Accepted Manuscript
Pediatric ¡!- [INS][A] -¿ aj !- [/INS] -¿ drenal ¡!- [INS][C] -¿ cj !- [/INS] -¿ ortical ¡! [INS][C] -¿ cj !- [/INS] -¿ arcinomas: Histopathological ¡!- [INS][C] -¿ cj !- [/INS] -¿ riteria and ¡! [INS][C] -¿ cj !- [/INS] -¿ linical ¡!- [INS][T] -¿ ti !- [/INS] -¿ rials. A ¡!- [INS][S] -¿ sj !- [/INS] -¿ ystematic ¡!- [INS][R] -¿ ri !- [/INS] -¿ eview
Contemporary Clinical Trials Design, Methods, and Analysis
Xia Xu, Consolato Sergi
| PII: | S1551-7144(16)30119-7 |
| DOI: | doi: 10.1016/j.cct.2016.07.011 |
| Reference: | CONCLI 1425 |
| To appear in: | Contemporary Clinical Trials |
| Received date: | 22 January 2016 |
| Revised date: | 1 June 2016 |
| Accepted date: | 10 July 2016 |
Please cite this article as: Xu Xia, Sergi Consolato, Pediatric ¡!- [INS][A] -¿ aj !- [/INS]- ¿drenal ¡! [INS][C] -¿ cj !- [/INS] -¿ ortical ¡!- [INS][C] -¿ cj !- [/INS] -¿ arcinomas: Histopatho- logical ¡!- [INS][C] -¿ cj !- [/INS] -¿ riteria and ¡!- [INS][C] -¿ cj !- [/INS] -¿ linical ¡!- [INS][T]- ¿tj !- [/INS] -¿ rials. A ¡!- [INS][S] -¿ sj !- [/INS] -¿ ystematic ¡!- [INS][R] -¿ rj !- [/INS] -¿ eview, Contemporary Clinical Trials (2016), doi: 10.1016/j.cct.2016.07.011
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Pediatric Adrenal Cortical Carcinomas: Histopathological Criteria and Clinical Trials. A Systematic Review
Xia Xu 1-2, Consolato Sergi 2-4
Affiliations:
1 Department of Oncology, University of Alberta
2 Department of Pathology and Laboratory Medicine, University of Alberta
3 Wuhan University of Science and Technology, Wuhan, Hubei, China
4 Department of Pediatrics, University of Alberta
Keywords: Clinical trials, Adrenal Tumors, Childhood
Address for Correspondence
Consolato Sergi, MD, PhD, MPH, FRCPC Department of Lab. Med. & Pathology, University of Alberta 8440 112 Street, T6G 2B7, Edmonton, AB, Canada sergi@ualberta.ca
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Abstract
Adrenal tumors are quite rare in infancy and childhood with the exception of neuroblastoma. In fact, adrenocortical tumors (ACT) account for only 0.2% of all malignant cancers in children and adolescents. According to a multicenter registry investigation, the median interval between first endocrine symptoms and the diagnosis of ACT is 5 months, and death is seen in 38% of patients, who suffer from tumor progression following the diagnosis in about 2 1/2 years. The prognosis of pediatric ACC is poor with a 5-year event-free survival of 54%. To face this dreadful scenario, a few decades ago the International Pediatric Adrenocortical Tumor Registry (IPACTR) was established. Moreover, Children’s Oncology Group (COG) and National Cancer Institute (NCI) have approved several clinical trials designed to investigate new treatment options in pediatric ACT. In this systematic review, we summarize the diagnostic histopathologic criteria, bio-markers, and clinical trials of this challenging diagnosis. Eleven pediatric ACT trials were reviewed in our investigation. Two out of 11 studies were conducted in Brazil showing apparently an increased rate of germline mutation-related pediatric ACT. A heterogeneous methodology was evident with four non-randomized clinical trials, three prospective cohort studies, and four retrospective case-control studies limiting higher statistical approach. Tumor histology remains the backbone to diagnose ACT creating a common investigative platform and potentially supporting studies aiming to increase international collaborative research, which is crucial for this challenging disease.
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Introduction
Adrenal tumors, apart from neuroblastoma, are quite rare in infancy and childhood substantiated by both universal teaching and clinical practice. In infancy and childhood, both benign and malignant tumors may be hormonally active and present clinically with excessive hormone production, which manifests in typical clinical syndromes (1). Adrenocortical carcinoma (ACC) is the rare malignant counterpart of adrenal neo-formations of childhood and adolescence, with an incidence of 1.5 per million per year (2).
Adrenocortical tumors (ACT) account for 0.2% of all malignancies in individuals younger than 20 years (3). The clinical manifestations and biologic behavior of pediatric ACT seem to be distinct from the ACC observed in adulthood. The most common manifestation is virilization, which can occur alone or in combination with other adrenal hormonal imbalances (3). According to a multicenter registry investigation (254 patients), the median interval between first endocrine symptoms and the diagnosis of ACT is 5 months, and 38% patients die due to tumor progression within 2 1/2 years approximately (1). There are no clinical differences between the two genders (4). Pediatric patients with ACT seem to present more endocrine dysfunction features (virilization or feminization) and TP53 mutations compared to adults indicating that there may be a robust association between TP53 mutations and ACT diagnosis in the first decade of life (5). As a fact rescountered in both textbooks and clinical practice, there is still difficulty to discriminate benign from malignant pediatric ACT based on histopathological criteria (4).
The prognosis of pediatric ACC is poor with a 5-year event-free survival of 54% (6). Therefore, an outcry in the scientific and lay communities brought to the creation of some form of new collaboration aiming to establish a systematic
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interdisciplinary consortium among different countries worldwide. A few decades ago was established the International Pediatric Adrenocortical Tumor Registry (IPACTR) to create a new investigative platform (7). IPACTR collects clinical and laboratory features, treatment practices, and outcome data for children with ACT, as well as systematically investigates how to improve patient outcomes. Other organizations such as Children’s Oncology Group (COG) and National Cancer Institute (NCI) have approved several clinical trials designed to investigate new treatment in pediatric ACT (8). In this systematic review, we will summarize the diagnostic criteria, biomarkers, clinical trials and discuss the current challenges, which seem to persist in pediatric ACT.
Material and methods
Histopathological criteria were revised in detail using reviews and studies identified on PubMed and Google Scholar using “histology”, “pathology”, “adrenocortical tumor”, and “review” (See below for details). This initial part should be considered a “narrative review”, while the “clinical trials’ section should be considered a “systematic review”.
To summarize the clinical trials in pediatric ACTs diagnosis, chemotherapy and surgical managements, we systematically searched the published literature in several main online databases including PubMed and government clinical trials databases from US, UK, and Europe. The inclusion standard criterions for literature are: 1) Studies published in the past 30 years from 1985-2015; 2) Studies focused on young patients ACTs and ACCs (age below 30 years old, including infants, children, adolescents and young adults). 3) Studies published in English, only peer reviewed and empirically published.
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After the duplicates were removed, 40 articles remained and considered appropriate according to our inclusion criteria. Both the pediatric ACT trials and solid tumor trials with available results were involved in our review (number=22). After reviewing the full text and screening age range and ACTs cases enrollment, 11 additional articles were classified as ineligible for our study and 11 peer-reviewed articles were included (Figure 1). Upon identification of the articles for review, we analyzed the enrollment number, inclusion criteria, purpose and outcomes of all reviews, which are presented in Table 4.
Histopathological criteria in pediatric adrenocortical carcinoma (ACC) & TP53
The most widely-used and valuable histopathological scoring criteria for predicting the behavior of a malignancy of the adreno-cortical is the so-called Weiss scoring system from the author, who originally identified some criteria to pick up malignant behavior in adrenocortical neoplasia (9, 10) .. Weiss criteria are most commonly utilized for distinguishing between benign and malignant lesions in adults ACT patients (9, 10). Weiss criteria consists of three main categories of parameters: structural (clearing of cells, diffuse pattern in architecture, and tissue necrosis), cytological (nuclear grade, mitoses/50 high power fields, and atypical mitoses), and invasion (venous invasion, sinusoidal invasion, and capsular infiltration) (10). Histopathologic criteria have been associated to endocrine dysfunction, but compared with the adult population, ACC in children more often presents as hormonally functional neoplasia (e.g. virilization), while the most common manifestation of ACC in adults is Cushing’s syndrome. The clinical difference in ACT between the two age groups suggests indeed two distinctive mechanisms of carcinogenesis (11). Two multicenter retrospective analyses in pediatric ACT demonstrated that histological
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features and clinical behaviors were not consistent when Weiss criteria were applied in the pediatric population (12, 13). Therefore, Weiss criteria do not accurately predict clinical outcome and are not entirely applicable to pediatric ACC. Lack of definitive and reliable histopathological criteria for malignancy in the childhood and youth is probably the greatest challenge of this rare diagnosis. In fact, in 2003, Wieneke et al. conducted a retrospective study based on 83 pediatric patients who were diagnosed with adrenocortical neoplasms (4). The aim of this study was to determine whether the adult histopathological scoring system could be straight applied to children. The authors found that 51 of 74 (69%) patients with histologically malignant-appearing tumors behave as a benign clinical manifestation without disease recurrence. A modified scoring system, also known as Wieneke criteria, has been since used. It can be used for evaluating the clinical outcome of children with adrenocortical neoplasms according to 9 histo-morphological features. (Table 1) In Wieneke et al.’s retrospective study, more aggressive clinical management and follow-up has been suggested in patients with a score of >4. Vena cava invasion, necrosis, and increased mitotic activity (>15 mitotic figures/20 high power fields) were shown to be independent factors suggesting malignant clinical behavior in pediatric patients harboring ACT (4).
There have been several studies validating the reliability of the Wieneke scoring system in pediatric ACT (14-16). In 2012, Magro et al. performed a retrospective analysis on 20 pediatric patients with ACT applying the Wieneke criteria (15). The results showed that the scoring system of Wieneke et al. was highly predictive of the clinical outcome. Subsequently, a similar conclusion was also obtained by Dall’Igna et al. and Chatterjee et al. (14, 16). Compared to Weiss criteria, Wieneke criteria have tumor weight, tumor size, inferior vena cava invasion, and
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other histological features resulting in a strong predictor of prognosis in pediatric ACT. Although tumor weight is also an essential parameter in pediatric ACC scoring system, Wieneke et al. and Magro et al. suggested that tumor weight cannot be used alone as a predictor of pediatric ACT malignancy (4, 15). Other gross criteria such as inferior vena cava invasion and periadrenal extension were proven to be 100% specific for the diagnosis of ACC by Chatterjee et al. (16). In addition to the histopathological criteria mentioned in the Wieneke score, another criterion was added by Papotti et al. who reported that focal myxoid stromal changes are also highly distinctive characteristics of ACC in children (17). Wieneke et al. study divided the patients into three groups combining clinical outcome with Weiss pathologic features. They observed that almost all pediatric patients of group B (clinically benign, but malignant pathologically) had good clinical outcome and achieved complete remission in 15-years follow-up (4). Definitely, adult criteria cannot accurately predict the clinical outcome of pediatric ACT and validate the reliability of Wieneke criteria in a pediatric setting.
Pediatric ACT is always associated with some constitutional genetic abnormalities (e.g. TP53). Genetic variations in the tumor suppressor gene TP53 contribute to human cancers in various ways (18). The inheritance of a TP53 mutation causes predisposition to early-onset cancers, including breast carcinomas, ACC, and brain tumors, which are features of Li-Fraumeni syndrome (LFS)(17). Once considered rare, LFS has been recently suggested making up to 17% of all familial cancer cases (19, 20).
The incidence of pediatric ACT is remarkably high in southern Brazil (21, 22). An investigation aiming to screen TP53 mutation in newborns showed that pediatric ACT most frequently occurs in carriers of TP53 mutations (23). Meanwhile, above
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nine out of 10 pediatric ACT patients carry a germline TP53 mutation in southern Brazil (southeast region) (24). Pediatric ACT is associated in Southeast Brazil to a germline Founder TP53 mutation (R337H). The general incidence of TP53 mutations is the highest among patients younger than 4 years and its prevalence declines with age (19). It is not surprising that patients in southern Brazil are diagnosed earlier, as pediatricias of that region are familiar with the first signs of ACT and promptly refer these young patients for treatment and genetic screening for germline TP53 mutations. Therefore, TP53 mutation has been implicated in ACT development and progression. Currently, TP53 mutation screening is not applicable as a worldwide diagnostic criterion of pediatric ACT malignancy. Nevertheless, the strong correlation between TP53 mutations and pediatric ACT merits some consideration for genetic testing of TP53 status in specific settings.
In addition to TP53 screening, there are some investigations focusing on the roles of other biological markers in pediatric ACT that may be paramount in the outcome prediction and distinction between benign and malignant forms. Table 2 summarizes an 11-year (2004-2015) search of biological markers systematic investigation on pediatric ACT.
There are two staging systems of malignancy diseases in adults, including the Tumor, Node, and Metastases (TNM) staging system of the American Joint Committee on Cancer (AJCC), and a modified staging system proposed by the European Network for the Study of Adrenal Tumors (ENSAT) (25). To the best of our knowledge, these two staging system have not been fully considered for children. In 2004, Children’s Oncology Group (COG) modified their previous pediatric ACC staging system based on clinical data from the International Pediatric Adrenocortical Tumor Registry (IPACTR) (1, 26) (Table 3). It seems that the outcome is stage-
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dependent, and the Children’s Oncology Group staging system up-to-date the most widely-used staging classification in pediatric ACC.
Clinical Trials
Among the 11 pediatric ACT trials reviewed in our systematic review, two studies were conducted in Brazil, which seems to have a high prevalence of germline mutation related pediatric ACT. Additional studies were conducted in the United States and Europe (Table 4). The number of observational and interventional studies recruited in our study was 3 and 8, respectively. Different methodologies were represented in the studies, including four non-randomized clinical trials, three prospective cohort studies, and four retrospective case-control studies.
The epidemiologic data regarding disease survival rates were presented in two largest studies, IPACTR(7) and GPOH-MET-97 trial(27). IACTR showed the 5-year event-free survival (EFS) being 54%, while overall survival (OS) was 65% in patients in GPOH-MET-97 trial. From the clinical perspective, disease stage, signs of endocrine dysfunction, and age were independent factors for outcomes in IPACTR study. Similarly, GPOH-MET-97 trial also considered that younger age was a positive prognostic factor in pediatric ACT. Moreover, duration of mitotane treatment >6 month, mitotane levels greater than 14 mg/l, tumor volume less than 300ml, and complete surgical removal were also demonstrated to be strongly associated with better EFS and OS for surgical and chemotherapeutic managements.
In addition to the Germany GPOH-MET-97 protocol, more than half of clinical trials summarized in our review were established to investigate the
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effectiveness of systematic chemotherapy, modified mitotane therapy or novel therapies of this rare cancer. Disease management is stage-dependent, including conventional surgery, adjuvant or neoadjuvant chemotherapy. Generally, mitotane monotherapy and mitotane-based combination therapy (e.g. cisplatin, etoposide, and doxorubicin) were considered as the most widely-used chemotherapy protocols in pediatric patients in advanced stages (stage III and stage IV) or inoperable adrenocortical tumors. It was strongly recommended that should be monitored 1.5 months after the beginning of treatment in order to maintain the levels between 14 and 20 mg/l. Apart from these traditional chemo-regiments, the methe plasma level of mitotane application of anti-IGF-I receptor monoclonal antibody (cixutumumab)(8) and oncolytic virus (Seneca valley virus-001) (49) combined with cyclophosphamide brought new insight into pediatric solid tumor management. The current chemotherapy protocols for pediatric ACC are illustrated in Table 5.
Discussion
Among these 11 clinical trials with various purposes, two largest clinical trials involved in our systematic review were the International Pediatric Adrenocortical Tumor Registry (IPACTR) (7) and the German Adrenocortical Carcinoma Registry (27). These two interdisciplinary multi-central studies in pediatric ACT were based on large population enrollment.
Firstly established in 1990, IPACTR aimed to improve the understanding in clinical and epidemiologic aspect of this kind of tumor (7). This research has a enormous historical significance, because stage classification, histopathologic criteria and prognosis in pediatric ACT were once based on adulthood ACT only for a long time (7). Undoubtelessly, some bias may occur even with the better organized
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investigative platforms. The majority of IPACTR participants were, indeed, from Southern Brazil with more than 90% of pediatric ACT patients showing the germline TP53 mutation (24). This unique TP53 mutation (Arg337His or R337H) may be considered as a biomarker in the diagnosis of pediatric ACT in a suitable clinical and geographical setting, because it has been associated with the distinctive early occurrence and, commonly, used as a predisposing factor for pediatric ACT.
To evaluate the effectiveness of chemotherapy in pediatric ACC management, the GPOH-MET 97 trial was initiated in 1997 by the German Healthcare Regulatory Body (27). In consistency with other studies, mitotane-based chemotherapy was considered as the first line protocol in pediatric ACC. To the best of our knowledge, this is the first clinical trial demonstrating that neoadjuvant chemotherapy including mitotane should be applied in pediatric patients with primarily incomplete or inoperable tumors. Although the impact of chemotherapy with VCR, IFO, ADR, CARBO, and VP16 has not been fully determined in this trial, no chemotherapy- related severe life-threatening adverse events and deaths have been observed.
Substantially, pediatric ACT is a quite rare disease and many challenges still remain. First of all, pediatric ACT patients often receive delayed diagnosis due to the initial asymptomatic onset and undetectable endocrine manifestations (6). Parental awareness of endocrine changes in children is unfortunately imperfect and incorporates often a delay in the diagnostic process. Secondly, adults with ACT tend to have Cushing’s syndrome or nonfunctional tumors at presentation, whereas most pediatric ACT patients have virilizing features. The clinical difference between pediatric and adults ACT suggest two distinctive and possibly different mechanisms of carcinogenesis. Although 80%-90% of pediatric ACT is carcinoma (1), ACC in children presents a less aggressive clinical behavior when compared to their adult
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counterpart. It was demonstrated that many children classified as having carcinoma have, conversely, a benign outcome according to Weiss criteria. Thus, Weiss criteria do not accurately predict clinical outcome. Weiss criteria are not entirely applicable to pediatric tumors. To date, there are three retrospective studies that have validated Wieneke criteria as the most predictable scoring system in pediatric ACC diagnosis and prognosis (14-16). Meanwhile, studies targeting prognostic analysis are still conducted using the Weiss criteria (28-30). Therefore, the number of bias and confounding factors may rise, if these studies are combined. Moreover, an agreement on common prognostic stratification in pediatric ACT has not been reached and this aspect is still challenging public health officials.
Lastly, despite the modifications in the pediatric ACC staging system, there are still additional important prognostic factors in pediatric ACT that are not currently included. One of the largest national retrospective studies observed that in patients aged 4 years or older, extension of the primary disease into adjacent structures, and presence of metastatic disease are significant predictors of outcomes in pediatric ACT (31). The staging system of pediatric malignancies ts complicate (32) (33) and we also consider that several ACT clinical studies emphasizing the age as important predictor in the prognosis of pediatric ACT is key (1, 34).
In conclusion, histopathology is still crucial in discriminating malignancy in pediatric ACT. Compared to Weiss criteria, Wieneke criteria have been shown to be more accurate in predicting clinical malignancy and prognosis in pediatric ACT. The heterogeneity is a permanent marker in the majority of studies we came across in this systematic review underlining and emphasizing that heterogeneity tests need to be done, as this initial investigation involved both different methodologies and different genetic background. Probably, the initial standardization of diagnostic criteria with or
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without molecular biology markers will help in reducing the challenges of this rare pediatric neoplasia. Once this may be targeted successfully, the incorporation of the Cochrane Central Register of Controlled Trials database may help to unify and correctly stratify the pediatric patients.
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childhood adrenocortical carcinoma: mitotane monitoring and tumor regression. Journal of pediatric hematology/oncology. 2006;28(8):513-24.
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46. Hovi L, Wikstrom S, Vettenranta K, Heikkila P, Saarinen-Pihkala UM. Adrenocortical carcinoma in children: a role for etoposide and cisplatin adjuvant therapy? Preliminary report. Medical and pediatric oncology. 2003;40(5):324-6.
47. Malunowicz EM, Ginalska-Malinowska M, Romer TE, Ruszczynska-Wolska A, Dura M. Heterogeneity of urinary steroid profiles in children with adrenocortical tumors. Hormone research. 1995;44(4):182-8.
48. Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Crawford ED. Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study. Cancer. 2000;88(5):1159-65.
49. Reibetanz J, Jurowich C, Erdogan I, Nies C, Rayes N, Dralle H, et al. Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Annals of surgery. 2012;255(2):363-9.
50. Children’s Oncology Group https://clinicaltrials.gov/ct2/show/NCT01048892
51. Children’s Oncology Group https://clinicaltrials.gov/ct2/show/NCT00304070
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Table1: Comparison between Wieneke and Weiss scoring system
Wieneke criteria
Weiss criteria
Tumor weight of >400 g
High nuclear grade
Tumor size >10.5 cm;
>5 mitosis/50 HPF
Extension into peri-adrenal soft tissues and/or adjacent organs
☐ Abnormal mitoses
Invasion into inferior vena cava
<25% clear cells
Venous invasion
>33% diffuse architecture
Capsular invasion
Tumor necrosis
Presence of tumor necrosis
Venous invasion
>15 mitoses per 20 high-power field (400x)
Sinusoid invasion
Presence of atypical mitotic figures
Capsular infiltration
Tablero hudba And Tnerhad ZEMANUSCRIP
Wieneke criteria: Tumors are defined as malignant when ≥ 4 criteria are present; in the presence of 3 or below 3 criteria, tumors are defined undetermined or benign, respectively.
Weiss criteria: The presence of 3 or more criteria correlates with malignancy.
| Stage | Description |
|---|---|
| I | Tumor completely excised with negative margins, tumor weight < 200 g, and absence of metastasis |
| II | Tumor completely excised with negative margins, tumor weight > 200 g, and absence of metastasis |
| III | Residual (presence of microscopic or gross tumor after surgical resection) or inoperable tumor |
| IV | Hematogenous metastasis at clinical presentation |
Table 2: Biology markers investigation in Pediatric ACT
| Study | Purpose | Methods | Results and Conclusion |
|---|---|---|---|
| 1. Angiogenic markers (2012) | Correlate the expression of VEGF and MVD with clinical and prognosis in pediatric ACT. | IHC | Endoglin MVD > 1 mv/field, CD34 MVD < 32 mv/field are associated with poor prognosis; |
| VEGF; CD105 (endoglin); CD34 for MVD (35) Enrollment is 27 | Endoglin and CD34 MVD values are potential histological markers in pediatric ACT. | ||
| 2. Immunomarkers (2006) | Assess the value of histone proteins &mRNA as prognostic markers in pediatric ACT. | In situ hybridization & IHC | Cut off point for malignancy in ACT diagnosis (Labeling indices *: 14.55 for Ki 67 and 5.75 for histone mRNA); |
| Histone mRNA& Ki 67 (36) Enrollment is 30 | Histone mRNA is a valuable marker in predicting the outcomes of pediatric ACT | ||
| 3. Immunomarkers (2005) | Assess the value of IHC markers in | IHC | Specific p53; Ki-67; c-Erb-B2 and Bcl-2 |
| p53; Ki-67; c-Erb-B2; Bcl-2 (37) Enrollment is 33 | predicting the outcomes of pediatric ACT. | IHC analyses could not predict prognosis of ACT in childhood. | |
| 4. Immunomarkers (2012) MMP-2; HLA class II antigens (15) Enrollment is 20 | Evaluate the potential prognostic expression of MMP-2 and HLA class II antigens in pediatric ACT. | IHC | Expression of MMP-2 or the loss of HLA class II antigens does not discriminate between benign and malignant pediatric ACT. |
| 5. Apoptosis-related genes (2012) CASP3, CASP8, CASP9, FAS, TNF, NFKB, and BCL2 (38) Enrollment is 60 | Evaluate the potential prognostic expression of apoptosis-related genes in pediatric ACT. | q-RT-PCR IHC | Association between tumor size ≥100 g and lower BCL2 and TNF levels; between Weiss score ≥3 and lower TNF level; between death and decreased BCL2; Low level of BCL2 and TNF genes suggests a poor prognosis in pediatric ACT. |
| 6. Genes in growth signaling pathways (2012) FGFR4 (39) Enrollment is 25 | Assess the value of FGFR4 as prognostic markers in pediatric ACT. | q-RT-PCR | FGFR4 overexpression is detected in all pediatric ACT except three cases (88%); FGFR4 overexpression is significant in pediatric ACT. |
|---|---|---|---|
| 7. Insulin growth factor receptor (2008) IGF-IR (29) Enrollment is 23 | Assess the value of IGF-IR as prognostic markers in pediatric ACT. | q-RT-PCR | IGF-IR expression is significantly high in pediatric ACC than adenomas (9.1 +/- 3.1 vs. 2.6 +/- 0.3; P = 0.0001); |
| IGF-IR overexpression is a biomarker of pediatric ACC. | |||
| 8. Adrenal cortex development related transcriptional factor (2004) SF-1 (40) (41) Enrollment is 9 and 36, respectively | Evaluate the association between copy number of SF-1 gene and adrenocortical tumorigenesis | FISH Tissue microarray q-RT-PCR | Increased copy number of the SF-1 gene in all 8 cases indicated the association between SF-1 gene copy number and pediatric ACT; Strong nuclear SF-1 expression by tissue microarray in 56% (20 of 36) and increased SF-1 copy number in 47% (8 of 17) in pediatric ACT. |
| 9. Wnt/beta-catenin pathway (2011) Wnt-related genes (e.g. CTNNB1, WNT4, SFRP1, DKK3, AXIN1, TCF7, MYC and WISP2)(42) Enrollment is 62 | Investigate presence of Wnt/B-catenin pathway abnormalities in childhood ACT P | q-RT-PCR IHC | Increased expression of ß-catenin and WISP2 and reduced expression of Wnt inhibitor genes (DKK3, SFRP1, and AXIN1) in pediatric ACT. CTNNB1 mutations are not common in childhood ACT. |
| 10. TP53 and somatic ATP-dependent helicase (ATRX) mutation (2015) Enrollment is 37(43) | Investigate the relationship between key genetic alterations and pediatric ACT initiation, progression | Whole-genome sequencing (WGS); whole- exome sequencing (WES) | Wild-type TP53 are observed in 28 ACTs (76%) Concomitant TP53 and ATRX mutations, associated genomic abnormalities (massive structural variations and frequent background mutations) are prognostic factors for pediatric ACT. |
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*Labeling index (LI) the number of Ki 67- positive tumor cell nuclei / number of histone mRNA-positive tumor cells per 100 tumor cells. Abbreviation: Vascular endothelial growth factor= VEGF; Intratumoral microvessel density =MVD; Immunohistochemistry= IHC; Matrix metalloproteinase 2=MMP-2; Human leucocyte-associated antigen =HLA; Quantitative real-time PCR= q-rt-PCR; Fibroblast growth factor receptor 4= FGFR4; Steroidogenic factor 1=SF-1; fluorescence in situ hybridization=FISH; enzyme immunoassay=EIA; Pheochromocytoma of Adrenal gland Scaled Score= PASS;
ACCLIKLOUŠKOLAVO
Recently, Pinto at al. (Nat Commun. 2015 Mar 6;6:6302. doi: 10.1038/ncomms7302. PubMed PMID: 25743702; PubMed Central PMCID: PMC4352712) analysed 37 ACTs by whole-genome, whole-exome and/or transcriptome sequencing and 91% of the cases showed loss of heterozygosity (LOH) of chromosome 11p, while IGF2 on chromosome 11p was overexpressed in 100% of the tumors and TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in about 3/4 of cases. Moreover, recurrent somatic mutations have been found in ATRX and CTNNB1 and HHV-6 integration (human herpesvirus-6) in chromosome 11p. Interestingly, worse outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities.
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Number of articles from databases from clinical trials. gov (N=30) 1985-2015
Number of additional records from PubMed (N=17), WHO (N=4), UK(N=3) and Europe (N=6) government databases (N=30)
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Number of articles after duplicates removed (N=40)
Articles excluded for not meeting inclusion criteria (only remained completed and recruiting trials with results) (N=18)
Number of articles meeting inclusion criteria for full text review (n=22)
ACCEP
Articles excluded after full text review (N=11)
Final number of articles included (N=11)
Table 4 Clinical trials of ACT in children, adolescents and young adults. (Interventional &Observational)
| Study, Design, Enrollment & Start date | Population Inclusion Criteria | Purposes | Bio specimen or Measures | Results and Conclusions |
|---|---|---|---|---|
| 1.International Pediatric Adrenocortical Tumor Registry (IPACTR) (7) Observational; Prospective cohort study; Enrollment is 67 till 2012 (May 2001 to Dec 2040) | Patients up to 21 years old; 1: Participant suspected /confirmed diagnosis of ACT; 2: Relative of participant with ACT and TP53 mutation who has diagnosis of malignancy; 3: Biological parent of ACT participant. | 1. Learn more about the clinical and epidemiological aspects, treatment modalities, and outcome of pediatric ACT; 2. Clarify the role of the TP53 gene and other genetic pathways in ACT. | 1.Samples with DNA; 2.Peripheral blood sample with DNA and RNA; 3.Tumor tissue; | 1. 62% patients survived; 38% patient died; 2. 5-year event-free survival (EFS) was 54%; 3. Multivariate analysis showed disease stage, endocrine dysfunction signs, and age is independently associated with prognosis. |
| 2. Seneca valley virus- 001 (NTX-010) & cyclophosphamide in young patient with rare tumors. Phase I (50) Interventional; Non-randomized controlled trials; Enrollment is 3/22 (Jan 2010 to Jan 2014) | Patients from 3 Years to 21 Years old; Relapsed/refractory pediatric patients with neuroblastoma, adrenocortical tumor, or other rare tumors with neuroendocrine features. | Study the side effects and best dose of Seneca Valley virus-001 in treating young patients with rare tumors. | 1.Tumor tissue (biomarker studies); 2. Blood and stool samples (for neutralizing antibody and viral clearance studies); 3. Additional blood samples (for presence &permissively of occult tumor cells; | In Phase I NTX-010 is feasible and tolerable at the dose levels in ACT and other rare tumors either alone or in combination with cyclophosphamide. |
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| 3.Trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors. Phase II (8) Interventional; Non-randomized controlled trials; ACC enrollment is 10/116; (Jan 2009 to Oct 2013) | Patients from 7 months to 30 years; 1. Histologically confirmed malignant solid tumor, e.g.ACC 2. Radiographically measurable disease 3. No known CNS metastsis | Study the side effects and how cixutumumab (anti- IGF-I receptor monoclonal antibody) works in treating patients with relapsed or refractory solid tumors (including recurrent ACC) | 1. Blood sample collection and biomarker analysis (e.g. IGF-I, insulin); 2. Response rate and toxicities and pharmacokinetics to cixutumumab; | Cixutumumab is well tolerated in children, adolescents and young adults with refractory solid tumors as a single-agent at 9 mg/kg. |
|---|---|---|---|---|
| 4. German GPOH-MET 97 trial in pediatric ACC (27) Interventional; Non-randomized controlled trials; Enrollment is 60 (1997 to 2012) | Patient from 2 months to 18 years old; Histologically confirmed ACC | 1.Evaluate pediatric ACC patients in Germany treated according to the GPOHMET-97 protocol (Systemic chemotherapy with VCR, IFO, ADR, CARBO, and VP16, and mitotane therapy) 2. Evaluation of mitotane therapy effectiveness | 1. Preoperative tumor size, diagnostic biopsies; 2. Invasive tumor growth and tumor rupture or spillage during operation. | 1. EFS and OS are 43% and 65%; 2. Duration of mitotane treatment >6 months and mitotane levels greater than 14 mg/l are associated with significant better survival; 3.Complete surgical removal of the tumor is crucial for good long- term prognosis; 4. Neoadjuvant chemotherapy mitotane for patients with inoperable tumors; 5. Tumor spillageis are indications for adjuvantchemo and mitotane thearpy. |
| 5. Cisplatin-Based Chemotherapy and/or Surgery in Treating Young Patients With Adrenocortical Tumor. Phase III (51) Interventional; Non-randomized controlled trials; Enrollment is 78 (Sept 2006 to Sept 2015) | Patient from 2 to 11 years old; Histologically confirmed ACC (No previous chemotherapy for adrenocortical carcinoma) | To investigate how well cisplatin-based chemotherapy (mitotane associated with cisplatin, etoposide, doxorubicin) and/or surgery works in treating young patients with stage I to IV ACC. | 1.Event-free survival (EFS); 2.Toxicity associated with mitotane; RIP 3.Feasibility and complications associated with radical adrenalectomy; 4. Frequency of tumor spillage and lymph node involvement; 5. Incidence and type of germline TP53 mutations | No published results. |
| 6. Mitotane associated with cisplatin, etoposide, doxorubicin (CED) in advanced Childhood ACC (44) Interventional; Prospective cohort study; Enrollment is 14 (May 2003 to Nov 2004) | Patient from 2 to 11 years old; Histologically confirmed ACC, not including adrenocortical adenoma. ACCE | To define a mitotane dose for pediatric patients with ACC that maintains therapeutic plasma levels (TL) between 14 and 20 mg/mL and to verify its antitumor efficacy in association with 8 cycles of CED. | 1. Mitotane Assay Patients and drug-free human plasma sample; 2. Steriod level (Testosterone, Dehydroepiandrosterone sulfate and cortisol); 3. Germline TP53 R337H mutation Collect tumor samples; | 1. Mitotane daily dose to maintain TL is variable and monitoring should start 1.5 months after the beginning of treatment; 2. CED combined with mitotane is the best available pharmacologic treatment for pediatric ACC; 3. Mitotane toxic effects are nausea, diarrhea, vomiting, neurologic alterations, gynecomastia, and CED-related hematologic toxic effects. |
| 7. Amplification of the insulin-like growth factor 1 receptor gene is a rare event in ACC: searching for potential mechanisms of overexpression (45) Interventional | Patient from 1 to 18 years old; Histologically confirmed ACC according to Weiss score | To investigate the potential mechanisms involved in IGF1R overexpression in pediatric and adult ACC MANUSZR | 1. Multiplex Ligation- Dependent Probe Amplification (MLPA) IGF1R copy number in ACC and normal adrenal cortex; 2. Real-time PCR; 3. IGF1R sequence analysis; 4. MicroRNAs expression; 5. P53 analysis in genomic DNA; | 1. Amplification and overexpression of IGF1R gene are uncommon in pediatric ACC; 2. IGF1R polymorphisms and abnormal microRNA expression do not correlate with IGF1R upregulation in pediatric ACC. |
| Retrospective case- control study; Enrollment is 25/64 (Jun 2014) | ||||
| 8. ACC in children: a role for etoposide and cisplatin adjuvant therapy? Preliminary report (46) Observational; Retrospective single group study; Enrollment is 5 (1990 to 1999) | Patient from 1.2-21 years old; Histologically confirmed ACC according to Weiss score. | ACCEP To investigate the role of chemotherapy in the management of childhood ACC. | 1. Ultrasound and CT scan; 2. Androgen secretion (plasma dehydroepiandrosterone, DHEA sulfate, testosterone and androstenedione); 3. Glucocorticoid secretion (plasma cortisol and free urinary cortisol); 4. TP53 gene mutation; 5. Glomerular filtration rate (GFR) and serum creatinine; | Chemotherapy with cisplatin and etoposide is well tolerated in pediatric patients. |
| 9. Heterogeneity of urinary steroid profiles in children with adrenocortical tumors (47) Observational; Retrospective case- control study; Enrollment is 11 (1995) | Patient from 0.8-16.5 years old; Histologically confirmed ACT including adrenocortical adenoma. | To investigate the patterns of urinary steroids in children with ACT. MANUSZE | 1.Urinary steroid profiles by gas chromatography (3 beta- hydroxy-5-ene steroids; 11 beta-hydroxyandrosterone); 2. Observe the clinical manifestation; | 1. 8/11 patients had virilization as the predominant feature; 2. 5 patients (3 carcinoma, 2 adenoma) had high level of 3 beta-hydroxy-5-ene steroids; 3. 2 patients (adenomas) had moderately elevated level of 11 beta-hydroxyandrosterone; 4.Urinary steroid pattern is not a reliable indicator of pediatric ACT malignancy. |
| 10. Evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic ACC. Phase II (48) Interventional Prospective cohort study; Enrollment is 45 (children and adults) (Jun 1989 to Dec 1995) | Patient from 12-72 years old; 1.Histologically confirmed ACC; 2. Patients have prior chemotherapy other than mitotane were not included. P | kas,. WIR H To evaluate the response rate to mitotane after disease progression on etoposide and cisplatin in patients with no prior mitotane therapy. | 1. Observe toxicity effect of cisplatin and etoposide; 2. X-ray and computed tomography (CT) for every 3 or 6 weeks to determine the size of measurable lesions. | 1.Combination of cisplatin and etoposide has minimal activity (responses were 11%) in advanced and metastatic ACC. 2. The most common toxic effects were hematologic, gastrointestinal, and neurologic. |
| 11. Impact of lymphadenectomy on the oncologic outcome of patients with ACC by German ACC Registry (49) | Patient from 1-87 years old; 1.Patients included: ENSAT stage I to III, complete resection and a 6 months follow-up; 2. Tumor-related death within 6 months, incomplete resection or distant metastases was excluded; 3. Patients with at least 5 excised LN were classified as LND group. | To investigate the impact of lymphadenectomy on the oncologic outcome of patients with ACC. | Thoracic and abdominal CT scan was performed every 3 months. | 1. Multivariate analysis revealed a significant reduction in both the risk of recurrence (P = 0.042) and disease-related death (P = 0.049) for LND patients when compared with no-LND patients; 2. Locoregional LND (lymph node dissection) improves tumor staging and leads to a favorable oncologic outcome in patients with localized ACC. |
| Interventional; Retrospective case- control study; Enrollment is 283 (children and adults) (1981 to 2009) | ACCEPTED MANUSZRIP |
| Therapy | Protocols | Chemo agents |
|---|---|---|
| 1. GPOH-MET-97 protocol (27) | 1. Adjuvant chemotherapy: Stage III with lymph-node involvement (T1-2, N1, MO): 2 cycles NN-1* and 2 cycles NN-2* plus 9-month mitotane; Higher Stage: 4 cycles NN-1 and 4 cycles NN-2 plus 18-month mitotane; 2. Neoadjuvant* chemotherapy: primary unresectable tumors: 2-4 cycles with mitotane before surgery; 3. Salvage chemotherapy *: local relapse or secondary metastases; | 1. NN-1: Vincristine+ Ifosfamide+ Adriamycin; 2. NN-2: Carboplatin+ VP-16; 3. Salvage chemotherapy protocols (PEI, TECC, Trophosphamid + VP16, or Taxotere+ Gemcitabine) |
| 2. Mitotane-based protocol (44, 48) | 1. Protocol 1: Mitotane+ CED: 8 cycles of CED* in ACC stage III or IV; 2. Protocol 2: Cisplatin and Etoposide followed by Mitotane* in advanced, unresectable, or metastatic ACCs (stage III or IV); | 1: CED: Cisplatin+ Etoposide+ Doxorubicin 2. Mitotane: 1000 mg 4 times/day |
| 3. Cisplatin-based protocol (50) | Chemotherapy+ surgery (Protocol in experimental stratum III) 1. Combination chemotherapy: 8 cycles of Cisplatin, Etoposide* and Doxorubicin hydrochloride, Filgrastim (G-CSF) before surgery (with retroperitoneal lymph node dissection); 2. Mitotane in first 2 to 4 cycles (induction phase) after combainational therapy for 2 months; 3. Conventional surgery after chemotherapy course 2 or 4. | 1. Etoposide other name: VP-16 |
| 4. Cixutumumab *- based Protocol (8) | 1. Relapsed or refractory solid tumors were treated with 9 mg/kg of cixutumumab as a 1-hour IV infusion once weekly, in a 28-day cycle. 2. Recommended phase 2 dose of 9 mg/kg. | 1. Anti-Insulin growth factor like receptor |