PHASE OF CARE: Multiple phases of care

Intervention types that were included in the meta-analysis were educational, psychological support, cognitive behavioral therapy, relaxation training, music therapy, coping skills training, and communication skills training. The majority of studies incorporated two or more interventions together. Fifteen studies showed overall significant effects on anxiety (d = -8.71, p < .001). The combination of education and psychological support (d = -8.17, p = .04) or education combined with relaxation training (d = -12.95, p < .001) were effective in reducing anxiety. Large combined effects were seen on depression (d = -8.12, p < .001). No analysis of effects for specific intervention types was possible. In greater than 69% of studies, the interventions were performed by nurses.

The findings of this study support the effectiveness of psychoeducational interventions to reduce anxiety and depression in patients with cancer in China.

The studies included in this analysis had numerous flaws. The meta-analysis was primarily done across all types of interventions. Because most of the studies used combined interventions, the effectiveness of individual components could not be determined. The authors noted that the trials were carried out in Chinese regions where almost no negative studies are reported, so publication bias cannot be ruled out.

The findings of these studies support the effectiveness of psychoeducational interventions for anxiety and depression in patients with cancer. Although these findings were only in Chinese patients, they are in agreement with the bulk of overall evidence in this area. These results suggest that psychoeducational interventions are likely to have similar levels of effectiveness in various cultural groups.

To evaluate the efficacy and safety of olanzapine compared with 5-hydroxtryptamine3 (5-HT₃) receptor antagonists for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) and to evaluate the impact of olanzapine on quality of life (QOL) of those receiving chemotherapy

Patients were randomized into the test group or the control group. On day 1, the test group received 10 mg oral olanzapine, 10 mg IV azasetron, and 10 mg IV dexamethasone; the control group received 10 mg IV azasetron and 10 mg IV dexamethasone. On days 2–5, the test group received 10 mg oral olanzapine and the control group received 10 mg IV dexamethasone. Patients were permitted to take other antiemetic therapy for nausea or emesis based on clinical circumstances. Assessments occurred on days 1–5 post-treatment, and QOL was measure on day 6.

• The study consisted of 229 participants.
• Men in the test group had a mean age of 54 ± 9.23; women in the test group had a mean age of 48.25 ± 12.7. Men in the control group had a mean age of 54.5 ± 10.33; women in the control group had a mean age of 49.58 ± 12.12.
• The test group was 40.5% female and 59.5% male. The control group was 40% was female and 60% male.
• Cancer diagnoses were breast (24%), lung (23%), colorectal (13%), lymphoma (10%), stomach (9%), esophageal (5%), ovarian (5%), teratoma (2%), thymus (2%), cervical (1%), gingival (1%), glioblastoma (1%), laryngeal (1%), malignant melanoma (1%), and oropharyngeal (1%),
• Chemotherapy agents were cisplatin (44%), oxaliplatin (23%), epirubicin (18%), adriamycin (8%), carboplatin (6%), and dacarbazine (1%).

The setting was not identified.

All patients were in active treatment.

This was a randomized controlled trial.

• The Common Terminology Criteria for Adverse Events, version 3 (CTAE v.3) observation table was used to grade CINV.
• The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was used to evaluate quality of life.

• No significant difference was noted between both groups for complete response (CR) for acute periods with HEC or MEC.
• Respective improvement in CR occurred in the test group for delayed nausea and vomiting with HEC (39%) and MEC (25%). The whole period of nausea improved 41% with HEC and 27% with MEC (p < 0.05).
• The olanzapine regimen protected more than two-thirds of patients from emesis after receiving HEC and MEC, thus avoiding the use of rescue therapy 2–4 days after chemotherapy.

Olanzapine can improve the CR of delayed nausea and vomiting and QOL in patients receiving HEC and MEC.

• The study was not blinded. The test group received oral medication, which the control group did not receive.
• Other antiemetic therapies were used as needed and not monitored or factored into the analysis.
• Validity and reliability of the measurement tools was not included.
• Drug safety and toxicity were not defined or monitored.
• Reporting of statistical results was unclear; the authors reported two values with each measurement (e.g., \"complete response for delayed nausea and vomiting in patients with HEC improved 39%, 22%\") without explanation of what these two measurements correspond to.
• Discrepeancies were reported with the QOL measurements.

Olanzapine may be effective in preventing delayed CINV in patients receiving HEC or MEC, but results should be used cautiously because of poor statistical evaluation and reporting.

To evaluate the efficacy and safety profile of pegylated liposomal doxorubicin (PLD) (Doxil^®) at different doses, as well as predictive factors of palmar-plantar erythrodysesthesia (PPE).

The regional cooling mechanism comprised application of ice packs to the wrists and ankles during PLD administration.

• The study reported on a sample of 330 women who received PLD as treatment for recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinomas.
• Median patient age was 60 years.

University of Texas MD Anderson Cancer Center in Houston

This was a retrospective chart review.

National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE); version not specified

• The proportion of patients with PPE was significantly higher among those who used a cooling mechanism compared to those who did not (39% versus 26%, p = 0.0067).
• Median overall survival and median progression-free survival did not differ between patients who received different doses of PLD.

Higher doses and additional cycles of PLD were associated with a higher incidence of adverse reactions, including PPE. Potential predictors of PPE were use of cooling mechanisms, higher numbers of PLD cycles given, occurrence of mucositis, neutropenia, and peripheral neuropathy.

This was a retrospective study only.

To evaluate trazodone for the treatment of insomnia in patients with cancer.

Patients were given trazodone 12.5 to 50 mg orally as needed for insomnia.

• The sample comprised 30 patients (40% male, 60% female).      
• Median age was 62 years (range 37–84).
• Patients had cancer and were experiencing insomnia that had not responded well to standard hypnotics.
• Diagnoses included gynecological, urological, breast, hepatobiliary-pancreatic, lung, colorectal, lymphoma, other cancers. 
• Patients were seeking palliative care consultations.

• Single site  
• University Hospital in Japan

• Patients were undergoing the end of life care phase of care.
• The study has clinical applicability for palliative care.

The study was an observational, retrospective review.

Chart review looking for requests for additional request for hypnotics within seven days of initiation of the intervention

Of the patients with cancer treated with trazodone, 50% did not request additional hypnotics within seven days. Two of four patients reported improved nightmares.

Low-dose trazodone (12.5–50 mg) may be useful in treating insomnia with and without nightmares in patients with cancer.

• The study had a small sample size, with less than 30 patients.       
• Baseline sample/group differences were of import.
• The study had risks of bias due to no control group, no blinding, no random assignment, and no appropriate attentional control condition.
• Unintended interventions or applicable interventions not described would have influenced the results.
• Measurement/methods were not well described.
• Measurement validity/reliability was questionable.
• Findings were not generalizable.
• This was an observational study only.

Low-dose trazodone may be helpful in treating insomnia and improving nightmares in patients with cancer and insomnia. Further prospective studies are warranted.

STUDY PURPOSE: To determine the effect of prophylactic or preemptive treatment with lamivudine for patients with breast cancer who were hepatitis B surface antigen positive on the following: (a) the rate of hepatitis B virus (HBV) reactivation, which was defined as an increase in HBV DNA levels more than 10 times or an absolute increase of HBV DNA levels that exceeded 1×109 copies/ml; (b) incidence of hepatitis, which was defined as greater than a three times increase in alanine aminotransferase (ALT) that exceeded the upper limit of normal range (ULN) or an absolute increase of ALT of more than 100 u/l; (c) rate of chemotherapy disruption, which was defined as either a premature termination of chemotherapy or a delay of more than eighty days of chemotherapy between cycles; and (d) overall mortality. Secondary outcomes included incidence of HBV-related hepatitis, rate of HBV-related chemotherapy disruption, HBV-related mortality, occurrence of YMDD mutations, and withdrawal hepatitis.

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 6
• TOTAL PATIENTS INCLUDED IN REVIEW = 430
• SAMPLE RANGE ACROSS STUDIES: 43–50 patients (median range)
• KEY SAMPLE CHARACTERISTICS: Patients with breast cancer undergoing systemic chemotherapy who were HBV carriers (HBsAg)

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Elder care

An early preemptive strategy is superior to a therapeutic strategy in decreasing the incidence of HBV reactivation, HBV-related hepatitis, and the rate of chemotherapy disruption in patients with breast cancer.

• Limited search
• High heterogeneity

In this study, 16% of patients who were HBsAg positive undergoing chemotherapy for breast cancer developed overt hepatitis. Using a preemptive strategy of prescribing lamivudine at the commencement of chemotherapy decreased the rate of hepatitis to 2.2%. The authors noted that, as level III evidence, the AASLD (American Association for the Study of Liver Diseases) recommends that HBV carriers receiving cancer chemotherapy or immunosuppressive therapy with a baseline HBV DNA of less than 2,000 iu/ml should start antiviral therapy at the commencement of treatment and continue it for six months after the completion of chemotherapy or immunosuppressive therapy.

To explore the effects of acupressure on fatigue and other symptoms in patients with lung cancer undergoing chemotherapy

Patients were hospitalized for four days. On day 1, a research assistant (RA) taught patients how to self-administer acupressure, and patients received a handbook including an acupoint map and acupressure methods. On days 2–4 and in subsequent hospitalizations for chemotherapy, an RA assisted patients in acupressure and confirmed their accuracy. Three acupoints were used, and the intervention was done once daily every morning for five months. Patients were instructed to do the acupressure at home each day. Patients were randomly assigned to one of three groups by a coin toss; group A received acupressure with essential oils, group B received only acupressure, and group C received sham acupressure using three sham acupoints. Study data were collected one day before starting chemotherapy, on day 1 of the third chemotherapy cycle, and on day 1 of the sixth chemotherapy cycle. Data were collected 30 minutes after the acupressure intervention.

• N = 45  
• MEAN AGE = 58.3 years
• MALES: 57.9%, FEMALES: 42.1%
• KEY DISEASE CHARACTERISTICS: All had lung cancer, the majority were stage IV
• OTHER KEY SAMPLE CHARACTERISTICS: Education level was varied with most patients having a sixth grade or less education. 70%–80% were married.

• SITE: Single-site    
• SETTING TYPE: Multiple settings    
• LOCATION: Taiwan

• PHASE OF CARE: Active antitumor treatment

Three-group, sham controlled, randomized trial

• Tang Fatigue Rating Scale 
• Eastern Cooperative Oncology Group (ECOG) Performance Status rating
• Hospital Anxiety and Depression (HADS) scale 
• Pittsburgh Sleep Quality Index

Adherence rates to acupressure varied significantly across groups – for group A, 93%, group B, 91.9%, and group C, 77.3%. Only subscale scores for fatigue in daily activity were lower for the two acupressure groups on day 1 of the third chemotherapy cycle. There were no other significant differences between groups for fatigue. There were no significant differences between groups in anxiety or depression scores. Sleep scores were lower for group A at one time point and group B at another time point compared to the sham control group (p < .05). However, these differences were not consistent across all study time points, and there were no other differences between groups in sleep results.

Potential benefits of acupressure for fatigue and sleep disturbance among patients receiving chemotherapy for lung cancer are not clear in this study. Differences in patient outcomes were not consistent across study time points according to the study group. No effect was demonstrated on anxiety or depression scores.

• Small sample (< 100)
• Risk of bias (no blinding)
• Key sample group differences that could influence results
• Subject withdrawals ≥ 10%
• Other limitations/explanation: The sham control group was significantly older than the other study groups. 21% were lost to follow-up for various reasons; no ITT analysis was described. Data were collected only 30 minutes immediately after acupressure when the patient was in the hospital, so response duration is not known. Repeated use of the same tools may have resulted in testing effect. Adherence was much lower in the control group, so actual group differences due to acupressure cannot be determined.

This study does not provide strong evidence in support of the effectiveness of acupressure for management of fatigue, sleep disturbance, anxiety, or depression. The study did show that self-administration of acupressure was feasible and had no associated adverse effects in patients with advanced lung cancer. This is a low-risk, low-cost intervention that some patients may be interested in using.

To determine the effect of a home-based walking exercise program on the sleep quality and quality of life (QOL) of cancer patients and to determine if enhanced sleep quality was associated with improvement in QOL over time.

Patients were recruited from oncology outpatient clinics in two university-based medical centers and were allocated to either usual care (n = 35) or a home-based walking exercise intervention for eight weeks (n = 36). The exercise intervention involved brisk walking for 30 minutes three times per week in the evening before supper, with a five-minute warm-up and five-minute cool-down. Questionnaires were delivered in interview format.

• The sample was comprised of 71 patients (24% male, 76% female).
• Mean age was 51.80 years (standard deviation = 12.13 years).
• Cancer sites included breast (n = 39), gastrointestinal (n = 11), nasopharyngeal (n = 7), lung (n = 4), and other (n = 10).
• Of the patients, 74% were married, 32% were working, and 30% were receiving cancer treatment.
• Mean time since diagnosis was 3.84 years.

• Multisite
• Outpatient
• Hospital in Taipei, Taiwan

Patients were undergoing the active treatment phase of care.

The study was a randomized, controlled trial.

• Pittsburgh Sleep Quality Index (PSQI), Taiwanese version
• Medical Outcomes Study Short Form-36 (MOS-SF), Taiwanese version
• Borg rating of perceived exertion (RPE) scale     
• Walking exercise log

Patients in the exercise group reported significant improvements in sleep quality (p < 0.01) at one and two months, and the mental health dimension of QOL; no change was reported in the control group. Physical components of QOL were also improved in the exercise group (p < 0.0001). Among patients who exercised, enhanced sleep quality also corresponded with reduced bodily pain and improvements over time in the mental health dimension of QOL.

A home-based walking exercise program can be easily incorporated into care for cancer patients who are suffering from sleep disturbances and may benefit sleep quality and aspects of QOL.

• The study had a small sample size, with less than 100 patients.
• Confounders of sleep (environment, light exposure, and social factors) were not controlled.
• Only subjective sleep data were collected.
• The objective measure of physical activity was not collected, and additional physical activity, apart from the walking intervention, was not measured.
• The short follow-up did not provide information about whether patients continued adherence to the walking program, and the benefits.  

A home-based exercise program appears promising for improving sleep quality and QOL for cancer patients that can easily be incorporated into care, but further study is warranted with more objective measures and measurement of potential confounding variables.

STUDY PURPOSE: To evaluate the effects of nonpharmacologic interventions on patient-reported sleep, pain, and well-being in people with cancer and other conditions

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 11
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,066
• SAMPLE RANGE ACROSS STUDIES: 28–276
• KEY SAMPLE CHARACTERISTICS: Included cancer, arthritis, fibromyalgia, musculoskeletal pain, and headache as painful conditions; six studies were of patients with cancer

PHASE OF CARE: Not specified or not applicable

All treatments had at least one component of cognitive behavioral therapy for insomnia. Subgroup analysis showed that the interventions tested were significant for both cancer and noncancer cases. Another subgroup analysis showed that effectiveness was significant for face-to-face interventions but not for those conducted via the phone or Internet. Analysis showed effects for sleep (standard mean difference [SMD] = 0.78, p < 0.0001 with high heterogeneity), pain (SMD = 0.18, p = 0.05), and fatigue (SMD = 0.38, p = 0.01).

Nonpharmacologic interventions involving components of cognitive behavioral therapy for insomnia were shown to be effective in improving sleep, pain, and fatigue among patients with and without cancer.

High heterogeneity

Interventions like cognitive behavioral for insomnia are beneficial to improve sleep, reduce fatigue, and positively affect pain.

To test the theory that the local benefit of opioids is related to opioid binding sites in peripheral bronchus.

Patients were given 20 mg of morphine dissolved in 5 mL of normal saline administered through an ultranebulizer. If no subjective relief resulted, the dose was increased to 40 mg and was tried again after four hours.

• The sample was comprised of 15 patients with thoracic cancer without cognitive changes who had dyspnea that was difficult to control with standard treatment (e.g., pleural drainage, antibiotics, and diuretics). 
• Median age was 61 years. 
• Seven patients were on continuous oxygen by cannula.
• Ten patients were already on systemic opioids.

Inpatient hospital in Japan

This was a pilot, open-label, nonrandomized, uncontrolled study.

• Dyspnea visual analog scale (VAS) was measured at baseline and at 60 minutes after inhalation.
• Outcome criteria was an improvement greater than 10% decrease in VAS.
• Respiratory rate (RR), hemoglobin, and oxygen saturation were also measured.
• A questionnaire about adverse effects and preferences was administered.

Significant decrease occurred in VAS after nebulization (p = 0.005). Eight of 15 patients evaluated treatment effective and requested continuation. No significant change occurred in RR or oxygenation. A not statistically significance tendency was found for patients on systemic opioids to benefit more compared to nonopioid patients.

• The study had a small sample size and was uncontrolled.
• The intervention placebo effect cannot be ruled out.
• The dose increase without a washout period possibly contaminated the findings.

To compile evidence from randomized controlled trials, case series, and case reports to identify the effectiveness of various therapeutic agents for prevention and treatment of skin toxicities associated with epidermal growth factor receptor (EGFR) inhibitor therapy

DATABASES: PubMed (January 2002–May 2009) and SCOPUS (January 2002–March 2009), manual searching for retrieval of additional references from articles reviewed

KEYWORDS: EGFR inhibitor, cetuximab, erlotinib, gefitinib, panitumumab, management, skin toxicity, and cutaneous effects

INCLUSION CRITERIA: Clinical trial, case series, case report, or clinical management guideline that studied treatment options of EGFR inhibitor-induced skin toxicities; EGFR inhibitor dosing regimen and treatment outcomes included in the publication

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Authors do not state the total volume of literature reviewed or decision-making regarding article exclusion processes. Authors report that randomized controlled trials, case series, and case reports were retrieved.

• FINAL NUMBER STUDIES INCLUDED = Final reports included in the analysis were two randomized controlled trials, three case series, and 10 case reports.
• TOTAL PATIENTS INCLUDED IN REVIEW = 156

Interventions were categorized as preventive intent or treatment intent. Interventions included in the review were topical antibiotics, systemic antibiotics, antiseptics, topical corticosteroids, retinoids, and other products. The majority of interventions were reported regarding effectiveness with EGFR inhibitor rash. Pruritus associated with the EGFR inhibitor-induced rash was documented in 47 patients in seven case reports; however, only three reports addressed pruritus treatment. Management of xerosis was mentioned in three case reports and one case series, for a total of 20 patients.

Preventive intent findings:

• Interventions found included topical erythromycin solution, systemic tetracyclines, and topical retinoid (tazarotene cream in combination with systemic antibiotics).
• Erythromycin solution was provided to two patients. These patients experienced only slight erythema without pustules, suggesting a protective effect.
• Two randomized controlled trials investigated the use of systemic tetracyclines to prevent EGFR inhibitor rash. In the total 51 patients across these trials, systemic antibiotic treatment did not prevent rash. Findings did suggest that the use of systemic antibiotic treatment along with EGFR inhibitor can decrease the severity of the rash during the first month of EGFR inhibitor treatment.
• Tazarotene cream, in combination with minocycline, demonstrated no effect on rash severity in 39 patients. The retinoid also was associated with significant skin irritation, causing one-third of the patients to discontinue its use.

Treatment intent findings:

• Interventions found for treatment of EGFR inhibitor skin toxicity included topical antibiotics, systemic antibiotics, antiseptics, topical corticosteroids, retinoids, colloidal sulfur galenic cream, and cream containing urea and vitamin K.
• Topical antibiotics were the most common treatments and were most often used in combination with other topical agents or systemic antibiotics. This intervention was reported in 49 patients.
  • Topical antibiotics used included clindamycin, erythromycin, fusidic acid, and metronidazole.
  • The majority of cases had either partial or complete responses with treatment.
• Systemic antibiotics were used to treat more severe EGFR inhibitor-induced rash in a total of 16 patients in several case reports and case series. Systemic tetracyclines were used in 12 patients in combination with topical medications for treatment of rash. In seven patients, non-tetracycline compounds (e.g., penicillin, clindamycin, fusidic acid) were used in combination with various topical agents.
  • Mixed results were seen. Some patients had complete or partial response, but in 58% of cases, results were confounded by concomitant delay or dose reduction in EGFR inhibitor treatment.
  • Results with non-tetracycline compounds also were confounded by withdrawal of EGFR inhibitor treatment.
• Antiseptics, including povidone iodine, hexamidine, benzoyl peroxide, and boric acid were reported in seven cases. In all cases, these were used in combination with other topical or systemic drugs. Response to these interventions was confounded by concomitant EGFR inhibitor dosage reduction in two patients who had a “complete response” to intervention with antiseptics.
• Retinoid interventions for rash treatment included oral isotretinoin in four patients and topical adapalene in three patients.
• Other intervention reports were retrieved that involved use of topical sulfur galenic cream and a cream containing urea and vitamin K. Improvement in these three patients was reported.

Strong evidence supports the use of topical antibiotics to manage EGFR inhibitor skin toxicities. Antibiotics are the most common treatment option. Use of anti-acne medications such as benzoyl peroxide and retinoids is controversial. Steroids are not recommended until well-designed clinical trials can demonstrate efficacy because steroid use can aggravate and induce acne.

This review did not identify strong evidence for any of the interventions reported for the management of skin toxicities associated with EGFR inhibitors. Antibiotics are most frequently used to manage EGFR inhibitor-induced skin toxicities, and more reports are available on the use of antibiotics than on the use of other approaches. The authors concluded that the evidence in support of the use of antibiotics is questionable. In this review, the total number of cases involved in the use of topical antibiotics was 49, and the total number of cases involved in the use of systemic antibiotics was 68. In many of the cases for systemic antibiotic use, reported findings were confounded by the additional intervention of dose modification (i.e., EGFR inhibitor dosages were reduced, delayed, or stopped).

• Reports reviewed involved a variety of mixed interventions, so identifying the combinations of interventions that appear to have the greatest promise for successful management of EGFR inhibitor-induced skin toxicities is difficult.
• This review only focused on skin toxicities associated with EGFR inhibitors. Little information on toxicities other than skin rash was found.
• This review, as well as the current literature evaluating the interventions, had a number of limitations. The review was limited by a lack of information found on pruritus and xerosis, as well as a lack of substantive, well-controlled research in this area. Most reports gave information about the resolution of rash in terms of lesion count but did not evaluate patient symptoms or specific patient-centered outcomes.
• Most reports did not provide a determination or measurement of the severity of skin problems. Most studies did not conduct a follow-up to determine long-term resolution. Reports of complete resolution of skin rash often involved discontinuation or dose reduction of the EGFR inhibitor, so efficacy of the intervention is likely to have been overestimated.

This review emphasized the need for well-designed research in this area that includes appropriate follow-up strategies. This review also discusses the widespread use of antibiotics to treat EGFR-induced skin toxicities. It notes that topical antibiotics are recommended for treatment of milder skin reactions, and systemic antibiotics (e.g., minocycline or doxycycline) are recommended for treatment of more severe rash. The authors state that their recommendations are aligned with several proposed treatment algorithms that have been obtained from international and interdisciplinary EGFR inhibitor dermatologic toxicity forums. As evident in this review, these recommendations are not based on strong evidence.