Can acutely ill patients predict their outcomes? A scoping review.

INTRODUCTION: The full impact of an acute illness on subsequent health is seldom explicitly discussed with patients. Patients' estimates of their likely prognosis have been explored in chronic care settings and can contribute to the improvement of clinical outcomes and patient satisfaction. This scoping review aimed to identify studies of acutely ill patients' estimates of their outcomes and potential benefits for their care. METHODS: A search was conducted in PubMed, Embase, Web of Science and Google Scholar, using terms related to prognostication and acute care. After removal of duplicates, all articles were assessed for relevance by six investigator pairs; disagreements were resolved by a third investigator. Risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Our search identified 3265 articles, of which 10 were included. The methods of assessing self-prognostication were very heterogeneous. Patients seem to be able to predict their need for hospital admission in certain settings, but not their length of stay. The severity of their symptoms and the burden of their disease are often overestimated or underestimated by patients. Patients with severe health conditions and their relatives tend to be overoptimistic about the likely outcome. CONCLUSION: The understanding of acutely ill patients of their likely outcomes and benefits of treatment has not been adequately studied and is a major knowledge gap. Limited published literature suggests patients may be able to predict their need for hospital admission. Illness perception may influence help-seeking behaviour, speed of recovery and subsequent quality of life. Knowledge of patients' self-prognosis may enhance communication between patients and their physicians, which improves patient-centred care.

Patients' Perspectives and Feasibility of Home Monitoring in Acute Care: The AcuteCare@Home Flash Mob Study.

Objective: To determine patients' perspectives on home monitoring at emergency department (ED) presentation and shortly after admission and compare these with their physicians' perspectives. Methods: Forty Dutch hospitals participated in this prospective flash mob study. Adult patients with acute medical conditions, treated by internal medicine specialties, presenting at the ED or admitted at the admission ward within the previous 24 h were included. The primary outcome was the proportion of patients who were able and willing to undergo home monitoring. Secondary outcomes included identifying barriers to home monitoring, patient's prerequisites, and assessing the agreement between the perspectives of patients and treating physicians. Results: On February 2, 2023, in total 665 patients [median age 69 (interquartile range: 55-78) years; 95.5% community dwelling; 29.3% Modified Early Warning Score ≥3; 29.5% clinical frailty score ≥5] were included. In total, 19.6% of ED patients were admitted and 26% of ward patients preferred home monitoring as continuation of care. Guaranteed readmission (87.8%), ability to contact the hospital 24/7 (77.3%), and a family caregiver at home (55.7%) were the most often reported prerequisites. Barriers for home monitoring were feeling too severely ill (78.8%) and inability to receive the required treatment at home (64.4%). The agreement between patients and physicians was fair (Cohens kappa coefficient 0.26). Conclusions: A substantial proportion of acutely ill patients stated that they were willing and able to be monitored at home. Guaranteed readmission, availability of a treatment team (24/7), and a home support system are needed for successful implementation of home monitoring in acute care.

Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma.

BACKGROUND: International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. METHODS: We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. PRIMARY ENDPOINT: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. RESULTS: In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT20-49Gy, tTTP was significantly longer for cRT50-60Gy (multivariate adjusted HR 0.10; 95% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. CONCLUSIONS: This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.

Performance of the APOP-screener for predicting in-hospital mortality in older COVID-19 patients: a retrospective study.

BACKGROUND: A variety of prediction models concerning COVID-19 have been proposed since onset of the pandemic, but to this date no gold standard exists. Mortality rates show a sharp increase with advancing age but with the large heterogeneity of this population in terms of comorbidities, vulnerability and disabilities, identifying risk factors is difficult. Therefore, we aimed to research the multidimensional concept of frailty, measured by the Acute Presenting Older Patient (APOP)-screener, as a risk factor for in-hospital mortality in older COVID-19 patients. METHODS: All consecutive patients of 70 years or older, with a PCR confirmed COVID-19 infection and a completed APOP-score, presenting at the Emergency Department (ED) of the Jeroen Bosch Hospital, the Netherlands, between February 27th 2020 and February 1st 2021 were retrospectively included. We gathered baseline characteristics and scored the CCI and CFS from patient records. The primary outcome was in-hospital mortality. RESULTS: A total of 292 patients met the inclusion criteria. Approximately half of the patients were considered frail by the APOP or CFS. 127 patients (43.5%) scored frail on the CFS, 158 (54.1%) scored high risk on the APOP-screener. 79 patients (27.1%) died during their hospital admission. The APOP-screener showed a significantly elevated risk of in-hospital mortality when patients scored both high risk of functional and evidence of cognitive impairment (OR 2.24, 95% 1.18-4.25). Significant elevation of in-hospital mortality was found for the high CCI-scores (≥ 5)(OR 1.78, 95% 1.02-3.11), but not for the highest CFS category (5-9, frail) (OR 1.35, 95% 0.75-2.47). The discriminatory performance of the APOP, CFS and CCI were comparable (AUC resp. 0.59 (0.52-0.66), 0.54 (0.46-0.62) and 0.58 (0.51-0.65)). CONCLUSION: Although the elevated risk for in-hospital mortality found for the most frail patients as scored by the APOP, this instrument has poor discriminatory value. Additionally, the CFS did not show significance in predicting in-hospital mortality and had a poor discriminatory value as well. Therefore, treatment decisions based on frailty or comorbidities alone should be made with caution. Approaching the heterogeneity of the older population by adding frailty as assessed by the APOP-score to existing prediction models may enhance the predictive value of these models.

Understanding what matters most to patients in acute care in seven countries, using the flash mob study design.

BACKGROUND: Truly patient-centred care needs to be aligned with what patients consider important, and is highly desirable in the first 24 h of an acute admission, as many decisions are made during this period. However, there is limited knowledge on what matters most to patients in this phase of their hospital stay. The objective of this study was to identify what mattered most to patients in acute care and to assess the patient perspective as to whether their treating doctors were aware of this. METHODS: This was a large-scale, qualitative, flash mob study, conducted simultaneously in sixty-six hospitals in seven countries, starting November 14th 2018, ending 50 h later. One thousand eight hundred fifty adults in the first 24 h of an acute medical admission were interviewed on what mattered most to them, why this mattered and whether they felt the treating doctor was aware of this. RESULTS: The most reported answers to "what matters most (and why)?" were 'getting better or being in good health' (why: to be with family/friends or pick-up life again), 'getting home' (why: more comfortable at home or to take care of someone) and 'having a diagnosis' (why: to feel less anxious or insecure). Of all patients, 51.9% felt the treating doctor did not know what mattered most to them. CONCLUSIONS: The priorities for acutely admitted patients were ostensibly disease- and care-oriented and thus in line with the hospitals' own priorities. However, answers to why these were important were diverse, more personal, and often related to psychological well-being and relations. A large group of patients felt their treating doctor did not know what mattered most to them. Explicitly asking patients what is important and why, could help healthcare professionals to get to know the person behind the patient, which is essential in delivering patient-centred care. TRIAL REGISTRATION: NTR (Netherlands Trial Register) NTR7538 .

When patients' invisible work becomes visible: non-adherence and the routine task of pill-taking.

While the biographical dimensions of chronic illness have been well researched, the concrete dimensions of patients' work have not been as thoroughly investigated as yet. With the growing concern for self-management, such research would be timely. This study aims to better understand patients' invisible work by highlighting the causes of unintentional non-adherence as well as strategies for adherence. For this purpose, it defines medical treatment adherence as the repetition of the pattern of tasks through which a patient succeeds, in a technical sense, in taking the right medication at the right time, in the right amount, for the right duration. Applying a failure modes and effects analysis approach to 48 semi-structured interviews with Dutch patients, it shows the negative impact of schedule changes, pressure, positioning changes, lack of backup pills and lack of verification tools. Symmetrically, it highlights the role of anchoring, sequencing, positioning, cueing, correcting and verifying. This result points to the need for an analytical approach of patients' work and treatment adherence that would build on the role of routines in organisations and in the workplace.

Strengths and weaknesses of the acute care systems in the United Kingdom and the Netherlands: what can we learn from each other?

BACKGROUND: The demand on Emergency Departments and acute medical services is increasing internationally, creating pressure on health systems and negatively influencing the quality of delivered care. Visible consequences of the increased demand on acute services is crowding and queuing. This manifests as delays in the Emergency Departments, adverse clinical outcomes and poor patient experience. OVERVIEW: Despite the similarities in the UK's and Dutch health care systems, such as universal health coverage, there are differences in the number of patients presenting at the Emergency Departments and the burden of crowding between these countries. Given the similarities in funding, this paper explores the similarities and differences in the organisational structure of acute care in the UK and the Netherlands. In the Netherlands, less patients are seen at the ED than in England and the admission rate is higher. GPs and so-called GP-posts serve 24/7 as gatekeepers in acute care, but EDs are heterogeneously organised. In the UK, the acute care system has a number of different access points and the accessibility of GPs seems to be suboptimal. Acute ambulatory care may relieve the pressure from EDs and Acute Medical Units. In both countries the ageing population leads to a changing case mix at the ED with an increased amount of multimorbid patients with polypharmacy, requiring generalistic and multidisciplinary care. CONCLUSION: The acute and emergency care in the Netherlands and the UK face similar challenges. We believe that each system has strengths that the other can learn from. The Netherlands may benefit from an acute ambulatory care system and the UK by optimizing the accessibility of GPs 24/7 and improving signposting for urgent care services. In both countries the changing case mix at the ED needs doctors who are superspecialists instead of subspecialists. Finally, to improve the organisation of health care, doctors need to be visible medical leaders and participate in the organisation of care.

Performance of the Manchester triage system in older emergency department patients: a retrospective cohort study.

BACKGROUND: Studies on the reliability of the MTS and its predictive power for hospitalisation and mortality in the older population have demonstrated mixed results. The objective is to evaluate the performance of the Manchester Triage System (MTS) in older patients (≥65 years) by assessing the predictive ability of the MTS for emergency department resource utilisation, emergency department length of stay (ED-LOS), hospitalisation, and in-hospital mortality rate. The secondary goal was to evaluate the performance of the MTS in older surgical versus medical patients. METHODS: A retrospective cohort study was conducted of all emergency department visits by patients ≥65 years between 01 and 09-2011 and 31-08-2012. Performance of the MTS was assessed by comparing the association of the MTS with emergency department resource utilisation, ED-LOS, hospital admission, and in-hospital mortality in older patients and the reference group (18-64 years), and by estimating the area under the receiver operating characteristics curves. RESULTS: Data on 7108 emergency department visits by older patients and 13,767 emergency department visits by patients aged 18-64 years were included. In both patient groups, a higher emergency department resource utilisation was associated with a higher MTS urgency. The AUC for the MTS and hospitalisation was 0.74 (95%CI 0.73-0.75) in older patients and 0.76 (95%CI 0.76-0.77) in patients aged 18-64 years. Comparison of the predictive ability of the MTS for in-hospital mortality in older patients with patients aged 18-64 years revealed an AUC of 0.71 (95%CI 0.68-0.74) versus 0.79 (95%CI 0.72-0.85). The majority of older patients (54.8%) were evaluated by a medical specialty and 45.2% by a surgical specialty. The predictive ability of the MTS for hospitalisation and in-hospital mortality was higher in older surgical patients than in medical patients (AUC 0.74, 95%CI 0.72-0.76 and 0.74, 95%CI 0.68-0.81 versus 0.69, 95%CI 0.67-0.71 and 0.66, 95%CI 0.62-0.69). CONCLUSION: The performance of the MTS appeared inferior in older patients than younger patients, illustrated by a worse predictive ability of the MTS for in-hospital mortality in older patients. The MTS demonstrated a better performance in older surgical patients than older medical patients regarding hospitalisation and in-hospital mortality.

Outcome of elderly emergency department patients hospitalised on weekends - a retrospective cohort study.

BACKGROUND: Studies investigating different medical conditions and settings have demonstrated mixed results regarding the weekend effect. However, data on the outcome of elderly patients hospitalised on weekends is scarce. The objective was to compare in-hospital and two-day mortality rates between elderly emergency department (ED) patients (≥65 years) admitted on weekends versus weekdays. METHODS: A retrospective cohort study of emergency department visits of internal medicine patients ≥65 years presenting to the emergency department between 01 and 09-2010 and 31-08-2012 was conducted. The weekend was defined as the period from midnight on Friday to midnight on Sunday. RESULTS: Data on 3697 emergency department visits by elderly internal medicine patients (mean age 78.6 years old) were included. In total, 2743 emergency department visits (74.2%) resulted in hospitalisation, of which 22.9% occurred on weekends. Comorbidity and urgency levels were higher in patients admitted on weekends. In-hospital mortality was 11.4% for patients admitted on weekends compared with 8.9% on weekdays (OR 1.3, 95%CI 0.99-1.8). Two-day mortality was 3.2% in patients hospitalised on weekends versus 1.9% on weekdays (OR 1.7, 95%CI 0.99-2.9). Multivariable adjustment for age, comorbidity and triage level demonstrated comparable in-hospital and two-day mortality for weekend and week admission (ORadj 1.2, 95%CI 0.9-1.7 and ORadj 1.5, 95%CI 0.8-2.6, resp.). CONCLUSION: A small weekend effect was observed in elderly internal medicine patients, which was not statistically significant. This effect was partly explained by a higher comorbidity and urgency level in elderly patients hospitalised on weekends than during weekdays. Emergency care for the elderly is not compromised by adjusted logistics during the weekend.

Dietary nitrate does not reduce oxygen cost of exercise or improve muscle mitochondrial function in patients with mitochondrial myopathy.

Muscle weakness and exercise intolerance negatively affect the quality of life of patients with mitochondrial myopathy. Short-term dietary nitrate supplementation has been shown to improve exercise performance and reduce oxygen cost of exercise in healthy humans and trained athletes. We investigated whether 1 wk of dietary inorganic nitrate supplementation decreases the oxygen cost of exercise and improves mitochondrial function in patients with mitochondrial myopathy. Ten patients with mitochondrial myopathy (40 ± 5 yr, maximal whole body oxygen uptake = 21.2 ± 3.2 ml·min-1·kg body wt-1, maximal work load = 122 ± 26 W) received 8.5 mg·kg body wt-1·day-1 inorganic nitrate (~7 mmol) for 8 days. Whole body oxygen consumption at 50% of the maximal work load, in vivo skeletal muscle oxidative capacity (evaluated from postexercise phosphocreatine recovery using 31P-magnetic resonance spectroscopy), and ex vivo mitochondrial oxidative capacity in permeabilized skinned muscle fibers (measured with high-resolution respirometry) were determined before and after nitrate supplementation. Despite a sixfold increase in plasma nitrate levels, nitrate supplementation did not affect whole body oxygen cost during submaximal exercise. Additionally, no beneficial effects of nitrate were found on in vivo or ex vivo muscle mitochondrial oxidative capacity. This is the first time that the therapeutic potential of dietary nitrate for patients with mitochondrial myopathy was evaluated. We conclude that 1 wk of dietary nitrate supplementation does not reduce oxygen cost of exercise or improve mitochondrial function in the group of patients tested.

Peritoneal Metastases from Gastroenteropancreatic Neuroendocrine Tumors: Incidence, Risk Factors and Prognosis.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms and data on peritoneal metastases (PM) from these tumors are scarce. OBJECTIVE: The aim of this study was to present population-based data on the incidence, risk factors, and survival of synchronous PM in GEP-NETs. METHODS: Data from all patients diagnosed with a GEP-NET during 2007-2013 were collected from the Netherlands Cancer Registry. Age-standardized incidence rates were calculated and risk factors for developing PM were determined using multivariable logistic regression analysis. Survival was investigated using Kaplan-Meier and Cox regression analyses. RESULTS: A total of 4114 patients were diagnosed with a GEP-NET. PM were diagnosed in 234 patients (19% of patients with metastasized disease, representing 6% of all GEP-NETs). The incidence of patients diagnosed with PM was 1.6:1,000,000 persons per year. Risk factors for developing PM were higher age (odds ratio [OR] 1.4, 95% CI 1.0-2.0) and primary tumor location in the small intestine (OR 3.5, 95% CI 2.1-5.7) or colon (OR 2.5, 95% CI 1.4-4.4). Small intestinal NETs with PM had the best survival, while appendiceal NETs with PM had the poorest survival (5-year survival rates of 67 and 7%, respectively). Multivariate analysis showed that survival in patients with PM was worse compared with patients without metastases; however, the presence of PM among all metastasized patients was not associated with worse survival. CONCLUSIONS: This nationwide population-based study provides relevant insight into the incidence and risk factors of PM in GEP-NETs, and reveals detailed site-specific data on the presence of PM and survival data that may contribute to develop individualized treatment strategies in patients with these heterogeneous neoplasms.

Identifying User Preferences for a Digital Educational Solution for Young Seniors With Diabetes.

The Eindhoven Diabetes Education Simulator project was initiated to develop an educational solution that helps diabetes patients understand and learn more about their diabetes. This article describes the identification of user preferences for the development of such solutions. Young seniors (aged 50-65 years) with type 2 diabetes were chosen as the target group because they are likely to have more affinity with digital devices than older people and because 88% of the Dutch diabetes population is >50 years of age. Data about the target group were gathered through literature research and interviews. The literature research covered data about their device use and education preferences. To gain insight into the daily life of diabetes patients and current diabetes education processes, 20 diabetes patients and 10 medical experts were interviewed. The interviews were analyzed using affinity diagrams. Those diagrams, together with the literature data, formed the basis for two personas and corresponding customer journey maps. Literature showed that diabetes prevalence is inversely correlated to educational level. Computer and device use is relatively low within the target group, but is growing. The interviews showed that young seniors like to play board, card, and computer games, with others or alone. Family and loved ones play an important role in their lives. Medical experts are crucial in the diabetes education of young senior diabetes patients. These findings are translated into a list of design aspects that can be used for creating educational solutions.

Intentional Nonadherence as a Means to Exert Control.

Medication adherence is a major issue for patients with a chronic illness, who sometimes rationally choose temporary nonadherence. This study aims at better understanding intentional nonadherence and especially why it seems to fluctuate over time. It is based on 48 semi-structured interviews conducted in a hospital in the Netherlands with patients who had been prescribed a medication for a chronic disease for at least 1 year, and who had either type 2 diabetes, hypertension, Parkinson's disease, inflammatory bowel disease, or chronic myeloid leukemia. The analysis uses a simplified version of the failure modes and effects analysis (FMEA) method. Intentional nonadherence appeared to be the result of the respondents' desire (a) to exert control over the treatment and its effects on their body, and (b) to control the hold of the treatment on their daily life. This result provides a rationale for the fluctuation of intentional nonadherence behavior.

Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study.

BACKGROUND: Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. METHODS: In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989. FINDINGS: Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0·94 [95% CI 0·61-1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. INTERPRETATION: Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. FUNDING: Astellas.

Impact of cancer on adherence to glucose-lowering drug treatment in individuals with diabetes.

AIMS/HYPOTHESIS: Adherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabolic control and improving prognosis. Because a diagnosis of cancer might have an impact on adherence to medication, this study explored changes in adherence to GLDs following a cancer diagnosis. METHODS: All new users of GLDs between 1998 and 2011 who lived in the Eindhoven Cancer Registry-PHARMO Database Network catchment area were selected. Those with a primary cancer diagnosis during follow-up were considered cases and matched with eligible controls without cancer during follow-up. Medication possession ratio (MPR) was used as indicator for medication adherence. Segmented linear auto-regression analysis with interrupted time series was used to assess changes in MPR for cases compared with controls (i.e. overall trend) due to (any) cancer diagnosis and specific cancer types. RESULTS: From the 52,228 GLD users selected, 3,281 cases with cancer and 12,891 controls without cancer during follow-up were included in the study. In our analyses, before cancer diagnosis the MPR increased by 0.10% per month (95% CI 0.10, 0.10). Besides a significant drop in MPR at the time of cancer diagnosis of -6.3% (95% CI -6.5, -6.0), there was an ongoing, yet lower, monthly decline in MPR (-0.20%; 95% CI -0.21, -0.20) after cancer diagnosis. The largest drops in MPR at the time of cancer diagnosis, in the range of 11-15%, were seen among patients with stage IV disease and gastrointestinal or pulmonary cancers. CONCLUSIONS/INTERPRETATION: Our findings indicate a clear decline in adherence to GLD treatment regimens following a cancer diagnosis. The reason for the decline in MPR needs to be further elucidated.

Combination chemotherapy in advanced adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS: We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS: For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS: Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).

Development of a pharmacokinetic model of mitotane: toward personalized dosing in adrenocortical carcinoma.

BACKGROUND: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy. METHODS: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients. RESULTS: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 ± 0.37 L/h and a volume of distribution in the steady state at 161 ± 68 L/kg of lean body mass. The mean prediction error was 14% ± 13%. CONCLUSIONS: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.

Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study.

INTRODUCTION: Historically, stage IV adrenocortical carcinoma (mACC) has a poor prognosis with a median overall survival (OS) of only 5 months. Based on the FIRM-ACT trial published in 2012, guidelines now advise first line systemic treatment with etoposide, cisplatin, doxorubicin and mitotane (EDP-M). The effect of EDP-M on patient survival in clinical practice in the Netherlands is unknown. METHODS: The data of all patients with mACC (2005-2020) were obtained from the Netherlands comprehensive cancer organization (IKNL). The effect of EDP-M on patient survival was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis including clinical, therapy and tumor characteristics. RESULTS: In total 167 patients with mACC were included. For patients diagnosed from 2014 onwards, EDP-M (in 22 patients (22%)) lead to a numerically but not statistically significant improved OS compared to those not receiving EDP-M (11.8 vs 5.6 months, p = 0.525). For systemic treatments, patients treated with mitotane only had the best 5-year OS (11.4%, p = 0.006) regardless of year of diagnosis. In multivariate Cox regression analysis EPD-M was not associated with OS; palliative adrenalectomy (HR: 0.26, p = <.001) and local treatment of metastases (HR: 0.35, p = 0.001) were associated with a better OS and a primary tumor Ki-67 index > 20% (HR: 2.67, p = 0.003) with a worse OS from 2014 onwards. Patients diagnosed before 2014 had a significantly poorer OS compared to from 2014 onwards (5-yr: 4.5 vs 8.4%, OS: 6.8 vs 8.3 months, p = 0.032). CONCLUSION: OS for mACC in the Netherlands has improved in the last decade. Receiving EDP-M did not significantly improve OS for patients with mACC. The use of multimodality treatment including palliative adrenalectomy, mitotane and local treatment of (oligo-)metastases in appropriately selected patients has improved the OS for mACC patients since 2014.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.