Immune Checkpoint Inhibitor Therapy-Toxicity Management

A practical guide to monitoring of endocrine integrity during use of Immune Checkpoint Inhibitors (ICPIs)

• Background
• Primary Thyroid dysfunction
  • Background
  • Diagnosis
  • Monitoring/Treatment
• Hypophysitis
  • Background
  • Investigation
  • Monitoring/Treatment
• Adrenalitis
  • Background
  • Investigation
  • Monitoring/Treatment
• Autoimmune Diabetes Mellitus
  • Background
  • Investigation
  • Monitoring/Treatment
• Collective screening for immune-related endocrinopathies (Figure 2)

Background

Endocrine immune-related adverse events (irAE) occur frequently when using checkpoint inhibitor therapy in the management of malignancy. The high frequency of occurrence necessitates a unified approach to screening and diagnosis between the oncology and endocrinology teams. Thyroid dysfunction, hypophysitis, adrenalitis, and insulin-dependent diabetes mellitus can occur, and can potentially lead to preventable morbidity and mortality if unrecognised. When endocrine irAE occur, early liaison with the endocrinology team as to further investigation and management of these patients is important. All efforts should be made to continue ICPI therapy even when the endocrine irAE is still evolving. The success of the ICPIs in cancer therapy, and use in an expanding numbers of tumour types, will undoubtedly lead to a significant increase in the number of patients requiring assessment. We consider the important aspects of the development of each recognised endocrine irAE individually, and have constructed a practical guide to enable holistic screening for potential endocrinopathies when using ICPIs.

For professionals working in the primary care setting, this guidance relates only to those patients receiving immune checkpoint inhibitor therapies (anti-PD-L1, anti-PD-1 and anti-CTLA4 monoclonal antibodies e.g. pembrolizumab, nivolumab, ipilimumab amongst others). Details of ICPI treatments can be found on the patient’s oncology letters. If you are concerned about a patient receiving treatment or having completed treatment in the last 6 months please contact the treating clinician or, if there is an acute toxicity concern this can be discussed with the on call clinical or medical oncology specialty registrar on call. It is not expected that this patients will require diagnostic work-up in primary care, however, due to the non-specific way in which toxicity can present, these patients may present to primary care in the first instance and therefore some background for the diagnostic work-up and management will hopefully be helpful.

Primary Thyroid dysfunction

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Background

Although there are case reports of Graves’ disease following ICPI treatment, the vast majority of cases of thyroid dysfunction represent a destructive thyroiditis. Presentation is either with a hyperthyroid phase (suppressed TSH & elevated fT4) followed by progressive hypothyroidism (elevated TSH & low normal / low fT4), or simply with progressive hypothyroidism.

Timing: The vast majority of thyroid dysfunction has onset within the first 18 weeks of initiation of ICPI therapy, although late-onset cases are recognised.

Risk: Greatest with combination therapy with CTLA4/PD1 inhibitors, followed by PD1 inhibitor monotherapy, and is least prevalent with CTLA4 inhibitors.

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Diagnosis

Screening:

• Baseline TFTs should be established before commencing ICPIs.
• Thereafter TFTs prior to each administration of ICPI (2-4 weekly) should be performed for at least the initial 18 weeks of therapy.
• Thereafter 6-8 weekly TFTs whilst the patient is maintained on ICPIs.

Symptoms: Most patients remain asymptomatic, though classic symptoms of hyper- and hypothyroidism may occur, generally when the biochemistry is more extreme. Thyroid storm is a potential, but rare, presentation.

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Monitoring/Treatment:

• During the initial hyperthyroid phase most patients can simply be observed with repeat of TFTs and clinical assessment every 2-3 weeks whilst the situation evolves.
• If the patient is symptomatic, has a tachycardia, or other overt signs of hyperthyroidism (tremor, sweating) then a b-blocker should be instituted if there is no contraindication (e.g. Propranolol 10-40mg TDS or Propranolol SR 80mg OD). Thionamide therapy (Carbimazole, Propylthiouracil) has no role in treatment of thyroiditis.
• Rarely, when severe cases occur, Prednisolone 30-40mg OD is of benefit.
• The cycle of thyroiditis from hyperthyroidism to hypothyroidism almost always evolves within 4 months.
• Hypothyroidism can be monitored whilst the patient remains asymptomatic, as a small proportion will show resolution with return to euthyroidism.
• Where the patient is symptomatic or TSH >10miu/l levothyroxine should be instituted with the aim of placing the TSH in the lower half of the normal range (0.2-2.0 miu/l). An initial levothyroxine dosage of 50micrograms OD will suit most patients, however, care should be taken in the elderly (>70 years) and those with ischaemic heart disease where levothyroxine 25micrograms would be a more appropriate starting dose, with a TSH target of 2.0-4.0 miu/l.
• Persistent hyperthyroidism without evolution to hypothyroidism signals the possibility of Graves’ disease. Thyroid stimulating antibodies (TRAb; TBII) should be checked at this stage. Thionamide therapy is likely required, and referral to Endocrinology is obligatory to manage this condition.

Hypophysitis

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Background:

Hypophysitis represents an inflammatory condition of the pituitary gland leading to loss of function of one or more pituitary axes. The most frequently affected is the thyroid axis, followed by the adrenal axis, and less frequently the gonadal axis. Less data are available on the impact on the growth hormone axis. Abnormalities of prolactin secretion are infrequent and rarely clinically relevant. There are a few case reports of development of diabetes insipidus.

Timing: When using anti-CTLA4 therapy, either as monotherapy or combination therapy, hypophysitis most frequently occurs after the third infusion, and less commonly after the second and fourth infusion. Hypophysitis is infrequent with use of anti-PD1 and anti-PD-L1 monotherapy, though it is important to be aware of possible late presentation of hypophysitis where use of anti-PD1 and anti-PD-L1 monotherapy is instituted after initial anti-CTLA-4 therapy.

Risk: Greatest with combination therapy with CTLA4/PD1 inhibitors, followed by CTLA4 inhibitor monotherapy, and least prevalent with PD1 inhibitor monotherapy. The development of hypophysitis with CTLA4 (ipilimumab) therapy is dose-dependent.

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Investigation:

Screening:

• Baseline 9am bloods including TFTs and cortisol should be measured before commencing ICPIs. Additionally, in males LH, FSH, SHBG, and 9am testosterone should be measured. In premenopausal women not on contraceptives monitoring of the reproductive axis should be clinical, with check of LH, FSH, oestradiol, and prolactin only if amenorrhoea ensues.
• TFTs, 9am cortisol, testosterone/SHBG (males) should be measured prior to each administration of ICPI (2-4 weekly) for at least the initial 18 weeks of therapy.
• Thereafter TFTs, 9am cortisol, testosterone and SHBG (males) should be monitored 6 weekly whilst on combined CTLA4/PD1 therapy or maintenance CTLA4 therapy. Because of the lower incidence of hypophysitis with PD1 and PD-L1 inhibitors screening can occur 2-3 monthly in the longer-term whilst maintained on PD1 and PD-L1 inhibitors.
• Importantly, it must be noted that the onset of hypophysitis can be acute in nature. Therefore a normal cortisol value within the week before onset of symptoms suggestive of hypophysitis does not necessarily exclude the diagnosis.

Symptoms: Symptoms of hypophysitis are generally non-specific, however, when present, headache and lethargy are the most frequent complaints. Additional symptoms primarily reflect cortisol insufficiency with postural dizziness, nausea, loose stools, anorexia, and mood changes.

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Monitoring/Treatment:

• Biochemical anomalies in hypophysitis include effects on the thyroid axis (TSH deficiency) defined by a fall in fT4 without a compensatory rise in TSH, the TSH level most frequently remaining in the normal range.
• Free T4 levels may be either below normal, or reside in the low normal range, however, will have shown a progressive fall in fT4 levels with consecutive blood results.
• In most cases TSH deficiency is transient and improves with time.
• Abnormalities of the thyroid axis are frequently the first to be recognised, with fT4 levels observed to decline in the two weeks before onset of ACTH deficiency, and showing recovery thereafter.
• If symptomatic or fT4 <7.0 pmol/l, treatment can be instituted with levothyroxine, titrating the dosage to achieve a fT4 value in the upper half of the normative range (15-20 nmol/l).
• Before starting levothyroxine for TSH deficiency it is important to be sure the patient does not have untreated co-existent ACTH deficiency as initiation of levothyroxine could potentially induce an adrenal crisis.
• The levothyroxine dose can be reduced at a later date to determine if the thyroid axis has recovered.

• A 9am cortisol level <100nmol/l is consistent with adrenal insufficiency (AI), whereas a value of >400nmol/l confirms a normal axis.
• Interpretation for values within the range of 100-400nmol/l is more difficult and require a practical approach.
• A repeat 9am cortisol level performed the following day should be the initial step in investigating further, and may be more conclusive as to the cortisol status of the patient. Where logistics prevent a repeat of the cortisol level the next day, the patient can safely be commenced on hydrocortisone (10mg on waking, 5mg midday, and 5mg early evening) with a repeat 9am cortisol taken before the morning hydrocortisone dosage when practical.
• Should similar non-diagnostic cortisol results be obtained, but the patient remains asymptomatic with a cortisol >250 nmol/l, further biochemical monitoring can be delayed until before the next ICPI is administered (2-3 weeks). The patient should be made aware of the symptoms of adrenal insufficiency and asked to present earlier should they occur.
• Where the patient is symptomatic or repeat 9am cortisol levels are <250 nmol/l the patient should be commenced on hydrocortisone and further investigation of the hypothalamo-pituitary-adrenal (HPA) axis undertaken (Figure 1).
• In these individuals the short synacthen test (SST) can prove falsely reassuring as adrenal atrophy occurs over a period of six weeks in the absence of ACTH, and potentially over a longer duration where partial ACTH deficiency is present. Thus where there is doubt as to the cortisol status, the diagnosis of AI requires the use of a dynamic test that requires integrity of the entire HPA axis to produce an adequate cortisol response (i.e. glucagon stimulation test or insulin tolerance test).
• To establish whether AI is secondary (ACTH deficiency) or primary (adrenal failure), requires measurement of 9am ACTH. ACTH levels are suppressed in secondary AI, and elevated in primary AI.
• Patients with proven, or suspected, AI should be commenced on glucocorticoids (i.e. hydrocortisone 10mg on waking, 5mg midday, and 5mg early evening) and referred to Endocrinology for further assessment and steroid education.
• Impairment of the adrenal axis in ICPI-induced hypophysitis is rarely reversible, necessitating life-long replacement therapy, so it is important the diagnosis is established robustly. Efforts to induce recovery of the hypophysitis, and the associated pituitary hormone deficits, by the use of high dose steroids have been unsuccessful, however, may be helpful in patients with severe headaches, visual disturbance, or where additional irAE are present (e.g. colitis).
• Once established on long-term hydrocortisone replacement therapy further measurement of cortisol levels is only warranted before the morning hydrocortisone dose to examine for potential recovery of the axis. Confounders to the diagnosis of hypophysitis include opioids and glucocorticoids, both of which are used frequently in cancer patients, and can cause ACTH deficiency, which is eminently reversible.

• Gonadotropin deficiency with subsequent sex steroid deficiency is defined by low gonadotropins with low sex steroid levels. In males the diagnosis is relatively simple after exclusion of confounders. Testosterone levels fall with increasing BMI.
• Opioids cause hypogonadotropic hypogonadism, as can acute illness.
• Recovery of the gonadal axis is observed in the majority of patients with immune-related hypophysistis.
• Where persistent hypogonadism occurs, replacement therapy is with testosterone aiming to bring levels back to within the normal range. The most frequently used testosterone replacements are the alcohol based gels and long-acting depot intramuscular testosterone undecanoate preparation, Nebido.

• In premenopausal women, the onset of amenorrhoea suggests the possibility of gonadotropin deficiency, particularly in the presence of additional pituitary hormone deficits.
• Interpretation of the gonadotropins is difficult due to the variation in levels throughout the menstrual cycle, unless the gonadotropins and oestrogen levels are fully suppressed. Replacement therapy is with HRT.
• Routine MRI imaging of the pituitary gland is not required as compromise of the optic nerves is rare. If however there are atypical features (unusual pattern of hormone deficiencies, cranial nerve palsies, visual field defect, etc) or severe headaches an MRI should be performed to exclude an alternate diagnosis (i.e. pituitary metastasis).
• It is imperative that proven and suspected cases of hypophysitis are referred to the Endocrinology team early for investigation, management, education and long-term follow-up. The is no definite reason to discontinue ICPIs when immune-related hypophysitis occurs, however, many Oncologists temporarily suspend or delay treatment where patients have acute symptoms of headache and require high dose glucocorticoids to alleviate this.

Adrenalitis

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Background:

Primary inflammation of the adrenal glands, adrenalitis, is an infrequent endocrine sequelea of ICPIs. Adrenalitis occurs in less than 1% of individuals, however, is reported to occur at greater prevalence in those receiving combined CTLA4/PD1 therapy. Primary adrenal insufficiency results in deficiency of both cortisol and aldosterone.

Risk: The greatest risk of adrenalitis occurs during combination therapy with CTLA4/PD1 inhibitors, with infrequent case reports when receiving CTLA4 inhibitor or PD1 monotherapy.

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Investigation:

Screening: Serum 9am cortisol should be measured before commencing ICPIs and prior to each administration of ICPI (2-3 weekly) for at least the initial 3-4 months of therapy. Thereafter 9am cortisol should be monitored 6 weekly whilst on combined CTLA4/PD1 therapy or 2-3 monthly whilst maintained on CTLA4 therapy, PD1 and PD-L1 inhibitors.

Symptoms: Symptoms of adrenalitis are those of primary adrenal failure. Patients may be asymptomatic, present with non-specific symptoms (lethargy, nausea, anorexia, weight loss, postural dizziness), or severely ill with a life threatening adrenal crisis (dehydration, hypoglycaemia, hypotension, hyponatraemia, and hyperkalaemia).

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Monitoring / Treatment:

Biochemical anomalies in adrenalitis are defined by low cortisol and aldosterone levels in association with elevated ACTH levels. This contrasts with hypophysitis where cortisol and ACTH levels are low, and aldosterone levels normal. As per hypophysitis, a 9am cortisol level <100nmol/l is consistent with adrenal insufficiency (AI), whereas a value of >400nmol/l confirms a normal axis. For values within the range of 100-400nmol/l a repeat 9am cortisol level performed the following day with a concomitant ACTH should be the initial step in investigating further. Should a similar non-diagnostic cortisol result be obtained, but the patient remain asymptomatic with a cortisol >250 nmol/l further monitoring can be delayed until before the next ICI is administered. Where the patient is symptomatic or repeat 9am cortisol levels are <250 nmol/l with a concomitantly elevated ACTH level a SST should be undertaken. The patient should be commenced on hydrocortisone replacement whilst being investigated; however, all diagnostic tests need to be performed prior to administering the morning hydrocortisone dose. If the patient is confirmed to primary adrenal insufficiency a renin level should be obtained.
Patients with adrenalitis require replacement therapy with both glucocorticoids and mineralocorticoids (fludrocortisone 50-150micrograms daily). The patient should be referred to Endocrinology when the suspicion of AI is raised to confirm the diagnosis, institute replacement therapy, and provide education. Patients with AI should be educated on when to increase their steroid dosage and how to self-administer hydrocortisone for intramuscular injection in severe illness or adrenal crisis. They will need to carry a steroid card and ideally a medical alert bracelet / pendant. There are insufficient long-term data to be certain, however, immune-related adrenalitis does not appear to recover.

Autoimmune Diabetes Mellitus

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Background:

Case reports of autoimmune diabetes mellitus have been reported with ICIs, though remain very infrequent.

Timing: Reports document the onset from one week to 12 months after commencing ICIs, although most cases occur within the first few months.

Risk: The data are currently limited in respect to this immune-related endocrinopathy, however the vast majority of reported cases have occurred in patients receiving anti-PD1 therapy in contrast to CTLA4 inhibitors.

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Investigation:

Screening: Capillary blood glucose levels should be checked prior to each administration of ICPI, with measurement of HbA1c levels every 6-8 weeks. As the risk of occurrence reduces with time the frequency of measuring HbA1c could potentially reduce to 3 monthly after the initial 3-4 months.

Symptoms: Presentation is classically with acute onset of polyuria, polydipsia, lethargy and weight loss. Of the described case reports most document an acute onset resulting in the patient presenting with diabetes ketoacidosis (DKA).

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Monitoring/Treatment:

ICPI-induced diabetes mellitus is characterised by insulin deficiency with low or undetectable C-peptide levels. Treatment with insulin is therefore obligatory, and the patient should be referred to the Diabetes / Endocrinology services urgently for management. If the patient presents with DKA, they should be admitted and managed as per local guidelines. Particular care should be taken when the patient is also receiving glucocorticoid therapy for their tumour or additional irAE.

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Collective screening for immune-related endocrinopathies (Figure 2)

Although the relative risks of developing individual immune-related endocrinopathies varies as to whether the patient receives CTLA4 inhibitors, PD1 therapy, PD-L1 therapy or combination therapy, the timelines are similar, and all the described endocrinopathies can occur with all ICI subtypes in clinical usage. It therefore appears practical to recommend a single screening guideline to be implemented when using any ICI or combination of ICIs. Furthermore, the risk of developing all individual immune-related endocrinopathies appear highest within the first 3-4 months. Given these observations we recommend the below screening regimen:

Baseline: U&E, 9am cortisol, TFTs (TSH & fT4), HbA1c, LH, FSH, testosterone/SHBG (males) and capillary blood glucose.
Week 2-18: 2-4 weekly U&E, 9am cortisol, TFTs (TSH & fT4), HbA1c, testosterone/SHBG (males) and capillary blood glucose undertaken prior to ICI administration.
Week 20 onwards whilst receiving ICIs: 6-8 weekly U&E, 9am cortisol, TFTs (TSH & fT4), HbA1c, testosterone/SHBG (males) and capillary blood glucose.

Further endocrine tests / MRI pituitary should be considered only if the screening tests show an abnormality. Importantly hyponatraemia can be a consequence of hypoadrenalism (hypophysitis or adrenalitis) and suggests urgent needs to examine the integrity of the cortisol axis. Once established on hydrocortisone measurement of cortisol levels is of no value, except if undertaken prior to the morning hydrocortisone dosage to examine for putative recovery of the HPA axis. Endocrine advice should be sought early for the management of immune-related hypophysitis, adrenalitis, and diabetes mellitus; and urgently where presentation is acute. Severe hyperthyroidism (symptoms or grossly elevated fT4 levels) should also be referred urgently.

It would be unusual for an endocrinopathy to lead to discontinuation of ICI therapy. In the majority of cases of endocrinopathies ICI therapy does not need to be delayed or suspended. I the setting of hypophysitis with significant headache which require acute high dose glucocorticoids and following acute presentation of insulin-dependent diabetes mellitus a delay in treatment would appear sensible whilst these irAE are addressed.

Figure 1: Interpretation of 9am cortisol values when used to screen for adrenal insufficiency in patients receiving immune checkpoint inhibitor therapy.

Figure 2: Screening program for endocrine immune-related adverse events (irAE) when using immune checkpoint inhibitors in cancer therapy.
(U&E, urea and electrolytes; TSH, thyroid stimulating hormone; fT4, free levothyroxine; HbA1c, haemoglobin-A1c; LH, lutenising hormone; FSH, follicle stimulating hormone; SHBG, sex hormone binding globulin; CBG, capillary blood glucose).