Anti-tumor treatment and healthcare consumption near death in the era of novel treatment options for patients with melanoma brain metastases

BACKGROUND: Effective systemic treatments have revolutionized the management of patients with metastatic melanoma, including those with brain metastases. The extent to which these treatments influence disease trajectories close to death is unknown. Therefore, this study aimed to gain insight into provided treatments and healthcare consumption during the last 3 months of life in patients with melanoma brain metastases. METHODS: Retrospective, single-center study, including consecutive patients with melanoma brain metastases diagnosed between June-2015 and June-2018, referred to the medical oncologist, and died before November-2019. Patient and tumor characteristics, anti-tumor treatments, healthcare consumption, presence of neurological symptoms, and do-not-resuscitate status were extracted from medical charts. RESULTS: 100 patients were included. A BRAF-mutation was present in 66 patients. Systemic anti-tumor therapy was given to 72% of patients during the last 3 months of life, 34% in the last month, and 6% in the last week. Patients with a BRAF-mutation more frequently received systemic treatment during the last 3 (85% vs. 47%) and last month (42% vs. 18%) of life than patients without a BRAF-mutation. Furthermore, patients receiving systemic treatment were more likely to visit the emergency room (ER, 75% vs. 36%) and be hospitalized (75% vs. 36%) than those who did not. CONCLUSION: The majority of patients with melanoma brain metastases received anti-tumor treatment during the last 3 months of life. ER visits and hospitalizations occurred more often in patients on anti-tumor treatment. Further research is warranted to examine the impact of anti-tumor treatments close to death on symptom burden and care satisfaction

Advance Care Planning in the Netherlands

The Dutch health care system fosters a strong public health sector offering accessible generalist care including generalist palliative care. General practitioners are well positioned to conduct ACP, for example, to continue or initiate conversations after hospitalization. However, research shows that ACP conversations are often ad hoc and in frail patients, ACP is often only initiated when admitted to a nursing home by elderly care physicians who are on the staff. Tools that raise awareness of triggers to initiate ACP, screening tools, information brochures, checklists and training have been developed and implemented with funding by national programs which currently focus on implementation projects rather than or in addition to, research. The programs commonly require educational deliverables, patient and public involvement and addressing diversity in patient groups. A major challenge is how to implement ACP systematically and continuously across sectors and disciplines in a way that supports a proactive yet person-centered approach rather than an approach with an exclusive focus on medical procedures. Digital solutions can support continuity of care and communication about care plans. Solutions should fit a culture that prefers trust-based, informal deliberative approaches. This may be supported by involving disciplines other than medicine, such as nursing and spiritual caregiving, and public health approaches.</p

A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor

Background: Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib. Methods: This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion. Results: Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8–4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%). Conclusions: The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing

Clinical utility of circulating tumor DNA as a response and follow-up marker in cancer therapy

Response evaluation for cancer treatment consists primarily of clinical and radiological assessments. In addition, a limited number of serum biomarkers that assess treatment response are available for a small subset of malignancies. Through recent technological innovations, new methods for measuring tumor burden and treatment response are becoming available. By utilization of highly sensitive techniques, tumor-specific mutations in circulating DNA can be detected and circulating tumor DNA (ctDNA) can be quantified. These so-called liquid biopsies provide both molecular information about the genomic composition of the tumor and opportunities to evaluate tumor response during therapy. Quantification of tumor-specific mutations in plasma correlates well with tumor burden. Moreover, with liquid biopsies, it is also possible to detect mutations causing secondary resistance during treatment. This review focuses on the clinical utility of ctDNA as a response and follow-up marker in patients with non-small cell lung cancer, melanoma, colorectal cancer, and breast cancer. Relevant studies were retrieved from a literature search using PubMed database. An overview of the available literature is provided and the relevance of ctDNA as a response marker in anti-cancer therapy for clinical practice is discussed. We conclude that the use of plasma-derived ctDNA is a promising tool for treatment decision-making based on predictive testing, detection of resistance mechanisms, and monitoring tumor response. Necessary steps for translation to daily practice and future perspectives are discussed

Early response evaluation using F-18-FDG-PET/CT does not influence management of patients with metastatic gastrointestinal stromal tumors (GIST) treated with palliative intent

Aim The aim of this study was to investigate the impact of F-18-FDG-PET/CT on treatment decision making in metastatic gastrointestinal stromal tumor (GIST) patients.Methods This study retrospectively evaluated F-18-FDG-PET/CT scans to monitor response of metastatic GIST patients treated with palliative intent. Data from the Dutch GIST Registry was used. Early scans ( 10 weeks after start of treatment) were scored on the impact in change of treatment.Results Sixty-one PET/CTscans were performed for treatment evaluation in 39 patients with metastatic GIST of which 36 were early scans and 25 were late scans. Early PET/CT scans led to a change in management in 5.6 % of patients and late PET/CT scans led to a change in management in 56 % of patients. Change in management was more often seen after scans with lack of metabolic response (48 % vs. 11 % in scans with metabolic response, p = 0.002). Neither metabolic response nor change in treatment were more often seen in patients with KIT mutations compared to patients with non-KIT mutations (metabolic response 65 % KIT vs. 46 % non-KIT, p = 0.33, and change in management 28 % KIT vs. 21 % nonKIT, p = 0.74).Conclusion(18)F-FDG-PET/CT is not recommended for early response evaluation in an unselected patient population with metastatic GIST, since it does not influence treatment decisions. F-18-FDG- PET/ CT, however, can be useful for late response assessment, especially in case of indeterminate CT results.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer

Background: This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer (BC). Patients and methods: Patients with advanced BC treated with palbociclib from 2017 to 2020 were included. The Kaplan-Meier method was used to calculate time to next treatment (TTNT) and overall survival (OS) for patients with or without dose reductions. These clinical outcomes were also compared in subgroup analyses for older patients (≥70 years) and younger patients (<70 years) and for patients discontinuing palbociclib early (<4 administrations). Results: A total of 598 patients with advanced BC were included, with a median age of 64 years. Palbociclib dose reductions occurred in 33% of all patients. Early discontinuation of palbociclib without dose reductions occurred in 23% of the patients. Patients who required a palbociclib dose reduction were older (median age 67 years vs. 63 years). Patients with dose reductions had a significantly higher TTNT of 16.9 vs. 11.4 months (p < 0.001) and median OS of 29.7 vs. 21.9 months (p = 0.003) compared to patients without dose reductions. The TTNT in older patients was significantly longer (16.9 vs. 11.6 months, p = 0.013) than younger patients, but OS was similar (20.7 vs. 26.7 months, p = 0.051). Conclusion: Palbociclib dose reductions occurred in real-world practice similarly to the PALOMA-3 trial. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS

Outcome in patients perceived as receiving excessive care across different ethical climates : a prospective study in 68 intensive care units in Europe and the USA

Whether the quality of the ethical climate in the intensive care unit (ICU) improves the identification of patients receiving excessive care and affects patient outcomes is unknown. In this prospective observational study, perceptions of excessive care (PECs) by clinicians working in 68 ICUs in Europe and the USA were collected daily during a 28-day period. The quality of the ethical climate in the ICUs was assessed via a validated questionnaire. We compared the combined endpoint (death, not at home or poor quality of life at 1 year) of patients with PECs and the time from PECs until written treatment-limitation decisions (TLDs) and death across the four climates defined via cluster analysis. Of the 4747 eligible clinicians, 2992 (63%) evaluated the ethical climate in their ICU. Of the 321 and 623 patients not admitted for monitoring only in ICUs with a good (n = 12, 18%) and poor (n = 24, 35%) climate, 36 (11%) and 74 (12%), respectively were identified with PECs by at least two clinicians. Of the 35 and 71 identified patients with an available combined endpoint, 100% (95% CI 90.0-1.00) and 85.9% (75.4-92.0) (P = 0.02) attained that endpoint. The risk of death (HR 1.88, 95% CI 1.20-2.92) or receiving a written TLD (HR 2.32, CI 1.11-4.85) in patients with PECs by at least two clinicians was higher in ICUs with a good climate than in those with a poor one. The differences between ICUs with an average climate, with (n = 12, 18%) or without (n = 20, 29%) nursing involvement at the end of life, and ICUs with a poor climate were less obvious but still in favour of the former. Enhancing the quality of the ethical climate in the ICU may improve both the identification of patients receiving excessive care and the decision-making process at the end of life

Individualized dosing patterns in the treatment of older patients with gastrointestinal stromal tumors: results of a registry-based observational national cohort study including 871 patients

BackgroundWhile the effectiveness of tyrosine kinase inhibitors (TKIs) seems similar in older patients with gastrointestinal stromal tumors (GIST) compared with younger patients, toxicities in older patients treated with TKIs more often lead to discontinuation of treatment.ObjectiveTo better understand the age-related pharmacology and pharmacodynamic differences in patients with GIST treated with TKIs, the primary aim of this study was to evaluate TKI dosing patterns in older patients with GIST, while the secondary aims were to evaluate differences in imatinib trough plasma concentrations between age groups and to compare the overall survival (OS) in patients with and without dose reductions in all treatment lines in a palliative setting.MethodsPatients (18 years of age or older) with histologically proven GIST diagnosed between January 2009 and June 2021 and treated with one or more lines of TKIs were selected from the Dutch GIST Registry (DGR) database. Age groups were divided into younger patients (age ResultsOverall, 871 patients were included in this study, including 577 younger patients and 294 older patients. Older patients more often had an adverse event as the reason for first adjustment of treatment with both imatinib (45.6%; p p = 0.224) compared with younger patients (19.5% and 42.7%, respectively). Adjustment of imatinib and sunitinib after starting on a standard dose because of an adverse event most often resulted in dose reduction in both age groups. Median trough plasma concentrations of all samples taken within the first year after initiation of imatinib were higher in older patients (1228 ng/mL, interquartile range [IQR] 959–1687) compared with younger patients (1035 ng/mL [IQR 773–1377]; p p = 0.270; sunitinib: p = 0.547; and regorafenib: p = 0.784).ConclusionOlder patients showed higher imatinib trough plasma concentrations compared with younger patients and also had earlier and more often adverse events as the reason for first adjustment of treatment with imatinib followed by dose reduction. However, in a landmark analysis, patients with imatinib dose reductions had no poorer outcomes compared with patients not requiring a dose reduction.Experimentele farmacotherapi