EJE
International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects
Maria Riedmeier,10 Sonir R.R. Antonini,2 Silvia Brandalise,3 Tatiana El Jaick B. Costa, 4
Camila M. Daiggi,3 Bonald C. de Figueiredo,5 Ronald R. de Krijger,6 Karla Emília De Sá Rodrigues,7 Cheri Deal,8 Jaydira Del Rivero,90 Gernot Engstler,1º Martin Fassnacht, 11 (D
Gabriela C. Fernandes Luiz Canali,12 Carlos A. Fernandes Molina, 13 Elmas Nazli Gonc, 14 Melis Gültekin, 15 Harm R. Haak, 16,17 Tulay Guran, 18[D Emile J. Hendriks Allaird, 19,20 Jan Idkowiak,21,22 Michaela Kuhlen,23[D David Malkin,24 Jagdish Prasad Meena,25 Christina Pamporaki,26 Emilia Pinto,27 Soraya Puglisi, 28ID Raul C. Ribeiro,29
Lester D.R. Thompson,3º Bilgehan Yalcin,31 Max Van Noesel,32,33 and Verena Wiegering1 .*
1University Hospital Würzburg, Department of Pediatrics, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Wuerzburg, Wuerzburg 97080, Germany
2Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo 14051-200, Brazil
3Boldrini Children’s Hospital, Department of Pediatrics, São Paulo 13083-210, Brazil
4Service of Pediatric Oncology, Hospital Infantil Joana de Gusmão, Florianópolis, SC 88025-301, Brazil 5Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba 80250-060, Brazil
6Department of Pathology, University Medical Center Utrecht, Utrecht 3584 CS, The Netherlands
7Pediatric Department, Barretos Cancer Hospital, São Paulo 14784-400, Brazil
8Research Center, CHU Sainte-Justine and University of Montreal, Montreal, Quebec H3T 1C5, Canada
9Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
10St. Anna Kinderspital, Department of Pediatrics, Medical University Vienna, Vienna 1090, Austria
11Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Wuerzburg, Wuerzburg 97080, Germany
12Oncologia, Pequeno Principe Hospital, Curitiba 80250-060, PR, Brazil
13Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao 15 Paulo, Ribeirao Preto, Sao Paulo 14049-900, Brazil 14Department of Pediatric Endocrinology, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey
15Department of Radiation Oncology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey
16Department of Internal Medicine, Máxima MC, Eindhoven 5631 BM/Veldhoven 5504 DB, The Netherlands
17 CAPHRI School for Public Health and Primary Care, Ageing and Long-Term Care, Maastricht University, Maastricht 616 6200 MD, The Netherlands
18Department of Paediatric Endocrinology and Diabetes, Marmara University School of Medicine, Istanbul 34722, Turkey
19Department of Paediatrics, University of Cambridge, Cambridge CB20QQ, United Kingdom
20 Department of Paediatric Endocrinology and Diabetes, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB20QQ, United Kingdom
21Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B152TT, United Kingdom
22Department of Endocrinology, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham B46NH, United Kingdom
23Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Augsburg 86135, Germany
24 Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G1X8, Canada
25 Division of Pediatric Oncology, Department of Pediatrics, Mother & Child Block, All India Institute of Medical Sciences, New Delhi 110029, India
26Department of Medicine III, University Hospital Carl Gustav Carus, TU Dresden, Dresden 01307, Germany
27 St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
28Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano 10043, Italy
29 Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN 38105, United States
30 Pathology, Head and Neck Pathology Consultations, Woodland Hills, CA 91364, United States
31 Department of Pediatric Oncology, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey
32Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht 3584 CS, The Netherlands
33Division Imaging & Cancer, University Medical Center Utrecht, Utrecht 3584 CS, The Netherlands
*Corresponding author: Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University Hospital Wuerzburg, Josef-Schneiderstr. 2, Würzburg 97080, Germany. Email: Wiegering_v@ukw.de
Abstract
Objective: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects.
Methods: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements.
Results: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m2/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required.
Conclusions: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.
Keywords: pediatric adrenal cortical cancer, pediatric adrenal cortical carcinoma, pediatric adrenal cortical tumor, adrenal cortical carcinoma, mitotane therapy
Significance
Herein, we present an international expert consensus on mitotane treatment in pediatric patients with adrenal cortical tu- mors (pACC). We assembled experts with extensive experience in managing pACC from 10 countries across 4 continents utilizing a Delphi process, and we conducted 3 rounds of questionnaires to reach consensus, resulting in the formulation of 21 statements categorized into environment, indications, therapy, and adverse effects. Given the lack of empirical data con- cerning the utilization of mitotane in pediatric cases, these consensus statements are indispensable for guiding healthcare professionals and establishing a standardized approach to mitotane treatment in pACC.
Introduction
Pediatric adrenal cortical carcinoma (pACC) is an extremely rare and in most cases (>90%) hormone-producing neoplasm with a dismal prognosis in the presence of advanced disease.1 In addition to surgery and chemotherapy, medical treatment with mitotane (o, p’-DDD (1-(o-chlorophenyl)-1- (p-chlorophenyl)-2,2-dichloroethane)]-an isomer of the insecticide p,p’-DDD, which is a metabolite of p,p’-DDT (dichlorodiphenyltrichloroethane)-is an important corner- stone of therapy for pACC.2,3 Currently, it is the only drug that is specifically approved worldwide for ACC with ad- vanced stage disease. As an antineoplastic agent with specific adrenocortical activity, mitotane leads to selective necrosis of (tumor) cells derived from the adrenal cortex and subse- quently to inhibition of the production of steroid hormones. 4-6 This inhibition causes adrenal insufficiency, often necessitating concurrent glucocorticoid replacement therapy employing hydrocortisone/cortisone acetate. However, the exact mechan- ism of action of mitotane remains poorly defined at a molecular level due to conflicting results generated by in vitro studies.7-9
Due to the lack of well-conducted studies, the indication for mitotane therapy varies considerably. For instance, the Children’s Oncology Group (COG) “ARAR0332 Protocol” and the EXPERT group recommend mitotane in combination with cisplatin, doxorubicin, and etoposide for patients with advanced tumor stages (III and IV), which includes patients with unresectable tumors or R1 resection, tumor spillage, retroperitoneal lymph node involvement, and/or the presence of distant metastases.3,
The rationale to use adjuvant mitotane therapy in pediatric patients is based on experience in adult patients with ACC
after radical resection. In this context, retrospective studies suggest an improved disease-free survival (DFS) and overall survival (OS) by addition of mitotane postoperatively.11- Thus, guidelines published by the European Society of Endocrinology and the European Society of Medical Oncology, while recognizing the low level of existing evidence, recommend adjuvant mitotane in adult patients at high risk of recurrence following surgery.14-16 Very recently, the random- ized ADIUVO study demonstrated no benefit of mitotane in patients with a low risk of recurrence [defined by the European Network for the Study of Adrenal Tumors (ENSAT) as tumor stage I-III, RO resection, and a low Ki67 in- dex ≤ 10%].17 There are no comparable pediatric studies pub- lished, and experience with the drug in an adjuvant setting is limited.
Furthermore, mitotane is toxic, with a glut of significant ad- verse effects. Due to this toxicity, the indications for mitotane use in pACC are still controversial.3,10 As pACC is rarer than in adults, reliable prognostic factors are also not well estab- lished. For staging purposes, some pediatric centers use the (modified) TNM classification,18 others the Sandrini classifi- cation,2,3,19,20 modified by Rodriguez-Galindo et al.21 We have recently tried to establish a prognostic score of pACC by adapting the adult S-GRAS score22 including histopatho- logical, clinical, and molecular data for pACC in a cohort of 733 children with ACC. Notably, our findings reveal a robust correlation between the proposed prognostic score and the overall prognosis of pACC.23 Assuming additional validation, this scoring system holds promise as a valuable tool for enhan- cing risk stratification, particularly in guiding the judicious use of mitotane treatment in future clinical management. In the long term, the identification and characterization of additional
molecular-genetic factors will play a crucial role in refining the definition of risk groups and in advancing personalized and ef- fective therapy approaches associated with pACC.
Due to the rarity of pACC, current practice is not guided by robust evidence and consequently differs widely between dif- ferent centers based on local opinion and experience. Therefore, we undertook a Delphi method to develop inter- national recommendations of experts on the indication for and management of mitotane in patients with pACC.
Methods
Participants
This consensus statement was compiled following discussions using the Delphi method (estimate-talk-estimate systematic structured communication) between December 2022 and November 2023 with 3 rounds of questionnaires to present and refine the criteria and opinions of the expert consortium to arrive at a group consensus.24
Experts were identified by their long-standing activity in the field of pACC management through membership in the ENSAT pediatric working group (ENSAT-PACT) and/or the International Consortium of pediatric adrenocortical tumors (ICPACT). Additional experts in pediatric oncology and endo- crinology were suggested by adult experts based on individual collaborations. The task force included 12 pediatric oncologists, 6 pediatric endocrinologists, 5 adult endocrinologists/internists, 1 adult oncologist, 1 imaging specialist, 1 surgeon, 1 associate scientist, and 2 endocrine organ pathologists. Participants come from 22 institutions, representing 10 countries across 4 continents (Europe, North America, South America, and Asia). Survey participation was voluntary without financial incentive.
According to our survey, the different centers used different staging systems as around 70% of participants staged their pa- tients according to the (modified) TNM classification, whereas around 30% of participants used the COG classification by Sandrini.
Consensus formation
A Delphi method was applied to establish consensus about the indication and management of mitotane in pediatric patients with ACC. M.R., M.F., and V.W. planned the workflow ac- cording to the Delphi technique. Statements were phrased and then judged by all panelists using a 5-point Likert scale (1, strongly agree; 2, agree; 3, neutral; 4, disagree; 5, strongly disagree). Participants could also abstain from answering a question, if they felt unqualified. Consensus was defined prior to the study as ≥70% for agreement among the participants (Likert scale 1 and 2) or disagreement (Likert scale 4 and 5). Responses with ≥70% agreement in 1 round were removed from the next round as consensus was reached. When no con- sensus was reached after 2 consecutive rounds due to opposite ratings or a majority of neutral ratings, the statement was re- moved from the consensus.
Questionnaire
Prior to the project, M.R. and V.W. performed a review of the literature on mitotane treatment in pACC, which was pro- vided and discussed during online meetings with the working groups ENSAT-PACT and ICPACT in advance of the initial survey. A subcommittee of 5 participants (M.R., J.I., S.R.R.A., M.F., and V.W.) reviewed and approved the
questions. The questions were divided into 3 sections: (1) indi- cation; (2) therapy, and (3) adverse effects. All questions were single choice (first round, n = 50; second round, n = 51; third round, n =20). After the initial questionnaire was drafted, the survey was conducted using the online platform Evasys and sent to participants via link. Participants were requested to answer the questionnaire within 20 days and were encour- aged to comment in free text to facilitate further discussion.
After all participants provided their answers in the online survey questionnaire, the 2 moderators, V.W. and M.R., ana- lyzed their answers and translated them into a series of state- ments. These statements were reviewed and approved by a virtual meeting with participants. In the second round of the Delphi process, the 56 statements were rated and commented on by each participant independently using the 5-point Likert scale. Statements that did not reach consensus were reviewed at a virtual meeting and adjusted according to participant dis- cussion and reformulated for a third round of rating. In the end, 47 of the 56 statements reached consensus and were sum- marized to 22 final statements below (see Tables 1-3).
An independent ethical committee was deemed unnecessary as there was no involvement of patient data in the research. Nevertheless, all our research endeavors strictly adhere to the tenets delineated in the Declaration of Helsinki.
Environment of management for pediatric ACC
Statement 1
The management of pediatric ACC patients necessitates a spe- cialized multidisciplinary approach and is ideally best per- formed in a center with expertise in handling ACC (details summarized in Table 1).
Comment on statement 1. While conclusive data may current- ly be lacking, the authors have collectively reached a consensus that patients stand to benefit from a multidisciplinary approach to managing pediatric ACC. Collaboration with interdisciplin- ary specialists in the field becomes crucial in such instances to optimize patient outcomes. These multidisciplinary teams, at a minimum, should encompass specialists in pediatric oncol- ogy, endocrinology, surgical oncology, radiology, and path- ology.15 Close cooperation with an experienced adult ACC center is advantageous. Given the rarity and varied presenta- tions of this tumor, it is reasonable to infer that centers lacking expertise in this specific tumor entity may encounter delays in diagnosis and the initiation of therapy. A recent analysis con- ducted in Germany concerning adrenalectomies in pediatric pa- tients revealed a notably uneven distribution of patient volumes across different hospitals.25 Studies concerning the adult popu- lation have unequivocally demonstrated a substantial correl- ation between surgical volume and improved clinical outcomes.26-28 Therefore, ENSAT guidelines for adults recom- mend a minimum caseload of 6 cases per year to ensure a sub- stantial level of experience in adrenal surgery.15 These aspects underscore the recommendation to conduct such procedures exclusively in highly specialized centers with a wealth of expert- ise and extensive experience.
Indications for mitotane treatment in childhood
Statement 2
Mitotane is indicated for all patients with advanced ACC, de- fined as surgically unresectable or metastatic tumors, patients
| Strongly agree (in %) | Agree (in %) | Neutral (in %) | Disagree (in %) | Strongly disagree (in %) | (in %) Absent | |
|---|---|---|---|---|---|---|
| Environment of ACC managementa The management of pediatric ACC patients necessitates a specialized multidisciplinary approach and is ideally best performed in a center with expertise in handling ACC. | 100 | 0 | 0 | 0 | 0 | 0 |
| Indication criteriaª | ||||||
| Mitotane is indicated for all patients with advanced ACC, defined as surgically unresectable or metastatic tumors, patients with incomplete resection (R1 or R2 resection status), and/or intraoperative tumor spillage. | 85.7 | 14.3 | 0 | 0 | 0 | 0 |
| In patients in whom complete resection is initially not possible, but could be reached after cytoreduction, mitotane (+/-cytotoxic chemotherapy) could be considered as neoadjuvant therapy. | 64.3 | 50.0 | 50.0 | 0 | 0 | 0 |
| Adjuvant mitotane is indicated in all patients with stages III and IV disease with complete tumor resection. | 71.4 | 21.4 | 0 | 0 | 0 | 7.1 |
| In patients with completely resected stage I ACC, mitotane therapy is generally not indicated. | 38.5 | 46.2 | 0 | 7.7 | 0 | 7.7 |
| The indication for adjuvant mitotane in patients with stage II disease depends on clinical and tumor-specific characteristics and is not generally recommended based on the current available evidence. Nonetheless, its consideration may be warranted in specific cases deemed to be of exceptionally high risk by the multidisciplinary team. | 64.3 | 21.4 | 7.1 | 0 | 7.1 | 0 |
aList of statements with consensus on environment and indication for mitotane therapy in pACC and the particular participants’ rating results of each statement (in percent) according the 5-point Likert Scale (1, strongly agree; 2, agree; 3, neutral; 4, disagree; 5, strongly disagree). Participants could also abstain from answering a question, if they felt unqualified.
Abbreviations: ACC, adrenal cortical carcinoma.
with incomplete resection (R1 or R2 resection status), and/or intraoperative tumor spillage (details summarized in Table 1).
Statement 3
In patients in whom complete resection is initially not possible, but could be reached after cytoreduction, mitotane (±cytotoxic chemotherapy) could be considered as neoadjuvant therapy.
Statement 4
Adjuvant mitotane is indicated in all patients with stages III and IV disease with complete tumor resection.
Statement 5
In patients with completely resected stage I ACC, mitotane therapy is generally not indicated.
Comments on statements 2-5. Although mitotane seems to be the most effective drug for the treatment of pACC, indications for mitotane therapy vary considerably due to the lack of international guidelines for pACC and are based on experi- ence in adult ACC. According to the results of previous studies of pACC, response rates to neoadjuvant therapy in cases of ad- vanced and/or relapsed disease, as well as adjuvant mitotane therapy following R1 resection, have been observed to vary within the range of 20%-40%.29-31 In our recent systematic review of the literature, we found that the frequency of mito- tane use in advanced stages in pACC is very low (<20%), es- pecially at younger ages (≤4 years).1 There is a broad international consensus that mitotane therapy is indicated in pediatric with advanced stages, R1/2 resection status, and/or tumor spillage.3,10 In cases of unresectable tumors, neoadju- vant chemotherapy in combination with mitotane is suggested by the GPOH-MET and the COG “ARAR0332” protocol in order to reduce tumor volume for subsequent surgery.
Statement 6
The indication for adjuvant mitotane in patients with stage II disease depends on clinical and tumor-specific characteristics and is not generally recommended based on the current avail- able evidence. Nonetheless, its consideration may be war- ranted in specific cases deemed to be of exceptionally high risk by the multidisciplinary team.
Comment on statement 6. For stage II patients, the indication for mitotane adjuvant therapy remains controversial for both pediatric and adult patients.3,11,17 There are no pediatric studies, and experience with the drug in an adjuvant setting is limited. There was consensus that age and germline genetic status (eg, TP53) should not influence the decision on adjuvant therapy. Furthermore, the expert consortium agreed that a high Ki67 in- dex could be a factor that favors mitotane treatment. However, to assess this with confidence, further studies are essential, espe- cially as there are studies from Brazil and Argentina which show that Ki67 has no prognostic value in younger children.20,32
Statement without consensus
If the indications for adjuvant mitotane in patients with stage II should depend on tumor size and volume remains controver- sial, and we could not find evidence to adjust recommenda- tions based on these parameters. This may change with the redefinition of tumor stage, particularly stage II. Currently, there are no data to support a role for tumor size/volume in the indication for mitotane treatment.
Management of mitotane therapy
Start of mitotane
Statement 7. The timing of initiating mitotane therapy de- pends on the clinical condition of the patient and the
| Management on mitotane treatmentª | Strongly agree (in %) | Agree (in %) | Neutral (in %) | Disagree (in %) | Strongly disagree (in | %) | Absent (in %) |
|---|---|---|---|---|---|---|---|
| The timing of initiation of mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. | 64.3 | 35.7 | 0 | 0 | 0 | 0 | |
| In the setting of advanced disease, mitotane should be started as soon as the diagnosis is established. Where upfront chemotherapy is being used, mitotane should be started no later than in parallel with the first cycle of chemotherapy. | 71.4 | 21.4 | 7.1 | 0 | 0 | 0 | |
| In the setting of adjuvant mitotane after surgery, treatment should be initiated as soon as clinically possible. | 85.7 | 14.3 | 0 | 0 | 0 | 0 | |
| In the setting of radiotherapy, the start of mitotane therapy should not be delayed and can be continued during radiotherapy. However, if the liver is in the radiation field, meticulous monitoring of liver enzymes should be performed. | 57.1 | 14.3 | 14.3 | 0 | 0 | 14.3 | |
| The starting dose of 50 mg/kg/d or 1500 mg/m2/d is reasonable. | 57.1 | 35.7 | 0 | 0 | 0 | 7.1 | |
| Within acceptable tolerability, mitotane can be increased up to 4000 mg/m2/d. | 57.1 | 28.6 | 0 | 0 | 0 | 14.3 | |
| To optimize stable mitotane drug levels, we suggest taking mitotane with oily or fatty foods while divided into 2-3 dosages/day. | 50.0 | 21.4 | 14.3 | 0 | 0 | 14.3 | |
| Mitotane should be continued during cytotoxic chemotherapy and in the time period between a cycle and the next one. Pausing of mitotane could lead to decrease in the mitotane blood level, which is to be avoided (except in the setting of unacceptable tolerability). Nevertheless, short suspensions (1 or 2 days) do not alter the concentrations of the drug consistently. | 78.6 | 21.4 | 0 | 0 | 0 | 0 | |
| Despite lack of reliable data in children, the target mitotane blood levels should be between 14 and 20 mg/L. Steady state will not be reached within the first months; therefore, monitoring should be done every (2-)4 weeks until steady state is reached with the aim of ensuring adherence and correct administration. In case of tolerance-limiting adverse effects, plasma levels should be measured immediately. | 42.9 | 57.1 | 0 | 0 | 0 | 0 | |
| If the mitotane level is below the therapeutic blood levels in the setting of acceptable tolerability, an increase of 20 mg/kg/d (500 mg/m2/d) every 1-2 weeks is reasonable in most patients. | 57.1 | 42.9 | 0 | 0 | 0 | 0 | |
| The duration of mitotane treatment depends on the clinical situation and tolerability. | 57.1 | 42.9 | 0 | 0 | 0 | 0 | |
| In an adjuvant setting, in patients with presumed high risk for recurrence, the standard duration is 24 months and may be longer in individual cases (up to 5 years). In patients with a poor tolerability, a duration of 12 months is acceptable. | 57.1 | 35.7 | 7.1 | 0 | 0 | 0 | |
| In advanced disease, there are no data on the ideal duration of mitotane treatment. Because of the delay in reaching therapeutic mitotane blood levels of 14-20 mg/ L, maximum efficacy is sometimes not achieved when initial disease progression is documented. Different options can be discussed individually with the patient/ parents: (1) discontinuation of mitotane in patients who experienced progressive disease after 1 year of mitotane, (2) discontinuation of mitotane when there is progressive disease despite mitotane blood levels above 14 mg/L, and (3) continuation of mitotane indefinitely (if it is well tolerated). However, it has to be considered that CYP3A4 induction by mitotane can greatly enhance the metabolism of many drugs, including many experimental anti-ACC compounds. | 35.7 | 42.9 | 21.4 | 0 | 0 | 0 |
aList of statements with consensus on management on mitotane therapy in pACC and the particular participants’ rating results of each statement (in percent) according the 5-point Likert Scale (1, strongly agree; 2, agree; 3, neutral; 4, disagree; 5, strongly disagree). Participants could also abstain from answering a question, if they felt unqualified.
Abbreviations: ACC, adrenal cortical carcinoma.
setting of the planned therapy (details summarized in Table 2).
7a) In the setting of advanced disease, mitotane should be started as soon as the diagnosis is established. Where upfront chemotherapy is being used, mitotane should be started no lat- er than in parallel with the first cycle of chemotherapy.
7b) In the setting of adjuvant mitotane after surgery, treat- ment should be initiated as soon as clinically possible.
7c) In the setting of radiotherapy, the start of mitotane ther- apy should not be delayed and can be continued during radio- therapy. However, if the liver is in the radiation field, meticulous monitoring of liver enzymes should be performed.
Comment on statement 7. The ideal timing of starting mito- tane in pACC is unknown. European guidelines on the man- agement of adult ACC recommend that therapy starts within
6 weeks after surgery but not later than 12 weeks.15 An essen- tial consideration upon commencing mitotane treatment is the occurrence of adrenal insufficiency, which typically mandates concurrent glucocorticoid replacement therapy in nearly all patients shortly after the initiation of treatment (see statement 18 for specific details). 15,33
Statement 8. The starting dose of 50 mg/kg/d or 1500 mg/m2/ d is reasonable.
Statement 9. Within acceptable tolerability, mitotane can be increased up to 4000 mg/m2/d.
Statement 10. To optimize stable mitotane drug levels, we suggest taking mitotane with oily or fatty foods while divided into 2-3 dosages/day.
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| Management on mitotane treatmenta | Strongly agree (in %) | Agree (in %) | Neutral (in %) | Disagree (in %) | Strongly disagree (in %) | (in %) Absent |
|---|---|---|---|---|---|---|
| Regular monitoring of mitotane-induced adverse effects is essential in order to detect adverse events at first onset. | 92.9 | 7.1 | 0 | 0 | 0 | 0 |
| Most patients experience adverse effects during mitotane treatment. Most adverse effects can be treated symptomatically and do not lead to discontinuation of therapy. | 78.6 | 21.4 | 0 | 0 | 0 | 0 |
| Most adverse effects (eg, neurological symptoms) seem to be correlated with the mitotane blood level, whereas others (eg, gastrointestinal symptoms) might be more dose related. To increase tolerability, supportive therapies should ideally start before severe toxicity develops. | ||||||
| As the spectrum of adverse effects of mitotane is wide-ranging, in addition to monitoring of mitotane blood levels, frequent clinical and neurological examinations (every 2 to 4 weeks), along with evaluation and assessment of liver enzymes, complete blood counts, coagulation, ACTH, cortisol, TSH, free T4, renin, aldosterone, cholesterol, testosterone, and SHBG, are essential for preventing and controlling adverse effects. | 73.3 | 26.7 | 0 | 0 | 0 | 0 |
| Endocrinologic adverse effects are common. In virtually all patients, mitotane treatment leads to adrenal insufficiency (except for patients with severe ongoing hypercortisolism). Therefore, frequent endocrinologic monitoring is necessary. Most of the patients require glucocorticoid replacement using hydrocortisone/ cortisone acetate and less frequently mineralocorticoid replacement shortly after beginning. However, after termination of mitotane, it is reversible in the majority of patients. | 46.7 | 40.0 | 6.7 | 0 | 0 | 6.7 |
| Most patients experience lab values that resemble central hypothyroidism, but its clinical relevance is uncertain. A trial treatment with thyroid hormones may be initiated. | 64.3 | 28.6 | 0 | 0 | 0 | 7.1 |
| As gastrointestinal adverse effects are common and might be dose-limiting, antiemetic and antidiarrheal drugs should be given to mitigate these symptoms. | 57.1 | 21.4 | 0 | 0 | 0 | 21.4 |
| Significant anemia and thrombocytopenia are rare. Whereas mild leukopenia is not infrequent, severe agranulocytosis is extremely rare which is why complete blood counts should be monitored regularly. In case of severe neutropenia (<500/uL) without other obvious explanation, mitotane treatment should be interrupted. | 57.1 | 28.6 | 0 | 0 | 0 | 14.3 |
| Neuropsychological side effects occur especially if blood levels are elevated. Adverse effects involving the central nervous system, such as ataxia, confusion, dizziness, decreased memory, or even lethargy, are common and can be life-threatening. | 64.3 | 21.4 | 0 | 0 | 0 | 14.3 |
aList of statements with consensus on adverse effects of mitotane therapy in pACC and the particular participants’ rating results of each statement (in percent) according the 5-point Likert Scale (1, strongly agree; 2, agree; 3, neutral; 4, disagree; 5, strongly disagree). Participants could also abstain from answering a question, if they felt unqualified. The frequencies of occurrence of the adverse effects were defined as follows: often >50%, sometimes 10-50%, rare <10%, very rare <1%.
Abbreviations: ACTH, adrenocorticotropic hormone; SHBG, sex hormone-binding globulin; T4, free thyroxine; TSH, thyroid-stimulating hormone.
Statement 11. Mitotane should be continued during cyto- toxic chemotherapy and in the time period between a cycle and the next one. Pausing of mitotane could lead to decrease in the mitotane blood level, which is to be avoided (except in the setting of unacceptable tolerability). Nevertheless, short suspensions (1 or 2 days) do not alter the concentrations of the drug consistently.
Comments on statements 8-11. As mitotane is lipophilic, it is supposed to be better absorbed from the intestine when taken with fatty foods.34 Pediatric data are lacking, and therapy rec- ommendations and expert suggestions mainly refer to one’s own experience and evidence from an adult practice setting.
Role of mitotane blood levels
Statement 12. Despite lack of reliable data in children, the target mitotane blood levels should be between 14 and 20 mg/L. Steady state takes several months to achieve, and therefore, monitoring should be done every (2-)4 weeks until steady state is reached with the aim of ensuring adherence and correct administration.
In case of tolerance-limiting adverse effects, plasma levels should be measured immediately.
Statement 13. If the mitotane level is below the therapeutic blood levels in the setting of acceptable tolerability, an in- crease of 20 mg/kg/d (500 mg/m2/d) every 1-2 weeks is reason- able in most patients.
Statement 14. The duration of mitotane treatment depends on the clinical response and tolerability.
14a) In an adjuvant setting, in patients with presumed high risk for recurrence, the standard duration is 24 months and may be longer in individual cases (up to 5 years). In patients with a poor tolerability, a duration of 12 months is acceptable.
14b) In advanced disease, there are no data on the ideal dur- ation of mitotane treatment. Because of the delay in reaching therapeutic mitotane blood levels of 14-20 mg/L, maximum efficacy is sometimes not achieved when initial disease pro- gression is documented. Different options can be discussed in- dividually with the patient/parents: (1) discontinuation of mitotane in patients who experienced progressive disease after
1 year of mitotane, (2) discontinuation of mitotane when there is progressive disease despite mitotane blood levels above 14 mg/L, and (3) continuation of mitotane indefinitely (if it is well tolerated). However, it has to be considered that CYP3A4 induction by mitotane can greatly enhance the me- tabolism of many drugs, including many experimental anti-ACC compounds.
Comments on statements 12-14. International standardized studies of mitotane drug monitoring are still lacking. Our statements are consistent with the limited recommendations in pACC about the need for regular drug monitoring with dos- age adjustment according to blood levels and tolerability and the therapeutic target plasma level of mitotane between 14 and 20 mg/L. Since it takes some time for the tissue to become sa- turated with mitotane, the plasma levels increase only slowly and it takes several months to reach a stable state, as Zancanella et al. were able to show for pediatric patients.6 Nonetheless, it is crucial to emphasize that almost all patients necessitate concurrent glucocorticoid replacement therapy shortly after initiating treatment due to the adrenal insuffi- ciency induced by mitotane (for details, see statement 18).15,33 As several authors state, the outcome of pediatric patients is related to the achievement of plasma target levels and duration of treatment.2,3,6,10,29 In a univariate retrospective analysis of key factors for effective mitotane therapy in pACC reported by Kuhlen et. al., mitotane therapy duration shorter than 9 months or low plasma levels below 14 mg/L had a significant negative prognostic impact on progression-free survival (PFS) and OS.29 Consequently, we advocate for a minimum treat- ment duration of 1 year, even in cases where the drug is poorly tolerated. However, recent studies have questioned whether mitotane levels actually correlate with prognosis or whether it is specific mitotane metabolites that determine mitotane ef- ficacy.35,36 As pediatric evidence is lacking, recommendation on treatment duration over 2 years in individual high-risk cases is based on the clinical approach used in adult patients. 15 Nevertheless, the extension of mitotane treatment, spanning up to 5 years, should be judiciously considered on a case-by-case basis, particularly in singular cases with a high risk of recurrence. Existing evidence suggests that treatment durations beyond 2 years may not confer substantial benefits for ACC patients characterized by low to moderate risk of re- currence (ie, stages I-III, RO/Rx) .. 37
Statements without consensus
Concerning the management of mitotane, no consensus was achieved for levels > 20 mg/L. The management differed from center to center. If neurological side effects develop, most ex- perts would stop mitotane treatment for at least for 3 days and continue treatment at a lower dose (agree 80%, grade A), but there was no consensus on how to proceed with high levels and no or tolerable adverse events: 66% would proceed without pausing or reducing dosage, whereas the remaining members would stop mitotane.
The influence of age on acceptable dosage and adverse ef- fects remains controversial without recommendations.
Management of adverse effects of mitotane General statements on adverse effects
Statement 15. Regular monitoring of mitotane-induced adverse effects is essential in order to detect adverse events at first onset (details summarized in Table 3).
Statement 16. Most patients experience adverse effects dur- ing mitotane treatment. Most adverse effects can be treated symptomatically and do not lead to discontinuation of therapy.
Most adverse effects (eg, neurological symptoms) seem to be correlated with the mitotane blood level, whereas others (eg, gastrointestinal symptoms) might be more dose related. To increase tolerability, supportive therapies should ideally start before severe toxicity develops.
Statement 17. As the spectrum of adverse effects of mitotane is wide-ranging, in addition to monitoring of mitotane blood lev- els, frequent clinical and neurological examinations (every 2 to 4 weeks), along with evaluation and assessment of liver enzymes, complete blood counts, coagulation, adrenocortico- tropic hormone (ACTH), cortisol, thyroid-stimulating hormone (TSH), free thyroxine (T4), renin, aldosterone, chol- esterol, testosterone, and sex hormone-binding globulin (SHBG), are essential for preventing and controlling adverse effects.
Comments on statements 15-17. Adverse effects of mitotane are common, wide-ranging, and potentially life-threatening. Even though common adverse effects are well described for adult ACC patients, only few data points regarding adverse ef- fects of mitotane are reported for pediatric patients.6,33,38
Endocrine adverse effects
Statement 18. Endocrinologic adverse effects are common. In virtually all patients, mitotane treatment leads to adrenal insufficiency (except for patients with severe ongoing hyper- cortisolism). Therefore, frequent endocrinologic monitoring is necessary. Most of the patients require glucocorticoid replacement using hydrocortisone/cortisone acetate and less frequently mineralocorticoid replacement shortly after begin- ning. However, after termination of mitotane, it is reversible in the majority of patients.
Comment on statement 18. Besides the common adverse ef- fects, treatment with mitotane can cause several endocrinopa- thies in pediatric and adult patients. Due to the inhibition of the adrenal cortex, mitotane treatment leads to an adrenal in- sufficiency very frequently requiring concomitant glucocortic- oid replacement using hydrocortisone/cortisone acetate.15,33 Pediatric data on timing of initiation and monitoring of endocrinologic adverse effects are lacking. The European guidelines of adults recommend initiating concurrent gluco- corticoid replacement therapy on the first day of mitotane treatment for all patients (except those with ongoing cortisol excess). Alternatively, it can be started 2-3 weeks later or at the onset of adrenal insufficiency. Therefore, at least twice, the standard replacement dose is usually necessary.15 This higher dosage required for steroid replacement is largely ex- plained by the strong induction of CYP3A4.9 There is insuffi- cient evidence concerning the management of pediatric patients experiencing ongoing cortisol excess due to hormone- producing ACC. We advocate for a closely monitored setting to prevent oversight of the imperative to commence cortisol re- placement, as cortisol production dynamics may undergo changes during mitotane treatment, Laboratory chemical, and potentially endocrinological, assessments under mitotane should be conducted at a minimum frequency of every 4 weeks.
However, mineralocorticoid deficiency with the requirement of mineralocorticoid replacement occurs less frequently, sug- gesting that the glomerulosa zone is less sensitive to the cyto- toxicity of mitotane. 7,39
Statement 19. Most patients experience lab values that resem- ble central hypothyroidism, but its clinical relevance is uncer- tain. A trial treatment with thyroid hormones may be initiated.
Comment on statement 19. Further, mitotane often leads to a clinical picture of central hypothyroidism with reduced levels of TSH, T4, and free T4 due to an increase of thyroxin-binding globulin (TBG) and altered activity of deiodinase. If clinical symptoms of hypothyroidism are present, replacement with levothyroxine is required.15,33,39,40
Further comment on endocrinologic adverse effects: Due to in- creased levels of hormone-binding globulins, such as SHBG, signs of hypogonadism are frequent findings in male patients and sometimes necessitate testosterone supplementation.39,- Whereas breast development is a common side effect of mito- tane in both boys and girls,15 peripheral contrasexual preco- cious puberty including gynecomastia can occur in boys and peripheral isosexual precocious puberty (PPP) including early breast development and advanced bone age in prepubertal girls.33 In this case, the mitotane dosage needs to be adjusted, and in individual cases, concomitant therapy with anastrozole could be considered. Clinicians should also be aware of the im- pairment of height growth in children during mitotane treat- ment due to the risk of overtreatment with glucocorticoid replacement and/or hypothyroidism. 42
Gastrointestinal adverse effects
Statement 20. As gastrointestinal adverse effects are common and might be dose-limiting, antiemetic and antidiarrheal drugs should be given to mitigate these symptoms.
Comment on statement 20. Gastrointestinal adverse effects such as nausea, vomiting, diarrhea, and ensuing anorexia are especially common during the first phase of treatment.15 Proton pump inhibitors (PPI) or anti-H2 drugs can also be ad- ministered to reduce gastrointestinal adverse effects.
Hematological adverse effects
Statement 21. Significant anemia and thrombocytopenia are rare. Whereas mild leukopenia is not infrequent, severe agran- ulocytosis is extremely rare which is why complete blood counts should be monitored regularly. In case of severe neutro- penia (<500/uL) without other obvious explanation, mitotane treatment should be interrupted.
Comment on statement 21. Previous study results showed that leukopenia as well as prolonged bleeding times were com- mon, while thrombocytopenia and anemia were rare. 6,15
Neuropsychological adverse effects
Statement 22. Neuropsychological side effects occur especial- ly if blood levels are elevated. Adverse effects involving the central nervous system, such as ataxia, confusion, dizziness, decreased memory, or even lethargy, are common and can be life-threatening.
Comment on statement 22. Several studies (of adults) showed increased neurotoxicity for mitotane blood levels >20 mg/ L.15,43-46 In the case of moderate adverse effects, reduction of mitotane dose by 1000-1500 mg/m2/day is recommended. If severe neurotoxicity or any other common life-threatening adverse effects occur, mitotane treatment should be paused until significant clinical improvement and should then be re- started at a reduced dose.15,46 However, most adverse effects, even severe neurotoxicity, are completely reversible after in- terrupting therapy with mitotane.
Conclusion
Despite a lack of evidence on mitotane treatment in pACC, this Delphi method enabled us to propose an expert consensus statement on the indications for use of mitotane in pACC, to guide clinicians, who may adapt them to their local and pa- tient situation.
The evidence on use of mitotane therapy in the pediatric ACC is still limited and has been generated from studies of relatively few pediatric patients. Significant knowledge has been extrapolated from the adult literature, and further stud- ies ideally prospective are needed to determine the differences and specificities in pediatric patients, especially as it relates to dosage, initiating treatment, and treatment duration.
Due to the 2 different staging systems used by the centers, there may be a slight bias in our results. A uniform staging sys- tem should be emphasized in prospective studies.
Ultimately, several questions remain unanswered. Better international networking is an important and effective ap- proach to consolidate evidence and experience through joint expert meetings, the establishment of international registries for pACC, and the identification of open questions and knowl- edge gaps. As a medical responsibility toward our pediatric pa- tients and their parents/families, it is important to record adverse effects prospectively and in a standardized manner. This should improve the understanding of the actual effective mitotane levels and record side effects, including long-term neuropsychological outcomes. In addition, particularly in pa- tients with stage II tumors, the indication is uncertain and there are potential factors that could help to assess whether mitotane treatment is appropriate. A new assessment and sub- sequent redefinition of tumor stage may be necessary to im- prove risk stratification and outcome. Another issue that must be addressed is the duration of mitotane treatment. The presented manuscript is intended to be an initial step to- ward these goals.
Acknowledgments
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 V.W. and C.P. are supported by COST Action CA20122 Harmonization.
Funding
This work was supported by a research grant Interdisziplinäres Zentrum für klinische Forschung (IZKF) training grant awarded to M.R. (project number: Z-02CSP/ 23), the Mildred Scheel program awarded to V.W. Project 70113303-6, and by the Deutsche Forschungsgemeinschaft
(DFG) German Research Foundation Project 314061271- TRR 205 to M.F. The funder had no role in study design, data collection and analysis, decision to publish, or prepar- ation of the manuscript.
Conflict of interest: None declared.
Authors’ contributions
Maria Riedmeier (Data curation [equal], Formal analysis [equal], Methodology [equal], Project administration [equal], Writing-original draft [equal]), Sonir Antonini (Data cur- ation [equal], Formal analysis [equal]), Tatiana El-Jaick B. Costa (Formal analysis [equal]), Camila M. Daiggi (Data curation [equal]), Bonald Figueiredo (Data curation [equal], Formal analysis [equal], Writing-review & editing [equal]), Ronald de Krijger (Data curation [equal], Writing-review & editing [equal]), Karla Emília De Sà Rodrigues (Formal ana- lysis [equal], Writing-review & editing [equal]), Cheri Deal (Data curation [equal], Writing-review & editing [equal]), Jaydira Del Rivero (Data curation [equal], Writing-review & editing [equal]), Gernot Engstler (Data curation [equal], Writing-review & editing [equal]), Martin Fassnacht (Data curation [equal], Formal analysis [equal], Methodology [equal], Supervision [equal], Validation [equal], Writing-re- view & editing [equal]), Carlos AF Molina (Formal analysis [equal], Writing-review & editing [equal]), Elmas Nazli Gonc (Data curation [equal], Writing-review & editing [equal]), Tülay Güran (Data curation [equal], Writing-re- view & editing [equal]), Silvia Brandalise (Data curation [equal]), Melis Gültekin (Formal analysis [equal]), Harm R. Haak (Data curation [equal], Writing-review & editing [equal]), Emile Joseph Hendriks Allaird (Data curation [equal], Writing-review & editing [equal]), Jan Idkowiak (Data curation [equal], Writing-review & editing [equal]), Michaela Kuhlen (Data curation [equal], Writing-review & editing [equal]), David Malkin (Formal analysis [equal], Writing-review & editing [equal]), Jagdish Prasad Meena (Formal analysis [equal], Writing-review & editing [equal]), Christina Pamporaki (Conceptualization [equal], Data cur- ation [equal], Formal analysis [equal], Writing-review & ed- iting [equal]), Emilia Pinto (Data curation [equal], Writing- review & editing [equal]), Soraya Puglisi (Data curation [equal], Writing-review & editing [equal]), Raul Ribeiro (Data curation [equal], Writing-review & editing [equal]), Lester Thompson (Formal analysis [equal], Writing-review & editing [equal]), Bilgehan Yalcin (Formal analysis [equal], Writing-review & editing [equal]), Max Van Noesel (Data curation [equal], Writing-review & editing [equal]), Verena Wiegering (Conceptualization [equal], Data curation [equal], Formal analysis [equal], Funding acquisition [equal], Investigation [equal], Methodology [equal], Project adminis- tration [equal], Supervision [equal], Validation [equal], Visualization [equal], Writing-original draft [equal]), and Gabriela Caus Fernandes Luiz Canali (Data curation [equal])
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