To investigate if the use of a second-generation 5-HT3 receptor antagonist (palonosetron) and a NK1 receptor agonist (aprepitant) could allow a decreased dose of dexamethasone based on nausea and vomiting in patients with breast cancer receiving highly emetogenic chemotherapy

Randomization was to Group A: palonosetron IV plus dexamethasone IV with oral aprepitant on day 1 followed by 8 mg dexamethasone IV and 80 mg aprepitant PO on days 2 and 3. Group B received a placebo instead of dexamethasone on days 2 and 3. Patients were treated in the hospital.

• N = 80   
• MEAN AGE = Group A: 53.5 years, Group B: 52.6 years
• AGE RANGE = 35–76 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Chemotherapy naïve patients with breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Six patients who were included had metastatic disease. Patients were chemotherapy naïve with confirmed breast cancer and older than 19 years. Patients received chemotherapy that included an anthracycline-cyclophosphamide combination.

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Japan

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

Phase-II, single-center, single-blind, placebo-controlled, parallel, randomized trial. Randomization was done on a one to one ratio using a minimization method.

• Self-report diary of nausea and vomiting
• Chart extractions measuring emetic episodes and use of rescue medications
• Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE), version 4.0.
• Patients were classified as having complete control if they used no rescue medications and had no emetic episodes and only mild nausea.
• Complete response (CR) was defined as no emetic episodes and no rescue medication.  
• Nausea was measured as none, mild, moderate, or severe, based on subjective patient reports.

This study showed that complete control and CR revealed equivalent findings in acute and delayed chemotherapy-induced nausea and vomiting (CINV) with 1 day or 3 days of dexamethasone. No statistical differences were noted between both groups. Subgroup analysis looked at patients younger than 50 years. This also did not show any differences.

Using one dose of dexamethasone is feasible in treating CINV.

• Small sample (< 100)
• Measurement validity/reliability questionable
• Findings not generalizable
• Uncertainty as to how patients were hospitalized for the duration of the study, but this certainly added to purer date 
• The researchers relied on self-reports of nausea and vomiting and medical records of emesis, which can lead to underestimation if the nausea and/or vomiting was not documented.

Reducing the use of dexamethasone may be possible in treating CINV prospectively. This may be critical in uncontrolled diabetics.

This was a twelve-week outpatient rehabilitation program combining physical exercise and psycho-education and delivered in a group setting (12–16 participants per group). Physical training was led by two physiotherapists for two hours twice a week. Sessions aims included improving movement skills, improving strength and endurance, coping with fatigue, enhancing feelings of control, and reducing stress. Each session consisted of individual strength and endurance training (one hour) or a group sports activity (one hour), paired with 30 minutes of aqua aerobics. Each session of the group sports activity had a central theme (i.e., capability and cooperation, coordination, throwing and catching, social contact, winning and losing, relaxation). Psychoeducation sessions were led by oncology health professionals and aimed at providing support in coping with cancer and enhancing self-confidence and autonomy. Participants were provided with information on cancer-related subjects and encouraged to share their experiences as cancer survivors. Patient outcomes were assessed at baseline, week 6, and week 12.

• N = 658
• MEAN AGE =50.6 years
• AGE RANGE = 18–75 years
• FEMALES: 77.8%
• KEY DISEASE CHARACTERISTICS: Participants with mixed solid tumors and hematologic malignancies. Approximately 50% of the sample had the diagnosis of breast cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: The majority was married or lived together (77.7%), most had children (76.9%), about half were employed at the time of diagnosis (48.3%). At the start of rehabilitation, only one-fifth (15.8%) was actually at work. The sample was a mean of 1.3 years from the conclusion of treatment, with a range of 0–14 years following treatment.
• EXCLUSION CRITERIA: Physically at risk owing to cancer or serious comorbidity, serious cognitive disturbances, restricting side effects of medication, or if needing more complex rehabilitation

• Longitudinal single-arm cohort design
  • No comparison group

• EORTC QLQ-C30

After six weeks, participants in the intervention group experienced a significant decline in fatigue (p < 0.001) in comparison to baseline measurements. After 12 weeks, participants experienced an even greater decline in fatigue (p < 0.0001) in comparison to baseline measurements.

• Unable to determine the benefits of exercise and psychoeducation components of intervention separately
• Lack of a neutral comparison group; therefore, unable to determine whether improvements in quality of life were a direct result of the rehabilitative program
• Long-term effects were not assessed in the study

Future research should incorporate objective physical strength and endurance tests and validated measurement instruments for more specific psychosocial parameters.

This 12-week physical fitness and psychoeducational rehabilitation program was conducted to enhance quality of life and recovery among cancer survivors of all types of cancer. Its physical fitness component was aimed at improving movement skills, strength, and endurance; helping participants cope with physical complaints (e.g., fatigue); and enhancing feelings of control and stress reduction. Its psychoeducational component was aimed at providing support in coping with cancer and enhancing self-confidence and autonomy.

 The intervention had three components.  

1. A physical fitness program involving two hours of training twice weekly with guidance from two expert physiotherapists. Each session consisted of

• One hour of individual training for endurance and strength or one hour of group sports and games
• 30 minutes of aqua-aerobics in an indoor pool.

2. A psychoeducational program consisting of seven two-hour sessions aimed at providing support in coping with cancer and enhancing self-confidence and autonomy.

3. Information on cancer-related subjects.

Subjective measures were completed prior to the intervention, 6 weeks into the intervention, and at 12 weeks at the intervention's end. 

• The number of enrolled participants was 665. Of the enrolled participants, 658 initiated the program, 634 completed 6 weeks of the program, and 579 completed the program's full 12 weeks. 
• The average age of the participants was 50.6 ± 9.5 years, with a range of 18–75 years.
• 54% of the participants had breast cancer. Other cancers included were lymphoma, digestive tract, gynecologic, and lung cancer.
• 77.8% of the participants were female and 21% were male. Gender was unknown for 1.2% of the participants. 
• The average time since diagnosis was 2.1 years, with a range of 0–25 years.
• The average time since end of treatment was 1.3 years, with a range 0–14 years.

This was a single-site study. 

This was a prospective trial. 

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC QLQ-C30) was used to measured global and functional quality of life using 6 subscales (global, physical, role, cognitive, emotional, social functioning) and one symptom scale on fatigue. Scores range from 0–100, with higher scores indicating higher quality of life for the global and functional scales. Higher symptom scores indicate greater fatigue.

The Tampa Kinesophobia Scale was used to measure excessive, irrational and debilitating fear of physical movement and activity resulting from a feeling of vulnerability to painful injury or re-injury. Two subscales were used to measure avoidance of activities (7 items) and pathologic somatic focus (4 items).

As measured by two items on the EORTC QLQ–C30, cognitive function improved at 12 weeks, but not at 6 weeks. There were significant improvements for all quality-of-life domains and fatigue for all cancer patients after 12 weeks (p < 0.05).

The authors suggest that exercise may improve cognitive functioning as well as other quality-of-life domains.

• Although subjective cognitive function improved over 12 weeks, this finding was not confirmed by objective cognitive-specific measures.
• A wide range of ages was included in the sample, but no age breakdown was recorded for the two cohorts; ge-related changes in cognitive function may influence the results between the two cohorts.
• The authors were unable to determine whether changes in quality of life were a result of the exercise versus the psychoeducational intervention or the combination of both.
• There was no control group as a comparison. 

To examine the effects of physical therapy (PT) versus physical therapy plus cognitive behavioral therapy (CBT) interventions on problem solving, anxiety, and depression in patients with cancer

Consecutive groups of patients referred to rehabilitation centers were randomly assigned to receive either PT or PT and CBT programs for 12 weeks. PT consisted of twice weekly two-hour sessions of aerobic training, muscle-strength training, and group sports and games. CBT sessions were provided in a group format in which participants learned to apply self-management skills in striving for personal goals. Psychologists gathered self-evaluations regarding the extent to which patients adhered to the intervention protocol, and the process was evaluated via case records. Study measures were obtained at baseline, 12 weeks postrehabilitation, and three and nine months postintervention. After week 6, patients started a home-based walking program.

• A total of 147 participants were analyzed, with 132 completing rehabilitation.
• Mean age of participants was 48.8 ± 10.9.
• The sample was 16.3% male and 83.7% female.
• Of the sample, 55.8% had breast cancer, all had completed treatment at least three months prior to inclusion, and the average time since treatment was 1.7 years.
• Nearly 71% were married and living with a spouse, and 86.4% had middle to high levels of education. 
• At baseline, less than one-third had anxiety or depression scores indicating clinically relevant symptoms.

• Multisite
• Setting unspecified
• Dutch rehabilitation centers

• Transition phase after initial treatment
• Late effects and survivorship

Prospective, single-blinded, randomized, two-group trial design

• Social Problem-Solving Inventory–Revised    
• Hospital Anxiety and Depression Scale (HADS)

Overall baseline anxiety and depression scores of participants were significantly higher than those in the general Dutch population (p < 0.001). Immediately after the 12-week program, both groups showed small to moderate effect-size reduction in anxiety (0.45–0.55 [p < 0.001]) and depression (0.44–0.59 [p < 0.001]). At three and nine months, average effects, as measured by HADS score, continued to be lower than baseline, with effect sizes ranging from 0.24 to 0.4. Participants in both groups showed comparable changes in problem solving, anxiety, and depression. Subgroup analysis between those with initially higher and lower levels of distress showed no difference in changes in problem solving. Patients with higher distress, in both intervention groups, showed significant reduction in anxiety (p < 0.01) and depression (p < 0.01) at all study time points. At all measurement points, patients with lower distress at baseline showed levels of distress in keeping with those of the general population.

Study findings did not show that the addition of CBT to PT resulted in effects on problem solving, anxiety, or depression that were greater than the effects of PT alone. Findings did not support the hypothesis that the addition of CBT would be of greater benefit for individuals who had higher distress levels initially. Study findings show beneficial effects of PT on anxiety and depression.

• The study had no appropriate control group.
• Subgroup analysis was done according to overall distress levels, then compared to outcomes regarding anxiety and depression. These are different concepts and patient experiences. Subgroup analysis would have been more relevant if researchers had compared actual anxiety and depression levels to each other, respectively. 
• The study provides no information about attendance rates for sessions, the amount of exercise continued after the initial 12-week session, or adherence to the home-based walking intervention.

Findings if this study support other findings regarding beneficial effects of physical activity in a supervised group setting. Findings of this study suggest that the addition of specific CBT interventions may not increase these effects. Analysis of results in those who had high versus low levels of distress demonstrates that those with low distress do not show a benefit.

To explore the effectiveness of standard laxative treatment in the prevention of oxycodone-induced constipation

From July 2013 to October 2013, standard laxative treatment consisting of polyethylene glycol (PEG) with electrolytes was started at the same time as opioid intake on day 1. Bisacodyl was prescribed, and patients took this as needed. Patients prescribed oxycodone at least 20 mg slow-release tables were started on the standard laxative treatment and followed for 28 days.

• N = 21  
• MEDIAN AGE = 65 years
• RANGE = 39-92 years
• MALES: 42%, FEMALES: 58%
• KEY DISEASE CHARACTERISTICS: There were chronic 23 with non-malignant pain and 1 patient with malignant pain.

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: Netherlands

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Elder care and palliative care

• Prospective, observational, pilot study

• Bowel Function Index (BFI), measured at the start and end of study
• Bristol stool form scale (BSF), indicates type of stool, numerical pain score, laxative, and a responder analysis using the following criteria: decrease of BFI by 12 points or patient did not develop constipation AND patient did not develop diarrhea AND patient did not discontinue laxative treatment due to adverse events

The dose of PEG and electrolytes varied between 0-3 sachets, and the bisacodyl dose varied from 5 mg-20 mg. Based on responder analysis criteria, 43% of patients (9 of 21) who were prescribed a standard laxative therapy regimen did not respond.

A standard laxative therapy regimen may not be effective in all patients given the type of opioid they may be prescribed and what their bowel function is at the start of opioid therapy.

• Small sample (less than 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Findings not generalizable
• Pilot study
• Observational study

Response to prophylactic PEG plus electrolytes is patients taking oxycodone SR is variable.

To determine the effect of a combination of oxycodone and naloxone prolonged release tablets (OXN PR) on opioid-induced constipation and pain in patients with moderate to severe cancer- or noncancer-related pain

Patients had received OXN PR in prior double-blinded, multicenter, randomized studies. In one previous study (also a pooled analysis of two Phase III studies), patients with noncancer-related pain received 12 weeks of OXN PR or oxycodone prolonged release (Oxy PR) at the dose equivalent of 20–50 mg per day or 60–120 mg per day. After a 7–28-day period, patients were titrated to an effective analgesic dose of Oxy PR. In a previous Phase II study, patients with moderate to severe cancer-related pain were screened for 3–10 days and then switched to OXN PR or Oxy PR for four weeks (20–120 mg per day). In all prior studies, bisacodyl at 10 mg per day could be taken orally as a rescue laxative 72 hours after a previous bowel movement or when the patient experienced discomfort for a maximum of five doses in seven consecutive days. In all previous studies, data were collected at screening, at the start of the intervention period, and at the end of the intervention period. Laxative use was documented throughout the intervention period in all studies.

• N = 75  
• MEDIAN AGE = 62 years (range = 40–80 years)
• MALES: Unknown, FEMALES: Unknown
• OTHER KEY SAMPLE CHARACTERISTICS: 53.3% of patients had cancer-related pain.

• SITE: Multi-site    
• SETTING TYPE: Not specified  
• LOCATION: Netherlands

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

Pooled analysis

• Bowel Function Index (BFI)
• Brief Pain Inventory Short Form (BPI-SF)
• Documentation of adverse effects 

The high BFI score at the time of screening indicated that both groups of patients experienced constipation and that patients with cancer-related pain experienced more symptoms. OXN PR clinically and statistically improved constipation in patients with chronic cancer- and noncancer-related pain. Laxative use decreased during the intervention period, and more patients fell within the range of normal bowel habits as the intervention progressed. Pain scores did not change during the intervention period although there was a nonsignificant trend of pain improvement in patients with cancer-related pain.

• Small sample (< 100)
• Findings not generalizable
• Other limitations/explanation: The studies that were used differed in length of treatment (4 versus 12 weeks). Demographic information was limited although the authors stated that there was no difference between the groups. Only 40 patients with cancer-related pain were included in the analysis. It appears as though some of the patients with cancer-related pain were receiving end-of-life care, but this is not entirely clear. Limited outcomes were reported for pain.

OXN PR may be a viable pharmacologic intervention to achieve pain control in patients with cancer-related pain while minimizing the symptoms of opioid-induced constipation. OXN PR reduced laxative use and increased the number of patients who reported normal bowel function. OXN PR did not change pain scores.

To evaluate the efficacy of a Japanese medicine called goshajinkigan (TJ-107) for preventing oxaliplatin-induced neuropathy, compared to placebo controls, and also to evaluate its safety

Patients were randomized to receive goshajinkigan ( TJ-107) 7.5 mg per day day, a mix of extracts of 10 crude herbs, or placebo for 26 weeks starting on the first day of chemotherapy. Neuropathy was measured before each chemotherapy cycle every two weeks until the eighth chemotherapy cycle and every four weeks thereafter until 26 weeks. Patients randomly were assigned to the intervention or control group.

• N = 89
• MEDIAN AGE = 64 years
• AGE RANGE = 36–88 years
• MALES: 53.9%, FEMALES: 41.6%
• KEY DISEASE CHARACTERISTICS: To be included in the study, patients had to be undergoing oxaliplatin-based chemotherapy for colorectal cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: Primarily Eastern Cooperative Oncology Group score of 0 upon enrollment

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

• PHASE OF CARE: Active treatment
• APPLICATIONS: Palliative and supportive care

• Double-blinded, randomized, placebo-controlled trial

• Neuropathy was measured by National Cancer Institute Common Terminology Criteria for Adverse Events (version 3) sensory items at baseline and every two weeks until the eighth cycle of chemotherapy and monthly until the 26th week.
• The FACT/GOG-NTX-12 also was completed by patients at baseline and before every chemotherapy cycle.

Although there was a trend toward lower neuropathy scores as measured by the FACT/GOG-NTX in the intervention group at eight weeks (p = .421) and 26 weeks (p = .151), the differences were not statistically significant. The incidence of grade 2 peripheral neuropathy or greater until the eighth cycle was 39% in the experimental group and 51% in the control group (RR = 0.76, 95% CI 0.47–1.21), and the incidence of grade 3 or greater neurotoxicity was 7% in the treatment group and 13% in the placebo group (RR = 0.51, 95% CI 0.14–1.92). The time to development of grade 2 or greater toxicity was 5.5 months in the experimental group and 3.9 months in the placebo group (RR = 0.65, 95% CI 0.36–1.17). No differences were observed between those getting the different FOLFOX regimens. The goshajinkigan was tolerated well. Adverse effects were similar between study groups and most likely caused by the chemotherapy, but vomiting was significantly less prevalent in the treatment group (p = .029).

Goshajinkigan may delay development of grade 2 or greater oxaliplatin-induced peripheral neuropathy, and there was a trend toward less severe chemotherapy-induced peripheral neuropathy in the intervention group at 8 and 26 weeks as compared to the control group.

• Small sample (less than 100)
• Findings not generalizable
• Other limitations/explanation: Not generalizable to people with neuropathy caused by any other drug than oxaliplatin

This study showed that administration of goshajinkigan, a traditional Japanese kampo medicine, was associated with reduced prevalence and severity of neurotoxicity among patients receiving oxaliplatin and was tolerated well by patients. Further study is needed to support the use of goshajinkigan for oxaliplatin-induced peripheral neuropathy. Goshajinkigan may not be widely available in the United States or outside of Japan.

To determine if hangeshashinto (TJ-14) is an effective treatment for oral mucositis

Patients with oral lesions 7–10 days after chemotherapy were given a 50 ml oral rinse with 2.5 g of TJ-14 and tap water three times per day for 7 days. Patients held the solution in their mouth for 10 seconds and spit it out. TJ-14 also was applied to the lesions with a cotton pellet as soon as the lesion appeared. Patients could not eat or drink 30 minutes before or after treatment. No other mucosal treatments were used during the study. Two blinded physicians graded mucositis.

• N = 14  
• MEAN AGE: 62 years
• AGE RANGE: 34–80 years
• MALES: 43%, FEMALES: 57%
• KEY DISEASE CHARACTERISTICS: Colorectal cancer

• SITE: Single site   
• SETTING TYPE: Outpatient   
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

• Non-randomized trial

• Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 mucositis scale

In this study, 92.8% of patients had improvements in oral mucositis. There was a significant reduction in CTCAE grades of mucositis for all participants from 2.4 ± 0.8 to 1.1 ± 0.8 (p = 0.0012). No adverse events or side effects from NJ-14 were reported.

NJ-14 was effective at improving oral mucositis and did not have any reported side effects in this small sample. However, caution must be used in interpreting this data due to the limitations of the study.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)

NJ-14 is a promising intervention to treat chemotherapy-induced oral mucositis; however, more research is needed from large RCTs.

To measure the effectiveness of laughter therapy for preventing radiation-induced dermatitis in patients with breast cancer who are receiving radiation therapy (RT)

Thirty-seven patients were enrolled in the study. Eighteen patients were assigned to the experimental group, which received laughter therapy during radiation treatment, based on their preference to participate. Nineteen patients who did not want to participate in the laughter therapy were assigned to the control group. The laughter therapy started at the beginning of therapy and continued until completion of RT. In this three-part intervention study, patients were assessed by staff observation or a questionnaire before and after laughter therapy. Patients in the control group were not allowed to use any prophylactic creams or lotion (p. 2054).

• N = 37  
• MEAN AGE = Experimental group: 59.1 years, control group: 49.3 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Confirmed pathology of unilateral breast cancer; no tumor invasion of the skin; complete breast conserving surgery with or without adjuvant chemotherapy
• OTHER KEY SAMPLE CHARACTERISTICS: Postoperative RT dose greater or equal to 45 Gy without bolus, no concurrent chemotherapy, no history of RT to the chest wall, no connective tissue disorders, no rashes or unilateral wound

• SITE: Not stated/unknown    
• SETTING TYPE: Not specified    
• LOCATION: Kyung Hee University Medical Center, Korea

PHASE OF CARE: Active antitumor treatment

Single-blind, two-group, prospective, nonrandom design

• Skin toxicity grading using the Radiation Therapy Oncology Group (RTOG) was completed by a radiation oncologist who was blinded to the subject’s assignment.
• Pain was evaluated using a visual analog scale (VAS). 
• Questionnaires were completed through staff observation.

The authors stated that, although laughter therapy showed favorable therapeutic efficacy in preventing dermatitis and alleviating pain, they could not draw a definite conclusion because of the lack of statistical significance. An additional study of a larger sample group is necessary. Some limitations exist in this small pilot study, which makes it difficult to interpret the data and draw conclusions.

This single-blind, prospective, pilot study showed that laughter therapy can be beneficial in preventing radiation-induced dermatitis in patient with breast cancer; however, a well-designed randomized study with a larger sample size is needed to confirm the efficacy of the study.

• Small sample (< 30)
• Risk of bias (sample characteristics)
• Key sample group differences that could influence results
• Eligibility criteria did not address whether patients had pre-existing medical histories of anxiety/depression or mood disorder/lability.
• Eligibility criteria included patients with or without adjuvant chemotherapy, which seems to be a potential factor for skewed results, perhaps because with chemotherapy, side effects can be long-lasting (i.e., peripheral neuropathy, alopecia, mood changes). This might affect patients undergoing laughter therapy.
• The authors noted that the assignment of patients was \"based on the patients’ preferences. The patients who wanted to receive laughter therapy were assigned to the experimental group, and the others were assigned to the control group\" (p. 2054). This might skew the data, presuming that patients who wanted the therapy were already biased and perhaps likely to receive the most benefit of the therapy (self-fulfilling prophecy in a way).
• Not allowing \"any prophylactic creams or lotions for radiation dermatitis\" (p. 2054) in either group might be seen as withholding treatment and unethical.
• Some patients received an electron boost; others had three-field treatment.
• Grade 3 dermatitis in 12 patients (35.3%) seems unacceptable/intolerable because no patients received skin care using topical emollients.
• The patient characteristics included smokers, nonsmokers, and diabetics, which might affect patient skin reactions and healing (i.e., poorer or delayed wound healing in smokers and possibly diabetics).
• The study was not conducted in the United States. This would likely prove more difficult in recruiting patients because the skin reactions were not being treated with topicals.
• No discussion regarding the use of pain medications existed. Patient use of pain medications (even over-the-counter analgesics, such as acetaminophen or ibuprofen, or hydrocodone, etc.) might influence their laughter response to the treatment and, therefore, the efficacy the authors cite.

Laughter therapy may have a beneficial effect on patients with radiation dermatitis undergoing breast cancer treatment. However, not enough data exist to support the sole use of this intervention during treatment.

To evaluate Instanyl^® for breakthrough pain in patients with cancer in real-life settings

This study followed adult patients with cancer receiving Instanyl^® in seven countries at 61 centers. The Brief Pain Inventory Short Form (BPI) and patient Treatment Satisfaction Scale (TSS) questionnaires were used to assess patient satisfaction with pain management. Descriptive statistics of the patient population were also collected. The Instanyl^® doses received by patients were 50, 100, and 200 micrograms, and data were collected at three time points: baseline, week 4, and week 13.

• N = 309 overall analysis (107 completed study)  
• AVERAGE AGE = 60 years
• MALES: 56%, FEMALES: 44%
• KEY DISEASE CHARACTERISTICS: Metastases present

• SITE: Multi-site    
• SETTING TYPE: Multiple settings    
• LOCATION: Multiple study centers in Norway, Denmark, France, Greece, Ireland, Sweden, and the United Kingdom

• PHASE OF CARE: Mutliple phases of care
• APPLICATIONS: Elder care, adult care, palliative care

Observational prospective cohort study

The primary outcome variables were success of titration, measured by whether maintenance dose level was achieved, and the dose level of Instanyl^® (maintenance dose). The secondary outcome variables measured were changes in maintenance dose and the level of background pain medication, severity and impact of pain on daily life (assessed by the BPI), and satisfaction with current pain medicine (assessed by the TSS). The BPI and TSS were only used in the United Kingdom and in France and were assessed at baseline and during week 4. Adverse drug reactions were measured as well as reasons for and time to Instanyl^® termination.

The successful titration of Instanyl^® to a maintenance dose was achieved in 84.5% of patients. There was a difference noted between different countries with successful titration rates highest in Greece and Norway and lowest in France and the United Kingdom. The majority of the patients who were successfully titrated achieved this with 50 micrograms of fentanyl, which was the lowest dose. Most patients showed no change in the maintenance dose strength throughout the study even though disease progression was expected. 49.8% of patients were successfully titrated at 50 micrograms, the lowest dose. Treatment was followed to the duration of 13 weeks. In 4.5% of patients, termination was due to lack of efficacy; in 2.3% it was due to adverse effects; and in 7.1% it was due to the inability to successfully titrate the medication. Patients' worst-pain scores, pain severity, and pain interference with activities declined significantly within the first four weeks (p < .001).

The rate of successful titration and pain management using Instanyl^® was high in this study, and successful titration was often achieved with the lowest possible dose of Instanyl^®. Patients were more satisfied with their pain management and had reductions in pain severity, worst-pain score, and pain interference with daily activities.

• 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)  
• Subject withdrawals ≥ 10% 
• Other limitations/explanation: Only about 35% of patients completed the study, there was a lack of a comparison arm, and adverse drug reactions were not reported.

This study adds to the body of evidence regarding the efficacy of opioid nasal spray for breakthrough pain. The authors suggest that patients who did not respond were likely those for whom titration to full dosage was not achieved. Nurses need to be aware of full dosage needs for efficacy. There continues to be a lack of evidence regarding the long-term effects and any potential adverse effects on the nasal cavity for this medication type.