High-Dose Mitotane-Induced Encephalopathy in the Treatment of Adrenocortical Carcinoma
We read with great interest the article of Reidy-Lagunes et al. in which the authors evaluated progression of disease and treatment-induced toxicity among a cohort of 36 patients treated with mitotane for metastatic adrenal cortical carcinoma (ACC) [1]. As mentioned by the authors and reported in many retrospective studies, the difficulty of this treatment is the probable requirement of high doses of mito- tane to maintain high blood levels within a narrow therapeu- tic range of concentrations (14-20 mg/L) to induce a beneficial outcome in patients with ACC [2-5]. Indeed, if starting high-dose mitotane monotherapy (4-6 g per day) seemed to induce prolonged survival in patients without sig- nificant increase in the rate of toxicity in comparison with low-dose regimen (2-3 g per day) [6, 7], mitotane is not exempt from toxicity. In addition to the toxicities reported by Reidy-Lagunes et al., we report herein a case of mitotane- induced encephalopathy.
A 25-year-old white female patient treated with high dose of mitotane (4 g per day) for ACC presented toxicity signs such as adrenal insufficiency and digestive and neurological toxicity (nausea, vomiting, anorexia, dizziness, memory troubles) that were similar to those reported by Reidy-Lagunes et al. and generally described by Reidy-Lagunes et al., Daffara et al., and Maiter et al. [1, 2, 8]. After 32 weeks of treatment, while a close monitoring and decrease of mitotane dose was already initiated due to an upper-limit concentration of mitotane (Fig. 1), neurological troubles (attention deficit disorder, memory loss, mental depression) worsened. Mitotane treatment was discontinued at 42 weeks of treatment and a performed elec- troencephalography suggested metabolic encephalopathy. Concomitantly, the determination of mitotane plasma concen- tration found a concentration of 47.8 mg/L and confirmed a mitotane overdose despite the decrease of its dosage 11 weeks before. Finally, the outcome was favorable after hospi- talization in an intensive care unit. One year after tumor resec- tion, no recurrence of malignancy was observed.
Although symptoms of neurotoxicity have already been reported, the specific entity of encephalopathy has been rarely described. Indeed, to the best of our knowledge, only Goto et al. reported a case of encephalopathy in a 4-year-old boy with a high-dose mitotane treatment for ACC [9]. Furthermore, a query in the French national pharmacovigilance database from 2004-the date of mitotane commercialization in France-to 2016 found only 14 cases of neurological adverse effects probably related to mitotane, including drowsiness, asthenia, memory disorders, confusion, concentration trou- bles, headaches, and space-time disorientations, but no case of encephalopathy [10]. It appears that encephalopathy can be a rare but severe adverse event preferentially encountered in high-dose mitotane treatment. A close therapeutic drug
60
Mitotane plasma concentration (mg/L)
50
Discontinued
40
30
3 g per day
4 g per day
20
10
0
0
4
8
12 16 20 24 28 32 36 40
Time after mitotane beginning (week)
monitoring should be performed in case of signs of neurologi- cal toxicity to evaluate the exposure of the patient to mito- tane. Finally, the decision of mitotane discontinuation should be considered from the early signs of neurotoxicity or in the presence of elevated mitotane blood concentration because mitotane presents a very long terminal half-life (several weeks to several months), leading to an important delay between the decision of treatment discontinuation and the effective decrease of exposure. This case was reported to our Regional Center of Pharmacovigilance.
ELISE PAPE
Department of Clinical Pharmacology and Toxicology, University Hospital of Nancy, Nancy, France
Ingénierie Moléculaire et Physiopathologie Articulaire, UMR 7365 CNRS-UL, University of Lorraine, Vandœuvre-lès-Nancy, France
CATHERINE FELIU Laboratory of Pharmacology and Toxicology, University Hospital of Reims, Reims, France
MÉLISSA YÉLÉHÉ-OKOUMA
Pharmacovigilance Center of Lorraine, University Hospital of Nancy, Nancy, France NATACHA COLLING Department of Clinical Pharmacology and Toxicology, University Hospital of Nancy, Nancy, France
ZOUBIR DJERADA Laboratory of Pharmacology and Toxicology, University Hospital of Reims, Reims, France
NICOLAS GAMBIER Department of Clinical Pharmacology and Toxicology, University Hospital of Nancy, Nancy, France
Ingénierie Moléculaire et Physiopathologie Articulaire, UMR 7365 CNRS-UL, University of Lorraine, Vandœuvre-lès-Nancy, France
GEORGES WERYHA Department of Endocrinology, University Hospital of Nancy, Vandœuvre-lès-Nancy, France JULIEN SCALA-BERTOLA Department of Clinical Pharmacology and Toxicology, University Hospital of Nancy, Nancy, France
Ingénierie Moléculaire et Physiopathologie Articulaire, UMR 7365 CNRS-UL, University of Lorraine, Vandœuvre-lès-Nancy, France
Disclosures
The authors indicated no financial relationships.
REFERENCES
1. Reidy-Lagunes DL, Lung B, Untch BR et al. Complete responses to mito- tane in metastatic adrenocortical carcinoma-A new look at an old drug. The Oncologist 2017;22:1102-1106.
2. Daffara F, De Francia S, Reimondo G et al. Prospective evaluation of mito- tane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer 2008;15:1043-1053.
3. Wängberg B, Khorram-Manesh A, Jansson S et al. The long-term survival in adrenocortical carcinoma with active surgical management and use of monitored mitotane. Endocr Relat Cancer 2010;17:265-272.
4. Haak HR, Hermans J, van de Velde CJ et al. Optimal treatment of adreno- cortical carcinoma with mitotane: Results in a consecutive series of 96 patients. Br J Cancer 1994;69:947-951.
5. Hermsen IG, Fassnacht M, Terzolo M et al. Plasma Concentrations of o,p’DDD, o,p’DDA, and o,p’DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: Results of a retrospective ENS@T multicenter study. J Clin Endocrinol Metab 2011;96:1844-1851.
6. Faggiano A, Leboulleux S, Young J et al. Rapidly progressing high o,p’DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: Preliminary results. Clin Endocrinol (Oxf) 2006;64:110- 113.
7. Baudin E, Pellegriti G, Bonnay M et al. Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p’DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer 2001;92: 1385-1392.
8. Maiter D, Bex M, Vroonen L et al. Efficacy and safety of mitotane in the treatment of adrenocortical carcinoma: A retrospective study in 34 Belgian patients. Ann Endocrinol (Paris) 2016;77:578-585.
9. Goto T, Miyako K, Kuromaru R et al. Case report: Adjuvant therapy with a high dose of mitotane for adrenocortical carcinoma in a 4-year-old boy. Clin Pediatr Endocrinol 2008;17:71-74.
10. Extraction of the French pharmacovigilance database, July 2016.
http://dx.doi.org/10.1634/theoncologist.2017-0426
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