Therapeutic efficacy and prognosis of childhood hepatoblastoma: retrospective analysis of 23 cases in a single center

doi:10.3877/cma.j.issn.1673-5250.2019.04.004

Objective

To explore the clinical and pathological features, therapeutic efficacy, survival, related risk factors of prognosis and clinical diagnosis and treatments of children with hepatoblastoma (HB).

Methods

A total of 23 cases of newly diagnosed HB children in Department of Pediatric Hematology and Oncology, West China Second University Hospital, Sichuan University, from January 2010 to September 2017, were enrolled in this study and selected as research subjects. The clinical data regarding age at diagnosis, gender, clinical manifestations, histopathological types, staging of pre-treatment extent of disease (PRETEXT) and divided group by Children′s Oncology Group (COG) of United States after operation, and clinical protocols, therapeutic effect, prognosis and chemotherapy-related adverse reactions and so on were retrospectively analyzed. Kaplan-Meier method was used for survival analysis of childhood HB, such as rates of 2-year overall survival (OS) and 2-year event-free survival (EFS), and log-rank test was employed for comparisons of OS and EFS curves between HB children with different clinical features. The incidences of adverse reactions between children treated with different chemotherapy regimens were compared by Fisher exact probability method. This study was in line with the requirements of World Medical Association Declaration of Helsinki revised in 2013.

Results

①The median age of 23 cases of children with HB at diagnosis was 25.9 months (2.3-155.0 months). There were 12 boys and 11 girls. Clinically, abdominal mass was the most frequent presenting manifestations, identified in 56.5% (13/23) of HB children. Rates of complete remission (CR) and partial remission (PR) were 65.2% (15/23) and 8.7% (2/23), respectively at the end of chemotherapy, and 5 cases (21.7%) died. ②With median follow-up time of 21.5 months (7.5-81.4 months), the rates of 2-year EFS and 2-year OS among the 23 cases of HB children were 60.1% and 75.0%, respectively. Univariate analysis revealed that the 2-year EFS rate was 38.9% in children with vascular involvement of HB, which was significantly lower than 81.8% in children without vascular involvement of HB, and the difference was statistically significant (χ²=4.293, P=0.038). The 2-year EFS rate of children with stage Ⅳ in PRETEXT stage was 33.3%, which was also significantly lower than 70.6% in children with stage Ⅰ-Ⅲ in PRETEXT stage, and the difference was statistically significant (χ²=5.258, P=0.022). The rates of 2-year EFS and OS in children with lung metastasis were 20.0% and 30.0%, respectively, which were statistically lower than those of 71.4% and 85.7%, respectively in children without lung metastasis, and both the differences were statistically significant (χ²=5.491, P=0.015; χ²=7.773, P=0.005). The rates of 2-year EFS and OS in children with failure of serum alpha-fetoprotein (AFP) normalization after 3 courses of postoperative chemotherapy were 27.2% and 37.7%, respectively, which were statistically lower than those of 91.7% and 100.0%, respectively in children with normalization in AFP after ≤ 3 courses of postoperative chemotherapy, and both the differences were statistically significant (χ²=9.837, P=0.015; χ²=8.682, P=0.003). ③Severe hematological toxicity was the most common chemotherapy associated adverse reaction, particularly in children who received the treatment of doxorubicin-based combination chemotherapy. Among the 22 cases of HB children who who received chemotherapy, the incidences of hematologic toxicity in grade 3 or higher and mild transaminase elevation in 14 children receiving doxorubicin-based combination chemotherapy were 100.0% (14/14) and 64.3% (9/14), respectively, which were significantly higher than those of 37.8% (3/8) and 0 (0/8) in children who did not receive doxorubicin in the chemotherapy regimen, and both the differences were statistically significant (P=0.002, P=0.006).

Conclusions

The children with HB collected in this study share similar clinical and pathological features as reported previously. Lung metastasis and failure of serum AFP normalization after 3 courses of postoperative chemotherapy are risk factors intimately associated with adverse clinical outcomes of HB children.

Key words: Hepatoblastoma, Drug toxicity, Chemotherapy, adjuvant, Disease-free survival, Multidisciplinary treatment, Prognosis, Alpha-fetoproteins, Child

表1 本组23例HB患儿的临床资料分析[例数(%)]

临床特征		构成比	临床特征			构成比
确诊时年龄(岁)		?	组织病理学类型			?
?	≤3	15(65.2)	?	上皮型		12(52.2)
?	3～8	6(26.1)	?	?	胎儿与胚胎混合型	8(34.8)
?	≥8	2(8.7)	?	?	单纯胎儿型	3(13.0)
性别		?	?	?	粗大小梁型	1(4.4)
?	男	12(52.2)	?	混合性上皮和间叶型		4(17.4)
?	女	11(47.8)	?	未分型		7(13.4)
首发临床表现		?	PRETEXT分期			?
?	腹部肿块	13(56.5)	?	Ⅰ期		4(17.4)
?	腹痛	5(21.7)	?	Ⅱ期		11(47.8)
?	腹泻	2(8.7)	?	Ⅲ期		2(8.7)
?	不明原因发热	1(4.4)	?	Ⅳ期		6(26.1)
?	孕期胎儿超声检查发现肝脏占位	2(8.7)	术后COG分期			?
初诊时血清AFP值≤100 ng/mL		?	?	Ⅰ、Ⅱ期		16(69.6)
?	是	2(8.7)	?	Ⅲ期		4(17.4)
?	否	21(91.3)	?	Ⅳ期		3(13.0)
初诊时肺转移(肺部结节直径≥10 mm)		?	?	?	?	?
?	是	3(13.0)	?	?	?	?
?	否	20(87.0)	?	?	?	?

表1 本组23例HB患儿的临床资料分析[例数(%)]

临床特征		构成比	临床特征			构成比
确诊时年龄(岁)		?	组织病理学类型			?
?	≤3	15(65.2)	?	上皮型		12(52.2)
?	3～8	6(26.1)	?	?	胎儿与胚胎混合型	8(34.8)
?	≥8	2(8.7)	?	?	单纯胎儿型	3(13.0)
性别		?	?	?	粗大小梁型	1(4.4)
?	男	12(52.2)	?	混合性上皮和间叶型		4(17.4)
?	女	11(47.8)	?	未分型		7(13.4)
首发临床表现		?	PRETEXT分期			?
?	腹部肿块	13(56.5)	?	Ⅰ期		4(17.4)
?	腹痛	5(21.7)	?	Ⅱ期		11(47.8)
?	腹泻	2(8.7)	?	Ⅲ期		2(8.7)
?	不明原因发热	1(4.4)	?	Ⅳ期		6(26.1)
?	孕期胎儿超声检查发现肝脏占位	2(8.7)	术后COG分期			?
初诊时血清AFP值≤100 ng/mL		?	?	Ⅰ、Ⅱ期		16(69.6)
?	是	2(8.7)	?	Ⅲ期		4(17.4)
?	否	21(91.3)	?	Ⅳ期		3(13.0)
初诊时肺转移(肺部结节直径≥10 mm)		?	?	?	?	?
?	是	3(13.0)	?	?	?	?
?	否	20(87.0)	?	?	?	?

图8 手术后接受3个疗程化疗，血清AFP值未恢复正常与手术后接受≤3个疗程化疗即恢复正常的HB患儿的OS曲线

表2 HB患儿预后影响因素的单因素分析

临床特征		例数	2年EFS			2年OS
临床特征		例数	EFS率(%)	χ²值	P值	OS率(%)	χ²值	P值
COG危险度分层		?	?	2.950	0.229	?	0.579	0.748
?	极低/低危HB	11	72.7	?	?	80.8	?	?
?	中危HB	9	51.9	?	?	71.4	?	?
?	高危HB	3	33.3	?	?	66.7	?	?
确诊时年龄(岁)		?	?	4.297	0.117	?	1.062	0.588
?	≤3	15	59.3	?	?	76.5	?	?
?	3～8	6	83.3	?	?	83.3	?	?
?	≥8	2	0	?	?	50.0	?	?
HB是否累及血管		?	?	4.293	0.038	?	2.918	0.088
?	是	12	38.9	?	?	59.4	?	?
?	否	11	81.8	?	?	88.9	?	?
PRETEXT分期		?	?	5.258	0.022	?	0.018	0.894
?	Ⅳ期	6	33.3	?	?	75.0	?	?
?	Ⅰ～Ⅲ期	17	70.6	?	?	75.1	?	?
术后是否存在HB残留		?	?	3.044	0.081	?	2.155	0.142
?	是	4	25.0	?	?	37.5	?	?
?	否	19	67.7	?	?	82.5	?	?
性别		?	?	0.806	0.369	?	0.082	0.775
?	男	12	50.0	?	?	71.3	?	?
?	女	11	71.6	?	?	80.0	?	?
术后化疗前血清AFP值>1×10⁴ ng/mL		?	?	1.762	0.184	?	1.643	0.200
?	是	9	40.0	?	?	51.4	?	?
?	否	14	71.4	?	?	85.7	?	?
是否存在肺转移		?	?	5.949	0.015	?	7.773	0.005
?	是	5	20.0	?	?	30.0	?	?
?	否	18	71.4	?	?	86.5	?	?
手术后接受≤3个疗程化疗，血清AFP值是否恢复正常		?	?	9.837	0.002	?	8.682	0.003
?	是	12	91.7	?	?	100.0	?	?
?	否	11	27.2	?	?	37.7	?	?

表2 HB患儿预后影响因素的单因素分析

临床特征		例数	2年EFS			2年OS
临床特征		例数	EFS率(%)	χ²值	P值	OS率(%)	χ²值	P值
COG危险度分层		?	?	2.950	0.229	?	0.579	0.748
?	极低/低危HB	11	72.7	?	?	80.8	?	?
?	中危HB	9	51.9	?	?	71.4	?	?
?	高危HB	3	33.3	?	?	66.7	?	?
确诊时年龄(岁)		?	?	4.297	0.117	?	1.062	0.588
?	≤3	15	59.3	?	?	76.5	?	?
?	3～8	6	83.3	?	?	83.3	?	?
?	≥8	2	0	?	?	50.0	?	?
HB是否累及血管		?	?	4.293	0.038	?	2.918	0.088
?	是	12	38.9	?	?	59.4	?	?
?	否	11	81.8	?	?	88.9	?	?
PRETEXT分期		?	?	5.258	0.022	?	0.018	0.894
?	Ⅳ期	6	33.3	?	?	75.0	?	?
?	Ⅰ～Ⅲ期	17	70.6	?	?	75.1	?	?
术后是否存在HB残留		?	?	3.044	0.081	?	2.155	0.142
?	是	4	25.0	?	?	37.5	?	?
?	否	19	67.7	?	?	82.5	?	?
性别		?	?	0.806	0.369	?	0.082	0.775
?	男	12	50.0	?	?	71.3	?	?
?	女	11	71.6	?	?	80.0	?	?
术后化疗前血清AFP值>1×10⁴ ng/mL		?	?	1.762	0.184	?	1.643	0.200
?	是	9	40.0	?	?	51.4	?	?
?	否	14	71.4	?	?	85.7	?	?
是否存在肺转移		?	?	5.949	0.015	?	7.773	0.005
?	是	5	20.0	?	?	30.0	?	?
?	否	18	71.4	?	?	86.5	?	?
手术后接受≤3个疗程化疗，血清AFP值是否恢复正常		?	?	9.837	0.002	?	8.682	0.003
?	是	12	91.7	?	?	100.0	?	?
?	否	11	27.2	?	?	37.7	?	?

表3 接受不同方案化疗HB患儿不良反应发生情况比较[例数(%)]

化疗方案	例数	3级以上血液学毒性反应	转氨酶升高	水、电解质紊乱	心脏毒性反应
包含多柔比星	14	14(100.0)	9(64.3)	5(35.7)	5(35.7)
未包含多柔比星	8	3(37.8)	0(0)	1(12.5)	4(50.0)
P值	?	0.002	0.006	0.351	0.662

表3 接受不同方案化疗HB患儿不良反应发生情况比较[例数(%)]

化疗方案	例数	3级以上血液学毒性反应	转氨酶升高	水、电解质紊乱	心脏毒性反应
包含多柔比星	14	14(100.0)	9(64.3)	5(35.7)	5(35.7)
未包含多柔比星	8	3(37.8)	0(0)	1(12.5)	4(50.0)
P值	?	0.002	0.006	0.351	0.662

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