Key factors for effective mitotane therapy in children with adrenocortical carcinoma
Michaela Kuhlen 01, Pascal Mier2, Marina Kunstreich2, Lienhard Lessel2, Dominik Schneider3, Ines Brecht4, Denis M Schewe2, Michael C Frühwald1, Peter Vorwerk2 and Antje Redlich2
1Paediatric and Adolescent Medicine, Faculty of Medicine, University Medical Centre Augsburg, Augsburg, Germany
2Department of Paediatric Haematology and Oncology, University Children’s Hospital, Otto-von-Guericke-University, Magdeburg, Germany 3Clinic of Paediatrics, Klinikum Dortmund, University Witten/Herdecke, Dortmund, Germany
4Paediatric Haematology/Oncology, Department of Paediatrics, University Hospital Tuebingen, Tuebingen, Germany
Correspondence should be addressed to M Kuhlen or A Redlich: michaela.kuhlen@uk-augsburg.de or Antje.Redlich@med.ovgu.de
Abstract
Adjuvant treatment with mitotane and chemotherapy is recommended for paediatric advanced and metastatic adrenocortical carcinoma (ACC). Yet, questions on the indication, dosage, and length of therapy are unanswered. Data from the German Paediatric Oncology Haematology-Malignant Endocrine Tumour studies were analysed retrospectively for patients receiving mitotane during first- and/or second-line therapy. Forty-three patients were identified (median age: 7.5 years (range: 0.2-17.8); 29 female) with median follow-up of 2.2 years (range: 0.04-12.71). Three-year overall (OS) and progression-free survival (PFS) were 44.9% and 28.5%, respectively. Eleven of 43 patients received mitotane as neoadjuvant treatment, and 4/11 tumours reached partial remission (PR). Twenty-seven of 43 patients received mitotane combined with chemotherapy in an adjuvant setting resulting in PR of measurable target lesions in 5/13 patients. Metastatic disease (hazard ratio (HR): 3.2; 95% CI: 1.2-18.6; P = 0.018), duration of mitotane treatment <9 months (HR: 5.6; 95% CI: 1.9-16.9; P = 0.002), and not achieving drug target range (TR) (HR: 28.5; 95% CI: 5.4-150.3; P < 0.001) significantly impacted as negative prognostic factors upon PFS and OS (metastatic disease: HR: 4.9; 95% CI: 1.6-15.5; P = 0.006; duration of mitotane treatment: HR: 7.0: 95% CI 1.9-26.0; P = 0.004; TR not reached: HR: 13.5; 95% CI 3.6-50.3; P < 0.001). Cox regression determined the risk of event decreasing by 10.4% for each month of mitotane treatment (P = 0.015). Re-treatment with mitotane after first-line treatment proved ineffective. The duration of mitotane treatment and reaching mitotane TR significantly impacted survival. Improving the efficacy of mitotane, including appropriate indications, needs to be evaluated in prospective randomized trials.
Key Words
adrenocortical carcinoma
child
mitotane
outcome
Endocrine-Related Cancer (2022) 29, 545-555
Introduction
Adrenocortical carcinomas (ACC) in children and adolescents are rare endocrine tumours with highly aggressive behaviour and dismal prognosis. The only curative treatment option is complete surgical tumour removal, while the role of adjuvant therapies remains to be defined. Although the outcome for patients with
early-stage completely resected tumours is basically deemed favourable, the Children’s Oncology Group (COG) reported post-operative recurrences in 46.7% of patients with stage II ACC following adrenalectomy and retroperitoneal lymph node dissection (Rodriguez-Galindo et al. 2021). Accordingly, the European Cooperative Study
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Group for Paediatric Rare Tumours suggested to consider adjuvant mitotane monotherapy in stage II patients (Virgone et al. 2021). For patients with advanced and metastatic ACC, adjuvant therapy with mitotane and chemotherapy is recommended in all cases (Virgone et al. 2021); however, the combination of mitotane and platinum-based chemotherapy resulted in significant toxicity in the COG trial with one-third of patients not completing the scheduled treatment (Rodriguez-Galindo et al. 2021).
Mitotane with its selective cytotoxicity on the fasciculate and reticular zones of the adrenal cortex constitutes the only specific and targeted therapy in ACC, up to now. Objective tumour responses have been observed in adult patients with advanced disease in approximately 20-30%, using mitotane alone, and hormonal responses in 75% of cases (Luton et al. 1990). Thus, the recommendation for the paediatric use of mitotane in an adjuvant setting is based on retrospective data from adult patients demonstrating improved recurrence-free survival upon adding mitotane (approx. 50% vs 18%) (Terzolo et al. 2007). In an early French retrospective study of children, the objective response rate to mitotane was 30% (Teinturier et al. 1999).
Maintaining ‘effective’ mitotane blood levels for an extended period of time was first recorded in adults as a prerequisite for tumour response and improved survival (Haak et al. 1994, Dickstein et al. 1998). We previously demonstrated superior survival in paediatric patients for plasma mitotane levels >14 mg/L and treatment with mitotane for >6 months (Redlich et al. 2012). Yet, a wealth of questions on mitotane treatment in children with ACC remains unanswered including appropriate indications, drug dosage, and optimal length of mitotane therapy, specifically in view of its limited tolerance.
Therefore, we investigated the use of mitotane in children and adolescents with ACC and adrenocortical tumours of uncertain malignant potential (ACx) reported to the German Paediatric Oncology Haematology-Malignant Endocrine Tumour (GPOH-MET) study centre since 1997. We asked which patients benefited from adjuvant mitotane treatment and analysed details of their therapy.
Patients and methods
Data of children and adolescents reported to the GPOH- MET study centre were analysed retrospectively. Inclusion criteria were histologically confirmed diagnosis of ACC or ACx and first- and/or second-line treatment with mitotane following surgery. Exclusion criteria were
missing data on mitotane drug levels and the duration of mitotane treatment. The follow-up for this study was closed in July 2021.
The GPOH-MET 97 and GPOH-MET 2013 databases were approved by the ethics committees of the University of Luebeck (approval number 97125) and Otto-von- Guericke-University Magdeburg (approval number 174/12), Germany. Written informed consent was obtained from patients aged 15 years or older and/or their parents or legal guardians, as appropriate.
The GPOH-MET 97 study and the GPOH-MET registry
Details of the GPOH-MET 97 study protocol, the GPOH- MET registry, and data collection are provided elsewhere (Redlich et al. 2012, Cecchetto et al. 2017). Briefly, mitotane treatment was advised for patients with stage III (T1-2, N1, M0) tumours over a 9-month period together with four cycles of alternating chemotherapy (NN-1: vincristine, ifosfamide, doxorubicin; NN-2: carboplatin, etoposide). For patients with stage IV tumours, mitotane was recommended over an 18-month period with eight cycles of alternating chemotherapy. The GPOH-MET protocol suggested mitotane with two to four cycles of neoadjuvant chemotherapy for patients with primary unresectable tumours to downstage the tumour and, thus, achieve resectability.
Tumour volumes and maximum diameter (herein referred to as size) were calculated from tumour measurements obtained from MRI, CT scans, or ultrasound examinations as provided by treating physicians or by pathology reports. The Ki67 index was evaluated histopathologically. We assigned retrospectively macro- and microscopic features of the tumour to one of three scores of the Wieneke index (Wieneke et al. 2003).
Complete remission (CR) was achieved if patients had normalized hormone profiles and no structural evidence of disease. Partial remission (PR) was defined as a decrease of volume >30% of existing lesions and progressive disease (PD) as an increase of volume >20% of existing lesions and/ or evidence of new lesions without a period of CR. Stable disease (SD) was defined as neither PR nor PD. Recurrence was defined as new hormonal or structural evidence of disease following any period of CR.
We assigned retrospectively the post-surgical tumour status to one of four post-operative COG stages (Sandrini et al. 1997, Ribeiro et al. 2012). For the purposes of this analysis, patients with tumour biopsy prior to resection as well as pre- and/or intraoperative tumour spillage were classified into COG stage III (herein referred to as spillage).
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Mitotane target drug levels
Mitotane plasma levels were monitored every 2 weeks until they reached the drug target range (TR) and every month thereafter. For the purpose of this analysis, patients with ≥3 measurements of plasma mitotane were eligible. We calculated the time in TR, defined as the time in which mitotane concentrations were ≥14 mg/L and <20 mg/L (Puglisi et al. 2020).
Statistical analyses
Overall survival (OS) and progression-free survival (PFS) were determined according to Kaplan-Meier estimates. OS was defined as the time from diagnosis to death of disease without regard for other causes. PFS was defined as the time from diagnosis to the event, defined as progression, relapse, or death of disease, whichever occurred first. To evaluate post-operative COG-stage, extent of resection and lymph node dissection, OS, and PFS were in derogation thereof calculated from the date of surgery until event. PFS after treatment for progression or relapse (PFS-R) was calculated from the start of second-line/relapse therapy until the next progression or relapse. Survivors were censored at the date of last follow-up.
Groups were compared using the log-rank test, and categorical data were compared using the chi-square test with Yates’ continuity correction where appropriate. For normally distributed numerical data, the independent t-test was used to compare the mean difference between subgroups; in all other cases, the Mann-Whitney U test was used.
The Cox proportional hazards model was applied to evaluate the impact of prognostic factors on OS and PFS in a univariate manner; however, analyses were exploratory, and P-values were considered as descriptive measures to detect and study meaningful effects. In particular, no significance level was fixed.
Statistical analyses were performed using SPSS version 26. Data visualization and graphs were created using SPSS and R version 4.0.5 using the ‘ggplot2’ and the ‘networkD3’ packages.
Results
Baseline characteristics of 43 children and adolescents with ACC including 1 child with ACx are reported in Table 1. An overview of the sequential therapeutical procedures up to the last follow-up or death is provided in Fig. 1. Median duration of mitotane treatment was 13.7 months (range: 1.3-51.7); mitotane withdrawal was
determined by adverse effects and non-response in 7/43 (16.3%) patients.
The median follow-up was 2.2 years (range: 0.04- 12.71 years). Three-year OS and PFS were 44.9% and 28.5%, respectively. Of 43 patients, 31 (72.1%) patients experienced progression or relapse with a median time to event of 0.6 years (range: 0.04-3.16 years). Seventeen (42.2%) and 13 (32.1%) patients were free of disease progression or relapse at 12 months and 24 months, respectively. At the end of the observation period, 23/43 (53.5%) patients had died of disease.
Differences in OS (calculated from first surgery) were observed concerning tumour volume at diagnosis (<200 mL vs ≥200 mL: 70.1% vs 30.1%, P=0.032) (Fig. 2A), post-operative COG stage (stage I vs II vs III vs IV: 100% vs 60.0% vs 41.7% vs 11.4%, P=0.008) (Fig. 2B), and extent of tumour resection at relapse (R) VS R1/2 VS no surgery: 50.5% vs 30.0% vs 0.00%, P<0.001) (Fig. 2C). In patients receiving mitotane ≥9 months, differences in OS were observed concerning the length of time within therapeutic drug TR (<9 vs ≥9 months: 34.7% vs 80.0%, P=0.022) (Fig. 2D).
No relevant differences in OS were observed for age (<4 years vs ≥4 years: 69.2% vs 29.3%, P=0.068), presence of Li-Fraumeni syndrome (no vs yes: 41.2% vs 44.4%, P=0.947), hormone excess at diagnosis (no vs yes: 16.7% vs 46.0%, P=0.059), tumour size (<5 cm vs ≥5 cm: 50.0% vs 41.4%, P=0.898; < 10.5 cm vs ≥10.5 cm: 54.0% vs 28.8%, P=0.105), Wieneke index (≤2 vs 3 vs >3: 85.7% vs 66.7% vs 24.1%, P=0.073), and Ki-67 index (≤15% vs>15%: 57.1% vs 38.2%, P=0.328). In patients receiving mitotane ≥18 months, no differences in OS were observed for length of time within therapeutic drug TR (<18 vs ≥18 months: 58.0% vs 100.0%, P=0.312).
Mitotane in first-line therapy
In 30 patients, mitotane was included in first-line therapy. The median duration of mitotane treatment was 9.1 months (range: 0.8-42.0); mitotane withdrawal was determined by adverse effects and non-response in 6/30 (20.0%) patients.
As neoadjuvant treatment
At diagnosis, 11/30 (36.7%) patients received mitotane in a neoadjuvant setting in combination with 2-4 cycles of NN-1 and NN-2 chemotherapy in 10 and an alternative regimen in 1 patient. Response evaluation after 2 or 4 cycles of chemotherapy demonstrated PR
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| Characteristics | All cases, n = 43 | First-line treatment, n = 30 | Second-line treatment, n = 13 | First- and second-line treatment, n = 9 |
|---|---|---|---|---|
| Sex, n (%) | ||||
| Male | 14 (32.6%) | 12 (40.0%) | 2 (15.4%) | 5 (55.6%) |
| Female | 29 (67.4%) | 18 (60.0%) | 11 (84.6%) | 4 (44.4%) |
| Age at diagnosis, years | ||||
| Median (range) | 7.5 (0.2-17.8) | 9.2 (0.2-17.8) | 4.6 (0.4-14.5) | 7.0 (3.2-17.8) |
| <3 years | 6 (14.0%) | 3 (10.0%) | 3 (23.1%) | 0 (0%) |
| ≥3 years | 37 (86.0%) | 27 (90.0%) | 10 (76.9%) | 9 (100%) |
| Li-Fraumeni syndrome | 10 | 6 | 4 | 3 |
| Children's Oncology Group stage at diagnosis, n (%) | ||||
| Stage I | 1 (2.8%) | 0 (0%) | 1 (11.1%) | 0 (0%) |
| Stage II | 5 (13.9%) | 3 (11.1%) | 2 (22.2%) | 1 (11.1%) |
| Stage III | 16 (44.4%) | 11 (40.7%) | 5 (55.6%) | 4 (44.4%) |
| Unresectable | 0 | 0 | 0 | 0 |
| Residual disease | 1 | 1 | 0 | 1 |
| Tumour spillage | 8 | 5 | 3 | 5 |
| Combined | 7 | 6 | 1 | 6 |
| Stage IV | 14 (38.9%) | 13 (48.1%) | 1 (11.1%) | 4 (44.4%) |
| Not available | 7 | 3 | 4 | 0 |
| Symptoms of hormone secretion, n (%) | ||||
| No | 7 (16.3%) | 7 (23.3%) | 0 (0%) | 3 (33.3%) |
| Yes | 36 (83.7%) | 23 (76.7%) | 13 (100%) | 6 (66.7%) |
| Tumour volume, mL | 381.5 (18.0-3645.0) | 472.4 (18.0-3645.0) | 267.9 (36.2-1260.0) | |
| Median (range) | 720.0 (108.0-3645.0) | |||
| Tumour size, cm | ||||
| Median (range) | 11.0 (4.0-30.0) | 12.0 (4.0-30.0) | 8.5 (4.6-18.0) | 13.0 (6.0-30.0) |
| Ki67 index | ||||
| ≤15% | 7 (16.3%) | 4 (13.3%) | 3 (23.1%) | 0 (0%) |
| >15% | 30 (69.8%) | 22 (73.3%) | 8 (61.5%) | 7 (77.8%) |
| Not available | 6 (14.0%) | 4 (13.3%) | 2 (15.4%) | 2 (22.2%) |
| Wieneke index | ||||
| ≤2 | 7 (16.3%) | 3 (16.3%) | 4 (30.8%) | 0 (0%) |
| 3 | 3 (7.0%) | 3 (16.3%) | 0 (0 %) | 0 (0%) |
| >3 | 16 (37.2%) | 13 (43.3%) | 3 (23.1%) | 5 (55.6%) |
| Not available | 17 (39.5%) | 11 (36.7%) | 6 (46.2%) | 4 (44.4%) |
| Duration of mitotane | 11.3 (0.8-51.7) | |||
| therapy, months Median (range) | 9.1 (0.8-42.0) | 17.5 (1.3-51.7) | 13.8 (5.0-25.1) | |
| Duration of mitotane in drug target range, months Median (range) | 3.6 (0-24.7) | 6.8 (0-27.1) | 4.4 (0-11.3) | Not applicable |
in 4/11 (36.4%) patients, SD in 4/11 (36.4%), and PD in 3/11 (27.3%) patients including the patient receiving alternative chemotherapy. Mean mitotane levels reached the TR earlier in patients achieving partial response as compared to patients with stable disease. In patients with tumour progression, mean mitotane levels did not reach TR.
Following neoadjuvant therapy, 8/11 patients proceeded to tumour resection and received additional adjuvant treatment, and 3/11 patients succumbed to rapid disease progression.
As adjuvant treatment
A total of 27/30 (90.0%) patients with advanced disease received mitotane combined with chemotherapy as adjuvant treatment. Following surgery, target lesions for response assessment to adjuvant treatment were measurable in 13/27 (48.1%) patients. In 5/13 (38.4%) patients, PR of the primary tumour or metastatic lesions was achieved, 1/13 patient showed stable disease, and 7/13 (53.8%) patients experienced tumour progression. In 2/5 patients with initial PR, progression occurred 8.4 months after tumour resection still during mitotane treatment and
neoadjuvant M+CTx (8)
surgery (8)
adjuvant M+CTx (6)
M+CTx in recurrence (2)
neoadjuvant M+CTx (3)
M+CTx in recurrence (8)
adjuvant M+CTx (20)
surgery (32)
M+CTx in recurrence (12)
2.9 months after discontinuation of a 6-month mitotane therapy, respectively.
The duration of mitotane treatment, including the preoperative phase for eight patients, proved a determinant of survival. While 5-year OS declined to 25.0% for stage-III patients suffering from progression prior to reaching 9 months and/or receiving less than 9 months of mitotane therapy, it was 80.0% for those with ≥9 months of mitotane exposure (Fig. 3A, P=0.057). Correspondingly, 5-year OS was 0.0% for stage-IV patients with progression and/or treatment <18 months compared to 100% for patients receiving ≥18 months mitotane (Fig. 3B, P=0.096). Five-year PFS dropped to 25.0% for stage-III patients not reaching 9 months of treatment compared to 57.1% for patients receiving ≥9 months (Fig. 3C, P=0.209). It was 0.0% for stage IV patients not reaching 18 months compared with 0.0% for those receiving ≥18 months (Fig. 3D, P=0.044).
In 23 of 27 (85.2%) patients, data on mitotane levels were available for further analysis. No difference in PFS was observed for mean mitotane plasma levels above or below the minimum target level (≥14 mg/L vs <14 mg/L: 44.9% vs 53.0%, P=0.777). In 19 (82.6%) of 23 patients, mitotane levels reached the defined drug TR. The mean time to reach the defined drug TR was 3.6 months (S.D., 2.1 months), and the median time in TR was 3.7 months (range: 0-24.7 months). Plasma mitotane concentrations were in TR in 31.8% (range: 0-73.1%) of the total treatment time.
Differences in PFS were observed between patients reaching TR vs those failing to reach TR (60.6% vs 0%, P<0.001) (Fig. 4A). In patients receiving mitotane ≥9 months, PFS dropped to 50.8% for patients maintaining TR <9 months compared to 80.0% for patients with ≥9
months within therapeutic drug TR (Fig. 4B, P=0.188). The impact of reaching and maintaining TR on OS is depicted in Fig. 4C and D.
Association of clinical factors with outcome in mitotane first-line therapy
In univariate analysis, COG stage IV, duration of mitotane treatment <9 months, and not achieving TR significantly impacted as negative prognostic factors upon PFS and OS. Cox regression determined that the risk of event or death decreased by 10.4% (range: 2.0-19.6%) for each month of mitotane treatment (P=0.015).
Neither age at diagnosis, presence of Li-Fraumeni syndrome, signs of hormone excess, resection status, lymph node dissection, tumour volume, tumour size, Ki67 index, Wieneke score nor time in TR significantly impacted as prognostic factors upon PFS and OS (Table 2).
Mitotane in second-line therapy
Without prior mitotane treatment
In 13 patients, mitotane was administered as second-line therapy for local relapse (n=1, 7.7%), combined relapse (n=7, 53.8%), distant relapse (n=4, 30.8%), and disease progression (n=1, 7.7%) following resection of tumour and/or metastases in 12 of 13 (92.3%) patients. In 11 of 13 (84.6%) patients, mitotane was administered in combination with NN-1 and NN-2 chemotherapy. At last follow-up, eight (61.5%) patients had died of disease, and five (38.5%) patients were still alive.
Data on mitotane plasma levels were available in 12/13 patients; TR was reached in 11 (91.7%) patients at a median
A
<200 ml (N=12)
>=200 ml (N=31)
B + COG I (N=1) -+ II (N=5) + . III (N=16) ++ IV (N=14
1.00
1.00
1.0
0.75
0.70
0.75
Overall survival
Overall survival
0.60
0.50
0.50
0.43
0.30
0.25
0.25
0.11
0.00
p=0.032
0.00
p=0.008
0
2.5
5
7.5
10
12.5
0
2.5
5
7.5
10
12.5
Years after diagnosis
Years after diagnosis
C + RO (N=29) -+- R1/2 (N=11) -+’ no surgery (N=3)
D
<9 months (N=18)
-+
>=9 months (N=11)
1.00
1.00
0.80
0.75
0.75
Overall survival
Overall survival
0.50
0.51
0.50
0.30
0.35
0.25
0.25
0.00
1 0.00
p<0.001
0.00
p=0.022
0
2.5
5
7.5
10
12.5
0
2.5
5
7.5
10
12.5
Years after diagnosis
Years after diagnosis
of 1.8 months (range: 0.8-7.1 months) following diagnosis of relapse and/or progression.
Differences in OS (calculated from the time of first event) were observed depending on treatment duration (<12 months vs ≥12 months: 0% vs 50.0%, P=0.002) and TR (reached vs not reached: 0% vs 40.4%, P=0.001).
Following first-line mitotane
In nine patients, first-line mitotane treatment was continued through local relapse (n=1), combined relapse (n=2), distant metastases (n=2), and disease progression (n=4). Six (66.7%) patients died of PD resulting in 1-year survival of 44.4%, 2-year survival of 14.8%, and 5-year survival of 0% (censored for three patients).
Mitotane TR was reached at a median of 0.7 months (range: 0.0-2.2) in six patients with data on plasma levels.
Association of clinical factors with outcome in patients receiving mitotane in second-line therapy only
In univariate analysis, neither resection status or Ki-67 index nor duration of mitotane treatment <9, treatment TR, or time in TR significantly impacted as negative prognostic factor upon OS and PFS-R (Table 3).
Toxic effects of mitotane treatment
In 27 of 43 patients with combination therapy (mitotane plus chemotherapy), information on tolerance was available. High tolerance was reported in 7/27 (25.9%) patients, moderate tolerance in 13/27 (48.1%), and poor tolerance in 7/27 (25.9%). In the absence of measurable therapeutic effects, all patients with poor
A
<9 months (N=4)
>=9 months (N=7)
B
<18 months (N=4)
>=18 months (N=7)
1.00
1.00
+1.00
0.80
0.75
0.75
Overall survival
Overall survival
0.50
0.50
0.25
0.25
0.25
0.00
p=0.057
0.00
0.00
p=0.096
0
2.5
5
7.5
10
12.5
0
1
2
3
Years after diagnosis
Years after diagnosis
C
<9 months (N=4)
>=9 months (N=7)
D
<18 months (N=4)
>=18 months (N=7)
1.00
1.00
Progression-free survival
0.75
Progression-free survival
0.75
0.57
0.50
0.50
0.25
0.25
0.25
0.00
p=0.209
0.00
0.00
0.00
p=0.044
0
2.5
5
7.5
10
12.5
0
1
2
3
Years after diagnosis
Years after diagnosis
tolerance permanently discontinued mitotane therapy. Neurotoxic and gastrointestinal side effects were reported in 4/27 (14.8%) patients each and hepatotoxicity and drug-induced QT prolongation in 1/27 (3.7%) patients each.
Discussion
In line with previous reports, our data confirm that advanced and metastatic ACC in children and adolescents is associated with a dismal prognosis (3-year OS: 44.9%, PFS: 28.5%) (Michalkiewicz et al. 2004, Zancanella et al. 2006, McAteer et al. 2013, Dall’Igna et al. 2014, Picard et al. 2020, Rodriguez-Galindo et al. 2021, Zambaiti et al. 2021). Duration of first-line mitotane therapy <9 months and not achieving treatment TR significantly impacted as negative prognostic factors upon PFS and OS in univariate analysis, while the risk
of event or death gradually dropped for patients tolerating prolonged exposure to adequate drug levels.
In the retrospective French series from 1999, the response rate to mitotane was 30% in 20 treated patients with microscopically incomplete resection and/or advanced and/or relapsed disease (Teinturier et al. 1999). In our study, response rates to neoadjuvant and adjuvant mitotane were 36.4% and 38.4%, respectively. In two of five patients with partial response to adjuvant mitotane, progression occurred while under and early after discontinuation of mitotane therapy. A study from Brazil reported on 11 patients with advanced childhood ACC receiving mitotane in combination with cisplatin, etoposide, and doxorubicin. Six of 11 patients showed some response including one PR and two CRs; however, only one of those patients survived without the disease. In a single-centre experience in Italy, seven patients were treated
A
+
fail to reach TR (N=4)
reach TR (N=19)
B
<9 months TR (N=9)
>=9 months TR (N=6)
1.00
1.00
Progression-free survival
Progression-free survival
0.89
0.75
0.75
0.61
0.50
0.50
0.51
0.25
0.25
0.00
0.00
p<0.001
0.00
p=0.188
0
2.5
5
7.5
10
12.5
0
2.5
5
7.5
10
12.5
Years after diagnosis
Years after diagnosis
C
+ fail to reach TR (N=4)
reach TR (N=19)
D
+ <9 months TR (N=9)
>=9 months TR (N=5)
1.00
1.00
1.00
0.75
0.65
0.75
Overall survival
+
Overall survival
0.57
0.50
0.50
0.25
0.25
0.00
0.00
p<0.001
0.00
p=0.111
0
2.5
5
7.5
10
12.5
0
2.5
5
7.5
10
12.5
Years after diagnosis
Years after diagnosis
with adjuvant mitotane for 12 months (Miele et al. 2020). Though all patients presented with just localized disease and underwent total tumour resection, 3/7 patients developed metastatic disease under treatment or during follow-up.
The pharmacokinetics of mitotane and the ability to maintain ‘effective’ blood levels (>14 mg/L) for an extended period of time directly impact tumour response in adults (Haak et al. 1994, Dickstein et al. 1998, Fassnacht et al. 2018). In the Brazilian study, 82% of patients reached mitotane TR after a mean of 6.4 months, exposure time in TR was not reported (Zancanella et al. 2006). In 76.9% of patients in our study, mitotane levels reached TR after a mean time of 3.6 months. Though, the median time in TR was only 3.7 months corresponding to 31.8% of treatment time. Patients who achieved PR reached TR earlier than patients just achieving SD. Duration of mitotane treatment ≥9 months and reaching drug TR impacted both PFS and
OS. Noteworthy, for each month of mitotane therapy, the relative risk for an event decreased by 10.4%. Thus, in line with previous reports from adults, our data suggest that patients benefit from (neo)adjuvant mitotane treatment only if effective therapeutic mitotane plasma levels are reached, and hence, effective treatment time is maintained over a longer period of time. Yet, we have to stress that we were not able to analyse the optimal duration of mitotane treatment in children and adolescents. The current proposal of up to 2 years from diagnosis is not based on mitotane data but covers the maximum risk period for relapse or dissemination.
In line with previous reports, our data suggest a role of mitotane treatment in second-line therapy (Picard et al. 2020). Noteworthy, patients with PD and/or relapsed disease did not benefit from continuation of and/or re-exposure to mitotane.
| Univariate analysis | PFS | OS | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | |
| Age at diagnosis ≥4 years | 1.6 | 0.5-4.8 | 0.422 | 3.1 | 0.7-13.9 | 0.134 |
| Li-Fraumeni syndrome | 2.0 | 0.7-5.5 | 0.207 | 1.5 | 0.4-5.2 | 0.564 |
| No signs of hormone excess | 2.8 | 1.0-7.8 | 0.045 | 2.6 | 0.9-7.7 | 0.084 |
| COG stage III | 3.3 | 0.4-24.7 | 0.250 | 3.2 | 0.4-24.9 | 0.260 |
| COG stage IV | 3.2 | 1.2-8.6 | 0.018 | 4.9 | 1.6-15.5 | 0.006 |
| R1/2 resection or no surgery | 2.1 | 0.8-5.3 | 0.123 | 2.8 | 1.0-7.8 | 0.052 |
| No lymph node dissection | 0.7 | 0.3-2.3 | 0.709 | 0.8 | 0.2-2.6 | 0.689 |
| Tumour volume ≥200 mL | 3.2 | 0.7-14.0 | 0.123 | 5.4 | 0.7-41.1 | 0.106 |
| Tumour size ≥5 cm | 0.3 | 0.03-2.2 | 0.229 | 0.1 | 0.01-1.1 | 0.058 |
| Tumour size ≥10.5 cm | 3.4 | 0.7-16.4 | 0.132 | 3.1 | 0.6-15.3 | 0.155 |
| Ki67 index >15% | 3.7 | 0.5-28.3 | 0.204 | 2.9 | 0.4-22.5 | 0.306 |
| Wieneke index >3 | 7.0 | 0.9-55.7 | 0.066 | 5.0 | 0.6-40.9 | 0.137 |
| Duration of mitotane <9 months | 5.6 | 1.9-16.9 | 0.002 | 7.0 | 1.9-26.0 | 0.004 |
| Therapeutic drug target range not | 28.5 | 5.4-150.3 | <0.001 | 13.5 | 3.6-50.3 | <0.001 |
| reached | ||||||
| Time in drug target range <9 months | 3.9 | 0.4-35.6 | 0.222 | 56.2 | 0.01-646667 | 0.398 |
COG stage, extent of tumour resection, and lymph node dissection were calculated from date of surgery. Impact of duration of mitotane therapy was analysed in patients surviving ≥9 months, and time in target range was analysed in patients receiving mitotane therapy ≥9 months. Bold indicates statistical significance.
In a meta-analysis of clinical prognostic factors in paediatric adrenocortical tumours conducted by Zambaiti et al., complete resection at diagnosis significantly impacted outcome (Zambaiti et al. 2021). As opposed to this, complete resection (of all tumour manifestations) was no determinant of PFS and OS in first- and second-line therapy in our study. Yet, our data have to be interpreted with caution due to small patient numbers. Corroborating the analysis of Zambaiti, survival of patients with complete resection is superior compared to patients with incomplete resection in our cohort.
When interpreting mitotane data, toxic effects of mitotane and poor adherence to treatment need to be considered. In 5 of 20 patients in the French study, serious side effects of mitotane therapy were reported, and 2 of those patients died of acute adrenal insufficiency (Teinturier et al. 1999). One of 11 patients
in the Brazilian study died of adrenal insufficiency; in 4 patients, it was necessary to temporarily discontinue mitotane treatment due to toxic side effects (Zancanella et al. 2006). In our study, mitotane treatment was permanently discontinued in 16.3% of patients because of side effects in the absence of measurable therapeutic effects. Nevertheless, our data highlight poorer outcomes in children and adolescents who did not reach mitotane treatment time >9 months or mitotane TR indicating that - when administering mitotane treatment - particular efforts are needed to attain sufficient treatment time and effective levels.
Our study has several limitations as follows:
- The impact of mitotane treatment on survival, particularly the impact of time in drug TR and in second-line treatment, may be underestimated due to small patient numbers.
| Univariate analysis | PFS-R | OS | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | |
| R1/2 resection or no surgery | 0.3 | 0.1-1.7 | 0.175 | 2.2 | 0.4-11.6 | 0.337 |
| Ki-67 index >15% | 1.2 | 0.2-6.2 | 0.843 | 1.2 | 0.2-6.4 | 0.809 |
| Duration of mitotane <9 months | 10.6 | 0.9-120.3 | 0.056 | 3.4 | 0.6-20.3 | 0.188 |
| Therapeutic drug target range not reached | na | 1,202,715 | 0-3.49 x 10287 | 0.966 | ||
| Time in drug target range <9 months | 3.4 | 0.4-30.2 | 0.280 | 4.0 | 0.4-36.1 | 0.219 |
Impact of duration of mitotane therapy was analysed in patients surviving ≥9 months, and time in target range was analysed in patients receiving mitotane therapy ≥9 months.
- The combination of chemotherapy and mitotane was recommended for all patients with advanced and/ or metastatic disease. Thus, the additional impact of chemotherapy was not evaluated due to the lack of comparative evaluable data.
- Availability of data on mitotane levels varied widely among patients. We may have missed the temporary discontinuation of mitotane treatment due to toxic side effects.
- Response assessments by the treating physicians were not centrally reviewed based on response evaluation criteria in solid tumours (Eisenhauer et al. 2009).
- Our study was not designed to analyse the best indications and optimal length of mitotane treatment. Likewise, we did not systematically capture data on the justification of treatment at diagnosis and during the course of the disease, for example, in relation to the Lansky or Karnofsky performance status.
The new era of molecular studies brings new insights into adrenal tumourigenesis. The heterogeneity in the outcomes of adrenocortical carcinomas supports the existence of different classes of tumours with distinct biological aberrations, probably reflecting variable underlying oncogenic mechanisms (Faria & Almeida 2012, Fragoso et al. 2012, Pinto et al. 2015, 2020, Ferreira et al. 2019, Martins-Filho et al. 2021). This progress may facilitate the development of targeted therapies according to molecular data, improving the decision for adjuvant therapies.
Conclusion
Response rates to (neo)adjuvant mitotane were about 35%. Duration of mitotane treatment ≥9 months and achieving effective mitotane levels are paramount prerequisites for a useful mitotane treatment in children and adolescents with ACC. This needs to be complemented by surgical resection of all tumoural sites. The efficacy of mitotane therapy plus- or-minus chemotherapy in children and adolescents with advanced and metastatic ACC needs to be evaluated in prospective randomized paediatric trials with continuous mitotane monitoring.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
| The GPOH-MET | study | and | registry | are | funded | by | Deutsche |
|---|---|---|---|---|---|---|---|
| Kinderkrebsstiftung (DKS | 2014.06, | DKS | 2017.16, | DKS | 2021.11), W.A. | ||
Drenckmann Stiftung, Mitteldeutsche Kinderkrebsforschung, and Magdeburger Förderkreis krebskranker Kinder e.V.
Author contribution statement
Mi Ku: Conceptualization, methodology, writing - original draft, visualization, data curation, project administration. P M: Investigation, writing - review. Project administration. Ma Ku: Writing - review, project administration. L L: Investigation, writing - review. D S: Investigation, writing - review. I B: Investigation, writing-review. DMS: Writing-review.MCF: Conceptualization, writing - review, supervision. P V: Conceptualization, resources, funding acquisition, writing - review, supervision. Project administration. A R: Conceptualization, methodology, formal analysis, visualization, resources, data curation, writing - original draft, project administration.
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Received in final form 22 June 2022 Accepted 6 July 2022 Accepted Manuscript published online 6 July 2022
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