Pharmacologic interventions, including opioids and anxiolytics, did not improve breathlessness, anxiety or exercise capacity compared with placebo in patients with advanced cancer, a systematic review and meta-analysis has shown. But experts question these conclusions.
In a review if 19 studies, 17 of which were randomized controlled trials (RCTs), opioids were not associated with greater effect than placebo for improving breathlessness at a standard mean deviation (SMD) of −0.14 (95% CI, −0.47 to 0.18) or exercise capacity at a SMD of 0.06 (95% CI, −0.43 to 0.55), Josephine Feliciano MD, Johns Hopkins University, Baltimore, Maryland, and colleagues reported in JAMA Network Open. Nor were anxiolytics associated with greater effectiveness than placebo for the treatment of either breathlessness or anxiety at a mean between-group difference of −0.52 (95% CI, −1.04 to 0.005), they added.
In contrast, evidence on harms from pharmacologic interventions were too limited to make any conclusions.
“Oncology guidelines and reviews endorse the use of opioids and anxiolytics as interventions for symptomatic relief of breathlessness in patients with advanced cancer,” Feliciano and colleagues observed. “Practitioners may need to reassess the role of pharmacologic agents, such as opioids and anxiolytics in the management of breathlessness for patients with advanced cancer, taking into consideration many patient-related factors.”
But are these findings showing an absence of effect from pharmacological interventions on breathlessness or simply an absence of evidence? Hayley Barnes, MBBS, MPH, Monash University, Melbourne, Australia, and Natasha Smallwood, MBBS, PhD, University of Melbourne, Melbourne, Australia, posed the question in an accompanying editorial.
Barnes and Smallwood noted that the population treated in the studies reviewed was “highly heterogeneous,” with different prognoses, some of whom were receiving palliative care but others who were treated in both the in- and the out-patient setting.
“Most trials included in the systematic review were small, short-term studies which measured breathlessness at different points (ranging from 6-172 minutes) after drug administration, either at rest, peak exercise or isotine,” they noted. They also suggested that the standardized mean difference used to assess the comparative effect of pharmacological interventions may have underestimated the true effect of the intervention assessed.
For these and related reasons, the evidence presented by Feliciano et al remains poor, Barnes and Smallwood suggested.
“The truth is that [we still] do not know whether there is no benefit from pharmacological treatments for breathlessness in people with advanced cancer or if [these] findings…are due to the limited, low-quality evidence in highly heterogeneous populations,” the editorialists wrote. “Therefore, we suggest that the main message from [this] study…is a call to arms: we urgently need high-quality, large, long-term multisite randomized clinical trials that robustly examine and report both benefits (particularly regarding quality of life) and harms of pharmacological interventions for breathlessness over multiple points in more homogeneous groups of people with advanced cancer.”
Feliciano and colleagues’ systematic review and meta-analysis included a total of 1,424 advanced cancer patients in which the benefits of medication for the management of breathlessness had been assessed.
“The most commonly reported type of cancer was lung cancer,” they noted.
Six RCTs compared the effect of opioids to that of placebo, most of which assessed the comparative effects of each intervention on exertional breathlessness. Four studies evaluated fentanyl products, one hydromorphone and the other subcutaneous morphine.
“On the basis of the overall pooled results from the meta-analysis, opioids were not more effective than placebo for improving breathlessness in patients with advanced cancer,” Feliciano and colleagues reported.
Only 2 RCTs evaluated the effect that anxiolytics had on the same endpoint—one involving buspirone and the other intranasal midazolam, both compared with placebo. And, neither study found any statistically significant difference between groups at a reported mean between-group difference of −0.52 (95% CI, −1.04 to 0.005) for the buspirone study, with no reported results for the intranasal midazolam study.
Only one study compared oral dexamethasone to placebo and again found no significant effect between the two interventions on breathlessness at a calculated SMD of −0.06 (95% CI, −0.70 to 0.58).
Investigators also compared the effect that different routes of administration and different doses of opioids might have on the treatment of breathlessness in this patient population.
In a meta-analysis of 7 RCTs, 4 studies found no difference between opioid doses or routes used, at a calculated SMD of 0.15 (95% CI, −0.22 to 0.52), leading the authors to conclude that there were no differences between opioid doses or routes of administration used on the breathlessness endpoint. However, it should be noted that 3 of the 7 RCTs were not included in this particular meta-analysis because of statistical incompatibility.
Two studies compared the effect that morphine had on breathlessness to that of midazolam or the combination of both morphine and midazolam. “The combination [of] morphine and midazolam… had a statistically significantly higher percentage of patients reporting breathlessness relief than either agent alone at 24 hours, which was persistent compared with the midazolam alone group at 48 hours,” the study authors wrote.
That said, the authors again concluded that opioids were not more effective than anxiolytics, specifically midazolam, for the treatment of breathlessness. The same group also examined the effect that anxiolytics had on anxiety again in patients with advanced cancer.
Of the two RCTs where anxiolytics were compared with placebo, there was no difference in anxiety following treatment with either anxiolytic relative to placebo.
Three RCTS looked at the effect that fentanyl had on the 6-minute walk test, again relative to placebo. A meta-analysis of these 3 studies found no difference in the 6-minute walk distance achieved between the 2 treatment arms at a calculated SMD of 0.06 (95% CI, −0.43 to 0.55), as Feliciano and colleagues noted.
“No study reported any significant effects from any drugs on physiologic outcomes,” investigators added.
“[And a]dverse effects led to dropout in a small percentage of patients (range, 3.2%-16%) for all types of pharmacologic interventions,” they observed.
Limitations of the study include its design and the fact that patient reported breathlessness is subjective, and the trials reported various types in various settings. “In addition, minimum clinically important differences that were defined in our analyses were extrapolated from studies that include broad patient populations, such as patients who have breathlessness from chronic obstructive pulmonary disease; these clinically important differences could be different in advanced cancer,” the study authors wrote.
-
Neither opioids nor anxiolytics improved breathlessness and anxiety in patients with advanced cancer.
-
Be aware that the poor quality of evidence in which pharmacological interventions were compared to placebo may mean only that there is no evidence and not no effect from the treatment of breathlessness in advanced cancer.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded in part by the Patient-Centered Outcomes Research Institute.
Feliciano reported receiving grants from Bristol Myers Squibb and AstraZeneca; serving on advisory boards for AstraZeneca, Genentech, and Eli Lilly; serving as a consultant for Merck, and participating in research collaboration for Genentech and Merck.
The editorialists had no relevant financial disclosures to make.
Cat ID: 118
Topic ID: 78,118,730,118,935,192,925
