To evaluate the significance of a protective environment (PE) on febrile neutropenia and mortality in patients with cancer with chemotherapy-induced neutropenia

The intervention was comprised of engineering and design interventions, incorporating high-efficiency particulate filters, positive air pressure, well-sealed rooms, and infection control routines according to international recommendations for a PE. Outcomes were compared to those of patients admitted prior to the implementation of standard environmental practices.

• N = 371
• MALES: 47%, FEMALES: 53%
• KEY DISEASE CHARACTERISTICS: Acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, chronic lymphoid leukemia, multiple myeloma, Hodgkin disease, non-Hodgkin lymphoma, myelodysplastic syndrome, other hematologic malignancies, aplastic anemia, solid tumors
• OTHER KEY SAMPLE CHARACTERISTICS: Risk categories of autologous hematopoietic stem cell transplantation (HSCT), allogeneic HSCT, acute myeloid leukemia, and other diseases

• SITE: Single site 
• SETTING TYPE: Inpatient hospital  
• LOCATION: Brazil

• PHASE OF CARE: Active treatment

• Descriptive cohort

• Cumulative incidence of febrile neutropenia and death were determined by the Kaplan-Meier method.
• The adjusted hazard ratios were computed in a Cox regression model.

Fever occurred in 74.7% of episodes of neutropenia in the PE group and in 86.7% in the control group (p = 0.003). Adjusting for length of neutropenia, risk, category, antibacterial prophylaxis, and central venous catheter use, the PE reduced febrile neutropenia (p = 0.009). The PE also decreased overall mortality (p = 0.001) and 30-day mortality (p = 0.002). Gram-negative bacterial infections were more frequent after the intervention (p = 0.18), while gram-positive bacterial infections were similar (p = 0.85). Fungal infections were more frequent in the control group (p = 0.04).

This study shows the advantages of the PE on reducing febrile neutropenia and mortality among patients with cancer and indicates that multiple infection control interventions significantly can diminish hospital-acquired infections.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)

Although the study does not delineate what they are, an important part of the intervention is infection control routines. These routines include hand hygiene and the routine use of personal protective equipment. Infection control is essential not only to protect nurses, but also to prevent the transmission of infection from one patient to another, particularly when those patients are at higher risk because of chemotherapy-induced neutropenia, and their importance cannot be overstated.

Databases searched were MEDLINE, EMBASE, and CINAHL (1966–2004). 

Search keywords were [neoplasms] AND [(mucositis OR stomatitis)] AND [limit to (clinical trial OR randomized-controlled trials)]. 

Studies were included in the review if they were

• Published in English.
• Were aimed at the prevention of mucositis in patients undergoing head and neck radiation, chemotherapy, or chemoradiation.

The search yielded 109 publications. Of these, five were not aimed at prevention, 13 were nonrandomized, and 29 did not contain data in a comprehensive form. Seventeen articles stood alone in terms of intervention, and 45 articles included meta-analyses. Studies with zero or infinite odds ratios were omitted because variances could not be calculated with accuracy. Sample sizes ranged from 14–502.

Patients with various cancer diagnoses receiving chemotherapy, radiation therapy, or combination chemoradiotherapy.

Of the 27 interventions identified for the prevention of oral mucositis, meta-analysis could be performed on eight. Four interventions showed a preventive effect on the development or severity of oral mucositis: PTA (polymyxin E, tobramycine, and amphotericin B) lozenges or paste, systemic administration of granulocyte macrophage–colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF), oral cooling, and amifostine.

Of 14 studies (each on a different intervention type), nine showed some positive results; however, methodological flaws (e.g., small sample sizes, lack of double-blind or placebo-controlled designs) prevented those studies from demonstrating effectiveness. One study of benzydamine (Epstein et al., 2001) showed an improved ulcer-free rate and decreased incidence of ulcer and erythema.

Palifermin demonstrated positive results for the prevention of mucositis in patients with hematologic malignancies undergoing autologous stem cell transplantation.

Tooth patches containing 15 mg flurbiprofen or placebo were applied once a day before sleep to the same natural tooth or the upper denture to the buccal side starting one week prior to radiotherapy (RT) until completion of RT. Treatment was discontinued at the first onset of grade 1 ulceration/pseudomembrane formation.

• The sample consisted of 22 patients, 12 in the treatment group and 10 historical controls.
• The median age was 57.7 – 59.2 years.
• Patients had head and neck cancer and were being treated with RT.

Oral Mucositis Assessment Scale (OMAS) and World Health Organization (WHO) scoring systems were used to evaluate mucositis. Oral pain, pain on swallowing, global assessment of eating function score, and oral washings for viability of mucosal epithelial cells and maturation were used.

• No difference was found in severity and duration of pseudomembranous mucositis.
• None of the patients applied the patch for the whole RT course because of development of mucositis.
• The treatment group experienced a later onset (p < 0.05).
• Based on the OMAS, development and degree of mucositis were lower during the first two weeks. This difference was statistically significant (p = 0.007). After three weeks, the difference was not significant. Results according to the WHO scale was similar with all patients scoring at least 2.
• The study showed a slight delay in the development of mucositis with the treatment; however, it was not effective in terms of prevention.
• Pain was significantly higher in the flurbiprofen group only after the second RT week (p = 0.03).

• The study size was small.
• Use of historical control administration may have been too minimal to see effects.

To determine the effect of a calcium phosphate (CP) mouth rinse on oral mucositis

Consecutive patients were asked if they were willing to use the CP mouth rinse. Those who were willing were assigned to the CP group, and those who refused served as controls and followed the standard oral care program.  Standard care with mouth rinsing with a salt and baking soda solution at least 8 times per day. The CP rinse was used twice per day. All patients received daily oral cleansing with a normal saline pressure spray and fluoride gel applications every other day to the teeth. The study period was 6 weeks. Outcomes were compared between groups and compared with historical controls.

• The study reported on a sample of 36 patients, with a mean age of 60.3 years.
• The sample was 64% male and 46% female.
• All patients had head and neck cancer.
• Some patients had radiation with intensity-modulated radiation therapy (IMRT), while others had 3D conformal radiation therapy (CRT).
• Significant differences existed between groups in use of conventional or accelerated fractionation of radiation and use and history of smoking.

The study was conducted at a single outpatient site in the Netherlands.

Patients were undergoing the active antitumor treatment phase of care.

This was a prospective, non-random comparison study.

• The World Health Organization (WHO) mucositis grading scale was used.
• The Oral Mucositis Daily Questionnaire was used.
• Oral pain was evaluated using a visual analog scale (VAS).
• Body weight was recorded.
• Use of nasogastric feeding was recorded.

No significant differences were found between groups in any of the outcome measures. Patients in the CP group had more severe mucositis scores at most weeks, but the difference was not statistically significant.

CP mouth rinsing had no effect on frequency, severity, or duration of oral mucositis in this group of patients.

• The sample size was small with fewer than 100 patients.
• Baseline sample and group differences of importance existed.
• Risk of bias exists because no control group, blinding, or random assignment was used.
• A risk of bias exists because of the population and sample group differences including use of IMRT and smoking behavior.
• No information was provided about use of analgesics or patient compliance with oral care.

This study did not show any benefit in the use of CP mouth rinses for the prevention and management of mucositis in patients receiving radiation therapy for head and neck cancer.

The sertraline intervention required patients to take 50 mg/day of the study drug or a matched placebo for the study period. Patients who developed symptoms of major depression were referred to a psychiatrist coinvestigator at the institution. If there was a definite indication for antidepressants or if patients decided to stop the study due to adverse events, the drug was discontinued gradually by reducing the dose to 25 mg/day for one week before stopping. Patient outcomes were assessed at baseline and 4, 8, 12, 16, 26, 39, and 52 weeks.

• The study was comprised of 189 patients with advanced cancer for whom the responsible oncologist doubted benefits of treatment with antidepressants.
• In the sertraline group (n = 95), the male-to-female ratio was 55:40. There were multiple primary cancer sites, and the majority had received prior chemotherapy (n = 78).
• In the placebo group (n = 94), the male-to-female ratio was 56:38. There were multiple primary cancer sites, and the majority had received prior chemotherapy (n = 78).
• Patients were excluded if they had major depression, delirium, coexisting disorders, were taking medications that contraindicated sertraline treatment, or had a history of psychiatric illness.

This was a multicenter trial conducted in the oncology clinics of several Australian hospitals.

Patients were undergoing the active treatment phase of care.

The study was a double-blind, placebo-controlled, centrally randomized trial that was stratified for institution, sex, anticipated future cytotoxic treatment, and Performance Score:

1. Sertraline (n = 95)
2. Placebo control (n = 94).

• Functional Assessment of Cancer Therapy–Fatigue (FACT-F)
• Utility-Based Questionnaire-Cancer (UBQ-C)
• Somatic and Psychological Health Report (SPHERE)

Sertraline had no significant effect in improving fatigue compared to placebo. Outcomes were compared on the basis of scores at baseline and four and eight weeks.

• The study population was poorly defined, and the exclusion criteria of major depression were arbitrary and left to the responsible oncologist.
• The study was closed at the first interim analysis because sertraline showed no benefit to patients.

To evaluate the safety and efficacy of oral aprepitant in combination with ondansetron and dexamethasone in the prevention of acute and delayed nausea and vomiting compared to ondansetron and dexamethasone alone in patients receiving highly emetogenic preparative regimens before autologous or allogeneic stem cell transplant (SCT).

Patients were stratified by gender and randomized to one of two treatments. The aprepitant group received 125 mg oral aprepitant on day one then 80 mg daily during the preparative regimen + 3 days, 7.5 mg dexamethasone IV, and 8 mg ondansetron by mouth every eight hours daily during preparative regimen + 1 day. The placebo group received an oral placebo daily during the preparative regimen + 3 days, 10 mg IV dexamethasone, and 8 mg oral ondansetron every eight hours daily during the preparative regimen +1  day. Lorazepam was used for breakthrough nausea or vomiting. Prochlorperazine was allowed only for repeated episodes of vomiting (defined as more than four episodes in any 12-hour period). The primary objective was complete response (CR) rate, defined as no emesis with no or mild nausea.

• The study was initiated with 181 randomized participants, of which 179 were eligible for analysis.
• The median age was 50 years with a range of 19-79.
• The sample was 57% male and 33% female.
• Cancer diagnoses were non-Hodgkin lymphoma (32%), acute myeloid leukemia (26%), multiple myeloma (19%), acute lymphoblastic leukemia (7%), Hodgkin lymphoma (7%), chronic myeloid leukemia (3%), and other (6%).
• Treatment groups were stratified based on gender and were balanced with respect to age, weight, and history of nausea and vomiting with prior chemotherapy. Graft type was comparable, however, autoperipheral blood progenitor cell transplantation (PBPCT) represented 53% in the placebo group and 44% in the aprepitant group.

The study was conducted at Loyola University Medical Center Cardinal Bernardin Cancer Center in Maywood, IL.

All patients were in active antitumor treatment.

This study was a single center, comparative (placebo controlled), randomized, double-blind, phase III trial.

Patients rated the number of emetic episodes and nausea severity on a 100-mm visual analog scale (VAS).

• Patients who received aprepitant had significantly higher CR rates (81.9% versus 65.8%; p < 0.001) and significantly better complete control (CC) of vomiting  (73.3% versus 22.5%; p = 0.001) compared to the standard ondansetron plus dexamethasone treatment.
• The percentage of days with one episode of emesis with major efficacy and less than grade 4 nausea was significantly higher in the aprepitant arm (p < 0.001), while those with a minor response or failed was significantly higher in the control arm.
• Fewer total rescue doses were given in the aprepitant arm than in the control arm (594 versus 852; p = 0.033).
• The majority of patients, in both arms, used lorazepam for breakthrough therapy (p = 0.979).
• Aprepitant did not have a negative effect on engraftment. Median time for engraftment and platelet recovery was similar (p =  0.778 and p = 0.8206, respectively).
• A nonsignificant, higher tacrolimus level was noted in the aprepitant group; however, this was not enough to recommend adjustment of standard dosing (p = 0.5858).

Aprepitant in combination with dexamethasone and ondansetron significantly decreased emesis and significant nausea, without an increase in regimen-related toxicities. The regimen did not affect short-term survival and had no significant impact on the use of as-needed antiemetics or overall nausea scores. It did not negatively affect patient outcomes.

Five myeloablative high-dose cyclophosphamide preparative regimens were used. Only two regimens included total body irradiation (TBI), which is thought to cause more nausea.

Similar to standard-dose chemotherapy regimens, aprepitant demonstrated a much higher impact on emesis than it did on nausea. Aprepitant in combination with dexamethasone and ondansetron significantly decreased emesis and significant nausea, without increasing toxicities or affecting short-term survival; the regimen had no significant impact on the use of as-needed antiemetics or overall nausea scores.  Findings suggest that aprepitant assisted in control of nausea as well as emesis.

To investigate the associations between physical activity and health-related outcomes in ovarian cancer survivors and examine any dose-response relationship and to investigate associations between physical activity and peripheral neuropathy, depression, anxiety, sleep latency, use of sleep medication, and daytime dysfunction

Participants with confirmed ovarian cancer from 1985–2005 were asked to complete and return a consent form and questionnaire. Non-responders were sent a reminder postcard after two weeks and a second questionnaire after four weeks. The study took place from May 2006–June 2007.

• N = 359 (51.4% response rate)  
• AGE: 60.2 years (SD = 12.6 years)
• FEMALES: 100%   
• KEY DISEASE CHARACTERISTICS: Months since diagnosis = 73.6 months (SD = 52.6 months); 85.8% were diagnosed with invasive disease; 82.7% were in remission; 97.8% had received surgery, 70.5% had received chemotherapy, 6.4% had received radiation therapy, and 9.2% were receiving treatment at the time of the study.
• OTHER KEY SAMPLE CHARACTERISTICS: 73.5% were married or partnered; 40.9% were working full- or part- time; body mass index was 27.1 kg/m² (SD = 5.4 kg/m²) with 37% being overweight and 24.2% being obese. One or more cormorbidities were reported in 78.1% of the sample.  
   

• SITE: Multi-site  
• SETTING TYPE: Home  
• LOCATION: Mailed surveys; Alberta, Canada
   

• PHASE OF CARE: During and after treatment
• APPLICATIONS: Late effects and survivorship
   

• Descriptive, mailed self-report surveys

• Demographic and medical data from the cancer registry, supplemented by self-report information
• Leisure Score Index of the Godin Leisure-Time Exercise Questionnaire    
• Functional Assessment of Chronic Illness Therapy—Fatigue Scale
• Neurotoxicity subscale of the Functional Assessment of Cancer Therapy
• Gynecologic Oncology Group—Neurotoxicity scale
• Pittsburgh Sleep Quality Index
• Center for Epidemiologic Studies Depression Scale (short version)
• State-Trait Anxiety Inventory
• Happiness measure
   

A total of 359 ovarian cancer survivors participated, of whom 31.1% were meeting the public health physical activity guidelines of the Centers for Disease Control and Prevention. Those meeting the guidelines reported significantly lower fatigue than those who did not meet the guidelines. Meeting the guidelines was significantly inversely associated with peripheral neuropathy, depression, anxiety, sleep latency, use of sleep medication, and daytime dysfunction and was positively associated with happiness, sleep quality, and sleep efficiency. No evidence existed of a dose-response relationship beyond meeting or not meeting the guidelines for any variables.

Ovarian cancer survivors who were meeting physical activity guidelines reported more favorable outcomes of fatigue, peripheral neuropathy, sleep, and psychosocial functioning, compared to those who were sedentary or reported low activity.

•  No appropriate control group
•  Surveys are cross-sectional and self-report
   

Results of this population-based study suggest that ovarian cancer survivors may have fewer and less severe symptoms (e.g., fatigue, depression, neuropathy) and more health-related benefits (e.g, better sleep, greater happiness), if they increase physical activity during or after cancer treatment.

Databases searched were MEDLINE, EMBASE, Cochrane Controlled Trials Register, CANCERLIT, CINAHL, PsycINFO, and SPORTDiscus through December 2003.

Thirty-three studies (25 randomized trials and eight nonrandomized studies) reported in 40 articles were included in the review. Data were pooled for 10 trials that assessed physical functioning and 12 trials that assessed fatigue.

Trials were included if they tested interventions involving regular exercise of any type (e.g., aerobic, resistance, and flexibility). Exercise could be the sole intervention or could be combined with other interventions (e.g., diet counseling).  Only prospective trials with a control arm were included.  Based on an a priori decision, both nonrandomized and randomized trials were included.  There were no restrictions on the outcomes assessed in trials. Nineteen studies tested aerobic exercise interventions, of which eight used cycle ergometers and eight used walking programs.  Three trials tested resistive exercise, 10 had combined aerobic and resistive programs, and one was based on team sport activities. Most trials compared an exercise intervention with no intervention; six that did not used information training, psychological therapies, stretching, or tai chi as comparison arms.

Trials of single exercise sessions that measured acute effects were excluded, as were trials that only investigated the effects of physiotherapy.  Control arms could not comprise an intervention (e.g., usual care), an alternative intervention (e.g., counseling, relaxation), or a different type of exercise (e.g., aerobic versus flexibility exercises). Trials with healthy or historical control groups were excluded. 

Exercise interventions lasted for 10 weeks or longer in 17 trials and two weeks or less in four studies. The longest intervention period of any trial was 26 weeks. Trial quality was assessed by recording whether the following features were incorporated in the study design:  randomization, allocation concealment, blinding of the main outcome assessment, and intention-to-treat analysis.

• Thirteen trials included patients with breast cancer during or after adjuvant therapy.
• Eleven trials involved adult patients with any cancer, and one involved pediatric cancer survivors.
• The remaining trials included patients undergoing treatment for prostate, lung, colorectal, or stomach cancers; multiple myeloma; or leukemia.

Reductions in cancer-related fatigue were reported in 10 studies, although statistical significance was not reached or not tested for in three of them.  No differences between groups were reported for fatigue in six trials immediately after the intervention or several months later.  Pooling the data from the 12 trials that assessed fatigue suggested that there was no overall effect of exercise on symptoms of fatigue (standardized mean difference [standard deviation (SD)] in fatigue = -0.15 [-0.38, 0.09]).  Heterogeneity between studies was not related to randomization, allocation concealment, intention-to-treat analysis, or choice of control.  However, the effect appeared to vary by population type.  Some evidence existed that no effect was found of exercise on fatigue symptoms in trials that recruited patients with any type of cancer and that those that recruited patients with breast cancer found a modest reduction in symptoms of fatigue among those allocated to exercise (standardized mean difference [SD] = -0.52 [-0.95,-0.09]).  There was no strong evidence of small study bias in this meta-analysis by the Beggs and Egger tests.

The authors generally concluded that there were methodologic limitations associated with many of the studies and that these limitations may have contributed to the inconsistencies among the results.

Limitations included

• Lack of a randomized allocation
• Failure to conceal allocation
• Failure to specify the primary outcome measures
• Small sample sizes
• Multiple statistical testing without adjustment of significance values.

Two studies may have included participants in the control group who had declined to undertake the intervention; in five other studies, it was unclear whether eligibility (including willingness to participate) was determined prior to group allocation or whether the control group may have solely or partly consisted of those who declined to be allocated to exercise.

To evaluate fatigue outcomes in patients who participated in a phase II trial of abiraterone acetate and prednisone versus placebo and prednisone in patients after docetaxel therapy for metastatic castration-resistant prostate cancer.

In the phase III trial, patients were randomized to receive either abiraterone acetate and prednisone or placebo and prednisone; they later were crossed over to the other intervention arm.  Abiraterone inhibits synthesis of testosterone and other androgens, leading to suppression of prostate cancer growth.  Patient-reported fatigue was evaluated at baseline and on the first day of each treatment cycle until treatment discontinuation.  Median treatment durations were eight and four months across study groups, and median duration of follow-up was 20.2 months.

• The study included 1,196 participants.
• Participant ages were not stated.
• All participants had failed docetaxel for metastatic prostate cancer.

• Multi-site
• Outpatient
• Multiple countries

Patients were undergoing multiple phases of care.

This was a randomized, controlled, single-blind, crossover study.

• The Brief Fatigue Inventory (BFI) showed fatigue intensity defined as the score for worst level of fatigue in the last 24 hours. 
• Fatigue interference was the average score of all interference scores on the BFI.

• Among patients with clinically significant baseline fatigue, more patients in the abiraterone acetate arm experienced improvement in fatigue intensity (58.1% versus 40.3%; p = 0.0001) and  fatigue interference (p = 0.0075). 
• Time to improvement in fatigue was shorter in the abiraterone acetate arm (p = 0.0117).

Treatment with abiraterone acetate and prednisone in this group of patients was associated with improvement in fatigue symptoms.

• The study had a risk of bias because blinding was not used; only patient blinding was used.
• The findings were not generalizable.
• Findings were specific to patients with castration-resistant metastatic prostate cancer.  Various analyses were performed between those with clinically significant fatigue at baseline and those without; however, the fatigue level considered significant was not defined specific to this study, and relevant differences in sample size per analysis were not provided. 
• No information was provided about whether patients used any other activities or interventions that could have affected fatigue outcomes.

Findings demonstrated that treatment with abiraterone acetate in addition to prednisone was effective in improving fatigue in patients with metastatic castration-resistant prostate cancer. This is an important step forward to manage fatigue in this group of patients. This approach can only be expected to be of benefit for this disease, based on the understood actions of the drug.  Nurses can advocate for the use of this approach in patients with severe fatigue.

To test the effectiveness of reflexology delivered by partners in patients with cancer 
 

An initial reflexology session of 30 minutes was provided in the hospital setting. The session included relaxing techniques, 15 minutes of reflexing areas of the feet corresponding to areas of the patient’s reported pain and body parts where cancer or pain was located. The final five minutes were used to reflex the entire area of the feet. Partners were taught how to perform a reflexing protocol and provided with associated written materials. Partners practiced the technique on the investigator or the patient and were given feedback on the technique. Signs and symptoms of deep vein thrombosis were reviewed to alert partners to avoid foot reflexology in that situation. Patients in the control group received usual care plus special attention for 30 minutes, consisting of reading a selection of the patient’s choice to the patient. Study data were obtained pre- and postintervention.

• The study reported on a sample of 86 patients.
• Mean patient age was 60 years (SD = 12.1 years) in the experimental group and 56 years (SD = 24.4 years) in the control group.
• The sample was 51% female and 49% male.
• The most prevalent types of cancer were lung, breast, colorectal, head and neck, and lymphoma.
• Of the total sample, 66% had a high school education or less, and 50% had an income less than $20,000.
• Baseline pain was 3.2 in the experimental patients and 4.5 in the control patients. Baseline anxiety was 5.0–5.6 (10-point scales).

• Multisite
• Inpatient setting
• North Carolina

• Patients were undergoing multiple phases of care.
• The study has clinical applicability for end-of-life and palliative care.

A randomized controlled trial design was used.

• Visual Analog Scale for Anxiety
• Brief Pain Inventory
• Short-Form McGill Pain Questionnaire

In the total sample, there were no significant differences between groups in pain outcome measures. In patients with higher baseline pain levels (≥ 5), significant differences were found in favor of the reflexology group in analysis of variance (p = 0.001, eta² for effect size = 0.12). Patients in the reflexology group had significant reduction in anxiety, with a 62% reduction from baseline to postintervention in those receiving reflexology versus 23% reduction in controls. Among those with higher levels of anxiety (≥ 5), significant differences were found in favor of reflexology (p = 0.001, eta² = 0.13).

Partner-delivered reflexology was associated with reduction in pain and anxiety compared to controls. The intervention appeared to be most effective in patients with higher levels of pain and anxiety.

• The study had a small sample, with less than 100 participants.
• The attentional control used was reading, rather than some use of touch. It is unclear if the specific technique of reflexology or touch was responsible for results observed.
• Limited demographic information was provided, so generalizability is not clear.
• The intervention was a single time point with pre- and post-measures. Longer term results or repeated use effects were not explored. The study was initially designed to include long-term follow-up after hospital discharge; however, attrition was so severe that this aspect of the research was dropped.
• There was no blinding, so there are associated risks of bias.
• No information was provided about medication use or any changes or differences between groups in overall pain management interventions.

Findings suggest that foot reflexology can be helpful for patients with cancer in reducing anxiety and perception of pain in the short term. Study findings suggest that partners can be taught to provide this type of intervention. Addition of partner-delivered reflexology might be a useful adjunct for anxiety and pain control; however, trained individuals need to be available to provide the teaching or the actual intervention.  Involvement of caretakers in patient care with this type of approach might be a useful way to empower patients and caregivers.