儿童肝母细胞瘤疗效及预后分析

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

目的探讨儿童肝母细胞瘤(HB)患儿的临床特征、疗效、生存情况、预后相关危险因素及其临床诊治。方法选择2010年1月至2017年9月,于四川大学华西第二医院儿童血液肿瘤科收治的23例新发HB患儿为研究对象。采用回顾性分析方法,收集其临床病例资料,包括患儿确诊时年龄、性别、首发临床表现、组织病理学类型、治疗前病变范围(PRETEXT)分期、术后儿童肿瘤协作组(COG)分期等临床资料,以及治疗方案、疗效、预后、化疗相关不良反应等。对本组HB患儿的生存分析,如2年总体生存(OS)率、无事件生存(EFS)率,采用Kaplan-Meier法,不同临床特征患儿的生存曲线比较采用log-rank检验。HB患儿接受不同化疗方案治疗的不良反应率比较,采用Fisher确切概率法。本研究遵循的程序符合2013年修订的《世界医学协会赫尔辛基宣言》要求。结果①本组23例HB患儿确诊时的中位年龄为25.9个月(2.3~155.0个月);男性患儿为12例,女性为11例;腹部肿块为最常见首发临床表现(56.5%,13/23)。其完全缓解(CR)率为65.2%(15/23),部分缓解(PR)率为8.7%(2/23),死亡为5例(21.7%)。②对23例患儿的中位随访时间为21.5个月(7.5~81.4个月),其2年EFS率、OS率分别为60.1%和75.0%。HB患儿预后影响因素的单因素分析结果显示,HB累及血管患儿的2年EFS率为38.9%,显著低于未累及者的81.8%,二者比较,差异有统计学意义(χ^2=4.293,P=0.038)。HB患儿PRETEXT分期为Ⅳ期者,其2年EFS率为33.3%,显著低于PRETEXT分期为Ⅰ~Ⅲ期者的70.6%,二者比较,差异有统计学意义(χ^2=5.258,P=0.022)。肺转移HB患儿的2年EFS率、OS率分别为20.0%、30.0%,均显著低于无肺转移者的71.4%、85.7%,二者分别比较,差异均有统计学意义(χ^2=5.491,P=0.015;χ^2=7.773,P=0.005)。手术后接受3个疗程化疗,血清甲胎蛋白(AFP)值未恢复正常患儿的2年EFS率、OS率分别为27.2%、37.7%,显著低于手术后接受≤3个疗程化疗即恢复正常者的91.7%、100.0%,二者比较,差异亦均有统计学意义(χ^2=9.837,P=0.002;χ^2=8.682,P=0.003)。③严重血液学毒性反应为本组HB患儿最常见化疗相关不良反应,尤其是采取包含多柔比星的联合化疗方案者更严重。本组术后接受化疗的22例HB患儿中,接受联合化疗方案包含多柔比星的14例患儿的3级以上血液学毒性反应、轻度转氨酶升高发生率分别为100.0%(14/14)、64.3%(9/14),显著高于未包含多柔比星患儿的37.8%(3/8)、0(0/8),二者分别比较,差异均有统计学意义(P=0.002,P=0.006)。结论本组儿童HB的临床特征、组织病理学类型与国内外相关临床报道结果基本一致。HB患儿肺转移及手术后接受3个疗程化疗,血清AFP值未恢复正常水平,与该病的不良预后密切相关。

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.Results①The 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(χ^2=4.293,P=0.038).The 2-year EFS rate of children with stageⅣin PRETEXT stage was 33.3%,which was also significantly lower than 70.6%in children with stageⅠ-Ⅲin PRETEXT stage,and the difference was statistically significant(χ^2=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(χ^2=5.491,P=0.015;χ^2=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(χ^2=9.837,P=0.015;χ^2=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.