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Advances in dermatology and venereology Acta Dermato-Venereologica
Isolated Adrenocorticotropic Hormone Deficiency in Melanoma Patients Treated with Nivolumab
Seiya KITANO 1 , Kazuki TATSUNO 1 , Junichi ISHIBE 1 , Takatoshi SHIMAUCHI 1 *, Toshiharu FUJIYAMA 1 , Taisuke ITO 1 , Noriyoshi OGAWA 2 and Yoshiki TOKURA 1
1
Department of Dermatology , and 2 Division of Immunology and Rheumatology , Department of Internal Medicine 3 , Hamamatsu University School of Medicine , 1-20-1 Handayama , Higashi-ku , Hamamatsu 431-3192 , Japan . E-mail : t-shima @ hama-med . ac . jp Accepted Feb 5 , 2018 ; Epub ahead of print Feb 6 , 2018
Agents that modulate immune checkpoint proteins , such as programmed death receptor-1 ( PD-1 ) and cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ), have become a main strategy in cancer treatment . Advanced melanoma is one of the major targets of immune checkpoint inhibitors ( 1 ). Their clinical benefit can be accompanied by immunerelated adverse events ( irAEs ), which affect the skin , gastrointestinal tract , liver , and endocrine system . The endocrine organs of irAEs include pituitary , thyroid , and adrenal glands , as well as other downstream target organs ( 2 ). The endocrine irAEs are typically grade 1 or 2 in severity and often present with non-specific symptoms . In particular , isolated adrenocorticotrophic hormone ( ACTH ) deficiency is characterized by general fatigue , appetite loss , weight loss , hypoglycaemia , hypotension , and hyponatremia . Thus , these adverse effects might be underdiagnosed .
We report here 2 patients with advanced melanoma , who developed isolated ACTH deficiency induced by nivolumab ( Nivo ). This rare type of irAE should be considered in patients receiving long-term administration of immune checkpoint inhibitors , such as those with advanced melanoma .
CASE REPORTS
Patient 1 . A 53-year-old Japanese man with a primary nodular melanoma on the left thigh with lymph node metastasis was referred to us and diagnosed as American Joint Committee on Cancer ( AJCC ) stage IIID ( pT4bN3bM0 ; Breslow tumour thickness , 8 mm ; Clark ’ s level V , with ulceration ; and Ki-67 index , approximately 50 %). The patient received an extended resection of the primary tumour area with a 2-cm margin and inguinal and pelvic lymph node dissection , followed by administration of weekly PEG-interferon-α , 7 courses , as post-operative adjuvant therapy . Four months after the operation , however , he developed multiple skin metastatic lesions on the left thigh . Molecular testing revealed a BRAF V600E mutation . Thus , he was treated with a combination of BRAF inhibitor ( dabrafenib ) and MEK inhibitor ( trametinib ) with a therapeutic effect . Because of their cardiac adverse effect , the drugs were discontinued , and Nivo , 3 mg / kg , was begun at a 2-week interval . At 14 weeks after initiation of Nivo , the patient had muscle pain , general fatigue and vomiting , but no fever . The patient ’ s creatinine phosphokinase ( CK ) increased gradually to 648 U / l at 36 weeks with eosinophilia . His serum sodium level did not decrease .
Endocrinologically , ACTH , 6.5 pg / ml ( normal 7 – 56 pg / ml ), cortisol , 0.4 μg / l ( normal 7.1 – 19.6 μg / l ), urinary free cortisol , < 9.0 μg / g of creatinine ( normal 11 – 80 μg / g ), were decreased , indicating failure of the hypothalamo-pituitary-adrenal axis . Although thyroid stimulating hormone ( TSH ) was slightly increased , free T3 ( FT3 ) and FT4 were normal , and anti-thyroidglobulin ( Tg ), thyroid peroxidase ( TPO ) and thyrotropin receptor ( TR ) antibodies were negative , indicating normal pituitary-thyroid function . Anti-diuretic hormone
( ADH ), growth hormone ( GH ), insulin-like growth factor-1 ( IGF- 1 ), luteinizing hormone ( LH ), and follicle stimulating hormone ( FSH ) were all within normal ranges . Magnetic resonance imaging ( MRI ) of the patient ’ s pituitary gland exhibited no abnormality in size or tumour lesion .
A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges was performed . The results showed a disturbance in the secretion of ACTH in the corticotrophin-releasing hormone ( CRH ) test ( Fig . S1 1 ). On the other hand , prolactin secretion was intact in the thyrotropin-releasing hormone ( TRH ) test , and the secretion of GH and LH / FSH was also normal in the GH-releasing peptide-2 ( GHRP-2 ) and LH-releasing hormone ( LH-RH ) tests , respectively ( Fig . S1 1 ).
His condition was diagnosed as isolated ACTH deficiency . At 36 weeks , he was treated with hydrocortisone , 15 mg daily , which improved muscle pain and general fatigue despite continuing Nivo treatment . At 16 months after initiation of Nivo , neither recurrence nor new metastatic lesion was found .
Patient 2 . A 72-year-old man was diagnosed with AJCC stage IV melanoma ( pTxNxM1b ( 0 )), because of metastatic lesions of the left inguinal lymph nodes and the upper field of the right lung . He received surgical removal of the inguinal lymph nodes and lung lesion . Molecular testing for a BRAFV600E mutation was not performed , and he was treated with Nivo , 3 mg / kg , at 2-week intervals . At 28 weeks , he had general fatigue without fever , followed by appetite loss and vomiting . CK and blood eosinophil count fluctuated after initiation of Nivo , and at 44 weeks , his serum sodium level was dramatically decreased to 126 mEq / l . He had weight loss of 13 kg for 3 months .
Endocrinologically , ACTH and urinary free cortisol were within normal limits ; however , cortisol ( 6.3 μg / l ) was decreased . TSH , FT3 and FT4 showed normal levels , and anti-Tg , TPO and TR antibodies were negative . ADH , GH , IGF-1 , LH , FSH were all within normal ranges . MRI of his pituitary gland exhibited no abnormality . Hypothalamic hormone challenges showed a disturbance in the secretion of ACTH in stimulation with CRH ( Fig . S1 1 ). Prolactin secretion was intact in the TRH test , and GH secretion and LH / FSH was also normal in the GHRP-2 and LH-RH tests , respectively ( Fig . S1 1 ).
We thus diagnosed his condition as isolated ACTH deficiency . He was treated with hydrocortisone , 10 mg daily , with continuing Nivo . His fatigability and appetite loss improved . After recurrence of appetite loss , the dose of hydrocortisone was increased to 15 mg daily . At 15 months after initiation of Nivo , the patient died of multiple metastasis of melanoma , including liver , bone , and lymph nodes .
DISCUSSION
A recent cohort study demonstrated that the incidence of endocrine irAE was 12.9 % in patients receiving ipilimumab ( CTLA-4 inhibitor ), Nivo , and / or pembrolizumab ( PD-1 inhibitor ), and the most common was thyroid dysfunction
1 https :// www . medicaljournals . se / acta / content / abstract / 10.2340 / 00015555-2902 doi : 10.2340 / 00015555-2902 Acta Derm Venereol 2018 ; 98 : 704 – 705
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