Adam, Safwaan

Cooksley, Tim

Gupta, Avinash

Higham, Claire

Ho, Jan Hoong

Knight, Tom

Lindsay, Duncan

Lorigan, Paul

Ambulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. Immune checkpoint inhibitor(ICI)-mediated hypophysitis is an important life-threatening complication of therapy. Patients presenting with clinical features and findings consistent with ICI-mediated hypophysitis were considered in the current study. In the absence of severe features (sodium &lt;125 mmol/L, hypotension, reduced consciousness, hypoglycaemia and/or visual field defect), patients were administered a single intravenous dose of hydrocortisone (100 mg), observed for at least 4 h and then discharged on oral hydrocortisone (20 mg, 10 mg and 10 mg). Patients were then seen urgently in the endocrinology outpatient setting for further management. Fourteen patients (median age 64, 10 male) were managed using the pathway. All patients had biochemically confirmed adrenocorticotropic hormone (ACTH) deficiency. Seven of the 14 were treated with combination ICI therapy, with four having pan-anterior hypopituitarism. There were no 30-day readmissions or any associated hypophysitis-related mortality. All patients continued ICI therapy without interruption.</p

The University of Manchester - Institutional Repository

AbstractAmbulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. Immune checkpoint inhibitor(ICI)-mediated hypophysitis is an important life-threatening complication of therapy.Patients presenting with clinical features and findings consistent with ICI-mediated hypophysitis were considered. In the absence of severe features (sodium <125mmol/L, hypotension, reduced consciousness, hypoglycaemia, visual field defect) patients were administered a single intravenous dose of hydrocortisone (100mg), observed for at least 4 hours and then discharged on oral hydrocortisone (20mg, 10mg and 10mg). Patients were then seen urgently in the endocrinology outpatient setting for further management.Fourteen patients (median age 64, 10 male) were managed using the pathway. All patients had biochemically confirmed ACTH deficiency. Seven of the fourteen were treated with combination ICI therapy with four having pan-anterior hypopituitarism. There were no 30-day readmissions nor any associated hypophysitis related mortality. All patients continued ICI therapy without interruption.KeywordsImmunotherapy; immune checkpoint inhibitors; hypophysitis; ambulatory careIntroductionAmbulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. [1] Its implementation is founded on the evidence that patients presenting with acute illnesses can be stratified as low risk for developing complications and therefore do not require traditional inpatient care. [2] There are a range of emergency oncology presentations that can be managed in this setting reducing pressures on inpatient services and the increasingly recognised risks of Emergency Department (ED) overcrowding that is a growing international problem. [3,4]Immune-mediated toxicities from immune checkpoint inhibitors (ICIs) stem from increased activity within the T cell lineage. They can affect any organ system with a range of severity from mild to life threatening. [5,6] Hypophysitis and, rarely adrenalitis, are potentially life-threatening complications of treatment.[7,8] ICI-mediated hypophysitis has two distinct patterns of presentation: isolated ACTH deficiency in those treated with anti-PD-1 agents and a lymphocytic hypophysitis-like condition with pituitary enlargement and multiple hormone deficiencies in those treated with anti-CTLA-4 agents/combination CTLA-4/PD-1 therapy.[9]ICI-mediated hypophysitis classically presents with features of cortisol deficiency, but often the clinical picture is more nuanced and is occasionally detected with incidental hypocortisolaemia in a clinic setting. [10] Emergency presentations with ICI-mediated hypophysitis are usually admitted for inpatient care and management. We recently reported a pilot study of managing acute presentations with ICI-mediated hypophysitis in an emergency ambulatory setting. [11] In this paper, we describe further results and experience from this pathway and consider the implications for wider ambulatory emergency management of ICI-mediated toxicities.MethodsOur ambulatory pathway for ICI-mediated hypophysitis was described in our pilot paper. [11] In short, patients acutely presenting with clinical features, such as marked fatigue and headache, with findings consistent with ICI-mediated hypophysitis at The Christie; a tertiary cancer/endocrinology hospital in the North West of England were considered. The hospital has an acute assessment unit (AAU) and a co-located acute ambulatory care unit (AACU) which receive emergency patients via a number of access points including directly from the hospital patient hotline, primary care, paramedic referrals, outpatient clinics and tertiary referrals from other hospitals. Commencing in September 2019, suitable patients were initially investigated and treated in accordance with the UK emergency management guidelines for ICI-mediated hypophysitis. [12] This includes initial clinical assessment, paired ACTH and cortisol levels, thyroid function tests and an initial dose of intravenous hydrocortisone (100mg). Patients with life-threatening features of hypophysitis, described as severe hyponatraemia (Na+ <125mmol/l), hypotension (SBP <90mmHg), reduced level of consciousness, hypoglycaemia (<4mmol/l) or visual field defect, were not considered as these presentations require inpatient care. Patients with a history of exogenous glucocorticoid use were also excluded. Patients with incidental asymptomatic hypocortisolaemia from outpatient clinic are commenced on oral hydrocortisone and referred to Endocrinology clinic and were also excluded from this study of acute presentations.After an initial observation period of at least 4 hours, patients were discharged with oral hydrocortisone (20, 10, 10 mg) and advice with regards to sick day rules.  All patients have access to a 24 hour specialist oncology telephone hotline. They were given clear instructions as to the signs and symptoms that should trigger them to seek medical assessment and representation to the hospital.Urgent outpatient MRI of the pituitary gland (when there was evidence of more than one pituitary deficiency), completion of anterior pituitary function tests and urgent Endocrinology follow up were arranged on discharge. Patients received a telephone follow up within 48 hours from the acute care team to ensure they were making good clinical progress. Patients are reviewed in an Endocrinology clinic within 2 weeks of acute presentation. Generally, at the first outpatient endocrinology visit, the dose of hydrocortisone was reduced to a lower physiological replacement dose. During the endocrine clinic patients receive an emergency hydrocortisone pack and are given a national emergency hydrocortisone alert card. Initiation of other hormone replacement therapy is commenced as indicated.All acute patients treated with ICI presenting to the AAU and AACU are recorded on a prospective database. Basic demographic details, presenting symptoms, site of primary cancer, the type and cycle of ICI, physiological parameters, biochemical results and MRI pituitary results were collected. The primary outcome measure was 30-day readmission related to hypocortisolaemia. Secondary outcome measures included delay in next cycle of ICI therapy and complications related to ICI-mediated hypophysitis.ResultsFourteen patients were managed on the emergency ambulatory ICI-mediated hypophysitis pathway from September 2019 until June 2022. Each patient had classical symptoms of hypocortisolaemia. (see table 1) The median age of the patients was 64 years (40-77 years) and 10 of the patients were male. All of the patients were keen to be managed in an ambulatory setting.Seven of the patients were receiving combination ICI therapy with Ipilumumab and Nivolumab and seven patients were receiving single agent PD-1 therapy. Six of the patients were being treated for melanoma, 3 for renal cancer, 2 for non-small cell lung cancer and one patient colorectal cancer and gastric cancer respectively (see table 1). None of the patients had received exogenous steroids prior to presentation. The patient with hypoglycaemia at presentation had known diabetes and was discharged with continuation of blood glucose monitoring and cessation of their Gliclazide therapy.Each patient was seen in an Endocrinology clinic within 2 weeks (median 8 (4-13) days). Five of the seven patients treated with combination ICI therapy were subsequently confirmed to have pan-anterior hypopituitarism with the other two patients having at least two hormone deficiencies. Each of the patients treated with single agent PD-1 therapy had isolated ACTH deficiency driving their hypocortisolaemia. There were no 30-day readmissions related to hypocortisolaemia. Indeed, there were no 30-day readmissions in the cohort. None of the patients had a delay to the next cycle of ICI therapy. None of the patients have died from hypocortisolaemia related complications. Only two patients in the cohort have died (one from progressive gastric carcinoma and one from COVID19; ten and five months post hypophysitis diagnosis respectively).DiscussionFourteen patients who presented acutely were managed on our ambulatory ICI-mediated hypophysitis with no significant complications, no 30-day readmissions and no delay in subsequent ICI therapy. This included a significant proportion of patients who subsequently were proven to have pan-anterior hypopituitarism as well as those with isolated ACTH deficiency.Therefore, the focus on the clinical severity at presentation with an emphasis on prompt treatment and education allows for the prevention of hospital admission as a routine. The key strength is the nature of collaborative working to develop innovative clinical pathways.Early recognition and management of ICI-mediated hypophysitis improves patient outcomes and reduces the risk of subsequent complications. There is increasing evidence that patients treated with physiological doses of glucocorticoids for ICI-mediated hypophysitis have superior oncological outcomes. [9,13] Our pathway facilitates rapid specialist endocrine assessment and therefore allows for dose adjustment to reduce the risk of both under- and over-replacement with glucocorticoids.Ensuring that emergency oncology patients have access to ambulatory care will require widening of access and careful modelling of services integrating with oncology care and other key specialties. [14] With the increasing indications for ICI therapy, there will inevitably be an increase in emergency presentations with ICI-mediated toxicities. It is important to try and identify patients with ICI-mediated toxicities traditionally managed in an inpatient setting that are suitable for ambulatory management to both reduce the impact on acute services but also reduce the nosocomial risks to patients exemplified by the COVID19 pandemic. This is particularly pertinent in more common toxicities such as colitis and hepatitis. This will require collaboration between acute medical, oncology and organ specialists. It is likely that hub and spoke models supported by national and regional expert groups will be required to deliver this effectively with regular evaluation during its initial implementation. [15]   It is likely this will need to be supported by regional expert groups. [15]This study is limited by both the small numbers and the ability of the pathway to be replicated in a number of centres due to a lack of specialist acute, endocrinology and oncological care. The aim should be for implementation alongside other ambulatory emergency oncology pathways as part of the wider strategy for delivery of acute oncological care.Our ambulatory care pathway has been utilised successfully to treat patients with ICI-mediated hypophysitis. There were no observable adverse outcomes related to its use and the adoption of this pathway for appropriate patients could potentially lead to reductions in hospital admissions, minimise interruptions to cancer care and enhance the patient experience.Disclosures: NoneReferencesConley J, O’Brien CW, Leff BA, et al. Alternative Strategies to Inpatient Hospitalization for Acute Medical Conditions: A Systematic Review. JAMA internal medicine 2016;176(11):1693-702Lasserson DS, Harris C, Elias T, Bowen J et al.  What is the evidence base for ambulatory care for acute medical illness?  Acute Med 2018; 17(3): 148-53.Cooksley T, Marshall W, Ahn S et al.  Ambulatory emergency oncology: A key tenet of future emergency oncology care.  Int J Clin Practice 2020; 74(1): e13436Kelen GD, Wolfe R, D'Onofrio G et al. Emergency department crowding: the canary in the health care system. NEJM Catalyst 2021Haanen J, Carbonnel F, Robert C et al.  Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow up.  Ann Oncol 2017; 28: iv119-iv142.Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet 2021; 398: 1002-1014.Cooksley T, Girotra M, Ginex P et al. Multinational Association of Supportive Care in Cancer (MASCC) clinical practice recommendations for the management of immune checkpoint inhibitor endocrinopathies and the role of advanced practice providers in the management of immune-mediated toxicities. Support Care Cancer 2020; 28(12): 6175-6181.Girotra M, Hansen A, Farooki A et al.  The current understanding of the Endocrine Effects from Immune Checkpoint Inhibitors and recommendations for management. JNCI Cancer Spectr 2018; 2(3): 21Iglesias P, Sánchez JC, Díez, JJ. Isolated ACTH deficiency induced by cancer immunotherapy: a systematic review. Pituitary 2021; 24, 630–643 Chang LS, Barroso-Sousa R, Tolaney S et al.  Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints.  Endocr Rev 2019; 40(1): 17-65.Cooksley T, Knight T, Gupta A, Higham C, Lorigan P, Adam S. Emergency ambulatory outpatient management of immune-mediated hypophysitis. Support Care Cancer 2020 Sep;28(9):3995-3999Higham CE, Olsson-Brown A, Carroll P et al.  SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Acute management of the endocrine complications of checkpoint inhibitor therapy.  Endocr Connect 2018; 7(7): G1-G7. Faje A, Lawrence D, Flaherty K et al.  High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma.  Cancer 2018; 124(18): 3706-3714.Marshall E. Ambulatory management in low risk neutropenic sepsis – A plea for integrated acute cancer care.  Acute Med 2019; 18(1): 5-6.Cooksley T, Gupta A, Al-Sayed T, Lorigan P.  Emergency presentations in patients treated with immune checkpoint inhibitors.  Eur J Cancer 2020; 130: 193-7.Funding statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.No competing interests.Cancer 	Disease 	group	ICI	Cycle	Presenting complaint	Blood Pressure	(mmHg)	Random	Blood	Glucose	mmol/L	Sodium	mmol/L	(133-146)		Cortisol	nmol/L	ACTH	ng/L	(5-46)	TSH	mU/L		Free T4	pmol/L	(10-22)	MRI	Pituitary	Time -	OPD Endo review	Combination ICI therapy												Melanoma	Ipi/	Nivo	1	Headache	150/80	7.9	138	<50	<5	0.13	9.0	NAD	6 DaysRenal	Ipi/	Nivo	4	Headache/	Fatigue	120/70	6.8	134	<50	<5	<0.02	14.4	NAD	7 DaysMelanoma	Ipi/Nivo	4	Headache/	Fatigue/ Postural dizziness	110/70	6.9	132	<50	< 5	0.05	10.8	Patient did not tolerate MRI	8 daysMelanoma	Ipi/Nivo	4	Headache/	Fatigue	110/70	3.7	131	<50	<5	9.01	14.1	NAD	8 daysRenal	Ipi/Nivo	3	Headache/	Fatigue/	Blurred vision	140/70	5.3	130	<50	<5	<0.02	19.8	Contra-indicated	4daysRenal 	Nivo		Prev	Ipi/Nivo	8	Fatigue/ Nausea/ Postural 	dizziness	110/70	5.5	136	<50	10	7.17	12.3	NAD	13 days Melanoma	Ipi/Nivo	4	Fatigue/ Nausea/ Headache	110/70	3.7	131	<50	<5	0.03	15.9	Pituitary inflamed 	8 daysSingle agent PD-1 therapy												Melanoma	Nivo	4	Headache/	Fatigue/	Postural dizziness	140/70	7.0	141	<50	<5	0.27	16.4	Not tolerated	7 DaysColorectal	Nivo	6	Headache/	Fatigue	140/70	5.8	125	<50	<5	5.61	18.1	NAD	7 DaysGastric 	Nivo	4	Fatigue	140/75	4.7	133	<50	<5	35.79	5.5	NAD	9 daysNSCLC	Pem	2	Headache/	Fatigue	100/60	4.9	129	<50	<5	7.72	15.3	NAD	13 daysNSCLC	Pem	13	Fatigue/	Postural dizziness	90/50	2.9	135	<50	6	0.25	19.5	NAD	8 daysColorectal	Pem	6	Fatigue	110/70	4.7	139	<50	<5	1.53	15.4	Not done	7 daysMelanoma	Pem	2	Headache/	Fatigue	110/70	6	139	<50	<5	2.76	10.7	NAD	8 days Table 1: Demographic details, clinical features, biochemical results, radiological findings and management of patients within the cohort. ICI: Immune Checkpoint Inhibitor; BP: Blood Pressure, ACTH: adrenocorticotrophic hormone; TSH: thyroid stimulating hormone; MRI: magnetic resonance imaging; OPD: outpatient department; Ipi: Ipilumimab; Nivo: Nivolumab; M: male; F: female.

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Immune checkpoint inhibitor-mediated hypophysitis:no place like home

Immune checkpoint inhibitor-mediated hypophysitis:no place like home

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