ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses

Abstract

mAbs are established targeted therapies for several diseases, including hematological and solid malignancies. These agents have shown a favorable toxicity profile, but, despite their high selectivity, new typical side-effects have emerged. In cancer patients, pituitary dysfunction may be mainly due to brain metastases or primary tumors and to related surgery and radiotherapy. Anticancer agents may induce hypopituitarism in patients cured for childhood cancers. These agents infrequently affect pituitary function in adult cancer patients. Notably, hypophysitis, a previously very rare disease, has emerged as a distinctive side-effect of ipilimumab and tremelimumab, two mAbs inhibiting the cytotoxic T-lymphocyte antigen-4 receptor, being occasionally seen with nivolumab, another immune checkpoint inhibitor. Enhanced antitumor immunity is the suggested mechanism of action of these drugs and autoimmunity the presumptive mechanism of their toxicity. Recently, ipilimumab has been licensed for the treatment of patients affected by metastatic melanoma. With the expanding use of these drugs, hypophysitis will be progressively encountered by oncologists and endocrinologists in clinical practice. The optimal management of this potentially life-threatening adverse event needs a rapid and timely diagnostic and therapeutic intervention. Hypopituitarism caused by these agents is rarely reversible, requiring prolonged or lifelong substitutive hormonal treatment. Further studies are needed to clarify several clinical and pathogenic aspects of this new form of secondary pituitary dysfunction.European Journal of Endocrinology 169 R153-R164

Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma

“…The patient did not have headaches, but exhibited thirst, and dehydration was apparent from elevated blood urea nitrogen and creatinine levels; however, blood glucose levels were normal (Table 1). Since nivolumab is known to cause endocrine irAEs such as hypophysitis, albeit rarely [8,[10][11][12], a hormonal examination was performed ( Table 2). ACTH and cortisol levels as well as dehydroepiandrosterone sulfate levels were low.…”

“…itor-induced hypophysitis was previously suggested to be caused by immune-mediated mechanisms [8,[10][11][12], we measured serum levels of anti-pituitary cell antibody-1, which recognizes the rat pituitary gland (Bio Medical Laboratories, Inc., Japan). However, the anti-pituitary cell antibody-1 was negative.…”

“…In addition to these evidence-based immune-mediated anti-cancerous effects, ipilimumab frequently induces several endocrine immune-related adverse events (irAEs) such as hypophysitis and destructive thyroiditis as a consequence of enhanced T cell functions [8][9][10][11][12]. Although hypophysitis induced by nivolumab has also been reported, its incidence in Western countries appears to be lower than that observed with ipilimumab [12].…”

The Mechanism of Checkpoint Inhibitors in Gynecologic Cancer

“…On reviewing the data of immune checkpoint-induced hypophysitis for CTLA-4 drugs, the incidence of hypophysitis for ipilimumab was 0-17%, (48,49) while that for tremelimumab (phase 1 and randomized clinical trial data) was 0.4-5% [49,50]. The incidence was relatively less for other immune checkpoint inhibitors such as nivolumab [51].…”

“…Primary thyroid dysfunction occurs in up to 15% of patients, with adrenalitis reported in approximately only 1%. The mean onset of endocrine side effects is 9 weeks after initiation (range 5-36 weeks) (49). Hypothyroidism was reported in approximately 2% of patients treated with ipilimumab and up to 8.3% of patients with treated with PD-1 inhibitors; the time to onset ranged from 0.7 weeks to 19 months in PD-1 inhibitor trials [52,53].…”