STUDY PURPOSE: To assess the efficacy of tapentadol for relief of cancer pain

TYPE OF STUDY: Systematic review

• FINAL NUMBER STUDIES INCLUDED = 4 
• TOTAL PATIENTS INCLUDED IN REVIEW: 1,029
• SAMPLE RANGE ACROSS STUDIES: 93–496 patients
• KEY SAMPLE CHARACTERISTICS: Pain intensity of at least 4 on a 10-point scale, age range was 50–75 years

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

Tapentadol was as effective as oxycodone or morphine in comparator studies. No substantial differences in side effects were seen between tapentadol and comparators.

Tapentadol is as effective as oxycodone or morphine for chronic pain management.

• Limited number of studies included
• Mixed study quality

Tapentadol was shown to be effective for management of cancer-related pain, but little suggests that it should be considered above other opioids. Further research would be helpful. The authors suggest that a reduction of pain intensity of at least 50% should be used to establish treatment efficacy, and note that tapentadol, as with all opioids, presents challenges in terms of benefits and side effects of treatment.

The objective was to investigate and compare emergency medical treatment of acute dyspnea in palliative care patients with advanced-stage cancer on the basis of several emergency medical therapy schemes.

The study consisted of a retrospective evaluation of emergency medical treatment initiated in response to palliative client complaints of “acute dyspnea” over a 24-month period. Data collected were based on the emergency service protocol of four different German emergency medical services. Patients were categorized into five groups based on the intervention utilized by emergency physicians in the management of their dyspnea. Group 1 used therapy with morphine IV and oxygen; Group 2 used morphine IV, bronchodilator-effective drugs (IV and per inhalation), and oxygen; Group 3 used bronchodilator therapy (IV and per inhalation); Group 4 used oxygen therapy only; and Group 5 utilized no therapy. The extent to which the symptom was relieved was measured by patients’ numeric rating of intensity of dyspnea compared to extent of “vital sign normalization” on the basis of patients’ arterial oxygen saturation and respiratory rate.

• The sample was comprised of 116 patients.
• Patients ranged in age from 49–91.
• The median patient age in Group 1 was 77 years, Group 2 was 69 years, Group 3 was 73 years, Group 4 was 74 years, and Group 5 was 71 years.
• Of the 116 patients, 47 were females and 69 were males.
• Only patients diagnosed with advanced stage of disease (i.e., palliative stage with no feasible curative therapy alternative) were included in the current study.
• Multiple cancer types were included.
• Patients with advanced non-cancer disease and non-cancer related dyspnea (e.g., COPD) were excluded.
• All 116 patients were pre-treated with opioids according to WHO III standards for symptomatic pain control. Fifty-six patients (48%) were also pre-treated with rescue opioid medication for breakthrough symptoms of acute dyspnea (estimated as 1/6 of pain opioid dose rate).

The study was conducted during multiple out-of-hospital emergency response/home visits by four emergency medical services in Germany.

This was a retrospective, descriptive study.

• Numeric Rating Scale (NRS) to subjectively measure intensity of dyspnea (0 = very bad, 6 = very good)
• Arterial oxygen saturation
• Respiratory rate
• Phone interview and directed survey of emergency physicians regarding expertise in emergency medical care and palliative medicine

Based on improvement in respiratory rate, arterial oxygen saturation, and patient’s numeric rating of dyspnea, 47 patients (41%) experienced relief of dyspnea from emergency medical treatment. Dyspnea was relieved in 14 Group 1 patients (67%), 15 Group 2 patients (52%), 8 Group 3 patients (22%), 5 Group 4 patients (18%), and 5 Group 5 patients (71%). Though no significant differences regarding relief of dyspnea were noted between Groups 1 and 2 and between Groups 3 and 4 (P > 0.05), a statistically significant difference was noted when Groups 1 and 2 were compared to Groups 3 and 4 (P <  0.001), indicating a higher success among the two groups that utilized opioid therapy in the management of dyspnea. Only Group 5 experienced a correlation between subjective dyspnea ratings and objective measurements (i.e., oxygen saturation and respiratory rate). The high success rate in dyspnea alleviation observed in Group 5 (no medical treatment) was achieved by the transfer of a tracheostomy tube, which was the noted cause of dyspnea in five patients. Morphine was the only medication used during opioid therapy, and no respiratory sedation was noted by emergency physicians.

Significant relief of acute dyspnea was observed when IV opioid therapy was used as opposed to oxygen and bronchodilator therapy alone.

The study was purely descriptive, with no structured study protocol with measures for comparison or randomization of subjects. Thoroughness and accuracy of each documented encounter analyzed is also questionable. The investigation was carried out on the basis of a German system of emergency/pre-hospital treatment options that are not wholly generalizable to the American paramedic emergency response system.

IV opioid therapy for the management of acute dyspnea in out-of-hospital encounters for palliative care patients appears to be more beneficial than use of oxygen therapy and bronchodilator (IV and per inhalation) alone. Integration of a palliative care team (preferably with 24-hour accessibility) in the subsequent alleviation of dyspnea in out-of-hospital emergency palliative encounters may prove beneficial. This study raises the question of how dyspnea among palliative care patients may be managed by pre-hospital services in the United States and pre-hospital service staff knowledge of symptom management for this group of patients.

The search strategy was not applicable or stated.

This article discussed underlying shared principles in chemotherapy-induced nausea and vomiting (CINV) guidelines from the American Society of Clinical Oncology (ASCO), the Multinational Association for Supportive Care in Cancer (MASCC), and the National Comprehensive Cancer Network (NCCN).

• Common goals among these guidelines are to prevent CINV and to identify the risk period for CINV asscociated with at least four days of moderate- and high-intensity emetogenic treatments.
• The guidelines report that oral and IV formulations of 5-HT₃ receptor antagonists are equally effective.
• Selection of an antiemetic regimen should be based on the emetic risk of the chemotherapy being used as well as patient factors and experience.
• Prophylactic antiemetics should be used when the risk of CINV is 10% or more.
• A table of chemotherapeutic medications by emetogenic risk was provided. The author noted that such risk assignment does not provide for moving up the CINV risk ladder according to differing patient experience. Current guidelines are similar in terms of antiemetic regimens but only outline this for the first course of chemotherapy.
• The article provided a brief review of current specific antiemetic recommendations provided in guidelines. Substantial differences exist between physician and nursing assignment of patient risk for delayed CINV, and limited evidence exists regarding the best approaches for breakthrough CINV.

Currently recommended agents for breakthrough CINV are prochlorperazine, metoclopramide with or without diphenhydramine, haloperidol, dexamethasone, dronabinol nabilone, lorazepam, alternating 5-HT₃ receptor antagonists, olanzapine, and promethazine. The author noted that guidelines are useful, but guideline adherence can only go to a certain extent in preventing CINV, particularly with delayed symptoms, multiple-day chemotherapeutic regimens, high-dose chemotherapy, breakthrough CINV, and refractory CINV.

CINV guidelines are a good clinical tool to help clinicians implement evidence-based practice; however, their use needs to be accompanied by accurate patient assessments throughout the period of CINV risk. A standard guideline may not fit the needs of all patients and recommendations need to be viewed as a starting point for individualized patient care. More study and attention needs to be given to issues of delayed, breakthrough, and refractory CINV. This article is expert opinion-based and does not provide evidence for all information provided.

To determine if peer telephone intervention would reduce distress among women with BRCA1/2.

Recruitment through familial cancer clinics; baseline questionnaire completed and then those who indicated interest in talking with a peer were randomly assigned to the intervention group (IG) or usual care group. Those in the IG received surveys four and six months after baseline. IG matched with peer to support. Peers were recruited and received a program manual and three days of training. Contact between peer and participant was to occur six times in a four-month period.

• N = 174
• MEAN AGE: 43.56 for the IG and 43.18 for controls
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Women; BCRA1/2 mutation carriers; received genetic counseling
• OTHER KEY SAMPLE CHARACTERISTICS: No advanced cancer; within five years of knowing genetic status; older than age 18 years

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

• PHASE OF CARE: Multiple phases of care

• Single blind randomized, controlled trial

Baseline questionnaires for socioeconomic information, cancer history and treatment, family history of cancer, age when notified of mutation status, BRCA1/2 mutation status of female relatives, risk-reducing surgeries, screening behaviors, and supportive care services used. At time 2, peer satisfaction was asked; Impact of Event Scale (IES) measuring distress; a single item question for anxiety; 16-item scale to measure unmet needs. 10-item cognitive appraisals about genetic testing scale.

There was little change in the mean scores on most outcome measures during the three time points. Unmet needs was the only outcome measure that decreased consistently over time. Breast cancer distress (IES) showed a significantly lower level of stress in the IG (p < 0.01). Anxiousness and stress were  lower in the IG at the first two time points (p < 0.03), but there was no difference after that. Telephone based intervention reduced distress and unmet information needs for this group. Percent of patients contacted continued to decline over time, and by the sixth phone call less than 25% had any contact.

Peer support programs may be effective at reducing distress and anxiety in those who are BRCA1/2 carriers.

• Risk of bias (no appropriate attentional control condition)
• Measurement validity/reliability questionable
• Intervention expensive, impractical, or training needs
• Subject withdrawals of 10% or greater 
• Other limitations/explanation: Usual care is not well defined; family members in the IG were not assigned to the same peer. A high percentage of the intervention group did not have actual contact after the third call, suggesting that the duration of the intervention was not practical or accepted. Those who dropped out had higher baseline stress scores. A single-item scale was used for measurement of anxiety.

Peer support among women with genetic mutations may prove to reduce distress. This type of support may be beneficial for other patient populations. Findings from this study suggest that the greatest needs and efficacy may be in the short term, since many patients did not have contact after the third phone call. As anxiety tends to decline over time, it is unclear from this study what the actual efficacy was for anxiety.

To assess the effectiveness of a volunteer-delivered, tailored telephone-based intervention in reducing unmet supportive care needs and elevated levels of anxiety and depression among people with colorectal cancer

The intervention utilized a checklist of unmet needs that patients with colorectal cancer completed. Specially trained volunteers then followed up with patients, by means of telephone consultation, to review needs and devise an action plan.

• The study reported on a sample of 653 patients with colorectal cancer.
• Mean patient age was 64.57 years (SD = 9.2 years).
• The sample was 40.5% female and 59.5% male.
• Of sample patients, 78% were married; 49% had undergone chemotherapy, 89% had undergone surgery, and 10% had undergone radiotherapy; and almost 90% had at least a high school education.

• Outpatient setting
• Australia

Transition phase of care

Randomized controlled trial

• Supportive Care Need Survey (SCNS)
• Hospital Anxiety and Depression Scale (HADS)
• Nine-item colorectal cancer symptom checklist (developed for study)
• Eleven-item questionnaire on the use of supportive care services (developed for study)
• Medical Outcome Study Social Support Survey (MOS-SSS)

• The prevalence of elevated anxiety decreased over time in the intervention group (p < 0.01).
• Compared to the control group, the intervention group reported a greater use of services (p < 0.01).

This study suggests that a volunteer-delivered, telephone-based intervention is plausible and acceptable to patients with cancer and that the intervention was effective in getting patients to use available services. This approach was associated with reduced anxiety over time, but did not have an impact on depression or prevalence of unmet needs as identified by the patients.

• The study design lacked an attentional control.
• The study did not include discussion regarding supportive services utilized and whether they met patients’ unmet needs.
• The intervention was delivered to patients three to four months postdiagnosis, and the highest period of unmet needs may actually be sooner in the treatment trajectory.

Tailoring support and interventions to only those patients with unmet needs might be a better allocation of resources while producing significant results.

To examine the potential benefits of wheatgrass extract in reducing severity and delaying the onset of acute radiation skin toxicity in breast irradiation.

• Agents:  wheatgrass extract (experimental) and sorbolene cream (control). Dosage, onset of application, frequency of application, and duration of application were not identified.
• Time Periods:  four weeks and six months after completion of radiation therapy (RT). The authors did not specify whether the first time point was the fourth week during treatment or four weeks after the completion of RT.
• Quality of life (QOL) was measured using the Spitzer Quality of Life Index (SQLI). The timing and frequency of SQLI administration was not identified. 
• RT:  The type and dose of RT was not identified.

• The sample was comprised of 20 women (10 in each treatment arm).
• Mean age was 55.3 years in the control group and 55.0 years in the experimental group.
• Patients had breast cancer and were treated with lumpectomy.

• Single site
• Australia

Patients were undergoing the active treatment phase of care.

The study was a prospective, pilot, single-blind (patients), randomized, controlled clinical trial with two arms:  wheatgrass extract (experimental) and sorbolene cream (control).

• ONS Radiation Dermatitis scale/NCI Common Toxicity Criteria v.2     
• SQLI:  lower scores = better performance

No statistically significant difference existed between the wheatgrass group and the sorbolene group with regard to onset and peak radiodermatitis development. There was a significant difference in QOL between the wheatgrass (M = 9.5) and sorbolene (M = 9.8; p = 0.014) groups when all time periods were measured, with better QOL in the wheatgrass group.

The study design and results were not strong enough to include as evidence for or against wheatgrass as a deterrent to the development of radiodermatitis. 

• The study had a small sample size, with less than 30 patients.
• The study groups were unequal with regard to breast and body size.
   

This potential intervention needs further study in a larger group. The findings are not valid for use as evidence at this stage of investigation.

The healing touch method was a noninvasive, noncondition-specific method in which hands were placed on various parts of the body for about 40 minutes; particular attention was given to areas of pain or discomfort. Four one-hour sessions were conducted over four to six weeks (or withdrawn).

• The sample was comprised of 35 patients (11 men and 23 women reported).
• Mean age was 57 years (range 24–80).
• About half of the sample had cancer for less than a year, and about half had cancer for one to five years.
• Cancer types were mixed, but 40% of patients had advanced disease.

• Outpatient center for complementary care
• Eskdale, Cumbria

Patients were undergoing the active treatment and long-term follow-up phases of care.

The study used a one-group, pre- and posttest feasibility design.

• EuroQol EQ-5D
• Visual analog scales:  Sleep disturbance was scored from 0 to 3 (sleeping too much), 4 to 7 (sleeping well), and 8 to 10 (sleeping poorly).

A statistically significant improvement was found from pre- to posttest for sleep disturbance.

• The study had a small sample size.
• Healthcare providers must be trained in healing touch.
• Participants’ baseline scores served as their own controls.

To investigate the receipt of colony-stimulating factor (CSF) prophylaxis and associated risks of febrile neutropenia (FN)

Data from two large U.S. claims repositories from 2006–2014 were obtained for analysis. Data included patients aged older than 18 years who received at least two cycles of myelosuppressive chemotherapy. The analysis was focused on the use of pegfilgrastim; patients who received other CSFs were excluded from the analysis. Patients who received and did not receive pegfilgrastim prophylaxis were matched according to variables in multivariate regression, including the being at intermediate/high risk for neutropenia and cancer type.

• N = 42,314   
• MEAN AGE = 54.6 years (SD = 10.7)
• MALES: 10.4%, FEMALES: 89.6%
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Patients with breast, colorectal, lymphoma, and lung cancer
• OTHER KEY SAMPLE CHARACTERISTICS: The majority were chemotherapy naive.

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: United States

• PHASE OF CARE: Active antitumor treatment

• Retrospective cohort comparison

FN episodes were identified based on hospital admission with a diagnosis of neutropenia, fever, or infection. FN episodes requiring outpatient care, including emergency department visits, were defined as Healthcare Common Procedure Coding System (HCPCS) code for IV antimicrobial therapy on the same date as a diagnosis of neutropenia, fever, or infection.

Of the patients, 5.3% were not given second-cycle pegfilgrastim prophylaxis. Second-cycle FN among comparison patients was 3.8% versus 2.2% among those who received propylaxis (95% confidence interval [CI] [1.2, 2.5], p = 0.002). With a narrower definition of FN, 3.5% without prophylaxis had FN compared to 0.8% in the group that received second-cycle pegfilgrastim (odds ratio [OR] = 3.5, p < 0.001).

The findings suggest that the odds of developing FN in the second cycle of chemotherapy are higher among patients who discontinue CSF prophylaxis compared to those who continue prophylaxis.

• Findings not generalizable
• Does not account for potential differences in absolute neutrophil count (ANC) between groups, which would account for different use of CSF prophylaxis
• No single diagnosis code exists for FN, so the definition is somewhat questionable, which could result in an under or overestimation of incidence.
• Included only patients younger than 65 years with private insurance, so it may not reflect other populations
• The study was funded by Amgen, Inc., which makes pegfilgrastim.

Some evidence suggest that ongoing CSF prophylaxis is not consistently provided in at-risk patients. This study, although it had some limitations, suggests that the discontinuation of prophylaxis along the course of treatment with myelosuppressive chemotherapy for patients at an intermediate or high risk for FN is associated with an increased incidence of FN.

To determine if the duration of filgrastim prophylaxis affects the risk of chemotherapy-induced neutropenic complications (CINC), healthcare costs, and mortality

This is a retrospective study of medicals claims from two large healthcare claims databases, the Thomson Reuters MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Database (MarketScan Database, 2001–2010) and the Intercontinental Marketing Services LifeLink Database (LifeLink Database, 2001–2008). Claims for chemotherapy, filgrastim, and hospital admissions were analyzed to determine the number of daily filgrastim doses following a chemotherapy cycle and neutropenic complications.

• N = 14,288 daily filgrastim prophylaxis patient cycles  
• AGE = 18 years and older
• MALES: About 20%, FEMALES: About 80%
• KEY DISEASE CHARACTERISTICS: Patients who initiated one or more courses of myelosuppressive chemotherapy for a solid tumor or non-Hodgkin lymphoma and who received daily filgrastim prophylaxis during one or more cycle

• SITE: Multi-site    
• SETTING TYPE: Multiple settings    
• LOCATION: United States

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

Retrospective study of medical claims

• Data collection from databases using HCPCS, ICD-9-CM, or UB-92 codes and analyzed with statistical analysis software

If patients were treated with one to three days of filgrastim prophylaxis, the risk of CINC during a cycle of chemotherapy was 2.9%. If they were treated with four to six days of filgrastim prophylaxis, the risk of CINC was 2.7%. If the patient was treated with seven or more days, the risk of CINC was 1.8%. In adjusted analyses, the odds of CINC were 2.4 (95% = CI, 1.6–3.4) higher with one to three days of filgrastim prophylaxis versus seven or more days and 1.9 (1.3–2.8) times higher with four to six days of filgrastim prophylaxis versus seven or more days. In the pivotal trials of filgrastim prophylaxis, 10–11 days of filgrastim prophylaxis were needed for adequate neutrophil recovery, yet this study demonstrated that in actual practice, 95% of patients received fewer than 10 days of filgrastim prophylaxis and 58% received only one to three days. In a subgroup of 358 patients who developed CINC and the healthcare expenditures were available, CINC-related healthcare expenditures were $18,912 (14,570– 23,581) with one to three days of prophylaxis (n = 225), $14,907 (11,155–19,728) with four to six days (n = 94), and $13,165 (9,595–17,144) with seven or more days (n = 39). In a subgroup of 228 patients for whom discharge status was available, in-hospital mortality was 8.4% (4.6–14.8) with one to three days of prophylaxis (n = 119), 4% (1.4–11.1) with four to six days (n = 75), and 0% (0–10.2) with seven or more days (n = 34).

Administration of less than seven days of daily filgrastim was not as effective as seven or more days of daily filgrastim to prevent chemotherapy-induced neutropenic complications. The use of seven or more days of filgrastim as primary prophylaxis to prevent chemotherapy-induced neutropenic complications also decreased healthcare costs and mortality.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results

In clinical trials evaluating the efficacy of CSF prophylaxis, patients were treated with 10 or more daily doses of filgrastim. However, in actual practice, the majority of patients receive prophylaxis with fewer than 10 doses of daily filgrastim, which increases the risk of chemotherapy-induced neutropenic complications, mortality, and healthcare costs. Clinicians need to be aware of most effective CSF dosing requirements.

The purpose of this study was to assess differences in risk of hospitalization for neutropenic complications among patients with solid tumors who received prophylactic filgrastim, pegfilgrastim, or sargramostim during their first observed course of chemotherapy from July 2001 to June 2007.

Prophylactic administration of filgrastim, pegfiltrastim, or sargramostim

• 208,401 participants
• Participants were 18–98 years old, with a mean age of 60 (filgrastim), 58 (pegfilgrastim), 61 (sargramostim), respectively.
• Males made up 53.6% of the participants; females made up 46.4%
• Cancers of the breast (female only), non-Hodgkin lymphoma, trachea, bronchus, lung, prostate, colon/rectum, Hodgkin disease, genitourinary, bone, connective tissue, and skin, with or without metastasis to bone or other sites who received filgrastim, pegfilgrastim, or sargramostim prophylaxis and/or chemotherapy cycles in which these colony-stimulating factors (CSFs) were administered as prophylaxis.
• Mean comobidity index 3.8 (pegfilgrastim), 3.7 (filgrastim), 3.6 (sargramostim)

• Multiple settings 
• Data obtained from two healthcare claims databases
• Includes patients treated nationwide in inpatient and outpatient settings

• The phase of care was active anti-tumor treatment
• Application was for elder care

Retrospective cohort study

Statistical analyses included using medical claims information from two large databases (Thomson Reuters MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Database), calculation of duration in days of use of each CSF, independent samples t test for continuous factors and chi-square for multilevel categorical factors. Generalized estimating equations were used to assess risk of hospitalizations.

Risk of hospitalization for neutropenia was 2.1% (filgrastim prophylaxis, n = 8,286), 1.1% (pegfilgrastim prophylaxis, n = 67,247), and 2.5% (sargramostim prophylaxis, n = 1,736) and, for nuetropenia, fever, or infection for prophylactic use of filgratim, pegfilgratim, and sargramostim was 4%, 2.6%, and 2.5%, respectively. Risk of hospitalizations for all causes was 7.9%, 5.3%, and 9.6%, respectively. Adjustments were made in the statistical analysis for patient characteristics, type of cancer, and chemotherapy regimen.

Prophylactic pegfilgrastim administration is associated with less risk of hospitalizations for neutropenia/neutropenic-related complications than either prophylactic filgrastim or sargramostim in patients undergoing chemotherapy treatments for a variety of cancers.

• Retrospective study using two  healthcare claims databases.
• Data were based on insurance claims, which may not be completely accurate.
• This also does not capture individuals on insurance plans not part of these databases or the non- or underinsured (however, it likely captures a large percent of the population treated for cancer in the United States).

Recommendation of the use of prophylactic pegfilgratim may be warranted. Patient education regarding neutropenia, neutropenic-related complications, and side effects of pegfilgratim is essential. Nurse-led discussions of using pegfilgratim instead of filgratim or sargramostim with the oncology healthcare team could ensue.