Morbidity in Patients with Chronic Adrenal Insufficiency - Cardiovascular Risk Factors and Hospitalization Rate Compared to Population Based Controls.

Patients with adrenal insufficiency (AI) have been found to have increased cardiovascular morbidity, partly associated with nonphysiologic glucocorticoid replacement. We included two separate cohorts (cohort 1 n=384 patients, cohort 2 n=180 patients) of patients with chronic primary and secondary AI under standard replacement therapy and compared them to two age- and sex-matched population-based studies (SHIP-TREND/DEGS). Odds ratios with 95% CI for hypertension, hyperlipidemia/HLP, type 2 diabetes/T2DM, obesity, and hospitalization with adjustment for confounders were evaluated by logistic regression. Patient cohort 1 had significantly lower ORs for obesity [0.4 (0.3-0.6), p<0.001] and hypertension [0.5 (0.3-0.6), p<0.001] compared to SHIP-TREND and for obesity [0.7 (0.5-0.9), p=0.01], hypertension [0.4 (0.3-0.5), p<0.001] and HLP [0.4 (0.3-0.6), p<0.001] compared to DEGS. In cohort 2, ORs were significantly lower for HLP compared to both SHIP-TREND [0.4 (0.2-0.7), p=0.001] and DEGS [0.3 (0.2-0.5), p<0.001] and for hypertension [0.7 (0.4-0.9), p=0.04] compared to SHIP-TREND. In patients with SAI from cohort 2, ORs for DM2 [2.5 (1.3-4.9) p=0.009], hypertension [2.5 (1.4-4.5), p=0.002] and obesity [1.9 (1.1-3.1), p=0.02] were significantly higher compared to DEGS, whereas ORs for HLP were significantly lower compared to both SHIP [0.3 (0.1-0.6), p=0.002] and DEGS [0.3 (0.1-0.6), p<0.001]. In most of our AI patients treated with conventional glucocorticoid doses, the risk for T2DM, obesity, hypertension, and HLP was not increased. The number of hospitalizations was significantly higher in AI patients compared to controls, which might reflect increased susceptibility but also a more proactive management of concomitant diseases by physicians and patients.

Primary adrenal insufficiency induced by immune checkpoint inhibitors: biological, clinical, and radiological aspects.

Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.

Steroid supplementation before minor oral surgical procedures in patients taking long-term glucocorticoids: A triple-blinded, randomized, placebo-controlled trial.

BACKGROUND: Patients undergoing long-term glucocorticoid therapy are administered additional glucocorticoids before minor dental procedures, although this is not supported by evidence. The authors designed this study to validate the hypothesis that routine blanket glucocorticoid supplementation is unnecessary during minor oral surgical procedures under local anesthesia. METHODS: The authors recruited 270 patients into 3 groups (1:1:1 allocation) from the dental outpatient department. Primary outcomes were changes in hemodynamic parameters and frequency of adverse events among the 3 groups. The secondary outcome was the association of preprocedural stress and procedural pain with periprocedural adverse events in the long-term glucocorticoid therapy group (groups I and II). RESULTS: No clinically relevant changes in hemodynamic parameters among the 3 groups were found. The authors also found low periprocedural adverse events in all 3 groups combined (n = 1), so they did not explore the secondary outcomes further. CONCLUSIONS: Among patients undergoing long-term glucocorticoid therapy for indications other than primary adrenal insufficiency, elective minor oral surgical procedures can be performed safely with only their daily dose of glucocorticoid when their medical conditions are optimized. Routine additional glucocorticoid supplementation appears unnecessary. The results of the study also revealed opportunities for value addition by means of integrating oral health care with medical follow-up for patients with multiple co-occurring medical conditions. PRACTICAL IMPLICATIONS: Routine blanket glucocorticoid supplementation among patients taking a long-term glucocorticoid for indications other than primary adrenal insufficiency appears unnecessary before minor oral surgical procedures under local anesthesia. This clinical trial was registered at Clinical Trial Registry-India. The registration number is CTRI/2017/02/007779.

Immune checkpoint inhibitor-associated new-onset primary adrenal insufficiency: a retrospective analysis using the FAERS.

BACKGROUND: Our study aimed to investigate the prevalence and demographic characteristics of immune checkpoint inhibitor-associated primary adrenal insufficiency (ICI-PAI) and to explore the risk factors of its clinical outcome using data from the US FDA Adverse Event Reporting System (FAERS). METHODS: This was a retrospective study. All cases of new-onset or newly diagnosed primary adrenal insufficiency associated with FDA-approved ICIs from 1 January 2007 to 31 December 2020 were identified and collected using FAERS. Data on age, sex category, body weight of the participating individuals, the reporting year and the prognosis of cases, and other accompanying endocrinopathies related to ICIs, were analysed. RESULTS: The incidence of ICI-PAI was 1.03% (1180/114121). Of the 1180 cases of PAI, 46 were "confirmed PAI", and 1134 were "suspected PAI". Combination therapy with anti-CTLA-4 and anti-PD-1 was related to a higher risk of PAI compared with the anti-PD-1-only group (χ2 = 92.88, p < 0.001). Male and elderly individuals showed a higher risk of ICI-PAI (male vs. female, 1.17% vs. 0.94%, χ2 = 12.55, p < 0.001; age < 65 vs. ≥ 65, 1.20 vs. 1.41%, χ2 = 6.89, p = 0.009). The co-occurrence rate of endocrinopathies other than PAI was 24.3%, which showed a higher trend in patients on nivolumab-ipilimumab treatment than in those on PD-1 inhibitors (χ2 = 3.227, p = 0.072). Body weight was negatively associated with the risk of death in the study population [p = 0.033 for the regression model; B = - 0.017, OR 0.984, 95% CI (0.969-0.998), p = 0.029]. CONCLUSION: ICI-associated PAI is a rare but important irAE. Male and elderly patients have a higher risk of ICI-PAI. Awareness among clinicians is critical when patients with a lower body weight develop PAI, which indicates a higher risk of a poor clinical outcome.

A Case of Cancer-Associated Hyponatraemia: Primary Adrenal Insufficiency Secondary to Nivolumab.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors is a new frontier for cancer treatment. On the safety profile, this drugs class is associated with a new spectrum of side effects, the so-called immune-related adverse events that can potentially affect any organs, mainly endocrine glands. Scant data are available to inform the appropriate strategy of their management and treatment. CASE PRESENTATION: A 74-years old man with a squamous non-small cell lung cancer on nivolumab was hospitalized for fatigue, nausea, vomiting and severe hyponatremia. Biochemical tests were significant for hypotonic hyponatremia with a high urine sodium concentration. Endocrine tests showed overt primary hypothyroidism and low serum cortisol and aldosterone levels associated with an elevated circulating level of adrenocorticotrophic hormone. Adrenal antibody screening and the search of adrenal lesion on CT abdomen were negative. Thus, a nivolumab-induced primary adrenal insufficiency was diagnosed. Nivolumab withdrawal and replacement treatment with glucocorticoid and mineralocorticoid allowed clinical and biochemical recovery. CONCLUSION: Physicians need to be aware of potential immune-related adverse events in all patients treated with an immune checkpoint inhibitor. Their timely recognition is essential to carry out the proper treatment.

Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 or programmed death 1 and its ligand (programmed death ligand 1) have been approved for the treatment of a variety of cancers. However, ICI therapy is associated with a risk of immune-related adverse events. In this study, we reviewed reported cases of adrenalitis and primary adrenal insufficiency (PAI)-rare but lethal endocrine immune-related adverse events-in patients who underwent ICI therapy. METHODS: We searched multiple databases (PubMed, Web of Science, Cochrane, and Scopus) up to February 2020 for case reports on adrenalitis and PAI caused by ICIs. RESULTS: We identified 15 case reports on ICI-induced adrenalitis and PAI and reviewed their clinical presentation, characteristics, immunologic and imaging features, and treatment. We also developed a screening strategy for PAI in patients treated with ICIs. CONCLUSION: Given the morbidity and mortality associated with acute adrenal crisis, physicians-especially endocrinologists and oncologists-should be aware of this particular risk. PAI caused by autoimmune adrenalitis predominantly occurs in patients treated with programmed death 1 inhibitor monotherapy. PAI often coexists with other endocrinopathies and requires mineralocorticoid as well as glucocorticoid replacement. Even after withdrawal of ICIs, PAI can persist and requires lifelong replacement therapy.

Reversible primary adrenal insufficiency related to anti-programmed cell-death 1 protein active immunotherapy: Insight into an unforeseen outcome of a rare immune-related adverse event.

The immune checkpoint inhibitors (ICPi) revolutionize the cancer therapeutics, though not being devoid of toxicity. The immune-related primary adrenal insufficiency (PAI) is a rare, yet potentially life-threatening, adverse event, posing diagnostic and therapeutic challenges. We report the first case of reversible PAI related to nivolumab (programmed cell-death 1 protein inhibitor) in a 42-year-old male with metastatic rectal adenocarcinoma. PAI manifested as profound fatigue, disorientation, hypotension, hyperpigmentation of palmar creases, and hyponatremia without hyperkalemia 16 weeks after initiation of nivolumab. Due to impending adrenal crisis, intravenous stress doses of hydrocortisone and hydration with normal saline were initiated. When the state of patient was stabilized, PAI was confirmed through 250 µg Synacthen test 24 h after temporary cessation of hydrocortisone. Hydrocortisone was fixed at maintenance dose, while mineralocorticoid substitution was not required. PAI was ascribed to nivolumab based on history, physical examination, and laboratory work-up with emphasis on positivity of anti-21-hydroxylase antibodies and exclusion of other causes of PAI by normal imaging of adrenal glands on computed tomography (CT). Reevaluation of adrenal function during follow up demonstrated complete recovery. A review of literature concerning the immune-related PAI indicated that the complete recovery of adrenal function, the normal CT imaging, and the positivity of anti-21-hydroxylase antibodies observed in our patient are exceptional findings of immune-related PAI. Finally, heightened suspicion of immune-related PAI in case of hyponatremia without hyperkalemia and constant vigilance for diagnosis of rare, but real, reversibility of immune-related PAI are of paramount importance.

Tyrosine Kinase Inhibitors' Newly Reported Endocrine Side Effect: Pazopanib-Induced Primary Adrenal Insufficiency in a Patient With Metastatic Renal Cell Cancer.

Tyrosine kinase inhibitors (TKIs) have been used in the treatment of multiple types of cancer. Pazopanib is one of the TKIs and is considered a first-line treatment for adult patients with metastatic renal cell carcinoma. Many endocrine-related adverse effects have been noted with the use of TKIs including hypothyroidism, vitamin D deficiency, altered bone density, secondary hyperparathyroidism, abnormal glucose metabolism, gynecomastia, and hypogonadism. Subclinical glucocorticoid deficiency and adrenal insufficiency have been reported with the use of TKIs in only a few cases so far; thus, its true prevalence and clinical significance have yet to be fully elucidated. The mechanism is still not fully understood; however, adrenal toxicity with hemorrhage and/or necrosis of the adrenal glands has been observed in studies. In this article, we describe the first reported case of pazopanib inducing primary adrenal insufficiency in a patient with metastatic renal cell carcinoma diagnosed after the exclusion of all other causes of primary adrenal insufficiency.

Endocrine adverse events related with immune checkpoint inhibitors: an update for clinicians.

Designated as scientific breakthrough of current decade, immune checkpoint inhibitors attenuate the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1)/ligand 1 (PD-L1) pathways, depriving cancer cells of a key strategy of evasion from immunosurveillance. The reinvigoration of immune response translates into clinical success, inevitably entwined with a novel constellation of immune-related adverse events. The present review dissects the endocrine immune-related adverse events, emphasizing their unique profile featured by unpredictable onset, irreversibility, nonspecific symptoms, wide clinical spectrum and sophisticated diagnostic work-up. Guidelines advocate individualized decision-making process guided by clinicians' judgement. Future perspective should be governed by five principles - prevention, anticipation, detection, treatment, monitoring - aiming to gain the optimal profit diminishing immunotoxicity.

An analysis of early morning acth levels in the first case of pembrolizumab-induced adrenalitis as a delayed immune-related event (dire) - case study.

OBJECTIVE: The aim: The levels of adrenocorticotrophic hormone (ACTH) are elevated in primary adrenal failure (Addison's disease) with a peak in the early morning hours. This also occurs under hydrocortisone replacement therapy due to the unphysiological substitution regime. The aim was to study ACTH levels under two different replacement regimens. This is exemplified in a patient with adrenalitis after immunotherapy for malignant melanoma (MM), since (elevated) levels of ACTH and its cleavage product alpha-melanocyte stimulating hormone (α-MSH) raise concerns since receptors for both hormones can be expressed in melanoma cells. PATIENTS AND METHODS: Material and methods: A female with MM had immunotherapy with pembrolizumab and developed adrenalitis with Addison crisis about one year after discontinuation of this therapy (delayed immune-related event = DIRE). ACTH levels were measured hourly (4-8 a.m.) during a "conventional" hydrocortisone replacement therapy and during a therapy with dual-release hydrocortisone. RESULTS: Results: Salient differences between the morning ACTH profiles under the "conventional" hydrocortisone replacement regimen with 10-5-5 mg/die compared to the single-dose regimen with 20 mg dual-release hydrocortisone were not discernible. CONCLUSION: Conclusion: DIRE could be an underestimated problem in immunotherapy and could put the patients at hazard. Especially in case of an endocrinological DIRE concerning the adrenocorticotrophic axis, life-threatening situations can arise for the patients. As for the special situation with M. Addison and MM, where hormonal feedback mechanisms may cause further problems beyond the normal hormonal replacement therapy, we observed no salient differences in the early morning ACTH profiles under different hydrocortisone replacement regimens.

Adrenal insufficiency following nivolumab therapy in patients with recurrent or metastatic head and neck cancer.

Nivolumab, an anti-programmed cell death-1 monoclonal antibody, is currently used to treat many types of advanced cancers including recurrent and metastatic head and neck cancer. However, there are increasing reports concerning immune-related adverse events related to nivolumab therapy. Here, we report three patients who presented with adrenal insufficiency following nivolumab therapy. Two were diagnosed as having isolated adrenocorticotropic hormone (ACTH) deficiency and one was diagnosed as having primary adrenal insufficiency. All three patients complained of progressive fatigue and appetite loss, so we measured their blood cortisol and ACTH levels and diagnosed them as having adrenal deficiency. Treatment with nivolumab was discontinued for all three patients, and replacement therapy using hydrocortisone was successful after a few days in all cases. Two patients subsequently resumed nivolumab therapy because their general condition had improved. Complaints of fatigue and appetite loss during cancer treatment are common and tend to be regarded as unimportant. Although adrenal insufficiency due to nivolumab is relatively rare, complaints of these symptoms could lead to the detection of adrenal insufficiency at an early stage. The present report highlights the importance of the early recognition of adrenal insufficiency.

[Endocrine side effects of checkpoint inhibitors]. / Endocriene bijwerkingen van checkpointremmers.

Checkpoint inhibition has emerged as a promising therapeutic strategy for several types of cancer. Immune-related adverse effects (irAEs) commonly involve the endocrine system. Distinguishing endocrine side effect-related symptoms from disease progression or treatment-related toxicity can be challenging. If not recognized in time, endocrine irAEs may be life-threatening. As the use of checkpoint inhibitors is expected to increase, there is a need for more awareness of endocrine irAEs amongst health care professionals. We describe three cases that illustrate the importance of timely recognition, patient education and the management of endocrinopathies. Two patients who were treated with the checkpoint inhibitor ipilimumab developed hypophysitis and subsequent episodes of hypocortisolism. These cases underline both the frequency of diagnostic delay and the importance of patient education with regard to glucocorticoid stress dosage. The third patient presented with diabetes mellitus after administration of nivolumab. A multidisciplinary approach is warranted to ensure optimal care for patients with endocrine irAEs.

Hypothesis: does adrenalitis caused by immune checkpoint-inhibitors put melanoma patients at an elevated risk for recurrence?

Primary adrenal failure (Addison's disease) is a rare complication of immune checkpoint inhibitor (ICI) therapy. Untreated - and also sometimes under adequate hydrocortisone replacement therapy - the levels of ACTH (Adrenocorticotropic hormone) and MSH (Melanocyte stimulating hormone) are elevated. This may be a reason for concern in patients with malignant melanoma (MM): Melanocortin receptors bind to ACTH and the different isoforms of MSH. For example, the melanocortin 1 receptor (MC1R) is overexpressed in many human melanoma cells. Since it is also involved in the proliferation of melanoma cells, the elevated levels of ACTH and its proteolytic cleavage product α-MSH typical for primary failure may lead to an activation of the receptor and, thus, put MM patients that suffered from primary adrenal failure after ICI therapy at an elevated risk for recurrence or an unfavorable course of the disease. Novel dual-release hydrocortisone therapy results in lower ACTH (and most probably lower α-MSH) levels due to the more physiological mode of hydrocortisone release. Given that the concern raised in this hypothesis is confirmed in future investigations, patients who suffer from primary adrenal failure after ICI therapy may benefit from a dual-release hydrocortisone replacement regimen.

A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors.

Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programed cell death 1 (PD-1), or its ligand (PD-L1) have become the mainstay for advanced malignancies. The incidence of endocrine adverse events provoked by these immune checkpoint inhibitors (ICI) is based on data from randomized controlled trials, which have their drawbacks. PubMed was searched through August 22nd, 2017, by 2 reviewers independently (J.d.F. and C.E.A.). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. The weighted incidence and risk ratio were estimated for hypophysitis, primary thyroid disease, primary adrenal insufficiency, and diabetes mellitus. Their management is discussed in a systematic review. A total of 101 studies involving 19 922 patients were included. Ipilimumab-treated patients experienced hypophysitis in 5.6% (95% CI, 3.9-8.1), which was higher than nivolumab (0.5%; 95% CI, 0.2-1.2) and pembrolizumab (1.1%; 95% CI, 0.5-2.6). PD-1/PD-L1 inhibitors had a higher incidence of thyroid dysfunction - particularly hypothyroidism (nivolumab, 8.0%; 95% CI, 6.4-9.8; pembrolizumab, 8.5%; 95% CI, 7.5-9.7; PD-L1, 5.5%; 95% CI, 4.4-6.8; ipilimumab, 3.8%; 95% CI, 2.6-5.5). Combination therapy was associated with a high incidence of hypothyroidism (10.2-16.4%), hyperthyroidism (9.4-10.4%), hypophysitis (8.8-10.5%), and primary adrenal insufficiency (5.2-7.6%). Diabetes mellitus and primary adrenal insufficiency were less frequent findings on monotherapy. Our meta-analysis shows a high incidence of endocrine adverse events provoked by single agent checkpoint blockade, further reinforced by combined treatment.

Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints.

Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.

Primary Adrenal Insufficiency During Lenvatinib or Vandetanib and Improvement of Fatigue After Cortisone Acetate Therapy.

Context: Two tyrosine kinase inhibitors (TKIs), lenvatinib and vandetanib, are often used to treat advanced radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) and medullary thyroid cancer (MTC), respectively. Fatigue is a common adverse event during treatment with these and other TKIs and a common cause of drug discontinuation or dosage reduction. Cases Description: We evaluated the basal and stimulated adrenal function in 12 patients with advanced RAI-R DTC and MTC treated with lenvatinib or vandetanib, respectively. Ten patients complaining of fatigue showed a progressive ACTH increase with normal cortisol levels. Moreover, six of 10 patients had a blunted cortisol response after ACTH stimulation, thus confirming the diagnosis of primary adrenal insufficiency (PAI). The causal relationship between TKIs and PAI onset was also demonstrated by the repeated testing of adrenal function before and during treatment. Patients with PAI received cortisone acetate replacement therapy, with a substantial and prompt improvement in the degree of fatigue, as assessed by the Common Terminology Criteria for Adverse Events version 4.03, thus supporting the major impact of impaired adrenal function in the genesis of this adverse event. Conclusions: We show that the occurrence of PAI may be a common cause of fatigue during lenvatinib and vandetanib treatment, and we therefore recommend testing adrenal function for a prompt start of replacement therapy to avoid treatment discontinuation, dosage reduction, and potentially severe PAI complications.

Delayed Presentation of Isolated Adrenocorticotropin Insufficiency after Nivolumab Therapy for Advanced Non-small-cell lung carcinoma (NSCLC).

We describe a 73-year-old man who developed adrenal insufficiency 7 months after completing nivolumab therapy for advanced non-small cell lung cancer. He presented with non-specific symptoms of malaise and fatigue with an insidious 13.6 kilogram weight loss, prompting an evaluation for disease progression, which was negative. Subsequent evaluation revealed isolated adrenocorticotropin insufficiency as the aetiology, attributed to a delayed side effect of nivolumab therapy.

[Immune checkpoint inhibitors and endocrinological side effects].

Immune checkpoint inhibitors including anti-cytotoxic T-lymphocyte-associated antigen-4 and anti-programmed cell death-1 have revolutionized cancer therapy but have also induced serious immune-related adverse events including hormonal dysfunction. The objective of this review is to characterize the incidence, clinical presentation, management and prognosis of the endocrine-related adverse events including hypophysitis, thyroid dysfunction and diabetes mellitus. Combination therapy is associated with an increased risk of adverse events. We recommend close monitoring of the hormone levels and glycaemic status during and a year after treatment.