Olanzapine for the prevention and treatment of cancer-related nausea and vomiting in adults.

BACKGROUND: Olanzapine as an antiemetic represents a new use of an antipsychotic drug. People with cancer may experience nausea and vomiting whilst receiving chemotherapy or radiotherapy, or whilst in the palliative phase of illness. OBJECTIVES: To assess the efficacy and safety of olanzapine when used as an antiemetic in the prevention and treatment of nausea and vomiting related to cancer in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase for published data on 20th September 2017, as well as ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform for unpublished trials. We checked reference lists, and contacted experts in the field and study authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of olanzapine versus any comparator with or without adjunct therapies for the prevention or treatment, or both, of nausea or vomiting in people with cancer aged 18 years or older, in any setting, of any duration, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. We used GRADE to assess quality of evidence for each main outcome. We extracted data for absence of nausea or vomiting and frequency of serious adverse events as primary outcomes. We extracted data for patient perception of treatment, other adverse events, somnolence and fatigue, attrition, nausea or vomiting severity, breakthrough nausea and vomiting, rescue antiemetic use, and nausea and vomiting as secondary outcomes at specified time points. MAIN RESULTS: We included 14 RCTs (1917 participants) from high-, middle- and low-income countries, representing over 24 different cancers. Thirteen studies were in chemotherapy-induced nausea and vomiting. Oral olanzapine was administered during highly emetogenic (HEC) or moderately emetogenic (MEC) chemotherapy (12 studies); chemoradiotherapy (one study); or palliation (one study). Eight studies await classification and 13 are ongoing.The main comparison was olanzapine versus placebo/no treatment. Other comparisons were olanzapine versus NK1 antagonist, prokinetic, 5-HT3 antagonist or dexamethasone.We assessed all but one study as having one or more domains that were at high risk of bias. Eight RCTs with fewer than 50 participants per treatment arm, and 10 RCTs with issues related to blinding, were at high risk of bias. We downgraded GRADE assessments due to imprecision, inconsistency and study limitations.Olanzapine versus placebo/no treatmentPrimary outcomesOlanzapine probably doubles the likelihood of no nausea or vomiting during chemotherapy from 25% to 50% (risk ratio (RR) 1.98, 95% confidence interval (CI) 1.59 to 2.47; 561 participants; 3 studies; solid tumours; HEC or MEC therapy; moderate-quality evidence) when added to standard therapy. Number needed to treat for additional beneficial outcome (NNTB) was 5 (95% CI 3.3 - 6.6).It is uncertain if olanzapine increases the risk of serious adverse events (absolute risk difference 0.7% more, 95% CI 0.2 to 5.2) (RR 2.46, 95% CI 0.48 to 12.55; 7 studies, 889 participants, low-quality evidence).Secondary outcomesFour studies reported patient perception of treatment. One study (48 participants) reported no difference in patient preference. Four reported quality of life but data were insufficient for meta-analysis.Olanzapine may increase other adverse events (RR 1.71, 95% CI 0.99 to 2.96; 332 participants; 4 studies; low-quality evidence) and probably increases somnolence and fatigue compared to no treatment or placebo (RR 2.33, 95% CI 1.30 to 4.18; anticipated absolute risk 8.2% more, 95% CI 1.9 to 18.8; 464 participants; 5 studies; moderate-quality evidence). Olanzapine probably does not affect all-cause attrition (RR 0.99, 95% CI 0.57 to 1.73; 943 participants; 8 studies; I² = 0%). We are uncertain if olanzapine increases attrition due to adverse events (RR 3.00, 95% CI 0.13 to 70.16; 422 participants; 6 studies). No participants withdrew due to lack of efficacy.We are uncertain if olanzapine reduces breakthrough nausea and vomiting (RR 0.38, 95% CI 0.10 to 1.47; 501 participants; 2 studies; I² = 54%) compared to placebo or no treatment. No studies reported 50% reduction in severity of nausea or vomiting, use of rescue antiemetics, or attrition.We are uncertain of olanzapine's efficacy in reducing acute nausea or vomiting. Olanzapine probably reduces delayed nausea (RR 1.71, 95% CI 1.40 to 2.09; 585 participants; 3 studies) and vomiting (RR 1.28, 95% CI 1.14 to 1.42; 702 participants; 5 studies).Subgroup analysis: 5 mg versus 10 mgPlanned subgroup analyses found that it is unclear if 5 mg is as effective an antiemetic as 10 mg. There is insufficient evidence to exclude the possibility that 5 mg may confer a lower risk of somnolence and fatigue than 10 mg.Other comparisonsOne study (20 participants) compared olanzapine versus NK1 antagonists. We observed no difference in any reported outcomes.One study (112 participants) compared olanzapine versus a prokinetic (metoclopramide), reporting that olanzapine may increase freedom from overall nausea (RR 2.95, 95% CI 1.73 to 5.02) and overall vomiting (RR 3.03, 95% CI 1.78 to 5.14).One study (62 participants) examined olanzapine versus 5-HT3 antagonists, reporting olanzapine may increase the likelihood of 50% or greater reduction in nausea or vomiting at 48 hours (RR 1.82, 95% CI 1.11 to 2.97) and 24 hours (RR 1.36, 95% CI 0.80 to 2.34).One study (229 participants) compared olanzapine versus dexamethasone, reporting that olanzapine may reduce overall nausea (RR 1.73, 95% CI 1.37 to 2.18), overall vomiting (RR 1.27, 95% CI 1.10 to 1.48), delayed nausea (RR 1.66, 95% CI 1.33 to 2.08) and delayed vomiting (RR 1.25, 95% CI 1.07 to 1.45). AUTHORS' CONCLUSIONS: There is moderate-quality evidence that oral olanzapine probably increases the likelihood of not being nauseous or vomiting during chemotherapy from 25% to 50% in adults with solid tumours, in addition to standard therapy, compared to placebo or no treatment. There is uncertainty whether it increases serious adverse events. It may increase the likelihood of other adverse events, probably increasing somnolence and fatigue. There is uncertainty about relative benefits and harms of 5 mg versus 10 mg.We identified only RCTs describing oral administration. The findings of this review cannot be extrapolated to provide evidence about the efficacy and safety of any injectable form (intravenous, intramuscular or subcutaneous) of olanzapine.

Subcutaneous levetiracetam for the management of seizures at the end of life.

OBJECTIVES: To report the results of a combined case series analysis of subcutaneous levetiracetam (Keppra) for the management of seizures in palliative care patients. METHODS: A comprehensive literature review on the use of subcutaneous levetiracetam was performed, and these data were combined with a prospective observational audit of its use in terminal care undertaken in a regional palliative care network. RESULTS: 7 papers were identified from the literature review-four case reports and three observational case series-reporting on a total of 53 cases where subcutaneous levetiracetam was administered.We report 20 further cases of subcutaneous levetiracetam administration from a prospective observational audit. Doses ranged from 250mg to 4000 mg daily. Oral to subcutaneous conversion ratios where stated were 1:1. Levetiracetam was reported as the sole administered antiepileptic drug (AED) in eight cases, and no seizures were reported until death in five cases. Five were switched back to enteral levetiracetam. In seven cases, levetiracetam was combined with AEDs to provide seizure control at the end of life. There was one report of a sterile abscess after 25 days of continuous subcutaneous administration. CONCLUSIONS: Combined analysis of 73 reported cases of subcutaneous levetiracetam suggests this treatment may have a role in the management of seizures at the end of life. However, randomised controlled trials are urgently needed to establish the efficacy and tolerability of subcutaneous levetiracetam administration. If proven to be safe and effective, subcutaneous levetiracetam offers the potential to prevent and treat seizures without causing unnecessary sedation at the end of life.

Oral tapentadol for cancer pain.

BACKGROUND: A large proportion of people with advanced cancer will experience moderate to severe pain. Tapentadol is a novel, centrally acting analgesic medicine acting at the µ-opioid receptor and inhibiting noradrenaline reuptake. The efficacy of tapentadol is stated to be comparable to morphine and oxycodone. OBJECTIVES: To assess the analgesic efficacy of tapentadol for the relief of cancer pain in adults, and the adverse events associated with its use in clinical trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from January 2005 to July 2015, together with reference lists of retrieved papers and review articles, and two clinical trial registries. Searches started from 2005 because this covered the period during which clinical trials were conducted. We contacted the manufacturer of tapentadol in the UK to find additional trials not identified by electronic searches. We did not restrict searches by language. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of tapentadol compared with placebo or active controls in adults with moderate to severe cancer pain. Pain had to be measured using a validated assessment tool, and studies had to include at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standard form and assessed risk of bias. We extracted available data on study design, participant details, interventions, and outcomes, including analgesic outcome measures, withdrawals, and adverse events. MAIN RESULTS: We included four studies with 1029 participants. All the studies used a parallel-group design, and included an initial titration phase to determine the maximum effective and tolerated dose, followed by a maintenance phase. Tapentadol medication was taken twice daily and doses ranged from 50 to 500 mg per day. Rescue medication (morphine or oxycodone immediate-release) was available to participants in all studies.Overall, 440 participants were randomised in classically designed RCTs, and 589 participants were enrolled in enriched-enrolment, randomised-withdrawal (EERW) trials. A total of 476 participants were randomised to titration with tapentadol and 338 participants took tapentadol throughout the maintenance phase of their trial.All studies used numerical rating scores, Patient Global Impression of Change scores, and use of rescue medication as measures of efficacy, and all reported on adverse events and withdrawals.All studies enrolled fewer than 200 participants per treatment arm and were therefore at risk of overestimating efficacy. One study was terminated early due to problems with supply of rescue medication, with fewer than 20 participants enrolled per treatment arm in the maintenance phase of the trial. We judged another study at high risk of bias due to an open-label design.There were insufficient data for pooling and statistical analysis. Response rates for pain intensity were comparable across treatment groups in each study. In one EERW study, response rates were high across both treatment and placebo arms during the maintenance phase (62% tapentadol, 69% morphine, 50% placebo). For pain relief, tapentadol is no more and no less effective than oxycodone or morphine (low quality evidence).Treatment emergent adverse event rates were high, approximately 50% to 90%. The most common adverse events were gastrointestinal (nausea, vomiting, constipation) (low quality evidence). There was no advantage of tapentadol over morphine or oxycodone in terms of serious adverse events. The number of people experiencing effects on consciousness, appetite, or thirst was low. AUTHORS' CONCLUSIONS: Information from RCTs on the effectiveness and tolerability of tapentadol was limited. The available studies were of moderate or small size and used different designs, which prevented pooling of data. Pain relief and adverse events were comparable between the tapentadol and morphine and oxycodone groups.

Sentinel lymph node biopsy in breast cancer: an analysis of the maximum number of nodes requiring excision.

Sentinel lymph node biopsy (SNB) is now the standard of care in assessment of patients with clinically staged T1-2, N0 breast cancers. This study investigates whether there is a maximum number of sentinel lymph nodes (SLN) that need to be excised without compromising the false-negative (FN) rate of this procedure. Data were prospectively collected for 319 patients undergoing SNB between February 2001 and December 2006 at our institution. This data were analysed, both in terms of the order of SLN retrieval and relative isotope counts of the SLNs, in order to determine the maximum number of SLNs that need to be retrieved without increasing the FN rate. Furthermore, we investigated the relationship between SLN blue dye concentration and the presence of SLN metastases. The SLN identification rate was 97% with no false-negative cases amongst patients undergoing simultaneous axillary clearance historically during technique validation. In patients with SLN metastases, excision of the first 4 SLNs encountered results in the identification of a metastatic SLN in all cases. Although the majority (86%) of SNB metastases are in the hottest node, the SLN containing the metastasis is in the first 4 hottest nodes in 99% of patients with nodal metastases. The remaining 1% of SLN metastases were identified by blue dye. There was no statistically significant association between the SLN blue dye concentration and the presence of SLN metastases. A policy to remove a maximum of four blue and/or hot SLNs along with any palpably abnormal lymph nodes does not result in an increased false-negative rate of detection of SLN metastases.