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SOCIÉTÉ INTERNATIONALE D’ONCOLOGIE PÉDIATRIQUE SKOP INTERNATIONAL SOCIETY OF PAEDIATRIC ONCOLOGY
aspho The American Society of Pediatric Hematology/Oncology
Exogenous steroid replacement in a pediatric patient with adrenocortical carcinoma receiving mitotane
To the Editor:
Mitotane is a key component in the treatment of pediatric and adult adrenocortical carcinoma (ACC), especially in the metastatic setting. 1-4 Mitotane exerts its therapeutic effects through inhibition of steroidogenesis.2 Additionally, mitotane is a strong CYP3A4 inducer, which is involved in metabolism of both endogenous and exogenous steroids.2,5 Most of the current literature recommends exogenous steroid dosing be initiated at two to three times standard dosing in the presence of concomitant mitotane, with some recommendations to consider up to five times standard dosing.2,5,6 Herein, we present a case of a young patient with ACC receiving mitotane, requiring higher doses of steroid replacement than suggested by literature.
Our patient is a 16-year-old female with a history of high-risk neuroblastoma at age 5, and subsequently diagnosed with a primary stage II (T2,N0,M0) ACC. As part of her previous neuroblastoma treat- ment, she underwent a right adrenalectomy along with chemotherapy and radiation. Her ACC treatment comprised a left adrenalectomy, postoperative radiation, and chemotherapy as per Children’s Oncol- ogy Group protocol ARAR0332 with cisplatin, etoposide, doxorubicin, and mitotane.1 Due to prolonged endogenous steroid exposure from the ACC, high-dose IV hydrocortisone replacement was initiated at the time of left adrenalectomy. Her hydrocortisone dose was slowly tapered to typical adrenal replacement doses, with an adrenal replace- ment plan consisting of: maintenance “green zone”: hydrocortisone 5 mg three times daily plus fludrocortisone 0.1 mg daily; stress “yel- low zone”: hydrocortisone 15 mg three times daily plus fludrocortisone 0.1 mg daily; and major stressor “red zone”: hydrocortisone 100 mg intravenously (IV) every 8 hours. Given her body surface area (BSA) of about 1.8 m2, her initial adrenal replacement doses were equivalent to institutional standard dosing.
She was stable on “green zone” steroid dosing until 2 days after initiation of mitotane, when she was admitted to the pediatric inten- sive care unit for adrenal crisis and hypotension. She was initiated on hydrocortisone 100 mg IV every 8 hours, fluids, and briefly required a norepinephrine infusion. She was also found to be febrile and neu- tropenic (absolute neutrophil count 0). She was initiated on empiric broad-spectrum antibiotics as per institutional standard for patients with indwelling central line on chemotherapy who present with fever and/or vital sign instability. She started improving promptly after the initiation of IV hydrocortisone, and she was able to deescalate to “yellow zone” steroids the following day. No infectious source was iden- tified. Given the interaction between mitotane and exogenous steroids, the decision was made to increase her adrenal action plan to: “green
zone”: 10 mg hydrocortisone three times daily plus fludrocortisone 0.1 mg daily; “yellow zone”: 30 mg hydrocortisone three times daily plus fludrocortisone 0.1 mg daily; and “red zone”: hydrocortisone 100 mg IV three times daily.
For primary adrenal insufficiency, the recommended dose for main- tenance glucocorticoid replacement is 8-12 mg/m2/day divided three times daily.7,8 The updated adrenal action plan for this patient con- sisted of doses roughly two times the standard dosing for maintenance and stress dosing. On several occasions after hospital discharge, reduc- ing steroid doses to the new “green zone” was attempted. During those trials, she experienced vomiting, fatigue, and sometimes hypotension; therefore, she remained at a daily replacement dose between the “green zone” and “yellow zone,” approximately three times the stan- dard daily adrenal replacement dose, for the duration of her mitotane therapy.
Mitotane is a strong inducer of CYP3A4, and therefore increases the metabolism of many exogenous steroids.2,5 Based on high urinary concentrations of 66-hydroxycortisol, a cortisol metabolite in the pres- ence of mitotane, it has been estimated that mitotane results in rapid inactivation of more than 50% of exogenous hydrocortisone.2,5 There is existing literature discussing the effects of other strong CYP3A4 induc- ers (e.g., rifampin) on exogenous steroids; however, data related specif- ically to mitotane are limited.9-11 This is especially true in the pediatric setting due to the rarity of ACC in this population.4 It is interesting to note the rapidity with which this presumed interaction was noted in our case, with adrenal crisis developing 2 days after mitotane initiation.
It is possible that complete reliance on exogenous steroid replace- ment from her prior cancers in each adrenal gland contributed to very high steroid requirements while on mitotane. Ultimately, she required three times the standard dose for maintenance steroid doses throughout her treatment with mitotane. This patient case demon- strates the importance of adequate dosing and close monitoring of steroid replacement in patients receiving mitotane.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Catherine E. Martin1 İD Alexis K. Kuhn1 ID Kaitlin N. Leopold2 Ana L. Creo2
Peter J. Schoettler3
Wendy A. Allen-Rhoades3
1 Department of Pharmacy - Ambulatory Service, Mayo Clinic, Rochester, Minnesota, USA
2 Department of Pediatric and Adolescent Medicine, Division of Pediatric Endocrinology, Mayo Clinic, Rochester, Minnesota, USA 3 Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence
Catherine E. Martin; Department of Pharmacy - Ambulatory Service, Mayo Clinic, 200 First St SW, Rochester, MN, USA.
Email: martin.catherine3@mayo.edu
ORCID
Catherine E. Martin (D https://orcid.org/0000-0003-2855-9503 Alexis K. Kuhn (D https://orcid.org/0000-0001-5256-5001
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