To investigate the long-term safety and tolerability of 9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray and THC spray in relieving pain in patients with advanced cancer

Patients who had previously participated in a two-week parent RCT to investigate the efficacy, safety, and tolerability of THC/CBD spray and THC spray in patients with cancer-related pain were invited to take part in the long-term, open-label, follow-up study. This study took place at 22 study sites in the United Kingdom and Belgium. Visits occurred at the conclusion of the RCT study or at extension study screening, 7–10 days later, then every four weeks, and at study completion or withdrawal. Adverse events, vital signs, blood sample analyses, changes in medication dosing and in current medical conditions were monitored at each visit. A pump action oromucosal spray was used to deliver the study medication. Each 100 uL actuation of THC/CBD spray delivered 2.7 mg of THC and 2.5 mg of CBD to the oral mucosa. Each actuation of THC delivered 2.7 mg of THC, and each actuation of placebo (in the parent RCT) delivered the excipients plus colorants.

N = 43  

MEAN AGE = 57.5 years for the THC/CBD group, 58.6 years for the THC group

MALES: THC/CBD: 59%, THC: 25%; FEMALES: THC/CBD: 41%, THC: 75%

KEY DISEASE CHARACTERISTICS: Breast (21%), prostate (16%), rectum (16%), lung (7%), and bone cancers (5%)

OTHER KEY SAMPLE CHARACTERISTICS: Those who had participated in the original RCT in Romania were not included in this study. The most commonly reported pain type was mixed pain, affecting more than half of all the patients, followed by neuropathic pain (37%) and bone pain (28%). Exclusion criteria included those with a history of severe cardiovascular, renal, hepatic, convulsive, or psychiatric disorder (other than depression associated with pain), patients currently taking levodopa, those pregnant or lactating or those not using adequate contraception, and those with oral cavity cancers or those whose previous treatments had included radiotherapy to the floor of the mouth.

• SITE: 22 study sites 
• SETTING TYPE: Not stated   
• LOCATION: United Kingdom and Belgium

• PHASE OF CARE: Palliative
• APPLICATIONS: Elder care, palliative care

Patients self-titrated THC/CBD spray (n = 39) or THC spray (n = 4) to symptom relief or maximum dose and were assessed regularly for safety, tolerability, and evidence of clinical benefit.

• Vital signs
• Adverse events
• Blood sample analyses
• Pain assessment
• Changes in medical condition
• Current dose of study medication
• European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)
• Brief Pain Inventory-Short Form (BPI-SF)

The efficacy end point of change from baseline in mean BPI-SF scores for both “pain severity” and “worst pain” domains demonstrated an improvement at each visit in the THC/CBD spray patients. The EORTC QLQ-C30 scores demonstrated an improvement from baseline in the domains of insomnia, pain, and fatigue.

Long-term use of the THC/CBD spray was generally well tolerated. No evidence was seen of a loss of effect for the relief of cancer-related pain with long-term use. Patients who continued the medication did not seek to increase their dose of THC/CBD or other pain medication over time, suggesting a useful benefit of cannabinoids in cancer-related pain.

Small sample (less than 100)

Findings not generalizable

No comparable information with the study group, making drawing conclusions from the results difficult

Discrepancy between patient continuation within the study and the level of satisfaction of clinicians with level of pain relief

For patients with cancer-related pain, pain is a major issue. The adjuvant use of cannabinoids in patient with cancer-related pain could provide a great benefit. The proportion of patients reporting satisfactory analgesia was greater for the THC/CBD spray than placebo overall. The results of this study show that patients and investigators considered that maintenance or treatment with THC/CBD spray was justified by the clinical importance of pain management in patients with cancer-related pain.

Patients assigned to the dog visit group participated in 15-minute sessions three times per week for four weeks with one or two visitor dogs. Two female dogs (a long-haired dachshund and a whippet), accompanied by a dog handler, were used. During visiting sessions, the dogs sat on the sofa with the participant. Participants combed, petted, played, and talked with the dog. The handlers ensured the participant’s safety and recorded the dog’s behavior and nature of the interaction during these sessions. Patients assigned to the friendly human visit group met with the same adult for 15-minute sessions three times per week for four weeks. Visitors were volunteer nursing students, emeritus nursing faculty, hospital administrative staff, and community members. Visitors were instructed to engage the participant in a superficial “park bench” type of conversation, such as talk about the weather, movies, and local events. All were instructed that visits should contain no discussion of personal health or controversial matters. Patients assigned to the silent reading group read research-provided magazines for 15 minutes three times per week for four weeks. Magazines were selected based on lack of content related to health and fitness, cancer and treatments, self-help, counseling, and animal-assisted therapy. Example magazines included Newsweek, Car and Driver, and Smithsonian.

• The study included 30 adults undergoing nonpalliative radiation therapy.
• The majority of participants were Caucasian (n = 28) and female (n = 21).
• Mean ages were 61, 59, and 58 years for the dog visit group, human visit group, and silent reading group, respectively.
• Most participants had some college education and were married.
• Participants had cancer at multiple sites, but the most common site was breast.
• Patients were excluded if they were younger than 18 years, non-English speaking, had known pet allergies, were more than four weeks past initial diagnosis, or were receiving radiation therapy for metastases.

Outpatient radiation therapy units of two hospitals in a midsized city in the midwestern United States

Patients were undergoing the active treatment phase of care.

The study used a longitudinal, randomized pre-/posttest design with three groups:

1. Dog visit group (n = 10)
2. Friendly human visit group (n = 10)
3. Silent reading group (n = 10).

Profile of Mood States (POMS)

Animal-assisted therapy did not result in improved fatigue compared to other groups. All groups experienced a decrease in fatigue scores between pre- and posttest scores; however, that difference did not reach statistical significance. In addition, the decline difference score for the dog visit group was smaller than the difference for both the human visit and reading groups.

• Disease progression during the time of the intervention was not measured, and worsened cancer and the accompanying symptoms may have affected the participants’ responses.
• The study had a small sample size.
• The intervention time was short.
• No neutral comparison group was included.

To determine whether an at-home weight lifting program was feasible and effective in patients with breast cancer-related lymphedema

Prior to the start of the intervention, all participants wore compression garments according to their usual protocols (determined from the previous three months, day and night or day only) for two weeks. All garments had to be less than one month old and be of at least Compression Class (CCL) II. At the end of the control period, patients introduced resistance exercises over a four-week period, beginning with five repetitions and ending with 10 repetitions maximum. If lymphedema was not exacerbated, weights were increased by .5–1 kg every other session until the 10-repetition maximum was reached. After the four-week introduction period, patients were provided with flexible dumbbells ranging from .5–12 kg and were asked to exercise three times per week with at least one day between sessions. Patients performed four sets of the following exercises in this order, resting one to three minutes between each set: 1) shoulder flexion in a standing position, 2) shoulder adduction, 3) elbow extension in a supine position, and 4) elbow flexion in sitting position. Patients used 50% of the recommended weight for the first set and the full weight for the remaining three sets. Weight resistance levels were individually adjusted according to guidelines by the American College of Sports Medicine. Patients completed a minimum of eight repetitions per set when possible, and weight was increased by .5 kg when patients could complete more than 12 repetitions per set. Participants were not required to wear a compression garment during the exercises, but they were to put it on immediately following the exercises. Data were collected at baseline and at the end of the 12-week intervention.

• N = 23 (10 women participated in an additional study)
• AVERAGE AGE = 58 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Patients had to be less than 70 years old 

• SITE: Single-site    
• SETTING TYPE: Home    
• LOCATION: Sweden

• PHASE OF CARE: Late effects and survivorship

Pre/post pilot study

• Log book (i.e., wearing compression garment, completing exercises per protocol)
• Water displacement method
• Bioelectrical impedance spectroscopy 
• Magnetic resonance imaging (MRI)
• Body weight
• Isometric muscle strength device

All patients in the study followed the minimum criteria for the protocol (exercise at least two times per week). All patients who participated had lymphedema (mean lymphedema relative volume was 19.6%, SD = 11.7%, range = 5.1%–53.5%). No significant changes in arm volume were observed during the control period. At the completion of the intervention, there was a significant reduction in absolute volume from 448 ml to 427 ml (p < .03) and relative volume from 19.2% to 18% (p < .005). Multiple muscle groups showed an improvement in strength at the conclusion of the study period (shoulder flexors p = .001, shoulder adductors p = .001, elbow flexors p = .003, and elbow extensors p = .002). Ten additional participants took part in a study with an MRI. There was no significant reduction in arm volume for these participants after the intervention.

This home-based weight lifting program did not exacerbate or worsen lymphedema in this study. Participants saw some improvement in absolute arm volume and relative arm volume at the conclusion of the 12-week study period. Additional improvements were seen in the strength of multiple muscle groups. Overall, patients found the study to be feasible, and the majority of patients were at least minimally compliant with the exercise protocol.

• Small sample (< 30)
• 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)  
• Other limitations/explanation: It is unclear how much the participants exercised prior to the intervention.

A home-based exercise program was acceptable for women with lymphedema following breast cancer treatment. Women were able to complete the minimum requirements of the protocol and exercise at least twice per week for 12 weeks. Nurses should assess women for readiness to participate in home-based exercise programs and provide appropriate recommendations for those who are motivated to participate in such a program. Home-based weight lifting is safe for patients with lymphedema and does not make lymphedema worse. In addition, weight lifting improves the strength of multiple muscle groups.

• Patients performed low-intensity resistance exercises for arm lymphedema with or without a compression sleeve.
• At least two weeks prior to start of the study, all participants had to wear a  compression sleeve according to their usual custom.
• Prior to entering study, the compression sleeve had to be no older than three months.
• The study had two training sessions, one with a compression sleeve and one without.

• The study sample was comprised of 31 patients.
• Patients were included in the study if they
  • Had unilateral arm lymphedema following breast cancer treatment
  • Measured at 10%–40% greater arm volume in the the lymphedema arm compared to the contralateral arm
  • Had an onset of edema more than three months after surgery that persisted for at least six months
  • Were younger than 70 years of age.
• Patients were excluded from the study if they had recurrent cancer, another disease affecting the swollen limb, or language or cognitive limitations. 
• Of the 42 eligible patients identified and randomly asked to participate in the study, four declined because of distance and seven did not reach the 10% volume criteria.

The study took place at Lund University in Sweden.

• Arm volume was measured using water displacement.
• Multiple frequency bioelectrical impedance analysis was used to measure body composition.
• Subjective sensations using a visual analog scale rated heaviness and tightness.
• Perceived exertion was measured using the Borg scale.
• The Physical Activity Questionnaire was used to assess level of weekly exercise, lasting 30 minutes over the past year.

Results showed no difference in arm volume between the the group without the compression sleeve (n = 15) and the group with the compression sleeve (n = 16). Controlled acute arm exercise program with low-intensity weights produced a slight arm volume increase that was transient and disappeared after 24 hours in the affected arm in patients with breast cancer experiencing lymphedema.

Wearing compression sleeve during exercise did not influence arm volumes but should be worn as prescribed the rest of the time.

• The sample size was small.
• All patients in the study had mild-to-low-moderate lymphedema.

More research is needed to validate results.

To evaluate the effect of a water-based exercise program on women with breast cancer-related lymphedema

Women were randomly assigned to the exercise group or a wait list control group. The exercise intervention involved an initial instructional session followed by 30-minute sessions, three times per week for eight weeks, of specific exercises or swimming at moderate intensity on the Borg scale. After the initial instruction, sessions were unsupervised. Both groups completed weekly diaries of exercises performed. Measurement of outcomes was done at baseline and at the end of the study.

• The study reported on 29 patients with a median age of 63 years (range = 56–74 years).
• The sample was 100% female.
• All patients had breast cancer-related lymphedema. Duration of lymphedema ranged from 32.8–101.7 months. Time since diagnosis ranged from 92–152 months. Lymphedema was defined as an arm volume difference of at least 5%.
• Women who expressed interest after participating in another study were recruited.

This was a single site study in an unspecified setting in Sweden.

This study has clinical applicability for late effects and survivorship.

This was a single blind, randomized controlled trial.

Perometry, bioimpedeance spectroscopy, local tissue water measurement via tissue dielectric constant measurement, shoulder range of motion (ROM) measures, and exercise diaries were used.

A quarter of the patients in the intervention group did not complete the interventions. No differences were found between groups in lymphedema. Some shoulder ROM measures were better in the exercise group (p ≤ 0.05).

The water-based exercise used was feasible, but had no obvious impact on lymphedema severity. The water-based exercise regimen was associated with better shoulder ROM compared to controls.

• The sample size was small, with fewer than 30 patients.
• A risk of bias exists because no appropriate attentional control condition was included.
• Unintended interventions or applicable interventions that were not described could influence results.
• The study had a participant withdrawal rate of 10% or more.

Water-based exercises and swimming may improve shoulder ROM but had no demonstrated effect on lymphedema severity in this study. In general, some evidence supports the benefit of exercise in lymphedema, but whether this type of water-based exercise is effective for actual lymphedema reduction is not clear.

To assess the efficacy of mindfulness-based therapy on pain and distress in women treated for breast cancer

After completing baseline questionnaires, patients were randomized to the intervention or waitlist control group. The intervention was adapted from a standard intervention manual to the use of a shorter two-hour session, shorter meditation exercises, more gentle yoga exercises, and the elimination of all day sessions. The intervention was delivered in groups during eight consecutive weeks. All sessions were facilitated by a trained mindfulness instructor. Study measurements were conducted after the intervention and at three and six months after completion.

• N = 107  
• MEAN AGE = 56.4 years
• FEMALES: 100%
• CURRENT TREATMENT: Not applicable
• KEY DISEASE CHARACTERISTICS: All had breast cancer and the majority had surgery and radiotherapy; 72% were on endocrine therapy. The average time since surgery was 40.6 months.
• OTHER KEY SAMPLE CHARACTERISTICS: Sixty-four percent were married or cohabitating, and 45.2% were retired.

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

PHASE OF CARE: Transition phase after active treatment

Randomized, controlled trial with waitlist control

• Carlson Comorbidity Index
• Short-Form McGill Pain Questionnaire (SP-MPQ)
• Hospital Anxiety and Depression Scale (HADS)
• Report of pain medication use
• Adherence assessed by sessions attended and time spent on homework via self-report

Pain intensity and neuropathic pain declined over time in the intervention group compared to the control group (p = 0.036). No differences in anxiety or depression over time were reported between groups. The average number of sessions attended was five, and the average amount of time spent on homework was 24 minutes per day. A direct correlation between number of sessions attended (p = 0.01) and time spent on practice (p = 0.01) was reported. The dropout rate was 22% across both study groups; only four dropouts were in the control group.

Participation in the mindfulness-based intervention was associated with a reported reduction in pain intensity; however, a large percentage of those allocated to the intervention dropped out of the study or were lost to follow-up, suggesting that the intervention as provided may not be practical to many patients.

• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Findings not generalizable
• Intervention expensive, impractical, or training needs
• Subject withdrawals ≥ 10%  
• Intention to treat analysis may have overestimated effects—the intervention group had lower pain scores at baseline and had a large percentage of dropouts.

Mindfulness-based group therapy may be helpful in the management of long-term pain with breast cancer but was not shown to have an affect on anxiety or depression over time. The strength of findings in this study is limited because of study limitations.

To assess the efficacy and safety of lubiprostone 24 mcg BID in patients with chronic constipation.

Patients were randomized to receive either oral lubiprostone 24-mcg capsules or placebo capsules. Patients continued to record information regarding bowel movements (BMs), use of rescue medications, and symptoms on a daily basis. Study drug capsules were counted to assess compliance every two weeks. Rescue medication comprised bisacodyl suppository and fleet enema if the suppository was not effective. Efficacy was defined as the frequency of spontaneous BMs during the first and subsequent study weeks. Patients were followed for four weeks.

• The study reported on a sample of 224 patients.
• Mean patient age was 48 (SD = 12.28) to 49 years (SD = 12.93) across study groups.
• The sample was 89% female and 11% male.
• Patients were excluded if they had mechanical obstruction. No other diagnosis information was provided.

• Multi-site
• Outpatient
• Midwestern United States

This was a double-blind, placebo-controlled randomized trial.

• Four-point Likert-type scales for symptoms of bloating, straining, and discomfort; stool consistency; and global treatment effectiveness
• Patient diary

• Patients in the lubiprostone group reported significantly more spontaneous BMs than those in the control group (p = 0.0001) during the first and subsequent weeks.
• Fifty-seven percent of patients in the lubiprostone group experienced a spontaneous BM within 24 hours of taking the first dose compared to 37% in the placebo group (p = 0.0024).
• Use of rescue medication was significantly lower in the lubiprostone group ( p = 0.036).
• Patients in the lubiprostone group reported significant improvement in all related symptoms compared to those in the placebo group (p < 0.05).
• No significant differences existed between groups in reported events. The most frequent event was nausea. Eight percent of patients in the lubiprostone group were discontinued from the study because of adverse events including nausea, headache, flatulence, and diarrhea.

Taking lubiprostone improved frequency of spontaneous BMs and constipation-related symptoms, with low incidence of treatment-related adverse events.

• Patient diagnoses were not provided, and whether any patients had issues such as opioid-induced constipation is not known.
• Use of rescue medications was stated to decline, but actual use was not reported and the definition of primary treatment efficacy did not specify spontaneous BM without rescue medication.
• Applicability to patients with cancer is not clear.

Lubiprostone effectively improved constipation in this study; however, applicability to patients with cancer is not clear. Nausea was the most common side effect, which could limit its use in patients with cancer, who may be on other medications and treatments that also cause nausea. Research involving patients with cancer-related constipation should be considered.

To estimate the prevalence of pneumonia after tracheotomy in patients with head and neck cancer, and to evaluate the effect of prophylactic antibiotics

Data on patients who underwent tracheotomy were obtained from health records, and patients were grouped according to whether they had been given prophylactic antibiotics. In all cases, tracheotomy was the primary operation. The comparison of ventilator-associated pneumonia was analyzed.

• N = 88  
• MEAN AGE = 68.3 years (SD = 9.9)
• MALES: 69%, FEMALES: 31%
• KEY DISEASE CHARACTERISTICS: All had head and neck cancer, and 71% had prior radiation therapy.
• OTHER KEY SAMPLE CHARACTERISTICS: Of the patients, 88% had underwent a because of stridor. The median time from radiation to the procedure was 160 days.

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

• PHASE OF CARE: Transition phase after active treatment

• Retrospective

Pneumonia was defined as the clinical suspicion of pneumonia or the postoperative administration of antibiotics.

More patients who did not receive prophylaxis received antibiotics postoperatively (p = 0.04). The hospital stays of those given prophylactic antibiotics were seven days shorter (p < 0.01).

Prophylactic antibiotic administration for patients undergoing tracheotomy may reduce the risk of postprocedure ventilator-associated pneumonia.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Measurement validity/reliability questionable
• No standard and objective measure of pneumonia

Prophylactic antibiotic use in patients undergoing surgical procedures has been shown to reduce postoperative infections. The findings from this study add to that body of evidence, suggesting that this approach prior to tracheostomy provides a similar benefit in preventing ventilator-associated pneumonia.

The article evaluated lipid-soluble formulations of amphotericin B compared with conventional amphotericin B.

The Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed (through November 2007) databases were searched, as were the proceedings from the Interscience Conference on Antimicrobial Agents and Chemotherapy (1990–2007), the General Meeting of the American Society of Microbiology (1990–2007), and European Congress of Clinical Microbiology and Infectious Diseases (1995–2007). In addition, the reference lists of articles were searched, and researchers in the field were contacted.

12 randomized trials

• 1,895 neutropenic patients with cancer.
• Most patients had acute leukemia or were undergoing hematopoietic stem cell transplantation (HSCT).

• Lipid-based amphotericin B was not more effective than conventional amphotericin B for mortality.
• Lipid-based amphotericin B decreased invasive fungal infections by 35%.
• Lipid-based amphotericin B decreased nephrotoxicity by 55%.
• Lipid-based amphotericin B decreased dropouts from the study by 22%.

There was no significant difference in mortality for the drug used in most patients, AmBisome (three trials, 1,149 patients), whereas it tended to be more effective than conventional amphotericin B for invasive fungal infection (RR = 0.63, 0.39 to 1.01, p = 0.053).

Despite a significant reduction in invasive fungal infections and nephrotoxicity seen with lipid-based amphotericin B formulations, the authors concluded that an advantage was unclear regarding the use of lipid-based amphotericin B formulations if conventional amphotericin B is administered under optimal circumstances.

In the trials reviewed, amphotericin B rarely was administered under optimal circumstances (routine premedication for the prevention of infusion-related toxicity and supplementation with fluid, potassium, and magnesium for the prevention of nephrotoxicity).

To examine fluconazole (oral or intravenous [IV]) compared with amphotericin B (oral or IV) in patients with cancer who were neutropenic.

Databases searched were The Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed (through November 2007).  The authors also searched the proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) (1990–2007), the General Meeting of the American Society for Microbiology (ASM) (1990–2007), and the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) (1995–2007). In addition, the authors contacted researchers in the field and industry and reviewed reference lists to identify unpublished trials.

• Seventeen randomized, controlled trials were reviewed.
• The total number of participants was 3,798.
• The sample consisted of patients with cancer who were neutropenic.
• Most patients had acute leukemia or were undergoing hematopoietic stem cell transplantation.

No significant difference was found between fluconazole and amphotericin B with regard to

• Mortality
• Invasive fungal infection
• Colonization
• Use of rescue therapy
• Dropouts.

The major adverse effects were hepatic impairment and gastrointestinal adverse effects with fluconazole and infusion-related toxicity, renal impairment, and gastrointestinal adverse effects with amphotericin B.

Considerable heterogeneity existed in the studies, and amphotericin B was not favored in several of the largest trials through the trial design or data analysis.  Of particular concern was that seven trials compared oral fluconazole to oral amphotericin B. Oral amphotericin B is poorly absorbed and is not recommended for prophylaxis or the treatment of systemic fungal infections. No trial report offered a rationale for this design, and attempts by the authors to obtain additional information from the investigators were unsuccessful.

In the 10 trials that compared oral or IV fluconazole to IV amphotericin B, the design disfavored the amphotericin B arm. Clinicians familiar with the optimal administration of amphotericin B routinely prescribe premedication to prevent infusion-related toxicity and fluids (potassium and magnesium) to prevent nephrotoxicity. Supplemental fluids (i.e., potassium and magnesium) were not prescribed in any trial reviewed, and premedication was prescribed in only two trials. 

The majority of these trials were sponsored by the company that manufactured fluconazole, and the authors were unable to obtain additional information or access to certain trial data held by the company.

The authors concluded that there was not sufficient data from the available trials to judge the effectiveness of fluconazole compared with amphotericin B. Amphotericin B should be preferred because it is the only antifungal for which evidence suggests an effect on mortality.