DOI Link: doi: 10.1056/NEJMoa1515725

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.

DOI Link: doi: 10.1007/s00520-012-1710-6

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.

DOI Link: doi: 10.1007/s00520-007-0248-5

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.

DOI Link: doi: 10.12788/jcso.0245

To compare the effectiveness of an olanzapine-based triple-drug antiemetic regimen with a fosaprepitant-based triple-drug regimen

Patients were randomized to either olanzapine, palonosetron, and dexamethasone (OPD) or fosaprepitant, palonosetron, and dexamethasone (FPD) before the first course of chemotherapy. The OPD regimen was palonosetron 0.25 mg and dexamethasone 20 mg IV prior to chemotherapy and 10 mg PO olanzapine on days 1–4. The FPD regimen was 12 mg dexamethasone, 0.25 mg palonosetron and 150 mg fosaprepitant IV prior to chemotherapy, followed by oral dexamethasone 4 mg twice daily on days 2–3. Patients were allowed to take rescue medication. All patients received a placebo to ensure that the medication provided looked identical to the patient. Daily episodes of vomiting, symptom intensity, and use of rescue therapy were recorded by the patient in a diary for five days.

• N = 101   
• MEDIAN AGE = 62 years
• AGE RANGE = 52–76 years
• MALES: 78.2%, FEMALES: 21.8%
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Patients with locally advanced head and neck or esophageal cancer receiving HEC and daily radiotherapy

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

PHASE OF CARE: Active antitumor treatment

• Single-blind, placebo-controlled, randomized trial

• MD Anderson Symptom Inventory (MDASI) mean of daily MDASI scores was used in analysis
• Visual analog scale (VAS) for nausea severity
• Complete response defined as no emesis and no use of rescue medication

No difference existed between groups in complete response for the acute period. For the delayed and overall periods, those on the olanzapine regimen showed a CR rate of 76% compared to 74% in the comparison group. Twelve percent of the OPD group required rescue during the acute phase, and 12% required rescue medication during the delayed period. In the FPD group, 10% required rescue during the delayed phase, and 26% required rescue medication in the acute period. The percentage of patients with no nausea was higher in the OPD group in all phases (p < 0.01). Patients on olanzapine had more drowsiness that was resolved by day 3–4.

Findings suggest that both the standard triple-drug antiemetic regimen and the olanzapine-based regimen were effective in controlling vomiting. As a greater proportion of those receiving olanzapine had no nausea, the olanzapine regimen may provide greater nausea control.

This study showed that both antiemetic regimens were similar in terms of control of emesis and need for rescue medications, and that nausea was better controlled with olanzapine. Nausea has been more difficult to control with currently used antiemetic regimens. These results suggest that olanzapine-based regimens may provide better nausea control. Olanzapine is also generally much less expensive than NK1s, providing a good treatment alternative at a lower cost.

DOI Link: doi: 10.1016/S1470-2045(13)70009-3

To determine the acceptability of solely using palliative noninvasive ventilation (NIV) versus oxygen therapy to manage breathlessness in patients with end-stage cancer and its effects in reducing dyspnea and opioid requirement

• All patients received a 5–10 minute demonstration on NIV prior to randomization.
• Patients were randomly assigned to either NIV (pressure-support mode and initiation based on patients’ request and mask comfort) or oxygen (Venturi or reservoir mask) group to achieve oxygen saturation > 90%.
• Based on a computerized randomization sequence, patients were further stratified and randomly assigned to hypercapnic (PaCO2 > 45 mm Hg) or nonhypercapnic (PaCO2 < 45 mm Hg) groups.
• An independent biostatistitian placed patients’ information in an opaque, sealed envelope.
• Subcutaneous morphine was given to reduce dyspnea scores by at least one point on the Borg scale (BS), and the total dose requirements over the first 48 hours were calculated.
• Arterial blood gas, vital signs, quantity of secretion, and dyspnea scores were measured at baseline and at one hour, 24 hours, and 48 hours.
• Mortality causes were recorded in the hospital and at three and six months after discharge.

• N = 200
• MEAN AGE = 71 years (NIV group), 70 years (oxygen group)
• MALES: 62%, FEMALES: 38%
• KEY DISEASE CHARACTERISTICS: Solid tumor cancers included lung, gastrointestinal, breast, head and neck, and esophageal. Respiratory failures included obstructive bronchus, carcinomatous, lymphangitis, and pleural effusion. Life expectancy was less than six months.
• OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria were a P/F ratio of 1:250 and one of the following: dyspnea with a BS ≥ 4, signs of respiratory distress, or a respiratory rate ≥ 30. Exclusion criteria were reversible respiratory failure such as cardiogenic pulmonary edema or the exacerbation of chronic pulmonary disorders, treatment refusal, a weak cough reflex, agitation or uncooperative behavior, anatomical abnormalities with mask fitting, uncontrolled cardiac ischemia or arrhythmias, ≥ 2 organ failure, opioid use within past two weeks, adverse effects to opioids, substance misuse history, contraindication to morphine use, acute renal failure, and recent head injury.

• SITE: Multi-site  
• SETTING TYPE: Inpatient  
• LOCATION: Seven intensive care units and critical care units in Italy, Spain, and Taiwan

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

Multi-center, randomized, controlled trial

• McCabe Cyclomatic Complexity Index (MCCI) to record demographic information
• Simplified Acute Physiology Score II (SAPS) and Palliative Prognostic Index Score (PPIS) to determine mortality risk
• Kelly and Matthay Scale (KMS) to assess neurological status in patient with respiratory disease
• Modified Borg Scale (BS) to assess intensity of dyspnea
• Symptom Distress Scale (SDS) self-administered questionnaire to assess cancer-related symptoms

• In the NIV group, 11 patients (11%) dropped out of the study, but there was no attrition in the oxygen group.
• The NIV group had a statistically significant reduction in dyspnea levels at one hour, 24 hours, and 48 hours (BS = -0.58; 95% CI -0.92, -0.23; p = 0.0012). The greatest reduction was seen in the hypercapnic NIV group after the first hour (BS = -0.91; 95% CI -1.42, -0.46; p < 0.0001). 
• The total amount of morphine required over 48 hours was lower in the NIV group (SD = 37.3 mg) compared to the oxygen group (SD = 67.1mg) with a mean difference of -32.4 mg (95% CI -47.5, -17.4).
• In-hospital mortality was the same between the groups.
• The NIV hypercapnic group had better expected survival rates than the oxygen hypercapnic group.
• At discharge, symptom distress scores were statistically improved in the NIV group compared to the oxygen group (SD = 10 versus SD = 7.6; p = 0.001).

NIV was feasible and effective in decreasing dyspnea intensity and reducing morphine requirements in patients with end-stage cancer experiencing respiratory failure. However, additional studies validating these findings and determining the effects of NIV on survival and quality of life are needed.

• Risk of bias (no blinding)
• Key sample group differences that could influence results
• Findings not generalizable
• Intervention expensive, impractical, or training needs
• Subject withdrawals ≥ 10% 
• Other limitations/explanation: The benefit of performing a blinded study using a sham ventilation could have potentially caused harm to the patients in the oxygen group. Therefore, the researchers chose to maintain patient safety.
• The NIV group had an attrition bias. Also, the duration and timing of the NIV treatment was based on patients’ preferences and mask comfort, leading to a threat in internal validity. The NIV treatment may not be practical or cost effective in all palliative care centers because specialized training and equipment are needed. 

This study offers clinicians a treatment modality that can be used in adjunct with opioids to significantly reduce breathlessness in patients with end-stage cancer. Additional studies are needed to determine the specific patient population that would benefit the most from this treatment, its cost effectiveness, patient satisfaction, the adverse effects of NIV, and the survival rate.

DOI Link: doi: 10.1056/NEJM198102193040802

To evaluate protective isolation versus no isolation.

The authors evaluated single protective isolation (single-bed room and clean gowns, gloves, and masks for people entering room) versus standard care (two-bed room and reminder sign to wash hands).

Forty-three episodes of neutropenia occurred in adult patients.

• Inpatient
• Hematology-oncology unit

This was a randomized study.

No significant difference was found between isolated and nonisolated patients regarding the incidence of infection, time of onset of first infection, and days with fever.

Comprehensive, evidence-based guidelines were developed to assist healthcare professionals in providing optimal psychosocial care. The guidelines are multidisciplinary in focus, with recommendations applicable to diverse treatment settings.

Evidence was presented using levels I, II, III-1, III-2, III-3, and IV rating system with level I representing the gold standard.

 Clinically relevant recommendations supported by level I and II evidence about depression include the following.

• Referring high-risk patients to specialized psychological services to minimize the likelihood of developing significant distress (level I)
• Using a range of psychoeducational interventions to decrease distress (level I)
• Managing depression by incorporating a combination of supportive psychotherapy, cognitive and behavioral techniques, and pharmacotherapy (levels I, II)
• There is no evidence that any particular antidepressant is superior to another in the management of depression in people with cancer (level I).
• Other therapies that may improve depression are art, music, painting, reading, poetry, wellness programs, meditation, hypnosis, acupuncture, relaxation, exercise, prayer, and laughter. (levels I, II, III-3, IV).

The treatment of depression should incorporate psychotherapeutic interventions and the use of medication.

Evidence of the efficacy of antidepressant medication in treating depression in patients with cancer is clear.

No evidence suggests that any particular antidepressant is superior to another.

• The sedating properties of tricyclics may be beneficial to some patients, as may their potentiation and enhancement of opioid analgesia in those with pain.
• Their anticholinergic side effects may aggravate stomatitis, exacerbate constipation, and affect cardiac rhythm.
• Patients with cancer may respond to a lower dose of tricyclic antidepressants.
• Selective serotonin reuptake inhibitors have been demonstrated to be effective in treating depression in patients with cancer.
• The long half-life of fluoxetine makes it less desirable in patients with hepatic or renal dysfunction where sertraline or paroxetine is preferable.

The National Comprehensive Cancer Network is an alliance of 21 of the world’s leading cancer centers, working together to develop treatment guidelines for most cancers and dedicated to research that improves the quality, effectiveness, and efficiency of cancer care.

The NCCN Clinical Practice Guidelines in Oncology: Distress Management (Anxiety) are updated continually and are based upon evaluation of scientific data integrated with judgment by multidisciplinary experts. The NCCN guidelines development process relies heavily on structured feedback. One group of experts, develop the guidelines and another group of experts review them, which leads to revisions and modifications, reinitiating the feedback process.

NCCN Categories of Consensus: Category 1: There is uniform NCCN consensus, based on high-level evidence, that the recommendation is appropriate. Category 2A: There is uniform NCCN consensus, based on lower level evidence including clinical experience, that the recommendation is appropriate. Category 2B: There is no uniform NCCN consensus (but no major disagreement), based on lower-level evidence, including clinical experience, that the recommendation is appropriate. Category 3: There is a major NCCN disagreement that the recommendation is appropriate. All recommendations are category 2A unless otherwise indicated.

Screening of every patient with cancer for evidence of distress. Any patient with a score of > 4 of 10 for distress should be referred to a psychosocial service. Anxiety disorder is common in most patients with cancer. Evaluate patient’s safety. Evaluate patient’s decision-making capacity. Evaluate patient to determine anxiety related to: general medical condition; withdrawal from alcohol or narcotics, pain; generalized anxiety disorder; panic disorder; post-traumatic stress disorder; phobic disorder; or obsessive-compulsive disorder. The treatment recommended for anxiety (after eliminating medical causes) is psychotherapy with (or without) an anxiolytic with or without an antidepressant. If no response, re-evaluate medication (consider neuroleptics), psychotherapy, support, and education. If no response, evaluate for depression and other psychiatric comorbidity.

DOI Link: doi: 10.1007/s12185-015-1735-y

To assess the additional effects of aprepitant in combination with conventional 5HT3 blocker-based prophylaxis for chemotherapy-induced nausea and vomiting (CINV) during highly or moderately emetic chemotherapy for hematologic malignancies

Patients were divided into two arms. Patients in the conventional antiemetic therapy arm received 5HT3 receptor antagonists (RAs) alone (19 patients, control arm), and patients in the treatment group received 5HT3 RAs plus aprepitant (22 patients, aprepitant arm). The incidence of CINV and the use of rescue medications were analyzed and compared between the two groups over the total period of 10 days from the start of chemotherapy. Oral food intake also was appraised by patients and sorted into four levels: (1) not impaired, (2) slightly impaired, (3) moderately impaired to about half of the usual amount, or (4) severely impaired.

• N = 41  
• AGE = ≥ 20
• MALES: 65.85%, FEMALES: 34.14%
• KEY DISEASE CHARACTERISTICS: Hematologic malignancies 
• OTHER KEY SAMPLE CHARACTERISTICS: The eligible chemotherapies were limited to the following: (a) preparative regimens for autologous hematopoietic stem cell transplantation for multiple myeloma or malignant lymphoma, (b) platinum-containing regimens for resistant or refractory malignant lymphoma mainly consisting of etoposide, methylprednisolone, cytarabine, and cisplatin or its modified variant, which substitutes carboplatin for cisplatin, or (c) induction or consolidation therapies for acute leukemia, which contain either anthracyclines, high-dose methotrexate, or high-dose cytarabine. Patients with poor performance statuses or with an estimated life expectancy of less than three months were disqualified. Patients had to have sufficient cognitive capacity, adequate blood counts, no significant hepatic or renal dysfunctions at the start of chemotherapy. Patients who had had a previous history of aprepitant administration also were excluded.

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: The University of Tokyo Hospital

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

Randomized, controlled study

• Vomiting was measured daily by the number of vomiting episode the patient reported.
• Nausea was measured by Visual Analog Scale (VAS).
• The amount of oral food intake was recorded daily on days 1–10 of chemotherapy administration. 
• Rescue medication use was recorded by the physicians.

This study revealed the benefit of adding aprepitant to highly emetic chemotherapy regimens for various hematologic malignancies. Sufficient antiemetic effects were achieved without obvious adverse events, and additional aprepitant use is recommended for patients who received chemotherapy for a hematologic malignancy. The additional research of individual chemotherapies that specifically prefer antiemetic intensification with aprepitant is warranted.

• Small sample (< 100)
• Measurement/methods not well described

 

Aprepitant is a good option for nurses to recommend for patients receiving chemotherapy for hematologic malignancies. NK1s such as aprepitant are recommended in relevant guidelines.

DOI Link: doi: 10.1038/sj.bmt.1705846

To assess the use of palifermin in the prevention of oral mucositis (OM) and acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT)

IV palifermin was administered at 60 mcg/kg for three consecutive days before and after conditioning therapy. These patients were compared to a retrospective control group.

• The study reported on a total of 106 patients, with 53 in the palifermin group and 53 in the control group.
• All patients received autologous or allogeneic transplantation with hematologic and nonhematologic diseases and had a Karnofsky score of 80 or higher.
• The palifermin group received transplantations between June 2005 and March 2006; the control group received transplantations between December 2000 and December 2005.
• Protocols were not indicated for either group.

This was a multicenter study conducted in Poland.

This was a retrospective control trial.

• The World Health Organization (WHO) Oral Toxicity Scale was used.
• Researchers recorded mucositis onset and incidence, use of analgesics, duration of total parenteral nutrition (TPN), incidence of febrile neutropenia, severe infections, and incidence of acute GVHD.

Incidence of all grades of mucositis was lower in the palifermin group (p < 0.001). Incidence of grades 3–4 was 13% in the palifermin group and 43% in the control group (p < 0.001). Mean duration was significantly lower (p < 0.001). No statistically significant differences in the onset of OM, duration of TPN, opioid use, incidence of febrile neutropenia, or severe infection were observed. No statistical significance in acute GVHD measures were observed, although the authors suggested that a decrease in acute GVHD may occur. Additional studies are necessary.

Adverse events (e.g., rash, pruritis, erythema, generalized edema, taste alteration, mouth or tongue thickness and discoloration, proteinuria) were mild in 15 patients, moderate in 15 patients, and severe but not life-threatening in 4 patients. No events caused discontinuation of palifermin.

• This was a retrospective trial.
• Expense was not addressed.
• The study used an IV formulation of palifermin.
• Ensuring all treatments were equal is not possible because of the study’s historical nature.