To compare the effectiveness of infused ondansetron, olanzapine, and palonosetron for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in recipients of hematopoietic stem cell transplantation (HSCT)

• Arm 1: Ondansetron 32 mg IV daily over 24 hours
• Arm 2: Olanzapine 10 mg PO wafer daily plus ondansetron 8 mg IV TID
• Arm 3: Palonosetron 0.25 mg IV (one dose) (did not receive ondansetron for three days)

• N = 62   
• AGE = 20–68
• MALES: 62.9%, FEMALES: 37.1%
• CURRENT TREATMENT: Chemotherapy, combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Recipients of allogeneic or autologous HSCT

• SITE: Not stated/unknown   
• SETTING TYPE: Not specified    
• LOCATION: Australia

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

Randomized, open-label, prospective study

• Patients documented the number of emesis events and severity of nausea, which was measured with a 100 mm VAS ranging from 0 (no nausea) to 100 (worst possible nausea).
• After patients were randomized into a treatment arm, data were collected at 24 hours and 48 hours postinitiation of treatment. Patients were asked to score the overall intensity and frequency of nausea for the previous 24 hours. 
• Rescue antiemetic doses were obtained from the medication record.

Olanzapine is an effective treatment for breakthrough CINV after an allogeneic or autologous hematopoietic stem cell transplantation when used with standard prophylaxis of ondansetron and aprepitant.

• Small sample (< 100)
• Risk of bias (no blinding)

For the treatment of breakthrough CINV in recipients of HSCT receiving prophylactic ondansetron and aprepitant, olanzapine is superior to palonosteron and ondansetron. This is an indication to include this as a part of patients' antiemetic regimens.

The intervention was a one-hour art therapy session administered by a registered art therapist/counselor.

The study reported on a sample of 50 adult inpatients with cancer.

A quasi-experimental design was used.

• State-Trait Anxiety Inventory (STAI-S): To measure state anxiety
• Edmonton Symptom Assessment Scale (ESAS)

Change in anxiety scores was reported on both the STAI-S and ESAS (no p values were reported).

• The study reported on a small sample that was not randomized or controlled.
• The study did not include data on dose, repeated measures, or longitudinal evaluation.
• The study did not include pharmacologic assessment.
• The study required specialized training of a registered art therapist/counselor.

STUDY PURPOSE: To determine the efficacy and safety of transdermal buprenorphine for treating cancer pain

TYPE OF STUDY: Meta-analysis a systematic review

DATABASES USED: MEDLINE, EMBASE, CINAHL, and the Cochrane Library up to May 2013

KEYWORDS: Search terms for the cancer type, including gastrointestinal, bladder, breast, stomach, colon, prostate, and lung; search term for buprenorphine

INCLUSION CRITERIA: Patients with cancer; RCTs; comparison of transdermal buprenorphine to placebo or any comparator drug; changes in cancer pain intensity measured by verbal rating scales, visual analog scales, numerical rating scales, or questionnaires

EXCLUSION CRITERIA: Sample size of less than 10 patients; pain that was not directly linked to the development of cancer or its treatment (i.e., chemotherapy-induced neuropathic pain); pain related to surgical procedures

TOTAL REFERENCES RETRIEVED = 212

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: The quality of the studies was assessed by two reviewers using the domain-based evaluation.

• FINAL NUMBER STUDIES INCLUDED = 8 studies
• SAMPLE RANGE ACROSS STUDIES = 17–189
• TOTAL PATIENTS INCLUDED IN REVIEW = 909 patients
• KEY SAMPLE CHARACTERISTICS: Not reported

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

Two studies of patients whose pain relief was at least satisfactory at all time points found a significant difference between transdermal buprenorphine and placebo in all three doses of transdermal buprenorphine, 35.5, 52.5, or 70 micrograms per hour (RR 1.74, 95% Cl 1.31–2.32; I² 0%). Pain-free sleep was improved in two studies comparing transdermal buprenorphine to placebo (RR 1.25, 95% Cl 0.84–1.88; I² 0%). Adverse effects such as nausea, vomiting, and constipation were less with transdermal buprenorphine compared to fentanyl, morphine, or placebo.

Transdermal buprenorphine appears to be an effective and safe treatment for cancer pain; however, further research is needed to confirm its effectiveness because of the low quality of published research. Information about the following research quality indicators was unclear for a majority of the studies.

• Random sequence generation
• Allocation concealment
• Blinding of participants
• Blinding of outcome assessment

• A major limitation of this meta-analysis is that few studies used the same outcome measurement, so pooling of outcome data was problematic.
• Follow-up of treatment effect was short (i.e, 15 days or less).

Although transdermal buprenorphine has been shown to have advantages over other opioids (i.e., noninvasive route, reduced respiratory depression, less frequent adverse effects), further research is needed to confirm its level of effectiveness in relieving cancer pain. In addition, the long-term effects of transdermal buprenorphine need to be determined. If nurses are caring for patients who are prescribed transdermal buprenorphine, they should be aware of the potential adverse effects, which are similar to other opioids.

RESOURCE TYPE: Expert opinion

PHASE OF CARE: Active antitumor treatment

Expert opinion level information

Nurses need to be aware of potential immune-related adverse events and current recommendations for management. Although some differences in opinion exist, overall management involves the use of systemic steroids for moderate symptoms, aggressive use of IV steroids for more severe symptoms, and consideration of immunosuppression for persistent or worsening severe symptoms.

STUDY PURPOSE: To review the evidence for effects of neurolysis for abdominal cancer pain

TYPE OF STUDY:  Meta-analysis and systematic review

DATABASES USED: MEDLINE, EMBASE, AMED, Web of Science, CINAHL from 1980–2011

KEYWORDS: Broad neurolysis terms were used. Terms included pain, quality of life, and possible side effects.

INCLUSION CRITERIA: All study designs and case reports involving percutaneous and endoscopic ultrasound-guided celiac plexus neurolysis, abdominal pain due to intra-abdominal cancers, and adults; English language

EXCLUSION CRITERIA: Noncancer pain; other neurolysis techniques

TOTAL REFERENCES RETRIEVED = 2,303

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Critical Appraisal Skills Programme was used to evaluate strength of evidence. For case series, a checklist was developed from the Joanna Briggs Institute.

• FINAL NUMBER STUDIES INCLUDED = 66 publications—32 case series, 24 case reports, one survey, and nine RCTs. Five studies were included in meta-analysis that compared celiac plexus neurolysis (CPN) with analgesic therapy.
• TOTAL PATIENTS INCLUDED IN REVIEW = 469 patients in RCTs
• SAMPLE RANGE ACROSS STUDIES = 20–100 patients
• KEY SAMPLE CHARACTERISTICS: Most had pancreatic cancer, but additional abdominal cancers were reported in case series and case reports.

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

Meta-analysis showed a mean difference with CPN (versus analgesics) of -0.87 (95% CI -1.47, -0.28, p = .004) in favor of neurolysis after one to two weeks. After four weeks, the mean difference in pain scores was -0.47 (95% CI -0.71, -0.23, p = .0001). At eight weeks, from four studies, the mean difference with CPN was -0.46 (95% CI -0.68, -0.25, p < .0001). In the two studies that evaluated pain after three months, neither showed a benefit of CPN at that time point.  For endoscopic ultrasound-guided CPN, mean difference at one to two weeks was -4.26 (95% CI -5.53, -3.0, p < .00001), at four weeks was -4.21 (95% CI -5.29, -3.13, p < .00001), and at eight weeks was -4.13 (95% CI -4.84, -3.43, p < .00001). At 12 weeks, only 60 patients could be evaluated. These results in meta-analysis showed a mean difference of -4.28 (95% CI -5.63, -2.94, p < .00001). Analysis also showed significant reduction in opioid consumption from one to four weeks. Meta-analysis of data related to side effects showed higher risk of diarrhea with CPN (p + .0003) and risk of constipation with opioids (RR = 0.34, p < .00001). More nausea and vomiting occured in patients on analgesics (RR = 0.44, p < .0001). Information on side effects, mainly from case series, is provided. Hypotension was shown in four studies to be more prevalent with CPN (RR = 7.43, p = .0003). Across three studies, opioid consumption was reduced with CPN (mean difference = -70.02, p < .0001).

Evidence suggests that CPN reduces abdominal cancer-related pain and that it is a relatively safe procedure. Diarrhea and hypotension are more prevalent with CPN, and constipation is more prevalent with analgesics alone. Analysis was only possible up to two to three months after the procedure, so longer-term efficacy is unknown. It is noted that a significant number of patients with advanced abdominal cancers do not have a long survival time, so this duration is likely clinically meaningful. More evidence is needed to evaluate differences between endoscopic ultrasound-guided and percutaneous CPN.

• There was significant heterogeneity among studies. 
• Methodologic quality of studies was sometimes low, and specific quality data are not reported in the analysis.
• The number of trials included in meta-analyses was low.
• Authors point out a lack of differentiation between somatic and visceral pain, and peritoneal involvement with advanced malignancies can confuse findings because related pain is not transmitted via the celiac plexus.

CPN is shown to be effective for reduction of pain from advanced abdominal cancers, with relatively few side effects. Current evidence, however, only shows duration of effects over about two to three months, so any longer-term efficacy is not known. This procedure may reduce opioid needs, reducing opioid-related complications such as constipation. Nurses should be aware that, although of low prevalence, CPN can be associated with severe complications, so patients need to be observed for these. It needs to be recognized that CPN only can be effective for pain that originates in areas innervated by the celiac plexus.

To investigate the efficacy and tolerability of oxycodone for oxaliplatin-induced peripheral neuropathy (OIPN) with FOLOFOX therapy in patients with colorectal cancer (CRC)

This was a single-center retrospective study of 64 patients with CRC receiving FOLFOX therapy. Controlled-release (CR) oxycodone was concomitantly administered to 29 patients (OXY group). An additional 35 patients (non-OXY group) were not given oxycodone during FOLFOX therapy. The incidence and severity of OIPN and the number of FOLFOX treatments were measured and compared.

• N = 64  
• MEAN AGE = 64.9 years (non-OXY); 62.7 years (OXY)
• MALES: 54.2% (non-OXY); 55.2% (OXY), FEMALES: 48.6% (non-OXY); 44.8% (OXY)
• KEY DISEASE CHARACTERISTICS: Advanced-stage disease (III or IV); all received a gross dissection of primary CRC and subsequently received curative-intent FOLFOX therapy; all were greater than 18 years of age; World Health Organization performance status of 0 or 1; life expectancy greater than six months; none could have preexisting peripheral neuropathy or exposure to previous neurotoxic chemotherapeutic agents
• OTHER KEY SAMPLE CHARACTERISTICS: All patients received standard FOLFOX therapy (bolus of 85 mg/m2 oxaliplatin, leucovorin, and 400 mg/m² 5-FU followed by a 48-hour continuous infusion of 5-FU at 2,500 mg/m² given every two weeks). Bevacizumab, cetuximab, or panitumumab was administered prior to mFOLFOX6 in 27 cases. FOLFOX was continued until disease progression, a decision to use alternative therapies was made, unacceptable toxicities occurred, or a patient refused additional treatment.

• SITE: Single-site    
• SETTING TYPE: Outpatient    
• LOCATION: Toho University Sakura Medical Center in Sakura, Japan

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

Patients in the OXY and non-OXY groups were evaluated for neurotoxicity. Severity of pain, sensory status, and motor dysfunction were evaluated.

The National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events (CTCAE) was used to evaluated neurologic toxicity. A peripheral sensory neuropathy subscale was used to grade clinical severity. Grade 1 could be asymptomatic or could include a loss of deep tendon reflex or paresthesia (including tingling) that did not interfere with function; grade 2 included sensory alterations or paresthesia (including tingling) that interfered with function but not with activities of daily living (ADL); and grade 3 included sensory alterations or paresthesia that interfered with ADL. Pain intensity was measured on a numeric scale after each cycle of FOLFOX therapy.

All patients in the OXY group and 33 out of 35 patients in the non-OXY group experienced grades 1 or 2 sensory neuropathy. Grade 3 neurotoxicity was not observed in the OXY group whereas two patients (5.7%) in the non-OXY group reported grade 3 sensory neuropathy. In the OXY group, sensory neuropathy grades improved in all patients. CR oxycodone was discontinued in 10 patients (34.5%) in the OXY group after completions of FOLFOX therapy. No discontinuations because of OIPN occurred in the OXY group, and 10 discontinuations occurred in the non-OXY group. Patients in the OXY group received a median of 13 cycles. Those in non-OXY group received a median of seven cycles. The median total oxaliplatin dose was higher in OXY group than the non-OXY group (1072.3 mg/m² versus 483 mg/m², respectively).

CR oxycodone may attenuate OIPN and extend FOLFOX therapy in patients with CRC.

• 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
• Measurement validity/reliability questionable
• Design observations and retrospective: Pain intensity in 23 patients (79.3%) in the OXY group remained mild throughout the entire study period with no significant change. No quantitative data regarding pain severity were provided. The CTCAE is not a sensitive measure of neuropathy, and it was completed by the provider rather than the patient. Neuropathy symptoms may have been masked by oxycodone.

Additional research on oxycodone and other opioid use for OIPN is needed. This study suggests changes caused by oxycodone, but it has several limitations.

Databases searched were MEDLINE, Cochrane Database of Abstracts of Reviews and Effects, Cochrane Register of Clinical Trials, hand searching from previous systematic reviews, National Guideline Clearinghouse, National Quality Measures Clearinghouse, and Web sites of professional organizations.

Search keywords were extensive and provided in an appendix. 

A panel of nine experts reviewed evidence to identify minimum standards of care. 

This report was part of the RAND Cancer Quality Assessing Symptoms Side Effects and Indicators of Supportive Treatment Project to develop evidence-based tools to evaluate aspects of supportive cancer care practice. The work was supported by a grant from Amgen to RAND.

• Assess for nausea and vomiting at each outpatient visit and within 24 hours of an inpatient visit.
• Evaluate emetogenic risk of every chemotherapy regimen for prevention.
• For highly emetogenic chemotherapy (HEC) and patients with breast cancer on anthracycline with aprepitant, use a three-drug regimen for acute and a two-drug regimen for delayed chemotherapy-induced nausea and vomiting (CINV) prevention.
• For MEC, use 5-HT₃ receptor antagonists and dexamethasone for acute and one of these for delayed CINV prevention.
• For low emetogenic chemotherapy (LEC), use dexamethasone if clinically appropriate.
• Consider electroacupuncture if the technique is available by a capable operator.
• Present alternative treatment options to patients with persistent symptoms within one month in an outpatient setting and within 48 hours in an inpatient setting.

• Minor differences are recommended here in the area of low emetogenic potential compared to some other guidelines, as prophylaxis is suggested here.
• Use of a one-month cutoff for presenting alternatives to people with persistent nausea and vomiting seems like a long time to wait for better symptom control.
• As noted, many pharmacologic options for antiemesis are available; however, in trials, often substantial proportions of patients still do not achieve symptom control. This points to the continuing need for research in this area, as well as individualization of regimens in clinical practice.
• The authors suggest that results of a 2005 systematic review of the effects and costs of 5-HT₃ receptor antagonists for delayed nausea cast doubt on the cost-effectiveness of this approach.

• To assess the analgesic efficacy of prolonged-release (PR) oxycodone in combination with orally administered naloxone PR in patients with severe, chronic pain; to evaluate the efficacy of that combination in improving bowel function
• To evaluate the optimal dose ratio of oxycodone PR to naloxone PR
• To evaluate patients’ and investigators’ treatment preference

In this three-phase study, patients with inadequate pain control entered the titration period, with stabilization at 40, 60, or 80 mg oxycodone PR/day. Those on stable oxycodone dosing who used laxatives to have three bowel movements per week were entered in the maintenance phase after a seven-day run-in period. After patients were stabilized, they were randomized into three naloxone treatment groups or a placebo group. Oxycodone was given open label; naloxone was given in double-blind fashion. After a patient was in the maintenance phase, no titration of oxycodone PR doses was allowed. Those using laxatives were advised to stop unless no bowel movement had occurred for three days. Patients were studied for four weeks, then assessed in a two-week follow-up phase. In the follow-up phase, no one received naloxone PR.

• The intent-to-treat (ITT) group, defined as those who were randomized and received at least one dose of naloxone or placebo and had at least one efficacy assessment, comprised 196 patients; 166 patients completed the study.
• Patients were older than 18 years.
• The sample was 62.9% female and 37.1% male.
• Specific cancer type was not reported.

• Multisite
• Outpatient
• Twenty-eight centers in Germany, May 2002 to April 2003

Prospective randomized double-blind, parallel-group, phase II trial

• Rating scale (1 = very good, 7 = very poor), to measure efficacy and tolerability, used independently by investigators and patients
• Preference, in regard to tolerability and efficacy, for maintenance phase or titration–run-in phase (1 = titration–run-in, 2 = maintenance, 3 = no preference)

• The efficacy of the 2:1 dose ratio of oxycodone PR to naloxone PR was ranked as good or very good by 70.4% of patients and investigators.
• The tolerability of the 2:1 dose ratio was ranked as good or very good by 81.5% of patients and investigators.
• The majority of patients in the treatment arm preferred the maintenance phase, in which they received both medications.
• Naloxone PR had no impact on the analgesic efficacy of oxycodone PR; naloxone PR improved bowel function and reduced laxative intake.

Concurrent administration of oxycodone PR and naloxone PR is effective for the treatment of patients with severe chronic pain, cancer-related or not. Patients tolerated naloxone PR well; naloxone created no  additional untoward effects.

• Exclusion of patients with severe cardiovascular or pulmonary issues limits the applicability of findings to patients with advanced cancers and those taking more than five medications per week to control breakthrough pain.
• Oxycodone PR dosing was limited to 40–80 mg/day.

This study's results relate to pain control and bowel function of patients with cancer. Additional research, to investigate widening application of the findings, is warranted.

To examine the effect of a single dose of palonosetron for the prevention of chemotherapy-induced nausea and vomiting (CINV) in children 18 years of age and younger with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate (HD MTX) (5 g/m²)

This study was a prospective analysis of the effectiveness of palonosetron given as a single dose (5 mcg/kg) prior to the administration of HD MTX in children 18 years or younger with ALL. Both MTX-naïve patients and previously treated patients were included.  Data was collected on 138 courses of chemotherapy with a total of 53 patients.  Response was determined by patient/parent questionnaires and patient records. Authors described the questionnaires as reporting the occurrence of emesis, the intensity of nausea, and the use of rescue therapy at six-hour intervals from day 1 until discharge. Intensity of nausea was measured using a visual analogue score (VAS) ranging from 0 to 10. Complete response was defined as no emetic episodes and no use of rescue medications during the acute phase (0–24 hours) and the delayed phase (24–66 hours).

• This study reported on 53 patients.
• Ages ranged from 2–18 years.
• The sample was 60% male and 40% female.
• All patients had been diagnosed with ALL and were receiving 5 g/m² HD MTX.

This was a multi-site study conducted in Denmark.

• Patients were in active antitumor treatment.
• This study has application for pediatrics.

This was a prospective trial.

• The questionnaire was not specifically identified, and no reliability data was provided.
• A 0–10 VAS was used to measure nausea intensity.

• Complete response (i.e., no emesis and no rescue therapy) was achieved in 84.1% of courses during the acute phase and 60.1% of courses during the delayed phase.
• During the acute phase, 92% of courses were completely free of emesis. During the delayed phase, 86.2% were free of emesis.
• During the acute phase 89.9% of patients did not receive any rescue therapy, compared to 65.2% during the delayed phase.
• Additionally, 76.8% of courses were free of nausea during the acute phase, and 78.3% of courses were free of nausea during the delayed phase.

This study demonstrated that a single dose of palonosetron was effective in the prevention of CINV in children 18 years old and younger with ALL receiving HD MTX both in the acute and delayed phases.

• The sample size was small with fewer than 100 patients.
• A risk of bias exists because no control group or random assignment was included. The sample characteristics also introduce a risk of bias.
• The measurements and methods were not well described and the validity and reliability of the tools was questionable.
• No data regarding the expected frequency of nausea or vomiting in this population or regimen was included.
• Some patients also received intrathecal (IT) MTX and anesthesia prior to receiving HD MTX, which could have impacted results.
• The investigators used multiple cycles from the same patients, which could introduce bias if patients had a history of CINV.

Palonosetron has been effective for moderate to highly emetogenic chemotherapy in acute and delayed CINV in adults. This study demonstrated that a single dose of palonosetron was effective in preventing both acute and delayed phase CINV in the majority of children under age 18 with ALL receiving HD MTX.  Prospective randomized controlled trials should be conducted in other pediatric oncology populations to determine generalizability of these findings.

To perform a systematic review of evidence of the efficacy and toxicity of nonsteroidal antiinflammatory drugs (NSAIDs) or paracetamol in addition to World Health Organization (WHO) step III opioid treatment for moderate to severe cancer pain in comparison to opioids alone

The type of study is systematic review.

Databases searched were MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials.
Search keywords were acetaminophen, paracetamol, neoplasm, pain, and NSAID.
Studies were included in the review if they were

• Written in English
• Had a publication date of 2002–2010
• Conducted with adult human participants experiencing chronic cancer pain
• A randomized controlled trial or a meta-analysis reporting on efficacy and/or side effects of NSAIDs or paracetamol in addition to opioids in comparison to opioids alone.

No specific exclusion criteria was identified.

A total of 803 references were retrieved. 

After further review by the authors, 12 studies were included in the literature review.

Each study was evaluated in terms of content and quality using the Cochrane Handbook for Systematic Reviews of Interventions as the tool for appraisal.

• A final number of 12 studies were included in the review.
• The total number of patient cases included in the review was 396.
• The article does not describe patient demographics or characteristics, including cancer diagnoses.

• Patients were undergoing multiple phases of care.
• The study has clinical applicability for palliative care.

Adjuvant use of NSAIDs has been demonstrated to provide an additive effect in either improving pain management or reducing opioid use. Paracetamol use did not demonstrate any significant improvement over opioid use alone.

The articles reviewed provide weak support of the addition of NSAIDs to WHO step III opioids to improve analgesia and/or reduce opioid dose amount. The addition of paracetamol in combination with step III opioids cannot be supported by the current research review.

Several limitations were identified during the process of systematic review, including small sample, large losses to follow-up, no intention-to-treat analysis completed, short follow-up (one to five days), and evidence of sponsorship by industries (bias).

This review adds to the body of evidence that routine use of acetaminophen to opioids for chronic pain management is not effective for pain reduction or reduction in opioid dosage needed for pain control. Acetaminophen does have potential negative effects with long-term or high-dose use, so this approach should not be implemented as a routine. A growing body of research is challenging the WHO ladder approach to pain management.