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Frontiers in Oncology 2023Mitotane, the only drug approved by the Food and Drug Administration (FDA) for the treatment of adrenocortical carcinoma, is associated with several side effects...
INTRODUCTION
Mitotane, the only drug approved by the Food and Drug Administration (FDA) for the treatment of adrenocortical carcinoma, is associated with several side effects including neurotoxicity. The aim of our study is to investigate the relationship between mitotane plasma levels and neurological toxicity.
METHODS
We have considered five patients affected by adrenocortical carcinoma treated with mitotane. The neurological assessment included a neurological examination, an electroencephalogram, event-related potentials (P300), and a neuropsychological assessment. All of the patients were first considered at the onset of symptoms of neurotoxicity or when mitotanemia levels were above 18 mg/L, for the second time at mitotanemia normalization and subsequently at its further increase, or in case of persistent neurological abnormalities, some months after normalization.
RESULTS
At the first neurotoxicity, four patients showed impaired neurological examination, electroencephalogram, and P300; three patients had impaired neuropsychological assessment; one patient, only P300. At mitotanemia normalization, the neurological examination became normal in all patients and electroencephalogram normalized in one patient, improved in another one, continuing to be altered in the other three. P300 latency and neuropsychological assessment normalized in two patients and persisted altered in the patient experiencing long-term mitotane toxicity. At the third evaluation, in the patient with prolonged mitotane toxicity, the normal mitotanemia in the previous 9 months restored P300 and improved the electroencephalogram but not the neuropsychological assessment. In the two patients experiencing a further rise of mitotanemia, neurological examination was normal but P300 and electroencephalogram were altered.
CONCLUSION
The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L.
PubMed: 37645432
DOI: 10.3389/fonc.2023.1222002 -
The Lancet. Diabetes & Endocrinology Oct 2023Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study.
BACKGROUND
Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence.
METHODS
ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete.
FINDINGS
Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths.
INTERPRETATION
Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment.
FUNDING
AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.
Topics: Humans; Mitotane; Adrenocortical Carcinoma; Disease-Free Survival; Adrenal Cortex Neoplasms
PubMed: 37619579
DOI: 10.1016/S2213-8587(23)00193-6