- Email: [email protected]
Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan
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Pediatrics and Neonatology xxx (xxxx) xxx
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Original Article
Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan Wei-Yun Hsu a,b, Hsiu-Hao Chang b, Meng-Yao Lu b, Yung-Li Yang b, Shiann-Tarng Jou b, Huey-Ling Chen b, Yen-Hsuan Ni b, Hong-Yuan Hsu b, Mei-Hwei Chang b, Jia-Feng Wu b,* a b
Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
Received Apr 24, 2019; received in revised form Aug 16, 2019; accepted Mar 18, 2020
Available online - - -
Key Words Hepatoblastoma; Risk stratification; SIOPEL
Backgorund: Hepatoblastoma is the most common primary liver malignancy in young children. Methods: To identify predictors of the clinical outcomes of hepatoblastoma, we retrospectively reviewed the medical records of 45 children with hepatoblastoma in the National Taiwan University Hospital from 1998 to 2018. All of the children were classified as high risk according to the pretreatment extent of disease (PRETEXT) staging system. The patients’ clinical data (sex, age at diagnosis, PRETEXT status, presence of metastasis or tumor rupture, tumor pathologic type, and clinical outcomes) were analyzed. Results: A total of 45 children with high-risk hepatoblastoma were diagnosed at an average age of 3.2 years. The survival analysis showed that the event-free survival duration was significantly longer in patients aged 1.25 years at diagnosis than those >1.25 years (hazard ratio Z 2.86, p Z 0.036). The absence of initial tumor rupture was associated with longer event-free survival (hazard ratio Z 2.74, p Z 0.039). Diagnosis at age >1.25 years was correlated with the presence of multifocal liver tumors (p Z 0.0002) and tumor rupture at diagnosis (p Z 0.02). There was no significant difference in event-free survival between the groups classified as intermediate versus high risk according to the Children’s Hepatic tumors International Collaboration hepatoblastoma stratification system (p Z 0.13). Conclusions: Diagnosis at 1.25 years of age and absence of initial tumor rupture were predictive of a good clinical prognosis in Taiwanese children with hepatoblastoma.
* Corresponding author. Department of Pediatrics, National Taiwan University Hospital; No. 8, Chung-Shan S. Rd., Taipei, Taiwan. Fax: þ(886-2)- 23114592. E-mail addresses: [email protected] (W.-Y. Hsu), [email protected] (H.-H. Chang), [email protected] (M.-Y. Lu), [email protected] (Y.-L. Yang), [email protected] (S.-T. Jou), [email protected] (H.-L. Chen), [email protected] (Y.-H. Ni), [email protected] (H.-Y. Hsu), [email protected] (M.-H. Chang), [email protected] (J.-F. Wu). https://doi.org/10.1016/j.pedneo.2020.03.012 1875-9572/Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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W.-Y. Hsu et al Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
1. Introduction Hepatoblastoma is the most common primary liver malignancy in young children, accounting for 1% of all pediatric malignancies, with an annual incidence of approximately 1.5 cases per million.1 Four major study groups; namely, the International Childhood Liver Tumour Strategy Group (SIOPEL), Children’s oncology Group (COG), Japanese Pediatric Liver Tumours Group (JPLT), and German Society for Paediatric Oncology and Haematology (GPOH), have proposed risk stratification systems and undertaken multiple prospective studies on hepatoblastoma (Supplementary Table 1).2 The SIOPEL group introduced the pretreatment extent of disease (PRETEXT) staging system, which is widely used for the management of hepatoblastoma (Supplementary Table 2). In the SIOPEL 2 study of high-risk hepatoblastoma, the complete tumorresection rate after preoperative chemotherapy was 67% and the progression-free survival rate was 48%.3 The SIOPEL 4 study established a new treatment regimen based on dose-dense weekly administration of cisplatin in combination with monthly doxorubicin and radical surgery, which improved the prognosis.4 In the SIOPEL 4 study, the complete tumor resection rate was 79% and the threeyear event-free survival (EFS) rate was 76%.4 Despite the good prognosis, current treatment regimens have documented risks of toxicities, including cisplatin-induced ototoxicity and nephrotoxicity, and doxorubicin-induced cardiomyopathy and hematological toxicity.4 In 2017, the Children’s Hepatic tumors International Collaboration (CHIC) developed a unified global approach to establishing a risk stratification system. The Pediatric Hepatic International Tumor Trial (PHITT) promoted further collaborative prospective trials and investigated whether reductions in therapy reduce the risk of side effects without compromising outcomes.5 The PRETEXT staging system is based on the initial alpha-fetoprotein (AFP) level (cutoff: 100 ng/mL) and metastatic disease for risk stratification, to which the CHIC hepatoblastoma stratification (CHICeHS) system adds VPEFR involvement,3 age at diagnosis (cutoffs: 3 and 8 years of age), and resectability at diagnosis.2 Predictive parameters other than those of the PRETEXT system have also been proposed.6e11 A better risk stratification system to guide the management of hepatoblastoma in children is required. We previously reported that diagnosis at 1.25 years of age is predictive of better overall and native liver survival in a small hepatoblastoma cohort in Taiwan.12 We explored which riskstratification system is superior for outcome prediction in Taiwanese children with SIOPEL high-risk hepatoblastoma.
2. Methods 2.1. Study subjects We enrolled 45 children with SIOPEL high-risk hepatoblastoma diagnosed at the National Taiwan University Hospital (NTUH) from 1998 to 2018 into this retrospective study. The diagnosis of hepatoblastoma was confirmed based on elevated serum alpha-fetoprotein (AFP) levels, typical radiographic images, and liver pathology. Risk stratification of these patients was performed using the SIOPEL PRETEXT classification system (Supplementary table 2) and CHICeHS. According to the CHICeHS, patients with metastatic disease are classified as high risk, irrespective of their other clinical characteristics. Patients of PRETEXT I with VPEFR involvement plus age at diagnosis 8 years, PRETEXT II/III with age at diagnosis 8 years or an AFP level 100 ng/mL, or PRETEXT IV with age at diagnosis 3 years or an AFP level 100 ng/mL, were also classified as high risk. Patients with the following were classified as intermediate risk: PRETEXT I/II with VPEFR involvement, PRETEXT III with an AFP level of 101e1000 ng/mL or >1000 ng/ mL plus VPEFR involvement, and PRETEXT IV. Patients with the following were classified as low risk: PRETEXT I without VPEFR involvement, PRETEXT II/III with age at diagnosis <8 years plus an AFP level >100 ng/mL, and without VPEFR involvement. Those with a resectable tumor at diagnosis were classified as the very low risk group.2 All patients were diagnosed and underwent chemotherapy, surgical intervention, and were followed-up at our institution. Clinical variables such as sex, age at diagnosis, initial disease extent, treatment response, and prognosis (event free survival duration) were also analyzed. The event-free survival (EFS) duration was defined as the time from initiation of primary treatment to the occurrence of any adverse event (including adjustment of the treatment regimen due to disease progression, tumor recurrence, new metastasis, or death). Data collection and medical chart reviews were approved by the Institutional Review Board for Human Subject Research (201809004RIND) of the NTUH.
2.2. Statistical analysis Statistical analyses were performed using STATA (version 14, StataCorp LP, College Station, TX, USA) and MedCalc (version 18.6; MedCalc Software, Ostend, Belgium) software. Categorical data were reported as numbers and percentages of subjects and continuous data as medians (interquartile range). The Chi-squared test or Fisher’s exact test was used to compare categorical variables between
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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Risk stratifications of hepatoblastoma
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two groups. Cox’s proportional hazard model and KaplaneMeier analysis were used for survival analysis. Pairwise correlations between two variables were assessed to determine correlation coefficients and p-values. A pvalue < 0.05 was considered statistically significant.
3. Results
end of follow-up. Two (4.4%) patients had liver transplants and 11 (24.4%) patients failed to achieve tumor-free status. None of these study subjects were lost to follow-up during therapy. None of the patients had BeckwitheWiedemann syndrome or familial adenomatous polyposis. The demographic and clinical parameters of the patients are listed in Tables 1 and 2. Using the CHICeHS risk stratification system, 31 (68.9%) patients were classified as intermediate risk and 14 (31.1%) as high risk (Table 3).
3.1. General characteristics and risk stratification 3.2. Predictors of clinical outcomes From 1998 to 2018, 45 patients (26 males and 19 females) with SIOPEL high-risk hepatoblastoma were managed at our hospital. The median age at diagnosis was 1.2 years (IQR, 0.83e3.33 years), with 24 (53.3%) patients diagnosed at 1.25 years of age. Biopsy of tumor tissue was performed in 44 subjects before chemotherapy and tumor resection was performed in other subjects after neoadjuvant chemotherapy. Histology from the specimens obtained before chemotherapy showed that 34 (75.56%) tumors were epithelial type and 10 (22.22%) were mixed epithelial and mesenchymal type. The initial pathology data were missing in one patient (2.22%), who was diagnosed based on typical image findings and elevated AFP levels. After neo-adjuvant chemotherapy, liver pathology obtained by surgical section was consistent with hepatoblastoma. However, the pathology could not be defined based on the cell type in the specimen obtained after chemotherapy. The distribution of patients according to the PRETEXT category was as follows: PRETEXT I in 2 (4.44%) patients, II in 7 (15.56%), III in 19 (42.22%), and IV in 17 (37.78%). The two PRETEXT I patients suffered from distant metastases and initial tumor rupture at diagnosis. Of the seven PRETEXT II patients, three had initial tumor rupture, three had involvement of the hepatic veins or main portal vein, and one had multifocal liver tumors. Of the patients, 12 (26.7%) received the SIOPEL 2 high-risk regimen, 30 (66.7%) received the SIOPEL 4 regimen, one (2.2%) received the COG regimen (Supplementary Table 1), one (2.2%) underwent surgical resection only, and one (2.2%) died soon after diagnosis due to early tumor rupture and hypovolemic shock. A total of 32 (71.1%) patients received completed tumor resection and 26 (57.8%) patients were event-free at the
We analyzed the clinical outcomes based on survival analysis according to the age at diagnosis (1.25 vs. > 1.25 years) and CHICeHS risk stratification system. Those with a younger diagnostic age (1.25 years vs. > 1.25 years) showed a better event-free survival rate (75% vs. 38%) at the end of follow-up (odds ratio Z 4.87; confidence interval Z 1.39e17.07) (Table 4). Cox proportional hazard analysis also showed that the EFS duration was significantly longer in patients aged 1.25 years at diagnosis compared with those aged >1.25 years (hazard ratio [HR] Z 2.86; 95% confidence interval [CI] Z 1.07e7.65; p Z 0.036). Absence of initial tumor rupture was associated with a longer EFS duration (HR Z 2.74; 95% CI Z 1.05e7.16; p Z 0.039). KaplaneMeier analysis of these two predictors yielded consistent results (Figs. 1 and 2). Notably, diagnosis at > 1.25 years of age was positively correlated with multifocal liver tumors and tumor rupture at initial diagnosis
Table 2 Distribution of histological sub-type of the study population before chemotherapy. Histology, n (%)
Study population (n Z 45)
Epithelial type, n (%) Fetal Mixed fetal & embryonal Macrotrabecular pattern Small cell Mixed epithelial & mesenchymal, n (%) Unidentifiable, n (%)
34 (75.5%) 18 (40%) 13 (28.9%) 2 (4.4%) 1 (2.2%) 10 (22.2%) 1 (2.2%)
Table 1 Demographic characteristics and treatments of the 45 patients with the International Childhood Liver Tumours Strategy Group (SIOPEL) high-risk hepatoblastoma.
Sex and age Male, n (%) Age, mean SD (median, IQR), y Rupture or metastasis, n (%) Resectable at diagnosis, n (%) Treatment regimen, n Z 45 SIOPEL 2 HR, n Z 12 (26.7%) SIOPEL 4, n Z 30 (66.7%) Others, n Z 3 (6.7%)
PRETEXT I (n Z 2)
PRETEXT II (n Z 7)
PRETEXT III (n Z 19)
PRETEXT IV (n Z 17)
1 (50%) 2.38 2.65 (2.38, 0.5e4.25) 2 (100%) 1 (50%)
5 (71.4%) 1.14 0.69 (1, 0.75e2) 3 (42.9%) 0 (0%)
11 (57.9%) 3.2 3.83 (1.17, 0.83e3.33) 4 (21.1%) 3 (15.8%)
9 (52.9%) 4.15 4.45 (1.5, 0.92e6.25) 7 (41.2%) 0 (0%)
0 1 (50%) 1 (50%)
2 (28.57%) 5 (71.43%) 0
6 (31.58%) 12 (63.16%) 1 (5.26%)
4 (23.53%) 12 (70.59%) 1 (5.88%)
PRETEXT, The Pretreatment Extent of Disease; SIOPEL, the International Childhood Liver Tumours Strategy Group; HR, high-risk.
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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W.-Y. Hsu et al Table 3 Risk stratification according to the Children’s Hepatic tumors International CollaborationdHepatoblastoma Stratification (CHICeHS) system. CHICeHS classification
Male gender, % Age, mean SD (median, IQR), y
Table 4
P
Intermediate risk (n Z 31)
High risk (n Z 14)
20 (64.52%) 1.37 1.04 (1.08, 0.75e2)
6 (42.86%) 7.26 4.55 (8.67, 2.5e10.5)
0.17 0.0002
Prognosis of hepatoblastoma children with different diagnostic age. Diagnostic age
Event-free survival, n (%)
1.25 years of age (n Z 24)
>1.25 years of age (n Z 21)
18 (75%)
8 (38%)
(correlation coefficients Z 0.53 and 0.34; p Z 0.0002 and 0.02, respectively) according to Pair wise correlation analysis. There was no significant difference in EFS duration between the CHICeHS intermediate- and high-risk groups (HR Z 2.07; 95% CI Z 0.81e5.27; p Z 0.13) (Fig. 3) or according to PRETEXT stage (HR Z 1.52; 95% CI Z 0.81e2.86; p Z 0.19) or presence of metastatic disease at diagnosis (HR Z 1.39; 95% CI Z 0.74e2.62; p Z 0.30).
OR (95% CI)
p
4.87 (1.39e17.07)
0.013
Age at diagnosis 1.25 years was correlated with the EFS duration, absence of multifocal tumors, and absence of tumor rupture in Taiwanese children with hepatoblastoma. In addition, age at diagnosis 1.25 years and absence of initial tumor rupture were significant predictors of longer EFS duration in our cohort. There was no significant difference in EFS duration between the CHICeHS
intermediate- and high-risk groups. Reductions in therapy as per the PHITT suggestion should be considered with caution in Taiwanese patients. Hepatoblastoma is the most common primary liver malignancy in children and is typically diagnosed before 6 years of age.13 The age-standardized incidence rate of hepatoblastoma in Taiwan is 0.76 per million person-years, peaking at 0e4 years of age (7.3 per million personyears).14 Most cases of hepatoblastoma are sporadic, whereas some are associated with BeckwitheWiedemann syndrome or familial adenomatous polyposis.15e17 Multicenter studies have proposed various staging systems for hepatoblastoma. Several factors at diagnosis, including age, tumor resectability, metastatic disease, AFP expression, and portal or hepatic venous involvement, reportedly have prognostic significance. Furthermore, histological type and the expression of certain genes are also associated with the prognosis of hepatoblastoma.8e11 Four multicenter prospective controlled studies of hepatoblastoma (COG, SIOPEL, GPOH, and JPLT) joined the CHIC consortium in 2016.18 Patient variables used in eight
Fig. 1 KaplaneMeier plot showing that the event-free survival duration was significantly longer in hepatoblastoma patients aged 1.25 years at diagnosis compared with those >1.25 years (p Z 0.017).
Fig. 2 The event-free survival duration was significantly longer in hepatoblastoma patients without than in those with initial tumor rupture (p Z 0.012).
4. Discussion
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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Risk stratifications of hepatoblastoma
Fig. 3 There was no significant difference in the event-free survival rate between the Children’s Hepatic tumors International CollaborationdHepatoblastoma Stratification (CHICeHS) intermediate- and high-risk groups according to KaplaneMeier analysis (p > 0.05).
studies of hepatoblastoma were pooled to create a database of 1,605 cases treated over a 25-year period.2,18 The CHICeHS risk stratification system incorporates the AFP level (cutoff 100 ng/mL), PRETEXT stage, and presence of metastasis, as well as VPEFR involvement, resectability at diagnosis, and age at diagnosis (cutoffs: 3 and 8 years).2 Using the five-year EFS rate as the primary outcome, the CHICeHS defined very low-, low-, intermediate-, and highrisk groups.2 According to CHICeHS risk stratification system, patients with metastatic disease are classified as high risk irrespective of their other clinical characteristics. Patients of PRETEXT I with VPEFR involvement plus age at diagnosis 8 years, PRETEXT II/III with age at diagnosis 8 years or an AFP level 100 ng/mL, or PRETEXT IV with age at diagnosis 3 years or an AFP level 100 ng/mL are also classified as high risk. Patients with the following are classified as intermediate risk: PRETEXT I/II with VPEFR involvement, PRETEXT III with an AFP level of 101e1,000 ng/mL or >1000 ng/mL plus VPEFR involvement, and PRETEXT IV.2 Based on the classification rule, all patients were in the intermediate or high risk group. This result may be related to the high rate of VPEFR involvement in PRETEXT I and PRETEXT II patients, and because the majority of our patients (80%) were PRETEXT III or IV. All patients in the study were originally classified as SIOPEL high risk group and received the SIOPEL 2 HR or SIOPEL 4 regimen treatment. The EFS rates of our study cohort are similar to the reported outcomes of the SIOPEL 2 HR and SIOPEL 4 regimen (Supplementary Table 1). Using the CHICeHS system, these SIOPEL high-risk subjects may be further classified into CHICeHS intermediate and high-risk groups. However, there was no significant difference in EFS duration between the CHICeHS intermediate- and high-risk groups. Based on our results, reductions in current therapy may compromise the prognosis in these SIOPEL high risk cases. In our previous study of 31 patients, a cutoff age at diagnosis 1.25 years showed the best prediction of
5 survival for patients with their native liver. In 2017, the Children’s Hepatic tumors International Collaboration (CHIC) developed a unified global approach and recruited data from 1,605 patients. The study demonstrated a predictive factor-diagnostic age cutoff of 3- and 8-years, which was different from our previous study. In this study, we included 45 patients and confirmed that diagnostic age with a cutoff 1.25 years is a powerful predictor of a good prognosis in Taiwanese patients. The absence of initial tumor rupture was also predictive of a good clinical outcome. Diagnosis at > 1.25 years of age was significantly correlated with multifocal liver tumors and initial tumor rupture, suggesting that delayed diagnosis leads to disease progression prior to treatment initiation, resulting in a worse prognosis. This study had several limitations. The sample size was relatively small and the follow-up time relatively short. Further large-scale, long-term follow-up studies are needed to identify other factors predictive of the clinical outcomes of Taiwanese children with hepatoblastoma. Low AFP level (100 ng/mL) at diagnosis was considered a poor prognostic factor in hepatoblastoma children.2e5 However, there was only one hepatoblastoma patient with an initial low AFP level (100 ng/mL) in our study cohort. This patient achieved event-free survival for 1.21 years until the end of data analysis. Hence, we did not have adequate statistical power to assess the prognostic role of low AFP (100 ng/mL) in our cohort.
5. Conclusion In this study, age at diagnosis 1.25 years and absence of initial tumor rupture were predictive of a good clinical prognosis in Taiwanese children with hepatoblastoma. There was no significant difference in EFS duration between the CHICeHS intermediate- and high-risk groups.
Declaration of Competing Interest There is no conflict of interest.
Acknowledgements The study was supported by the National Taiwan University Hospital (NTUH 103-P02), and Taiwan Children Liver Foundation.
References 1. Spector LG, Birch J. The epidemiology of hepatoblastoma. Pediatr Blood Cancer 2012;59:776e9. 2. Meyers RL, Maibach R, Hiyama E, Ha ¨berle B, Krailo M, Rangaswami A, et al. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s Hepatic tumors International Collaboration. Lancet Oncol 2017;18: 122e31. 3. Perilongo G, Shafford E, Maibach R, Aronson D, Brugie `res L, Brock P, et al. Risk-adapted treatment for childhood hepatoblastoma: final report of the second study of the International Society of Paediatric OncologydSIOPEL 2. Eur J Cancer 2004; 40:411e21.
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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6 4. Zsiros J, Brugieres L, Brock P, Roebuck D, Maibach R, Zimmermann A, et al. Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 2013;14:834e42. 5. Moroz V, Morland B, Tiao G, Hiyama E, Kearns P, Wheatley K. The paediatric hepatic international tumour trial (PHITT): clinical trial design in rare disease. Trials 2015;16:P224. 6. Meyers RL, Rowland JR, Krailo M, Chen Z, Katzenstein HM, Malogolowkin MH. Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2009;53:1016e22. 7. Fuchs J, Rydzynski J, Von Schweinitz D, Bode U, Hecker H, Weinel P, et al. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer 2002;95:172e82. 8. von Schweinitz D. Hepatoblastoma: recent developments in research and treatment. Semin Pediatr Surg 2012;21:21e30. 9. Wu JF, Lee CH, Chen HL, Ni YH, Hsu HY, Sheu JC, et al. Copynumber variations in hepatoblastoma associate with unique clinical features. Hepatol Int 2013;7:208e14. 10. Cairo S, Armengol C, De Reynie `s A, Wei Y, Thomas E, Renard CA, et al. Hepatic stem-like phenotype and interplay of Wnt/b-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell 2008;14:471e84. 11. Cairo S, Wang Y, de Reynie `s A, Duroure K, Dahan J, Redon MJ, et al. Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Proc Natl Acad Sci U S A 2010;107: 20471e6.
W.-Y. Hsu et al 12. Wu JF, Chang HH, Lu MY, Jou ST, Chang KC, Ni YH, et al. Prognostic roles of pathology markers immunoexpression and clinical parameters in Hepatoblastoma. J Biomed Sci 2017;24: 62. 13. Hiyama E. Pediatric hepatoblastoma: diagnosis and treatment. Transl Pediatr 2014;3:293e9. 14. Hung GY, Lin LY, Yu TY, Lee CY, Yen HJ, Horng JL. Hepatoblastoma incidence in Taiwan: a population-based study. J Chin Med Assoc 2018;81:541e7. 15. Cohen Jr MM. Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenetic perspectives. Pediatr Dev Pathol 2005;8:287e304. 16. Garber JE, Li FP, Kingston JE, Krush AJ, Strong LC, Finegold MJ, et al. Hepatoblastoma and familial adenomatous polyposis. J Natl Cancer Inst 1988;80:1626e8. 17. Maas SM, Vansenne F, Kadouch DJ, Ibrahim A, Bliek J, Hopman S, et al. Phenotype, cancer risk, and surveillance in BeckwitheWiedemann syndrome depending on molecular genetic subgroups. Am J Med Genet A 2016;170:2248e60. 18. Czauderna P, Haeberle B, Hiyama E, Rangaswami A, Krailo M, Maibach R, et al. The Children’s Hepatic tumors International Collaboration (CHIC): novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer 2016;52:92e101.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.pedneo.2020.03.012.
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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Pediatrics and Neonatology xxx (xxxx) xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.pediatr-neonatol.com
Original Article
Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan Wei-Yun Hsu a,b, Hsiu-Hao Chang b, Meng-Yao Lu b, Yung-Li Yang b, Shiann-Tarng Jou b, Huey-Ling Chen b, Yen-Hsuan Ni b, Hong-Yuan Hsu b, Mei-Hwei Chang b, Jia-Feng Wu b,* a b
Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
Received Apr 24, 2019; received in revised form Aug 16, 2019; accepted Mar 18, 2020
Available online - - -
Key Words Hepatoblastoma; Risk stratification; SIOPEL
Backgorund: Hepatoblastoma is the most common primary liver malignancy in young children. Methods: To identify predictors of the clinical outcomes of hepatoblastoma, we retrospectively reviewed the medical records of 45 children with hepatoblastoma in the National Taiwan University Hospital from 1998 to 2018. All of the children were classified as high risk according to the pretreatment extent of disease (PRETEXT) staging system. The patients’ clinical data (sex, age at diagnosis, PRETEXT status, presence of metastasis or tumor rupture, tumor pathologic type, and clinical outcomes) were analyzed. Results: A total of 45 children with high-risk hepatoblastoma were diagnosed at an average age of 3.2 years. The survival analysis showed that the event-free survival duration was significantly longer in patients aged 1.25 years at diagnosis than those >1.25 years (hazard ratio Z 2.86, p Z 0.036). The absence of initial tumor rupture was associated with longer event-free survival (hazard ratio Z 2.74, p Z 0.039). Diagnosis at age >1.25 years was correlated with the presence of multifocal liver tumors (p Z 0.0002) and tumor rupture at diagnosis (p Z 0.02). There was no significant difference in event-free survival between the groups classified as intermediate versus high risk according to the Children’s Hepatic tumors International Collaboration hepatoblastoma stratification system (p Z 0.13). Conclusions: Diagnosis at 1.25 years of age and absence of initial tumor rupture were predictive of a good clinical prognosis in Taiwanese children with hepatoblastoma.
* Corresponding author. Department of Pediatrics, National Taiwan University Hospital; No. 8, Chung-Shan S. Rd., Taipei, Taiwan. Fax: þ(886-2)- 23114592. E-mail addresses: [email protected] (W.-Y. Hsu), [email protected] (H.-H. Chang), [email protected] (M.-Y. Lu), [email protected] (Y.-L. Yang), [email protected] (S.-T. Jou), [email protected] (H.-L. Chen), [email protected] (Y.-H. Ni), [email protected] (H.-Y. Hsu), [email protected] (M.-H. Chang), [email protected] (J.-F. Wu). https://doi.org/10.1016/j.pedneo.2020.03.012 1875-9572/Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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W.-Y. Hsu et al Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
1. Introduction Hepatoblastoma is the most common primary liver malignancy in young children, accounting for 1% of all pediatric malignancies, with an annual incidence of approximately 1.5 cases per million.1 Four major study groups; namely, the International Childhood Liver Tumour Strategy Group (SIOPEL), Children’s oncology Group (COG), Japanese Pediatric Liver Tumours Group (JPLT), and German Society for Paediatric Oncology and Haematology (GPOH), have proposed risk stratification systems and undertaken multiple prospective studies on hepatoblastoma (Supplementary Table 1).2 The SIOPEL group introduced the pretreatment extent of disease (PRETEXT) staging system, which is widely used for the management of hepatoblastoma (Supplementary Table 2). In the SIOPEL 2 study of high-risk hepatoblastoma, the complete tumorresection rate after preoperative chemotherapy was 67% and the progression-free survival rate was 48%.3 The SIOPEL 4 study established a new treatment regimen based on dose-dense weekly administration of cisplatin in combination with monthly doxorubicin and radical surgery, which improved the prognosis.4 In the SIOPEL 4 study, the complete tumor resection rate was 79% and the threeyear event-free survival (EFS) rate was 76%.4 Despite the good prognosis, current treatment regimens have documented risks of toxicities, including cisplatin-induced ototoxicity and nephrotoxicity, and doxorubicin-induced cardiomyopathy and hematological toxicity.4 In 2017, the Children’s Hepatic tumors International Collaboration (CHIC) developed a unified global approach to establishing a risk stratification system. The Pediatric Hepatic International Tumor Trial (PHITT) promoted further collaborative prospective trials and investigated whether reductions in therapy reduce the risk of side effects without compromising outcomes.5 The PRETEXT staging system is based on the initial alpha-fetoprotein (AFP) level (cutoff: 100 ng/mL) and metastatic disease for risk stratification, to which the CHIC hepatoblastoma stratification (CHICeHS) system adds VPEFR involvement,3 age at diagnosis (cutoffs: 3 and 8 years of age), and resectability at diagnosis.2 Predictive parameters other than those of the PRETEXT system have also been proposed.6e11 A better risk stratification system to guide the management of hepatoblastoma in children is required. We previously reported that diagnosis at 1.25 years of age is predictive of better overall and native liver survival in a small hepatoblastoma cohort in Taiwan.12 We explored which riskstratification system is superior for outcome prediction in Taiwanese children with SIOPEL high-risk hepatoblastoma.
2. Methods 2.1. Study subjects We enrolled 45 children with SIOPEL high-risk hepatoblastoma diagnosed at the National Taiwan University Hospital (NTUH) from 1998 to 2018 into this retrospective study. The diagnosis of hepatoblastoma was confirmed based on elevated serum alpha-fetoprotein (AFP) levels, typical radiographic images, and liver pathology. Risk stratification of these patients was performed using the SIOPEL PRETEXT classification system (Supplementary table 2) and CHICeHS. According to the CHICeHS, patients with metastatic disease are classified as high risk, irrespective of their other clinical characteristics. Patients of PRETEXT I with VPEFR involvement plus age at diagnosis 8 years, PRETEXT II/III with age at diagnosis 8 years or an AFP level 100 ng/mL, or PRETEXT IV with age at diagnosis 3 years or an AFP level 100 ng/mL, were also classified as high risk. Patients with the following were classified as intermediate risk: PRETEXT I/II with VPEFR involvement, PRETEXT III with an AFP level of 101e1000 ng/mL or >1000 ng/ mL plus VPEFR involvement, and PRETEXT IV. Patients with the following were classified as low risk: PRETEXT I without VPEFR involvement, PRETEXT II/III with age at diagnosis <8 years plus an AFP level >100 ng/mL, and without VPEFR involvement. Those with a resectable tumor at diagnosis were classified as the very low risk group.2 All patients were diagnosed and underwent chemotherapy, surgical intervention, and were followed-up at our institution. Clinical variables such as sex, age at diagnosis, initial disease extent, treatment response, and prognosis (event free survival duration) were also analyzed. The event-free survival (EFS) duration was defined as the time from initiation of primary treatment to the occurrence of any adverse event (including adjustment of the treatment regimen due to disease progression, tumor recurrence, new metastasis, or death). Data collection and medical chart reviews were approved by the Institutional Review Board for Human Subject Research (201809004RIND) of the NTUH.
2.2. Statistical analysis Statistical analyses were performed using STATA (version 14, StataCorp LP, College Station, TX, USA) and MedCalc (version 18.6; MedCalc Software, Ostend, Belgium) software. Categorical data were reported as numbers and percentages of subjects and continuous data as medians (interquartile range). The Chi-squared test or Fisher’s exact test was used to compare categorical variables between
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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Risk stratifications of hepatoblastoma
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two groups. Cox’s proportional hazard model and KaplaneMeier analysis were used for survival analysis. Pairwise correlations between two variables were assessed to determine correlation coefficients and p-values. A pvalue < 0.05 was considered statistically significant.
3. Results
end of follow-up. Two (4.4%) patients had liver transplants and 11 (24.4%) patients failed to achieve tumor-free status. None of these study subjects were lost to follow-up during therapy. None of the patients had BeckwitheWiedemann syndrome or familial adenomatous polyposis. The demographic and clinical parameters of the patients are listed in Tables 1 and 2. Using the CHICeHS risk stratification system, 31 (68.9%) patients were classified as intermediate risk and 14 (31.1%) as high risk (Table 3).
3.1. General characteristics and risk stratification 3.2. Predictors of clinical outcomes From 1998 to 2018, 45 patients (26 males and 19 females) with SIOPEL high-risk hepatoblastoma were managed at our hospital. The median age at diagnosis was 1.2 years (IQR, 0.83e3.33 years), with 24 (53.3%) patients diagnosed at 1.25 years of age. Biopsy of tumor tissue was performed in 44 subjects before chemotherapy and tumor resection was performed in other subjects after neoadjuvant chemotherapy. Histology from the specimens obtained before chemotherapy showed that 34 (75.56%) tumors were epithelial type and 10 (22.22%) were mixed epithelial and mesenchymal type. The initial pathology data were missing in one patient (2.22%), who was diagnosed based on typical image findings and elevated AFP levels. After neo-adjuvant chemotherapy, liver pathology obtained by surgical section was consistent with hepatoblastoma. However, the pathology could not be defined based on the cell type in the specimen obtained after chemotherapy. The distribution of patients according to the PRETEXT category was as follows: PRETEXT I in 2 (4.44%) patients, II in 7 (15.56%), III in 19 (42.22%), and IV in 17 (37.78%). The two PRETEXT I patients suffered from distant metastases and initial tumor rupture at diagnosis. Of the seven PRETEXT II patients, three had initial tumor rupture, three had involvement of the hepatic veins or main portal vein, and one had multifocal liver tumors. Of the patients, 12 (26.7%) received the SIOPEL 2 high-risk regimen, 30 (66.7%) received the SIOPEL 4 regimen, one (2.2%) received the COG regimen (Supplementary Table 1), one (2.2%) underwent surgical resection only, and one (2.2%) died soon after diagnosis due to early tumor rupture and hypovolemic shock. A total of 32 (71.1%) patients received completed tumor resection and 26 (57.8%) patients were event-free at the
We analyzed the clinical outcomes based on survival analysis according to the age at diagnosis (1.25 vs. > 1.25 years) and CHICeHS risk stratification system. Those with a younger diagnostic age (1.25 years vs. > 1.25 years) showed a better event-free survival rate (75% vs. 38%) at the end of follow-up (odds ratio Z 4.87; confidence interval Z 1.39e17.07) (Table 4). Cox proportional hazard analysis also showed that the EFS duration was significantly longer in patients aged 1.25 years at diagnosis compared with those aged >1.25 years (hazard ratio [HR] Z 2.86; 95% confidence interval [CI] Z 1.07e7.65; p Z 0.036). Absence of initial tumor rupture was associated with a longer EFS duration (HR Z 2.74; 95% CI Z 1.05e7.16; p Z 0.039). KaplaneMeier analysis of these two predictors yielded consistent results (Figs. 1 and 2). Notably, diagnosis at > 1.25 years of age was positively correlated with multifocal liver tumors and tumor rupture at initial diagnosis
Table 2 Distribution of histological sub-type of the study population before chemotherapy. Histology, n (%)
Study population (n Z 45)
Epithelial type, n (%) Fetal Mixed fetal & embryonal Macrotrabecular pattern Small cell Mixed epithelial & mesenchymal, n (%) Unidentifiable, n (%)
34 (75.5%) 18 (40%) 13 (28.9%) 2 (4.4%) 1 (2.2%) 10 (22.2%) 1 (2.2%)
Table 1 Demographic characteristics and treatments of the 45 patients with the International Childhood Liver Tumours Strategy Group (SIOPEL) high-risk hepatoblastoma.
Sex and age Male, n (%) Age, mean SD (median, IQR), y Rupture or metastasis, n (%) Resectable at diagnosis, n (%) Treatment regimen, n Z 45 SIOPEL 2 HR, n Z 12 (26.7%) SIOPEL 4, n Z 30 (66.7%) Others, n Z 3 (6.7%)
PRETEXT I (n Z 2)
PRETEXT II (n Z 7)
PRETEXT III (n Z 19)
PRETEXT IV (n Z 17)
1 (50%) 2.38 2.65 (2.38, 0.5e4.25) 2 (100%) 1 (50%)
5 (71.4%) 1.14 0.69 (1, 0.75e2) 3 (42.9%) 0 (0%)
11 (57.9%) 3.2 3.83 (1.17, 0.83e3.33) 4 (21.1%) 3 (15.8%)
9 (52.9%) 4.15 4.45 (1.5, 0.92e6.25) 7 (41.2%) 0 (0%)
0 1 (50%) 1 (50%)
2 (28.57%) 5 (71.43%) 0
6 (31.58%) 12 (63.16%) 1 (5.26%)
4 (23.53%) 12 (70.59%) 1 (5.88%)
PRETEXT, The Pretreatment Extent of Disease; SIOPEL, the International Childhood Liver Tumours Strategy Group; HR, high-risk.
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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W.-Y. Hsu et al Table 3 Risk stratification according to the Children’s Hepatic tumors International CollaborationdHepatoblastoma Stratification (CHICeHS) system. CHICeHS classification
Male gender, % Age, mean SD (median, IQR), y
Table 4
P
Intermediate risk (n Z 31)
High risk (n Z 14)
20 (64.52%) 1.37 1.04 (1.08, 0.75e2)
6 (42.86%) 7.26 4.55 (8.67, 2.5e10.5)
0.17 0.0002
Prognosis of hepatoblastoma children with different diagnostic age. Diagnostic age
Event-free survival, n (%)
1.25 years of age (n Z 24)
>1.25 years of age (n Z 21)
18 (75%)
8 (38%)
(correlation coefficients Z 0.53 and 0.34; p Z 0.0002 and 0.02, respectively) according to Pair wise correlation analysis. There was no significant difference in EFS duration between the CHICeHS intermediate- and high-risk groups (HR Z 2.07; 95% CI Z 0.81e5.27; p Z 0.13) (Fig. 3) or according to PRETEXT stage (HR Z 1.52; 95% CI Z 0.81e2.86; p Z 0.19) or presence of metastatic disease at diagnosis (HR Z 1.39; 95% CI Z 0.74e2.62; p Z 0.30).
OR (95% CI)
p
4.87 (1.39e17.07)
0.013
Age at diagnosis 1.25 years was correlated with the EFS duration, absence of multifocal tumors, and absence of tumor rupture in Taiwanese children with hepatoblastoma. In addition, age at diagnosis 1.25 years and absence of initial tumor rupture were significant predictors of longer EFS duration in our cohort. There was no significant difference in EFS duration between the CHICeHS
intermediate- and high-risk groups. Reductions in therapy as per the PHITT suggestion should be considered with caution in Taiwanese patients. Hepatoblastoma is the most common primary liver malignancy in children and is typically diagnosed before 6 years of age.13 The age-standardized incidence rate of hepatoblastoma in Taiwan is 0.76 per million person-years, peaking at 0e4 years of age (7.3 per million personyears).14 Most cases of hepatoblastoma are sporadic, whereas some are associated with BeckwitheWiedemann syndrome or familial adenomatous polyposis.15e17 Multicenter studies have proposed various staging systems for hepatoblastoma. Several factors at diagnosis, including age, tumor resectability, metastatic disease, AFP expression, and portal or hepatic venous involvement, reportedly have prognostic significance. Furthermore, histological type and the expression of certain genes are also associated with the prognosis of hepatoblastoma.8e11 Four multicenter prospective controlled studies of hepatoblastoma (COG, SIOPEL, GPOH, and JPLT) joined the CHIC consortium in 2016.18 Patient variables used in eight
Fig. 1 KaplaneMeier plot showing that the event-free survival duration was significantly longer in hepatoblastoma patients aged 1.25 years at diagnosis compared with those >1.25 years (p Z 0.017).
Fig. 2 The event-free survival duration was significantly longer in hepatoblastoma patients without than in those with initial tumor rupture (p Z 0.012).
4. Discussion
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012
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Risk stratifications of hepatoblastoma
Fig. 3 There was no significant difference in the event-free survival rate between the Children’s Hepatic tumors International CollaborationdHepatoblastoma Stratification (CHICeHS) intermediate- and high-risk groups according to KaplaneMeier analysis (p > 0.05).
studies of hepatoblastoma were pooled to create a database of 1,605 cases treated over a 25-year period.2,18 The CHICeHS risk stratification system incorporates the AFP level (cutoff 100 ng/mL), PRETEXT stage, and presence of metastasis, as well as VPEFR involvement, resectability at diagnosis, and age at diagnosis (cutoffs: 3 and 8 years).2 Using the five-year EFS rate as the primary outcome, the CHICeHS defined very low-, low-, intermediate-, and highrisk groups.2 According to CHICeHS risk stratification system, patients with metastatic disease are classified as high risk irrespective of their other clinical characteristics. Patients of PRETEXT I with VPEFR involvement plus age at diagnosis 8 years, PRETEXT II/III with age at diagnosis 8 years or an AFP level 100 ng/mL, or PRETEXT IV with age at diagnosis 3 years or an AFP level 100 ng/mL are also classified as high risk. Patients with the following are classified as intermediate risk: PRETEXT I/II with VPEFR involvement, PRETEXT III with an AFP level of 101e1,000 ng/mL or >1000 ng/mL plus VPEFR involvement, and PRETEXT IV.2 Based on the classification rule, all patients were in the intermediate or high risk group. This result may be related to the high rate of VPEFR involvement in PRETEXT I and PRETEXT II patients, and because the majority of our patients (80%) were PRETEXT III or IV. All patients in the study were originally classified as SIOPEL high risk group and received the SIOPEL 2 HR or SIOPEL 4 regimen treatment. The EFS rates of our study cohort are similar to the reported outcomes of the SIOPEL 2 HR and SIOPEL 4 regimen (Supplementary Table 1). Using the CHICeHS system, these SIOPEL high-risk subjects may be further classified into CHICeHS intermediate and high-risk groups. However, there was no significant difference in EFS duration between the CHICeHS intermediate- and high-risk groups. Based on our results, reductions in current therapy may compromise the prognosis in these SIOPEL high risk cases. In our previous study of 31 patients, a cutoff age at diagnosis 1.25 years showed the best prediction of
5 survival for patients with their native liver. In 2017, the Children’s Hepatic tumors International Collaboration (CHIC) developed a unified global approach and recruited data from 1,605 patients. The study demonstrated a predictive factor-diagnostic age cutoff of 3- and 8-years, which was different from our previous study. In this study, we included 45 patients and confirmed that diagnostic age with a cutoff 1.25 years is a powerful predictor of a good prognosis in Taiwanese patients. The absence of initial tumor rupture was also predictive of a good clinical outcome. Diagnosis at > 1.25 years of age was significantly correlated with multifocal liver tumors and initial tumor rupture, suggesting that delayed diagnosis leads to disease progression prior to treatment initiation, resulting in a worse prognosis. This study had several limitations. The sample size was relatively small and the follow-up time relatively short. Further large-scale, long-term follow-up studies are needed to identify other factors predictive of the clinical outcomes of Taiwanese children with hepatoblastoma. Low AFP level (100 ng/mL) at diagnosis was considered a poor prognostic factor in hepatoblastoma children.2e5 However, there was only one hepatoblastoma patient with an initial low AFP level (100 ng/mL) in our study cohort. This patient achieved event-free survival for 1.21 years until the end of data analysis. Hence, we did not have adequate statistical power to assess the prognostic role of low AFP (100 ng/mL) in our cohort.
5. Conclusion In this study, age at diagnosis 1.25 years and absence of initial tumor rupture were predictive of a good clinical prognosis in Taiwanese children with hepatoblastoma. There was no significant difference in EFS duration between the CHICeHS intermediate- and high-risk groups.
Declaration of Competing Interest There is no conflict of interest.
Acknowledgements The study was supported by the National Taiwan University Hospital (NTUH 103-P02), and Taiwan Children Liver Foundation.
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Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.pedneo.2020.03.012.
Please cite this article as: Hsu W-Y et al., Clinical risk stratification of children with SIOPEL high-risk hepatoblastoma in Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.012