Society for Endocrinology
Mitotane dosage, plasma levels, and anthropometric measurements in pediatric adrenocortical carcinoma
Maria Riedmeier01, Heidi Frey1, Sonir R Antonini 02, Gabriela Fernandes Luiz Canali3, Carl Friedrich Classen4, Nerea Domínguez-Pinilla5, Martin Fassnacht6,7, Jasmin Finger8, Steffen Fuchs9,10,11, Marika Grönroos12, Mariana P Halah2, Christoph Härtel1, Dominika Janus13, Antoinette Jaspers-Bakker14, Ronald R de Krijger14,15, Tezer Kutluk16, Mouna Mezoued17,18, Jessica Munarin19,20, Max van Noesel14, Nihal Ozdemir Köse1, Simon H Pearce21, Thomas Perwein22, Soraya Puglisi23, Paul-Gerhardt Schlegel1,7,24, Vera Binder-Blaser25, Gerdi Tuli19,20, Justyna Walenciak26, Bilgehan Yalcin16 and Verena Wiegering 1,7,24,27
1University Hospital Würzburg, Department of Pediatrics, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg, Germany
2Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil
3Oncologia, Pequeno Principe Hospital, Curitiba, Paraná, Brazil
4Division of Pediatric Oncology, Hematology and Palliative Medicine Section, Department of Pediatrics and Adolescent Medicine, University Medicine Rostock, Rostock, Germany
5Pediatric Hematology and Oncology Unit, University Hospital 12 de Octubre, i+12 Research Institute, Madrid, Spain
6Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg, Germany 7Comprehensive Cancer Centre CCC WERA, University of Wuerzburg Medical Centre, Wuerzburg, Germany 8Pediatric Hematology, Oncology and BMT, University Hospital Münster, Münster, Germany
9Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany
10Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
11German Cancer Consortium (DKTK), Partner Site Berlin, A Partnership Between DKFZ and Charité-Universitätsmedizin Berlin, Berlin, Germany
12Department of Pediatrics, Turku University Hospital, Turku, Finland
13Department of Pediatric and Adolescent Endocrinology, Jagiellonian University Medical College, University Children Hospital, Krakow, Poland 14Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
15Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
16Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey
17Department of Endocrinology and Metabolism Bologhine Hospital, Algiers, Algeria 18Research Laboratory of Endocrinology and Metabolism (LEM1), Benyoucef Benkhedda University, Algiers, Algeria 19Department of Pediatric Endocrinology, Regina Margherita Children’s Hospital, Turin, Italy
20Department of Pediatrics, University of Turin, Turin, Italy
21Department of Endocrinology, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
22Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
23Internal Medicine, Department of Clinical and Biological Sciences, S Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy 24KIONET, Pediatric Oncology Network and Bavarian Center for Cancer Research, Würzburg, Germany
25Department of Pediatric Oncology and Hematology, Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich, Munich, Germany 26Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland
27Mildred Scheel Early Career Center, University Hospital Wuerzburg, Wuerzburg, Germany
Correspondence should be addressed to M Riedmeier: riedmeier_m@ukw.de
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Abstract
Objective: Mitotane is an effective treatment for advanced adrenocortical carcinoma (ACC). Given the limited pediatric data available, this study aims to evaluate the associations between mitotane dosage, plasma drug levels, and anthropometric measurements, as well as their potential impact on dosage requirements to optimize therapeutic outcomes in pediatric patients with ACC (pACC).
Design and methods: A retrospective, international, multicenter study was conducted on pediatric ACC patients treated with mitotane across 18 centers. Mitotane serum levels were obtained from the Lysosafe Online® database or directly from the centers. Data from the cohort with plasma levels within the target range (≥14 mg/L; n = 319) were analyzed and compared to those with levels outside this range (n = 320).
Results: Fifty pediatric patients (60% female) diagnosed between 2004 and 2023 were included, with a median follow-up of 34.5 months and a 10-year overall survival of 33 months. The median age at diagnosis was 8.6 years, with most tumors (84%) hormone-secreting. Among 49 patients undergoing surgery, 31 (62%) achieved R0 resection. The median treatment duration was 18 months, with a median mitotane dose of 87 mg/kg/day in patients within the target plasma level range, showing no significant difference from those outside the range. However, BMI was significantly associated with doses of plasma levels in target range (P = 0.001), as underweight (105.4 mg/kg/day) and healthy weight patients (98.4 mg/kg/day) required higher doses than overweight/obese patients (44.4 mg/kg/day). No significant differences in daily dose levels (mg/kg/day and mg/m2/day) were observed based on body weight.
Conclusion: This study supports estimating mitotane dosages in pediatric ACC, emphasizing the need for close monitoring and frequent follow-ups at specialized centers due to individualized dosing and a narrow therapeutic window.
Keywords: pediatric adrenocortical carcinoma; mitotane; pediatric adrenocortical tumor; mitotane dosage; mitotane plasma level
Introduction
Pediatric adrenocortical carcinoma (pACC) is an exceptionally rare malignancy, with an incidence of 0.2-0.3 cases per million children under the age of 20 per year (1, 2) and differs clinically and histopathologically from adult ACC tumors (3, 4, 5, 6, 7). The prognosis for patients with advanced pACC is unfavorable, and effective risk stratification remains a subject of ongoing debate (8, 9, 10, 11).
En bloc surgical resection of the tumor is the primary and most effective treatment for pediatric adrenocortical carcinoma, with complete tumor removal leading to a cure in most cases (9, 12, 13, 14). In addition, systemic therapy is indicated for advanced tumor stages with a high risk of recurrence (9, 12, 15, 16). Since prospective clinical randomized trials are lacking so far, systemic treatment regimens remain highly heterogeneous. Following the recommendations of the Children’s Oncology Group (COG) (12) and the German GPOH-MET 97 strategy (17), the most commonly used chemotherapeutics to date are cisplatin, etoposide, and doxorubicin (EDP).
In addition to chemotherapy, mitotane - an antineoplastic agent with specific adrenocortical activity - is clearly indicated in pACC patients with advanced stages (III-IV), incomplete tumor resection, tumor spillage, or primary unresectable tumors. In patients with stage II disease, the indication for mitotane therapy depends on the clinical course and tumor-specific characteristics; for example, a high Ki-67 index has been discussed as a potential factor supporting mitotane treatment, although evidence remains limited (9, 15, 18, 19).
However, not all patients have access to mitotane treatment in every country, and the evaluation of mitotane plasma levels is not always feasible. Given the limited evidence from studies on mitotane treatment in pACC, the recently published international expert consensus recommends close monitoring of mitotane serum levels in pACC patients, with a target plasma range of 14-20 mg/L (9, 12, 16, 17, 18, 20). The recommended standard duration of mitotane treatment in children - depending on clinical response and tolerability - is 24 months, with a minimum treatment
duration of at least 1 year (18). Adverse effects during mitotane therapy are frequent and encompass a broad spectrum of clinical manifestations, including hematological, endocrinological, gastrointestinal, and neurological toxicities. Especially neurological adverse effects (e.g., ataxia, confusion, and dizziness) show a strong correlation with elevated plasma concentrations and may be life-threatening, underscoring the importance of regular monitoring of mitotane blood levels, along with close clinical and neurological surveillance, to ensure early detection and prevention of toxicity (15, 18, 21, 22, 23, 24, 25, 26).
Given the limited understanding of pharmacokinetic correlations of mitotane in pACC patients, this study aims to evaluate the associations between mitotane dosage, plasma drug levels, and anthropometric measurements, and their potential impact on dosage requirements to optimize therapeutic outcomes.
Methods
For this international multicenter study, data from 50 pediatric patients with adrenocortical carcinoma treated with mitotane were retrospectively collected from 18 centers across 10 countries (Germany, Brazil, Spain, Poland, Netherlands, Turkey, Algeria, Italy, Austria, and Finland).
Inclusion criteria for the analyses of the cohort were histopathologically confirmed diagnosis of ACC according to the Wieneke criteria (27), treatment with mitotane, availability of at least three mitotane plasma levels, and follow-up data. Patients were staged using the TNM/ENSAT (28) and COG staging systems (12).
Consistent with the previous literature, a mitotane plasma level of ≥14 mg/L was defined as the threshold, representing the lower limit of the target range established in several studies (9, 12, 16, 17, 18, 20). For body mass index (BMI) calculation, the official WHO BMI classification was used with slight modification, as overweight and obese patients were combined into a single group due to limited patient numbers: underweight <18.5 kg/m2, healthy weight 18.5-24.9 kg/m2, and overweight/obesity ≥25.0 kg/m2.
Some of the mitotane concentration levels and dosages were directly obtained from the centers where the patients were treated. However, the majority of the concentrations were collected from the Lysosafe Online® database (www. lysosafe.com), a secure online platform designed for determining, monitoring, and managing mitotane levels in patients with ACC. This platform allows registered physicians to collect, store, and analyze pseudonymized patient data related to mitotane concentrations, ensuring that the drug is administered at therapeutic levels while minimizing toxicity. The collaborating centers took screenshots of the pseudonymized mitotane plasma
levels and dosages from the Lysosafe Online® database and sent them via email.
Due to the differing standards for monitoring plasma levels across treatment centers during mitotane therapy, the frequency of available plasma level measurements varied. In addition, a few patients (n = 3-4) were still receiving mitotane treatment at the end of the data collection period. For pediatric patients undergoing mitotane therapy, the dosage was commonly administered based on body weight.
The project received approval from the Würzburg local ethics committee (20231016 02, Würzburg, Germany 2023).
Statistical analyses were performed using R Studio to evaluate the findings of the study. The Kolmogorov-Smirnov test was used to determine the normality of the distribution of the parameters. Descriptive statistical methods (mean, median, range) were applied, and the Mann-Whitney U test was used for comparisons between groups with non-normally distributed parameters. The Spearman’s rho correlation coefficient was calculated to analyze the relationship between two continuous variables. The relationship between the two variables was modeled using linear regression analysis. Chi-square test and Fisher’s exact test were used for comparison of qualitative data. Survival curves were constructed by the Kaplan-Meier method, and the results were compared by univariate and multivariate Cox regression analysis. Results are presented as hazard ratio with 95% confidence intervals (95% CI). Statistical significance was conventionally set at P < 0.05.
Results
Patients’ baseline characteristics
This study included 50 pediatric patients diagnosed with adrenocortical carcinoma between 2004 and 2023 and treated with mitotane. The median age at diagnosis was 107 months (range: 1-241 months), with 12 patients (24%) being younger than 4 years. The gender distribution was nearly equal, with a slight predominance of female patients (n = 3, 60%). The majority of patients (84%) had hormone-secreting tumors, with androgen- secreting tumors being the most common (n = 23, 46%). Among patients with available genomic testing results, 11 of 27 (41%) were diagnosed with a cancer predisposition syndrome, specifically Li-Fraumeni syndrome. Given that mitotane is typically administered in advanced tumor stages, 35 patients (70%) presented with stage 3 or 4 tumors, while 13 patients had tumors in earlier stages. Most of these patients had additional risk factors, such as tumor spillage, incomplete resection, or a high Ki-67 index, which contributed to the decision to pursue more intensive therapy on an individual basis. Almost half of the patients (n = 24, 48%) had tumors
| Clinical characteristics* | Patients (n = 50) | |
|---|---|---|
| Age at diagnosis | Median/mean/range (months) | 107/107.5/1-241 |
| (n; %) | <4 years | 12; 24 |
| 4-11.9 years | 20; 40 | |
| 12-18 years | 15; 30 | |
| >18 years | 3; 6 | |
| Sex (n; %) | Female | 30; 60 |
| Male | 20; 40 | |
| Hormonal secretion | No | 5; 10 |
| (n; %) | Mixed | 10; 20 |
| Androgen | 23; 46 | |
| Glucocorticoid | 9; 18 | |
| No information | 3; 6 | |
| available | ||
| Tumor stage (n; %) | I | 2; 4 |
| II | 11; 22 | |
| III | 15; 30 | |
| IV | 20; 40 | |
| No information | 2; 4 | |
| available | ||
| Ki-67 status/rate of | Low; 0-9% | 5; 10 |
| mitosis (n; %) | Intermediate; | 1; 14 |
| 10-19% | ||
| High; ≥20% | 24; 48 | |
| No information | 14; 28 | |
| available | ||
| Resection status (n; %) | R0 | 31; 62 |
| R1 | 5; 10 | |
| R2 | 8; 16 | |
| Not resected | 1; 2 | |
| Spillage | 4; 8 | |
| No information | 1; 2 | |
| available | ||
| Radiotherapy (n; %) | No | 36; 72 |
| Yes | 11; 22 | |
| No information available | 3; 6 | |
| Relapse/tumor | No | 25; 50 |
| progression (n; %) | Yes | 24; 48 |
| No information | 1; 2 | |
| available | ||
| Long-term outcome | No evidence of | 24; 48 |
| (n; %) | disease | |
| Alive with disease | 10; 20 | |
| Dead of disease | 16; 32 | |
| Follow-up (months) | Median/mean/range | 34.5/45.3/2-187 |
| 10-year OS (months) | Median/mean/range | 33/42.5/2-120 |
| Duration of mitotane treatment (months) | Median/mean/range | 18/20.4/2-60 |
| Brazilian cohort (n; %) | No | 42; 84 |
| Yes | 8; 16 | |
| pS-GRAS groups (n; %) | 1 | 10; 20 |
| 2 | 16; 32 | |
| 3 | 3; 6 | |
| 4 | 1; 2 | |
| Treatment (n; %) | Mitotane | 7; 14 |
(Continued)
| Clinical characteristics* | Patients (n = 50) | |
|---|---|---|
| Mitotane + chemotherapy | 40; 80 | |
| No information | 3; 6 | |
| available | ||
| Body weight (n; %) | 0-9 kg | 3; 6.4 |
| 10-19 kg | 8; 17 | |
| ≥20 kg | 35; 75 | |
| No information available | 1; 2.1 | |
| BMI classification (n; %) | Underweight (<18.5 kg/m2) | 22; 47 |
| Healthy weight (18.5-24.9 kg/m2) | 14; 30 | |
| Overweight/obesity (≥25 kg/m2) | 10; 21 | |
| No information | 1; 2 | |
| available | ||
| Cancer predisposition | Yes | 11; 22 |
| syndrome (n; %) | No | 16; 32 |
| No information available | 23; 46 |
*Clinical characteristics including number of patients (n), age at diagnosis, sex, hormonal secretion, tumor stage, Ki-67 status/rate of mitosis, resection status, radiotherapy, relapse/tumor progression, long-term outcome, follow-up time, 10-year OS (overall survival), duration of mitotane treatment, number of the Brazilian cohort, pS-GRAS groups, treatment, body weight, BMI classification, and cancer predisposition syndrome (in total n and %).
characterized by a high mitotic rate, with Ki-67 ≥ 20%. All but one patient underwent primary surgical intervention, with 31 patients (62%) achieving R0 resection. However, incomplete resection (R1 and R2) was observed in 13 patients (26%), and tumor spillage occurred in 4 patients (8%). The median treatment duration of mitotane was 18 months (ranging from 2 to 60 months). Roughly 25% of the patients were of Brazilian origin. While most patients had a total body weight of ≥20 kg (75%), nearly half of the cohort (47%) was classified as underweight based on a BMI < 18.5 kg/m2 (for details see Table 1).
The follow-up period was 34.5 months in the median (range: 2-187 months), and the 10-year overall survival (OS) was 33 months. During long-term follow-up, 24 patients (48%) experienced a relapse or tumor progression. At the last follow-up, 24 patients (48%) had no evidence of disease, 10 patients (20%) were alive with disease, and 16 patients (32%) had died of disease (see Table 1).
Patients were divided into two treatment groups based on the therapeutic approach. Seven patients received mitotane monotherapy, while forty patients underwent combination therapy with mitotane and chemotherapy, mostly utilizing the EDP-M regimen (etoposide, cisplatin, doxorubicin, and mitotane). Data on chemotherapy were unavailable for three patients. The group that received both mitotane
| Clinical characteristics1 (n = 47)2 | Mitotane + chemotherapy Mitotane (n = 7) (n = 40) P | |||
|---|---|---|---|---|
| Age at diagnosis | Median/mean/range (months) | 60/89.9/26-199 | 108/109.6/1-241 | 0.4723 |
| (n; %) | <4 years | 3; 42.9 | 8; 20 | 0.3304 |
| ≥4 years | 4; 57.1 | 32; 80 | ||
| Sex (n; %) | Female | 3; 42.9 | 24; 60 | 0.4384 |
| Male | 4; 57.1 | 16; 40 | ||
| Hormonal secretion (n; %) | No | 0; 0 | 5; 12.8 | 0.5875 |
| Mixed | 0; 0 | 10; 39 | ||
| Androgen | 4; 66.7 | 17; 43.6 | ||
| Glucocorticoid | 2; 33.3 | 7; 17.9 | ||
| Tumor stage (n; %) | I | 0; 0 | 1; 2.6 | 0.0975 |
| II | 4; 57.1 | 6; 15.8 | ||
| III | 2; 28.6 | 13; 34.2 | ||
| IV | 1; 14.3 | 18; 47.4 | ||
| Ki-67 status/rate of mitosis (n; %) | Low; 0-9% | 1; 20 | 3; 10.7 | 0.3855 |
| Intermediate; 10-19% | 2; 40 | 5; 17.9 | ||
| High; ≥20% | 2; 40 | 20; 71.4 | ||
| Resection status (n; %) | R0 | 7; 100 | 21; 53.8 | 0.2575 |
| R1 | 0; 0 | 5; 12.8 | ||
| R2 | 0; 0 | 8; 20.5 | ||
| Not resected | 0; 0 | 1; 2.6 | ||
| Spillage | 0; 0 | 4; 10.3 | ||
| Radiotherapy (n; %) | No | 7; 100 | 28; 73.7 | 0.3204 |
| Yes | 0; 0 | 10; 26.3 | ||
| Relapse/tumor progression (n; %) | No | 7; 100 | 16; 41 | 0.0094, ** |
| Yes | 0; 0 | 23; 59 | ||
| Long-term outcome (n; %) | No evidence of disease | 7; 100 | 15; 37.5 | 0.0095, ** |
| Alive with disease | 0; 0 | 10; 25 | ||
| Dead of disease | 0; 0 | 15; 37.5 | ||
| Follow-up (months) | Median/mean/range | 80/91.4/8-187 | 27/37.3/2-135 | 0.0263,* |
| Duration of mitotane treatment (months) | Median/mean/range | 24/24.3/8-60 | 17.5/20.2/2-60 | 0.5083 |
| Brazilian cohort (n; %) | No | 6; 85.7 | 33; 82.5 | 1.0004 |
| Yes | 1; 14.3 | 7; 17.5 | ||
| pS-GRAS criteria (n; %) | 1 | 3; 75 | 6; 25 | 0.2575 |
| 2 | 1; 25 | 14; 58.3 | ||
| 3 | 0; 0 | 3; 12.5 | ||
| 4 | 0; 0 | 1; 4.2 | ||
| Cancer predisposition syndrome (n; %) | Yes | 1; 20 | 10; 47.6 | 0.3564 |
| No | 4; 80 | 11; 52.4 | ||
1Clinical characteristics comparing the two treatment groups: mitotane alone vs mitotane plus chemotherapy. 2Three of 50 patients were excluded from the treatment subgroup analysis due to the unavailability of chemotherapy data. 3Mann-Whitney U test. 4Fisher’s exact test. 5Pearson Ki-Kare test. * P < 0.05. ** P < 0.01.
and chemotherapy exhibited significantly higher rates of relapse and disease-related mortality (P < 0.01). When evaluated using the recent prognostic scoring recommendations for pACC patients (pS-GRAS) (8), the group receiving both mitotane and chemotherapy tended to fall into higher risk groups compared to the group treated with mitotane monotherapy (see Table 2 for details).
Dosages of mitotane in relation to anthropometric measurements and mitotane therapeutic plasma levels
Evaluation of mitotane dosage in the pediatric cohort - comprising 670 measurements from 47 patients with available treatment data - revealed a significant
positive correlation between mitotane dosage and body weight, body length, body surface area (BSA), and BMI at the start of treatment (P = 0.001) (see Table 3).
To determine the optimal average mitotane dosage in pediatric patients and to investigate potential differences in dosages between patients with plasma levels within and outside the target range, data from the pediatric cohort with plasma levels within the target range (≥14 mg/L; n = 319) were analyzed and compared to those with levels outside this range (n = 320). The median dose of values in the target range was 87.2 mg/kg/d (ranging from 6.0 to 11,255.0 mg/kg/d) and 1,802.8 mg/m2/d (ranging from 126.0 to 1,664.0 mg/m2/d). The median dose of values outside the target range did not differ significantly (see Table 4).
| Mitotane dosage (mg/day)1 | ||
|---|---|---|
| r's | P-value | |
| Body weight at start of mitotane (kg) | 0.526 | 0.001 ** |
| Body length at start of mitotane (cm) | 0.625 | 0.001 ** |
| Body surface area (BSA) at start of mitotane (m2) | 0.534 | 0.001 ** |
| BMI (kg/m2) | 0.212 | 0.001 ** |
1Correlation of mitotane dosage (mg/day) and body weight (kg), body length (cm), body surface area (BSA) (m2), and BMI (kg/m2) of pACC patients (n patients = 47, n measurements = 670) at the start of mitotane treatment using Spearman’s rho correlation coefficient ( ** P < 0.01, *P < 0.05).
To assess the influence of individual anthropometric measurements on mitotane dosages and plasma levels, all plasma level values within the target range (≥14 mg/L) from the patient cohort (n = 47) were grouped according to body weight (0-9 kg, 10-19 kg, ≥20 kg) and BMI (<18.5 kg/m2, 18.5-24.9 kg/m2, ≥25.0 kg/m2). No significant differences in daily dosage levels (mg/kg/day and mg/m2/day) were observed based on body weight, although children and toddlers with lower weights (0-9 kg) tended to require higher mitotane dosages compared to those with higher body weights (see Table 5). However, when examining BMI, a statistically significant difference in dosage (mg/kg/day) was found (P = 0.001): the Mann-Whitney U test showed that the median dosages for the underweight group (105.4 mg/kg/day) and the healthy weight group (98.4 mg/kg/day) were significantly higher than those for the overweight/obese group (44.4 mg/kg/day). No significant difference was observed between the underweight and healthy weight groups (see Table 5).
Discussion
Besides surgical resection and systemic chemotherapy, mitotane is an effective and approved pillar of treatment in adult and pediatric patients with advanced ACC (9, 12, 15, 16, 17, 18, 29, 30). The recommended starting dose of mitotane for children is 50 mg/kg/day or 1,500 mg/m2/day, with the possibility of increasing the dose to a maximum
of 4,000 mg/m2/day (18). Like many other drugs, mitotane is metabolized in the liver via cytochrome P450 enzyme CYP3A4 and also induces its activity (31, 32, 33). However, CYP3A4 activity varies significantly between individuals due to genetic, physiological, and pharmacological factors (34, 35). This aligns with our findings, as mitotane dosages varied significantly among individual patients, and those outside the therapeutic target range received dosages similar to those within the range. In addition, age is an important determinant of CYP3A4 function, as enzyme activity is reduced during the first months of life due to immature hepatic expression, with adult CYP3A4 levels reached between 1 and 1.5 years of age (36, 37, 38). No significant differences were observed between weight groups; however, these findings are limited by the small cohort size, particularly the low number of infants. Further studies with larger cohorts are warranted to investigate the age dependency of mitotane dosing more robustly.
Mitotane is a lipophilic drug, resulting in extensive distribution into adipose tissue. In obese patients, the increased fat mass leads to a larger volume of distribution, which prolongs the time required to reach therapeutic target levels. Once the therapeutic target level is achieved, the maintenance dose should be carefully adjusted, as obesity contributes to mitotane’s prolonged half-life and delayed kinetics, increasing the risk of drug accumulation and toxicity (32, 39, 40, 41). When analyzing the association between BMI and mitotane dosage in the current pediatric cohort, a statistically significant difference was observed in dosages within the therapeutic target range. Specifically, patients in the underweight/healthy-weight group (BMI < 25 kg/m2) received significantly higher doses compared to those in the overweight/obese group (BMI ≥ 25 kg/m2). This finding highlights the role of mitotane accumulation in adipose tissue, which leads to lower required dosages once the therapeutic target level is reached, especially considering that most patients received mitotane treatment for an extended period, with a median duration of 18 months.
Major limitations of the study were the small number of patients, the retrospective character of the study, and the international and multicenter nature of the study, leading to variations in treatment and follow-up protocols.
| Dosage | Mitotane plasma level (mg/L)1 | P | |
|---|---|---|---|
| <14 mg/L (n measurements = 320) Median (min-max) | ≥14 mg/L (n measurements = 319) Median (min-max) | ||
| mg/d | 4,000.0 (60.0-13,000.0) | 3,500.0 (50.0-13,000.0) | 0.438 |
| mg/kg/d | 87.5 (7.2-1,125.0) | 87.2 (6.0-1,125.0) | 0.872 |
| mg/m2/d | 1,854.6 (151.1-16,642.0) | 1,802.8 (126.0-16,642.0) | 0.414 |
1Mitotane dosage evaluation (in mg/day, mg/kg/day, and mg/m2/day) for the two groups of pACC patients (n patients = 47, n measurements plasma level = 639) with mitotane plasma levels <14 mg/L and ≥14 mg/L, analyzed using the Mann-Whitney U test.
| Dosage | Body weight1 | P | ||
|---|---|---|---|---|
| 0-9 kg (n value = 18) Median (min-max) | 10-19 kg (n value = 57) Median (min-max) | ≥20 kg (n value = 234) Median (min-max) | ||
| mg/d | 900.0 (50.0-4,500.0) | 1,500.0 (400.0-4,000.0) | 4,000 (500-13,000) | 0.001 ** |
| mg/kg/d | 108.4 (6.02-1,125.0) | 79.4 (26.7-267.7) | 92.4 (7.3-300.0) | 0.928 |
| mg/m2/d | 2,267.6 (125.9-16,642.0) | 1,239.7 (356.0-4,385.8) | 1,893.8 (183.7-4,057.3) | 0.190 |
| BMI classification1 | ||||
|---|---|---|---|---|
| Underweight (<18.5 kg/m2) (n value = 138) | Healthy weight (18.5-24.9 kg/m2) (n value = 110) | Overweight/obesity (≥25.0 kg/m2) (n value = 61) | ||
| mg/d | 2,500.0 (400.0-9,000.0) | 4,000.0 (50.0-13,000.0) | 4,500.0 (500-9,000) | 0.001 ** |
| mg/kg/d | 105.4 (22.7-1,125.0) | 98.4 (6.0-397.6) | 44.44 (7.3-142.9) | 0.001 ** |
| mg/m2/d | 1,788.9 (356.0-16,624.0) | 1,936.9 (126.0-8,314.4) | 1,314.8 (183.7-3,794.9) | 0.109 |
1Mitotane dosage evaluation (in mg/day, mg/kg/day, and mg/m2/day) for the three different body weight groups and BMI classification of the pACC patient cohort (n = 46, because weight information is missing for one patient, n measurements of plasma level = 309). The analysis was done with patient values only within the target plasma range of >14 mg/L using the Kruskal-Wallis test ( ** P < 0.01, *P < 0.05). The Mann-Whitney U test was used for pairwise comparisons.
Nevertheless, the authors are convinced that, despite its limitations, the existing data provide essential insights into the treatment with mitotane in a pediatric cohort and will serve as a foundation for prospective studies already planned in this field.
In summary, this study aims to support the estimation of required mitotane dosages throughout the treatment course in pediatric ACC patients. However, due to the highly individualized dosage requirements and the narrow therapeutic window, precise dosing remains challenging. Therefore, close, frequent follow-up visits with therapeutic drug monitoring at specialized pediatric ACC treatment centers - particularly at the initiation of mitotane therapy - are essential for optimizing individualized treatment.
A second part of the current study was based on the multivariable analysis of adult patients conducted by Puglisi et al., which demonstrated that both the time required to reach the target plasma range of ≥14 mg/L and the duration of mitotane plasma levels maintained within this range (=time in target range, TTR) significantly influence the risk of recurrence (42, 43). Accordingly, a cut-off value for TTR of >37.8 weeks was identified for the current pediatric cohort. This cut-off was used to stratify patients according to their mortality risk, indicating that a TTR >37.8 weeks is associated with a lower risk of death (see Supplementary Tables 1 and 2, and Supplementary Fig. 1 (see section on Supplementary materials given at the end of the article). The study focused on the primary outcome OS, defined as the time from the initial diagnosis to death or the last follow-up. Although TTR appeared to influence patient OS, no significant difference was observed in the univariable or multivariable analyses. We assume this lack of significance is due to the very limited number of patients included in the survival
analysis. Another limitation is that patients in advanced stages often die of disease early during treatment, making it difficult to draw definitive conclusions about the optimal treatment duration and its threshold. In addition to TTR, a relationship was found between the time needed to achieve the first target level (with a cut-off defined as < 15.8 weeks) and patient outcomes, suggesting that patients benefit from a quicker attainment of mitotane levels within the target range (see Supplementary Tables 1 and 2, and Supplementary Fig. 1). Similar to TTR, no significant differences were observed between the two groups. Given the limited statistical power of the small pediatric cohort, these results are included only in the Supplementary materials as preliminary findings and will be evaluated in further prospective studies.
Although definitive conclusions cannot be drawn, these results reinforce the importance of adequate mitotane treatment duration and close follow-up in specialized centers to maintain target drug levels in pACC patients. To improve long-term treatment strategies, larger international studies with standardized data are needed. A centralized system linking mitotane plasma levels with clinical data would be a valuable tool for optimizing therapy and ensuring patient safety. To achieve this goal - which will substantially advance the understanding of treatment - collaborative efforts and initiatives are already in progress.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EO-24-0081.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
This work was supported by a research grant ‘Interdisziplinäres Zentrum für klinische Forschung (IZKF) training grant awarded to MR (Project number: Z- 02CSP/23), the ‘Mildred Scheel program’ awarded to VW (Project 70113303-6), and by the ‘Deutsche Forschungsgemeinschaft’ (DFG) German Research Foundation (Project 314061271-TRR 205) to MF. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author contribution statement
MR and WV conceived the study and wrote the paper, HF, MR, SRA, GFLC, CFC, NDP, JF, SF, MF, MG, MPH, CH, DJ, AJ, RRK, TK, MM, JM, MVN, SHP, TP, SP, PGS, VBB, GT, JW, BY, and VW collected data, MR, VW, and NOK performed experiments and analyzed data statistically. All authors revised the manuscript.
Acknowledgements
This work was supported by a research grant from the Tour of Hope Foundation. We would like to thank the Parents Initiative Group for Children with Leukemia and Solid Tumors Würzburg e.V. for their continuous support. Authors VW and MR are supported by COST Action CA20122 Harmonization. SF is a participant in the BIH-Charité Clinician Scientist Program funded by the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health (BIH).
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