Expert opinion on pituitary complications in immunotherapy

Abstract Hypophysitis is a frequent toxic endocrine side-effect of immunotherapy. Prevalence is higher with anti-CTLA-4 antibodies (4–20%) or in association with PD-1 inhibitors (8%). Diagnosis is presumptive, based on poorly specific clinical symptoms (usually, headache and asthenia) and/or hyponatremia and/or at least one pituitary deficit and/or abnormal imaging. Visual disorder or polyuropolydipsic syndrome are exceptional. In decreasing order of frequency, deficits are thyrotropic (86–100%), gonadotropic (85–100%) or corticotropic (50–73%); somatotropin deficit or abnormal prolactin level are rarer. Pituitary MRI in acute phase shows variable moderate increase in pituitary volume, ruling out differential diagnoses, especially pituitary metastasis. Treatment of corticotropin deficiency requires systematic emergency replacement therapy, with the usual modalities, while treatment of other deficits depends on clinical status and progression. Thyrotropin and gonadotropin deficits usually recover, but corticotropin deficiency persists over the long term, requiring education and specialized endocrinologic follow-up. Onset of hypophysitis does not contraindicate continuation of immunotherapy and does not usually require high dose synthetic glucocorticoids. Recommendations • R1: Diagnosis of hypophysis under immunotherapy is based on suggestive clinical symptoms (usually, headache or asthenia) and/or hyponatremia and/or at least one pituitary deficit and/or abnormal imaging. • R2: Surgical biopsy for histologic confirmation of hypophysitis under immunotherapy is not indicated if there is no evidence of other pituitary pathology such as metastasis. • R3: In suspected hypophysitis: ∘ blood ionogram should be performed; ∘ hormonal work-up should include: – T4L (and TSH, given the risk of thyroid involvement under immunotherapy), – cortisolemia and ACTH (given reports of rare cases of primary adrenal insufficiency) at 8 am (except in acute cases; see R6) in the absence of glucocorticoid drug treatment, with dynamic testing according to findings, – LH, FSH and estradiol in non-menopausal females without oral contraception in case of menstrual disorder, or FSH in menopausal females; LH, FSH and total testosterone in males, – blood prolactin. All these results are to be interpreted in the light of the context (cancer treatment, polymedication) and compared with the initial hormonal work-up (cf. R10). ∘ Polyuropolydipsic syndrome should systematically be screened for clinically (given reports of rare cases of diabetes insipidus). ∘ Screening for somatotropin deficiency is unnecessary. ∘ MRI should be performed, centered on the pituitary gland, with gadolinium injection, ideally in acute phase, to confirm diagnosis and rule out differential diagnoses (notably, pituitary metastasis). Normal MRI does not rule out diagnosis. • R4: If MRI suggests hypophysitis but with no pituitary deficit, close biological monitoring of 8-am cortisolemia should be initiated, weekly for 1 month then as in usual follow-up (cf. R11). Dynamic corticotropic function test may be performed, depending on 8-am cortisolemia and clinical status. • R5: In proven hypophysitis, high-dose glucocorticoid drugs are not systematically recommended, but may be used symptomatically for severe headache not responding to usual analgesia and/or for visual disorder. • R6: In suspected acute corticotropin insufficiency under immunotherapy, emergency plasma cortisol assay should be performed regardless the time of day. Intravenous, intramuscular or subcutaneous 100 mg hydrocortisone hemisuccinate injection should be followed by 24 hours’ continuous infusion of 100 mg hydrocortisone hemisuccinate, as in acute corticotropin insufficiency unrelated to immunotherapy, without awaiting cortisol and ACTH assay results. When clinical and biological symptoms begin to improve, oral hydrocortisone relay should be initiated at 60 mg per 24 hr divided in 3 doses, then progressively reduced to the replacement dose. • R7: In chronic corticotropin insufficiency under immunotherapy, daily hydrocortisone dose is 15–20 mg/day in 2–3 doses per day, adapted to clinical parameters. The patient should be followed up by an endocrinologist for therapeutic education. How to adapt hydrocortisone to acute events should also be explained to the patient and the oncologist. • R8: ∘ in case of thyrotropin deficiency, levothyroxine therapy should be considered on a case-by-case basis, according to severity, clinical tolerance and/or clinical and biological progression (free T4) assessed on the evaluation at 1 month, ∘ in case of gonadotropin deficiency, estroprogestative replacement in under-50 year-old females or androgen replacement in males is considered according to progression during the first 3 months’ monitoring if there are no oncologic contraindications, ∘ diabetes insipidus is to be treated systematically, ∘ in this oncologic context, no replacement therapy for somatotropin deficiency is indicated (cf. R2). • R9: Hypophysitis does not contraindicate continuation of immunotherapy, which may, however, be interrupted during the acute phase of symptomatic hypophysitis. Onset of hypophysitis secondary to administration of one immunotherapy molecule (anti-CTLA-4, anti-PD-1 or anti-PD-L1) does not contraindicate switching to another. History of pituitary pathology does not contraindicate immunotherapy; replacement therapy may need to be adapted. • R10: We recommend systematic blood ionogram, and assays of 8-am cortisol (in the absence of glucocorticoid drug treatment); TSH and T4L; LH, FSH and total testosterone in males, or LH, FSH and estradiol in non-menopausal females without oral contraception in case of menstrual disorder, or FSH in menopausal females ahead of first immunotherapy injection. Pituitary MRI ahead of immunotherapy is not recommended. • R11: We recommend taking an ionogram, with clinical and hormonal monitoring (8-am cortisol in the absence of glucocorticoid drug treatment, TSH, T4L, total testosterone in males and interview on menstrual disorder in non-menopausal females) at each immunotherapy course for the first 6 months. If the patient is asymptomatic and hormonal work-up is normal, monitoring should then be done every 2 months for 6 months and only in case of suggestive symptoms after 12 months. Systematic pituitary MRI during follow-up is not recommended. • R12: In patients developing hypophysitis, clinical and hormonal assessment (pituitary assessment to screen for new deficits and adapt treatment) should be performed at each immunotherapy course for 6 months, then in specialist consultation every 3 months for 6 months, then twice yearly. Given the possibility of hormonal functional recovery, gonadotropin and thyrotropin axis replacement therapy may, depending on clinical status, be withdrawn under specialized monitoring. Pituitary MRI should be repeated once at 3 months to rule out differential diagnosis of pituitary metastasis and assess progression of pituitary inflammation.