To provide an evidence-based review of empiric literature, about depression in patients with cancer, that focuses on occurrence, assessment, and treatment

The search examined literature published January 1966–September 2001 and cited in PubMed, PsycINFO, CINAHL, or BIOSIS Citation Index.

Common interventions for depression are behavioral and cognitive counseling. Because hundreds of articles exist about these topics, the review was limited to several meta-analyses of psychosocial interventions. Some measured emotional adjustment or distress rather than depression. All studies cited were conducted prior to 1998. Eleven randomized, controlled trials of medication treatment for depression in patients with cancer were identified. Tools for measuring depression included the Hamilton Depression Rating Scale, Clinical Global Impression, Hospital Anxiety and Depression Scale, and Montgomery-Asberg Depression Rating Scale. Descriptive reports—but no randomized, controlled trials—were found regarding complementary treatments.

Eleven randomized, controlled trials of medication treatment for depression in patients with cancer included data from 755 patients, averaging 58 patients per study.

Some data exist regarding the efficacy of psychosocial and pharmacologic treatments for depression in people with cancer. Studies conforming to usual practices of antidepressant trials demonstrated benefit. Studies measuring at less than five weeks tended to show less benefit. Randomized, controlled trials of alternative or complementary interventions were not found.

Investigate the effect of receiving early palliative care (EPC) on changes in depression from baseline to 12 weeks and the possible impact that treatment of depression may have on survival.

For parent study patients in an outpatient thoracic oncology clinic were approached for study participation and assessed for eligibility by the clinic medical oncologists. Consented patients were randomly assigned to EPC with standard of care or standard care alone. Patients in EPC group met with a certified member of the palliative care team within 3 months of enrollment and monthly thereafter until death. The standard care group only met with palliative care upon request.

AGE  mean age 64.4 (9.6)

MALES (%) 48.3   FEMALES (%) 51.7  

KEY DISEASE CHARACTERISTICS  within 8 weeks of diagnosis with NSCLC

OTHER KEY SAMPLE CHARACTERISTICS  ECOG score of 0-2, English speaking, not already receiving palliative care
 

SITE Single site   SETTING TYPE Outpatient setting   LOCATION Massachusetts General Hospital; Boston MA
 

PHASE OF CARE End of life care

APPLICATIONS End of Life and Palliative Care
 

Secondary analysis of clinical trial data

• PHQ-9 (Depression questionnaire): Major depression syndrome (MDS) measured at baseline and 12 weeks.    
• Survival: calculated by time of enrollment until death or time of censoring data  
   

At baseline, 14% of the sample met criteria for Major Depressive Syndrome (MDS).  Median survival was shorter for patients with MDS at baseline. (5.4 months for those with MDS versus 10 months for those without MDS; p=.001). This remained after controlling for demographic variables (p=.02). PHQ-9 scores were also associated with survival, controlling for demographic factors (p<.001). Participants in the EPC group had greater improvement in PHQ-9 scores from baseline to 12 weeks compared to the standard of care group, with a mean score change of -0.96 ± 4.53 (SD). In patients with baseline MDS ( 21 patients ) those in the EPC group had greater rates of depression response at 12 weeks than the standard of care group (p=.04). Rates of new antidepressant prescriptions and mental health visits did not differ significantly between groups.

Depression is associated with survival in this sample of NSLC patients. EPC was shown to slightly improve depression score in patients with MDS scores at 3 months.

No appropriate control group

Due to the exploratory methods of the secondary analysis study causality of survival or the depression outcome cannot be inferred from the results. There is limited data to support that the intervention is associated with survival benefit related to depression.  The study was carried out at a single site which limits generalizabilty. The control group did not have any attention control intervention also limiting interpretation of study results. Impact on depression scores was only seen in 21 patients who had MDS at baseline, and the change in score was very small, with very high variability as shown by the standard deviation.  Standard care was stated to include palliative care upon patient request - the number of those who did request and also receive palliative care is not reported
 

Conclusions from this study are difficult to interpret into specific nursing intervention. Findings suggest that for those patients with a major depressive disorder, earlier and proactive involvement of a palliative care team might be of benefit in managing the depression.

To investigate the efficacy and side effects of the 186Re-hydroxyethylidene diphosphonate (HEDP) radiopharmaceutical for the treatment of pain from skeletal metastases in patients with different types of cancer

Whole-body scans and assessments were done, and patients' symptoms were evaluated to determine whether they had simple metastatic bone pain. Patients were admitted to the day-care unit and received 1,480–3,330 MBq of 186Re-HEDP in saline intravenously over 10 minutes. All patients received oral or intravenous hydration before and after infusion. Whole-body scanning was done 4–24 hours later, and external dosimetry was done at zero, one, two, four to six, and 24 hours after injection.

• N = 20  
• MEAN AGE = 55 years (range = 30–75 years)
• MALES: 40%, FEMALES: 60%
• KEY DISEASE CHARACTERISTICS: Breast, prostate, colon, renal cell, neuroendocrine, and synovial sarcoma
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were excluded if they had impending or actual fracture, impending or existing spinal cord compression, or had received hemi- or whole-body radiation in the previous three months.

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

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

Phase-II observational study

• Visual Analogue Scale (VAS, 0–10)
• Dosage and type of pain medication graded from 0 (non opioids) to 3 (strong opioids) 
• Bone-scan index calculated as sum of scores of anatomic regions

The mean dose administered was 2,882 ± 675 MBq. The distribution of the tracer was seen within 4–24 hours and was correlated with the pretreatment whole-body scan. Pain relief began at around seven days after treatment. Response was observed for at least one week in 78.9% of patients and for two weeks in 63.2%. The mean duration of pain relief was 5.26 weeks (range = 1–8 weeks). There was a significant reduction of greater than three points in the first week (p = .0001) and, on average, the pain scale rating remained about 3 points below baseline at week 8 (p = .007). A transient decrease in platelets, white blood cells (WBC), and hemoglobin counts was seen. Four patients showed grade-3 platelet toxicity, 56% had at least grade-1 WBC toxicity, and 14.3% had at least a grade-2 decline in hemoglobin. A flare reaction, with a short-term worsening of bone pain, was seen in 53.5% of those who responded to the treatment and appeared to be dose-related.

186Re-HEDP may be an effective radiopharmaceutical for the palliation of metastatic bone pain.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Other limitations/explanation: The toxicity grading used was not described. Pain medications used are not described, and prior approaches in bone pain management are not described.

Pain from bone metastases is one of the most challenging areas in patients with advanced cancer. This radiopharmaceutical may provide another alternative option for pain management; however, further research is needed to determine its efficacy and toxicities and to determine the actual duration of effects. Patients receiving this agent need to be observed for bone marrow toxicities.

To identify appropriate prophylactic and therapeutic interventions for the assessment and management of skin toxicities including rash, dryness, pruritus, paronychia, hair abnormality, and mucositis in patients with cancer receiving treatment including epidermal growth factor receptor inhibitors (EGFR-Is) (e.g., cetuximab) alone or in combination with chemotherapy or radiotherapy.

In the absence of definitive evidence from clinical trials, a group of Italian expert clinicians produced recommendations for skin toxicity management in patients receiving EGFR-Is. The RAND Corporation/University of California, Los Angles (UCLA) Appropriateness Method was used for obtaining consensus on the expert opinions.

The consensus panel comprised an advisory board of nine expert clinicians from different clinical settings (six medical oncologists, two radiation oncologists, and one dermatologist). A group of 40 panelists was identified.

The database searched was MEDLINE (2005 to October 2009). Potentially relevant abstracts presented at annual meetings or gastrointestinal symposia of the American Society of Clinical Oncology and the European Society of Medical Oncology were examined.

Search keywords were EGFR inhibitors, cetuximab, skin toxicity, skin rash, and radiation dermatitis.

Studies were included in the review if they were

• In English language
• Observational, prospective studies about assessment and treatment
• Randomized, double-blind, placebo-controlled, or uncontrolled
• Retrospective and uncontrolled
• Systematic reviews and meta-analyses
• Consensus guidelines
• Reporting on available data for drugs tested in phase 3 (including abstracts).

Studies were excluded if they were published before 2005.

Patients were undergoing the active treatment phase of care.

General Prophylactic Measures Before Starting Cetuximab Treatment:

• Perform medical history and full-body skin evaluation with attention to xerosis, atopic dermatitis, and severe acne vulgaris.
• Education and general interventions may include the following.
  • Use sunscreens.
  • Avoid habits or products that can produce dry skin (e.g., hot water, alcohol-based cosmetics).
  • Enhance skin hydration (e.g., use bath oils).
  • Use alcohol-free moisturizing creams frequently.
  • Use tocopherol oil or gel.
  • Avoid tight shoes.
  • Avoid excessive beard growth, shaving with a regular shaving razor (e.g., sharp multiblade), using pre–shaving cream emollients and moisturizing aftershave, using alcohol and aftershave, or using an electric razor.

Rash

Management of Grade 1 Skin Rash (Adapted From the National Cancer Institute [NCI] Common Toxicity Criteria [CTC], Version 3):

• For skin lesions and symptoms including papules, pustules, or symptom-free erythema, do not modify cetuximab dose, interrupt treatment, or use topical or systemic treatment.
• Administer general educational and prophylactic measures.

Management of Grade 2 Skin Rash:

• Skin lesions include eruption with papules (grade 2A) or pustules (grade 2B) covering less than 50% of the body surface, with moderate symptoms and that do not interfere with daily activities.
• Do not modify cetuximab dose or interrupt treatment.
• Topical treatments include the following.
  • Antibiotics: clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel, BID until improvement to grade 1.
  • Avoid benzoyl peroxide products.
  • Use erythromycin 2% lotion for lesions of the scalp.
• Systemic treatments include the following.
  • Prevalence of pustules (grade 2A): No systemic treatment is recommended.
  • Prevalence of pustules (grade 2B): Antibiotics include oral semisynthetic tetracyclines. Use minocycline or doxycycline 100 mg orally once per day for more than four weeks and until the rash is asymptomatic.

Management of Grade 3 Skin Rash:

• Skin lesions and symptoms include eruption with papules (grade 3A) or pustules (grade 3B) covering more than 50% of the body surface, with severe symptoms that interfere with daily activities.
• Cetuximab dose modification or treatment interruptions include the following.
  • First occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to grade lower than 2. If the rash improves, continue at 250 mg/m². If the rash does not improve, discontinue therapy.
  • Second occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to lower than grade 2. If the rash improves, continue at a reduced dose of 200 mg/m². If the rash does not improve, discontinue therapy.
  • Third occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to lower than grade 2. If the rash does not improve, continue at a reduced dose of 150 mg/m². If the rash still does not improve, discontinue therapy.
  • Fourth  occurrence: Discontinue therapy definitively.    
• Topical treatment:
  • Antibiotics: Use clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel BID until improvement to grade 1. Avoid benzoyl peroxide products. 
  • Use erythromycin 2% lotion for lesions of the scalp.
• Systemic treatment:
  • Antibiotics include oral semisynthetic tetracyclines. Use minocycline or doxycycline 100 mg orally once per day for more than four weeks and until the rash is asymptomatic.
  • Corticosteroids: Use methylprednisolone 0.4 mg/kg orally or prednisone 0.5 mg/kg orally for up to 10 days.
• Systemic treatment for grade 3, highly symptomatic or nonresponsive patients:
  • Retinoids: isotretinoin 0.3–0.5 mg/kg orally
  • Corticosteroids: methylprednisolone or dexamethasone via IV
  • Antihistamines: clorfenamine intramuscularly (IM) or via IV
  • Antibiotics: amoxicillin or clavulanic acid and gentamicin via IV

Management of Grade 4 Skin Rash:

• Skin lesions include generalized rash with severe symptoms that require emergency treatment.
• Discontinue therapy immediately and definitively.
• Topical treatment:
  • Antibiotics: Use clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel BID until improvement to grade 1. Avoid benzoyl peroxide products.
  • Use erythromycin 2% lotion for lesions of the scalp.
• Systemic treatment:
  • Retinoids:  isotretinoin 0.3–0.5 mg/kg orally
  • Corticosteroids:  methylprednisolone or dexamethasone via IV
  • Antihistamines: chlorpheniramine IM or via IV
  • Antibiotics: amoxicillin or clavulanic acid and gentamicin via IV
  • Hydration via IV
  • Hospitalization

Xerosis, Fissures, and Eczema

Prevention:

• General educational and prophylactic measures are important.
• Regular use of emollient ointments, almond oil, and preparation of polyethylene glycol is recommended.

Management:

• For eczema, use topical treatment with medium-potency corticosteroids for one to two weeks.
  • Betamethasone dipropionate 0.05%–0.1% cream
  • Clobetasone 0.05% cream
  • Ointment fluocinolone acetonide
  • Hydrocortisone butyrate 0.1% cream
  • Consider simple or occlusive dressing for the extremities.
  • Topical antibiotic is recommended for superinfection.
    • Fusidic acid 2% cream
    • Bacitracin cream
    • Mupirocin 2% cream

Paronychia

Prevention:

• Avoid friction and pressure on the nail fold (e.g., avoid tight shoes).

Management:

• Wash with antiseptics including diluted hydrochloric acids solution or boric acid solution 3%.
• Use creams containing corticosteroids and antiseptics.
  • Betamethasone 0.05% plus clioquinol 3% ointment
  • Betamethasone 0.1% plus gentamicin 0.05% cream
  • Betamethasone 0.1% plus gentamicin 0.1% cream
  • Betamethasone valerate 0.1% plus fusidic acid 2% cream
  • Triamcinolone acetonide 3% plus chlortetracycline 0.1% ointment
  • Triamcinolone benetonide 2% plus fusidic acid 0.03% cream
• Use oral antibiotics for superinfection.
  • Amoxicillin or clavulanic tablets
  • Cefalexin tablets
  • Clindamycin capsules
• Use analgesic drugs (nonsteroidal anti-inflammatory drugs) orally.

The use of cetuximab in treating colorectal and head and neck cancer has significantly affected patient outcomes. A strategic approach to managing skin toxicities that includes consensus recommendations from experts will guide clinicians in minimizing the incidence of skin rash, improve compliance, and optimize patient outcomes.

Nurses who will be managing grade 1 and 2 skin toxicities should receive education. In addition, use of a multidisciplinary approach when managing skin rashes is paramount. Facilities may choose to create algorithms as an effective strategy to establish consistent processes for the assessment and management of skin toxicities induced by EGFR-I therapy.

The purpose of this meta-analysis and systematic review was to obtain pooled estimates of comparative efficacy of pegfilgrastim and filgrastim.

The PubMed and EMBASE databases were used.

Key words were neupogen, filgrastim, recombinant methionyl human granulocyte–colony-stimulating factor, G-CSF, CSF, longrastim, polyethylene glycol conjugated filgrastim and related terms

Studies were included if they were randomized, controlled trials (RCTs) if the patients were adults with non-myeoloid cancer, had a test of a single 6 mg dose or 100 mcg/ke of pegfilgrastim after start of chemotherapy, and a daily filgrastim comparator. Endpoints included grade 4 neutropenia, febrile neutropenia, and time to ANC recovery.

94 total references were retrieved.

• Five studies were included in the final analysis.
• The sample consisted of 617 patients, and size range across the five studies was 27–296.
• Key characteristics were breast cancer,  lymphoma, and non-Hodgkin lymphoma.

Active anti-tumor treatment

Standard mean difference (SMD) for time to ANC recovery showed mixed results across studies and pooled SMD to time to recovery was not statistically significant. There was no significant difference between drugs in rates of bone pain. Multiple different grouping and analyses of data were done to try to show differentiation of effect and when meta-analysis was limited to two phase III trials. Relative risk (RR) for febrile neutropenia for pegfilgrastim relative to filgrastim was 0.56 (95% CI [0.35, 0.89], p < 0.016).  Rates for neutropenia were not different.

Results suggest that daily filgrastim and single-dose pegfilgrastim provide essentially the same effect for time to ANC recovery, grade 4 neutropenia rates, and bone pain.

Some studies had very small samples, and heterogeneity with all studies was significant. Studies involved the use of different chemotherapy regimens which could have influenced findings here.

Both pegfilgrastim and filgrastim appear to provide similar clinical effects for prevention of neutropenia and febrile neutropenia. The side effect of bone pain was similar with both treatments. Pegfilgrastim dosing requires fewer subcutaneous injections.

To test the hypothesis that a home-based exercise intervention would improve fitness and physical activity and to determine the intervention effects on fatigue, self-reported physical functioning, and quality of life (QOL).

Those randomized to the exercise program received in-person instructions on how to exercise at a moderate intensity level, monitoring heart rate and how to warm-up and cool-down with exercise. Patients in the exercise group were asked to keep activity logs and were encouraged to exercise at least 10 minutes two days per week, increasing to 30 minutes per day, at least five days per week. Each received a weekly telephone call for the 12-week study to identify problems and reinforce participation, using cognitive-behavioral processes of change tailored to each patient. Patients in the control condition received weekly calls for 12 weeks for the administration of a symptom questionnaire and problem monitoring. Patients then received monthly telephone calls for three months. Telephone calls were audiotaped, and 25% of the tapes were reviewed for content to ensure fidelity to the study protocol. Study measures were obtained at baseline and at 3, 6, and 12 months.

• The sample was comprised of 46 patients (56.5% female, 43.5% male). 
• Mean age was 55.6 years (standard deviation [SD] = 8.24 years) in the control group and 59.5 years (SD = 11.2 years) in the exercise group. 
• All patients had colorectal cancer, with an average of three years since diagnosis.
• All patients had undergone surgery, and most did not receive radiation or chemotherapy treatment. 
• A majority of the patients had attended college and had a median income of greater than $60,000.

• Single site
• Home
• Rhode Island

Patients were undergoing multiple phases of care.

The study was a randomized, controlled trial.

• Seven-day Physical Activity Recall (7-day PAR)
• Treadwalk maximal fitness test
• Community Health Activities Model Program for Seniors (CHAMPS) questionnaire
• Functional Assessment of Cancer Therapy–Fatigue and Colorectal subscales (FACT-F and FACT-C)
• Short Form 36 (SF-36) physical functioning subscale

Both groups showed improvement in fitness and physical functioning over time, as well as increased physical activity. The exercise group showed a greater increase in physical activity at three months, but there was no difference from the control group at 6 or 12 months. During the first three months, the exercise group also showed significant improvement from baseline in CHAMPS energy expenditure and motivational readiness; however, these effects declined after three months. The intervention group demonstrated better submaximal aerobic fitness than the control group at all time points (p < 0.02). There were no significant intervention effects on fatigue, physical functioning, or QOL. These outcomes improved in all patients, and these improvements were sustained throughout the 12 months of follow-up. The authors speculated that the lack of apparent impact on fatigue may be associated with the fact that patients were highly functioning, although their baseline fatigue levels were lower than those seen in other studies in which exercise was effective.

The home-based exercise program improved patients’ physical activity, motivation, and fitness; however, it did not demonstrate an impact on fatigue or QOL. Activity and motivation were most improved during the first three months, when they received weekly telephone calls, suggesting that frequent contact may have been important in these results.

• The study had a small sample size, wth less than 100 patients.
• No information was provided regarding patient adherence to the recommended exercise program from patient logs.
• The lack of differences in CHAMPS between groups suggests that their actual activity levels were not substantially different.
• The majority of patients were highly educated and in a higher socioeconomic status and almost 100% were white, suggesting that these findings may not be applicable to other types of patients.

The findings suggest that a home-based exercise program can improve physical activity and aerobic fitness, but it did not appear that these improvements translated into reduced fatigue. Further research in the area of exercise and fatigue are needed to determine if exercise may be most effective in patients with greater fatigue at baseline.

To determine the efficacy of topical vitamin K1 as prophylaxis for cetuximab-induced skin rash (CISR) in patients with metastatic colorectal cancer

• N = 41
• MEAN AGE =  67.2 years (SD = 8.2 years)
• MALES: 25 (61%), FEMALES: 16 (39%)
• KEY DISEASE CHARACTERISTICS: Metastatic colorectal cancer (mCRC)
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were receiving cetuximab with or without chemotherapy. 61% of patients had a single metastatic site (mostly in the liver). Cetuximab was the first- or second-line treatment in nearly 73% of patients mainly in association with irinotecan; only one patient had a relevant skin comorbidity (e.g., previous temporal herpes zoster). 

• SITE: Single-site  
• SETTING TYPE: Outpatient  
• LOCATION: Turin, Italy

• PHASE OF CARE: Active antitumor treatment

Prospective, single cohort study design

• The investigators collected demographic data, the degree of disease extension, and occurrence and assessment data regarding the degree of cetuximab-induced skin reactions (CISR) including rash, xerosis, paronychia, and nail and hair changes.
• National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI, CTCAE) v3.0

Overall, 34 patients (82.9%) experienced CISR of any grade. During the first eight weeks of treatment, the grade and incidence of patients’ skin toxicity was grade 0 (6 patients, 15%); grade 1 (18 patients, 45%); grade 2 (10 patients, 25%); and grade 3 (6 patients, 15%). No grade 4 CISR was reported. The mean time to development of the maximum grade of rash was 34.7 days, and the median time was 28 days (SD = 24.7). All patients with grades 2–3 rashes were managed with topical or systemic antibiotics. Dermatologic consultation was provided to all six patients with grade 3 rash.

Overall, this study found that patients with mCRC who were treated with cetuximab and used vitamin K1-based cream prophylactically experienced a lower proportion of grade 2 rash (25%) and grade 3 rash (15%), which corresponds to the lower limit reported in the literature. Also, patients tolerated this treatment well.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (sample characteristics)
• Findings not generalizable
• Other limitations/explanation: Study involved only one disease type: mCRC. Forty-one consecutive patients were enrolled. No control.

The topical application of vitamin K1-based cream may reduce the risk of developing skin rashes to the lower limits of rash reported elsewhere in the literature. Prophylactic use of vitamin K1 cream is tolerated well by patients receiving cetuximab therapy.

To determine effectiveness of an hyaluronic acid-based emulsion to reduce development of greater than or equal to grade 2 radiodermatitis in women receiving adjuvant breast radiation

Women were randomly assigned to use topical hyaluronic acid on the medical or lateral half of the irradiated breast, and a control, petrolatum-based substance to the other half of the breast. Agents were to be applied three times daily beginning one day before the start of radiation therapy and continuing throughout the treatment period. Agents were not applied within four hours prior to radiation treatment. Patients were not to apply other topical products unless otherwise instructed by the physician. All other agents used were to be documented.

• The study sample (N = 65) was comprised of female patients with breast cancer.
• Mean age of the sample was 55.4 years.
• Of patients in the sample, 93% had medium or large breast size.
• Patients were treated with intensity-modulated radiation therapy (IMRT), receiving 50 Gy in 25 daily fractions with or without a boost of 10–16 Gy. 
• Fifteen percent of the study sample were African American and 15% were Hispanic.

The study took place at MD Anderson Cancer Center in Houston, TX.

Patients were undergoing active anti-tumor treatment.

The study used a single-blind controlled trial design.

The National Cancer Institute Common Toxicity Criteria (version 3) for skin toxicity grading was used.

Twelve percent dropped out of the study for a variety of reasons. In weeks 1–5 there were no differences between groups in severity of dermatitis in intent to treat and evaluable patient groups. In week 6 the side of the breast treated with hyaluronic acid was scored worse (p = 0.009). No associations were found between severity of dermatitis and body mass index, breast size, smoking history, diabetes or radiation dose. Forty-nine percent of control areas developed greater than grade 2 dermatitis compared to 61% of evaluable areas using hyaluronic acid emulsion. Overall, 1.4% developed grade 3 radiodermatitis.

Prophylactic application of a hyaluronic acid-based emulsion did not reduce the incidence of greather than or equal to grade 2 radiodermatitis in this group of women receiving adjuvant radiation therapy for breast cancer.

• The sample size was small, with less than 100 participants.
• Findings are not generalizable to other patient groups based on radiation therapy dosage and site.
• No information regarding patient adherence to the protocol is provided. 
• Procedures state that the attending physician had discretion to order additional treatments; however, no information is provided as to whether this occurred or not. 
• The study was ended early.

In the study, hyaluronic acid gel was not as effective as a petrolatum based gel for reducing the severity of radiodermatitis. Authors noted that the radiation therapy approach was forward-planned IMRT, which may also have led to significant reduction in severe dermatitis, since the percent of patients with grade 3 dermatitis in the study was lower than reported elsewhere. Other studies that showed hyaluronic acid to be effective were in patients who had higher doses of radiation. It is also not clear if there is a difference in effect of hyaluronic acid for prevention or treatment of radiodermatitis.

To evaluate the efficacy of oral transmucosal fentanyl citrate (OTFC) in the treatment of dyspnea on exertion in patients with advanced cancer

Subjects were chosen over the course of one year. The participants were assigned to one of two treatment groups. The study administered a dosage of 200 µg to patients who were not receiving opioid treatment and 400 µg to those using opioids for other cancer-related symptoms. Prior to testing, the patients remained at rest for five minutes. They were then given OTFC, and the 6-Minute Walk Test (6MWT) was carried out. During visit 2, patients who had been receiving the investigational product were given the placebos and vice versa. At least two days passed between visits 1 and 2 to perform the 6MWT. The follow-up of patients covered a maximum period of seven calendar days.

• N = 13
• MEAN AGE = 65.2 years
• MALES: 84.6% (n = 11), FEMALES: 15.4% (n = 2)
• KEY DISEASE CHARACTERISTICS: Average time after diagnosis was 1.88 years; locations of primary tumors were lung (n = 10; 76.9%), kidney (n = 1; 7.7%), breast (n = 1; 7.7%), and stomach (n = 1; 7.7%)
• OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria included moderate dyspnea defined as dyspnea caused by basic activities of daily living in the past 24 hours with an intensity of at least 3 on a scale from 0–10; Karnofsky index score > 50; hemoglobin levels within the past month exceeding 10 mg/dl; and SaO2 >90%. Exclusion criteria included patients with advanced chronic obstructive pulmonary disease. 

• SITE: Not stated/unknown  
• LOCATION: Not specified

• APPLICATIONS: Palliative care

Randomized, double-blinded, crossover, placebo-controlled clinical trial

• Edmonton System Assessment System (ESAS), a numeric rating scale to determine changes and severity of breathlessness.
• Dyspnea intensity scale, a numeric scale from 0–10 (0 = no dyspnea and 10 = maximum severity)
• Karnofsky Performance Status (KPS)

Patients were classified into three categories according to the differences observed in dyspnea before and after completion of the 6MWT. 1) Better response to the treatment obtained in the first period, 2) same response to both the periods, and 3) better response to the treatment obtained in the second period. No differences between treatments were demonstrated (P = 1). There were no differences between the change in oxygen saturation level before and after the 6MWT (P = 0.7541). The distance walked in the different sequences did not vary independently (P = 0.6550). There were no differences in the relation to the Edmonton Symptom Assessment System before or after the 6MWT (P = 0.1234). No secondary effects associated with the medication were observed. Type 2 error was ruled out with a confidence level exceeding 5%.

The study concluded that it could not demonstrate that OFTC improved exertion dyspnea in patients with advanced cancer. A placebo effect was observed in all the patients. This study had a small sample size of 13 patients. It was observed that OTFC may reduce dyspnea in the first three minutes of initiating the test, but this lacked statistical significance.

• Small sample (< 30)
• Measurement/methods not well described
• Findings not generalizable
• Other limitations/explanation: Study was costly because of the cost of developing a placebo with the characteristics of OTFC. Only a select number of laboratories agreed to manufacture the placebo, increasing the cost of the clinical trial. The study had a single point in time evaluation.

Dyspnea is one of the most common and distressing symptoms experienced by patients with advanced cancer. This study demonstrated some benefit of transmucosal fentanyl citrate on dyspnea with exertion in the first three minutes, but this result was not statistically significant. Overall, transmucosal fentanyl did not ffect dyspnea with exertion in these patients. This study was small with only 13 participants, and a placebo effect was observed in all patients.

STUDY PURPOSE: To compare second-generation azoles with first-generation azoles in patients with hematologic malignancies by comparing rates of proven or probable invasive fungal infections (IFIs), invasive aspergillosis, receipt of empirical antifungal therapy, overall mortality, and withdrawal from studies related to development of adverse effects

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: MEDLINE, EMBASE, and Cochrane Registry of Controlled Trials databases; conference proceedings from the American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, and European Group for Blood and Marrow Transplantation from 2002–2012

KEYWORDS: voriconazole or posaconazole and prophylaxis or prevention

INCLUSION CRITERIA: Studies written in English; prospective and randomized controlled trials comparing second-generation and first-generation azole antifungal agents with regards to antifungal prophylaxis in patients with hematologic malignancies who were neutropenic following cytotoxic chemotherapy or hematopoietic stem cell transplantation, or receiving immunosuppressive therapy

EXCLUSION CRITERIA: IV administration of azole antifungal agents, unless the IFI was proven or suspected; prospective studies in which the control arm used a historical cohort; ongoing trials

TOTAL REFERENCES RETRIEVED = 168 reviewed (Of these, 18 were identified as potentially relevant; of these, 14 were screened out.)

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two reviewers independently screened the literature for eligibility for inclusion, and two other reviewers independently extracted the data from included studies and assessed for quality parameters.

• FINAL NUMBER STUDIES INCLUDED = 4
• SAMPLE RANGE ACROSS STUDIES = 465–602
• TOTAL PATIENTS INCLUDED IN REVIEW: 2,267 patients (Although elsewhere in the article, the authors note 2,165 patients.)
• KEY SAMPLE CHARACTERISTICS: Multi-center, two-arm, parallel, prospective, randomized controlled trials. Three of the four studies included patients who received allogeneic stem cell transplantation. The fourth study included patients experiencing prolonged neutropenia following induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome.

PHASE OF CARE: Transition phase after active treatment

Prophylaxis using second-generation azole antifungal agents significantly reduced IFIs as compared to first-generation agents (OR = 0.47, 95% CI 0.32–0.69, I² = 0%, p = 0.0001; four trials, 2,267 patients) and also significantly reduced invasive aspergillosis (OR = 0.28, 95% CI 0.17–0.48, I² = 28%, p < 0.00001; four trials, 2,267 patients). Additionally, posaconazole significantly reduced the incidence of fungal infection (OR = 0.40, 95% CI 0.19–0.87, I² = 52%, p = 0.02; two trials, 1,202 patients), but voriconazole did not (OR = 0.56, 95% CI 0.30–1.04, I² = 0%, p = 0.06; two trials, 1,065 patients). Second-generation azoles significantly reduced IFIs (OR = 0.47, 95% CI 0.31–0.71, I² = 0%, p = 0.0003; three trials, 1,744 patients) and invasive aspergillosis (OR = 0.31, 95% CI 0.13–0.52, I² = 44%, p < 0.0001; three trials, 1,744 patients) when compared to fluconazole. When compared to itraconazole, second-generation azoles resulted in significantly fewer IFIs (OR = 0.35, 95% CI 0.14–0.87, I² = 35%, p = 0.02; two trials, 827 patients) and cases of invasive aspergillosis (OR = 0.11, 95% CI 0.03–0.40, I² = 0%, p = 0.0008; two trials, 827 patients).

Significantly fewer patients receiving prophylaxis with second-generation azoles required empirical antifungal therapy (OR = 0.62, 95% CI 0.50–0.77, I² = 0%, p < 0.0001; three trials, 1,667 patients). Despite these findings, no difference was noted in overall mortality in patients receiving antifungal prophylaxis with second-generation or first-generation azoles (OR = 0.81, 95% CI 0.64–1.01, I² = 0%, p = 0.06; three trials, 1,802 patients).

Patients with hematologic malignancies are at increased risk of IFIs, with invasive aspergillosis being particularly worrisome. Second-generation azoles appear to be superior to first-generation azoles in regards to prevention of IFIs, including invasive aspergillosis, without increased risk of adverse events. Second-generation agents also have better bioavailability and fewer drug-drug interactions than first-generation agents.

• Small number of studies (four)
• Variation between studies regarding duration of administration of antifungal agents
• No subgroup analysis of specific study populations
• The risk of heterogeneity is moderate to low, as significant heterogeneity appeared in only a portion of subgroup analyses.

This meta-analysis suggests that antifungal prophylaxis with second-generation azoles is more effective than first-generation azoles in prevention of IFIs, and without increase in adverse events. Interestingly, no difference was observed in overall mortality.