Efficacy of metyrapone for symptoms of adrenocortical carcinoma
Yuka Okuda D, Toshiyuki Kuriyama, Tomoyuki Kawamata
Department of Anesthesiology, Wakayama Medical University, Wakayama, Japan
Correspondence to
Dr Yuka Okuda, Department of Anesthesiology, Wakayama Medical University, Wakayama, Japan; yuuka-o@wakayama-med.ac.jp
Received 28 February 2023 Accepted 20 April 2023 Published Online First 2 May 2023
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@ Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.
To cite: Okuda Y, Kuriyama T, Kawamata T. BMJ Supportive & Palliative Care 2023;13:e971-e973.
ABSTRACT
Elevated cortisol by adrenocortical carcinoma leads to a variety of symptoms. We report on the efficacy of metyrapone in treatment of a variety of distressing symptoms caused by elevated cortisol in a patient who refused advanced treatment for adrenocortical carcinoma.
BACKGROUND
Adrenocortical carcinoma is a very rare disease with an incidence of 0.5-2 per million people.1 Surgical resection is the cornerstone of the treatment, but around 80% of patients have recur- rence.2 The prognosis is poor, with an estimated 5-year overall survival <15%.1 Adrenocortical carcinoma commonly is hormone-producing and resultant symp- toms are often the trigger for diagnosis including hypertension, oedema, sleep disturbance and significant psycholog- ical distress. While there have been many reports on the treatment of adrenocor- tical carcinoma, there are few papers on the management of disease-induced distressing symptoms. We report the effi- cacy of metyrapone in the treatment of a variety of distressing symptoms caused by elevated cortisol in a patient who declined advanced treatment for advanced adreno- cortical carcinoma. The patient provided consent to reporting his case.
CASE
A 38-year-old Japanese man underwent right adrenal lumpectomy for adreno- cortical carcinoma. Postoperative adju- vant treatment, using mitotane, which irreversibly destroys adrenocortical cells, was planned, but it was declined by the patients as he wished to return to work as soon as possible. Three years later, hyper- tension, facial and leg oedema appeared. CT showed lung and liver metastases, but the patient opted against further cancer
treatment. Three months later, he had low back pain due to multiple lumbar frac- tures. He was admitted to our hospital to control his symptoms. His clinical course is shown in figure 1.
On admission, his blood pressure was 169/111mm Hg despite telmisartan 40 mg/day and heart rate was 76 beats per minute. He had a moon face, thin- ning skin, leg oedema and buffalo hump similar to Cushing syndrome. He also had insomnia despite taking triazolam 0.25 mg/day. Further, he had severe pain on movement, scoring 8 out of 10 on the Numeric Rating Scale (NRS). CT showed fractures of the ninth thoracic and fourth lumbar vertebrae due to oste- oporosis. Using the Edmonton Symptom Assessment System (ESAS) (0-10 score, 0 representing no symptoms and 10 indi- cating the highest possible severity in each symptom), he scored 8 for pain, 8 for tiredness, 10 for anxiety, 10 for insomnia, 5 for lack of motivation and 9 for depres- sion. Laboratory examination showed elevated serum cortisol levels 28.8 µg/ dL (normal range: 7.0-19.6 µg/dL) with no diurnal variation. We therefore deter- mined that the patient’s variety of symp- toms were due to excessive cortisol, secreted from the recurrent adrenocor- tical carcinoma. Antitumour therapy with mitotane was initiated to improve some of the symptoms caused by the tumour. Although the dose of mitotane was adjusted to 2.5 g/day, plasma cortisol level remained high (24.2 ug/dL) and there was no improvement of symptoms. His blood pressure was 159/101mm Hg, despite increasing the dose of telmisartan to 80 mg/day and adding nifedipine 40 mg/ day. Therefore, metyrapone (0.75 g/day), which is an inhibitor of 11ß-hydroxylase, was added 2 weeks after starting mito- tane therapy. Two days after the addi- tion of metyrapone, the serum cortisol
BMJ
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Case report
metyrapone
0.75 g
0.1 g
0.125 g
mitotane
0.1 g
0.15 g
2.5 g
40
180
35
160
30
140
25
serum cortisol
[ug/dL]
Blood Pressure (BP)
[mmHg]
20
120
15
100
10
80
5
0
60
0
5
10
15
20
25
30
35
cortisol
systolic BP
diastolic BP
level decreased to 16.5 µg/dL, and blood pressure decreased to 138/98 mm Hg. Other symptoms except for back pain were also improved after the addition of metyrapone. Metyrapone was gradually increased from 0.75 g/day to 1.25 g/day 10 days later. At the time of discharge, with 2.5 g of mitotane and 1.25 g of metyrapone per day, the cortisol level had decreased to 10.1 µg/dL. Blood pressure was 123/90 mm Hg, and insomnia improved without using triazolam. For the back pain, we administered teriparatide formulation 600 µg and loxoprofen 60mg and the patient wore a rigid corset. When he was discharged from the hospital, his NRS score was 2 out of 10 and was able to walk. Additionally, his ESAS score was tiredness 1, anxiety 0, insomnia 1, lack of motivation 1 and depression 1. The addition of metyrapone to mitotane dramatically improved a wide variety of elevated cortisol-induced symptoms. Two months after discharge, he returned to work while continuing mitotane and metyrapone.
DISCUSSION
Surgery is recommended as the first choice of treatment of adrenocortical carcinoma when complete resection is possible.1 Adjuvant mitotane treatment is recom- mended for the patients at high risk for recurrence after surgery.1 Chemotherapy is the recommended therapy for advanced or recurrent disease, that is, mitotane monotherapy or mitotane plus a combina- tion of etoposide, doxorubicin and cisplatin (EDP).2 Adrenocortical carcinoma often induces a variety of symptoms by excessive secretion of cortisol, referred to as Cushing syndrome and negatively affects patient’s quality of life.12 When managing patient’s symptoms,
it is important to clarify whether or not the symptoms are due to excessive cortisol secretion. If they are, the symptoms can be improved by decreasing plasma cortisol. Mitotane irreversibly destroys adrenal cortical tissue but it takes 3 months to reach therapeutic plasma concentrations.3 Conversely, metyrapone, 11B-hy- droxylase inhibitor, rapidly decreases plasma concen- tration of cortisol.3 A case study in which metyrapone was added to mitotane plus combination chemo- therapy reported that Cushing’s syndrome was rapidly improved without severe side effects.4 In our case, the patient opted against anticancer therapy and wished to return to work as soon as possible. Metyrapone was therefore used earlier in order to rapidly improve his symptoms.
Excessive cortisol causes osteoporosis, resulting in back pain. Our patient had already had a vertebral fracture. Bisphosphonate is used for osteoporosis, and calcitonin is used for acute pain in fractures.5 Teri- paratide is a human parathyroid hormone (1-34) gene recombinant, and is used for osteoporosis. Teriparatide is not the first choice, but it can be used for severe osteoporosis, in cases in which there have already been fractures. Additionally, significant analgesic effect on osteoporosis-induced back pain has recently been shown.5 We therefore used teriparatide in addition to loxoprofen and the patient wore a rigid corset for pain control. Palliative radiotherapy for advanced or recur- rent adrenocortical carcinoma is also recommended for symptoms including pain caused by bone metas- tasis and large adrenocortical carcinoma. However, prognosis must be considered because it takes time for effects to appear.2
.
CONCLUSION
Metyrapone was effective in treating a variety of distressing symptoms caused by elevated cortisol in a patient who declined treatment for advanced adreno- cortical carcinoma.
Acknowledgements We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University.
Contributors All authors critically reviewed and revised the manuscript draft and approved the final version for submission.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Consent obtained directly from patient(s).
Ethics approval This study involves human participants but was not approved because it is a case report. Participants gave informed consent to participate in the study before taking part.
Provenance and peer review Not commissioned; internally peer reviewed.
ORCID iD
Yuka Okuda http://orcid.org/0000-0001-7883-3940
REFERENCES
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2 Fay AP, Elfiky A, Teló GH, et al. Adrenocortical carcinoma: The management of metastatic disease. Critical reviews in oncology/ hematology 2014;92:123-32.
3 Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing’s syndrome: An endocrine society clinical practice guideline. The Journal of clinical Endocrinology and metabolism 2015;100:2807-31.
4 Claps M, Cerri S, Grisanti S, et al. Adding Metyrapone to chemotherapy plus Mitotane for Cushing’s syndrome due to advanced Adrenocortical carcinoma. Endocrine 2018;61:169- 72.
5 Committee for the preparation of a guideline for the prevention and treatment of osteoporosis. A guideline for the prevention and treatment of osteoporosis. Tokyo: Life Science Publishing Co., Ltd, 2015.