These guidelines do not provide any information about search strategy or any specific evaluation of evidence. Notes state that most direct evidence is of low quality, but recommendations do result from unanimous consensus.

The guidelines provide detailed recommendations regarding:

• Screening and assessment
• Management of pain in opioid-naive as well as opioid-tolerant patients
• Ongoing care of adult patients with cancer and related pain management
• Comprehensive pain assessment and use of pain ratings
• Interventions for specific types of pain syndromes
• Opioid prescribing, titration, and ongoing management
• Management of adverse effects related to opioids
• Psychosocial support and patient and family education
• Nonpharmacologic interventions.

In general, opioids are first-line interventions. The NCCN guidelines suggest that antidepressants and anticonvulsants can be first-line treatments for adjuvant pain, although the recommendation for using them as such is still based on anecdotal experience or guidelines relating to patients who do not have cancer.

The NCCN guidelines provide comprehensive algorithms for pain management, from screening to ongoing maintenance. The guidelines recommend considering a variety of nonpharmacologic interventions. Psychosocial support, including coping-skills training, is recommended, as is comprehensive patient and family education. The guidelines provide useful information and an overview of the full range of pain management. The work points to the ongoing need to consider multiple adjuvant and supportive interventions to achieve pain relief that works for the individual patient.

NCCN categories of evidence and consensus are described. Unless otherwise stated, all recommendations are reported to be category 2A, indicating a low level of evidence and uniform NCCN consensus. Specific process for evidence rating and consensus development is not described in the document. In addition, a search strategy was not described.

The NCCN guidelines document recommends universal screening for pain and provides an algorithm for comprehensive assessment and management approaches based on etiology of pain and current status with regard to pharmacologic management.

For opioid-naïve patients:

• Rapidly titrate short-acting opiods for moderate and severe pain, and consider for mild pain.
• Consider nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild pain.
• Consider addition of co-analgesics for all pain levels based on the specific pain syndrome.

For opioid-tolerant patients:

• An algorithm is provided for dose increases based on timing of peak effect and patient response. Initial calculation for titration is 10%–20% of the previous 24-hour dose, and if pain is unchanged or increased, an increased dose of 50%–100%.

For all cases, recommendations include:

• Regular pain medication dosing with rescue medications as needed
• Ongoing reassessment and regimen modification to manage pain and minimize adverse effects

For specific pain syndromes:

• Inflammation–A trial of NSAIDS or glucocorticoid
• Nerve compression or inflammation–A trial of glucocorticoid
• Bone pain without emergency–NSAIDS titrated to effect, consideration of nerve block or local radiation therapy for local pain, trial of biphophonates, hormonal or chemotherapy, and radioisotopes for diffuse bone pain
• Neuropathic pain–A trial of antidepressants, anticonvulsants, or topical agents

The major limitations of these guidelines are:

• Recommendations are mainly consensus based
• Recommendations are associated with low levels of evidence

The NCCN guidelines document provides comprehensive decision making algorithms for assessment, severity grading, and management of cancer-related pain. The guidelines also provide assessment tools, titration schedule examples, and conversion tables for medications and conversion to transdermal fentanyl. An additional offering are suggestions regarding the management of a variety of opioid adverse effects. (A trial of adjunctive medications are suggested for neuropathic pain as a pain management approach.)

RESOURCE TYPE: Evidence-based guideline

PHASE OF CARE: Multiple phases of care

One hundred seventy-one articles were retrieved via aPubMed search. No information was provided regarding which articles were selected as relevant to these guidelines, and no discussion of any method used for rating the quality of included evidence exists.

Limited database used. Recommendations are a combination of evidence- and consensus-based suggestions, and most nonpharmacologic interventions are by consensus.

Provides multiple evidence- and consensus-based recommendations for prophylaxis and the management of nausea and vomiting due to chemotherapy or radiation therapy. Recommendations provide a list of chemotherapy agents, including oral agents and categorization as to emetic potential.

RESOURCE TYPE: Evidence-based guideline

DATABASES USED: Not provided

KEYWORDS: Not provided

INCLUSION CRITERIA: Not provided

EXCLUSION CRITERIA: Not provided

PHASE OF CARE: Multiple phases of care

Not provided.

The guidelines recommends no prophylaxis for those with a low risk of infection; consideration of bacterial, fungal, and viral prophylaxis for intermediate risk (anticipated neutropenia 7–10 days), considerations of fluoroquinolone prophylaxis, antifungal prophylaxis until resolution of neutropenia, and viral prophylaxis during neutropenia in high-risk patients (e.g., anticipated neutropenia longer than 10 days, allogeneic HCT, acute leukemia induction or consolidation). It provides a recommended vaccination schedule for patients undergoing HCT, recommends annual influenza vaccine and pneumococcal vaccine to newly diagnosed patients based on individual assessment, and suggests fluoroquinolone prophylaxis in patients at high risk for mucositis.

• Provides limited information about search strategies and evidence base
• Most recommendations reported to be low quality evidence and high consensus

The guidelines provide general recommendations for prevention and management of infection, and useful algorythms for work up and management of signs and symptoms of infection by site.

The objective of this study was to assess the efficacy of a rapid titration of either morphine or midazolam for reduction of dyspnea.

Patients were randomized to receive oral morphine or oral midazolam. Starting dose of morphine was 3 mg, and midazolam was 2 mg. Two steps of 25% increases in dosage were given as needed to achieve 50% reduction in symptoms and to establish the “effective dose” for the follow-up period. Dyspnea relief was assessed 30 minutes after each medication dose during the rapid titration phase. In the follow-up phase, the effective dose was taken every four hours around the clock while awake. Breakthrough dyspnea was managed with rescue doses, and the dose was adjusted daily during the five-day follow-up period based upon need.

• The study reported on a sample of 63 participants.
• The mean age in the morphine arm was 55 years, with a range of 30–80 years.
• The mean age in the midazolam arm was 59 years, with a range of 36–82 years.
• Gender distribution was not reported.
• Of the participants, 16 of 63 had lung cancer, 15 of 63 had breast cancer, 6 of 63 had head and neck cancer, and 26 of 63 had other cancers.
• Other clinical contributing risk factors for dyspnea were present in most patients.
• Exclusion criteria included active or uncontrolled COPD, noncompensated heart failure, and severe renal or hepatic failure.

The study was conducted in a single outpatient setting in Buenos Aires.

Patients were undergoing end-of-life and palliative care.

The study was a random-assignment, single-blind intervention trial.

• Mini-mental status (MMS) exam for cognitive ability to participate in trial
• Dyspnea numeric rating scale (NRS) of 0–10 for breathlessness in which 0 means no breathlessness and 10 means worst possible breathlessness (used to establish baseline dyspnea and for follow-up phase)
• Dyspnea descriptors patients used first to characterize their dyspnea
• Semi-structured questionnaire for healthcare providers regarding possible active causes of dyspnea for each patient, dyspnea syndromes, and treatment or diagnostic approaches
• Dyspnea relief five-point scale (used only during rapid titration phase): none, slight, moderate, a lot, complete

• No serious adverse events required drug discontinuation, but about 50% in both arms developed mild somnolence.
• All patients in both arms of rapid titration were alleviated of dyspnea and continued into the follow-up phase
• Median intensity for dyspnea at baseline was 9 on NRS, and day one showed a significant decrease in dyspnea in both arms (morphine [9–6] and midazolam [9–4.5, p < .001]). Subsequent days continued to decrease or stayed low.
• The midazolam arm maintained significantly lower dyspnea levels as compared to the morphine arm on days three to five (p < .0002).
• Therapeutic failure (defined as less than 50% reduction in breathlessness) was seen in 20% of those on morphine and 0% of those on midazolam.

Midazolam alone or in combination with opioids may be beneficial for dyspnea management.

• The study had a limited sample size of less than 100 patients.
• Patients were eliminated if their symptoms were rated greater than or equal to 3/10, which is inconsistent with the stated criteria of moderate to severe dyspnea.
• Only patients and caregivers were stated to be blinded.
• No clear description was provided of whether patients could tell the difference in medications used.
• Patients were ambulatory and followed daily in the clinic; findings here may not apply to individuals with worse performance status.
• Though stated that patients could use rescue doses, no discussion ofuse of rescue medication took place between groups.
• Whether this was dypsnea at rest or dyspnea on exertion was unclear.
• Some patients on midazolam were also on opiods for other reasons, but no differentiation was made of these patients, and the number of the sample involved with use of both drugs was not described.

Midazolam may be useful in the management of dyspnea, but well designed clinical trials are needed to establish supporting evidence for this intervention.

To assess the role of midazolam as adjunct therapy to morphine in patients with advanced cancer with severe dyspnea during their last week of life

 Patients randomly were assigned to one of three treatment groups.

• Group Mo (n = 35): morphine 2.5 mg every four hours around the clock (ATC) for opioid-naive patients or 25% above the daily dose for those receiving baseline opioids with midazolam 5 mg rescue doses for breakthrough dyspnea (BD)
• Group Mi (n = 33): midazolam 5 mg every four hours ATC with 2.5 mg morphine rescue doses for BD
• Group MM (n = 33): morphine ATC (same dose as Group Mo) plus midazolam 5 mg every four hours ATC with morphine 2.5 mg rescue doses for BD

All drugs were given subcutaneously through a butterfly needle in the infraclavicular space. Random assignments were performed using a random number generator in 1:1:1 ratio in blocks of nine.

• N = 101
• KEY DISEASE CHARACTERISTICS: Patients with advanced cancer experiencing severe dyspnea during their last week of life
• OTHER KEY SAMPLE CHARACTERISTICS: Eligible patients had to have low performance status (PS = 4), severe dyspnea, and life expectancy less than one week and had to be coherent (more than 23/30 on the mini-mental state examination [MMSE]).

• Randomized, single-blind

• Modified Borg scale was performed at baseline and 24 and 48 hours after randomization.
• The number of breakthrough dyspnea episodes was recorded daily.
• MMSE was used to monitor cognitive impairment daily.
• Pulse oximetry also was monitored.
• Common Toxicity Criteria for Adverse Events v2.0 was used to score adverse events.
• Study endpoints were dyspnea intensity (measured by Borg scale), dyspnea relief (yes-no) after the intervention, and number of episodes of breakthrough dyspnea requiring rescue medication.
• Side effects from rescue medication also were monitored.

A significant correlation existed between dyspnea and anxiety at baseline and 24 and 48 hours. No correlation existed between dyspnea and anxiety and the other variables. No significant difference was found in oxygen saturation among the groups. Also, the groups did not differ significantly with respect to dyspnea intensity. Dyspnea relief at 24 hours was 69% Mo, 46% Mi, and 92% MM (p = 0.0004 for MM versus Mi, p = 0.03 for MM versus Mo). Patients with no dyspnea relief were 12.5% Mo, 26% Mi, and 4% MM (p = 0.04 for MM versus Mi). Percentage of breakthrough dyspnea episodes were 34.3% Mo, 36.4% Mi, and 21.2% MM (p = not significant) at 24 hours and was 38%, 38.5%, and 21.2%, respectively, at 48 hours. Authors asserted that clinicians should prescribe the combination.

The addition of midazolam to morphine improved the control of baseline dyspnea.

• Single blinding was a potential limitation.
• The physician’s knowledge of the drug regimen that patients were receiving may have influenced the need for administering rescue medication for breakthrough dyspnea.

More evidence, in addition to this one randomized, uncontrolled trial, is needed to validate findings.

To investigate whether the oral antidepressant fluoxetine affected symptoms of depression, adjuvant treatment completion, or quality of life

Intervention was daily oral fluoxetine (20 mg) for 6 months. Fluoxetine is a selective serotonin reuptake inhibitor. Data were collected at baseline, 3 months, and 6 months.

• The sample size was 180 (90 in the intervention group and 90 in the control group).
• Patients' mean age was 55.9 (range = 37–85).
• All patients were female.
• Patients had stage I or II breast cancer only.
• Patients had symptoms of depression but not a diagnosis of depression.

Four community outpatient settings

Active treatment

Prospective, randomized, placebo-controlled trial with double blinding

• The Functional Assessment of Cancer Therapy-General (version 3) for quality of life.
• The completion of adjuvant treatment was recorded.
• 11-item brief Zung Self-Rating Depression Scale for depressive symptoms.
• Two-question screening survey (TQSS) at baseline, to screen patients with symptoms of depression.

The use of fluoxetine for six months in each adjuvant therapy group (chemotherapy alone, hormonal therapy alone, chemotherapy plus hormonal therapy), was associated with, compared to the control group:

• An improvement in quality of life (p < 0.01 in each group)
• A higher completion of adjuvant treatment (p < 0.01 in each group)
• A reduction in symptoms of depression (p < 0.01 in each group).

An antidepressant may be effective for patients with early-stage breast cancer who have symptoms of depression and who are receiving adjuvant treatment. Given study limitations, more evidence is needed.

• The time lapsed since cancer therapy was unknown.
• The number of patients who showed a significant improvement in each measurement was statistically tested. However, it is unclear how the significant improvement was determined. Data for both the main outcome measures (quality of life and depression) were not reported.
• No data were recorded about reliability, validity, sensitivity, or specificity for TQSS.
• The study included patients with early-stage breast cancer only, and the size of each adjuvant therapy subgroup was small.

Oncology nurses can inform patients that oral fluoxetine may be an option for decreasing symptoms of depression.

To evaluate olanzapine for chemotherapy-induced nausea and vomiting (CINV) prophylaxis in patients receiving highly emetogenic chemotherapy (HEC) and to evaluate potential toxic effects

Patients were stratified according to gender, chemotherapy regimen, and the specific 5HT3 used. All patients were on triplet antiemetic regimens. In addition, patients received 10 mg oral olanzapine daily or placebo on days 1–4. Patients were to complete daily records of vomiting, nausea severity, and use of rescue therapy.

• N = 369   
• MEDIAN AGE = 57 years
• MALES: 27.6%, FEMALES: 72.4%
• KEY DISEASE CHARACTERISTICS: Most had breast cancer, and 12% had lung cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: All patients were chemotherapy-naïve, 35% were on cisplatin-based regimens, and 64% were on anthracycline and cyclophosphamide.

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: United States

PHASE OF CARE: Active antitumor treatment

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

• Visual analog scale (VAS) for nausea severity
• Complete response rated in acute and delayed phase
• Use of rescue medications

During the acute phase, 73.8% on olanzapine had no nausea compared to 45.3% on placebo (p < 0.001), and in the delayed phase, 42.4% on olanzapine and 25.4% on placebo had no nausea (p = 0.001). The complete response rate with olanzapine in the acute phase was 85.7% compared to 64.6% with placebo (p < 0.001). In the delayed phase, complete response was 66.9% with olanzapine and 53.4% with placebo (p = 0.007). Those on olanzapine had significantly more sedation on day 2, which then resolved in the following days.

The addition of olanzapine as an adjunct to standard triplet antiemetic regimens for patients receiving HEC was more effective than placebo for CINV control.

Findings suggest that the use of olanzapine as an adjunct to usual triplet therapy for CINV control was effective in improving complete response rates and nausea, although complete response rates reported here are not higher than those often reported with standard triplet therapy. Nausea was also improved with olanzapine, although almost half the participants still had nausea in the delayed phase. Clinicians can consider the addition of olanzapine to standard antiemetic regimens for individuals at high risk for CINV or those who may have had inadequate CINV control in previous chemotherapy cycles. Ongoing research is still needed to achieve greater nausea control.

To compare the effectiveness of a regimen using olanzapine versus a regimen using metoclopramide for breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC)

Patients receiving HEC were randomly assigned to receive either a regimen containing olanzapine or metoclopramide for breakthrough CINV. All patients received prophylactic antiemetics of 12 mg IV dexamethasone, 0.25 mg IV palonosetron, and 150 mg IV fosaprepitant on day 1 prior to chemotherapy. On days 2-4, patients received 4 mg oral dexamethasone, twice per day. The metoclopramide regimen was 10 mg orally every 8 hours for 72 hours. The olanzapine regimen was 10 mg daily for 72 hours. 

Those on olanzapine also received placebo once daily so that the number of pills were the same for both groups, so patients were blinded to the study group. Patients were instructed to begin the breakthrough treatment within 30 minutes after any emesis or nausea level greater than 3 on a visual analog scale (VAS). If the breakthrough treatment was begun, patients were to discontinue the oral dexamethasone, notify the on-call nurse, and begin recording nausea and any emesis. Patients were contacted by phone every 24 hours to remind them to complete information and assess toxicities.

• The study consisted of 276 patients; of these, 108 used a breakthrough regimen and were analyzed.
• Median age was 62 years with a range of 38–79.
• The study sample was 46.3% male and 53.7% female.
• Cancer diagnoses were breast, bladder, lung, and lymphoma.
• All patients were receiving HEC.

The study was conducted at multiple outpatient sites in Indiana.

All patients were in active antitumor treatment.

This was a randomized, parallel group trial.

The M.D. Anderson symptom assessment scale was used.

A total of 39% of patients randomized needed to begin the breakthrough CINV regimen as assigned.  Over the 72 hour observation period, 70% of those on olanzapine had no further emesis, compared to 31% of those on metoclopramide (p < 0.01), and 68% on olanzapine had no further nausea, compared to 23% with no nausea in the metoclopramide group (p < 0.01). The pattern of symptom control showed that the incidence of nausea and vomiting declined each study day.

A regimen of breakthrough CINV treatment using olanzapine was more effective than metoclopramide for relief of breakthrough nausea and vomiting in patients receiving HEC.

Olanzapine can be more effective than metoclopramide to manage breakthrough CINV. The breakthrough regimen tested here involved the provision of consistent medication, rather than treatment of each breakthrough episode individually, which may not be the usual approach for management. Findings here showed that about 40% of patients required a breakthrough regimen, despite use of aggressive standard antiemetic therapy. Olanzapine was found to be more effective in relieving nausea, which has been more difficult to effectively control than vomiting.  Strong consideration should be given to use of this type of olanzapine regimen and immediate patient-initiated use of such a regimen based on self assessment of CINV severity early in the course of treatment. Most current guidelines provide limited recommendations for breakthrough CINV.

To examine the effectiveness of olanzapine in the treatment of chemotherapy-induced nausea and vomiting without the use of dexamethasone after day 1

A 10-mg oral dose of olanzapine was given every day, four times a day for prevention (rather than breakthrough) nausea and vomiting. On day 1 of chemotherapy, patients received 0.25 mg IV palonosetron and dexamethasone (8 mg for moderately emetogenic chemotherapy [MEC], 20 mg for highly emetogenic chemotherapy [HEC]) as well as 10 mg oral olanzapine. On days 2-4, patients received only 10 mg olanzapine daily. The same antiemetic regimen was continued for as many cycles as the patient completed (1-6 cycles). Patients received no other antiemetics on days 2-4. Patients were permitted to take rescue therapy.

The sample consisted of 40 patients who were chemotherapy-naive and receiving HEC or MEC.

This was a prospective, nonrandomized trial with no control or comparison group, consisting of descriptive analysis only (percentage of patients with response described).

• The M.D. Anderson Symptom Inventory (MDASI) was used.
• Patients recorded daily episodes of vomiting and retching.

Complete response (CR), defined as no emesis and no rescue medications administered and no nausea, was found in 100% of HEC patients and 97% of MEC patients in the acute period (0-24 hours after chemotherapy).

Responses for the delayed period (24-120 hours) decreased. Seventy-five percent of patients reported CR in the delayed and overall periods for emesis and even fewer for control of nausea (50% of HEC patients with CR for nausea and 78% of MEC patients with CR for nausea in the delayed and overall periods). No adverse events to study drugs were noted (no grade 3 or 4 toxicities). Olanzapine was not associated with sedation, weight gain, or hyperglycemia.

• The sample size was small.
• Investigators stated that combination olanzapine, dexamethasone, and palonosetron was effective in controlling acute and delayed CINV in patients receiving both HEC and MEC; however, no control or comparison group was included in the study.
• The investigators stated that the results indicated effectiveness compared to studies using triple-drug regimens; however, no head-to head comparison was done in this study. This is especially problematic given that aprepitant was not used and is now recommended per guidelines.
• Half of the patients in the HEC group still experienced nausea in the delayed and overall study periods (0-120 hours after chemotherapy). In the MEC group, 22% of patients still experienced nausea in the delayed and overall periods.
• Use of rescue medications was not described, although these were allowed and patients were permitted to continue in the study even if rescue medications were used.