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.

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 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 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 evaluate patient-reported satisfaction with treatment, quality of life (QoL), and dyspnea outcomes for four treatment strategies for malignant pleural effusion.

Four treatment regimens (indwelling pleural catheter [IPC] alone, video-assisted thoracic surgery [VATS] and IPC, bedside chest tube and talc slurry; and VATS with talc poudrage) for malignant pleural effusion (MPE) were evaluated using patient-reported outcome tools. The primary outcome of treatment satisfaction was measured immediately after treatment, as well as two and six weeks post-completion using the Functional Assessment of Chronic Illness Therapy-Treatment Satisfaction (FACIT-TS) tool. Secondary outcomes of improvement in dyspnea and QoL were measured at baseline, two, and six weeks post-treatment. Functional Assessment of Chronic Illness Therapy-Palliative (FACIT-Pal) was used to measure QoL; the London Chest Activity of Daily Living scale was used to measure dyspnea.

• N = 104   
• AGE: Median age = 61, range = 26-89
• MALES: 36%  
• FEMALES: 64%
• CURRENT TREATMENT: Other
• KEY DISEASE CHARACTERISTICS: Confirmed diagnosis of cancer with symptomatic pleural effusion confirmed on chest x-ray included; those with endobronchial obstruction, empyema, allergy to talc, or prior treatment for ipsilateral pleural effusion excluded. 
• OTHER KEY SAMPLE CHARACTERISTICS: Must be able to read and write in English. Lung cancer most common, breast cancer second most common diagnoses

• SITE: Multi-site   
• SETTING TYPE: Inpatient urban hospitals
• LOCATION: Canada

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

Prospective cohort study

Functional Assessment of Chronic Illness Therapy-Palliative (FACIT-Pal) was used to measure health-related QoL; the London Chest Activity of Daily Living scale was used to measure dyspnea; Functional Assessment of Chronic Illness Therapy-Treatment Satisfaction (FACIT-TS) was used to measure treatment satisfaction. Post-treatment pain measured on 0-10 scale, and ECOG performance status measurement was added mid-study.

No statistical difference in patient-reported outcomes was identified when comparing results for each of the four treatment modalities: indwelling pleural catheter (IPC), video assisted thoracic surgery (VATS), chest tube and talc slurry; and VATS talc poudrage. There was a statistically significant trend of improvement in overall FACIT-PAL score (p < 0.0001) and trend in decreasing breathlessness measured with both London Chest Activity Daily Living scale (p = 0.003) and FACIT-Pal shortness of breath score (p = 0.0007) when evaluating all study participants as a whole; there was no statistical difference between groups. Treatment satisfaction at six-week point was highest with VATS plus pleurodesis group and lowest with chest tube group; however, difference was NOT statistically significant.

Each of the treatment options for treating malignant pleural effusions are efficacious in improving health-related QoL and decreasing breathlessness with no statistically significant difference in patient-reported satisfaction when comparing each intervention.

• Risk of bias (sample characteristics)
• Key sample group differences that could influence results
• Measurement validity/reliability questionable
• Other limitations/explanation: The subject accrual period was from 2007 to 2013; variability in individuals performing interventions and setting (some outpatient, some inpatient). Difficulty recruiting from multicultural population due to inability to read/write in English influenced participant selection. Sample size small at 104. London Chest Activity of Daily Living scale reliability and validity only tested with COPD population, not MPE.

Nurses educating individuals living with symptomatic malignant pleural effusions need to understand and share data regarding the experience of other patients; patients will benefit from knowledge that other individuals with MPE report an improvement in health-related QoL and a decrease in breathlessness regardless of MPE treatment option utilized. More research is needed in development of measurement tools for breathlessness in individuals with MPE. Additional studies with larger sample sizes are needed to evaluate treatment of dyspnea in patients with cancer because dyspnea is commonly experienced by individuals with advanced disease.

To test the effects of reflexology on chemotherapy-induced peripheral neuropathy (CIPN), compared to standard care and CIPN education alone, in cancer survivors who have grade II-IV peripheral neuropathy.

Standard care control: All participants received verbal education and a brochure on CIPN at baseline, and standard care. 

Intervention: (a) same CIPN verbal education and brochure; (b) reflexology: rhythmic massaging of the head, neck, feet/toes, and fingers applied by a certified reflexologist or a family member trained by the reflexologist. Duration is 20 minutes, twice per day, for six weeks.

• N = 60 (30 in intervention group; 30 in control group)
• AGE: 58 years
• MALES: 53%  
• FEMALES: 47%
• CURRENT TREATMENT: Not applicable
• KEY DISEASE CHARACTERISTICS: Had (a) grade II-IV (mostly grade II) peripheral neuropathy at baseline and had been referred for a neurology examination by their physician; (b) CIPN duration consistent in 68% of patients; (c) received any chemotherapy regimen (mostly taxane- or oxaliplatin-based) and an average of about seven chemotherapy agents; and (d) any cancer type (mostly breast or gastrointestinal cancers). Cancer treatment status unknown. 
• OTHER KEY SAMPLE CHARACTERISTICS: Nearly all patients (93%) had stopped work due to their present illness. Less than 30% completed secondary school or higher. Most (92%) were married.

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: Trakya University Balkan Oncology Hospital in Edirne, Turkey

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Elder care, palliative care

Pilot randomized controlled trial

• Measurement time points: baseline (before the intervention), three weeks (midpoint), and six weeks (intervention completion).
• Brief Pain Inventory (BPI)–Patient-reported outcome (PRO) measure of pain severity and pain interference with general activities (e.g., walking, sleep, enjoyment of life).
• European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Chemotherpay-Induced Peripheral Neuropathy Form (EORTC QLQ-CIPN20)–PRO measure of sensory, motor, and autonomic CIPN symptoms
• NCI CTCAE v4.0–Physician-graded scale of neurotoxicity.
• Neurologic examination–Conducted by physician (only at baseline and six weeks)

Pain interference (BPI), and CIPN motor and autonomic symptoms (EORTC QLQ-CIPN20) improved from baseline to sixweeks in the reflexology group (p ≤ 0.017); but no difference was found between groups at any time point. In the reflexology group, sensory CIPN (EORTC QLQ-CIPN20) improved from baseline to six weeks (p < 0.001) and was significantly less severe at the six-week time point than the standard care group (p = 0.024). The control group’s pain/CIPN severity scores also decreased (non-significantly) over time.

Although reflexology may provide some benefit and relief for cancer survivors with peripheral neuropathy, this study does not support its efficacy in treating CIPN.

• Small sample (< 100)
• Risk of bias (no blinding)
• 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
• Measurement/methods not well described
• Measurement validity/reliability questionable 
• Findings not generalizable
• Questionable protocol fidelity
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: Patient’s current cancer treatment status was unclear; participants could have had peripheral neuropathy from other causes; not all participants received neurotoxic chemotherapy; other CIPN-influencing factors were not controlled for (e.g., diabetes status, concomitant CIPN treatments); sample and eligibility criteria was poorly described; unclear measurement methods–unclear whether patients were interviewed or individually responded to the questionnaires; if interviewed, unclear if the interviewer was blinded; no results reported for the NCI CTCAE v4.0 measure, neurologic exam, or BPI pain severity items; measurement or control for potential contamination, compensatory intervention (by the patients’ doctors), or issues with fidelity; unclear how family members were trained and checked-off to perform the intervention; unclear how many reflexology sessions were conducted by the reflexologists versus the family members, and whether this number was standardized across participants; unclear how they measured patient/family member’s adherence to the protocol; simple (assumed to be convenience) sampling used; Mann Whitney u and Wilcoxon ranked tests were used instead of a repeated measures ANOVA or other more powerful statistical test.

This study suggests reflexology could help to reduce CIPN severity; however, it had several critical limitations. Further research is needed to rigorously evaluate the effects of reflexology on specific types and symptoms of CIPN (e.g., taxane-induced chronic painful CIPN versus oxaliplatin-induced non-painful CIPN)—controlling for key CIPN-influencing factors such as participants’ phase of chemotherapy treatment; baseline CIPN duration, stability, and severity; functional status; concomitant CIPN treatments (e.g., duloxetine); and peripheral neuropathy-related comorbidities—in diverse populations. Subsequently, research is needed to evaluate the specific doses of and mechanisms by which reflexology reduces and/or prevents CIPN.

Evaluate the effectiveness of cold therapy on prevention of CIPN in those receiving paclitaxel-based therapy for breast cancer.

Patients wore glycerine-containing Elasto-Gel glove and sock on one extremity and nothing on the other extremity. Elasto-Gel glove/sock were cooled to -25 to -30 C in a freezer for at least three hours prior to administration; was worn for a total of 210 minutes, and changed every 45-50 minutes during infusion. A total of nine data points were collected.

• N = 33 enrolled; 29 evaluable at time point 1; 7 evaluable at time point 6; study terminated after time point 6.  
• AGE: 47.3 years (range = 35-68)
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All patients had breast cancer; adjuvant therapy in 62%; neoadjuvant therapy in 38%.
• OTHER KEY SAMPLE CHARACTERISTICS: 55% married; 31% single; 14% divorced; 88% nonsmoker; 8% current active smoker; 4% quit smoking. BMI average 28.5 (17.5 to 44.4).

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: Robert H. Lurie Comprehensive Cancer Center

PHASE OF CARE: Active anti-tumor treatment

Randomized controlled study of taxane-naïve patients receiving dose dense anthracycline plus paclitaxel therapy. Patients were own paired control.

Symptoms of neuropathic pain, including pain severity and sensory severity. Measured with NPSI, BPI, and QST for measurement of pain, pain severity, and sensory severity, respectively).

No significant difference in pain as measured by NPSI; all measurements of pain severity were increased with the BPI, including interference with daily activity, worst pain in the last 24 hours, average pain in 24 hours, and pain currently experienced. No significant difference in any of the five QSTs used for sensory severity, including sensitivity to innocuous touch, sensitivity to noxious stimuli, sensitivity to vibration, manual dexterity, and fine motor dexterity.

Study was stopped early at time point 6 due to high dropout rate from discomfort related to intervention; when stopped, no evidence of decreased CIPN was seen.

• Small sample (< 30)
• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Risk of bias (sample characteristics)
• Measurement/methods not well described
• Intervention expensive, impractical, or training needs
• Subject withdrawals ≥ 10%
• Other limitations/explanation: Sample characteristics include patients with only one disease and one type of therapy. Intervention would require significant buy-in from institution as it would require freezers in location of therapy and would require nursing or other staff to change glove/sock every 45-50 minutes.

Education about current therapies. Further research needed on cryotherapy for prevention of CIPN.

To investigate if acupuncture plus methlycobalamin is an effective treatment compared to methlycobalamin alone in reducing CIPN in patients with multiple myeloma.

Acupuncture plus methylcobalamin (Met + Acu) was compared with methylcobalamin alone to evaluate effectiveness on CIPN as measured by VAS, FACT-GOG-NTX (functional assessment of neurotoxicity) and nerve conduction velocity compared to methlycobalamin (Met) alone in patients with multiple myeloma.

Patients with multiple myeloma randomized to treatment group (Met+Acu) or control group (Met). Intervention duration for both groups was 84 days
                                               
Methylcobalamin administration protocol x 3 cycles/84 days: 1 cycle = 500 mcg IM qod x 20 days(10 injections) then two months oral met 500 mcg tid                                                                                                                                                                                           

Acu administration of protocol x 3 cycles: 1 cycle = bilateral acupuncture needles at designated acupoints (aseptic adm by senior physician (15 years of experience) at depth 0.3-1 inches x 30 minutes; initially in prone position with needle retention then administered to same acupoints in supine position x 3 days then qod x 10 days

• N = 98  (49 in treatment, 49 in control group) 
• AGE: Mean = 64 years
• MALES: 57%  
• FEMALES: 43%
• CURRENT TREATMENT: Chemotherapy, combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Multiple myeloma: subtypes IgG, IgA, IgD, light chain (kappa/lamda)
• OTHER KEY SAMPLE CHARACTERISTICS: Baseline EMG showed impairment of median and peroneal nerve conduction, no central nervous system or other disease related preexisting peripheral neuropathy, no pre-chemo peripheral neuropathy; baseline PN occurring after initiation of chemotherapy assessed by NCI-CTCAE at grade 2-4; baseline VAS 5.5-5.57/10; baseline FACT/GOG-NTX scores 36.48-36.63; no significant differences in baseline characteristics between treatment and control group.

• SITE: Single site   
• SETTING TYPE: Not specified    
• LOCATION: Multiple Myeloma Center, Bone Marrow Transplantation Center, Department of Hematology: The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Elder care, palliative care

Prospective randomized controlled trial to investigate effect of Met + Acu versus Met on CIPN, sx neurotoxicity and nerve conduction

VAS pain score (neuropathic pain); FACT/GOG-NTX questionnaire (functional assessment of neurotoxicity); EMG (nerve conduction velocity)

Evaluated outcome measures before and after treatments within and between Met + Acu and Met groups:

• VAS decreased in both Met + Acu and Met group (p < 0.001); Significant decrease VAS in Met + Acu compared to Met control group (p < 0.01)
• FACT/GOG-Ntx scores significant improvement within Met + Acu group (p < 0.001) and between Met + Acu group compared to Met control group (p < 0.05)
• Nerve conduction velocity: Motor conduction velocity significant improvement in Met + Acu group of bilateral median (p < 0.05) and peroneal nerves (p < 0.01); sensory conduction velocity showed significant improvement within Met + Acu group and between Met + Acu and Met control group of only sural nerve (p < 0.01); No improvement in FACT/GOG-NTX scores or in nerve conduction velocity in Met control group.

In 98 patients with multiple myeloma with grade 2 or higher CIPN, there was significant reduction in PN pain in Met + Acu and Met groups but more significant relief with Met + Acu. Only Met + Acu group had significant improvement in functional assessment of neurotoxicity symptoms and nerve conduction; no improvement in Met control group

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no appropriate attentional control condition) 
• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions not described that would influence results
• Measurement/methods not well described
• Measurement validity/reliability questionable 
• Findings not generalizable
• Other limitations/explanation: CIPN grade using NCI-CTCAE was not re-evaluated after baseline; CIPN severity assessment not reported and used a different grading system than baseline; randomization procedures not explained; sampling methods not described, uncertain whether VAS was specific to neuropathic pain in the hands/feet or general pain; FACT/GOG-NTX instrument validated for platinum/paclitaxel-induced peripheral neuropathy, and findings of specific categories of FACT/GOG-NTX not reported; only combined scores (this instrument measures peripheral neuropathy on multiple dimensions physical, social, emotional, functional, neurotoxicity sx); Actual p values not reported; no effect size reported; a two-way ANOVA should have been used to compare within- and between-group differences, an independent sample t test was used for the same group when a paired t test should have been used; prior/current treatment regimens of sample not identified to determine distinct pharmacologic origin of CIPN; not specified if patients actively receiving treatment or off treatment or time from last treatment; analgesics/neuroleptics/other CIPN treatments prior to or during study not identified, prior acupuncture (i.e., contamination) not identified

Acupuncture plus methylcobalamin may relieve CIPN-related pain, function, and nerve conduction in patients with multiple myeloma. Large multi-center, randomized controledl trials are needed to validate these findings and investigate their effects related to pharmacotherapies specific to MM utilizing rigorous measurement tools and validated instruments specific to patients with MM.

STUDY PURPOSE: To evaluate the evidence related to use of herbal medicine for prevention and treatment of chemotherapy-induced peripheral neuropathy

TYPE OF STUDY: Systematic review

DATABASES USED: 13 electronic databases including Medline, CENTRAL, EMBASE, AMED, China National Knowledge Infrastructure, Wanfang Database, CQVIP database, Korean Studies Information, DBPIA, Korea Institute of Science Technology Information, Research Information Center for Health Database, Korean Traditional Knowledge Portal, KoreaMed

YEARS INCLUDED: (Overall for all databases) through May 2017, no other limitations on publication date

INCLUSION CRITERIA: Randomized controlled trials that tested herbal medicine for preventing or treating CIPN. Participants in the studies were at least 18 years old, diagnosed with cancer, had received chemotherapy, and had CIPN diagnosed by clinical assessment.

EXCLUSION CRITERIA: Only the first treatment period data was analyzed for crossover trials. If the authors could not separate the results of the first and second periods in the crossover trial, they excluded the study. RCTs with unreliable or unavailable methods or results

TOTAL REFERENCES RETRIEVED: 819

FINAL NUMBER STUDIES INCLUDED: 28

TOTAL PATIENTS INCLUDED IN REVIEW: 2,174

SAMPLE RANGE ACROSS STUDIES: 31-186

KEY SAMPLE CHARACTERISTICS: Various solid tumors and one study in multiple myeloma, studies investigated oral herbals foot baths, IV, and fumigation. Oxaliplatin was used in 20 studies, paclitaxel was used in two, docetaxel was used in one, and various chemotherapy regimens were used in four studies.

PHASE OF CARE: Active anti-tumor treatment

The authors were unable to perform planned meta-analysis because of the heterogenicity of herbal treatments, doses, outcome measures, and small sample sizes.

Unable to draw any conclusions about the efficacy of herbal treatments for prevention or treatment of CIPN

• No quality evaluation
• High heterogeneity
• Low sample sizes

No changes to clinical practice can be recommended based on this article.

STUDY PURPOSE: Examine whether goshajinkagin prevents CIPN in patients receiving neurotoxic chemotherapy.

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: PubMed, EMBASE, Ichushi, Cochrane Central Register of Controlled Trials

YEARS INCLUDED: (Overall for all databases) inception through August, 2017

INCLUSION CRITERIA: Randomized controlled trials that assessed efficacy and safety of goshajinkagin in preventing CIPN; patients had to be undergoing neurotoxic chemotherapy (taxanes, vinca alkaloids, platinum agents); adult patients older than age 18 years ; prophylactic doses of goshajinkagin (7.5 g per day)

EXCLUSION CRITERIA: Patients that had already developed CIPN; dosing of goshajinkagin that was given as treatment for CIPN rather than prophylaxis

TOTAL REFERENCES RETRIEVED: 234 articles retrieved; five articles evaluable after inclusion/exclusion applied

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Five trials with 397 total patients; 3 colon cancer, 2 breast cancer

FINAL NUMBER STUDIES INCLUDED: 5 

TOTAL PATIENTS INCLUDED IN REVIEW: 397

SAMPLE RANGE ACROSS STUDIES: Included patients with breast cancer or colon cancer, receiving FOLFOX 4 or FOLFOX 6, and weekly paclitaxel- or docetaxel-based chemotherapy. Studies ranged from 18-186 patients; studies ranged from 12-26 weeks in duration. Two trials with placebo comparator; two trials with no interventions for control; one trial administered mecobalamin for comparison; one trial terminated early due to incidence of increased CIPN. Two different definitions of CIPN used, those from NCI-CTCAE in four studies (measuring severity) and that from the Neurotoxicity Criteria of Debiopharm (DEB-NTC) in one study (measuring duration)

KEY SAMPLE CHARACTERISTICS: 35-88 years old; breast cancer and colon cancer

PHASE OF CARE: Active anti-tumor treatment

Overall, the use of goshajinkagin was not related to a decreased incidence of CIPN; though in the one study there was reduced incidence of grade 1 and grade 3 CIPN, but no difference in grade 2 CIPN. One study with increased incidence of CIPN (stopped early).

No evidence to support the use of goshajinkagin for prevention of CIPN.

• Limited number of studies included
• High heterogeneity
• Different criteria for grading of CIPN

Further research on use of the medication may be warranted. Education of patients about the inconsistent results.