Systemic Treatment of Adrenocortical Carcinoma in Children: Data from the German GPOH-MET 97 Trial
Systemische Therapie von Nebennierenrindenkarzinomen im Kindesalter: Ergebnisse des GPOH-MET-97-Protokolls
Authors
A. Redlich1, N. Boxberger1, D. Strugala1, M. C. Frühwald2, I. Leuschner3, S. Kropf4, P. Bucsky5, P. Vorwerk1
Affiliations
Affiliation addresses are listed at the end of the article
Key words
adrenocortical carcinoma
GPOH-MET-97 protocol
mitotane
@ neoadjuvant therapy
· pediatric oncology
Schlüsselwörter
· Nebennierenrindenkarzinom
GPOH-MET-97 Protokoll
Mitotane
· neoadjuvante Chemo- therapie
· Kinderonkologie
Bibliography
DOI http://dx.doi.org/ 10.1055/s-0032-1327579 Klin Padiatr 2012; 224: 366-371 @ Georg Thieme Verlag KG Stuttgart . New York ISSN 0300-8630
Correspondence
Peter Vorwerk, MD, PhD Pediatric Oncology Otto von Guericke University Childrens Hospital Leipziger Street 44 39120 Magdeburg Germany Tel .: +49/391/6724 009 Fax: +49/391/6729 0562 Peter.Vorwerk@med.ovgu.de
Abstract
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Background: Adrenocortical cancer (ACC) in childhood is a rare disease with poor prognosis. Complete surgical resection, systemic chemo- therapy, and mitotane therapy are important curative treatment options for patients with advanced-stage tumors. Since 1997, pediatric ACC patients in Germany have been treated according to the non-randomized, single arm study GPOH-MET-97.
Patients and methods: Data regarding disease course, treatment, and survival rates of 60 patients (age 0.24-17.8 years) with ACC treated according to the GPOH-MET-97 protocol were collected and analyzed to determine outcome, with a focus on examining the effectiveness of mitotane therapy.
Results: Among all patients, event-free survival and overall survival were found to be 43.3% and 64.8%, respectively. Chemotherapy with VCR, IFO, ADR, CARBO, and VP16 had been provided to 34 patients (56.6%) in different settings (neoad- juvant, adjuvant, and salvage) and mitotane ther- apy to 32 patients (53.3%). Duration of mitotane treatment longer than 6 months and mitotane levels greater than 14mg/l were found to be asso- ciated with significantly better survival. Local relapse was found to be associated with a worse prognosis compared to distant metastasis only. Conclusions: Systemic chemotherapy and mitotane therapy are important therapeutic options in the treatment of advanced pediatric ACC patients. Neoadjuvant therapy should be considered for patients with primarily incom- plete resectable or inoperable tumors, and tumor spillage is an indication for adjuvant chemo- and mitotane therapy. All pediatric ACC patients should be treated in pediatric oncological centers according to a consistent protocol in a highly interdisciplinary setting.
Zusammenfassung
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Hintergrund: Nebennierenrindenkarzinome (ACC) sind bei Kindern seltene Tumoren, die eine hohe Letalität besitzen. Neben der kompletten chirurgischen Resektion des Tumors sind die sys- temische Chemo- und Mitotanetherapie wich- tige Optionen für einen kurativen Ansatz. Seit 1997 werden Kinder mit ACC in Deutschland nach der einarmigen, nicht-randomisierten GPOH- MET-97 Studie behandelt.
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Patienten und Methoden: 60 Patienten mit ACC im Alter zwischen 2 Monaten und 18 Jahren wurden nach dem GPOH-MET-97-Protokoll behandelt. Erkrankungsverlauf, Therapie und Ergebnisse wurden unter besonderer Berück- sichtigung der Mitotanetherapie analysiert.
Ergebnisse: Das ereignisfreie Überleben von allen Patienten betrug 43.3%, das Gesamtüberle- ben 64.8%. Die Chemotherapie bestehend aus VCR, IFO, ADR, CARBO und VP16 erhielten 34 Patienten (56.6%) in unterschiedlichen Settings (neoadjuvant, adjuvent, salvage). Mit Mitotane wurden insgesamt 32 Patienten behandelt (53.3%). Mitotanebehandlung länger als 6 Monate und Mitotanespiegel >14mg/l waren mit einem sig- nifikant besseren Überleben assoziiert. Patienten mit lokalem Rezidiv hatten eine schlechtere Prognose als Patienten mit Fernmetastasen.
Schlussfolgerung: Die Behandlung von Patienten mit ACC mit Chemotherapie und Mitotane ist eine wichtige Option bei Kindern mit fortge- schrittenem ACC. Eine neoadjuvente Therapie sollte bei Patienten mit primär inkomplett rese- zierbar oder inoperablen Tumoren in Betracht gezogen werden. Tumor Spillage ist eine Indi- kation für systemische Chemo- und Mito- tanetherapie. Alle Kinder mit ACC sollten in pädiatrisch-onkologischen Zentren in enger interdisziplinärer Zusammenarbeit nach ein- heitlichen Therapieprotokollen betreut werden.
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Adrenocortical carcinoma (ACC) is a rare malignant disease of childhood and adolescence, with an incidence of 1.5 per million population per year [13]. As ACC patients have a poor prognosis, with a high percentage developing recurrent disease even after
| age, years (N=60) | |
| mean/median | 7.2/5.9 |
| range | 0.24-17.8 |
| sex, number of patients (N=60) | |
| male | 20 |
| female | 40 |
| prediagnostic symptomatic interval, months (N=53) | |
| mean/median | 13.7/5.2 |
| range | 0.4-147.2 |
| mean male/female | 21.0/10.0 |
| tumor stage, number of patients (N=60) | |
| stage 1 | 5 |
| stage 2 | 26 |
| stage 3 | 4 |
| stage 4 | 25 |
| diagnosis, number of patients (N=60) | |
| ACC | 50 |
| ACx* | 10 |
| central review, children's tumor registry, number/ percentage of patients (N=60) | 45/75% |
| weiss score, mean/range (N=53) | 4/0-9 |
| primary metastasis site, number of patients (N=12) | |
| lymph nodes | 4 |
| lungs | 10 |
| liver | 4 |
| skeleton | 3 |
| central nervous system | 1 |
| surgery, number of patients (N=60) | |
| primary surgery | 48 |
| salvage surgery | 21 |
| inoperable tumor | 4 |
| chemotherapy, number of patients (N=34) | |
| neoadjuvant | 12 |
| adjuvant | 20 |
| salvage | 16 |
| mitotane treatment, number of patients (N=34) | |
| neoadjuvant | 11 |
| adjuvant | 8 |
| salvage | 15 |
| maximum mitotane plasma level, mean/range, mg/l (N=24) | 21.6/3.1-38.3 |
| duration of mitotane therapy, mean/range, months | 9.7/0.16-27.5 |
| percutan radiation, number of patients | 7 |
| mean dosage/range of radiation, Gy | 45/40-56 |
| time to death, mean/range, years (N= 19) | 1.4/0.04-3.7 |
| follow-up period, mean/median/range, years (N=60) | 4.4/3.2/0.1-15 |
*ACx adrenal tumors of unclear dignity
radical surgery [6,15,17], the development of more effective forms of systemic treatment is essential. In 1997, Bucsky et al. initiated the GPOH-MET 97 trial, the first interdisciplinary mul- ticenter trial of treatment of ACC in children and adolescents in Germany [5,22]. In this non-randomized, single-arm study, sys- temic chemotherapy with VCR, IFO, ADR, CARBO, and VP16, as well as mitotane therapy, was integrated into a regimen based on surgery, chemotherapy, and, in some cases, radiotherapy.
Although many studies have been conducted in adults with advanced ACC, relatively few large trials have been conducted in children with ACC [3,4,7,11,19,26]. In recent years, new sec- ond- and third-line therapies, including targeted therapies against tyrosine kinases or growth factors and their receptors, have been developed [2], but most have not been approved for the treatment of children. The aim of this study was to fill this research gap by evaluating and discussing the outcome of pedi- atric ACC patients in Germany treated according to the GPOH- MET-97 protocol, focusing on evaluation of the effectiveness of mitotane therapy as a component of this protocol.
Materials and methods
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Patients
In Germany, almost all children and adolescents with ACC and adrenocortical tumors of unclear dignity (ACx) are treated according to the GPOH-MET 97 protocol [5,22,23]. A detailed analysis of the symptoms and surgical aspects of these patients was recently published [17]. In the trial, 60 patients (~ Table 1), 50 with ACC and 10 with ACx, were treated at 30 different pedi- atric oncological centers.
Study protocol
The study protocol was approved by the ethical board of the Uni- versity of Kiel, Germany (97-125) and informed consent was obtained from all patients. Staging was performed according to the international TNM classification system. For patients with completely resected stage I and II tumors or with completely resected stage III tumors without lymph node involvement (T3, N0, M0), no additional chemotherapy was recommended. For patients with stage III tumors with lymph-node involvement (T1-2, N1, MO), 2 cycles of NN-1 and 2 cycles of NN-2 chemo- therapy with mitotane over a 9-month period were recom- mended. For patients with tumors at higher stages, 4 cycles of NN-1 and 4 cycles of NN-2 chemotherapy with mitotane over an 18-month period were recommended (~ Table 2). For patients with primary unresectable tumors, 2-4 cycles of neoadjuvant chemotherapy with mitotane were recommended to enable subsequent surgery. Since the malignant potential of ACx is unpredictable, all ACx patients were treated in the same manner as ACC patients if not otherwise specified.
| day | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Course NN-1 | Vincristine | 1.5 mg/m2 i. v., maximal single dose 2.0 mg | x | x | ||||||
| Ifosfamide | 1 000 mg/m2 p.i. (1 h) | x | x | x | x | x | ||||
| Adriamycin | 35 mg/m2 p.i. (4h) | x | x | |||||||
| Course NN-2 | Carboplatin | 125 mg/m2 p.i. (1 h) | x | x | x | x | x | |||
| VP-16 | 100 mg/m2 p.i. (2h) | x | x | x | x | x |
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Data collection and analysis
Data were prospectively collected, analyzed, and associated with treatment outcome. Associations between treatment outcome and tumor size, clinical presentation, preoperative management and surgical aspects of treatment have been reported previously [17].
Statistical analysis
All statistical analyses were performed using SPSS v.19 and the results were approved by the study statistician. Explorative anal- yses were performed without correction for p-values of multiple testing. The Mann-Whitney U-test was used for comparison of continuous outcome variables between independent patient groups. Correlations have been assessed and tested with Spear- man’s rank correlation coefficient. 5-year event-free survival (EFS) and overall survival (OS) were calculated by Kaplan-Meier estimation and compared using the log-rank test. P-values <0.05 were considered statistically significant.
Results
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Clinical characteristics
· Table 1 summarizes the clinical characteristics of the 60 patients examined in this study.
Realization of central histological review, which had been achieved for 75.0% of the patients over the entire study period, was characterized by an increase from 61.5% until 2002 to 85.3% from 2003 onward.
The mean tumor size was 471.8 ml (median 169.9ml; range 8.8 ml-3 645 ml) and significantly correlated with age (r’s=0.40, p<0.001). However, ACx patients had significantly smaller tumors than ACC patients (523.4ml vs. 213.8 ml, p=0.02).
Clinical signs of hormone excess (80%) or increased hormonal activity in laboratory testing (88.1%) were found in most patients. The prediagnostic symptomatic interval (PSI) could be estimated from the primary medical reports in 53 patients. The mean time from the first symptoms to diagnosis reported by the patients’ parents had been 13.7 months (median 5.2 months). Although no significant differences were identified in PSI accord- ing to age, diagnosis, year of diagnosis or gender, PSI was found to be twice as long in males compared to females (· Table 1). However, this difference did not reach the level of statistical sig- nificance.
The mean Weiss score (WS) was 4.0 (range 0-9) and significantly higher in ACC patients (n=43, mean WS=4.4) compared to ACx patients (n=10, mean WS=2.6; p=0.002). However, no signifi- cant differences were found between ACC and ACx patients regarding age, gender or tumor size.
12 patients had primary metastases, of whom 10 had lung metastases, 4 liver metastases, 4 lymph-node metastases, 3 bone metastases and 1 central nervous system (CNS) metastasis. During the course of the disease, 14 patients relapsed locally and 23 developed distant metastases, of whom 10 developed liver metastases, 7 lymph-node metastases, 4 skeletal metastases and 2 intracranial metastases.
Surgical treatment
48 patients (80%) had undergone primary surgery. 21 had undergone salvage surgery, 10 due to local relapse and 11 due to metastases. A detailed analysis of pre- and perioperative man- agement with regard to surgical aspects of GPOH-MET patients was recently reported [17].
Chemotherapy
Neoadjuvant chemotherapy had been administered to 12 patients, 11 to treat primarily inoperable tumors and 1 to treat a suspected nephroblastoma (SIOP 93-01 protocol). All 11 patients with primarily inoperable tumors had administered concomi- tant mitotane therapy according to the protocol. In 8 of these patients, subsequent surgical treatment of the tumor after chemotherapy had been possible, with complete removal of the tumor in 5 patients.
Although 29 patients had initially been assigned to receive adju- vant chemotherapy after surgery, in accordance with the proto- col, only 20 patients (69.0%) ultimately received chemotherapy. In 4 patients with stage II tumors, chemotherapy had been administered due to tumor rupture during primary surgery.
Salvage chemotherapy with the GPOH-MET protocol was con- ducted in 16 patients, in 9 to treat local relapse with or without secondary metastases and in 7 to treat secondary metastases without local relapse. 5 patients were treated with salvage chemotherapy after 2-6 cycles of adjuvant chemotherapy. One patient with an initially small tumor (15 ml) and primary liver metastases had undergone 8 additional cycles of GPOH-MET chemotherapy and mitotane therapy after the development of a brain metastasis subsequent to 4 previous adjuvant GPOH-MET cycles. This patient, who had also been administered cranial radiotherapy at a dose of 40 Gy, remains alive 8 years after diag- nosis. Additional 4 patients who had undergone adjuvant GPOH- MET chemotherapy, received different salvage chemotherapy protocols (PEI, TECC, Trophosphamid + VP16, or Taxotere + gem- citabine therapy), but did not survive the disease. 10 patients without chemotherapeutic pretreatment received GPOH-MET chemotherapy inclusive mitotane as salvage protocol. 4 of these patients died 0.6-3.7 years after diagnosis while 6 remained alive 1.2-7.0 years after diagnosis. The mean time from initial diagnosis to initiation of salvage chemotherapy was 0.6 years in patients with local relapse but 1.2 years in patients with second- ary metastases.
Chemotherapy-related adverse events were experienced by 34 patients, including septic episodes during neutropenia (n=5), severe mucositis (n=1), liver toxicity (n=1), and allergic reac- tion to etoposide (n=1). None had experienced a serious adverse event (SAE) that was life threatening or therapy-related mortality.
Mitotane therapy
All patients with primarily inoperable tumors and in a salvage situation received mitotane therapy. However, only 8 of the 29 patients with primary stage III and IV tumors who had initially assigned to receive mitotane therapy according to the protocol had received adjuvant mitotane treatment. Until 2004, measure- ment of mitotane plasma level was difficult and only performed sporadically in different laboratories using different methods. In 2004, HRA Pharma began providing the Lysosafe® service, which allows precise and accurate measurement of mitotane level. Adverse events experienced by 16 patients included gastrointes- tinal symptoms (n=13, 40.6%), neurotoxicity (n=8, 25.0%), and hepatotoxicity (n=1, 6.3%). In 6 patients mitotane therapy was terminated due to gastrointestinal side effects (n=3) or on parental request (n=3).
Radiation therapy
Among the patients who were in a salvage situation, 7 received additional percutaneuos radiation therapy at doses ranging from 40-56Gy (mean 45Gy) to control either local tumor region
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a
b
1.0
1.0
0.9
2003-2011 (N=34; 0.82)
0.9
max mitotane level ≥ 14 mg/l (N=19; 0.68)
0.8
0.8
overall survival OS
0.7
overall survival OS
0.7
0.6
0.6
0.5
1997-2002 (N=26; 0.46)
0.5
0.4
0.4
0.3
0.3
max mitotane level < 14 mg/l
(N=5; 0.20)
0.2
0.2
0.1
0.1
0
Log rank p=0.003
0
Log rank p=0.003
0
2
4
6
8
10
12
14
16
0
2
4
6
8
10
12
years after diagnosis
years after diagnosis
c
1.0
d
1.0
0.9
mitotane treatment ≥6 month
0.9
no event (N=28; 1.0)
0.8
(N=20; 0.60)
0.8
dist. metastases only, no local rec.
overall survival OS
0.7
overall survival OS
0.7
(N=14; 0.68)
0.6
0.6
0.5
0.5
0.4
0.4
local recurrence +/- dist. metast.
(N=14; 0.16)
0.3
mitotane treatment < 6 month
0.3
0.2
(N=10; 0.15)
0.2
0.1
0.1
0
Log rank p < 0.001
inoperable tumors (N=3; 0.00)
0
Log
rank p < 0.001
0
2
4
6
8
10
12
0
2
4
6
8
10
12
14
16
years after diagnosis
years after diagnosis
(n=6) or distant metastases (CNS, n=1; axilla, n=1). 5 of these patients remain alive.
Outcome
In all patients EFS was 43.3% and OS 64.8% respectively. Patients with stage I tumors (n=5) were cured with primary surgery alone. EFS and OS were 43.9% and 70.0%, respectively, in patients with stage II tumors (n=26); 25% and 75%, respectively, in patients with stage III tumors (n=4); and 36% and 51%, respec- tively, in patients with stage IV tumors (n=25). A significant change in OS (p=0.003) but not in EFS (p=0.34) was found between patients diagnosed between 1997 and 2002 and patients diagnosed between 2003 and 2011 (· Fig. 1a). A WS less than 4 and an age younger than 4 years were found to be associated with better OS (85.6% for WS <4 vs. 55.6% for WS ≥4, p=0.032; 82.8% for age <4 years vs. 50.3% for age ≥4 years, p=0.011) but not with better EFS. A tumor volume greater than 300 ml was found to be strongly associated with EFS and OS (60.1% EFS and 80.5% OS with tumor volume ≤300ml vs. 20.8% EFS and 41.7% OS with tumor volume ≥300 ml; p=0.001).
In patients who had been treated with mitotane, an association between outcome and mitotane plasma level as well as duration of mitotane treatment was found. Specifically, the survival of patients with plasma mitotane levels greater than 14mg/l (n=19, mean maximal plasma mitotane level=25.5 mg/l, EFS=26.3%, OS=68.5%) was found to be significantly better than that of patients with plasma mitotane levels below 14 mg/l (n=5, mean maximal mitotane plasma level=7.9mg/l, EFS=0%, OS=20.0%; · Fig. 1b). Treatment with mitotane for more than 6 months (n=20, mean=13.5 months, OS=45%) was found to be
significantly associated with better OS than treatment with mitotane for less than 6 months (n=10, mean=2.2 months, OS=12%; · Fig. 1c). The OS of patients with local relapse, both with and without distant metastases, was found to be signifi- cantly worse (n=14, OS=16.1%) than that of patients with dis- tinct metastases alone (n=14, OS=67.5%; p=0.023; · Fig. 1d).
Discussion
▼
For the last 15 years, children diagnosed with ACC in Germany were treated according to the GPOH-MET 97 protocol. Since ACC is a very rare disease in childhood, all patients should be regis- tered and treated in national trials [12,28]. Surgery has been found to be the most important component of ACC treatment [6]. In a previous study, we demonstrated that preoperative tumor biopsy and tumor rupture or spillage is associated with poor EFS and OS in pediatric ACC patients [17]. In the present study, we found that local tumor recurrence is strongly associ- ated with poor EFS and OS compared to recurrence in the form of distant metastases alone in pediatric ACC patients, independ- ent of initial tumor size. Furthermore, we found that a WS of less than 4 and an age of less than 4 years are associated with better prognosis.
Central histopathological review, which plays a key role in the diagnosis of ACC, was realized for only 75% of the patients exam- ined in this study, but has been approaching 100% in recent years. Currently, different histopathological classification sys- tems [30], staging systems [8,26,27] and therapeutic strategies are used to classify and treat pediatric ACC patients, all of which
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differ from those used for adult ACC patients [1,9,10, 18,20, 24,29]. Adult ACC patients in Germany are registered in the German adrenocortical carcinoma registry and treated accord- ing to the FIRM-ACT trial [11]. Initial results of this trial showed that a combination of etoposide, doxorubicin, cisplatin, and mitotane was more effective than a combination of streptozo- tocin and mitotane. However, the 12-month progression free survival for the favorable group was only 26%, indicating the dif- ferent biological and clinical background in children and adults [11]. Due to the small numbers of newly diagnosed pediatric patients, prospective randomized pediatric trials are only feasi- ble in a European or transatlantic context.
The mean PSI in pediatric ACC patients is very long, having been more than 1 year in the patients examined in this study (· Table 1).
Systemic chemo- and mitotane therapy is indicated for patients with advanced disease or at high risk of tumor recurrence (e.g., due to tumor spillage), but reports of its effectiveness are con- troversial [14, 16,25,26,29]. The International pediatric adreno- cortical tumor registry [21] reported a 54.2% EFS and OS for all patients (n=254), but only a 20% EFS and OS for stage III and IV patients. In contrast to these findings, the GPOH-MET trial reported a 70% OS for all patients.
Due to improvement in supportive therapy and central determi- nation of mitotane plasma levels, acceptance of the use of aggressive chemotherapy protocols and highly toxic mitotane treatment in first line-therapy has increased over recent years. However, because several patients in this study were initially not treated according to the protocol, their EFS rates differ sig- nificantly from OS rates. At the beginning of the trial, the aggres- siveness and danger posed by the disease may have been underestimated by local physicians and parents, resulting in refusal of adjuvant chemo- or mitotane therapy in some cases and, ultimately, decreased EFS.
To examine the impact of mitotane treatment, the influence of mitotane plasma levels and duration of mitotane therapy on dis- ease outcome was investigated. At the beginning of the trial, mitotane was mainly administered by its clinical tolerability. However, as plasma level measurement was initially difficult and non-standardized, overdosage of mitotane with severe side effects often resulted. After the introduction of the Lysosafe® service from HRA Pharma, which provides precise measurement of plasma levels, the extent of noncompliance and therapy drop- out rates markedly decreased. Analysis of these data indicates that mitotane levels greater than 14mg/l and duration of mito- tane therapy for more than 6 months are significantly associated with better OS. However, due to the small number of patients, it was difficult to determine the precise impact of adjuvant mito- tane treatment. Nevertheless, mitotane is the only drug approved for the treatment of ACC, and institutional reports as well as the results of adult studies justify its use in treating pediatric patients with advanced ACC. The impact of chemotherapy with VCR, IFO, ADR, CARBO, and VP16 (· Table 2) was difficult to determine, as conducting randomized trials was not feasible and confounding factors had to be considered. However, the signifi- cant difference found between EFS and OS and the absence of severe life-threatening adverse events during chemotherapy and therapy-related mortality demonstrates the role of systemic chemotherapy, especially in salvage situations.
Local percutaneous radiation therapy had been performed to control local tumor recurrence or distinct metastases in 7 patients. Since postoperative radiotherapy has been found capa-
ble of preventing local recurrence in adult patients in an adju- vant setting [24], its use should be considered in pediatric ACC patients, while remaining aware that careful consideration of its use is required for the significant percentage of these patients who carry p53-germline mutations.
Conclusion
▼
Although systemic chemotherapy and mitotane treatment are important therapeutic options in the treatment of pediatric ACC, a rare disease with a poor prognosis, complete surgical removal of the tumor is crucial for good long-term prognosis. Neoadju- vant chemotherapy including mitotane should be considered in patients with primarily incomplete or inoperable tumors. Tumor spillage during diagnosis and surgical therapy are also indica- tions for adjuvant chemo- and mitotane therapy. All pediatric ACC patients should be treated at pediatric oncological centers by experienced surgeons and oncologists according to a consist- ent protocol in a highly interdisciplinary setting.
Acknowledgements
▼
The authors thank all participating GPOH-MET study centers. The study was supported by the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung), the W. A. Drenck- mann Stiftung, the Peter-Escher-Stiftung and the Magdeburger Förderkreis krebskranker Kinder e.V.
Conflict of interest: The authors have no conflict of interest to disclose.
Affiliations
1 Pediatric Oncology, Otto-von-Guericke-University, Magdeburg, Germany
2 Pediatric Oncology, University Childrens Hospital Münster, Münster, Germany
3 Institut für Pathologie der Universität Kiel, Kiel, Germany
4 Institute of Biometry and Medical Informatics, Otto-von-Guericke- University, Magdeburg, Germany
5 Pediatric Oncology, University of Lübeck, Lübeck, Germany
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