This multi-site, double blind, parallel arm, fixed dose, randomised placebo controlled phase III study compared megestrol acetate 480 mg/day with dexamethasone 4 mg/day for their net effects on ...appetite in people with cancer anorexia. Patients with advanced cancer and anorexia for ≥ 2 weeks with a score ≤ 4 (0-10 numeric rating scale (NRS) 0 = no appetite, 10 = best possible appetite) were recruited. Participants received megestrol 480 mg or dexamethasone 4 mg or placebo daily for up to 4 weeks. Primary outcomes were at day 7. Responders were defined as having a ≥ 25% improvement in NRS over baseline. There were 190 people randomised (megestrol acetate n = 61; dexamethasone n = 67, placebo n = 62). At week 1 (primary endpoint), 79·3% in the megestrol group, 65·5% in the dexamethasone group and 58·5% in the placebo group (p = 0.067) were responders. No differences in performance status or quality of life were reported. Treatment emergent adverse events were frequent (90·4% of participants), and included altered mood and insomnia. Hyperglycemia and deep vein thromboses were more frequent when on dexamethasone than the other two arms. There was no difference in groups between the three arms, with no benefit seen over placebo with anorexia improving in all arms.Trail registration: The trial was registered on 19/08/2008 with the Australian New Zealand Clinical Trials Registry (ACTRN12608000405314).
Chronic breathlessness is a clinical syndrome that results in significant distress and disability. Morphine can reduce chronic breathlessness when the contributing etiologies are optimally treated.
...Does oxycodone reduce chronic breathlessness compared with placebo?
A multisite, randomized, placebo-controlled, double-blind, parallel-arm, fixed-dose trial of oral controlled-release oxycodone 15 mg (5 mg, eight hourly) or placebo (ACTRN12609000806268 at www.anzctr.org.au). As-needed immediate-release morphine (2.5 mg per dose; six and less doses/day) was available for both arms as required by one ethics committee overseeing the trial. Recruitment occurred from 2010 to 2014 in 14 inpatient and outpatient respiratory, cardiology, and palliative care services across Australia. Participants were adults, with chronic breathlessness (modified Medical Research Council Scale 3 or 4), who were opioid naive. The primary end point was the proportion of people with greater than 15% reduction from baseline in the intensity of breathlessness now (0–100 mm visual analogue scale) comparing arms Days 5–7. Secondary end points were average and worst breathlessness, quality of life, function, and harms.
Of 157 participants randomized, 155 were included (74 oxycodone and 81 placebo), but the study did not reach target recruitment. There was difference in neither between groups for the primary outcome (P = 0.489) nor any of the prespecified secondary outcomes. Placebo participants used more as-needed morphine (mean 7.0 vs. 4.2 doses; P ≤ 0.001). Oxycodone participants reported more nausea (P < 0.001).
There was no signal of benefit from oxycodone over placebo. Future research should focus on investigating the existence of an opioid class effect on the reduction of chronic breathlessness.
Biostatisticians - take a chance Sandra Louw; Philip McCloud
Australasian biotechnology,
07/2015, Letnik:
25, Številka:
2
Journal Article
If there were no random variation in the world, clinical trial design would be simple. We would only need to enrol two patients. One would receive the experimental treatment and one would receive the ...control. In the absence of between patient heterogeneity and random variation from other sources, the results for these patients would be applicable to everyone. However, in our world where random variation runs rife, clinical trial design is frustratingly difficult. Biostatisticians can help to quantify and manage this uncertainty.
Endogenous opioids (endorphins) have been reported to modulate exercise-induced breathlessness, but the relative contribution of peripheral opioid receptors has not been tested.
This was a ...double-blind, randomised, three-arm, cross-over trial in outpatients with spirometry-verified moderate to severe chronic obstructive pulmonary disease. Participants undertook an incremental symptom-limited treadmill test followed by five endurance treadmill tests at 75% of their maximal work rate; two tests for familiarisation and three tests 30 min after intravenous injection of either methylnaltrexone 0.3 mg·kg
(blocking peripheral opioid receptors only) or naloxone 0.1 mg·kg
(blocking both central and peripheral opioid receptors) or normal saline, in randomised order. The primary end-point was the regression slope between breathlessness intensity (0-10 numerical rating scale) and oxygen consumption (
'
) during the walk tests, comparing methylnaltrexone and placebo using a paired t-test.
17 participants completed the trial: median (range) 66 (55-82) years; 15 males; mean±sd forced expiratory volume (FEV
) 53.8±17.6% predicted; FEV
/forced vital capacity ratio 0.55±15.9. There was no statistically or clinically significant difference in the primary end-point (regression slope of breathlessness intensity and
'
) for methylnaltrexone (p=0.498) or naloxone (p=0.804), compared to placebo. Secondary outcomes were similar between the three treatment groups, including peak and mean breathlessness intensity and unpleasantness, exercise capacity, endurance time and leg fatigue.
Blocking peripheral opioid receptors (methylnaltrexone) or peripheral and central opioid receptors (naloxone) did not appear to modulate breathlessness intensity nor exercise capacity when compared with placebo (no blockade).
Does sertraline provide symptomatic relief for chronic breathlessness in people with advanced disease whose underlying cause(s) are optimally treated?223 participants with chronic breathlessness ...(modified Medical Research Council breathlessness scale ≥2) who had optimal treatment of underlying cause(s) were randomised 1:1 to sertraline 25-100 mg (titrated upwards over 9 days) or placebo for 4 weeks. The primary outcome was the proportion who had an improvement in intensity of current breathlessness >15% from baseline on a 100-mm visual analogue scale.The proportion of people responding to sertraline was similar to placebo for current breathlessness on days 26-28 (OR 1.00, 95% CI 0.71-1.40) and for other measures of breathlessness. Quality of life in the sertraline arm had a higher likelihood of improving than in the placebo arm over the 4 weeks (OR 0.21, 95% CI 0.01-0.41; p=0.044). No differences in performance status, anxiety and depression, or survival were observed. Adverse event rates were similar between arms.Sertraline does not appear to provide any benefit over placebo in the symptomatic relief of chronic breathlessness in this patient population.
Background
Pain in people with advanced cancer is prevalent. When a stable dose of opioids is established, people still experience episodic breakthrough pain for which dosing of an immediate release ...opioid is usually a proportion of the total daily dose.
Methods
This multi‐site, double blind, randomized trial tested three dose proportions (1/6, 1/8, 1/12 of total daily dose) in two blocks, each block with three dose proportions in random order (6 numbered bottles in total). When participants required opioid breakthrough doses and it was their first breakthrough dose for that study day, they took the next numbered bottle rather than their usual breakthrough dose. (Subsequent doses on that day reverted to their usual dose.)
Results
Eighty‐five people were randomized in this study of whom 81 took at least one dose and 73 (90%) took at least block one (one of each dose proportion). No dose was found to be optimal at 30 min with approximately one‐third of participants showing maximal reduction with each dose proportion. Median time to pain relief was 120 min. There were no differences in harms: drowsiness, confusion, nausea or vomiting at 30, 60 or 120 min.
Conclusions
This adequately powered study did not show any difference with three dose proportions for reduction in pain intensity, time to pain relief, pain control on the subsequent day nor any difference in harms. From first principles, this suggests 1/12 the 24 hourly dose should be used as the lowest dose that delivers benefit. Future studies should include a placebo arm.
Significance
Despite the widespread use of immediate release morphine solution for breakthrough cancer pain, the ideal dose derived from background dose has not been determined in an adequately powered randomized, double‐blind, crossover, dose ranging study. This study tested three dose levels in people with advanced cancer. Given no differences in time to onset, level of analgesia achieved, nor side effects, the lowest dose tested (1/12th of the daily dose) should be used.
IMPORTANCE: Chronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release morphine may relieve breathlessness, but evidence about ...its efficacy and dosing is needed. OBJECTIVE: To determine the effect of different doses of extended-release morphine on worst breathlessness in people with COPD after 1 week of treatment. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, placebo-controlled randomized clinical trial including people with COPD and chronic breathlessness (defined as a modified Medical Research Council score of 3 to 4) conducted at 20 centers in Australia. People were enrolled between September 1, 2016, and November 20, 2019, and followed up through December 26, 2019. INTERVENTIONS: People were randomized 1:1:1 to 8 mg/d or 16 mg/d of oral extended-release morphine or placebo during week 1. At the start of weeks 2 and 3, people were randomized 1:1 to 8 mg/d of extended-release morphine, which was added to the prior week’s dose, or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was change in the intensity of worst breathlessness on a numerical rating scale (score range, 0 none to 10 being worst or most intense) using the mean score at baseline (from days −3 to −1) to the mean score after week 1 of treatment (from days 5 to 7) in the 8 mg/d and 16 mg/d of extended-release morphine groups vs the placebo group. Secondary outcomes included change in daily step count measured using an actigraphy device from baseline (day −1) to the mean step count from week 3 (from days 19 to 21). RESULTS: Among the 160 people randomized, 156 were included in the primary analyses (median age, 72 years IQR, 67 to 78 years; 48% were women) and 138 (88%) completed treatment at week 1 (48 in the 8 mg/d of morphine group, 43 in the 16 mg/d of morphine group, and 47 in the placebo group). The change in the intensity of worst breathlessness at week 1 was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, −0.3 95% CI, −0.9 to 0.4) or between the 16 mg/d of morphine group and the placebo group (mean difference, −0.3 95%, CI, −1.0 to 0.4). At week 3, the secondary outcome of change in mean daily step count was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, −1453 95% CI, −3310 to 405), between the 16 mg/d of morphine group and the placebo group (mean difference, −1312 95% CI, −3220 to 596), between the 24 mg/d of morphine group and the placebo group (mean difference, −692 95% CI, −2553 to 1170), or between the 32 mg/d of morphine group and the placebo group (mean difference, −1924 95% CI, −47 699 to 921). CONCLUSIONS AND RELEVANCE: Among people with COPD and severe chronic breathlessness, daily low-dose, extended-release morphine did not significantly reduce the intensity of worst breathlessness after 1 week of treatment. These findings do not support the use of these doses of extended-release morphine to relieve breathlessness. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02720822
To assess the outcomes of the most elderly cohort of patients with a diagnosis of glioblastoma multiforme (GBM) after intensity modulated radiation therapy (IMRT).
The data of patients with GBM who ...had underwent IMRT from May 2007 to December 2015 were entered into a prospective database. Analysis was performed on the data from patients diagnosed during or after 75 years of age. The primary endpoint was the median survival. Univariate and multivariate analyses were performed with respect to survival for patients aged 74 to 80 versus >80 years, Eastern Cooperative Oncology Group performance status of 0 to 1 versus 2 to 3, extent of resection, a high radiation dose (60 Gy) versus any hypofractionated schedule, MGMT methylation status, planning target volume, and the use of temozolomide (TMZ) versus no TMZ.
Of the 108 patients, 35 received best supportive care, 1 received TMZ alone, 40 received RT alone, and 32 received combined RT and TMZ. IMRT was delivered with a hypofractionated technique (40 Gy) in 58 patients or long-course RT (60 Gy) in 11 patients. The median age was 79 years, with 61.6% of patients aged 74 to 80 years and 38.4% aged >80 years. Of the 108 patients, 64 died during the follow-up period, with a median survival of 10 months (95% confidence interval 7.1-11.9), projected 12-month survival rate of 35.6%, and 24-month survival rate of 7.9%. On univariate analysis, the independent predictors of survival included younger age (P=.02), better performance status (P=.014), greater resection extent (P=.002), and TMZ use (P<.001). MGMT methylation status, RT dose, and planning target volume showed no significant differences between the groups. Only chemotherapy use remained statistically significant (P=.035) on multivariate analysis.
The current data underrepresent elderly patients aged >75 years with GBM. Despite elderly patients having a worse prognosis, the results of the present study suggest the presence of survival benefits with IMRT for selected patients that can be further extended with addition of TMZ. Further study of this cohort and an understanding of the appropriate selection criteria are warranted.
Biostatisticians - take a chance Sandra Louw; Philip McCloud
Australasian biotechnology,
07/2015, Letnik:
25, Številka:
2
Journal Article
If there were no random variation in the world, clinical trial design would be simple. We would only need to enrol two patients. One would receive the experimental treatment and one would receive the ...control. In the absence of between patient heterogeneity and random variation from other sources, the results for these patients would be applicable to everyone. However, in our world where random variation runs rife, clinical trial design is frustratingly difficult. Biostatisticians can help to quantify and manage this uncertainty.
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