RESOURCE TYPE: Consensus-based guideline

This publication has important updates for the nurse regarding the inclusion of oral antineoplastics, radiation emetogenicity, and treatments, and the addition of two new NK₁ receptor antagonists: netupitant and rolapitant. Both require further study before recommendations can be made. Although control of vomiting is markedly improved, nausea remains a challenge.

To determine if dexamethasone is superior to aprepitant in the prevention of delayed emesis in patients with breast cancer receiving chemotherapy that includes anthracyclines and cyclophosphamide

Patients were randomized using computer generated numbers, and blinding was performed by a special company. On day 1, 30 minutes prior to chemotherapy, all patients received palonosetron at 0.25 mg IV in a 30-second bolus and dexamethasone at 8 mg IV diluted in 100 ml of saline IV over 15 minutes. Aprepitant at 125 mg was administered orally one hour prior to chemotherapy. On days 2 and 3, patients randomly received either dexamethasone at 4 mg twice daily or aprepitant at 80 mg daily. Patients receiving aprepitant took a placebo in the evenings, and all pills were placed in identical capsules. On days 1–5, patients could receive either prochlorperazine at 10 mg via a suppository or metoclopramide at 10 mg intramuscularly as rescue medication. Adherence to medications on days 2 and 3 was checked by counting the remaining pills. Data were collected on days 1–6 after chemotherapy.

• N = 551  
• MEAN AGE = 53 years (median = 50 years)
• MALES: < 1%, FEMALES: > 99%
• KEY DISEASE CHARACTERISTICS: Breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy-naïve patients with breast cancer receiving anthracyclines plus cyclophosphamide

• SITE: Multi-site    
• SETTING TYPE: Outpatient    
• LOCATION: Italy

• PHASE OF CARE: Active antitumor treatment

Randomized, double-blinded, parallel study

• Daily diary to record the number of vomiting episodes, adverse events, rescue medications, and the presence, intensity, and duration of nausea
• Functional Living Index–Emesis (FLIE)
• Visual Analog Scale (VAS) for nausea

There was no significant difference in complete responses between the two groups in the acute (p = 0.39) or delayed phases (p = 1). There were no statistically significant differences in total control (p = 0.27), vomiting (p = 0.39), nausea (p = 0.24), significant nausea (p = 0.10), number of emetic episodes (p = 0.07), maximum severity of nausea (p = 0.26), or duration of nausea (p = 0.13) between the two groups in the delayed phase. Patients receiving dexamethasone experienced more insomnia (p = 0.02) and heartburn (p = 0.03) than those in the aprepitant group. More patients in the aprepitant group reported sedation and anorexia, but these results were not statistically significant.

In patients with breast cancer receiving chemotherapy containing anthracyclines and cyclophosphamide, dexamethasone and aprepitant have similar efficacy for the management of delayed chemotherpy-induced nausea and vomiting (CINV) when the optimal prophylactic treatment for acute CINV is administered. Patients who receive dexamethasone may experience a slight increase in adverse events compared to those taking aprepitant.

Nurses can help patients consider the differences in efficacy, safety, and cost of dexamethasone versus aprepitant when selecting an appropriate pharmacologic intervention for delayed CINV. In addition, nurses can help ensure that patients receive the optimal prophylactic treatment recommended for CINV with chemotherapy regimes that contain anthracyclines and cyclophosphamides.

This Perugia consensus panel was composed of 10 committees that reported findings to a 23-member expert panel from 10 different countries. The panel determined level of evidence and made changes in 2004 guidelines if evidence supported a greater than 10% increase in benefit. Updates were approved by the European Society of Medical Oncology (ESMO) Guidelines Working Group. All author relationships were reported. The panel used MEDLINE and other databases, which were not specified.

Emetogenicity of agents:

• As new agents are developed, often limited recording of common toxicities is provided in order to accurately reflect emetogenic potential.
• Increased use of oral agents and chronic oral administration creates issues regarding whether emetogenicity is defined by a single dose or a full course, and chronic use has blurred the lines between acute and delayed chemotherapy-induced nausea and vomiting (CINV).
• The authors provided an updated list of chemotherapy agents and levels of emetogenicity. Classification of oral agents was provided on the basis of a full course of treatment.

Prevention of acute CINV:

• Minimal risk: No routine prophylaxis
• Low risk: Day 1—dexamethasone or 5-HT₃ receptor antagonists or dopamine receptor antagonist
• Moderate emetogenic chemotherapy (MEC)
  • With anthracycline: Day 1—5-HT₃ receptor antagonist + dexamethasone + aprepitant or fosaprepitant; days 2 and 3—aprepitant
  • Without anthracycline: Day 1—palonosetron + dexamethasone; days 2 and 3—dexamethasone
• Highly emetogenic chemotherapy (HEC): Day 1—5-HT₃ receptor antagonist + dexamethasone + aprepitant or fosaprepitant; days 2 and 3—dexamethasone + aprepitant; day 4—dexamethasone
• Although studies have shown effectiveness of casopitant, the producer discontinued regulatory filings, so this was not recommended for use.
• All 5-HT₃ receptor antagonists were found to show the same efficacy. More studies are needed to determine if palonosetron is more effective with cisplatin-based therapies.

Prevention of delayed CINV:

• Aprepitant should be used to prevent delayed CINV.
• Whether dexamethasone is as effective or if the combination of dexamethasone and aprepitant would be more effective is not known. The optimal dose and duration of dexamethasone is not defined.
• Prevention with multiple-day cisplatin was not clear. Aprepitant + dexamethasone for acute and dexamethasone for delayed CINV was recommended. The possible role of ​neurokinin 1 (NK1) was not clear.

Refractory CINV and rescue:

• Maximally effective prophylaxis should be used.
• The addition of cannabinoids, olanzapine, and nonpharmacologic interventions could be considered.

Prevention of anticipatory CINV:

• The best way to prevent this learned response is maximum effective control of acute and delayed CINV.
• Anticipatory CINV is difficult to control with medication.
• Benzodiazepines are the only drugs identified as effective, but efficacy tends to decrease as chemotherapy continues.

Prevention of CINV with high-dose chemotherapy:

• Complete protection is currently only achieved in a minority of patients.
• Current standard is dexamethasone + 5-HT₃ receptor antagonists.
• Evaluation of the addition of aprepitant is needed.

Radiation-induced nausea and vomiting:

• Risk level and antiemetic guidelines are provided.
• Generally, prophylaxis with 5-HT₃ receptor antagonists + dexamethasone and rescue with 5-HT₃ receptor antagonists are recommended.

Antiemetics in children:

• All pediatric patients receiving MEC or HEC should receive prophylaxis with 5-HT₃ and dexamethasone. Optimal dosing requires further study.
• No studies have evaluated approaches for prevention of anticipatory CINV.
• Metoclopramide, phenothiazines, and cannabinoids have shown only moderate efficacy.

The guidelines provide a clear set of recommendations and review of the relevant evidence strength assessed for various cancer treatment scenarios.

A complete listing of databases used for evidence retrieval was not provided.

Control of emesis has markedly improved in recent years; however, nausea remains a challenge and future research should shift attention to this aspect. Current trials generally define complete response end points that exclude consideration of the experience of nausea rather than vomiting. Trials suggest that some agents are more effective for acute vomiting, others are more effective for delayed vomiting, and some may be more effective for nausea. Identification of these differences and incorporation into the rationale for treatment needs to continue.

Further research is needed in the areas of prevention with high-dose chemotherapy and stem cell support, combined chemotherapy and radiation therapy, and anticipatory nausea and antiemetic use in children. Practitioners need to be aware of the impact of oral therapy and chronic oral chemotherapy treatment on current approaches to antiemetic treatment, timing, and definitions of acute and delayed CINV. Practitioners also need to be aware that current chemotherapy risk determination does not apply to combined radiotherapy and chemotherapy.

To update the recommendations for the prophylaxis of delayed emesis induced by moderately emetogenic chemotherapy via a systematic review

The database searched was PubMed.

Search keywords were moderately, chemotherapy emesis, casopitant, aprepitant, granisetron, ondansetron, dolasetron, tropisetron, palonosetron antagonists, and dopamine receptor antagonists

Studies were included in the review if they 

• Were randomized, controlled trials (RCTs).
• Described subjects receiving moderately emetogenic chemotherapy (MEC) as defined by the Multinational Association of Supportive Care in Cancer (MASCC).

Papers were excluded if they were not in English.

The number of references retrieved was not provided. The method of study evaluation was the presence of vomiting.

• The final number of studies included in the review was nine RCTs.
• The total sample size was 4,177; however, not all numbers were included. The study sample sizes ranged from 99–1,114 participants.
• All patients were receiving MEC.

• Patients were undergoing the active treatment phase of care.
• The study has clinical applicability for late effects and survivorship.

• This study of aprepitant and casopitant demonstrated that, when added to a 5-HT₃ receptor antagonist and dexamethasone, a neurokinin 1 (NK1) receptor antagonist reduces the incidence of acute and delayed emesis induced by anthracycline- and cyclophosphamide-based chemotherapy.
• For patients receiving MEC, one dose of palonosetron administered before chemotherapy was more efficacious in reducing the incidence of delayed emesis than a single dose of a 5 -HT₃ receptor antagonist with a shorter half-life.
• Weak evidence suggested that a dopamine receptor antagonist may improve the control of delayed emesis.

• Patients receiving MEC, which is known to be associated with significant incidence of delayed nausea and vomiting, should receive antiemetic prohylaxis for delayed emesis.
• In patients with breast cancer receiving a combination of anthracycline plus cyclophosphamide treated with a combination of aprepitant, a 5-HT₃ receptor antagonist, and dexamethasone to prevent acute nausea and vomiting, aprepitant should be used to prevent delayed nausea and vomiting.
• Multiday oral dexamethasone is the preferred treatment for the prevention of delayed emesis in patients receiving chemotherapy with moderate emetic risk. 
• Insurance concerns continue with 5-HT₃ as well as NK1 receptor agonsists.  Nurses need to consider this when assisting patients with nausea, and they should consider the need for precertification or prior authorization of medications.

To examine mediators of fatigue effects of an exercise intervention

Patients were randomized to an exercise intervention or control group. The intervention combined walking and strength training with resistance bands. Walking was gradually increased by week 9 to 40 minute sessions of moderate intensity, four times per week, and participants attended 26 individual exercise sessions supervised by an exercise specialist. Resistance training was two times per week in the last 10 weeks of the study with the supervised aerobic walking sessions. Resistance was advanced as tolerated. Six group meetings with a psychologist also were provided every other week to provide support and improve exercise adherence. The control group was instructed to maintain usual exercise behavior.

• N = 42  
• MEAN AGE = 56.2 years (SD = 7.7)
• KEY DISEASE CHARACTERISTICS: All patients had breast cancer, were at least four weeks post-completion of primary treatment, had an average fatigue score of at least 3 in the past week, or had sleep dysfunction
• OTHER KEY SAMPLE CHARACTERISTICS: Multiple chronic concurrent conditions were excluded

• RCT

• MTI actigraph
• Fatigue Symptom Inventory
• PROMIS general fatigue scale
• PROMIS scales for depression, anxiety, and sleep/wake disturbance
• Serum samples for interleukins (IL-6, -8, -10) and tumor necrosis factor alpha

Adherence to supervised exercise sessions was 91%–93%. Exercise goals for at home were met in 65% of the weeks during the study. General fatigue declined significantly in the intervention group compared to controls (d = –0.49, p < .01). Fatigue interference (d = –0.38, NS) declined in the intervention group. Fatigue intensity increased in the intervention group and declined in controls (d = 0.3, NS). There were no significant differences in depression. Anxiety declined in the intervention group (d = –0.54, p < .05). Sleep/wake dysfunction declined in both groups over time, but more in the intervention group (d = –0.054, p < .01). Positive effects in fatigue intensity were significantly mediated by IL-6, IL-10, IL-6:IL-10, and TNF alpha:IL-10.

The exercise program used here showed a small to medium non-significant effect on fatigue intensity and interference, as measured in this study. Effects of exercise on fatigue were mediated by some cytokine system responses.

• Small sample (< 30)
• Baseline sample/group differences of import
• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Other limitations/explanation: Fatigue and sleep disruption measures at baseline were lower in the intervention group, although the difference was not statistically significant, these could have influenced the general trends shown in the study.

Although this study has limitations, findings do provide additional support for positive effects of exercise on cancer-related fatigue among cancer survivors. Findings here show evidence of potential effects through the cytokine system. Adherence to the exercise program in this study was very good, using a support group interaction and the combination of supervised exercise sessions and home-based exercise recommendations. This type of additional support may help many patients adhere to an exercise program.

To determine the feasibility of conducting a randomized, controlled trial of exercise in patients with head and neck cancer receiving radiation therapy

Patients were randomly assigned to the intervention group or a control group. Control patients received only nutritional counseling from a registered dietician. Patients in the intervention group received nutritional counseling plus the exercise intervention. Exercise included twice-weekly, supervised exercise sessions for six weeks followed by six weeks of twice-weekly home-based sessions supported by weekly telephone counseling, written materials, and a DVD.

• N = 13 (completed 12 weeks); 15 (completed six weeks)  
• MEAN AGE = 60.5 years (SD = 43–88 years)
• MALES: 80%, FEMALES: 20%
• KEY DISEASE CHARACTERISTICS: All patients had head and neck cancer. About one half had had neck dissection, and one half also received concurrent chemotherapy.

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

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

Pilot randomized, controlled trial

• Lean body mass measured by biometric impedance
• Functional Assessment of Cancer Therapy–Fatigue (FACT-F)
• Functional Assessment of Cancer Therapy–Head and Neck (FACT-H&N)
• Physical performance tests

Over the first six weeks, fatigue increased in both groups with no significant difference between groups. Between weeks 6 and 12, fatigue declined in both groups but showed a greater decline in the intervention group. Exercise adherence was 87% in the first six weeks and 57% weeks 7–12.

Less than one half of patients offered the study consented to participate, suggesting low interest and limited feasibility. The final sample size was very small, so no firm conclusions about effects can be drawn.

• Small sample (< 30)
• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)

This study provides minimal support for the feasibility and efficacy of implementing an exercise intervention among patients with head and neck cancer undergoing radiation therapy. These findings are not in concert with findings from other similar studies.

STUDY PURPOSE: To assess the effects of compression bandages, sleevers, intermittent pneumatic compression, and active exercise on lymphedema related to breast cancer

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 60 (32 in systematic review, 9 in RCT meta-analysis, and 19 in pre/post meta-analysis)
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,340
• SAMPLE RANGE ACROSS STUDIES: 14–141
• KEY SAMPLE CHARACTERISTICS: All had breast cancer.

PHASE OF CARE: Multiple phases of care

The findings suggest that the use of compression bandaging and exercise in combination has the strongest beneficial effects for lymphedema management among women with breast cancer–related lymphedema. Bandaging had consistent positive effects, whereas other interventions as stand alone approaches yielded somewhat inconsistent results.

• Mostly low quality/high risk of bias studies
• Low sample sizes

The findings suggest that the combination of active exercise and compression bandaging is more effective than other interventions for managing upper extremity lymphedema. This review did not include an examination of complete decongestive therapy along with other interventions, which has been shown to be effective as well. Nurses can educate patients about the use of compression bandaging and exercise for lymphedema management. The findings here suggest that compression sleeves do not aid in lymphedema reduction in the acute phase but may be helpful in the maintenance phase.

To compare the efficacy of hydrocodone-acetaminophen with that of tramadol in the management of cancer pain; to compare the tolerability of hydrocodone-acetaminophen and tramadol used to relieve cancer pain

Patients were assigned to receive either hydrocodone-acetaminophen (25 mg hydrocodone, 2,500 acetaminophen) or tramadol (200 mg) for 21 days. Patients rated pain intensity at the beginning of the study, two days after the beginning of the study, and once weekly for three weeks. Patients were to note all adverse events.

• The sample was composed of 118 patients.
• In the hydrocodone-acetaminophen group, mean patient age was 62 years. In the tramadol group, mean patient age was 57.1 years.
• In the hydrocodone-acetaminophen group, 35.5% were female and 64.5% were male. In the tramadol group, 62.5% were female and 37.5% were male.
• In the entire sample, 13.5% of patients had pain due to gastric cancer; 12%, to breast cancer; 13.5%, to prostate cancer; and 89%, to lung cancer.

• Multisite
• Outpatient
• Colombia

Randomized double-blind comparative trial

• Visual analog scale, 100 mm, to measure pain intensity
• Scale of adverse events (none = 0, mild = 1, moderate = 2, severe = 3)

• The difference in pain relief between the groups was not significant. Tramadol caused significantly more nausea (P = 0.03), vomiting (P = 0.02), dizziness (P = 0.03), loss of appetite (P = 0.02), and weakness (P = 0.019) than did hydrocodone-acetaminophen.
• Authors noted no significant differences between groups in regard to dry mouth or constipation.

In this study, tramadol and hydrocodone-acetaminophen were equally efficacious in relieving cancer pain. Patients taking hydrocodone-acetaminophen experienced fewer side effects than did patients who took tramadol.

All analgesics, except medications for neuropathic pain, were discontinued. Note that the group that took tramadol contained significantly more women than did the group that took hydrocodone-acetaminophen. This difference may relate to the differing side-effect profiles.

This study showed that hydrocodone-acetaminophen and tramadol were equally effective at treating cancer pain; however, tramadol was associated with more adverse effects. Nurses should keep this in mind and provide patients with anticipatory guidance as appropriate.

To determine if methylnaltrexone is an effective treatment for opioid-induced constipation in pediatric patients with cancer

Data were collected from pharmacy records and medical chart reviews. They included demographic data, history of constipation, history of vinca alkaloid use, history of abdominal surgery, history of laxative use and dose, duration of opioid use prior to methylnaltrexone administration, the dose and frequency of methylnaltrexone administration, and the patients' responses to the intervention. Opioid doses were converted to oral morphine equivalents. Bowel regimens were compared to pediatric practice guidelines to determine if the bowel regimen had been optimized prior to administration of methylnaltrexone. Patients were given methylnaltrexone in a single subcutaneous injection. The mean dose was 0.15 ± 0.02 mg/kg per dose (range = 3–12 mg per dose).

• N = 15  
• MEDIAN AGE = 14 years (range = 4–17)
• MALES: 33%, FEMALES: 67%
• KEY DISEASE CHARACTERISTICS: Sarcoma, lymphoma, and neuroblastoma

• SITE: Single-site    
• SETTING TYPE: Inpatient    
• LOCATION: Canada

• APPLICATIONS: Pediatrics

Retrospective chart review

• Naranjo Adverse Drug Reaction Probability Scale (Naranjo Scale)

Ten patients had a bowel movement within 30 minutes of receiving methylnaltrexone. Four patients had a bowel movement between 30 minutes and 4 hours of administration. Four patients were noted to have decreased abdominal girth and active bowel sounds after the intervention. No patients reported a decrease in pain control.

Methylnaltrexone is one effective intervention to treat opioid-induced constipation for pediatric patients after other interventions have failed. The use of methylnaltrexone to relieve constipation did not lead to an increase in pain for the patients in this study.

• 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) 
• Measurement/methods not well described
• Other limitations/explanation: Very small sample size; retrospective review

Methylnaltrexone should be considered for pediatric patients when other interventions have failed to relieve opioid-induced constipation.

STUDY PURPOSE: To provide a critical analysis of the contemporary published research that pertains to complementary, alternative, and other noncomplete decongestive therapies for treatment of lymphedema (LE) and to provide practical applications of that evidence to improve care of patients with or at risk for LE

TYPE OF STUDY: Systematic review

DATABASES USED: PubMed, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, PapersFirst, Proceedings-First, Worldcat, PEDro, National Guideline Clearing House, ACP Journal Club, DARE, and the authors' archives

KEYWORDS: Best practice for the management of lymphoedema, plus expanded terms for all literature related to lymphedema (2004–2012)

INCLUSION CRITERIA: No specific inclusion criteria identified

EXCLUSION CRITERIA: No gray literature was included; nonrefereed articles, abstracts, and dissertations were excluded. Exclusion of 574 articles took place due to duplication, inability to obtain the English translation, inadequate sample size, insufficient level of evidence due to study design, and failure to meet inclusion criteria. Another 47 articles were rejected because they fell outside the systematic review inclusion criteria by definition of four categories (i.e.,botanical, pharmaceutical, physical agent modalities, and modalities of contemporary value), by design, or for lack of an English translation. The categories of pharmaceuticals and botanicals were excluded as well.

TOTAL REFERENCES RETRIEVED: 659 articles were reviewed.

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: The authors used first screening, second screening, and third screening to determine final body of reviewed articles. The level of evidence for each study assessed by using the research grading system from the Putting Evidence into Practice (PEP) level of evidence guidelines.

• FINAL NUMBER STUDIES INCLUDED = 22
• SAMPLE RANGE ACROSS STUDIES/TOTAL PATIENTS INCLUDED IN REVIEW: Not applicable; included several singles and several review articles
• KEY SAMPLE CHARACTERISTICS: Human being with lymphedema and animal model with lymphedema (i.e., a rabbit ear model with “created” secondary lymphedema and rat tail model with “created” secondary lymphedema)

PHASE OF CARE:  Multiple phases of care

Limited high-level evidence was available for all categories. Well-constructed randomized, controlled trials related specifically to lymphedema were limited. Objective outcome measures over time were absent from several studies. The rationale for the use and benefits of the specific modality, as related to lymphedema, was often anecdotal. Participant numbers were fewer than 50 for most studies.

No interventions were ranked as "recommended for practice." Two treatment modalities (low-level laser therapy and Kinesio taping combined with decongestive lymphatic therapy and pneumatic compression, with Kinesio taping compared with compression bandaging) in three studies were ranked as "likely to be effective." The literature review indicated that many of the physical agent modalities demonstrated long-standing support within the literature, with broad parameters for therapeutic application and benefit for secondary conditions associated with lymphedema. However, additional investigation regarding the individual contributory value and the factors that contribute to their efficacy specific to lymphedema is critically needed.

Inclusion criteria were not clearly stated. Sample range across studies and total patients included in review were not specified.

More rigorous human research in complementary and alternative modalities is needed to optimize patient outcomes.