REVIEW Clinical Medicine 2021 Vol 21, No 2: e212–22

Endocrine complications of immunotherapies: a review

Authors: Rosie Hattersley, A Melanie NanaB and Andrew J LansdownC

Use of immune checkpoint inhibitors in cancer treatment CTLA-4 acts in the early stage of triggering an antigen response,
ABSTRACT

has increased vastly over the past decade, as both single while PD-1 and PD-L-1 act in modulating the interaction with
and combination agent therapies. While having a positive peripheral tissue.8 For this reason, combination therapy has been
impact on survival rates, adverse effects have been noted, demonstrated to be effective.5,8 The mechanisms of action are
with endocrine effects in around 10% of patients. Thyroid summarised in Fig 1.
disease and hypophysitis are the most commonly encountered, Ipilimumab, a CTLA-4 inhibitor, became the first approved
with diabetes mellitus and primary adrenal insufficiency also checkpoint inhibitor in 2011, with 1–2-year survival rates
reported, as well as more rare endocrinopathies. Patient and doubling for metastatic melanoma, including for patients with
clinician education to raise awareness of these effects, as well advanced disease.7 By 2014, the PD-1 inhibitors nivolumab and
as regular monitoring to enable early recognition, diagnosis and pembrolizumab were approved, showing superior and sustained
prompt treatment of the immune side effects, are key. In this increases in melanoma survival.8 PD-1 inhibitors and newer PD-L-1
review, we discuss the aetiology, presentation and management inhibitors are now licensed to treat a variety of other cancers,
of the endocrine complications of immunotherapies that including renal cell carcinoma and non-small cell lung cancer
are relevant to the general physician, as well as highlighting (Table 1).9,10 Combination of CTLA-4 and PD-1 inhibitors has been
important areas where further research is still needed.

KEYWORDS: immunotherapy, cancer, endocrine, thyroid,

hypophysitis a b
T-cell 2
An-PD-1
DOI: 10.7861/clinmed.2020-0827 mAb
PD-1 Increased
immune
response
T-cell An-PD-
L-1 mAb
Introduction 3 An-
PD-L-1 CTLA-4
The advent of immunotherapy has revolutionised cancer treatment Decreased PD-1
2
mAb
immune CD-80
across the world. Through harnessing the immune system to target response
PD-L-1
CTLA-4
1
Cancer cell
malignant cells, previously untreatable cancers now have radically
CTLA-4
improved survival rates.1 The use of immunotherapy has increased CD-80
CD-28
T-cell
over the past decade, becoming commonly used for a number T-cell
of solid tumours and haematological malignancies.2 However, a 1

predicted 60–95% of patients experience ill effects, which, if left CD-28

untreated, may be life-threatening.3,4 Fig 1. Simplified illustration of the mechanism of checkpoint inhibitor
Checkpoint inhibitors are a group of monoclonal antibody modulation of the immune response to cancer cells. a) Normal physi-
therapies that can be used in isolation or in combination. They ological state. In the unaltered physiological state, detection of cancer cell
are given via intravenous infusion, typically every 3–6 weeks, for antigens, either via antigen-presenting cells or cancer cells themselves, causes
up to 2 years. They exert their effect by upregulating the immune T-cell activation. Pictured are two physiological mechanisms that reduce exag-
response to malignant cells, blocking the usual inhibitory pathways gerated immune response, but also immunosurveillance and therefore elimina-
of T-cell regulation.5 The receptors cytotoxic T-lymphocyte antigen tion of cancer cells. (1) CTLA-4 outcompetes CD-28 to bind to CD-80. Instead
of further activation by CD-28, CTLA-4 sends inhibitory signals to deactivate
4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its
T-cells. (2) Binding of PD-L-1 on the cancer cell or antigen-presenting cell to
associated ligand (PD-L-1) are targeted by the inhibitors.6,7 The PD-1 on a T-cell activates inhibitory signals to immune response and encour-
immune system can be manipulated at two different stages, as ages apoptosis of immune cells. b) State with checkpoint inhibitor therapy.
Checkpoint inhibitor therapy acts on both mechanisms via three targets. (1)
Anti-CTLA-4 mAb binds to CTLA-4, resulting in subsequent promotion of T-cell
activation and survival by the CD-28 pathway. (2) Anti-PD-1 mAb binds to
Authors: Ainternal medicine trainee, Velindre Cancer Centre, PD-1 on T-cells, preventing a negative feedback pathway. (3) Anti-PD-L-1 mAb
Cardiff, UK; Bspecialty registrar in diabetes and endocrinology, binds to PD-L-1 on cancer cells, preventing the same negative feedback. CTLA-4
University Hospital of Wales, Cardiff, UK; Cconsultant = cytotoxic T-lymphocyte antigen 4; mAb = monoclonal antibody; PD-1 =
endocrinologist, University Hospital of Wales, Cardiff, UK protein death 1; PD-L-1 = protein death ligand 1.

e212 © Royal College of Physicians 2021. All rights reserved.

 Table 1. List of checkpoint inhibitors and their uses, with notable adverse effects
Drug Mechanism Cancer sites with EMA Notable adverse Notable endocrine Dose-dependent Other comments
approval for treatment effects effects10,14,16 adverse effects?
Ipilimumab Anti-CTLA-4 Melanoma >10% fatigue/rash/ Greater risk of hypophysitis Yes Inferior effects on survival compared with
(Yervoy) mAb diarrhoea than other monotherapy (3%) other checkpoint inhibitor monotherapy

© Royal College of Physicians 2021. All rights reserved.

2–5% thyroid dysfunction or combination
1% adrenal insufficiency
Tremelimumab Anti-CTLA-4 Not approved by EMA/FDA Less known, likely similar Yes Granted ODD by FDA for treating HCC in
mAb currently to ipilimumab combination with durvalumab
Pembrolizumab Anti-PD-1 Melanoma >20% fatigue/nausea/ 5–10% thyroid dysfunction No Patients with tumours expressing high
(Keytruda) mAb NSCLC (PD-1 expressing or diarrhoea Greater risk of hyperthyroid PD-L-1 levels have a better response and
non-squamous) compared with anti-PD-L-1 this is used to stratify treatment choice
34% skin effects3
in NSCLC
Hodgkin’s lymphoma Highest incidence diabetes
Urothelial mellitus (1%)
RCC 1% adrenal insufficiency
Head and neck SCC
CRC (with MMR/MSI)
Nivolumab Anti-PD-1 Melanoma >10% fatigue/nausea/ 5–10% thyroid dysfunction No Studies proving benefit after failure of
(Opdivo) mAb NSCLC appetite loss (greater risk of hyperthyroid platinum-based chemotherapy
Hodgkin’s lymphoma 34% skin effects3 compared with anti-PD-L-1)
Urothelial 0.5–1% diabetes mellitus
RCC 1% adrenal insufficiency
Head and neck SCC

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Endocrine complications of immunotherapies
e214
Table 1. List of checkpoint inhibitors and their uses, with notable adverse effects (Continued)
Drug Mechanism Cancer sites with EMA Notable adverse Notable endocrine Dose-dependent Other comments
approval for treatment effects effects10,14,16 adverse effects?
Atezolizumab Anti-PD-L-1 NSCLC and SC lung cancer >10% fatigue/arthralgia/ Most associated with adrenal No Generally for advanced or metastatic
(Tecentriq) mAb Breast cancer (triple nausea/rash/diarrhoea insufficiency (1–2%) disease, proven to improve survival
negative) Fewer other endocrinopathies particularly in combination with
than other drugs chemotherapy
Urothelial
Avelumab Anti-PD-L-1 Merkel cell carcinoma >10% fatigue/nausea/ 1% diabetes mellitus No Granted conditional marketing
(Bavencio) mAb authorisation in EU in 2017, awaiting
Rosie Hattersley, Melanie Nana and Andrew J Lansdown

RCC diarrhoea/constipation Fewer adrenal effects than

other anti-PD-L-1 mAb further clinical evidence

Durvalumab Anti-PD-L-1 NSCLC >20% rash/cough/ENT 1% diabetes mellitus No Used when tumours express high PD-L-1
(Imfinzi) mAb infections 1% adrenal insufficiency levels
>10% drug-related Greater thyroid dysfunction
pneumonia than other PD-L-1 mAb
Ipilimumab and Anti-CTLA-4 Melanoma >50% fever, fatigue, rash 20% thyroid dysfunction Yes Used for high-risk RCC as first line, and for
nivolumab mAb and RCC 6% hypophysitis melanoma with low PD-L-1 expression.
Greater incidence of all
anti-PD-1 Generally more effective than
Head and neck SCC immune-related adverse 5–7% adrenal insufficiency
mAb monotherapy
effects
Unless specified above, information from EMA website.10 CRC = colorectal cancer; CTLA-4 = cytotoxic T-lymphocyte antigen 4; ENT = ear, nose and throat; EMA = European Medicines Agency; EU = European Union; FDA = US
Food and Drug Administration; HCC = hepatocellular carcinoma; mAb = monoclonal antibody; MMR = mismatch repair gene; MSI = microsatellite instability; NSCLC = non-small cell lung cancer; ODD = orphan drug designation;
PD-1 = programmed cell death protein 1; PD-L-1 = programmed cell death protein ligand 1; RCC = renal cell cancer; SCC = squamous cell carcinoma.

© Royal College of Physicians 2021. All rights reserved.

 Endocrine complications of immunotherapies

shown to be effective in metastatic melanoma, colorectal and Typically the disease process is a thyroiditis, which includes a brief,
renal cancer, with a 58% 3-year survival for metastatic melanoma self-limiting thyrotoxic phase that lasts 3–6 weeks, followed by a
patients (which had previously been 20%).9 These survival rates prolonged hypothyroid phase.19,20 This phase is irreversible in two-
demonstrate that these immunotherapy treatments have thus thirds of patients.16 The most common mechanism described in
revolutionised the treatment of certain malignancies with a the literature is an inflammatory destruction of the thyroid gland
historically poor prognosis. by cytotoxic T-cells, causing either excess thyroid hormones due
Despite these encouraging survival data, the drugs are to thyroid tissue breakdown, or inadequate hormone synthesis.15
not without adverse effects, ranging from mild biochemical Rarely, isolated hyperthyroidism or hypothyroidism may be
abnormalities to fatal events (incidence reported as 0.64%).4 seen, and CTLA-4 or PD-1 inhibitors can cause an autoimmune-
The mechanism is due to the exaggerated immune response mediated Graves’ disease.
towards non-cancerous cells, causing significant inflammation
and destruction.11 The most commonly affected systems Clinical presentation
include the skin, gastrointestinal system, endocrine system and Presenting symptoms mirror those outside the use of
liver.2,12 The National Cancer Institute produced the Common immunotherapy and include lethargy, weight gain, dry skin and
Terminology Criteria for Adverse Events (CTCAE) to categorise constipation in hypothyroidism, and weight loss, palpitations,
the spectrum of toxicities from mild (grade 1) to death (grade 5), anxiety and sweating in hyperthyroidism.16,18 Patients may also be
with severe symptoms requiring hospitalisation defined as grade identified on routine screening with few or no symptoms. Severe,
3 and above.13 Incidence of severe events is reported as 26% for life-threatening illness, such as myxoedema coma or thyrotoxic
monotherapy and increases to 55% with combination therapy.3,14 storm, is rare, occurring in 0.1% of cases.15,18
Immune-related endocrinopathies affect around 10% of all
patients treated with checkpoint inhibitors.15 In those receiving
PD-1 and CTLA-4 inhibitors, thyroid disease and hypophysitis
Diagnosis
Diagnosis is confirmed using routine thyroid function tests
are the most commonly encountered.16 Effects on the adrenal
(Fig 2). Autoantibodies should be tested if a diagnosis of Graves’
glands, pancreas and parathyroid glands have also been reported
disease is considered (usually in the presence of ophthalmopathy,
(Table 2). Most endocrinopathies present with non-specific
persistent thyrotoxicosis or a goitre).17,18,21
symptoms, posing a diagnostic challenge as this patient group
also can experience vague symptoms from malignant disease
and anti-cancer treatment. The most commonly reported side Treatment
effect of checkpoint inhibitors is fatigue, mostly without endocrine Those patients who develop mild or self-limiting thyroid disease
cause. Because of this, symptoms can dangerously be dismissed do not require treatment and can be managed by the oncology
or attributed to other, less treatable causes. Diagnosis is also team. They require little to no disruption to their immunotherapy
complicated by extensive use of corticosteroids, anti-emetics treatment and simply require monitoring blood tests. Those
(co-administered with checkpoint inhibitors) and episodes of with symptoms or severe biochemical abnormalities should
severe illness secondary to immunosuppression, which complicates be discussed with an endocrinologist and treatment initiated
diagnostic testing of hormonal axes. promptly. In such patients, immunotherapy may need to be
While it is not fully understood why endocrine tissue is held.17,18,22
particularly vulnerable, hypotheses have been proposed. These Treatment guidelines are summarised in Fig 2. In patients
include the expression of CTLA-4 in pituitary tissue and the role of with hypothyroidism, adrenal insufficiency must be excluded
PD-1/PD-L-1 in immune tolerance disruption in the pathogenesis (or, if identified, treated) prior to commencing thyroid hormone
of autoimmune endocrinopathy. Additionally, endocrine tissue is replacement in order to prevent exacerbating an adrenal
non-regenerative and very low volume, so an immune destruction crisis.17,18,23 Levothyroxine should be titrated according to
has large consequences on essential hormone secretion. Given thyroid-stimulating hormone (TSH) in primary hypothyroidism,
the increasing use of these therapies, many such patients may and thyroxine (T4) levels in secondary hypothyroidism. For
present on the unselected medical intake. UK guidelines from those with hyperthyroidism, symptomatic treatment is often
the Society for Endocrinology provide practical guidance for this adequate as many self-resolve.16,22 Blockade of thyroid hormone
setting, but these are only useful if the general physician considers synthesis is ineffective for inflammatory hyperthyroid disease,
this differential diagnosis.17 Awareness should be raised as to the so unless there is convincing evidence of Graves’ disease, it is not
risk of such effects in patients on these medications among all recommended.17,18
physicians in order to avoid preventable morbidity and mortality.
Pituitary
Endocrinopathies Incidence and aetiology
Hypophysitis is the most common endocrinopathy caused by
Thyroid CTLA-4 inhibitors.24 It refers to inflammation of the pituitary
Incidence and aetiology gland or stalk, causing disruption of the hypothalamic–pituitary
Primary thyroid disease represents the most common endocrine axis. Incidence is reported as 1.3% overall, with incidence on
immune-related adverse effect.4,15,16 Overall incidence is CTLA-4 inhibitors and combination therapy reported as 3% and
reported as 8% for primary hypothyroidism and 3% for primary 6% respectively.15 Disruption of the hypothalamic–pituitary axis
hyperthyroidism.15,16 Thyroid abnormalities are more commonly occurs due to pituitary damage, likely secondary to complement-,
associated with PD-1 inhibitors and typically occur 4–10 weeks antibody- and lymphocyte-driven processes, with pituitary
after initiation of treatment, but can occur up to 3 years later.16,18 necrosis occurring in severe disease.25 Hypophysitis can typically

© Royal College of Physicians 2021. All rights reserved. e215

 Table 2. Summary of the adverse endocrine effects of immune checkpoint inhibitors

e216
Gland Incidence15,16 Most Typical Symptoms16,45 Screening Suggested Treatment3,17 Prognosis16
commonly time from advised? Investigations3,17
associated treatment
checkpoint onset16
inhibitors3,16
Thyroid Hypothyroid: Anti PD-1 mAb 6 weeks Hypothyroid: fatigue, TSH with TSH, T4, T3 Hypothyroid: Continue Typical disease
overall 8%, or combination (range 4–10 dry skin, constipation, every cycle or Consider pituitary immunotherapy course 3–6 weeks
combination up weeks) depression, cold monthly, and screen if abnormal Hyperthyroid: continue hyperthyroid, then
to 13% sensitivity, weight gain 4–6 weeks immunotherapy if prolonged hypothyroid
If thyrotoxicosis: anti-
Hyperthyroid: Hyperthyroid: fatigue, after final cycle asymptomatic, hold if Two-thirds required
TPO Ab, anti-TSHR Ab,
overall 2.9%, palpitations, diarrhoea, cortisol, glucose symptomatic and restart long-term thyroid
combination 8% anxiety, insomnia, when symptoms resolve replacement
If clinical uncertainty:
weight loss See Fig 2 Hyperthyroidism
thyroid uptake scan
rarely persists
Pituitary Overall 1.3%, Anti-CTLA-4 12 weeks General: fatigue, nausea Nil Cortisol (ideally 9am, Hold immunotherapy until Secondary adrenal
combination mAb or (range 3–72 Hormone deficiency: Low threshold random if unwell), symptoms controlled, then insufficiency (ACTH
Rosie Hattersley, Melanie Nana and Andrew J Lansdown

6.4% combination weeks) hypothyroid (see thyroid), for screening ACTH, TSH, T4, LH/ most can restart deficiency) mainly
low cortisol (see adrenal) FSH, oestradiol (if Continue if asymptomatic irreversible
and sex hormone premenopausal), Thyroid and sex
See Fig 3
deficiency (erectile testosterone (men), hormones tend to
dysfunction, menstrual IGF-1, prolactin recover within 3
disturbance, loss of libido) MRI pituitary months
Mass effect: headache,
visual loss
Pancreas Overall 0.5%, Anti-PD-1 or 7 weeks Thirst, polyuria, fatigue, Regular blood Glucose, ketones, Hold while blood glucose Irreversible
1% with anti- Anti-PD-L-1 mAb (range 1–52 weight loss glucose Hba1c, C-peptide, anti- uncontrolled, restart once
PD-1/anti-PD-L-1 weeks) Two-thirds present with monitoring GAD Ab, ICA Ab insulin initiated or stable
DKA No imaging advised Most need insulin
therapy. If mild, trial oral
antihyperglycaemic agents
Adrenal Monotherapy Anti-PD-1 or 10 weeks Fatigue, dizziness, Nil Cortisol, ACTH, TFT High-dose steroids initially, Irreversible
1% Anti-CTLA-4 (range 1–36 weakness, nausea, Low threshold CT adrenals wean to hydrocortisone
Combination mAb or weeks) abdominal pain for 9am cortisol 20–30 mg/day
5–7% combination Fludrocortisone if postural
hypotension persists
ACTH = adrenocorticotrophic hormone; CTLA-4 = cytotoxic T-lymphocyte antigen 4; FSH = follicular stimulating hormone; GAD = glutamic acid decarboxylase; ICA = islet cell antigen; IGF-1 = insulin-like growth factor 1; LH =
luteinising hormone; mAb = monoclonal antibody; PD-1 = programmed cell death protein 1; PD-L-1 = programmed cell death protein ligand 1; T4 = thyroxine; T3 = triiodothyronine; TPO = thyroid peroxidase; TSH = thyroid-
stimulating hormone; TSHR = thyroid-stimulating hormone receptor.

© Royal College of Physicians 2021. All rights reserved.

 Endocrine complications of immunotherapies

Clinical suspicion of thyroid dysfuncon or roune test

Hypothyroid Hyperthyroid

Low/normal TSH, low T4 High TSH, low T4 High TSH, normal T4 Low TSH, high T4
Normal TSH, high T4
(secondary hypothyroidism) (primary hypothyroidism) (subclinical hypothyroidism) (primary hypothyroidism)

Possible pituitary case, If asymptomac, recheck next If asymptomac, recheck next Recheck next cycle without If asymptomac, recheck next
check pituitary screen cycle without starng treatment. cycle without starng treatment. treatment. cycle without starng treatment.
Diagnosis

including 9am corsol. If symptomac, start If symptomac and TSH >10 mU/L, If persistent, discuss with If symptomac, start treatment,
If asymptomac, recheck levothyroxine. start levothyroxine. endocrine team uptake scan and autoanbodies.
TFT and corsol with next
cycle without starng thyroxine. Symptomac Symptomac
or persistent or persistent

Start beta-blocker, if required (propranol or atenolol).

Treatment

If co-exisng low corsol, Start at low dose levothyroxine 75 µg (or 25–50 µg, if elderly,
must replace for >48 hours cardiac issues or severe symptoms). If suspicion of Grave's disease, refer to endocrine for
before thyroid replacement. Inform oncology team. Connue checkpoint inhibitor therapy. TSHR Ab and consideraon of carbimazole.
Inform oncology team. Hold checkpoint inhibitor therapy
if unwell, restart when symptoms controlled.
Monitoring

Screen for all endocrinopathies.

Recheck TFT and corsol with next cycle. Screen for all endocrinopathies.
Note: TSH will not respond to levothyroxine for 6 weeks. Repeat TFT and corsol in 1–2 weeks.

Life long

Titrate dose to TSH in primary hypothyroidism and T4 levels in

Long term

secondary hypothyroidism. If develops hypothyroid, If persists for

Refer to endocrine if difficulty stabilising thyroid funcon. manage as per pathway. endocrine input.
TSH monitoring may gauge thyroid follicle recovery.

Fig 2. Management of thyroid dysfunction secondary to checkpoint inhibitors: a clinical guide. Information as per Society for Endocrinology guidelines
and UK Oncology Nursing Society.17,45 Ab = antibody; T4 = thyroxine; TFT = thyroid function test; TSH = thyroid-stimulating hormone; TSHR = thyroid-
stimulating hormone receptor.

present approximately 8–10 weeks following initiation of therapy, that this is done on an urgent basis, particularly if headache,
less commonly after the first 3 months, although presentation diplopia or cranial nerve palsies are present.17 The pituitary may
many months later can be seen.16 The incidences of pituitary show mild to moderate enlargement in the acute phase and
hormone deficiencies are reported as 83% for secondary adrenal possible stalk thickening.27 Resolution of changes is often seen on
deficiency, 77% for secondary hypothyroidism and 53% for repeat imaging within days to weeks.2,27
hypogonadotrophic hypogonadism.18,19,26 It is common for
patients to exhibit multiple deficiencies, with three being the most Treatment
commonly reported number.25 Management involves hormone replacement and referral to
an endocrinologist. Those patients requiring glucocorticoid
Clinical pres entation replacement usually require this for the long term. As previously
Presentation can be non-specific, including symptoms of nausea, mentioned, glucocorticoid should be initiated prior to thyroid
fatigue and headache, many of which are common in cancer patients replacement to avoid precipitating an adrenal crisis. Physiological
and often associated with its treatment. At presentation, 60% of doses are advised, with no evidence that high-dose steroid improves
patients have a headache.25 Other symptoms relate to secondary survival or reversibility.17,27 Intravenous methylprednisolone is only
hormone deficiency, with 72% of patients exhibiting symptoms recommended for neurological complications of hypophysitis.17
of secondary cortisol deficiency at presentation (dizziness, fatigue, Maintenance of 5 mg prednisolone once daily or hydrocortisone 10
nausea, vomiting, abdominal pain).25 Posterior lobe disorders are rare; mg twice daily is generally sufficient. Patient education is important,
in those who do experience this, symptoms mainly relate to secondary particularly regarding sick day rules and parenteral hydrocortisone
hormone deficiencies.18 Visual disturbance is rare in comparison to administration if severely unwell.23 Mineralocorticoids do not need
primary pituitary disorders as minimal pituitary enlargement occurs, to be replaced as they are still produced due to renin–angiotensin
thus reducing the risk of optic chiasm involvement.25 regulation.3,15
In patients requiring thyroid and gonadal hormone
Diagnosis replacement, this is usually on a temporary basis. Thyroid
Diagnosis includes biochemical assessment of the hypothalamic– replacement should start at a low dose and be titrated to T4
pituitary axis and imaging of the pituitary. If hypophysitis is levels, with TSH monitoring useful for indication of pituitary
suspected, a full pituitary screen is recommended, as summarised thyrotroph recovery.3 Sex hormone replacement can be
in Fig 3. considered with oestradiol for premenopausal women and
Imaging of the pituitary is pertinent in ruling out metastatic testosterone for men, with caution paid to contraindications
disease, with magnetic resonance imaging (MRI) being the gold – particularly malignancy related and risk of thrombosis with
standard.3,17,21 Society for Endocrinology guidelines recommend oestrogen replacement. 29

© Royal College of Physicians 2021. All rights reserved. e217

Rosie Hattersley, Melanie Nana and Andrew J Lansdown

Symptomac of hypothyroid or Clinical suspicion of pituitary dysfuncon

roune tesng: low/normal TSH Symptomac of adrenal insufficiency.
and low T4.

Endocrine panel: corsol (ideally 9am, but random if unwell), ACTH, TSH, free T4, free T3,
LH, FSH, testosterone/oestrogen, prolacn, consider IGF-1, blood glucose and roune bloods.

If corsol or ACTH deficiency strongly suspected, while awaing diagnosc tesng:

treat with oral hydrocorsone (10 mg / 5 mg / 5 mg) or, if signs of severe and possibly life-threatening hypoadrenalism, hydrocosone IV/IM 100 mg followed by
a hydrocosone infusion with IV fluids 200 mg / 24 hours.
Diagnosis

Low/normal FSH/LH,
Low/normal TSH, low T4
low testosterone/oestrogen Low/normal ACTH, low corsola Low IGF-1, low GH

Diagnosis of hypophyss suggested by above blood test results.

Arrange urgent MRI pituitary to exclude metastases; refer to endocrine team.
Inform oncology team; connue checkpoint inhibitor therapy if no or mild symptoms, hold if severe or unwell.

If co-exisng adrenal insufficiency, To be iniated by endocrinologist. If on stress dose steroids, wean as Replacement of GH not required
Rule out contraindicaons (eg hormone drive symptoms allow, unl on
Treatment

give steroids >48 hours first. so do not change management.

If asymptomac, recheck without malignancy: prostate or breast). hydrocorsone 10 mg / 5 mg / 5 mg Can help if diagnosc uncertainty.
treatment. Baseline PSA/HCT/testosterone for men. per day.
If symptomac for levothyroxine, Baseline VTE risk assessment for women, Paent educaon: compliance, sick days,
starng dose 25–75 µg severe cauon with HRT, rarely replaced. IM administraon and alert card. a Corsol interpretaon:
9am or random >450 nmol/L,
AI unlikely.
9am 200–450 nmol/L or
Monitoring

Check 9am corsol weekly, inially. Men: 3 monthly for 6 months, then Monitor electrolytes and BP to random 100–450 nmol/L,
Titrate thyroxine dose to T4 levels. 6 monthly PSA, testosterone and HCT. ensure adequately treated. AI possible – consider connuing
Women: seek specialist advice. steroids if delay in endocrine review.
9am <200 nmol/L or random <100 nmol/L,
Symptomac or persistent Life long
AI likely, connue steroids.

Monitor TSH for indicaon of Endocrine follow-up. Endocrine follow-up.

Long term

thyrotroph recovery. Most do not need long-term Most not need long-term
Most do not need thyroxine in the replacement. replacement without recovery.
long term.

Fig 3. Management of hypophysitis secondary to checkpoint inhibitors: a clinical guide. Information as per Society for Endocrinology guidelines and
UK Oncology Nursing Society.17,45 Ab = antibody; ACTH = adrenocorticotrophic hormone; AI = adrenal insufficiency; BP = blood pressure; FSH = follicular
stimulating hormone; GH = growth hormone; HCT = haematocrit; IGF-1 = insulin-like growth factor 1; IM = intramuscular; IV = intravenous; LH = luteinis-
ing hormone; PSA = prostate specific antigen; T4 = thyroxine; T3 = triiodothyronine; TFT = thyroid function test; TSH = thyroid-stimulating hormone;
TSHR = thyroid-stimulating hormone receptor.

Pancreas pancreatic tissue, and only a mildly elevated HbA1c, given the acuity
of the disease process.16,30 Autoantibodies are positive in about half
Incidence and aetiology of patients, with cases of both pre-existing and newly developed
While less common than thyroid or pituitary disease, the life- autoantibodies both reported.16,19,32 Despite this, Society for
threatening consequences of pancreatic tissue destruction caused by Endocrinology guidelines state that pancreatic autoantibodies (islet
checkpoint inhibitors are clinically important. PD-1 and PD-L-1 agents cell and GAD (glutamic acid decarboxylase)) should be taken, with
are associated with a 1% incidence of diabetes mellitus (DM), either potential use to distinguish between type 1 and 2 DM.17
new-onset type 1 DM or worsening type 2 DM.16,30 The mechanism
appears similar to the permanent autoimmune process of type 1 Treatment
DM, but with faster, aggressive destruction of beta islet cells, likely Given the aggressive pathophysiology, insulin therapy is usually
mediated by T-cells, requiring rapid insulin replacement.30,31 Of those essential. It is noted that, unlike other immune-related adverse
developing type 1 DM secondary to immunotherapy, approximately events, the disease process is worsened by glucocorticoids as a
70% of patients exhibit a recognised genetic predisposition to DM.32 consequence of increased insulin resistance with no evidence
The alternative cause of corticosteroid use should also be considered to support reversal of the beta cell damage.30 Routinely,
as a more common cause for hyperglycaemia. immunotherapy is held until the hyperglycaemia is controlled, but
cessation of treatment is not always required.3,22 In those patients
Clinical presentation in whom new hyperglycaemia is mild (less than 11 mmol/L) or
Presenting symptoms include thirst, polyuria, polydipsia, type 2 DM is pre-existing, treatment may continue uninterrupted,
dehydration, weight loss and lethargy.16 Approximately two-thirds with counselling on lifestyle modification and consideration of oral
of patients present in diabetic ketoacidosis, with the remainder antihyperglycaemic agents, with microvascular and macrovascular
with severe hyperglycaemia.32 The median time from treatment complication management as per the National Institute for Health
initiation to presentation is 7–17 weeks, with a small number of and Care Excellence (NICE) guidelines for type 2 DM.3,21
cases presenting years after treatment initiation.30,33
Adrenal
Diagnosis Incidence and aetiology
Investigations tend to reveal an elevated plasma glucose, a very Primary adrenal insufficiency (PAI) is reported as 1% with either
low or absent serum C-peptide, reflecting the rapid destruction of CTLA-4 or PD-1 monotherapy, and 5–7% on combination

e218 © Royal College of Physicians 2021. All rights reserved.

 Endocrine complications of immunotherapies

therapy.13,15 Its likely cause is irreversible antibody-mediated, phosphate and vitamin D should be monitored alongside
and possible T-cell-mediated, immune destruction of the adrenal calcium. Ruling out alternative causes for hypoparathyroidism,
glands.16,34,35 Production of glucocorticoids is predominantly such as previous surgery, should be included in the work-up.
affected, with only one-third of patients symptomatic of Electrocardiography should be performed to assess the QT interval.
mineralocorticoid deficiency.19
Treatment
Clinical presentation Management is of calcium replacement, either intravenously or
Presenting symptoms are non-specific including fatigue, nausea, orally depending on the severity of deficiency. Cardiac monitoring
dizziness and anorexia, so a high clinical index of suspicion is may be needed. Ongoing management is then with the initiation
required. In a review of 451 patients with PAI secondary to and titration of alfacalcidol according to serum calcium levels.
checkpoint inhibitors, 90% presented with adrenal crisis, and There is insufficient evidence to dictate whether cessation of
mortality was recorded as 7%.34 Time of onset can range from immunotherapy is necessary, and this should therefore be decided
6 days to 18 months post-treatment initiation.34 on a case-by-case basis.
A thorough history of recent steroid use is needed, including In addition, when considering calcium disorders, the relevance
inhaled, topical or injected therapy. All can suppress adrenal of other oncology factors must be taken into consideration, such
function and adrenal insufficiency from exogenous steroid use is a as the presence of skeletal metastases and drugs relevant to their
more common diagnosis than adrenalitis. management, such as the use of bisphosphonates or denosumab.
Hypocalcaemia is an important side effect of these drugs.
Diagnosis
Electrolyte monitoring may aid diagnostic suspicion and should Other rare endocrinopathies
also be monitored following diagnosis, as hyponatraemia and Diabetes insipidus
hyperkalaemia can occur. Diagnosis can be made from a low Diabetes insipidus (DI) is rarely reported in immunotherapy – only
morning cortisol with a high morning adrenocorticotropic hormone two cases to date – in comparison to pituitary metastasis as a
(ACTH), with confirmation provided by a poor response to synthetic cause. It is thought to be a consequence of inadequate antidiuretic
ACTH.21 Computed tomography (CT) of the adrenal glands may hormone (ADH) secretion secondary to hypophysitis affecting
demonstrate atrophy or adrenalitis and facilitate exclusion of other the posterior pituitary.26,43 Patients presented with polyuria,
causes. Anti-21-hydroxylase antibodies may also be helpful in polydipsia, thirst and fatigue, with diagnosis being confirmed
excluding autoimmune aetiology, but are not commonly done.17,21,34 by serum osmolality >295 mmol/kg and urine osmolality
<600 mmol/kg. Spontaneous remission was demonstrated
Treatment in both cases, with one requiring no treatment and the other
Management requires prompt replacement of glucocorticoids demonstrating reversibility after 6 weeks of desmopressin
(hydrocortisone 20–30 mg/day), and mineralocorticoids (DDAVP).26 It is important to note that there is potential for DI to
(fludrocortisone) if required. If the patient is acutely or life-threateningly be masked until concomitant ACTH deficiency is treated.
unwell initially, Society for Endocrinology guidelines advocate Furthermore, only one case of ACTH-dependent Cushing’s
higher-dose glucocorticoids, tapering to physiological dose following syndrome has been reported.19,44 Presentation included mild
clinical recovery, with prompt endocrine referral.17 As with pituitary- symptoms of cortisol excess (weight gain, depression and fatigue)
related insufficiency, patient education in terms of sick day rules and and there was spontaneous resolution, then development of
emergency hydrocortisone is vital. Patients can be supplied with an secondary cortisol insufficiency. By far a more common cause
NHS steroid card to improve management in the emergency setting.36 is iatrogenic Cushing’s syndrome, with corticosteroids used
It is advised to hold immunotherapy while unwell, with scope for frequently for cancer-related symptoms, non-endocrine immune-
continuing it later when stable on hormone replacement.21,22 related adverse events and hypersensitivity reactions.
Polyglandular endocrinopathies have also been described,
Parathyroid commonly the thyroid gland and one of the other aforementioned
endocrinopathies.19
Incidence and aetiology
Parathyroid involvement appears to be exceedingly rare, with
only five case reports of hypoparathyroidism reported and no Other considerations
hyperparathyroidism.37–41 Unlike other endocrinopathies, most Clinician and patient education
patients have described a reversible inflammatory process.39 Onset Endocrine complications of checkpoint inhibitors require prompt
is later, reported between 4 and 11 months following initiation of diagnosis in order to prevent significant morbidity and mortality.
either PD-1 inhibitor or combination therapy.39 Patient education of these adverse effects is important to aid early
recognition of the endocrinopathies and prevent delay in diagnosis.
Clinical presentation Patients should be counselled to inform healthcare professionals
Hypocalcaemia can present as nausea, vomiting, paraesthesia, if they are currently or previously receiving checkpoint inhibitors.
cramps, abdominal pain, confusion and fatigue.40,42 If severe, life- Dissemination of information to physicians in both primary and
threatening arrhythmias or seizures can occur. secondary care is also pertinent in supporting prompt diagnoses.45

Diagnosis Screening
Diagnosis is confirmed by a low serum calcium with a low or Since the presentation of these complications may be indolent
non-elevated parathyroid hormone level. Serum magnesium, and non-specific, screening offers a potentially useful tool. Regular

© Royal College of Physicians 2021. All rights reserved. e219

Rosie Hattersley, Melanie Nana and Andrew J Lansdown

monitoring of thyroid function and blood glucose is universally like SARS-CoV-2.48,50 Experience from previous viruses suggests
recommended, but screening for adrenal and pituitary disease is that the latter rarely occurs. To reduce the risk in vulnerable
more challenging.3,21 Although the consequences of glucocorticoid patients, regular screening for COVID-19 plus prompt recognition
deficiency carry high morbidity and mortality, and thus screening and management of any immune-related adverse effects is
may appear sensible, this is a topic of debate. No national recommended.
guidance is available regarding UK endocrinopathy screening.
In terms of being able to identify individuals at increased risk Conclusion
of developing complications, early work suggests that genetic
Checkpoint inhibitors offer huge benefits for those with advanced
predispositions may play a role in this.9
cancer and although adverse effects are significant, the increase
Fluorodeoxyglucose–positron emission tomography (FDG-PET)
in survival that these treatments offer justifies this risk. Prompt
scans can also incidentally diagnose immunotherapy-mediated
identification and management of endocrine effects can minimise
endocrinopathies by diffuse uptake. Comparison with baseline
impact on patient experience and mortality. Further research is
scans is required and often only patients with curative intent will
needed to improve understanding of predisposing and protective
receive regular PET scans, which doesn’t typically align with those
factors, and ways of improving current management. ■
receiving immunotherapy currently. Patients may not exhibit
symptoms at this point, which poses a therapeutic dilemma.
Key points
The role of high-dose steroids
>> Endocrine adverse effects of checkpoint inhibitor
There is debate as to whether high-dose steroids may be helpful
immunotherapy occur in around 10% of patients.
in the management of checkpoint-induced endocrinopathies.
>> Thyroid disease and hypophysitis are the most common, which
Current UK Society for Endocrinology guidelines advise that
can occur from weeks to many months after treatment.
there is no indication for intravenous methylprednisolone for
>> Primary adrenal insufficiency and diabetes mellitus are also
routine management of endocrinopathies, with hypophysitis
reported, along with other more rare endocrinopathies.
with associated neurological features being the only exception.17
>> Early recognition and management are key, with referral to an
In contrast, European guidelines recommend use in severe
endocrinologist for ongoing management.
hypophysitis and severe thyrotoxicosis or thyroiditis; however,
>> Non-specific symptoms require a high index of suspicion for
there have not been proven benefits for milder disease or other
investigation.
endocrinopathies.3 Limited evidence is available to support
>> Patient and clinician education and awareness of these effects
these guidelines, but benefit likely outweighs risks when pituitary
are vital.
oedema is causing severe headache, cranial nerve palsy or visual
>> Some debate remains surrounding the use of screening for
disturbance.29
endocrinopathies and high-dose steroids in their treatment.
Immunotherapy itself is not the only endocrine consideration
>> Early data suggest that endocrine adverse effects may be
in cancer treatment. While taking checkpoint inhibitors,
associated with better cancer survival outcomes.
one-third of patients take corticosteroids, mainly to treat
non-endocrine adverse effects or for brain metastases.46
Awareness of detrimental effects of steroids, such as steroid- References
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49 Pinato DJ, Zambelli A, Aguilar-Company J et al. Clinical portrait Address for correspondence: Dr Andrew Lansdown,
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