Chemotherapy and Tyrosine Kinase Inhibitors in the last month of life in patients with metastatic lung cancer: A patient file study in the Netherlands.

OBJECTIVE: Chemotherapy in the last month of life for patients with metastatic lung cancer is often considered as aggressive end-of-life care. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) is a relatively new treatment of which not much is known yet about use in the last month of life. We examined what percentage of patients received chemotherapy or TKIs in the last month of life in the Netherlands. METHODS: Patient files were drawn from 10 hospitals across the Netherlands. Patients had to meet the following eligibility criteria: metastatic lung cancer; died between June 1, 2013 and July 31, 2015. RESULTS: From the included 1,322 patients, 39% received no treatment for metastatic lung cancer, 52% received chemotherapy and 9% received TKIs. A total of 232 patients (18%) received treatment in the last month of life (11% chemotherapy, 7% TKIs). From the patients who received chemotherapy, 145 (21%) received this in the last month of life and 79 (11%) started this treatment in the last month of life. TKIs were given and started more often in the last month of life: from the patients who received TKIs, 87 (72%) received this treatment in the last month of life and 15 (12%) started this treatment in the last month of life. CONCLUSION: A substantial percentage of patient received and even started chemotherapy or TKIs in the last month of life. For chemotherapy, this might be seen as aggressive care. TKIs are said to have less side effects, do not lead to many hospital visits and due to the rapid response, are considered good palliation. However, it is not known, yet possible that, when patients still receiving treatment until shortly before death, this might influence preparing for death in a negative way.

Relatives of deceased patients with metastatic lung cancer's views on the achievement of treatment goals and the choice to start treatment: a structured telephone interview study.

BACKGROUND: Lung cancer has a high impact on both patients and relatives due to the high disease burden and short life expectancy. Previous studies looked into treatment goals patients have before starting a systemic treatment. However, studies on relatives' perceptions of treatment at the end of life are scarce. Therefore, we studied the perspectives of relatives in hindsight on the achievement of treatment goals and the choice to start treatment for metastatic lung cancer of their loved one. METHODS: We conducted a structured telephone interview study in six hospitals across the Netherlands, one academic and five non-academic hospitals, between February 2017 and November 2019. We included 118 relatives of deceased patients diagnosed with metastatic lung cancer who started a systemic treatment as part of usual care (chemotherapy, immunotherapy or targeted therapy with tyrosine kinase inhibitors (TKIs) and who completed a questionnaire on their treatment goals before the start of treatment and when treatment was finished. We asked the relatives about the achievement of patients' treatment goals and relatives' satisfaction with the choice to start treatment. This study is part of a larger study in which 266 patients with metastatic lung cancer participated who started a systemic treatment and reported their treatment goals before start of the treatment and the achievement of these goals after the treatment. RESULTS: Relatives reported the goals 'quality of life', 'decrease tumour size' and 'life prolongation' as achieved in 21, 37 and 41% respectively. The majority of the relatives (78%) were satisfied with the choice to start a treatment and even when none of the goals were achieved, 70% of the relatives were satisfied. About 50% of relatives who were satisfied with the patients' choice mentioned negative aspects of the treatment choice, such as the treatment did not work, there were side effects or it would not have been the relatives' choice. Whereas, 80% of relatives who were not satisfied mentioned negative aspects of the treatment choice. The most mentioned positive aspects were that they tried everything and that it was the patient's choice. CONCLUSION: The majority of relatives reported patients' treatment goals as not achieved. However, relatives were predominantly satisfied about the treatment choice. Satisfaction does not provide a full picture of the experience with the treatment decision considering that the majority of relatives mentioned (also) negative aspects of this decision. At the time of making the treatment decision it is important to manage expectations about the chance of success and the possible side effects of the treatment.

Patients with Metastatic Lung Cancer and Oncologists' Views on Achievement of Treatment Goals and Making the Right Treatment Decision: A Prospective Multicenter Study.

BACKGROUND: Previous studies have investigated patients' treatment goals before starting a treatment for metastatic lung cancer. Data on the evaluation of treatment goals are lacking. AIM: To determine if patients with metastatic lung cancer and their oncologists perceive the treatment goals they defined at the start of systemic treatment as achieved after treatment and if in hindsight they believe it was the right decision to start systemic therapy. DESIGN AND PARTICIPANTS: A prospective multicenter study in 6 hospitals across the Netherlands between 2016 and 2018. Following systemic treatment, 146 patients with metastatic lung cancer and 23 oncologists completed a questionnaire on the achievement of their treatment goals and whether they made the right treatment decision. Additional interviews with 15 patients and 5 oncologists were conducted. RESULTS: According to patients and oncologists, treatment goals were achieved in 30% and 37% for 'quality of life,' 49% and 41% for 'life prolongation,' 26% and 44% for 'decrease in tumor size,' and 44% for 'cure', respectively. Most patients and oncologists, in hindsight, felt they had made the right decision to start treatment even if they had not achieved their goals (72% and 93%). This was related to the feeling that they had to do 'something.' CONCLUSIONS: Before deciding on treatment, the treatment options, including their benefits and side effects, and the goals patients have should be discussed. It is key that these discussions include not only systemic treatment but also palliative care as effective options for doing 'something.'

What Goals Do Patients and Oncologists Have When Starting Medical Treatment for Metastatic Lung Cancer?

BACKGROUND: Metastatic lung cancer is an incurable disease that can be treated with systemic therapy. These treatments might prolong survival and reduce symptoms, but they may also cause serious adverse effects. We studied the treatment goals of patients with metastasized lung cancer and their oncologists before starting systemic therapy, concordance between patients' and oncologists' goals, and feasibility of these goals. PATIENTS AND METHODS: This research was conducted between November 2016 and April 2018 in 1 academic and 5 nonacademic hospitals across the Netherlands. A total of 266 patients with metastatic lung cancer and their prescribing oncologists (n = 23) filled out a questionnaire about their treatment goals and the estimated feasibility of these goals before treatment was started. Additional interviews were conducted with patients and oncologists. RESULTS: Patients and oncologists reported quality of life (respectively, 45% and 72%), life prolongation (45% and 55%), decrease in tumor size (39% and 66%), and cure (19% and 2%) as treatment goals. The interviews showed that the latter appeared to be often as motivation to stay alive. Concordances between patients' and oncologists' treatment goals were low (ranging from 24% to 33%). Patients had slightly higher feasibility scores than oncologists (6.8 vs. 5.8 on a 10-point scale). Educational level, age, religious views, and performance status of patients were associated with treatment goals. CONCLUSION: Patients and oncologists set various goals for the treatment they receive/prescribe. Low concordance might exist because different goals are set or because the patient misunderstands something. Clear communication about treatment goals should be integrated into clinical care.

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.

Is In-Hospital Mortality Higher in Patients With Metastatic Lung Cancer Who Received Treatment in the Last Month of Life? A Retrospective Cohort Study.

CONTEXT: Metastatic lung cancer is an incurable disease that results in a high burden of symptoms, a poor quality of life, and an expected prognosis of less than one year after diagnosis. Treatment shortly before death may result in potential burdensome and inappropriate hospital admissions and hospital deaths. Dying at home is, at a population level, considered a quality for good end-of-life care. OBJECTIVES: We examined what percentage of patients with metastatic lung cancer died inside the hospital and if hospital death, or other characteristics of the patient, oncologist or health care, were associated with treatment in the last month of life. METHODS: This retrospective cohort study evaluated the medical records of 1322 patients with metastatic lung cancer who received care at one of 10 hospitals across The Netherlands and died between 1/6/2013 and 31/7/2015. Demographic and clinical characteristics were obtained from the medical records. RESULTS: In total, 18% of the patients died during a hospital admission. This percentage was higher for patients who received chemotherapy (42%) or targeted therapy with tyrosine kinase inhibitors (25%) in the last month of life. Patients younger than 60 years of age, patients who received chemotherapy in the last month of life, and patients in whom tyrosine kinase inhibitors were started in the last month of life were more likely to die inside the hospital. CONCLUSION: In The Netherlands, fewer than one in five patients with metastatic lung cancer died in the hospital and in-hospital death was associated with the relatively late use of chemotherapy or targeted therapy. Careful selection of patients for disease-modifying therapy might enhance the opportunity for patients to die at their preferred place.

Dissociation between behavior and motor cortical excitability before and during ballistic wrist flexion and extension in young and old adults.

PURPOSE: Aging is associated with slow reactive movement generation and poor termination. OBJECTIVE: We examined the hypothesis that the build-up of excitability in the primary motor cortex in the agonist muscle to generate ballistic wrist flexion and extension and in the antagonist to stop the movement, is lower and slower in old compared with young adults. METHODS: We measured the size of the motor potentials evoked (MEP) produced by transcranial magnetic stimulation (TMS), background integrated EMG (iEMG), and the MEP:iEMG ratio in healthy young (23 y, n = 14) and old adults' (73 y, n = 14) wrist flexors and extensors as they rapidly flexed or extended the wrist in response to an auditory cue. TMS was delivered at 80% of resting motor threshold randomly in 20 ms increments between 130 and 430 ms after the tone. RESULTS: Even though old compared to young adults executed the two wrist movements with ~23% longer movement duration and ~15% longer reaction time (both p < 0.05), the rise in MEP:iEMG ratio before the main similar in the two age groups. CONCLUSION: These data suggest that an adjustment of current models might be needed to better understand how and if age affects the build-up excitability accompanying movement generation and termination.