exercise program using the revised Physical Activity Readiness Questionnaire (PAR-Q) and a submaximal fitness assessment.
• Diagnoses included breast cancer (40.9%), colon cancer (9.4%), lymphoma (6.2%), ovarian cancer (5.2%), gastric cancer (4.2%), melanoma, and mixed solid tumors (21.8%).

• Single site
• Outpatient comprehensive cancer center

Patients were undergoing the active treatment and long-term follow-up phases of care.

This was a randomized, controlled trial with a crossover for the control group receiving group psychotherapy alone.

Functional Assessment of Cancer Therapy–Fatigue (FACT-F)

No difference existed between expressive supportive therapy and stress management and relaxation therapy in group psychotherapy effect in either group. Group psychotherapy and exercise improved quality of life beyond group psychotherapy only in cancer survivors (active treatment and long-term follow-up). The group psychotherapy intervention did not significantly reduce fatigue; however, the addition of moderate-intensity exercise resulted in a statistically significant improvement in fatigue.

• The group was relatively homogeneous with regard to race (most were Caucasian), educational level (59% had completed university), and socioeconomic status (67% had a median annual family income greater than $40,000).
• The exercise program was only 10 weeks in length and provided no long-term follow-up because of the control group crossover design.
• Some exercise, adherence, and contamination problems were noted; about 20% of the patients in the exercise condition did not meet the minimum cut point of 60 minutes per week of moderate or strenuous exercise, and 20% of patients in the control group met this cut point.
• Contamination may have resulted from having the control condition monitor patients and report their exercise on a weekly basis or because previous exercisers were allowed to participate.
• All patients were selected from among patients who declared themselves interested in a group psychotherapy intervention; thus, the results are generalizable to patients who voluntarily join group psychotherapy classes.
• The authors did not differentiate outcomes achieved by patients who were receiving active treatment and those on long-term follow-up.
• Nontolerance of exercise and safety parameters for exercise in the group psychotherapy and exercise groups was not described.
• For group psychotherapy, a therapist experienced in stress management, relaxation therapy, and expressive-supportive therapy is required. A certified fitness appraiser must appraise and design each individual program.
• Skills and equipment for performing a submaximal cardiovascular treadmill test are needed to evaluate the fitness level of patients prior to having them commence an exercise program.

Databases searched were MEDLINE, CANCERLIT, CINAHL, HERACLES, PsycINFO, and SPORTDiscus through 1997. Studies restricted solely to movement therapy and/or stretching/flexibility exercises for rehabilitation of range of motion were excluded. Studies were also excluded if they presented insufficient detail to allow for critical review.

Eighteen intervention studies (10 quasiexperimental and eight experimental designs) of physical exercise designed to improve cardiovascular and/or muscular fitness were included.

Outcomes were fatigue, health-related quality of life, symptom distress, immune function, physical exercise capacity (maximal oxygen consumption), and other physical performance measures.

Treatment evaluated cycle ergometer (eight studies), walking either alone or in combination with some other exercise mode (six studies), resistance training (one study), and unspecified (three studies).

Length of the intervention was 12 weeks or less in 14 studies, between four and six months in three studies, and one year in one study. Exercise was supervised (13 studies), unsupervised home-based (three studies), and partially supervised (two studies).

• The sample sizes ranged from eight to 70 participants.
• Most of the studies were conducted in patients with or survivors of breast cancer or those who were predominantly stage I and II.
• A few studies evaluated exercise in patients with leukemia following allogeneic stem cell transplantation and in patients with solid tumors following autologous stem cell transplantation.
• Single studies were found for survivors of head and neck, colorectal, and childhood cancer.

The reviewed studies indicated promising effects on both physiological and psychological outcomes. Three studies reported a significant reduction in fatigue. Although effect sizes could not be summarized across studies due to the diversity of outcomes with small numbers of effect sizes, the effects appeared to be robust and clinically significant.

• Small convenience samples were used.
• The study design lacked appropriate control groups.
• The range of cancer sites was restricted. 
• The intervention period was short (the exercise treatment lasted 12 weeks or less in most studies).

Additional studies are needed to examine the effect of exercise, specifically on the endpoint of fatigue.

To examine the effects of exercise dose and type on psychosocial distress in patients with breast cancer receiving chemotherapy

Patients were computer-stratified by center and protocol and randomly assigned in a 1:1:1 ratio to standard (STAN), combination (COMB), or high-volume (HIGH). Participants exercised for the duration of their chemotherapy schedules. STAN treatment followed the Physical Activity Guidelines for Americans. The guidelines recommend a minimum of 75 minutes per week of vigorous aerobic exercise over three days per week. HIGH followed double the minimum guidelines of 150 minutes per week, and COMB followed the STAN guideline with the addition of a standard strength training program for three days per week. Exercise was supervised, and attendance, duration, and the intensity of aerobic exercise, weight, sets, and repetitions of strength training were recorded.

• N = 301  
• AGE RANGE = 45–55 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer stages I–III initiating adjuvant chemotherapy

• SITE: Multi-site    
• SETTING TYPE: Multiple settings    
• LOCATION: Canada

• PHASE OF CARE: Active antitumor treatment

Randomized trial

• Short version of Center for Epidemiological Studies-Depression Scale (CES-D)
• Short form of the Spielberger State-Trait Anxiety Inventory (STAI)
• Perceived Stress Scale (PSS)
• Rosenberg Self-Esteem Scale (RSES)

There were no significant differences in managing depressive symptoms with HIGH and COMB exercises compared to the STAN exercise. COMB and HIGH exercises were effective in managing depressive symptoms in patients with clinical levels of depressive symptoms at baseline. There were no differences between the groups in anxiety scores.

Compared to standard exercise, higher volumes of exercise did not improve depressive symptoms, but it was effective in managing depressive symptoms in patients with clinical levels of depressive symptoms at baseline.

• Risk of bias (no blinding)

Depression is the most common psychological symptom in patients with cancer. Oncology nurses should encourage patients to perform standard aerobic exercise to improve depressive symptoms. Exercise also has been shown to be beneficial for anxiety and fatigue.

The three-armed study reported on an exercise intervention with supervised aerobic exercise (AET) and supervised resistance exercise (RET) versus usual care (UC). The exercise sessions were started one to two weeks after starting chemotherapy and ended three weeks after completion of chemotherapy. Exercise trainers administered the intervention.

• AET group participants (n = 78) exercised three times per week on a cycle, a treadmill, or an elliptical machine, beginning at 60% of their maximal oxygen consumption for weeks 1–6 and then progressing to 70% during weeks 7–12, and 80% beyond week 12. Exercise duration began at 15 minutes for weeks 1–3 and increased by five minutes every three weeks until the duration reached 45 minutes at week 18.
• RET group participants (n = 82) exercised three times per week, performing two sets of 8–12 repetitions of nine different exercises at 60%–70% of their estimated one-repetition maximum. Resistance was increased by 10% when participants completed more than 12 reps.
• UC group participants (n = 82) were asked not to initiate an exercise program and were offered a one-month exercise program after postintervention assessments.

Data were collected at three time points: baseline (one to two weeks after starting chemotherapy), midpoint (three to four weeks after starting chemotherapy), and at six-month follow-up.

The study reported on a sample of 242 women with breast cancer receiving adjuvant chemotherapy.

Multiple centers in Canada

A randomized controlled trial (RCT) design was used.

• Functional Assessment of Cancer Therapy–Anemia scale (FACT-A)
• Rosenberg Self-Esteem Scale
• Center for Epidemiologic Studies–Depression scale (CES-D)
• Spielberger State Anxiety Inventory (STAI)
• Peak oxygen consumption
• Expired gases
• Body weight and height
• Dual x-ray absorptiometry scan for assessment of whole body fat and lean tissue
• Lymphedema measurements
• Chemotherapy completion rate assessed as the average relative dose intensity for the originally planned regimen based on standard formulas

Mixed-model analysis measured at three time points compared the differences across groups in changes over time. Neither AET nor RET interventions significantly improved cancer-specific quality of life, fatigue, depression, or anxiety, although the trends favored the exercise groups. AET improved self-esteem, aerobic fitness, and percent of body fat. RET improved self-esteem, muscle strength, lean body mass, and chemotherapy completion rates.

The study is an RCT with an adequate sample size but null findings for anxiety levels.

The intervention required exercise trainers.

To determine if oral synthetic tetrahydrocannabinol (THC) and smoked marijuana are effective in the treatment of chemotherapy-induced nausea and vomiting (CINV), and to evaluate the side effects and patient preferences for treatment

Databases searched were MEDLINE (1966–present), CINAHL (1982–present), and the Cochrane Library.  A search of article reference lists also was performed.

Search keywords were nausea, vomiting, cancer, chemotherapy, cannabis, marijuana, and dronabinol.

Studies were included in the review if they

• Reported on human clinical trials.
• Involved treatment with smoked marijuana or oral synthetic THC for CINV.
• Were in English.

The author retrieved 18 relevant citations, 10 of which were clinical trials and included in the review. The author evaluated the quality of the reference based on strength of evidence, study design, sample size, and purpose. Specific criteria were not described.

• A total of 929 patients were involved across the 10 included studies.
• Sample sizes ranged from 15 to 214.
• Subjects had a variety of diagnoses and were receiving various types of chemotherapy.
• Six studies involved the use of chemotherapy that was of moderate to high emetogenic potential.

• Two studies evaluated the efficacy of oral synthetic THC versus placebo. In both studies, THC was significantly better than placebo at reducing CINV (p < 0.001).
• A one-group study tested crude marijuana; 78% of patients reported it to be moderately or highly effective. However, 18 patients dropped out of the study because they did not accept the smoking route of administration.
• Three studies examined oral synthetic THC versus phenothiazines. Two of these studies found that THC was significantly more effective in controlling CINV (p < 0.05) while the third found no difference. Timing and dosages differed across studies. In one study, patients who took THC reported significantly more sedation, incoordination, and feelings of being high than those receiving compazine or placebo.
• One study found that the combination of THC and antiemetics was most successful in mitigating severity and duration of CINV.
• In one study of smoked marijuana versus phenothiazines, no differences were found between groups.
• In a comparison of oral THC versus smoked marijuana, both were found to be effective with no significant differences found between these approaches.
• One study compared oral THC versus 5-HT₃ receptor antagonists (RAs) in a randomized, controlled, double-blind design. All patients received a standard antiemetic protocol of dexamethasone and ondansetron prior to chemotherapy and then were randomly assigned to also receive THC, placebo, or other drugs alone or in combination. All drugs were more effective than placebo, but no significant differences were found between those who took the THC and the other medication groups.
• A number of these studies had small sample sizes, and one lacked a control group.

• Both oral THC and smoked marijuana were found to be more effective than placebo and as equally effective as other commonly used antiemetics in controlling CINV.
• Oral THC appears to be as effective as smoked marijuana.
• THC was associated with more side effects (sedation, lack of coordination, and feeling “high”).
• Some patients found the inhalation route for marijuana use to be unacceptable.
• Some patients may not be able to tolerate the harsh smoke, and, because crude marijuana may contain bacteria or fungi, concerns exist for immunocompromised patients.
• Cannabinoids appear to have value as adjuvant medication, and the evidence supports their use for mitigation of CINV. They appear to be most effective in combination with other antiemetics.

Nurses need to review potential sides effects. Individual patients can have differing concerns as a result of other problems or preferences. Oral THC may be the best option for use among patients with cancer.

To evaluate the effect of ¹⁵³Sm–ethylenediamine tetramethylene phosphonate (Sm-EDTMP) for relief of pain from bone metastases

Consecutive patients referred to nuclear medicine who met eligibility criteria (life expectancy greater than six months, no chemotherapy within the previous four weeks, and acceptable blood values) were entered into the study. Each patient was asked to evaluate his or her pain daily using a visual analog and a verbal rating scale. Pain palliation was assessed using the patient’s mean scores. Sm-EDTMP was given intravenously in a solution of 37 MBq per kilogram body weight. Patients had blood work daily, and a TcMDP bone scan was done on the fifth day.

• N = 277  
• MEAN AGE = 64 years (range = 24–92 years)
• MALES: Not reported, FEMALES: Not reported
• KEY DISEASE CHARACTERISTICS: The majority of patients had prostate cancer.

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

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

Observational

• Visual Analogue Scale (VAS)
• Verbal Rating Scale (VRS)

Pain was reduced in patients with prostate cancer by 74%, in breast by 67%, in renal by 78%, in thyroid by 67%, in lung by 75%, in cervical by 80%, in colon and rectum by 73%, and by 100% in patients with osteosarcoma. There were no significant changes in blood work values of leukocyte counts, hemoglobin, or platelets at 3 or 12 weeks after treatment. Pain scores were significantly reduced at 3 and 12 weeks (p = .001). There was a relatively high variability in pain score differences.

Sm-EDTMP was effective in reducing pain from bone metastases from multiple tumor types over a 12-week period.

• Risk of bias (no control group)
• Unintended interventions or applicable interventions not described that would influence results
• Measurement/methods not well described
• Other limitations/explanation: No information was provided regarding other medications, etc., used for pain control or any changes in medications during the study. It is not clear if the VRS or VAS was used for analysis, and it was not stated whether the scale was a 10-point or 100-point VAS. The study duration was relatively brief. The sample sizes of patients with various tumor types were not stated.

Radiopharmaceuticals such as Sm-EDTMP may be effective for the management of pain from bone metastases. Further research comparing various pain control approaches is warranted with longer follow-up.

The intervention included weekly sessions with a nurse research practitioner, lasting one hour, using counseling, breathing retraining, relaxation, and the teaching of alternate coping and adaptation strategies. The interventions are the same as those commonly used to treat patients with chronic pulmonary disease. Patients were randomized either to an intervention group or control group. The intervention group met over a three- to six-week period. Additional follow-up sessions were available if necessary. The number of sessions was not stated. The control group received usual nursing care such as breathing assessment with documentation in the medical record.

The study reported on a sample of 20 patients with lung cancer. The patients had completed either chemotherapy or radiotherapy and were experiencing breathlessness.

The study was conducted in a nurse-led clinic in a specialist cancer center.

Randomized, controlled pilot study

• A 10-point VAS measuring three time frames (best, worst, and usual) to rate breathlessness over the previous week
• Distress caused by breathlessness
• Functional Capacity Scale
• HADS

Median scores on all measures were improved. Distress from breathlessness improved 53%, breathlessness at worst improved 35%, and functional capacity improved by 21%. Distress in the control group worsened by a median of 10%. Significant improvements compared with the control group were observed in breathlessness at best (p < 0.02) and at worst (p < 0.5), distress caused by breathlessness (p < 0.01), and functional capacity (p < 0.02). Improvements were not observed for anxiety or depression.

The study demonstrates that patients with lung cancer and breathlessness benefit from a rehabilitative approach.

The effect of time and attention on a weekly basis independent of intervention is unknown. The contribution of each component of the intervention is unknown. Are all components needed to achieve the same outcome, or was one aspect of the intervention most significant? The study had a small sample, and baseline data show that the intervention group rated distress caused by breathlessness higher than did the control group.

The study is valuable as a pilot study with an aim to test feasibility.

The purpose of this article was to study the primary prophylaxis of invasive fungal infections (IFI) in patients with hematologic malignancies. Eighty-six trials were reviewed, with a total patient population of 16,922.

In order to compile this resource, data were extracted and a draft manuscript was written by two of the authors and reviewed by a committee of hematologists and infectious disease specialists assigned by the Infectious Diseases Working Party of the German Society for Haematology and Oncology. The consensus draft was secondarily reviewed by the review committee of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. In cases where uniform consensus was not reached, the majority vote was adopted. Treatment recommendations were categorized using the evidence categories of the Infectious Disease Society of America ( IDSA). The categories indicate the strength of evidence and the quality of evidence. 

• A: Good evidence to support  a recommendation for use.
• B: Moderate evidence to support a recommendation for use.
• C: Poor evidence to support a recommendation for use.
• D: Moderate evidence to support a recommendation against use.
• E: Good evidence to support a recommendation against use.

I = evidence from at least one properly randomized, controlled trial; II = evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), from multiple time series, or from dramatic results of uncontrolled experiments; III = evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

For the search stragety, the following databases were used: Medline, CancerLit, Embase, Cochrane Library and conference proceedings of Advances Against Aspergillosis, ASH, EBMT, ECCMID, ESMO, Focus on Fungal Infections, and ICAAC/IDSA. Keywords included invasive fungal infection, antifungal prophylaxis, itraconazole, fluconazole, posaconazole, amphotericin B, and liposomal. Inclusion was based on the research being clinical trials on antifungal prophylaxis. Exclusion criteria were trials published as abstracts, only, and meta-analyses.

Active treatment

Fluconazole 400 mg per day was significantly superior to placebo in both the reduction of breakthrough invasive fungal infection and the decrease of IFI attributable mortality; showed a lower incidence of intestinal graft-versus-host disease (GVHD); and is protective against cyclophosphamide toxicity. Doses lower than 400 mg per day failed to show a marked benefit. Also, breakthrough infections are seen with molds and Candida krusei due to their intrinsic resistance to fluconazole. Itraconazole is broader in spectrum than fluconazole, but has a start-up delay; therefore, it is not recommended as a start-up for prophylaxis of invasive fungal infection.

One study found itraconazole suspension at a dose of 2.5 mg/kg bid plus nystatin 500,000 IU qid versus nystatin alone to be a more effective reduction in the rate of fatal candidemia from 2% to 0; however, invasive mold infections and death due to fungal infection were not prevented. Itraconazole was not shown to be more effective than fluconazole in patients with hematologic malignancies and was associated with more adverse outcomes.

At a dose of 600 mg per day, posaconazole resulted in a significant reduction in proven and probable IFIs, mainly by reducing the incidence rate of aspergillosis along with an attributable and overall mortality reduction. Safety, including the overall rate of patients with serious adverse events, was comparable between posaconazole, flucanazole, and itraconazole. The only difference was a higher rate of patients on posaconazole experiencing possibly or probably related serious adverse events than patients on fluconazole or itraconazole prophylaxis. Posaconazole 600 mg per day was associated with decreased mortality associated with GVHD in HCT recipients.

Voriconazole exposure has been associated with a reduction of invasive aspergillosis, but an increase in breakthrough zygomycosis.

Ketoconazole, miconazole, and clotrimazole have not been proven effective.

Amphotericin B, a broad spectrum anti-fungal, does not appear to be significantly effective and is associated with adverse events in all forms (inhalation, deoxycholate infusion, and lipid-based formulations).

Primary prophylaxis with fluconazole 400 mg per day is recommended since it reduces the incidence of invasive candidiasis and mortality after HSCT (AI). The recommended antifungal prophylaxis in patients with neutropenia (ANC < 500 cell/mcl for more than seven days): posaconazole 200 mg PO TID for patients with AML/MDS receiving induction chemotherapy (AI); liposomal amphotericin B 12.5 mg twice a week by inhalation (BII); liposomal amphotericin B 50 mg q 48 hours via IV (CII); itraconazole oral solution 2.5–7.5 mg/kg/d (CI), fluconazole 400 mg per day PO (CI), itraconzole capsules, any dose (CI); caspofungin 50 mg per day IV (CI); conventional amphotericin, any dose IV or 20 mg per day inhalation (EI). 

The recommended antifungal prophylaxis in patients undergoing allogeneic HSCT: fluconazole 400 mg per day PO (until the development of GVHD) (AI); posaconazole 200 mg TID PO (in the setting of GVHD) (AI); itraconazole oral solution 400 mg per day PO (CI); micafungin 50 mg per day IV (CI).

Other recommendations for antifungal prophylaxis: itraconazole, any dose of capsules (CI); voriconazole (CII), fluconazole less than 400 mg per day (EI); ketoconazole, any dose (EII); miconazole, any dose (EII); clotrimazole, any dose (EII); nystatin, any dose (EII).

Fluconazole 400 mg per day is recommended to prevent IFIs in allogeneic stem cell recipients until the development of GVHD. Posaconazole is recommended to prevent IFI in allogeneic stem cell recipients with severe GVHD, and in patients with acute myelogenous leukemia or myelodysplastic syndrome undergoing induction chemotherapy. There is no benefit to the use of  fluconazole in the non-transplantation setting to prevent IFI. Itraconazole, voriconazole, caspofungin, and micafungin are not recommended to prevent IFI since there is limited data. Aerosolized liposomal amphotericin B appears to be effective to reduce the risk of invasive pulmonary aspergillosis in patients with prolonged neutropenia, but it was given with concomitant fluconazole. Conventional amphotericin B is strongly NOT recommended due to toxicity and the availability of other less-toxic effective agents.

Study patients received  200 mg of posaconazole in an oral suspension three times daily, 400 mg of fluconazole in an oral suspension once daily, or 200 mg of itraconazole in an oral solution twice daily.

Patients who were unable to tolerate the oral study drug could receive IV prophylaxis at the same dose for three days or less per chemotherapy cycle. Patients in either group were permitted to receive amphotericin B or another systemic agent as empirical antifungal therapy for a suspected invasive fungal infection.

Antifungal prophylaxis was administered with each chemotherapy cycle, starting either 24 hours after the last anthracycline dose or, in patients not  receiving an anthracycline-based regimen, on the first day of chemotherapy.

Prophylaxis was continued until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks from randomization, whichever came first. Patients were followed for 100 days after randomization and for 30 days after the last dose of the study drug administered during the last chemotherapy cycle.

• 602 total patients
• Patients aged 13 years or older who had or were anticipated to have neutropenia with an absolute neutrophil count of 500 cells/mcl or lower for seven days or longer resulting from remission-induction chemotherapy for newly diagnosed or the first relapse of acute myelogenous leukemia or myelodysplastic syndrome.
• Exclusion criteria included an invasive fungal infection within the previous 30 days.
   

Eighty-nine centers worldwide.

Prospective, randomized trial.

An independent data review committee of infectious disease experts who were unaware of the treatment assignments reviewed and classified all cases of fungal infection as proven, probable, or possible, according to the consensus criteria of the European Organisation for the Research and Treatment of Cancer and the Mycoses Study Group.

• Incidence of proven or probable invasive fungal infection during the treatment phase.
• Incidence of invasive aspergillosis.
• Incidence of invasive fungal infection within 100 days after randomization and treatment success (versus failure) during the treatment phase. Treatment failure was defined as the occurrence of a proven or probable invasive fungal infection; receipt of an IV study drug for four consecutive days or more, or 10 days in total; receipt of any other systemic antifungal agent for four days or more for suspected invasive fungal infection; the occurrence of an adverse event possibly or probably related to the study treatment, resulting in the discontinuation of treatment; or withdrawal from the study with no additional follow-up.
• Survival was evaluated 100 days after randomization.
   

Proven or probable invasive fungal infections occurred during the treatment phase in 7 of the 304 patients (2%) in the posaconazole group and in 25 of the 298 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group = –6%; 95% confidence interval [CI] [–9.7, –2.5]; p < 0.001).

During the 100-day period after randomization, 14 of 304 patients (5%) in the posaconazole group had a proven or probable fungal infection, as compared with 33 of 298 patients (11%) in the fluconazole or itraconazole group (p = 0.003).

The mean time to invasive fungal infection was 41 (SD = 26) days in the posaconazole group and 25 (SD = 26) days in the fluconazole or itraconazole group.

Kaplan-Meier analysis of the time to invasive fungal infection showed a significant difference in favor of posaconazole (p = 0.003).

The analysis of the time to first use of empirical antifungal therapy during the 100-day period revealed a significant difference in favor of posaconazole over fluconazole or itraconazole (p = 0.02).

Of the 304 patients in the posaconazole group, 49 (16%) died during the study period, as did 67 of 298 patients (22%) in the fluconazole or itraconazole group (p = 0.048); 44 patients (14%) and 64 patients (21%), respectively, died within 100 days.

The relative reduction in mortality at day 100 in the posaconazole group, as compared with the fluconazole or itraconazole group, was 33%.

The analysis of the time to invasive fungal infection or death also showed a significant benefit in favor of posaconazole (p = 0.01).

The incidence of treatment-related adverse events was similar among the treatment groups.

• All 602 patients in the intention-to-treat population were included in the safety evaluation.
• The different dosing schedules of the three study drugs and the logistics of their IV alternatives precluded a double-blind design.