Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial.

BACKGROUND: The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response. METHODS: The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs. DISCUSSION: From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients. TRIAL REGISTRATION: The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

Soundscape Awareness Intervention Reduced Neuropsychiatric Symptoms in Nursing Home Residents With Dementia: A Cluster-Randomized Trial With MoSART.

OBJECTIVES: Auditory environments as perceived by an individual, also called soundscapes, are often suboptimal for nursing home residents. Poor soundscapes have been associated with neuropsychiatric symptoms (NPS). We evaluated the effect of the Mobile Soundscape Appraisal and Recording Technology sound awareness intervention (MoSART+) on NPS in nursing home residents with dementia. DESIGN: A 15-month, stepped-wedge, cluster-randomized trial. Every 3 months, a nursing home switched from care as usual to the use of the intervention. INTERVENTION: The 3-month MoSART+ intervention involved ambassador training, staff performing sound measurements with the MoSART application, meetings, and implementation of microinterventions. The goal was to raise awareness about soundscapes and their influence on residents. SETTING AND PARTICIPANTS: We included 110 residents with dementia in 5 Dutch nursing homes. Exclusion criteria were palliative sedation and deafness. METHODS: The primary outcome was NPS severity measured with the Neuropsychiatric Inventory-Nursing Home version (NPI-NH) by the resident's primary nurse. Secondary outcomes were quality of life (QUALIDEM), psychotropic drug use (ATC), staff workload (workload questionnaire), and staff job satisfaction (Maastricht Questionnaire of Job Satisfaction). RESULTS: The mean age of the residents (n = 97) at enrollment was 86.5 ± 6.7 years, and 76 were female (76.8%). The mean NPI-NH score was 17.5 ± 17.3. One nursing home did not implement the intervention because of staff shortages. Intention-to-treat analysis showed a clinically relevant reduction in NPS between the study groups (-8.0, 95% CI -11.7, -2.6). There was no clear effect on quality of life [odds ratio (OR) 2.8, 95% CI -0.7, 6.3], psychotropic drug use (1.2, 95% CI 0.9, 1.7), staff workload (-0.3, 95% CI -0.3, 0.8), or staff job satisfaction (-0.2, 95% CI -1.2, 0.7). CONCLUSIONS AND IMPLICATIONS: MoSART+ empowered staff to adapt the local soundscape, and the intervention effectively reduced staff-reported levels of NPS in nursing home residents with dementia. Nursing homes should consider implementing interventions to improve the soundscape.

The impact of endoxifen-guided tamoxifen dose reductions on endocrine side-effects in patients with primary breast cancer.

BACKGROUND: Tamoxifen is important in the adjuvant treatment of hormone-sensitive breast cancer and substantially reduces recurrence; however, almost 50% of patients are non-compliant mainly due to side-effects. The aim of this study was to investigate whether endoxifen-guided tamoxifen dose reduction could lead to fewer side-effects. MATERIALS AND METHODS: Effects of tamoxifen dose reduction were investigated in patients with bothersome side-effects and endoxifen levels ≥32 nM and compared to patients with side-effects who remained on tamoxifen 20 mg. Endocrine symptoms and health-related quality of life (HR-QOL) were assessed after 3 months with the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire. RESULTS: Tamoxifen dose was reduced in 20 patients, 17 of whom were assessable for side-effect analyses. A clinically relevant improvement of >6 points was observed in endocrine symptoms and HR-QOL in 41% and 65% of the patients, respectively. In total, there was a significant and clinically relevant improvement in endocrine symptoms [5.7, 95% confidence interval (CI) -0.5-11.5] and HR-QOL (8.2, 95% CI 0.9-15.4) after dose reduction. This was not seen in patients whose doses were not reduced (n = 60). In 21% of patients, endoxifen dropped slightly below the 16-nM threshold (12.8, 15.5, 15.8, 15.9 nM). CONCLUSIONS: Endoxifen-guided dose reduction of tamoxifen significantly improved tamoxifen-related side-effects and HR-QOL. Nearly 80% of patients remained above the most conservative endoxifen threshold.