Corticosteroids, Systemic

To survey the use of dexamethasone on the palliative care wards at this cancer center when prescribed according to the guidelines, to document both the indication for use and any benefit obtained, and to document all side effects incurred.

Consecutive patients started on dexamethasone between April and December 1996 were entered into the survey. The department’s corticosteroid-prescribing policy is as follows: start at moderate dose (8-12 mg per day), wean rapidly to lowest effective dose, monitor closely, prescribe prophylactic nystatin (1 ml four times per day), prescribe prophylactic gastric protectants to all patients with a history of PUD or taking NSAIDs; if no benefit, then discontinue.

• N =106 patients enrolled; by week 6, only 24 patients remained. Only 13 (12.26%) had dyspnea. 
• AGE: Not stated
• MALES (%): Not stated 
• FEMALES (%): Not stated
• CURRENT TREATMENT: Not applicable, other
• KEY DISEASE CHARACTERISTICS: All patients had advanced malignant disease, median survival date of all patients from date of commencement of dexamethasone was 40.5 days.
• OTHER KEY SAMPLE CHARACTERISTICS: Mot common indication for steroids was spinal cord compression (6%), while anorexia (19%), nausea (12%), and low mood (12%) were the most common nonspecific indications. The most common reason for stopping steroids was death or deteriorating condition (48%). Seven patients were taking steroids by the end of eight weeks.

• SITE: Single site   
• SETTING TYPE: Inpatient and outpatient 
• LOCATION: England-Royal Marsden Trust hospitals (London and Surrey)

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care

Prospective survey

A performa was used to record the reason for starting steroids, the starting and any subsequent doses, the symptoms being palliated, any side effects, and the reasons for stopping steroids. The performa was updated weekly by the ward doctors or research nurses for a maximum of eight weeks. Following discharge, patients were followed-up in the outpatient clinic or at home by telephone. Symptoms were rated on a four-point scale (ranging from 0 to 3) corresponding to none, mild, moderate, and severe. Symptom responses were subsequently recorded as better (decrease in symptom score), worse (increase in symptom score), or no change compared to baseline. Response over time was shown by documenting the proportion of patients with an improvement in a symptom score from baseline at two specific time points: week 2 and at the last assessment. “Best overall response” relates to the best response documented at any time during the treatment with steroids. Side effects were also documented according to the four-point scale. Specific for dyspnea, 5 of 13 (38.5%) patients reported better, 6 of 13 (46.1%) reported unchanged, and 2 of 13 (15.4%) reported worse.

The most common specific reason for initiating steroids was spinal cord compression (6%), followed by cerebral metastases (4%) and then lymphangitis carcinomatosa (4%). The most common nonspecific indications were anorexia (19%), nausea (12%), and low mood (12%). The median starting dose for specific and non-specific indications was 12 mg and 8 mg respectively. In 96 cases, the median duration use was 21.5 days. The most common reasons for stopping steroids include; death/deterioration (48%), tailed off steroids (16%), and trail of steroids ineffective (9%). The symptoms that appeared to get better with steroids are anorexia (73%), nausea (92%), pain (86%), vomiting (94%), bone pain (100%), and all others (73%). The majority of patients complaining of dyspnea or poor mobility showed no change or worsening of symptoms. The most common side effects were oral candida (23% mild and 11% moderate), bruising/petechiae (16% mild and 10% moderate), and proximal myopathy (10% milk and 13% moderate).

Dexamethasone did not improve the symptom of dyspnea in this study. Thirty-nine percent of patients stated the symptom was better, 46% of patients reported no change, and 15% of patients reported dyspnea worsening with steroid use.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)
• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions not described that would influence results
• Selective outcomes reporting
• Key sample group differences that could influence results
• Measurement validity/reliability questionable 
• Findings not generalizable
• Questionable protocol fidelity
• Subject withdrawals ≥ 10%
• Other limitations/explanation: This study simply reported the findings by reviewing patients in the palliative care program with advanced cancer. No statistical analysis was used to determine if the intervention was successful or not. There is no demographic information regarding the participants other than they all had advanced cancer (no breakdown of age, male or female). No notation of concomitant intervention, no baseline dyspnea statistics (example, how many patients were severe at baseline?). Unknown if more groups were more likely to respond (example, were severe dyspnea patients more likely to respond than mild?). Comorbidities were not identified. Steroid choice and dose not controlled.

If nurses administer dexamethasone, it is imperative they assess for the s/s of oral candida. Nursing staff needs educated on the importance of nystatin as a prophylactic for oral candida. Nursing should be aware of other potential side effects from dexamethasone such as bruising and proximal myopathy.

To determine the feasibility of conducting a randomized trial of dexamethasone in patients with cancer and the estimated efficacy of dexamethasone in the treatment of dyspnea.

Patients were randomly assigned to a 1:1 ratio to receive either dexamethasone 8 mg (two capsules of 4 mg) orally twice a day for four days, then 4 mg given orally twice a days for three days or identical-appearing placebo capsules. After one week, patients received dexamethasone 4 mg orally twice a day for seven days in open-label fashion.

• N = 41 patients; 77 eligible for study, 52 enrolled, 11 became ineligible or declined to continue  
• AGE: Mean age = 63 years (range = 48-78)
• MALES: 39%  
• FEMALES: 61%
• CURRENT TREATMENT: Radiation 
• KEY DISEASE CHARACTERISTICS: A majority of patients (88%) had advanced cancer, with lung cancer being the most common diagnosis (81%). If not primary lung cancer, all had clinical or radiologic evidence of lung involvement.
• OTHER KEY SAMPLE CHARACTERISTICS: Other requirements: average dyspnea of 4 or greater over past week, Karnofsky PS of 40% or greater, undergoing radiation therapy, but not chemotherapy within one week. Exclusions: uncontrolled diabetes, severe anemia, oxygen at less than 90% on greater than 6 L per minute oxygen, megestrol use, delirium, open unhealed wound, recent corticosteroid use for greater than 14 days

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: University of Texas MD Anderson Cancer Center

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

Double-blind, parallel, placebo-controlled, randomized trial

Dyspnea was assessed at baseline, day 4+ or -2, day 7+ or -2, and day 14+ or -2. The Edmonton Symptom Assessment System (ESAS) was used. Dyspnea “now” was assessed using the Modified Dyspnea Borg Scale. The Cancer Dyspnea Scale as well as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-C30) was used. MicroLoop Spirometer was used at baseline to obtain FEV1, FVC, FEV1/FEV2, peak inspiratory flow, and peak expiratory flow. Patients used the portable Microlife PF 100 Peak Flow Meter daily to measure peak flow and FEV1. A priori was considered that the study was feasible if at least 50% of patient completed the study. Twenty patients per arm provided 80% power to detect an effect size as small as 0.66 within arms with a two-tailed alpha of 0.05. To estimate effect size, the within-arm mean differences between baseline and day 4, 7, and 14 along with the 95% CI for dyspnea was determine and applied the Wilcoxon signed-rank test. The Statistical Analysis System was used for statistical analysis.

Dexamethasone was associated with a significant reduction in ESAS dyspnea NRS of -1.9 (p = 0.01) by day 4 and -1.8 (p = 0.02) by day 7. Placebo was associated with a reduction of -0.7 (p = 0.38) by day 4 and -1.3 (p =  0.03) by day 7. After one week of open-label treatment, both arms had improvement in dyspnea by day 14 (p = 0.01 for dexamethasone, placebo p = 0.004). The dyspnea numeric scale showed similar results by day 14. EORTC showed improvements in dyspnea in the dexamethasone arm by day 4 (p = 0.04). ESAS drowsiness improved in the dexamethasone arm by day 4 (p = 0.03) and day 7 (p = 0.01), but not by day 14; however, baseline drowsiness was higher in the dexamethasone arm. Dexamethasone was well-tolerated with no grade 3 toxicities.

Dexamethasone showed to improve dyspnea with minimal adverse effects. Feasibility of a randomized controlled trial without unacceptable attrition was validated. More testing needs to be completed to determine absolute efficacy.

• Small sample (< 100)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results
• Subject withdrawals ≥ 10%
• Other limitations/explanation: 85% of patients completed week 1 of the study and 71% of patients completed week 2. This study focused on patients who had lung involvement with cancer. The sample size was small and hence the study was not powered to detect differences.  Co-interventions were not defined. The study was not powered to compare dexamethasone to the placebo, so no definitive conclusion can be made regarding the efficacy of dexamethasone compared to the placebo. The study description said patients were stratified into FEV1/FVC groups, but group differences were not reported.

Nurses may consider using corticosteroids management of dyspnea for patients with severe dyspnea when no obvious reversible etiologies and targeted interventions exist. Nurses need to be aware of the potential adverse reactions associated with corticosteroids and educate patients on such. Nurses need to be aware of the various routes of administration for corticosteroids.

To evaluate the differences in the effects of various opioids administered concurrently with corticosteroids on severity of dyspnea in patients with terminal-stage cancer.

This study retrospectively investigated the EHRs of patients with terminal cancer who were hospitalized, received oral or IV corticosteroid treatment with an opiate medication for dyspnea, and died while hospitalized. Patients were excluded if they received invasive interventions, received oral corticosteroids prior to admission, or did not receive both medications concomitantly. The effectiveness of combined opioids and corticosteroids treatment for dyspnea was assessed from the first to last administration using the STAS-J. The effectiveness of combined opioids and corticosteroid treatment for dyspnea was compared with time of corticosteroid initiation and maximum effect against dyspnea, as determined by changes in the evaluation score. Data was recorded daily from initiation to death. Opioid doses were recorded to the point at which max efficacy could be confirmed (responders) and at the time at which the assessment began (nonresponders) and compared between groups.

• N = 20 patients; 49 were screened and 29 did not meet full inclusion criteria  
• AGE: Mean age = 71 years (range = 49-94)
• MALES: 65%  
• FEMALES: 35%
• CURRENT TREATMENT: Not applicable
• KEY DISEASE CHARACTERISTICS: Terminal cancer; primary lesions mainly colon cancer, stomach cancer, or lung cancer. 70% of patients presented with pleural effusions, 25% had lung area metastatic spread, and 15% had lymphangitis carcinomatosis.  
• OTHER KEY SAMPLE CHARACTERISTICS: Median opioid dose 30 mg

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Kasugai Municipal Hospital, Japan

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care

Retrospective review

Wilcoxon signed-rank test was used to test the effectiveness of opioids in the terms of changes in the STAS-J score. This tool contains many questions about symptoms. The authors stated they used “only questions concerning effectiveness of combined opioid and corticosteroid treatment and opioid doses. They reported score changes as their measurement of interest, but it is unclear if this was a total STAS-J score or a subscale score. It is uncertain if this tool has been validated using individual questions. Logistic regression analysis was used to compare the opioid doses and responders versus nonresponders. Responders were defined as a patient who the STAS-J score decreased by greater than or equal to 2 points. Nonresponders were defined as a patient whose STAS-J score did not decrease or only decreased by 1 point.

Significant difference in STAS-J score at initiation and lowest STAS-J score (p = 0.0034) for patients currently treated with morphine and corticosteroids. STAS-J scores increased by 2 or more points in 14 patients with concomitant opioid and corticosteroid use. The logistic regression analysis did not show a significant impact of the opioid dose on dyspnea alleviation.

Use of morphine and corticosteroids has the potential to alleviate dyspnea in patients with terminal cancer. More research is needed to determine the efficacy of opioids and corticosteroids in reducing dyspnea.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)  
• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results
• Measurement/methods not well described
• Intervention expensive, impractical, or training needs
• Other limitations/explanation: The scale used for measurement of dyspnea is a multi-item scale but the authors used only selected questions and did not validate the reliability of using select questions. It is unclear how selecting questions influenced the total score that is reported.

Nurses may consider combining corticosteroids and opiates for management of dyspnea in terminally ill patients. Nurses need to be aware of the potential adverse reactions associated with both opioids and corticosteroids and educate patients on such. Nursing needs to be aware of the various routes of administration for corticosteroids and opioids.

To evaluate the effectiveness of corticosteroid to improve dyspnea and prolong survival in patients with terminal cancer

Retrospective chart review of 52 patients with terminal cancer who received corticosteroid for dyspnea. Effectiveness of corticosteroid to reduce dyspnea was assessed using the Support Team Assessment Schedule (STAS-J) and patients were classified as responders (n = 30) and non-responders (n = 22) based on STAS-J scores. Survival was compared between the groups, with patient survival being the primary endpoint.

• N = 52   
• MEAN AGE: 70 years (total sample)
• MALES: 57.7%  
• FEMALES: 42.3%
• CURRENT TREATMENT: Not applicable
• KEY DISEASE CHARACTERISTICS: Terminal phase of cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Dyspnea from pleural effusion, lymphangitis carcinomatosis, and lung metastasis

• SITE: Not stated/unknown   
• SETTING TYPE: Not specified    
• LOCATION: Municipal hospital in Japan

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care 

Retrospective chart review of terminal patients who received either oral or IV corticosteroids. Patients were classified as responders or non-responders and survival was compared between the groups.

Effectiveness of corticosteroids to alleviate dyspnea was assessed using the Support Team Assessment Schedule (STAS-J) dividing patients into responders and non-responders. The Mann-Whitney U test compared survival between responders and non-responders, the chi-square test analyzed patient background information, and the Common Terminology Criteria for Adverse Events (CTCAE), version 4, evaluated adverse effects.

There was significant improvement in survival for patients who responded to corticosteroids with reduced dyspnea then those that did not using the Mann-Whitney U test (8.5 versus 5 days, p = 0.0019). Side effects observed with corticosteroids included insomnia (15.4%), delirium (11.5%), and hyperglycemia (3.8%).

The use of corticosteroid alone or in combination with opioid did reduce dyspnea in some patients at end of life and, therefore, resulted in prolonged survival. However, side effects of corticosteroids must be taken into consideration when assessing reduced dyspnea and evaluating the benefit of prolonged survival.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: Retrospective study, lacks power to detect in depth statistical differences, no effective dose of corticosteroid established.

Dyspnea occurs at end of life and can be difficult to manage. Therapies to effectively reduce dyspnea at end of life are needed. Corticosteroid therapy may alleviate dyspnea in some patients at end of life. Nurses must continue to assess effectiveness of corticosteroids to reduce dyspnea along with side effects that may occur from therapy.

To explore potential factors predicting the response to corticosteroids for dyspnea in patients with advanced cancer.

Measurement variables were recorded at two time points as a part of routine practice for patients who received corticosteroids: baseline (day 1) and in the evening on day 2 after administration of corticosteroids. Patients were followed until one month after administration of corticosteroids and dates of discontinuation or death were recorded. Recommended doses of corticosteroids were betamethasone 2-8 mg per day; dexamethasone 2-8 mg per day, prednisolone 15-60 mg per day, methylprednisolone 10-40 mg per day, and hydrocortisone 50-200 mg per day given orally, IV, or subcutaneously.

• N = 74 patients: 82 enrolled, 6 patients died before day 3, and 2 patients had missing values of numerical rating scale (NRS) of dyspnea on day 3 for unknown reasons.  
• AGE: Mean age = 68 years
• MALES: 53%  
• FEMALES: 47%
• CURRENT TREATMENT: Unknown
• KEY DISEASE CHARACTERISTICS: Patients were included if they had metastatic or locally advanced cancer, were receiving specialized palliative care services, and had a dyspnea intensity of greater than 3 on NRS, worst during the last 24 hours. Patients were excluded if they were unable to communicate verbally due to delirium, dementia, or organic brain disorders; had contraindications to corticosteroids; had dyspnea due to acute exacerbation of underlying non-malignant comorbidities; or were planned or did undergo a thoracentesis during the study period.  
• OTHER KEY SAMPLE CHARACTERISTICS: The following patient characteristics were noted: primary lung tumor (39%), primary tumor of the stomach, colon, or rectum (18%), primary tumor of the uterus and ovary (14%). Other patient characteristics include: metastasis to lung (58%), metastasis to pleura (54%), metastasis to peritoneum (31%), metastasis to liver (30%), and metastasis to brain (8.1%). The majority of patients (84%) had an Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4; 76% had palliative prognostic index (PPI) greater than 6; 64% used supplemental oxygen. Median oxygen flow rate was 2 L per minute and median survival was 26 days.

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: 17 sites in Japan

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care

Prospective, observational study

Primary end-point of worst dyspnea by NRS the last 24 hours was on the evening of day 3. NRS format for dyspnea from the Japanese version of the MD Anderson Symptom Inventory (MDSAI) was used. A response to corticosteroids was defined as a priori greater than or equal to one-point reduction in NRS of dyspnea. Secondary endpoints included support team assessment schedule, Japanese version (STAS-J), patient-perceived changes in dyspnea, confusion assessment method, short version (CAM), and memorial delirium assessment scale. Potential predictors of response to corticosteroids were recorded prior to administration of corticosteroids by the treating palliative care physicians. Potential predictors included patient demographics, indicators of general conditions, palliative prognostic score (PaP), laboratory findings and oxygen variables, etiologies of dyspnea and clinical manifestations, physician-predicted response of a six-point Likert-type scale, baseline dyspnea severity, and dose of corticosteroid.  
Survival times were calculated using Kaplan-Meier methods. Paired student t tests were used to compare NRS values of dyspnea before and after the administration of corticosteroids. Patients with missing dyspnea NRS values on day 3 due to severe dyspnea or delirium caused by corticosteroids were classified into a non-responder group and Last Observation Carried Forward method was applied. Frequencies and 95% confidence intervals of the proportion of patients with positive CAM tests and those with MDAS item 9 scores greater than or equal to 1 were calculated. Cohen’s kappa was calculated to explore the agreement between CAM-positive and MDAS item great than or equal to 1. Treatment responses between patients with and without each potential predictor was compared using chi-square tests. A logistic multivariate regression analysis was used to identify independent factors predicting greater than or equal to one-point reduction in dyspnea NRS. An alpha (two sided) and power = 0.8, 28 patients per group was needed to determine differences.

Patients had a 1.9 reduction of mean dyspnea NRS worst after administration of corticosteroids (p < 0.001). 50 patients showed a greater than one-point reduction in NRS worst, and 40 patients showed a greater than two-point reduction. 47 patients perceived their condition to be better. Predictor factors that were associated with greater than or equal to one-point reduction in dyspnea were age 70 years or older (p = 0.008), absence of liver mets (p = 0.001), presence of pleuritis carcinomatosa with small collection of pleural effusions (p = 0.011), and presence of audible wheezes (p = 0.002).  Major airway obstruction (p = 0.088), non-purulent serous secretions (p = 0.088), and absence of liver mets (p = 0.055) were associated with a two-point reduction in NRS. Multivariate analysis showed that independent factors predicting response to corticosteroids were PPI greater than 6 (p = 0.021), baseline NRS of dyspnea greater than or equal to 7 (p = 0.036), and absence of liver mets (p = 0.029).

Corticosteroids improved the majority of patients mean dyspnea NRS score. Patients also perceived that the corticosteroids improved their dyspnea. Caution should be taken to monitor for the development of delirium with starting corticosteroids in this patient population.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)
• Selective outcomes reporting
• Other limitations/explanation: Patients received co-interventions such as palliative treatment; therefore, effects cannot be exclusively attributed to corticosteroids. There was no set protocol about the dose and administration methods of corticosteroids therapy. The validity and inter-rater reliability of detecting etiologies and clinical manifestations were not formally tested. Some predictors were based solely on clinical impression. The sample size was not large enough to identify some predictors, such as major airway obstruction. It is unclear how steroids affect patients who have delirium or the inability to interpret symptoms. The benefits of steroids was measured after only 3 days of treatment. Some patients had treatable causes for their dyspnea, which may have contributed to a decreased dyspnea rating.

Nurses may consider using corticosteroids management of dyspnea in the palliative setting based on certain predictors such as bronchial constriction and no evidence liver mets. Even if patients are cognitively impaired, they may still experience symptoms of dyspnea and should be considered a candidate with alternative means of assessing dyspnea.