The need for ambulatory emergency oncology: exemplified by the management of immune checkpoint inhibitor toxicity.

Cancer patients seeking emergency care can be vulnerable in increasingly overcrowded Emergency Departments and timely delivery of care is often aspirational rather than reality in many acute care systems. Ambulatory emergency care and its various international models are recognized as contributing to the safety and sustainability of emergency care services. This schema can logically be extended to the emergency oncology setting. The recent proliferation of immune checkpoint inhibitors (ICIs) has led to another opportunity for the management of oncologic complications in the ambulatory emergency care setting. More nuanced risk stratification of currently perceived high-risk toxicities may also afford the opportunity to personalize acute management. Virtual wards, which predominantly provide virtual monitoring only, and hospital at home services, which provide more comprehensive in-person assessment and interventions, may be well suited to supporting care for ICI toxicity alongside hospital-based assessment. Emergency management guidelines for immune-mediated toxicities will increasingly need to be both pragmatic and deliverable, especially as larger numbers of patients will present outside cancer centers. Identifying and modelling those suitable for emergency ambulatory care is integral to achieving this.

Improved outcomes with early immunosuppression in patients with immune-checkpoint inhibitor induced myasthenia gravis, myocarditis and myositis: a case series.

PURPOSE: Myasthenia gravis (MG) is a rare but life-threatening complication of immune-checkpoint inhibitor (ICI) therapy and often co-presents with myositis and myocarditis. Previous case series of ICI-related MG have reported high mortality rates. We present a series of ten patients from a tertiary oncology centre outlining outcomes of an early multi-modal immunosuppression strategy. METHODS: We reviewed The Christie Hospital database of immunotherapy-related toxicity from 2017 to 2020. Symptom severity was assessed using the Myasthenia Gravis Foundation of America (MGFA) classification. RESULTS: Ten patients with ICI-related MG were identified. All patients presented following 1 (n = 4) or 2 (n = 6) cycles of ICI. Symptom progression was rapid with a median of 3 days from onset of symptoms to admission. Concomitant myositis and myocarditis were observed in nine patients. AChR or MuSK autoantibodies were positive in six patients. All patients received urgent treatment with intravenous methylprednisolone (IVMP) and eight received intravenous immunoglobulin (IVIG). A single patient died from myasthenia-related symptoms; the remaining 9 patients were successfully discharged. CONCLUSION: In our cohort, we demonstrate good outcomes associated with early intensive immunosuppressive treatment with IVIG and IVMP. An agreed national treatment protocol or clinical discussion forum would be beneficial.

A prospective, real-world, multinational study of febrile neutropenia (FN) occurrence in oncology patients receiving chemotherapy with intermediate risk of FN: a MASCC Neutropenia, Infection, and Myelosuppression Study Group initiative.

PURPOSE: Limited knowledge is available on the incidence of febrile neutropenia (FN) in intermediate-risk patients and the rationale for use of granulocyte colony-stimulating factor (G-CSF) in these patients. We aimed to estimate the rate at which patients associated with intermediate risk (10-20%) of FN would develop ≥ 1 episode of FN with a commonly used chemotherapy regimen in clinical practice. METHODS: This prospective, real-world, observational, multinational, multicenter study (December 2016-October 2019) recruited patients with solid tumors or Hodgkin's/non-Hodgkin's lymphoma. Patients receiving chemotherapy with intermediate risk of FN, but not G-CSF as primary prophylaxis were included and observed for the duration of the chemotherapy (≤ 6 cycles and ≤ 30 days after the last chemotherapy administration). RESULTS: In total, 364 patients (median age, 56 years) with 1601 cycles of chemotherapy were included in the analysis. The incidence of FN was 5% in cycle 1, 3% in cycles 2-3, and 1% in cycles 4-6. The rate of patients with ≥ 1 episode of FN was 9%, and 59% of FN events were reported during cycle 1. The rate of grade 4 neutropenia in cycle 1 was 11%, and 15% of patients experienced ≥ 1 episode of grade 4 neutropenia. CONCLUSIONS: Overall, the incidence of FN was low, with a high incidence in cycle 1 and a decrease in the subsequent cycles. These results provide the real FN risk for common chemotherapy regimens in patients generally excluded from clinical trials. Prophylactic G-CSF in intermediate-risk patients could be considered as per clinician's judgement.

Risk stratification for clinical severity of pulmonary embolism in patients with cancer: a narrative review and MASCC clinical guidance for daily care.

Pulmonary embolism (PE) is a leading cause of morbidity and mortality in patients with cancer. The clinical presentation and outcomes of PE range from an acute life-threatening condition requiring intensive care to a mild symptomatic condition associated with favorable outcomes and potentially candidate for early hospital discharge. The wide clinical spectrum of PE has led to the development of risk stratification models aimed at the triage of patients in emergency care departments and optimizing the utilization of health care resources. Incidental or unsuspected PE (UPE), detected during routine staging computed tomography scans, make up a significant proportion of this cohort among the oncology population. The present narrative review is aimed at examining the currently available PE risk assessment models developed for the general population and for patients with cancer including UPE. We include general recommendations for the daily care of patients with cancer-related PE and hypothesize on the factors that would potentially favor hospitalization with early discharge or ambulatory management in this setting.

Catheter-related thrombosis (CRT) in patients with solid tumors: a narrative review and clinical guidance for daily care.

Central venous access devices (CVADs) including central venous catheters and peripherally inserted central catheters (PICCs) are essential in the treatment of cancer. Catheter-related thrombosis (CRT) is the most frequent non-infectious complication associated with the use of central lines. The development of CRT may cause to delays in oncologic treatment and increase morbidity leading to potentially life-threatening complications. Several local and systemic risk factors are associated with the development of CRT and should be taken into account to prevent CRT by standardizing appropriate catheter placement and maintenance. The use of primary pharmacological thromboprophylaxis in order to avoid CRT is not routinely recommended, although it can be considered in selected cases. Recommendations for the management of established CRT are based on the extrapolation of anticoagulation for lower limb venous thrombosis. The present review summarizes the current evidence and recommendations for the prevention and management of CRT and identifies areas that require further research.

Frailty assessment and acute frailty service provision in the UK: results of a national 'day of care' survey.

BACKGROUND: The incorporation of acute frailty services into the acute care pathway is increasingly common. The prevalence and impact of acute frailty services in the UK are currently unclear. METHODS: The Society for Acute Medicine Benchmarking Audit (SAMBA) is a day of care survey undertaken annually within the UK. SAMBA 2019 (SAMBA19) took place on Thursday 27th June 2019. A questionnaire was used to collect hospital and patient-level data on the structure and organisation of acute care delivery. SAMBA19 sought to establish the frequency of frailty assessment tool use and describe acute frailty services nationally. Hospitals were classified based on the presence of acute frailty services and metrics of performance compared. RESULTS: A total of 3218 patients aged ≥70 admitted to 129 hospitals were recorded in SAMBA19. The use of frailty assessment tools was reported in 80 (62.0%) hospitals. The proportion of patients assessed for the presence of frailty in individual hospitals ranged from 2.2 to 100%. Bedded Acute Frailty Units were reported in 65 (50.3%) hospitals. There was significant variation in admission rates between hospitals. This was not explained by the presence of a frailty screening policy or presence of a dedicated frailty unit. CONCLUSION: Two fifths of participating UK hospitals did not have a routine frailty screening policy: where this existed, rates of assessment for frailty were variable and most at-risk patients were not assessed. Responses to positive results were poorly defined. The provision of acute frailty services is variable throughout the UK. Improvement is needed for the aspirations of national policy to be fully realised.

Response to winter pressures in acute services: analysis from the Winter Society for Acute Medicine Benchmarking Audit.

BACKGROUND: There is increased demand for urgent and acute services during the winter months, placing pressure on acute medicine services caring for emergency medical admissions. Hospital services adopt measures aiming to compensate for the effects of this increased pressure. This study aimed to describe the measures adopted by acute medicine services to address service pressures during winter. METHODS: A survey of acute hospitals was conducted during the Society for Acute Medicine Benchmarking Audit, a national day-of-care audit, on 30th January 2020. Survey questions were derived from national guidance. Acute medicine services at 93 hospitals in the United Kingdom completed the survey, evaluating service measures implemented to mitigate increased demand, as well as markers of increased pressure on services. RESULTS: All acute internal medicine services had undertaken measures to prepare for increased demand, however there was marked variation in the combination of measures adopted. 81.7% of hospitals had expanded the number of medical inpatient beds available. 80.4% had added extra clinical staff. The specialty of the physicians assigned to provide care for extra inpatient beds varied. A quarter of units had reduced beds available for providing Same Day Emergency Care on the day of the survey. Patients had been waiting in corridors within the emergency medicine department in 56.3% of units. CONCLUSION: Winter pressure places considerable demand on acute services, and impacts the delivery of care. Although increased pressure on acute hospital services during winter is widely recognised, there is considerable variation in the approach to planning for these periods of increased demand.

Editorial - The NHS urgent and emergency care crisis: how much worse could it get?

NHS urgent and emergency care is under intolerable strain. This strain is increasingly causing harm to patients. Timely and high-quality patient care is often not being delivered due to overcrowding driven by workforce and capacity constraints. This drives low staff morale perpetuating burn out and high absence levels which currently dominate. Whilst COVID19 has accentuated and arguably expedited the crisis; the spiral of decline in urgent and emergency care has been decade long and unless urgent action is taken, we may not yet have reached its nadir.

Guest Editorial - Curry clubs, uncertain times, and social media.

COVID-19, the eternal hospital winter, heatwaves, global warming, energy costs, inflation, and an unnecessary war. We truly do live in uncertain times. That said, we would wager our grandparents said the same thing. What gets us through is family, friends and out shared communities, including acute medicine. Which brings us to this edition of the journal, where many excellent articles will hopefully distract our reader from all the doom and gloom, and instead light up your grey cells.

Supportive care for new cancer therapies.

PURPOSE OF REVIEW: The past decade has witnessed unprecedented delivery to the clinical arena of a range of novel, innovative, and effective targeted anticancer therapies. These include immunotherapies, most prominently immune checkpoint inhibitors, as well as agents that target growth factors and cancer-related mutations. Many of these new cancer therapies are, however, associated with an array of toxicities, necessitating insight and vigilance on the part of attending physicians to achieve high-quality supportive care alongside toxicity management. In this review, we consider some of the key supportive care issues in toxicity management. RECENT FINDINGS: Although both supportive care and targeted therapies have brought significant benefits to cancer care, the management of novel cancer therapy toxicities is nevertheless often complex. This is due in large part to the fact that target organs differ widely, particularly in the case of checkpoint inhibitors, with minor dermatological disorders being most common, while others, such as pneumonitis, are more severe and potentially life threatening. Accordingly, efficient management of these immune-related adverse events requires collaboration between multiple medical specialists. SUMMARY: Supportive care is a key component in the management of new cancer therapy toxicities and needs to be incorporated into treatment pathways.

Emerging challenges in the evaluation of fever in cancer patients at risk of febrile neutropenia in the era of COVID-19: a MASCC position paper.

Patients with cancer are at higher risk of more severe COVID-19 infection and have more associated complications. The position paper describes the management of cancer patients, especially those receiving anticancer treatment, during the COVID-19 pandemic. Dyspnea is a common emergency presentation in patients with cancer with a wide range of differential diagnoses, including pulmonary embolism, pleural disease, lymphangitis, and infection, of which SARS-CoV-2 is now a pathogen to be considered. Screening interviews to determine whether patients may be infected with COVID-19 are imperative to prevent the spread of infection, especially within healthcare facilities. Cancer patients testing positive with no or minimal symptoms may be monitored from home. Telemedicine is an option to aid in following patients without potential exposure. Management of complications of systemic anticancer treatment, such as febrile neutropenia (FN), is of particular importance during the COVID-19 pandemic where clinicians aim to minimize patients' risk of infection and need for hospital visits. Outpatient management of patients with low-risk FN is a safe and effective strategy. Although the MASCC score has not been validated in patients with suspected or confirmed SARS-CoV-2, it has nevertheless performed well in patients with a range of infective illnesses and, accordingly, it is reasonable to expect efficacy in the clinical setting of COVID-19. Risk stratification of patients presenting with FN is a vital tenet of the evolving sepsis and pandemic strategy, necessitating access to locally formulated services based on MASCC and other national and international guidelines. Innovative oncology services will need to utilize telemedicine, hospital at home, and ambulatory care services approaches not only to limit the number of hospital visits but also to anticipate the complications of the anticancer treatments.

Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor Therapy.

As part of immune surveillance, killer T lymphocytes search for cancer cells and destroy them. Some cancer cells, however, develop escape mechanisms to evade detection and destruction. One of these mechanisms is the expression of cell surface proteins which allow the cancer cell to bind to proteins on T cells called checkpoints to switch off and effectively evade T-cell-mediated destruction. Immune checkpoint inhibitors (ICIs) are antibodies that block the binding of cancer cell proteins to T-cell checkpoints, preventing the T-cell response from being turned off by cancer cells and enabling killer T cells to attack. In other words, ICIs restore innate antitumor immunity, as opposed to traditional chemotherapies that directly kill cancer cells. Given their relatively excellent risk-benefit ratio when compared to other forms of cancer treatment modalities, ICIs are now becoming ubiquitous and have revolutionized the treatment of many types of cancer. Indeed, the prognosis of some patients is so much improved that the threshold for admission for intensive care should be adjusted accordingly. Nevertheless, by modulating immune checkpoint activity, ICIs can disrupt the intricate homeostasis between inhibition and stimulation of immune response, leading to decreased immune self-tolerance and, ultimately, autoimmune complications. These immune-related adverse events (IRAEs) may virtually affect all body systems. Multiple IRAEs are common and may range from mild to life-threatening. Management requires a multidisciplinary approach and consists mainly of immunosuppression, cessation or postponement of ICI treatment, and supportive therapy, which may require surgical intervention and/or intensive care. We herein review the current literature surrounding IRAEs of interest to anesthesiologists and intensivists. With proper care, fatality (0.3%-1.3%) is rare.

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 .

Emergency Presentations of Immune Checkpoint Inhibitor-Related Endocrinopathies.

BACKGROUND: Immune checkpoint inhibitors (ICI) are an important component of anticancer treatment, with indications across an increasing range of oncological diagnoses. ICIs are associated with a range of immune-mediated toxicities. Immune-related endocrinopathies pose a distinct challenge, given the nonspecific symptom profile and potentially life-threatening sequelae if not recognized. OBJECTIVES: To determine the frequency and clinical presentations of immune-mediated endocrinopathies in patients treated with ICIs presenting as emergencies. METHODS: A prospective observational cohort study was undertaken at a specialist oncology hospital in North West England from May 20, 2018 to May 19, 2020. Within the hospital, the Oncology Assessment Unit (OAU) acts as the receiving unit in which assessments are undertaken of all emergency presentations. All patients treated with ICIs presenting to the OAU were included. The primary outcome was diagnosis of an immune-mediated endocrinopathy. Length of inpatient stay, and 7- and 30-day mortality rates were examined. RESULTS: During the study period, 684 patients treated with ICIs presented to the OAU. Twenty-four (3.5%) patients had an acute immune-mediated endocrinopathy, of which 17 had hypophysitis, 4 diabetes mellitus, 2 thyrotoxicosis, and 1 adrenalitis. Median length of stay for patients with hypophysitis was 1 day. No patient with an immune-mediated endocrinopathy died within 30 days of presentation. CONCLUSIONS: Presentations to emergency settings with acute immune-mediated endocrinopathies are rare. Early recognition of immune-mediated toxicities is important, and particularly pertinent in ICI-related endocrinopathies, where even in life-threatening cases, the presentation can be vague and nonspecific.

Emergency management of immune-related toxicity.

PURPOSE OF REVIEW: Emergency presentations in patients treated with immune checkpoint inhibitors (ICIs) are a clinical challenge. Clinicians need to be vigilant in diagnosing and treating immune-mediated toxicities. In this review, we consider the approach to managing an acutely unwell patient being treated with ICIs presenting as an emergency. RECENT FINDINGS: A minority of acutely unwell patients treated with ICIs will have an immune-mediated toxicity. Early recognition and intervention in those with immune-mediated toxicity can reduce the duration and severity of the complications. The use of early immunosuppressive agents along corticosteroid therapy may improve outcomes in patients with life-threatening immune-mediated toxicity. SUMMARY: Individualized management of immune-mediated toxicities is a key challenge for emergency oncology services; this has become part of routine cancer care.

Emergency ambulatory outpatient management of immune-mediated hypophysitis.

PURPOSE: Immune-mediated hypophysitis is an important toxicity related to immune checkpoint inhibitors (ICI). Optimal management is associated with improved outcomes. It represents a wide spectrum of clinical presentations, and a proportion may be suitable for emergency ambulatory management. METHODS: Emergency ambulatory management of patients presenting with clinical features and findings consistent with ICI-induced hypophysitis was considered at a tertiary cancer/endocrinology hospital. Suitable patients were initially investigated and treated in accordance with the UK emergency management guidelines for ICI induced hypophysitis. After an initial observation period of 4 h, patients were discharged with oral hydrocortisone (20, 10, 10 mg). RESULTS: An initial cohort of 4 patients with emergency presentations of ICI-induced hypophysitis has been managed in an ambulatory fashion in the first 3 months. There were no 30-day readmissions. CONCLUSION: Carefully selected emergency presentations with immune-mediated hypophysitis may be suitable for ambulatory management.

Do mHealth applications improve clinical outcomes of patients with cancer? A critical appraisal of the peer-reviewed literature.

PURPOSE: Patients undergoing systemic anti-cancer treatment experience distressing side effects, and these symptoms are often experienced outside the hospital setting. The impact of usage of cancer-related mobile health (mHealth) applications on patient-related outcomes requires investigation. METHODS: A critical appraisal of the literature was performed for the following question: 'In patients with cancer have mHealth applications been compared with usual care to examine impact on commonly used clinical outcomes'. Literature searches were undertaken with the help of a research librarian and included Medline, Cochrane Collaboration, clinical trial databases and grey searches. RESULTS: Seventeen studies including between 12 and 2352 patients were identified and reviewed. Smartphone applications or internet portals collected data on symptoms or patient activity. Several studies showed statistically significant differences in patient-reported outcomes when symptom monitoring using mobile health application was compared to usual care. Change in mobility was the only outcome that was related directly to toxicity. Only limited data on mortality, cancer-related morbidity including complications of care, health-economic outcomes or long-term outcomes were reported. CONCLUSIONS: Studies on mHealth applications might improve aspects of symptom control in patients with cancer, but there is currently little evidence for impact on other outcomes. This requires future research in interventional studies.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors.

Immune-related adverse events (IrAEs) affecting the gastrointestinal (GI) tract and liver are among the most frequent and most severe inflammatory toxicities from contemporary immunotherapy. Inflammation of the colon and or small intestines (entero)colitis is the single most common GI IrAE and is an important cause of delay of discontinuation of immunotherapy. The severity of these GI IrAEs can range from manageable with symptomatic treatment alone to life-threatening complications, including perforation and liver failure. The frequency and severity of GI IrAEs is dependent on the specific immunotherapy given, with cytotoxic T lymphocyte antigen (CTLA)-4 blockade more likely to induce severe GI IrAEs than blockade of either programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1), and combination therapy showing the highest rate of GI IrAEs, particularly in the liver. To date, we have minimal prospective data on the appropriate diagnosis and management of GI IrAEs, and recommendations are based largely on retrospective data and expert opinion. Although clinical diagnoses of GI IrAEs are common, biopsy is the gold standard for diagnosis of both immunotherapy-induced enterocolitis and hepatitis and can play an important role in excluding competing, though less common, diagnoses and ensuring optimal management. GI IrAEs typically respond to high-dose corticosteroids, though a significant fraction of patients requires secondary immune suppression. For colitis, both TNF-α blockade with infliximab and integrin inhibition with vedolizumab have proved highly effective in corticosteroid-refractory cases. Detailed guidelines have been published for the management of low-grade GI IrAEs. In the setting of more severe toxicities, involvement of a GI specialist is generally recommended. The purpose of this review is to survey the available literature and provide management recommendations focused on the GI specialist.

Cancer immunotherapy-related adverse events: causes and challenges.

Despite the success and ongoing promise of monoclonal antibody-targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint-targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-related adverse events: pulmonary toxicity.

The immune checkpoints associated with the CTLA-4 and PD-1 pathways are critical modulators of immune activation. These pathways dampen the immune response by providing brakes on activated T cells, thereby ensuring more uniform and controlled immune reactions and avoiding immune hyper-responsiveness and autoimmunity. Cancer cells often exploit these regulatory controls through a variety of immune subversion mechanisms, which facilitate immune escape and tumor survival. Immune checkpoint inhibitors (ICI) effectively block negative regulatory signals, thereby augmenting immune attack and tumor killing. This process is a double-edged sword in which release of regulatory controls is felt to be responsible for both the therapeutic efficacy of ICI therapy and the driver of immune-related adverse events (IrAEs). These adverse immune reactions are common, typically low-grade and may affect virtually every organ system. In the early clinical trials, lung IrAEs were rarely described. However, with ever-expanding clinical applications and more complex ICI-containing regimens, lung events, in particular, pneumonitis, have become increasingly recognized. ICI-related lung injury is clinically distinct from other types of lung toxicity and may lead to death in advanced stage disease. Thus, knowledge regarding the key characteristics and optimal treatment of lung-IrAEs is critical to good outcomes. This review provides an overview of lung-IrAEs, including risk factors and epidemiology, as well as clinical, radiologic, and histopathologic features of ICI-related lung injury. Management principles for ICI-related lung injury, including current consensus on steroid refractory pneumonitis and the use of other immune modulating agents in this setting are also highlighted.