Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach

EJINME-03647; No of Pages 8 European Journal of Internal Medicine xxx (2017) xxx–xxx

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Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach☆ Pedro Iglesias Department of Endocrinology, Hospital Ramón y Cajal, Ctra. de Colmenar, Km 9.100, 28034 Madrid, Spain

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Article history: Received 11 May 2017 Received in revised form 11 August 2017 Accepted 16 August 2017 Available online xxxx Keywords: Cancer Immunotherapy Endocrinopathies Hypophysitis Thyroiditis Adrenalitis Type 1 diabetes

a b s t r a c t Cancer immunotherapy has proven to be effective in a wide variety of tumors. The use of immune checkpoint blocking monoclonal antibodies has become a standard treatment regimen in some of them as advanced melanoma. However, given the mechanism of action, its use may be associated with immune-related adverse events that may complicate the clinical course and prognosis of patients. Among these are autoimmune endocrine adverse effects, such as hypophysitis, hypo and hyperthyroidism, and adrenal insufficiency. This review focuses on the most relevant and new aspects related to the incidence, clinical presentation, diagnosis and treatment of these adverse effects associated with different types of immune checkpoint inhibitors in cancer immunotherapy. © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction Immunotherapy uses different therapeutic approaches to target the immune system against cancer. These include: 1) the use of cytokines (preferably interferon and interleukins); 2) manipulation of T lymphocytes (adoptive cell transfer); 3) therapeutic vaccines; and 4) monoclonal antibodies that bind to specific T lymphocyte receptors to stimulate the immune response against tumor cells (immune checkpoint inhibitors). The use of these monoclonal antibodies has shown important clinical benefits in different types of cancer, including metastatic melanoma, renal carcinoma, non-small cell lung cancer, head and neck cancer, urothelial carcinoma and Hodgkin's lymphoma [1,2]. However, despite its important therapeutic advantages, the use of these antibodies is not free of adverse effects derived from its own mechanism of action, and therefore, associated with an immunological hyperactivity. These immune-related adverse events (irAEs) can become serious and even life-threatening [3,4]. The main irAEs associated with these antibodies, among others, are cutaneous, digestive (gastrointestinal and hepatic) and endocrine (hypophysitis, thyroiditis and adrenal insufficiency) [3–11] (Table 1). The relative risk for developing the endocrine irAEs associated with immune checkpoint inhibitors is 22 for hypophysitis, 8.3 for all forms of hypothyroidism, 5.5 for all forms of hyperthyroidism, and 3.9 for adrenal insufficiency [12]. In the present ☆ The author has no conflict of interest and financial support in relation to the present manuscript. E-mail address: [email protected].

review, the most novel and relevant aspects related to autoimmune endocrinopathies induced by immune checkpoint inhibitors in the treatment of cancer have been reviewed. For this purpose, all full-text papers and relevant case reports published in Pubmed until May 2017 using “cancer”, “immunotherapy”, “endocrinopathies”, “hypophysitis”, “thyroiditis”, “adrenalitis”, and “type 1 diabetes”, as key words, were considered. 2. Immune checkpoints Immune checkpoints are receptors for T lymphocytes that, after binding to their ligands, modulate the immune system, either by stimulating it (stimulatory checkpoint molecules) or inhibiting it (inhibitory checkpoint molecules) [1]. There are multiple co-stimulatory immune control points, such as CD-28, ICOS, OX40 and CD46. Most of the ligands for these co-stimulatory receptors are induced by the activation/maturation of antigen presenting cells (APCs). On the other hand, the main co-inhibitory immune control points are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD1) [1]. CTLA-4 is a molecule that is expressed on the surface of most activated T lymphocytes during the initial activation phase in lymphatic tissue by dendritic cells and by other APCs. Its main action is inhibitory, regulating homeostasis and peripheral immune tolerance, inhibiting the activation of T lymphocytes through mechanisms of negative signaling and competitive antagonism of the CD28/B7-mediated co-stimulatory pathway [1].

http://dx.doi.org/10.1016/j.ejim.2017.08.019 0953-6205/© 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Iglesias P, Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.019

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Table 1 Main immune checkpoints antibodies, target molecules, doses, tumor types with demonstrated clinical effects, and main associated autoimmune endocrinopathies. Immune checkpoint inhibitors

Immunoglobulin type

Target molecule

Dosage

Tumor type

Autoimmune endocrinopathies

Ipilimumab (MDX-010)

IgG-1κ

CTLA-4

3 to 10 mg/kg iv every 3 weeks (4 doses)

Advanced melanoma

Tremelimumab (CP-675,206)

IgG2b

CTLA-4

15 mg/kg every 90 days up to 4 doses

Pembrolizumab (MK-3475)

IgG-4κ

PD-1

2–10 mg/kg every 2 weeks

Renal carcinoma Breast cancer Malignant mesothelioma Advanced melanoma Non-small cell lung cancer

Nivolumab (MDX-1106)

IgG4

PD-1

2–10 mg/kg every 2 weeks

Hypophysitis (11%) Hypothyroidism Subclinical (6%) Overt (1–6%) Hyperthyroidism Subclinical (16%) Overt (b2.5%) Adrenalitis (0.3–1.5%) Insulinitis (Ipilimumab + nivolumab) Parathyroiditis (Ipilimumab + nivolumab) Hypophysitis (1–2%) Thyroid dysfunction (2.5%) Adrenalitis (0.3–1.5%) Thyroid dysfunction (20–40%) Hypophysitis (b1%) Insulinitis Thyroid dysfunction (20–40%) Hypophysitis (b1%) Insulinitis Parathyroiditis (Ipilimumab + nivolumab)

PD-1 is another co-inhibitory membrane receptor expressed in T cells activated during the effector phase in peripheral tissues. The binding of PD-1 to its PD-L1 (B7-H1) and PD-L2 (B7-DC) ligands that are expressed in tumor cells and tissue macrophages causes an inhibition of T lymphocyte activation facilitating immunological tolerance, thus preventing tumor rejection by the immune system [1]. 3. Immune checkpoint inhibitors Blocking of immune checkpoints (CTLA-4 and PD-1) with inhibitory antibodies is accompanied by stimulation and proliferation of activated T lymphocytes against tumor cells [1,13,14]. The anti-CTLA-4 (ipilimumab and tremelimumab) and anti-PD1 antibodies (pembrolizumab, nivolumab and pidilizumab) are the main inhibitors of the immune checkpoints that are being used in cancer immunotherapy. Other developing antibodies are anti-PD-L1, such as atezolizumab, durvalumab and avelumab. Ipilimumab (MDX-010), a recombinant human monoclonal (IgG-1κ) antibody, was the first inhibitor of immune checkpoints that demonstrated its efficacy in advanced melanoma. It was approved in 2011 by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of metastatic melanoma given its ability to prolong survival in these patients compared with other therapies, contributing to a plateau in the survival curve that begins at 3 years and lasts up to 10 years of follow-up in some patients [15,16]. In addition, ipilimumab as an adjuvant treatment for stage III high-risk melanoma has been associated with significantly higher rates of relapse-free survival, overall survival, and distant metastasis-free survival compared to placebo [17]. It has also shown its effectiveness in advanced renal cell carcinoma and is being tested in other cancers, such as non-small cell lung cancer [18]. The induction treatment with ipilimumab consists of administration of 3 to 10 mg/kg intravenously in 90 min every 3 weeks, with a total of 4 doses, followed or not by maintenance doses every 3 months. Tremelimumab (CP-675,206) is a recombinant human anti-CTLA-4 monoclonal antibody (IgG2b) that although has not demonstrated increased survival on chemotherapy in patients with advanced melanoma [19], at the present time it is being evaluated in other tumors such as malignant mesothelioma and renal cell carcinoma [20,21]. The dose of tremelimumab is 15 mg/kg every 90 days up to 4 doses. In spite of the therapeutic advantage of ipilimumab, its use in advanced melanoma has decreased due to the development of new

Advanced melanoma Recurrent head and neck squamous cell carcinoma

inhibitory antibodies to the immune checkpoints that have been shown to be more effective and better tolerated, such as anti-PD-1 [22,23]. The main anti-PD-1 antibodies, pembrolizumab (MK-3475) and nivolumab (MDX-1106), are humanized monoclonal antibodies type IgG-4κ e IgG4, respectively. These antibodies have been approved in 2014 by the FDA and in 2015 by the EMA for the treatment of advanced melanoma. In addition, they have shown their efficacy in other tumors such as non-small cell lung cancer [24]; and recurrent head and neck squamous cell carcinoma [25], respectively. Doses of pembrolizumab and nivolumab are 2–10 mg/kg every 2 weeks and 3 mg/kg every 2 weeks, respectively, until progression or unacceptable toxicity. Pidilizumab (CT-011), another humanized antibody anti-PD-1 type IgG-1κ, has shown promising efficacy in phase II trials in patients with diffuse large B-cell lymphoma after hematopoietic stem cell transplantation [26] and combined with rituximab in patients with relapsed follicular lymphoma [27]. Lastly, combined treatment with anti-CTLA-4 (ipilimumab) and anti-PD1 antibodies (nivolumab or pembrolizumab) seems to be an attractive therapeutic alternative in advanced melanoma as it is associated with greater therapeutic efficacy; however, it also presents greater toxicity [28,29]. Other anti-PD-L1 antibodies, such as atezolimumab (MPDL3280A) (IgG-1κ), durvalumab (MEDI4736) (IgG-1κ), avelumab (MSB0010718) (IgG1) and MDX 1105 (IgG4) are being evaluated at the present time in different types of tumors. 4. Hypophysitis The irAEs associated with the use of anti-CTLA-4 antibodies have been reviewed in a recent meta-analysis of 81 articles, with a total of 1265 patients from 22 clinical trials [3]. The study showed a global incidence of irAEs and an incidence of high-grade irAEs of 72% and 24%, respectively. In addition, the risk of developing irAEs was dose dependent [3]. In the study, autoimmune hypophysitis was the most common endocrine adverse event, documented in up to 13% of clinical trials. 4.1. Hypophysitis induced by anti-CTLA-4 antibodies Hypophysitis associated with the use of anti-CTLA-4 antibodies is an autoimmune hypophysitis similar to primary lymphocytic hypophysitis

Please cite this article as: Iglesias P, Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.019

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although with some differences. While the former is more common in males, generally older than 60 years, the latter is more frequent in females (female/male ratio 5:1), mean age 35 years and, often, related to gestation or postpartum period [30,31]. Ipilimumab is the immune checkpoint inhibitor most frequently associated with autoimmune hypophysitis. Moreover, autoimmune hypophysitis is the endocrine irAE most commonly reported with the use of ipilimumab even more than thyroid involvement [12]. The first clinical case of ipilimumab-induced hypophysitis (IIH) was reported in 2003 by Phan et al. [32] in a 54-year-old man diagnosed with advanced melanoma with pulmonary, cerebral, and subcutaneous metastases after the fifth ipilimumab dose. Since then, isolated cases [33–34] or small series [3,15,30,35–45] that, as a whole, do not exceed one hundred patients, have been reported. Although most patients had advanced melanoma as the underlying disease, it has also been documented in patients with prostate cancer [39,46], lung cancer [47], and renal cancer [48]. The prevalence of IIH is around 11% (range, 1.5%–25%) [3,10,11,15, 23,30,44,45,49–54]. This wide range of prevalence could be related to several factors. On the one hand, with the definition of hypophysitis used, since some authors consider hypophysitis and hypopituitarism separately. On the other hand, with the influence of acute disease and treatment with corticosteroids on gonadal, thyroid and adrenal cortical function. Lastly, with the different doses of ipilimumab used [9,15,16,45, 54,55]. In this setting, hypophysitis has been reported in 1.5–6% of patients (2–3% of cases with grade 3–4 hypophysitis) treated with low doses (3 mg/kg) [51], and in 18% (grade 3 hypophysitis in 5%) in those treated with high doses (10 mg/kg) [52]. However, recent meta-analysis studies have not been able to find the dose dependence in endocrine irAEs, unlike what happens with other irAEs associated with immunotherapy [3,12]. The main risk factors for developing hypophysitis in patients treated with ipilimumab are male sex and age (N60 years) [30,45, 49,50,56]. Treatment combined with chemotherapy and other targeted therapies do not appear to increase the risk of developing hypophysitis [49]. The use of tremelimumab in patients with melanoma or advanced solid tumors has also been associated with hypophysitis [19,57,58]. However, the frequency of hypothalamic-pituitary involvement induced by tremelimumab appears to be lower than that of ipilimumab [11,19]. In a randomized phase III trial comparing tremelimumab (15 mg/kg once every 90 days) with standard chemotherapy (temozolomide or dacarbazine) in patients with advanced melanoma, hypophysitis appeared in 6 patients (2%) (4 of them with hypophysitis grade ≥ 3) compared to no patient in the chemotherapy group [19]. A recent review of 613 patients treated with tremelimumab revealed a prevalence of hypophysitis of 1.3% [11].

4.2. Hypophysitis induced by anti-PD-1 and anti-PDL-1 antibodies Anti-PD-1 antibodies are also associated with hypophysitis, albeit with a much lower frequency than with anti-CTLA-4 [10,59,60]. The prevalence of hypophysitis associated with anti-PD1 antibodies is generally b1% [10,11,61,62]. The marked differences in the incidence of hypophysitis induced by anti-PD1 and anti-CTLA-4 could be related to functional differences in the process of activation of T lymphocytes and ectopic expression of CTLA-4 in pituitary cells [46,63]. In addition, unlike ipilimumab, pituitary involvement induced by anti-PD1 is less frequent than thyroid involvement [6,10,64]. Likewise, its prevalence is similar in the different tumors. For example, a recent meta-analysis on the toxicity profile of anti-PD-1 antibodies (pembrolizumab and nivolumab) in solid tumors showed that the absolute risk of hypophysitis was 0.47% [4]. To date, no endocrine irAEs associated with pidilizumab have been reported [12]. Neither, anti-PD-L1 antibodies-induced hypophysitis has been reported.

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4.3. Hypophysitis induced by combined therapy (anti-CTLA-4 and anti-PD1antibodies) Combined therapy with anti-CTLA-4 and anti-PD-1 increases antitumor efficacy but also the frequency of irAEs such as hypophysitis (11, 28, 64). The prevalence of hypophysitis with combined treatment is greater than when the antibodies are used separately (around 8%) [11]. Treatment with nivolumab, ipilimumab or with both combined antibodies in patients with advanced untreated melanoma was associated with a prevalence of hypophysitis of 0.6%, 3.9%, and 7.7%, respectively [64]. However, hypophysitis associated with combined treatment (ipilimumab and nivolumab), although more frequent, seems to be milder (10% grade 1–2 vs 2% grade 3) than that observed with ipilimumab monotherapy [28]. 4.4. Pathogenesis The pathogenic mechanism of hypophysitis induced by immune checkpoint inhibitors seems to be related to the development of a process of immunological activation at pituitary level that manifests itself as an autoimmune hypophysitis. These antibodies could act negatively on the regulatory T lymphocytes [65]. In 2014, Iwama et al. [46] reported for the first time the expression of CTLA-4 in pituitary endocrine cells in murine models. They also demonstrated that blockade with antiCTLA-4 antibodies resulted in a deposition of complement components in lactotropes and thyrotropes, a mononuclear cell infiltration (pituitary lymphocytes and macrophages), and the production of antibodies against adenohypophysial endocrine cells. The same authors confirmed the appearance of anti-pituitary antibodies in serum, mainly against the thyrotrophic, gonadotropic and corticotropic cells, in those patients who developed hypophysitis after starting treatment with ipilimumab [46]. Both ipilimumab and tremelimumab, being IgG1 and IgG2, can activate the classical complement pathway and antibody-dependent cellmediated cytotoxicity [46,66]. More recently CTLA-4 expression has been reported in both normal pituitary and pituitary adenomas in humans [10]. Lastly, it has been suggested to investigate the possible existence of polymorphisms in the CTLA-4 gene that could be associated with the development of hypophysitis [31]. These previously mentioned mechanisms do not seem to explain the pathogenesis of hypophysitis associated with anti-PD-1 antibodies. It is possible that PD-1 is expressed in adenohypophysis cells or in pituitary lymphocytes as described for PD-L1 in pituitary adenomas and infiltrating lymphocytes in these tumors [67]. On the other hand, as they are IgG-4κ and IgG4 monoclonal antibodies, they are likely to share common pathogenic mechanisms with IgG4-related hypophysitis [31]. 4.5. Clinical presentation IIH is the best known type of hypophysitis induced by immune checkpoint inhibitors. This is because, in addition to being the first described, it has been the most frequently reported. IIH usually appears from 8 to 10 weeks after starting treatment, generally between the second and fourth doses, although its diagnosis can be delayed, until 4 months after the end of therapy [3,30,50,68]. The clinical presentation of IIH is similar in all cases and does not depend on the underlying type of cancer [48]. In 2014 Faje et al. [30] analyzed 154 patients with metastatic melanoma treated with ipilimumab and found 17 patients [11%; 15 (88.2%) males; mean age 68.2 years] with IIH. The mean time from onset of treatment to the development of hypophysitis was 8.4 weeks (range, 6.9–10.3). The main symptom was headache (n = 16, 94.1%), followed by fatigue (n = 10, 58.8%), and anorexia (n = 4, 23.5%). Colitis (n = 3, 17.6%), ileitis, dermatitis, and elevated pancreatic enzymes were the main associated irAEs. Hyponatremia was the most frequently described analytical alteration at diagnosis (n = 8, 47%), generally with plasma sodium values ranging from 113 to 134 mEq/l. Pituitary function was compromised in all patients. Central hypothyroidism and

Please cite this article as: Iglesias P, Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.019

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secondary hypogonadism appeared in 100% of cases, followed by hypoprolactinemia (92%), secondary adrenal insufficiency (50%) and, finally, GH deficiency (17%). Magnetic resonance imaging (MRI) of the pituitary showed a mild to moderate diffuse pituitary enlargement in all patients and, in half of the cases, these morphological alterations preceded the clinical diagnosis. Chiasmatic compression was absent. Analysis of several series of 15 or more patients with IIH [30,40,44, 45] showed similar findings of prevalence (10.9%); predominance among males (72.4%); mean age at diagnosis (61 years); and mean time to diagnosis (9.7 weeks). However, the hormonal involvement was slightly different. The thyrotrope axis was the most frequently compromised (83.9%), followed by corticotrope (77.8%) and gonadotrope (71%) axes. Hypoprolactinemia (47.2%) and GH deficiency (17.9%) were infrequent [50]. Both diabetes insipidus [39,69] as the syndrome of inadequate ADH secretion [70] associated with treatment with ipilimumab are exceptional. Isolated cases with normal pituitary function have also been reported [45]. MRI alterations have been reported in the majority (80.2%) of patients with IIH [50]. They are generally described as a generalized, uniform and homogeneous enlargement of the pituitary gland that may sometimes precede the clinical picture of hypophysitis [30,38,40,71] (Fig. 1). Sometimes the hyperintense signal of the neurohypophysis disappears and, generally, there is usually no compression of the optic chiasm, so it is usually not associated with a compromise of the visual fields [30,33]. Although MRI lesions are sensitive and specific to IIH, a routine pituitary MRI is not recommended as most (~90%) of patients do not develop it. However, the presence of a morphological alteration makes it necessary to rule out the presence of hypopituitarism. 4.6. Diagnosis and therapeutic approach For all patients treated with immune checkpoint inhibitors, preferably ipilimumab, with headaches, fatigue, and hyponatremia (Na b 135 mmol/l), especially if it is between the second and fourth doses, an autoimmune hypophysitis should be ruled out. In this case, hormonal pituitary study and imaging study by MRI will establish the diagnosis. Treatment of choice for IIH is corticosteroids. To date, there are no prospective studies comparing replacement doses with pharmacological doses in patients with immune checkpoint inhibitors-induced autoimmune hypophysitis. Different therapeutic regimens have been recommended depending on the severity of the pituitary involvement. In severe cases (hypophysitis grade ≥ 3) associated with severe headache, severe hyponatremia (Na b 125 mmol/l), significant increase in pituitary volume or association with other irAEs, high doses of iv corticosteroids (dexamethasone, 4 mg/6 h, or methylprednisolone,

prednisolone or prednisone, 1–2 mg/kg/day) with a progressive dose reduction until reaching replacement doses within the first 4 weeks after starting treatment are appropriated [10,33,44,45]. In mild cases (grade 1–2 hypophysitis) treatment with oral hydrocortisone at replacement doses (20–30 mg/day) may be sufficient [35,45,72]. The use of high doses of corticosteroids does not appear to improve the recovery of pituitary function or affect overall survival [49]. In addition, a hormone replacement therapy should be performed on all affected hypothalamic-pituitary axes, except for somatotrope, since the treatment with GH would not be indicated due to tumor disease. Hyponatremia usually responds to treatment with corticosteroids, associated or not with water restriction [70]. Some authors have found an association between ipilimumab-induced irAEs and a better tumor response in patients with metastatic melanoma [10,30,37]. IIH was accompanied by a greater survival (21.4 vs 9.7 months, p = 0.008) in these patients compared to those who did not develop it [10]. Therefore, the development of IIH is not a reason for discontinuation of ipilimumab treatment [45]. Lastly, corticosteroids used in the management of IIH do not appear to influence negatively on its therapeutic benefit [30,32,35,49,68]. 4.7. Clinical evolution Complete recovery of pituitary function in IIH is exceptional [30,40,45, 49]. A prospective observational study of 6 years (2006–2012) performed in 15 patients with IIH and metastatic melanoma showed that the corticotropic, thyrotropin, and gonadotropic function persisted in 87% (13/15); 13% (2/15), and 13% (2/15) of patients, respectively [45]. The possibility of the adverse effect of radiotherapy on pituitary function in patients with metastatic brain involvement should be taken into account. MRI alterations are usually resolved in b 40 days after treatment [10, 30]. The persistent enlargement of the pituitary gland is exceptional and is usually resolved in the majority of cases [10]. However, some authors have described a persistent pituitary abnormality in MRI in a high percentage (78%, 11/14) of patients [45]. Note that the persistence of a pituitary enlargement for N60 days after diagnosis might indicate a secondary (metastatic) involvement of the pituitary [30]. 5. Thyroiditis Cancer immunotherapy-induced thyroiditis is another known irAE increasingly reported [30,44,73,74]. It may manifest as hyperthyroidism or hypothyroidism, either subclinically or overt and in an isolated or sequential way in the same patient over time [73,74].

Fig. 1. A sagittal pituitary MRI scan (T1 sequence) in a 75-year-old male with advanced melanoma diagnosed with ipilimumab-induced hypophysitis. A. At diagnosis of hypophysitis showing a generalized increase of the pituitary with thickening of the pituitary stalk. B. At 3 months after starting treatment with corticosteroids where a significant reduction in pituitary volume is observed (white arrows).

Please cite this article as: Iglesias P, Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.019

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5.1. Prevalence The incidence and prevalence of thyroiditis induced by immunotherapy depends on the type of antibody used, the mode of administration (monotherapy or combined treatment), the presence or absence of thyroid dysfunction pre-treatment and the degree of thyroid dysfunction (subclinical or overt) considered [64,74]. In general, thyroid disorders associated with cancer immunotherapy are more common in women [74]. The prevalence of overt thyroid dysfunction associated with ipilimumab is lower than that observed in hypophysitis. Thus, overt hypothyroidism occurs in 1–6%, whereas frank hyperthyroidism occurs in b2.5% of patients [15,30,39,44,64,74]. However, subclinical thyroid dysfunction is more common (6.4% and 15.9%) for subclinical hypothyroidism and subclinical hyperthyroidism, respectively [74]. Thyroid dysfunction has been reported in a smaller percentage (~2.5%) of tremelimumab-treated patients [75], percentages similar to those of hypophysitis. In contrast, the prevalence of thyroiditis is clearly higher than that of hypophysitis in patients treated with antiPD1 antibodies (pembrolizumab and nivolumab). In this case, a prevalence of total thyroid dysfunction has been reported in up to 18–39% of patients treated with anti PD1 [73,74]. The percentage of hypothyroidism (overt and subclinical) is around 13%, for each of them, while that of hyperthyroidism (frank and subclinical) is b 12% [73,74]. Lastly, thyroid dysfunction appears in about half of patients treated with combination therapy (ipilimumab plus nivolumab), primarily at the expense of overt hypothyroidism (22%) and subclinical hyperthyroidism (22%) [74]. 5.2. Pathogenesis. The pathogenic mechanism of thyroid involvement seems to be related to the development of a process of immunological activation at the thyroid level manifesting in the form of an autoimmune thyroiditis (destructive thyroiditis) induced by immunological and/or inflammatory mechanisms. Regarding thyrotoxicosis, some studies have shown that patients with immunotherapy-induced hyperthyroidism have low or absent Tc99m uptake on thyroid scintigraphy and negativity for anti-TSH receptor (TSI), suggesting an inflammatory thyroiditis (destructive) rather than an authentic Graves' disease (GD) [73,74,76]. Although cases of GD hyperthyroidism associated with ipilimumab treatment have also been reported, even with Graves' ophthalmopathy [77–79]. The onset of persistent primary hypothyroidism following the thyroid hyperfunction phase would support the diagnosis of silent thyroiditis [73]. Some studies have detected positive thyroid autoimmunity in more than half of thyrotoxicosis patients who progressed to hypothyroidism by suggesting an autoimmune pathogenesis [73,74]. Also, the abrupt onset of thyrotoxicosis and the short period of time of primary hypothyroidism following immunotherapy would also be compatible with inflammatory thyroid destruction rather than with thyroid stimulation by TSI [73]. Lastly, diffuse uptake of 18FDG by the thyroid in the 18FDG-PET/CT imaging study in patients with immunotherapy-induced hyperthyroidism would argue in favor of inflammatory thyroiditis.

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serum concentrations of free T4 remained elevated for 15–30 days and began to fall to the hypothyroid range by 6 weeks [73] (fig. 2). The clinical picture of thyrotoxicosis is usually mild (oligosymptomatic) and transient and easily controlled with betablockers. Given its pathogenic mechanism, treatment with antithyroid drugs does not appear to be adequate, unless GD is proven as the etiology of hyperthyroidism. In GD patients, clinical manifestations may be more evident and, in some cases, may manifest as a thyrotoxic storm, requiring treatment with beta blockers, antithyroid agents, and corticosteroids [80]. Isolated cases of Graves' euthyroid ophthalmopathy have also been reported in patients with advanced melanoma treated with ipilimumab with adequate corticosteroid response [77]. Hypothyroidism is more common in women (male:female ratio 6:9) and is generally manifested as asthenia, which can often be confused with that associated with its underlying disease or its treatment [44]. The onset of hypothyroidism is variable and usually occurs within 5– 9 months, although it may be late onset (up to 3 years after initiation of treatment) [44,74]. Spontaneous recovery of thyroid function is unusual, although isolated cases have been reported that were surprisingly treated with high doses of corticosteroids, as part of the treatment of other irAEs, such as hepatitis and colitis or were the previous thyrotoxicosis treated with corticosteroids [74]. Also, severe forms of hypothyroidism, even myxedema coma, associated with nivolumab have been reported [81]. Lastly, as is the case with hypophysitis, immunotherapy-induced thyroid dysfunction has been associated with improved outcomes. Overall survival with pembrolizumab in patients with advanced nonsmall-cell lung cancer was significantly longer in patients who developed thyroid dysfunction [82]. 6. Adrenalitis Primary adrenal insufficiency associated with immunotherapy is very uncommon, although it may be underestimated due to concomitant treatment with corticosteroids or the coexistence of secondary adrenal insufficiency [83]. It has been described in 0.3–1.5% of patients treated with anti-CTLA-4 (ipilimumab and tremelimumab) [19,44,56]. The first case associated with nivolumab has been recently reported [84]. Before establishing its diagnosis it is necessary to rule out as the cause of primary adrenal insufficiency the metastatic infiltration of both adrenal glands [44]. As in the pituitary gland, a bilateral reversible enlargement of the adrenal glands has been reported following the initiation of ipilimumab [83]. The diffuse uptake of 18-FDG by both adrenal glands 4 months after starting treatment with ipilimumab in a patient with advanced melanoma with primary adrenal insufficiency suggested a possible bilateral adrenal metastatic involvement, however, uptake was negativized 2 months later confirmed previous development of bilateral, non-metastatic, inflammatory drug induced adrenalitis by immunotherapy [85]. The same has also been demonstrated with nivolumab [84]. Clinically it is usually manifested as asthenia and may occasionally cause chronic hyponatremia. Treatment with hydrocortisone and fludrocortisone controls symptoms, restores hyponatremia, and allows continued immunotherapy treatment [84].

5.3. Clinical presentation, evolution and therapy approach

7. Insulinitis

In a recently published series, mean age of patients who developed hyperthyroidism associated with immunotherapy (ipilimumab, nivolumab or combination therapy) was 64 years old, predominantly male (male:female ratio 2:1) [74]. TSH began to alter in a median time of 18 days, reaching a nadir, with undetectable TSH levels, at 35 days after the start of treatment. In the case of pembrolizumab, the median time to onset of thyrotoxicosis was 8.6 weeks (range, 6–11) for the case of isolated thyrotoxicosis and 3.1 weeks (range, 3–21) for the thyrotoxicosis that evolved to hypothyroidism [73]. In the latter case,

Immunotherapy has also been associated with autoimmune type 1 diabetes mellitus (T1DM). This adverse effect has recently been reported with nivolumab [86–90], pembrolizumab [86,90,91], and combined treatment with ipilimumab and nivolumab [92]. This complication has been developed in both naive patients and those previously treated with chemotherapy, as well as in patients with and without a history of autoimmune endocrinopathies [91]. It may appear after a treatment period ranging from 1 week to 12 months for nivolumab and up to 4 years for pembrolizumab [91]. Immunological activation derived

Please cite this article as: Iglesias P, Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.019

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Fig. 2. Serum concentrations of TSH, free T4, and free T3 in a 67-year-old female with advanced melanoma treated with ipilimumab plus nivolumab diagnosed of immunotherapy-induced thyroiditis.

from PD1 receptor blockade of T lymphocytes has been proposed as a pathogenic mechanism which would be accompanied by the production of anti-GAD and anti-IA2 antibodies together with the infiltration of T lymphocytes into the pancreatic islets [91]. Also, some high-risk HLA genotypes for T1DM have been reported in patients who have developed this complication [91,92]. At the present time, the treatment of choice is hormone replacement therapy with insulin, whereas the therapeutic role of corticosteroids on the evolution of T1DM induced by immunotherapy is unknown.

8. Parathyroiditis The first case of primary hypoparathyroidism associated with treatment with immunotherapy has been recently reported [93]. He was a 73-year-old man with metastatic melanoma who showed severe hypocalcemia (Ca 5 mg/dl) associated with hyperphosphatemia (P 6.6 mg/dl) with normoalbuminemia and undetectable PTH (b1 pg/ml) just one and a half month after starting immunotherapy (ipilimumab plus nivolumab). Shortly after the patient developed thyroiditis with

Please cite this article as: Iglesias P, Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.019

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hyperthyroidism and later hypothyroidism. At 4 months after diagnosis, parathyroid and thyroid function had not been recovered, requiring chronic therapy with oral calcium, calcitriol, and levothyroxine. 9. Clinical recommendations for monitoring patients under cancer immunotherapy It is important to keep in mind about the risk of developing endocrine irAEs in any patient who is going to initiate cancer immunotherapy. Before starting therapy it would be advisable to perform a hormonal study in all patients evaluating thyroid function measuring TSH and free T4 serum levels. In those patients treated with ipilimumab basal determination of plasma ACTH and serum cortisol with periodic monitoring would be adequate. A low or suppressed serum cortisol level with inappropriately low ACTH levels in the absence of exogenous corticosteroid treatment establishes the diagnosis of secondary adrenal insufficiency. On occasions symptoms as headache and/or fatigue, as well as analytical alterations (hyponatremia) should make us suspect the diagnosis of IIH. When hormonal study is compatible with secondary adrenal insufficiency or central hypothyroidism, a complete pituitary hormonal study and imaging study (pituitary MRI) should be performed. Due to the higher incidence of thyroid dysfunction associated with anti-PD1 antibodies (pembrolizumab and nivolumab), monitoring of thyroid function tests (serum TSH and free T4 levels) before each dose is advisable. It is important to interpret these results in the context of the use of imaging studies with iodinated contrast. In addition, the possibility of developing an autoimmune type 1 diabetes mellitus or an autoimmune hypoparathyroidism should be considered. Therefore, it would be also recommended to periodically monitor glycemia and calcemia in these patients. 10. Conclusions Endocrine irAEs associated with cancer immunotherapy are increasingly reported. To date, an involvement of the pituitary, thyroid, parathyroid, adrenal glands and endocrine pancreas has been reported. The pathogenic mechanism seems to be related to a process of immunological/inflammatory activation at the glandular level that, in many cases, is accompanied by a hormonal deficiency in the long term, which forces a permanent hormone replacement therapy. It is essential to know the clinical behavior and therapeutic management of these endocrine irAEs within a multidisciplinary team context in conjunction with the oncologist and the rest of the medical specialties potentially involved in the management of other non-endocrine irAEs associated with cancer immunotherapy. References [1] Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013;19:5300–9. [2] Ito A, Kondo S, Tada K, Kitano S. Clinical development of immune checkpoint inhibitors. Biomed Res Int 2015;605478. http://dx.doi.org/10.1155/2015/605478. [3] Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 2015;13:211. [4] Costa R, Carneiro BA, Agulnik M, Rademaker AW, Pai SG, Villaflor VM, et al. Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. Oncotarget 2017;8:8910–20. [5] Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One 2013;8:e53745. [6] Torino F, Corsello SM, Salvatori R. Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol 2016;4:278–87. [7] Joshi MN, Whitelaw BC, Palomar MT, Wu Y, Carroll PV. Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review. Clin Endocrinol 2016;3:331–9. [8] Marrone KA, Ying W, Naidoo J. Immune-related adverse events from immune checkpoint inhibitors. Clin Pharmacol Ther 2016;3:242–51. [9] Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016;44:51–60.

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Please cite this article as: Iglesias P, Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.08.019