In the context of a therapeutic opioid epidemic, particularly in the USA, where increasingly stringent screening for ‘at risk’ individuals and close monitoring of opioid prescription and use is ...strongly recommended, the issue of misuse within the cancer population must be addressed. Most patients with advanced cancer will have pain requiring opioid therapy at some stage during their disease course. In the majority, this will provide good pain relief with no short‐ or longer‐term adverse sequelae. A subset will present with substance misuse issues that will influence management and prescribing practice. The potential ethical issues of limiting effective analgesia on the basis of addiction risk or history must be acknowledged. Both a judgemental or ‘relaxed’ approach to such patients is problematic. Ignoring the situation will not be in the patient's best interest, but an undue focus on this aspect may damage therapeutic relationships with clinicians and adversely affect a holistic approach to care. Clinical practitioners must be aware of the risk factors for opioid misuse and in patients who are not under palliative care consider screening prior to commencing opioids. Clinicians must be able to manage and monitor those identified as having an opioid misuse problem.
Background
Fatigue is the most commonly reported symptom in people with advanced cancer. Cancer‐related fatigue (CRF) is pervasive and debilitating, and can greatly impact quality of life (QoL). CRF ...has a highly variable clinical presentation, likely due to a complex interaction of multiple factors. Corticosteroids are commonly used to improve CRF, but the benefits are unclear and there are significant adverse effects associated with long‐term use. With the increasing survival of people with metastatic cancer, the long‐term effects of medications are becoming increasingly relevant. Since the impact of CRF can be immensely debilitating and can negatively affect QoL, its treatment warrants further review.
Objectives
To determine the benefits and harms of corticosteroids compared with placebo or an active comparator in adults with advanced cancer and CRF.
Search methods
We searched CENTRAL, MEDLINE, Embase, CINAHL, Science Citation Index (ISI Web of Science), LILACS, and two clinical trial registries from inception to 18 July 2022.
Selection criteria
We included randomised controlled trials in adults aged ≥18 years. We included participants with advanced cancer who were suffering from CRF. We included trials that randomised participants to corticosteroids at any dose, by any route, administered for the relief of CRF; compared to placebo or an active comparator, including supportive care or non‐pharmacological treatments.
Data collection and analysis
Three review authors independently assessed titles identified by the search strategy; two review authors assessed risk of bias; and two extracted data. We extracted the primary outcome of participant‐reported fatigue relief using validated scales and secondary outcomes of adverse events, serious adverse events and QoL. We calculated the risk ratio with 95% confidence intervals (CIs) between groups for dichotomous outcomes. We measured arithmetic mean and standard deviation, and reported the mean difference (MD) with 95% CI between groups for continuous outcomes. We used standardised mean difference (SMD) with 95% CIs when an outcome was measured with different instruments measuring the same construct. We used a random‐effects model to meta‐analyse the outcome data. We rated the certainty of the evidence using GRADE and created two summary of findings tables.
Main results
We included four studies with 297 enroled participants; data were available for only 239 participants. Three studies compared corticosteroid (equivalent ≤ 8 mg dexamethasone) to placebo. One study compared corticosteroid (dexamethasone 4 mg) to an active comparator (modafinil 100 mg). There were insufficient data to evaluate subgroups, such as dose and duration of treatment. One study had a high risk of performance and detection bias due to lack of blinding, and one study had a high risk of attrition bias. Otherwise, we assessed risks of bias as low or unclear.
Comparison 1: corticosteroids compared with placebo
Participant‐reported fatigue relief
The was no clear difference between corticosteroids and placebo (SMD ‐0.46, 95% CI ‐1.07 to 0.14; 3 RCTs, 165 participants, very low‐certainty evidence) for relief of fatigue at one week of the intervention. We downgraded the certainty of the evidence three times for study limitations due to unclear risk of bias, imprecision, and inconsistency.
Adverse events
There was no clear difference in the occurrence of adverse events between groups, but the evidence is very uncertain (3 RCTs, 165 participants; very low‐certainty evidence).
Serious adverse events
There was no clear difference in the occurrence of serious adverse events between groups, but the evidence is very uncertain (2 RCTs, 118 participants; very low‐certainty evidence).
Quality of lIfe
One study reported QoL at one week using the Edmonton Symptom Assessment System (ESAS) well‐being, and found no clear difference in QoL between groups (MD ‐0.58, 95% CI ‐1.93 to 0.77). Another study measured QoL using the Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs (QoL‐ACD), and found no clear difference between groups. There was no clear difference between groups for either study, but the evidence is very uncertain (2 RCTs, 118 participants; very low‐certainty evidence).
Comparison 2: corticosteroids compared with active comparator (modafinil)
Participant‐reported fatigue relief
There was improvement in fatigue from baseline to two weeks in both groups (modafinil MD 10.15, 95% CI 7.43 to 12.87; dexamethasone MD 9.21, 95% CI 6.73 to 11.69), however no clear difference between the two groups (MD ‐0.94, 95% CI ‐4.49 to 2.61; 1 RCT, 73 participants, very low‐certainty evidence). We downgraded the certainty of the evidence three times for very serious study limitations and imprecision.
Adverse events
There was no clear difference in the occurrence of adverse events between groups, but the evidence is very uncertain (1 RCT, 73 participants; very low‐certainty evidence).
Serious adverse events
There were no serious adverse events reported in either group (1 RCT, 73 participants; very low‐certainty evidence).
Quality of lIfe
One study measured QoL at two weeks, using the ESAS‐well‐being. There was marked improvement in QoL from baseline in both groups (modafinil MD ‐2.43, 95% CI ‐2.88 to ‐1.98; dexamethasone MD ‐2.16, 95% CI ‐2.68 to ‐1.64), however no clear difference between the two groups (MD 0.27, 95% CI ‐0.39 to 0.93; 1 RCT, 73 participants, very low‐certainty evidence).
Authors' conclusions
There is insufficient evidence to support or refute the use of systemic corticosteroids in adults with cancer and CRF.
We included four small studies that provided very low‐certainty of evidence for the efficacy of corticosteroids in the management of CRF.
Further high‐quality randomised controlled trials with larger sample sizes are required to determine the effectiveness of corticosteroids in this setting.
Blood transfusions are associated with a range of adverse patient outcomes, including coagulopathy, immunomodulation and haemolysis, which increase the risk of morbidity and mortality. Consideration ...of these risks and potential benefits are necessary when deciding to transfuse. Patient blood management (PBM) guidelines exist to assist in clinical decision-making, but they are underutilised. Exploration of barriers to the implementation and utilisation of the PBM guidelines is required. This study aimed to identify common barriers and implementation strategies used to implement PBM guidelines, with a comparison against current expert opinion.
A restricted review approach was used to identify the barriers to PBM guideline implementation as reported by health professionals and to review which implementation strategies have been used. Searches were undertaken in MEDLINE/PubMed, CINAHL, Embase, Scopus and the Cochrane library. The Consolidated Framework for Implementation Research (CFIR) was used to code barriers. The Expert Recommendations for Implementing Change (ERIC) tool was used to code implementation strategies, and subsequently, develop recommendations based on expert opinion.
We identified 14 studies suitable for inclusion. There was a cluster of barriers commonly reported: access to knowledge and information (n = 7), knowledge and beliefs about the intervention ( = 7) and tension for change (n = 6). Implementation strategies used varied widely (n = 25). Only one study reported the use of an implementation theory, model or framework. Most studies (n = 11) had at least 50% agreement with the ERIC recommendations.
There are common barriers experienced by health professionals when trying to implement PBM guidelines. There is currently no conclusive evidence to suggest which implementation strategies are most effective. Further research using validated implementation approaches and improved reporting is required.
Background
Dyspnoea is a common symptom in advanced cancer, with a prevalence of up to 70% among patients at end of life. The cause of dyspnoea is often multifactorial, and may cause considerable ...psychological distress and suffering. Dyspnoea is often undertreated and good symptom control is less frequently achieved in people with dyspnoea than in people with other symptoms of advanced cancer, such as pain and nausea. The exact mechanism of action of corticosteroids in managing dyspnoea is unclear, yet corticosteroids are commonly used in palliative care for a variety of non‐specific indications, including pain, nausea, anorexia, fatigue and low mood, despite being associated with a wide range of adverse effects. In view of their widespread use, it is important to seek evidence of the effects of corticosteroids for the management of cancer‐related dyspnoea.
Objectives
To assess the effects of systemic corticosteroids for the management of cancer‐related breathlessness (dyspnoea) in adults.
Search methods
We searched CENTRAL, MEDLINE, Embase, CINAHL, Science Citation Index Web of Science, Latin America and Caribbean Health Sciences (LILACS) and clinical trial registries, from inception to 25 January 2018.
Selection criteria
We included randomised controlled trials that included adults aged 18 years and above. We included participants with cancer‐related dyspnoea when randomised to systemic corticosteroids (at any dose) administered for the relief of cancer‐related dyspnoea or any other indication, compared to placebo, standard or alternative treatment.
Data collection and analysis
Five review authors independently assessed trial quality and three extracted data. We used means and standard deviations for each outcome to report the mean difference (MD) with 95% confidence interval (CI). We assessed the risk of bias and quality of evidence using GRADE. We extracted primary outcomes of sensory‐perceptual experience of dyspnoea (intensity of dyspnoea), affective distress (quality of dyspnoea) and symptom impact (burden of dyspnoea or impact on function) and secondary outcomes of serious adverse events, participant satisfaction with treatment and participant withdrawal from trial.
Main results
Two studies met the inclusion criteria, enrolling 157 participants (37 participants in one study and 120 in the other study), of whom 114 were included in the analyses. The studies compared oral dexamethasone to placebo, followed by an open‐label phase in one study. One study lasted seven days, and the duration of the other study was 15 days.
We were unable to conduct many of our predetermined analyses due to different agents, dosages, comparators and outcome measures, routes of drug delivery, measurement scales and time points. Subgroup analysis according to type of cancer was not possible.
Primary outcomes
We included two studies (114 participants) with data at one week in the meta‐analysis for change in dyspnoea intensity/dyspnoea relief from baseline. Corticosteroid therapy with dexamethasone resulted in an MD of lower dyspnoea intensity compared to placebo at one week (MD –0.85 lower dyspnoea (scale 0–10; lower score = less breathlessness), 95% CI ‐1.73 to 0.03; very low‐quality evidence), although we were uncertain as to whether corticosteroids had an important effect on dyspnoea as results were imprecise. We downgraded the quality of evidence by three levels from high to very low due to very serious study limitations and imprecision.
One study measured affective distress (quality of dyspnoea) and results were similar between groups (29 participants; very low‐quality evidence). We downgraded the quality of the evidence three times for imprecision, inconsistency, and serious study limitations.
Both studies assessed symptom impact (burden of dyspnoea or impact on function) (113 participants; very low‐quality evidence). In one study, it was unclear whether dexamethasone had an effect on dyspnoea as results were imprecise. The second study showed more improvement for physical well‐being scores at days eight and 15 in the dexamethasone group compared with the control group, but there was no evidence of a difference for FACIT social/family, emotional or functional scales. We downgraded the quality of the evidence three times for imprecision, inconsistency, and serious study limitations.
Secondary outcomes
Due to the lack of homogenous outcome measures and inconsistency in reporting, we could not perform quantitative analysis for any secondary outcomes. In both studies, the frequency of adverse events was similar between groups, and corticosteroids were generally well tolerated. The withdrawal rates for the two studies were 15% and 36%. Reasons for withdrawal included lost to follow‐up, participant or carer (or both) refusal, and death due to disease progression. We downgraded the quality of evidence for these secondary outcomes by three levels from high to very low due to serious study limitations, inconsistency and imprecision.
Neither study examined participant satisfaction with treatment.
Authors' conclusions
There are few studies assessing the effects of systemic corticosteroids on cancer‐related dyspnoea in adults with cancer. We judged the evidence to be of very low quality that neither supported nor refuted corticosteroid use in this population. Further high‐quality studies are needed to determine if corticosteroids are efficacious in this setting.
Background
One of the most feared symptoms associated with cancer is pain. Opioids remain the mainstay of pain treatment but corticosteroids are often used concurrently as co‐ or adjuvant analgesics. ...Due to their anti‐inflammatory mechanism of action, corticosteroids are said to provide effective analgesia for pain associated with inflammation and in the management of cancer‐related complications such as brain metastasis and spinal cord compression. However, corticosteroids have a wide range of adverse effects that are dose and time dependent.
Objectives
To evaluate the efficacy of corticosteroids in treating cancer‐related pain in adults.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), MEDLINE (OVID) (1966 to 29 September 2014), EMBASE (OVID) (1970 to 29 September 2014), CINAHL (1982 to 29 September 2014), Science Citation Index (Web of Science) (1899 to 29 September 2014) and Conference Proceedings Citation Index ‐ Science (Web of Science) (1990 to 29 September 2014).
Selection criteria
Any randomised or prospective controlled trial that included patients over 18 years with cancer‐related pain were eligible for the review. Corticosteroids were compared to placebo or usual treatment and/or supportive care.
Data collection and analysis
All review authors independently assessed trial quality and extracted data. We used arithmetic means and standard deviations for each outcome to report the mean difference (MD) with 95% confidence interval (CI).
Main results
Fifteen studies met the inclusion criteria, enrolling 1926 participants. The trial size varied from 20 to 598 patients. Most studies compared corticosteroids, particularly dexamethasone, to standard therapy. We included six studies with data at one week in the meta‐analysis for pain intensity; no data were available at that time point for the remaining studies. Corticosteroid therapy resulted in less pain (measured on a scale of 0 to 10 with a lower score indicating less pain) compared to control at one week (MD 0.84 lower pain, 95% CI 1.38 to 0.30 lower; low quality evidence). Adverse events were poorly documented. Factors limiting statistical analysis included the lack of standardised measurements of pain and the use of different agents, dosages, comparisons and routes of drug delivery. Subgroup analysis according to type of cancer was not possible. The quality of this evidence was limited by the risk of bias of the studies and small sample size. The results were also compromised by attrition, with data missing for the enrolled patients.
Authors' conclusions
The evidence for the efficacy of corticosteroids for pain control in cancer patients is weak. Significant pain relief was noted in some studies, albeit only for a short period of time. This could be important for patients with poor clinical status. Further trials, with increased numbers of participants, are needed to evaluate the safety and effectiveness of corticosteroids for the management cancer pain in adults, and to establish an ideal dose, duration of therapy and route of administration.
The anesthetic ketamine is widely used for pain related to cancer, but the evidence to support its use in this setting is weak. This study aimed to determine whether ketamine is more effective than ...placebo when used in conjunction with opioids and standard adjuvant therapy in the management of chronic uncontrolled cancer pain. Ketamine would be considered of net benefit if it provided clinically relevant improvement in pain with limited breakthrough analgesia and acceptable toxicity.
In this multisite, dose-escalation, double-blind, randomized, placebo-controlled phase III trial, ketamine or placebo was delivered subcutaneously over 3 to 5 days.
In all, 185 participants were included in the primary analysis. There was no significant difference between the proportion of positive outcomes (0.04; 95% CI, -0.10 to 0.18; P = .55) in the placebo and intervention arms (response rates, 27% 25 of 92 and 31% 29 of 93). Pain type (nociceptive v neuropathic) was not a predictor of response. There was almost twice the incidence of adverse events worse than baseline in the ketamine group after day 1 (incidence rate ratio, 1.95; 95% CI, 1.46 to 2.61; P < .001) and throughout the study. Those receiving ketamine were more likely to experience a more severe grade of adverse event per day (odds ratio, 1.09; 95% CI, 1.00 to 1.18; P = .039). The number of patients needed to treat for one additional patient to have a positive outcome from ketamine was 25 (95% CI, six to ∞). The number needed to harm, because of toxicity-related withdrawal, was six (95% CI, four to 13).
Ketamine does not have net clinical benefit when used as an adjunct to opioids and standard coanalgesics in cancer pain.
Abstract Context Does octreotide reduce vomiting in cancer-associated bowel obstruction? Objectives To evaluate the net effect of adding octreotide or placebo to standardized therapies on the number ...of days free of vomiting for populations presenting with vomiting and inoperable bowel obstruction secondary to cancer or its treatment. Methods Twelve services enrolled people with advanced cancer presenting with vomiting secondary to bowel obstruction where surgery or anti-cancer therapies were not indicated immediately. In a double-blind study, participants were randomized to placebo or octreotide (600 μg/24 hours by infusion). Both arms received standardized supportive therapy (infusion of ranitidine 200 mg/24 hours, dexamethasone 8 mg/24 hours, and parenteral hydration 10–20 mL/kg/24 hours). The primary outcome was patient-reported days free of vomiting at 72 hours. Results In a study that recruited to the numbers identified in its power calculation, 87 participants provided data at 72 hours (45, octreotide arm). Seventeen people (octreotide) and 14 (placebo) were free of vomiting for 72 hours ( P = 0.67). Mean days free of vomiting were 1.87 (SD 1.10; octreotide) and 1.69 (SD 1.15; placebo; P = 0.47). An adjusted multivariate regression of the incidence of vomiting over the study showed a reduced number of episodes of vomiting in the octreotide group (incidence rate ratio = 0.40; 95% CI: 0.19–0.86; P = 0.019); however, people in the octreotide arm were 2.02 times more likely to be administered hyoscine butylbromide ( P = 0.004), potentially reflecting increased colicky pain. Conclusion Although there was no reduction in the number of days free of vomiting, the multivariate analysis suggests that further study of somatostatin analogues in this setting is warranted.
Soil-atmosphere fluxes of trace gases (especially nitrous oxide (N₂O)) can be significant during winter and at snowmelt. We investigated the effects of decreases in snow cover on soil freezing and ...trace gas fluxes at the Hubbard Brook Experimental Forest, a northern hardwood forest in New Hampshire, USA. We manipulated snow depth by shoveling to induce soil freezing, and measured fluxes of N₂O, methane (CH₄) and carbon dioxide (CO₂) in field chambers monthly (bi-weekly at snowmelt) in stands dominated by sugar maple or yellow birch. The snow manipulation and measurements were carried out in two winters (1997/1998 and 1998/1999) and measurements continued through 2000. Fluxes of CO₂ and CH₄ showed a strong seasonal pattern, with low rates in winter, but N₂O fluxes did not show strong seasonal variation. The snow manipulation induced soil freezing, increased N₂O flux and decreased CH₄ uptake in both treatment years, especially during winter. Annual N₂O fluxes in sugar maple treatment plots were 207 and 99 mg N m⁻² yr⁻¹ in 1998 and 1999 vs. 105 and 42 in reference plots. Tree species had no effect on N₂O or CO₂ fluxes, but CH₄ uptake was higher in plots dominated by yellow birch than in plots dominated by sugar maple. Our results suggest that winter fluxes of N₂O are important and that winter climate change that decreases snow cover will increase soil:atmosphere N₂O fluxes from northern hardwood forests.
Medications commonly used for symptom control along with other known risk factors have the potential to prolong ventricular repolarization as measured by the QT interval (the time from the start of ...the Q wave to the end of the T wave) on a standard electrocardiogram (ECG).
To document the prevalence of a prolonged QT interval corrected for heart rate (QTc) interval in the palliative/oncology setting, compare automatic ECG QTc measurements with manual readings and identify any correlation between QTc prolongation and the use of drugs or other risk factors.
A convenience sample of consecutive patients with cancer, admitted under or known to the palliative/supportive care teams in two metropolitan hospitals, and willing to provide an ECG recording and basic demographic information including QTc risk factors were included. Both automated and manually calculated QTc intervals were recorded. Multivariable analysis was used to determine risk factors independently associated with prolonged QTc intervals.
Of the 389 participants, there was a significant difference in mean QTc between sites using automated but not manual calculations. Manual readings were therefore used with predetermined cutoffs of 0.44 seconds (males) and 0.46 seconds (females). Seventy-two (18.5%) of the participants had a prolonged QTc with six (1.5%) having a prolongation of >0.50 seconds. At-risk drugs were being taken by 218 participants (56.0% of total cohort). Factors shown to be associated with QTc prolongation included age, gender, performance status, and hypocalcemia. No specific medication was associated with increased risk.
Although almost 20% of patients receiving palliative care had prolongation of QTc, the possibility of serious consequences appeared to be low despite the frequent occurrence of risk factors.
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