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Endocrine
Research
Adverse Events of Adjuvant Mitotane Treatment for Adrenocortical Carcinoma
Ivana Dora Vodanović, Anja Barač Nekić, Lana Šambula, Karin Zibar Tomšić, Tina Dušek & Darko Kaštelan
To cite this article: Ivana Dora Vodanović, Anja Barač Nekić, Lana Šambula, Karin Zibar Tomšić, Tina Dušek & Darko Kaštelan (2025) Adverse Events of Adjuvant Mitotane Treatment for Adrenocortical Carcinoma, Endocrine Research, 50:1, 50-56, DOI: 10.1080/07435800.2024.2402311
To link to this article: https://doi.org/10.1080/07435800.2024.2402311
Published online: 15 Sep 2024.
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Adverse Events of Adjuvant Mitotane Treatment for Adrenocortical Carcinoma
Ivana Dora Vodanović Da, Anja Barač Nekića, Lana Šambulab, Karin Zibar Tomšić (Dª, Tina Dušeka,c, and Darko Kaštelan (Da,c
aDepartment of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia; bDepartment of Nephrology, Endocrinology and Diabetology, General Hospital Tomislav Bardek, Koprivnica, Croatia; ‘School of Medicine, University of Zagreb, Zagreb, Croatia
ABSTRACT
Background: Mitotane is the cornerstone of adjuvant adrenocortical cancer (ACC) treatment. However, its use is burdened with frequent adverse events.
Methods: A retrospective analysis of adverse events was performed in 26 ACC patients adjuvantly treated with mitotane.
Results: Mitotane toxicity was present in all patients (100%). Two (7.7%) patients developed 1-3 adverse events, 15 (57.7%) experienced 4-6 adverse events and 9 (34.6%) patients had more than 6 adverse events. Two (7.7%) patients discontinued mitotane due to adverse events.
Conclusion: Careful monitoring and timely management are essential for ensuring mitotane treatment adherence and maximizing its benefits.
ARTICLE HISTORY
Received November 26, 2023 Revised August 1, 2024 Accepted September 4, 2024
KEYWORDS
Adjuvant treatment; adrenal insufficiency; adrenocortical carcinoma; adverse event; hydrocortisone replacement; mitotane
Introduction
Adrenocortical carcinoma (ACC) is a rare malignant disease affecting both sexes and all age groups. It may present with nonspecific symptoms related to tumor mass and/or more specific symptoms caused by excess hormone secretion. Occasionally, the diagnosis is estab- lished as an incidental finding during the asymptomatic phase.1 General prognosis is poor and radical surgery is paramount in treatment. In addition, tumor stage, pro- liferative activity and hypercortisolism have been recog- nized as independent prognostic factors. In case of high risk of tumor recurrence, several adjuvant treatment strategies are available, either systemic (mitotane ther- apy, cytotoxic drugs) or regional (irradiation).2
Adjuvant mitotane treatment has been shown to increase recurrence-free survival (RFS) as well as overall survival (OS) in patients with ACC.3,4 The therapeutic effect of mitotane is two-fold: it induces adrenocortical cell death and inhibits steroidogenesis, reducing symp- toms of hormone-producing ACC.5
On the other hand, mitotane is characterized by a narrow therapeutic range (14 to 20 mg/L) and conse- quent high toxicity6 reflecting in frequent and numer- ous endocrine, gastrointestinal, and neurological adverse effects. Not only that they compromise treat- ment compliance and the quality of life but they also potentially represent a serious health threat. A previous study on 311 ACC patients treated with mitotane
reported that 14.5% of them permanently discontinued the drug due to adverse events.7 Therefore, balancing the benefits of mitotane treatment with its side effects represents a major clinical challenge. Timely recogni- tion and management of these side effects is crucial in optimizing patients’ compliance to treatment and achieving an appropriate treatment outcome.
Therefore, the main aim of this study was to analyze the onset, type, and frequency of adverse events in patients with ACC treated with mitotane in an adjuvant setting. Additionally, we aimed to identify the clinical and biochemical parameters that might predict the occurrence of adverse events associated with adjuvant mitotane treatment.
Subjects and Methods
This retrospective single-center study reviewed the medical records of patients with ACC referred to our center from March 2010 to April 2022. Only patients with complete tumor resection (R0) who were adju- vantly treated with mitotane were included in the study. On the other hand, patients with advanced dis- ease (ENSAT IV), tumor resection other than R0 and follow-up of less than 6 months after introduction of mitotane, were excluded. Data on age, sex, BMI, medical history, date of diagnosis, histopathological reports, autonomous hormone secretion, duration of adjuvant
mitotane treatment, time in target range, peak mitotane concentration, as well as the type, frequency, and sever- ity of adverse events were extracted from patients’ elec- tronic health records.
Patients were followed for signs of mitotane toxicity every 1-1.5 months during the first three months of mitotane treatment, every 3 months in the following three years and every 6-12 months thereafter. In a patient treated with adjuvant chemotherapy alongside mitotane, analyses of mitotane toxicity were made after the discontinuation of chemotherapy.
The regular patients’ assessment consisted of medical history updates, physical examination and laboratory tests including measurement of mitotane plasma con- centration, routine biochemical parameters, and hor- mone evaluation. To analyze the achievement and maintenance of the target mitotane concentration we calculated the percentage of time, from the beginning to the end of mitotane treatment, in which the concentra- tion of mitotane was >14 mg/L (time in target range - TTR).
Since mitotane inevitably induces adrenal insuffi- ciency, hydrocortisone replacement was administered in all patients, two weeks after the start of mitotane treatment, and dose adjustment was based on clinical assessment as well as on sodium, potassium, and ACTH blood levels. Once mitotane was discontinued, HPA axis was assessed after 6 months and then every 3 months until recovery. Complete HPA axis recovery was defined by morning cortisol level of ≥350 nmol/L or ≥440 nmol/L after stimulation with ACTH 1 mcg (the Synacthen test). In contrast, partial HPA axis recovery was defined by morning cortisol level of 250-350 nmol/L without cortisol increase ≥440 nmol/ L in the Synacthen test.8
Mineralocorticoid deficiency was defined by pre- sence of any of the following criteria: (i) elevated plasma renin activity, (ii) hyperkalemia and/or hyponatremia of no other probable cause, (iii) orthostatic arterial hypo- tension (adapted from)9
Thyroid gland function was assessed by measure- ment of free T3, free T4 and TSH. Free T4 level below normal range, along with normal/low TSH concentra- tion, was consistent with the diagnosis of central hypothyroidism. Hypogonadism in males was defined by free testosterone level below normal range. In females, disorders of menstrual cycle (amenorrhea, oli- gomenorrhoea, polymenorrhoea) were recorded whereas estradiol, FSH and LH were not routinely mea- sured. In addition, formation of ovarian cysts larger than 2 cm in diameter was documented by imaging.
General gastrointestinal and neurological symptoms were evaluated based on patient recall and self-
assessment. For patients with severe neurological disor- ders (grade 4 or higher), brain imaging was performed.
All adverse events were graded according to the Common Terminology Criteria for Adverse Events ver- sion 5.0, on a scale of 1-5.
Statistical Analysis
Statistical analysis was conducted using the SPSS ver- sion 17.0 for Windows. Variables were described as median and range, whereas nominal variables were pre- sented as frequencies. The differences between the vari- ables were tested using the Mann-Whitney test or x2 test, as appropriate. Correlations between the onset and grade of adverse events with different clinical and bio- chemical parameters were tested using the non- parametric Spearman’s correlation test. Binary logistic regression analysis was used (Hosmer-Leveshow good- ness-of-fit test) to test the association between adverse events and individual clinical/demographic parameters, reporting odds ratios (OR) with 95% confidence inter- vals (CI). Significance level was set at p < 0.05.
Results
Subjects
A total of 31 patients who received adjuvant mitotane treatment following R0 resection of ACC were consid- ered as candidates for inclusion in this retrospective study. However, after 5 patients were excluded from the study because of absence of clinical data in the electronic medical records (n =2) or follow-up of less than 6 months (n = 3), the final number of patients for the analysis was 26 (8 males and 18 females; median age 47 (18-72) years). Sixteen (61.5%) patients had secre- tory tumors with autonomous secretion of various hor- mones: cortisol and androgens (n=8), cortisol and estrogen (n= 1), cortisol (n =1), aldosterone (n= 1), androgens (n=3), estrogen (n=1), and 11- deoxycorticosterone (n =1). All but three patients, of which two were enrolled in the ADIUVO study,10 had high risk of disease recurrence indicated by Ki-67> 10%. In addition to adjuvant mitotane, one patient also received three cycles of adjuvant etoposide and cisplatin due to particularly poor prognostic mar- kers (Ki67 60%, >100 mitoses/50 HPF). No hormone deficiencies were present prior to mitotane treatment initiation.
During follow-up of 72.5 (6-136) months, 10 patients had disease recurrence after a median of 31.5 (7-84) months following mitotane initiation.
| Variable | |
| Male gender (n, %) | 8 (30.8%) |
| Female gender (n, %) | 18 (69.2%) |
| Age (years) | 47 (18-72) |
| BMI (kg/m2) | 25 (15-39) |
| Tumor size (mm) | 97.5 (35-250) |
| Excess glucocorticoid secretion (n, %) | 11 (42.3%) |
| ENSAT stage (n, %) | |
| I | 1 (3.8%) |
| 14 (53.8%) | |
| 11 (42.4%) | |
| Ki67%) | 18 (4-65) |
| Weiss score | 7 (3-9) |
| Adjuvant chemotherapy (n) | 1 |
| Follow-up (months) | 72.5 (6-136) |
One patient died of pneumonia, 20 months after mito- tane initiation.
Demographic and clinical characteristics of the patients are provided in Table 1 whereas the list of adverse events and their corresponding grades is pro- vided in Table 2.
Mitotane Treatment
As for the initiation of mitotane administration, low-dose and high-dose approach was used in 5 and 21 patients, respectively. The planned duration of adjuvant mitotane treatment was 24 months in patients with Ki67 ≤ 20%, and 36 months in patients with Ki67 > 20%.11
Twenty five (96.2%) patients reached target mitotane plasma concentration of >14 mg/L after a median time of 75 (26-300) days, and the remaining patient discontinued mitotane after 49 days of treatment due to severe liver toxi- city. Overall, average TTR was 72% (0-100%); in four patients it was < 50%, in six 50-75% whereas in 16 patients TTR was> 75%. No statistically significant difference was found between the low-dose versus high-dose approach and time to reaching therapeutical mitotane plasma concentra- tion (>14 mg/L) (p =0.308). After mitotane discontinuation, it took 12.5 (5-29) months for the concentration of the drug to fall below the limit of assay detection (1 mg/L).
Nineteen patients discontinued mitotane treatment as scheduled, after completing treatment duration of 24 months (n= 12) or 36 months (n =7). Three patients had disease recurrence during adjuvant mitotane treat- ment and mitotane was continued in a palliative setting, whereas in two patients adjuvant mitotane was ongoing at the time of data collection. Two patients discontinued mitotane due to adverse events: one patient discontin- ued mitotane permanently after 49 days of treatment because of liver toxicity. The other patient had a temporary treatment interruption due to exfoliative dermatitis and eventually ceased mitotane therapy
permanently after 18 months of treatment due to recur- ring multiple neurological adverse events. All patients experienced some adverse events; two (7.7%) patients developed 1-3 adverse events, 15 (57.7%) experienced 4-6 adverse events and 9 (34.6%) had more than 6 adverse events.
Gastrointestinal Disorders
Sixteen (61.5%) patients reported gastrointestinal symp- toms after 4 (1-17) months of mitotane treatment: nausea (n = 16, 61.5%), vomitus (n = 11, 42.3%), dys- pepsia (n = 3, 11.5%), diarrhea (n = 4, 15.4%), anorexia and/or weight loss (n = 13, 50%).
Elevation of GGT levels (at least 2x ULN) was observed in all but one patient (n = 25, 96.2%). Out of them, in 13 (50%) patients GGT level was > 5x ULN. In addition, one patient had a moderate (2-5x ULN) eleva- tion of AST and ALT whereas another one had a moderate elevation in AST (2-5x ULN) and severe elevation in ALT (>5x ULN) and therefore permanently discontinued mitotane.
Neurological Disorders
Twenty (76.9%) patients experienced general neurolo- gical symptoms that included vertigo, dizziness, head- ache and fatigue. Additionally, in total 14 (53.8%) patients experienced various forms of cognitive disor- ders, such as decreased memory, mental slowness, and confusion. One patient developed aphasia due to high mitotane concentration, which resolved after the nor- malization of mitotane levels.
Lipid Profile
Twenty-three patients (88.5%) experienced an elevation in cholesterol levels (grade 1 (1-2)), whereas 20 patients
| Adverse event | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
|---|---|---|---|---|---|
| Adrenal crisis | 8 (30.8%) | ||||
| Central hypothyroidism | 6 (23.1%) | 13 (50%) | |||
| Hypogonadism in males (N = 8) | 1 (12.5%) | 3 (37.5%) | |||
| Gynecomastia in males (N = 8) | 1 (12.5%) | ||||
| Oligomenorrhoea in females of reproductive age (N = 10) | 1 (10%) | 2 (20%) | |||
| Metrorrhagia in females (N = 18) | 1 (5.6%) | 2 (11.1%) | |||
| Increase in lipid levels | |||||
| - Total cholesterol | 12 (46.1%) | 9 (34.6%) | 2 (7.7%) | ||
| - Triglycerides | 13 (50%) | 5 (19.2%) | 1 (3.8%) | 1 (3.8%) | |
| Neurological disorders | |||||
| - Asthenia and/or fatigue | 5 (19.2%) | 9 (34.6%) | 1 (3.8%) | ||
| - Confusion | 3 (11.5%) | 6 (23.1%) | 1 (3.8%) | ||
| - Depression | 2 (7.7%) | 1 (3.8%) | 1 (3.8%) | ||
| - Personality change | 2 (7.7%) | ||||
| - Anxiety and/or agitation | 1 (3.8%) | ||||
| - Concentration impairment | 3 (11.5%) | 9 (34.6%) | 1 (3.8%) | ||
| - Amnesia | 6 (23.1%) | 2 (7.7%) | |||
| - Aphasia | 1 (3.8%) | ||||
| - Dysnomia | 1 (3.8%) | ||||
| - Dysarthria | 4 (15.4%) | ||||
| - Ataxia | 5 (19.2%) | 3 (11.5%) | 2 (7.7%) | ||
| - Vertigo/gait disturbance | 3 (11.5%) | 11 (42.3%) | 1 (3.8%) | ||
| - Myalgia/muscle weakness | 1 (3.8%) | 1 (3.8%) | 1 (3.8%) | ||
| - Tremor | 1 (3.8%) | ||||
| - Blurred vision/flashing lights | 4 (15.4%) | ||||
| Gastrointestinal disorders | |||||
| - Diarrhea | 2 (7.7%) | 2 (7.7%) | |||
| - Nausea | 3 (11.5%) | 11 (42.3%) | 2 (7.7%) | ||
| - Vomiting | 3 (11.5%) | 7 (26.9%) | 1 (3.8%) | ||
| - Anorexia and/or weight loss | 2 (7.7%) | 8 (30.8%) | 3 (11.5%) | ||
| - GGT increase | 3 (11.5%) | 10 (38.5%) | 8 (30.8%) | 4 (15.4%) | |
| - ALT or AST increase | 12 (46.2%) | 1 (3.8%) | |||
| - ALP increase | 1 (3.8%) | 3 (11.5%) | |||
| Rash/eczema/urticaria | 1 (3.8%) | 1 (3.8%) |
(76.9%) had an elevation in triglyceride levels (grade 1 (1-2)) following mitotane administration.
Adrenal Insufficiency
After mitotane initiation, all patients received hydro- cortisone replacement with a median daily dose of 58 (32-97) mg. In addition, 5 (19.2%) patients also devel- oped mineralocorticoid deficiency and received fludro- cortisone replacement. Finally, 8 (30.8%) patients, among whom were all those with mineralocorticoid deficiency, developed acute adrenal crisis during mito- tane treatment. No difference in hydrocortisone dose was observed between patients who had an adrenal crisis and those who had not (p = 0.266).
As for the recovery of hypothalamus-pituitary- adrenal (HPA) axis after mitotane discontinuation, out of 19 patients eligible for the analysis, 10 (52.6%) achieved complete recovery after a median time of 27 (12-41) months whereas partial HPA axis recovery was recorded in 3 (15.8%) patients after a median time of 13 (7-36) months. In contrast, in 6 (31.6%) patients HPA axis did not recover after a respective follow-up of 9, 12, 14, 69, 74, 94 months after mitotane discontinuation.
Maximum ACTH levels during mitotane treatment differed significantly between patients with complete HPA axis recovery (12.1 (4.8-16.2) pmol/L) vs. partial HPA axis recovery (47.5 (13.8-60.4) pmol/L) vs. absence of HPA axis recovery (123.1 (74.6-164.0) pmol/L); p = 0.018.
Neither peak mitotane concentrations nor TTR were significantly different between the patients with com- plete or partial HPA axis recovery and those with no HPA axis recovery (p = 0.535 for peak mitotane concen- trations, p = 0.569 for TTR).
Central Hypothyroidism
No patients had abnormal thyroid function tests prior to adjuvant mitotane treatment initiation. However, dur- ing treatment, 19 (73.1%) patients developed central hypothyroidism after a median time of 9 (1-32) months.
Gonadal Dysfunction
Four (50%) male patients developed hypogonadism after a median time of 13 (6-23) months. On the other hand, three out of 10 female patients of reproductive age devel- oped oligomenorrhoea after mitotane introduction. In
addition, three female patients experienced metrorrhagia, whereas in 10 female patients mitotane treatment was associated with a formation of ovarian cysts.
Association of Clinical/Demographic Parameters with the Onset of Adverse Events
In a univariate analysis that included age, gender, BMI, histopathological characteristics of the tumor, hormone secretion, mitotane starting dose (low-dose vs. high-dose), TTR, and peak mitotane concentration, patients who developed central hypothyroidism were found to be younger (42 years (minimum-maximum 18-72) vs. 54 years (47-66); p=0.022) and had a longer TTR (86% (minimum-maximum 39-100) vs. 58% (0-87); p=0.007). However, in a multivariate model, after adjusting for age and sex, binary logistic regression showed that only TTR was associated with the onset of central hypothyroidism (p = 0.047, OR 1.068, 95% CI 1.001-1.140).
Additionally, a higher proportion of females devel- oped general neurological symptoms compared to males (94.4% (17/18) vs. 37.5% (3/8); p = 0.004).
No other adverse events related to mitotane were associated with any of the clinical and demographic parameters analyzed in the model.
Discussion
Mitotane is the cornerstone of adjuvant treatment for adrenocortical carcinoma, but its use is burdened by various adverse events. It has been reported that a significant number of patients discontinues mitotane due to adverse events,7 which compromises their RFS and OS. Therefore, management of adverse events in order to improve treatment adherence seems to be of utmost importance.
The literature on adverse effects of mitotane treat- ment is still scarce. Previous studies demonstrated that almost all patients experience some adverse events, often occurring already at the beginning of the course of the treatment. 9,10,12-14
In our study group, all patients had at least one adverse event, while over 90% of them had more than four, with adrenal insufficiency, hyperlipidemia, central hypothyroidism, general neurological symptoms, and elevation in GGT levels being the most common. However, mitotane discontinuation due to adverse events was required in only two patients in our study group.
Consistent with previous studies,7,10 neurological adverse effects of mitotane treatment were common in our group of patients, especially among women,
and vertigo, gait disturbances, fatigue, and concen- tration impairment were the most frequent. It has been suggested that occurrence of neurological symptoms might be associated with higher mitotane doses5 or longer mitotane treatment duration,7 but this finding has not been consistent across studies. A recent study by Mormando et al.15 systematically examined mitotane neurotoxicity in 5 ACC patients using thorough neurological assessment, including a neurological examination, electroencephalogram, event-related potentials (P300), and a neuropsycho- logical assessment. The study demonstrated that neu- rological toxicity of mitotane is associated with mitotane plasma concentration above 18 mg/L. Additionally, the authors suggested that some neuro- logical alterations associated with mitotane treatment might be irreversible. However, the merit of these data is limited due to the small number of patients included in the study and the concurrent use of chemotherapeutic agents, which might also exhibit neurotoxic effects. In contrast to these findings, the ADIUVO study,10 as well as our data, found no correlation between the onset or grade of neurologi- cal adverse events and mitotane plasma levels or the duration of mitotane treatment.
In addition to neurological toxicity, gastrointestinal symptoms are the most common adverse events asso- ciated with mitotane treatment, reported in approxi- mately 80% of patients.16 These symptoms typically include nausea, vomiting, diarrhea, anorexia, and weight loss.5,7,10,12 Gastrointestinal symptoms generally occur early in the course of mitotane treatment with milder grades, and tend to improve over time.12 Nevertheless, relapses were observed with increases of mitotane dosage regimen.12 In our cohort, about 60% of patients reported gastrointestinal symptoms, with nau- sea, vomiting, anorexia and weight loss being the most common.
Adrenal insufficiency develops in all patients shortly after mitotane initiation due to its ability to induce adrenocortical cell death and inhibit steroidogenesis.5 Therefore, all patients should receive hydrocortisone treatment. The hydrocorti- sone dose should be higher than the usual dose in patients with Addison’s disease since mitotane increases glucocorticoid clearance rate.17 In a Canadian-Italian cohort of ACC patients on adju- vant mitotane treatment, the mean maximal hydro- cortisone dose or cortisone acetate dose was 51.6 (25-100) mg and 69.4 (50-87.5) mg, respectively.18 In another study including 74 patients, the daily median hydrocortisone-equivalent dose of 0.67 (0.22-1.20) mg/kg had been used.9 In our study,
average daily hydrocortisone dose was 58 (32- 97) mg. Despite administering a relatively high hydrocortisone dose, 8 of our patients developed acute adrenal crisis during mitotane treatment. Patients with additional mineralocorticoid deficiency were more likely to experience adrenal crisis, and all of them did so. Additionally, it is important to note that some of gastrointestinal as well as neurological symptoms might result from inadequately managed adrenal insufficiency.
The recovery of the HPA axis after mitotane dis- continuation can vary, with some patients not reco- vering function at all.18,19 In our study, even 31.6% of patients did not achieve HPA axis recovery after a median follow-up of 41.5 (9-94) months after mitotane discontinuation. The duration of HPA axis insufficiency was not influenced by time in target range or peak mitotane concentration, but it corre- lated with maximum ACTH levels during mitotane treatment.
As in other studies, biochemical central hypothyroid- ism and hypogonadism occurred frequently in our patients and resolved spontaneously after mitotane dis- continuation. The benefit of hormone replacement in these patients is uncertain, as patient-reported out- comes of replacement therapy have not been thoroughly assessed.9,13 Therefore, the decision to start hormone replacement treatment should be tailored to each indi- vidual patient.
Besides the mitotane effect on the function of various endocrine glands, its metabolic effects man- ifest in an increase in lipid concentrations observed in many published studies9,12 as well as in ours. Mitotane has a complex and not yet fully elucidated molecular mechanism of action regarding lipid reg- ulation. It stimulates hydroxymethylglutarate- coenzyme A (HMG-CoA) reductase, induces endo- plasmic reticulum (ER) stress and alters lipid-related genes.20,21 It is still unclear whether the changes in lipid panel are of clinical significance regarding the cardiovascular system,22 especially since the rise in HDL levels might counteract atherogenic effects of other lipids.21,23 Besides that, a correlation has been found between the increase in LDL levels and the onset of general neurological symptoms. It is hypothesized that increased LDL, which binds plasma mitotane, facilitates mitotane access into the brain as a target tissue.24 Ultimately, future research should provide better insight on potential benefits of combined mitotane and statin treatment on ACC outcomes.
Concerning the mitotane dosing, some studies suggested that gradual and slower increase of
mitotane dose at the beginning of the treatment (“low dose approach”) might be associated with bet- ter drug tolerability,4 but this may be at the expense of the delay in reaching the target mitotane concen- tration. In our study, in more than 80% of patients “high dose approach” was used which potentially increased the number of side effects.
Our study has several limitations, with the most sig- nificant ones being its retrospective nature and small patient group. However, the fact that all the patients were treated at the same center using a standardized protocol ensures the consistency and validity of the collected data, which is a major strength of the study.
In conclusion, almost all patients experience adverse events while taking mitotane. Gastrointestinal and neu- rological symptoms are common and can significantly impact quality of life and treatment adherence. All patients require treatment for adrenal insufficiency, which is the most dangerous and potentially life- threatening side-effect. Patients with accompanying mineralocorticoid deficiency are at increased risk of acute adrenal crisis. Some patients may require pro- longed or lifelong glucocorticoid supplementation even after stopping mitotane. Careful monitoring, timely management, and good patient-doctor commu- nication are essential for improving quality of life and treatment adherence. The complexity of mitotane treat- ment underscores the need to provide it exclusively at centers with a high level of expertise.
Disclosure Statement
D.K. served on the H.R.A. pharma advisory board. Other authors have no conflict of interest to declare.
Funding
The author(s) reported that there is no funding associated with the work featured in this article.
ORCID
Ivana Dora Vodanović (D http://orcid.org/0000-0002-5380- 4411
Karin Zibar Tomšić (D http://orcid.org/0000-0002-1694-6891 Darko Kaštelan (D http://orcid.org/0000-0003-3034-5598
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, [I.D.V.], upon reasonable request.
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