martes, 16 de abril de 2019

Childhood Liver Cancer Treatment (PDQ®) 3/4 —Health Professional Version - National Cancer Institute

Childhood Liver Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Childhood Liver Cancer Treatment (PDQ®)–Health Professional Version




Hepatoblastoma


Incidence

The annual incidence of hepatoblastoma in the United States appears to have doubled, from 0.8 (1975–1983) to 1.6 (2002–2009) cases per 1 million children aged 19 years and younger.[1,2] The cause for this increase is unknown, but the increasing survival of very low-birth-weight premature infants, which is known to be associated with hepatoblastoma, may contribute.[3] In Japan, the risk of hepatoblastoma in children who weighed less than 1,000 g at birth is 15 times the risk in normal birth-weight children.[4] Other data have confirmed the high incidence of hepatoblastoma in very low-birth-weight premature infants.[5] Attempts to identify factors resulting from treatment of infants born prematurely have not revealed any suggestive causation of the increased incidence of hepatoblastoma.[3]
The age of onset of liver cancer in children is related to tumor histology. Hepatoblastomas usually occur before the age of 3 years, and approximately 90% of malignant liver tumors in children aged 4 years and younger are hepatoblastomas.[6]

Risk Factors

Conditions associated with an increased risk of hepatoblastoma are described in Table 4.
Table 4. Conditions Associated With Hepatoblastoma
Associated DisorderClinical Findings
Aicardi syndrome [7]Refer to the Aicardi syndrome section of this summary for more information.
Beckwith-Wiedemann syndrome [8,9]Refer to the Beckwith-Wiedemann syndrome and hemihyperplasia section of this summary for more information.
Familial adenomatous polyposis [10-12]Refer to the Familial adenomatous polyposissection of this summary for more information.
Glycogen storage diseases I–IV [13]Symptoms vary by individual disorder.
Low-birth-weight infants [3-5,14,15]Preterm and small-for-gestation-age neonates.
Simpson-Golabi-Behmel syndrome [16]Macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of Wilms tumor.
Trisomy 18, other trisomies [17]Trisomy 18: Microcephaly and micrognathia, clenched fists with overlapping fingers, and failure to thrive. Most patients (>90%) die in the first year of life.

Aicardi syndrome

Aicardi syndrome is presumed to be an X-linked condition reported exclusively in females, leading to the hypothesis that a mutated gene on the X chromosome causes lethality in males. The syndrome is classically defined as agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms, with a characteristic facies. Additional brain, eye, and costovertebral defects are often found.[7]

Beckwith-Wiedemann syndrome and hemihyperplasia

The incidence of hepatoblastoma is increased 1,000-fold to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome.[9,18] The risk of hepatoblastoma is also increased in patients with hemihyperplasia, previously termed hemihypertrophy, a condition that results in asymmetry between the right and left side of the body when a body part grows faster than normal.[19,20]
Beckwith-Wiedemann syndrome is most commonly caused by epigenetic changes and is sporadic. The syndrome may also be caused by genetic mutations and be familial. Either mechanism can be associated with an increased incidence of embryonal tumors, including Wilms tumor and hepatoblastoma.[9] The expression of both IGFR2 alleles and ensuing increased expression of insulin-like growth factor 2 (IGF-2) has been implicated in the macrosomia and embryonal tumors seen in patients with Beckwith-Wiedemann syndrome.[9,21] When sporadic, the types of embryonal tumors associated with Beckwith-Wiedemann syndrome have frequently also undergone somatic changes in the Beckwith-Wiedemann syndrome locus and IGF-2.[22,23] The genetics of tumors in children with hemihyperplasia have not been clearly defined.
To detect abdominal malignancies at an early stage, all children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia are screened regularly for multiple tumor types by abdominal ultrasonography.[20] Screening using alpha-fetoprotein (AFP) levels has also been quite helpful in the early detection of hepatoblastoma in these children.[24] Because the hepatoblastomas that are discovered early are small, it has been suggested to minimize the use of adjuvant therapy after surgery.[18] However, a careful compilation of published data on 1,370 children with (epi)genotyped Beckwith-Wiedemann syndrome demonstrated that the prevalence of hepatoblastoma was 4.7% in those with Beckwith-Wiedemann syndrome caused by chromosome 11p15 paternal uniparental disomy, less than 1% in the two types of alteration in imprinting control regions, and absent in CDKN1Cmutation.[25] The authors recommended that only children with Beckwith-Wiedemann syndrome caused by uniparental disomy be screened for hepatoblastoma using abdominal ultrasonography and AFP levels every 3 months from age 3 months to 5 years.

Familial adenomatous polyposis

There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene have an 800-fold increased risk of hepatoblastoma. However, hepatoblastoma has been reported to occur in less than 1% of FAP family members, so screening for hepatoblastoma in members of families with FAP using ultrasonography and AFP levels is controversial.[10-12,26] However, one study of 50 consecutive children with apparent sporadic hepatoblastoma reported that five children (10%) had APC germline mutations.[26]
Current evidence cannot rule out the possibility that predisposition to hepatoblastoma may be limited to a specific subset of APC mutations. Another study of children with hepatoblastoma found a predominance of the mutation in the 5' region of the gene, but some patients had mutations closer to the 3' region.[27] This preliminary study provides some evidence that screening children with hepatoblastoma for APC mutations and colon cancer may be appropriate.
In the absence of APC germline mutations, childhood hepatoblastomas do not have somatic mutations in the APC gene; however, hepatoblastomas frequently have mutations in the beta-catenin gene, the function of which is closely related to APC.[28]

Screening children predisposed to hepatoblastoma

An American Association for Cancer Research publication suggested that all children with more than a 1% risk of developing hepatoblastoma be screened. This includes patients with Beckwith-Wiedemann, hemihyperplasia, Simpson-Golabi-Behmel, and trisomy 18 syndromes. Screening is by abdominal ultrasound and alpha-fetoprotein determination every 3 months from birth (or diagnosis) through the fourth birthday, which will identify 90% to 95% of hepatoblastomas that develop in these children.[29]

Genomics of Hepatoblastoma

Genomic abnormalities related to hepatoblastoma include the following:
  • Hepatoblastoma mutation frequency, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[30-32]
  • Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1 mutations have been reported in 70% of cases.[30] Rare causes of WNT pathway activation include mutations in AXIN1, AXIN2, and APC (APCseen only in cases associated with familial adenomatosis polyposis coli).[33]
  • The frequency of NFE2L2 mutations in hepatoblastoma specimens was reported to be 4 of 62 tumors (7%) in one study [31] and 5 of 51 specimens (10%) in another study.[30]
    Similar mutations have been found in many types of cancer, including hepatocellular carcinoma. These mutations render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.
  • Somatic mutations were identified in other genes related to regulation of oxidative stress, including inactivating mutations in the thioredoxin-domain containing genes, TXNDC15 and TXNDC16.[31]
  • Figure 2 shows the distribution of CTNNB1, NFE2L2, and TERT mutations in hepatoblastoma.[30]
    ENLARGEChart showing the distribution of CTNNB1, APC, NFE2L2, and TERT mutations for hepatoblastoma.
    Figure 2. Mutational status and functional relevance of NFE2L2 in hepatoblastoma. Clinicopathological characteristics and the mutational status of the CTNNB1, APC, and NFE2L2 genes, as well as the TERT promoter region are color-coded and depicted in rows for each tumor of our cohort of 43 hepatoblastoma (HB) patients and four transitional liver cell tumour (TLCT) patients and 4 HB cell lines. Reprinted from Journal of Hepatology, Volume 61 (Issue 6), Melanie Eichenmüller, Franziska Trippel, Michaela Kreuder, Alexander Beck, Thomas Schwarzmayr, Beate Häberle, Stefano Cairo, Ivo Leuschner, Dietrich von Schweinitz, Tim M. Strom, Roland Kappler, The genomic landscape of hepatoblastoma and their progenies with HCC-like features, Pages 1312–1320, Copyright 2014, with permission from Elsevier.
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.

Diagnosis

Biopsy

A biopsy of a pediatric liver tumor is always indicated to secure the diagnosis of a liver tumor, with the exception of the following circumstances:
  • Infantile hepatic hemangioma. Biopsy is not indicated in infantile hemangioma of the liver with classic findings on magnetic resonance imaging (MRI). If the diagnosis is in doubt after high-quality imaging, a confirmatory biopsy is done.
  • Focal nodular hyperplasia. Biopsy may not be indicated or may be delayed in focal nodular hyperplasia with classic features on MRI using hepatocyte-specific contrast agent. If the diagnosis is in doubt, a confirmatory biopsy is done.
  • Children's Oncology Group (COG) surgical guidelines (AHEP0731 [NCT00980460]appendix) recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRE-Treatment EXTent of disease (PRETEXT) group I tumors and PRETEXT group II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins. Therefore, biopsy is not usually recommended in this circumstance.
  • Infantile hepatic choriocarcinoma. In infantile hepatic choriocarcinoma, which can be diagnosed by imaging and markedly elevated beta-human chorionic gonadotropin (beta-hCG), chemotherapy without biopsy is often indicated.[34]

Tumor markers

The AFP and beta-hCG tumor markers are very helpful in the diagnosis and management of liver tumors. Although AFP is elevated in most children with hepatic malignancy, it is not pathognomonic for a malignant liver tumor.[35] The AFP level can be elevated with either a benign tumor or a malignant solid tumor. AFP is very high in neonates and steadily falls after birth. The half-life of AFP is 5 to 7 days, and by age 1 year, it should be less than 10 ng/mL.[36]

Prognosis and Prognostic Factors

The 5-year overall survival (OS) rate for children with hepatoblastoma is 70%.[37,38] Neonates with hepatoblastoma have outcomes comparable to older children up to age 5 years.[39]
Individual childhood cancer study groups have attempted to define the relative importance of a variety of prognostic factors present at diagnosis and in response to therapy.[40,41] A collaborative group consisting of four study groups (International Childhood Liver Tumors Strategy Group [SIOPEL], COG, Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH], and Japanese Study Group for Pediatric Liver Tumor [JPLT]), termed Childhood Hepatic tumor International Collaboration (CHIC), have retrospectively combined data from eight clinical trials (N = 1,605) conducted between 1988 and 2010. The CHIC published a univariate analysis of the effect of clinical prognostic factors present at the time of diagnosis on event-free survival (EFS).[42,43] The analysis confirmed many of the findings described below. The statistically significant adverse factors included the following:[42]
  • Higher PRETEXT group.
  • Positive PRETEXT annotation factors:
    • V: Involvement all three hepatic veins and/or intrahepatic inferior vena cava.
    • P: Involvement of both left and right portal veins.
    • E: Contiguous extrahepatic tumor extensions (e.g., diaphragm, adjacent organs).
    • F: Multifocal tumors.
    • R: Tumor rupture.
    • M: Distant metastases, usually lung.
  • Low AFP level (<100 ng/mL or 100–1,000 ng/mL to account for infants with elevated AFP levels).[43]
  • Older age. Patients aged 3 to 7 years have a worse outcome in the PRETEXT IV group.[42] Patients aged 8 years and older have a worse outcome than do younger patients in all PRETEXT groups.
    In contrast, in the SIOPEL-2 and -3 studies, infants younger than 6 months had PRETEXT, annotation factors, and outcomes similar to that of older children undergoing the same treatment.[44][Level of evidence: 3iiA]
In contrast, sex, prematurity, birth weight, and Beckwith-Wiedemann syndrome had no effect on EFS.[42]
A multivariate analysis of these prognostic factors has been published to help develop a new risk group classification for hepatoblastoma.[43] This classification was used to generate a risk stratification schema to be used in international clinical trials. (Refer to the International risk classification model section of this summary for more information.)
Other studies of factors affecting prognosis observed the following:
  • PRETEXT group: In SIOPEL studies, having a low PRETEXT group at diagnosis (PRETEXT I, II, and III tumors) is a good prognostic factor, whereas PRETEXT IV is a poor prognostic factor.[42] (Refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for more information.)
  • Tumor stage: In COG studies, stage I tumors that were resected at diagnosis and tumors with well-differentiated fetal histology have a good prognosis. These tumors are treated differently than tumors of other stages and histologies.[42]
  • Treatment-related factors:
    Chemotherapy: Chemotherapy often decreases the size and extent of hepatoblastoma, allowing complete resection.[45-49] Favorable response of the primary tumor to chemotherapy, defined as either a 30% decrease in tumor size by Response Evaluation Criteria In Solid Tumors (RECIST) or 90% or greater decrease in AFP levels, predicted the resectability of the tumor; in turn, this favorable response predicted overall survival among all CHIC risk groups treated with neoadjuvant chemotherapy on the JPLT-2 Japanese national clinical trial.[50][Level of evidence: 2A]
    Surgery: Cure of hepatoblastoma requires gross tumor resection. Hepatoblastoma is most often unifocal and thus, resection may be possible. If a hepatoblastoma is completely removed, most patients survive, but because of vascular or other involvement, less than one-third of patients have lesions amenable to complete resection at diagnosis.[42] Thus, it is critically important that a child with probable hepatoblastoma be evaluated by a pediatric surgeon; the surgeon should be experienced in the techniques of extreme liver resection with vascular reconstruction and have access to a liver transplant program. In advanced tumors, surgical treatment of hepatoblastoma is a demanding procedure. Postoperative complications in high-risk patients decrease the rate of overall survival.[51]
    Orthotopic liver transplant is an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy;[52,53] however, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome.[54,55] This may be due to the additional courses of chemotherapy that are administered before or after resection.[45,46,54]
    (Refer to Table 6 for more information on outcomes associated with specific chemotherapy regimens.)
  • Tumor marker–related factors:
    Ninety percent of children with hepatoblastoma and two-thirds of children with hepatocellular carcinoma exhibit the serum tumor marker AFP, which parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP levels during treatment are compared with the age-adjusted normal range. Lack of a significant decrease in AFP levels with treatment may predict a poor response to therapy.[56]
    Absence of elevated AFP levels at diagnosis (AFP <100 ng/mL) occurs in a small percentage of children with hepatoblastoma and appears to be associated with very poor prognosis, as well as with the small cell undifferentiated variant of hepatoblastoma.[42] Some of these variants do not express INI1 and may be considered rhabdoid tumors of the liver; all small cell undifferentiated hepatoblastomas are tested for loss of INI1 expression by immunohistochemistry.[57-62]
    Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[63,64]
  • Tumor histology:
    Refer to the Histology section of this summary for more information.
Other variables have been suggested as poor prognostic factors, but the relative importance of their prognostic significance has been difficult to define. In the SIOPEL-1 study, a multivariate analysis of prognosis after positive response to chemotherapy showed that only one variable, PRETEXT, predicted OS, while metastasis and PRETEXT predicted EFS.[57] In an analysis of the intergroup U.S. study from the time of diagnosis, well-differentiated fetal histology, small cell undifferentiated histology, and AFP less than 100 ng/mL were prognostic in a log rank analysis. PRETEXT was prognostic among patients designated group III, but not group IV.[61,65]

Histology

Hepatoblastoma arises from precursors of hepatocytes and can have several morphologies, including the following:[66]
  • Small cells that reflect neither epithelial nor stromal differentiation. It is critical to discriminate between small cell undifferentiated hepatoblastoma expressing INI1 and rhabdoid tumor of the liver, which lacks the INI1 gene and INI1 expression. Both diseases may share similar histology. Optimal treatment of rhabdoid tumor of the liver and small cell undifferentiated hepatoblastoma may require different approaches and different chemotherapy. (Refer to the Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver section of this summary for a more extensive discussion of the differences between small cell undifferentiated hepatoblastoma and rhabdoid tumor of the liver.)
  • Embryonal epithelial cells resembling the liver epithelium at 6 to 8 weeks of gestation.
  • Well-differentiated fetal hepatocytes morphologically indistinguishable from normal fetal liver cells.
Most often the tumor consists of a mixture of epithelial hepatocyte precursors. About 20% of tumors have stromal derivatives such as osteoid, chondroid, and rhabdoid elements. Occasionally, neuronal, melanocytic, squamous, and enteroendocrine elements are found. The following two histologic subtypes have clinical relevance:

Well-differentiated fetal (pure fetal) histology hepatoblastoma

An analysis of patients with initially resected hepatoblastoma tumors (before receiving chemotherapy) has suggested that patients with well-differentiated fetal (previously termed pure fetal) histology tumors have a better prognosis than do patients with an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues. Studies have reported the following:
  1. A study of patients with hepatoblastoma and well-differentiated fetal histology tumors observed the following:[47]
    • The survival rate was 100% for patients who received four doses of single-agent doxorubicin. This suggested that patients with well-differentiated fetal histology tumors might not need chemotherapy after complete resection.[67,68]
  2. In a COG study (COG-P9645), 16 patients with well-differentiated fetal histology hepatoblastoma with two or fewer mitoses per 10 high-power fields were not treated with chemotherapy. Retrospectively, their PRETEXT groups were group I (n = 4), group II (n = 6), and group III (n = 2).[69]
    • Survival was 100% with no chemotherapy given.
    • All 16 patients entered on this study were alive with no evidence of disease at a median follow-up of 4.9 years (range, 9 months to 9.2 years).
Thus, complete resection of a well-differentiated fetal hepatoblastoma may preclude the need for chemotherapy.

Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver

Small cell undifferentiated hepatoblastoma is an uncommon hepatoblastoma variant that represents several percent of all hepatoblastomas. It tends to occur at a younger age (6–10 months) than do other cases of hepatoblastoma [61,70] and is associated with AFP levels that are normal for age at presentation.[60,70]
Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts.[71]
Small cell undifferentiated hepatoblastoma may be difficult to distinguish from malignant rhabdoid tumor of the liver, which has been conflated with small cell undifferentiated hepatoblastoma in past studies. They can be distinguished by the following characteristic abnormalities:
  • Chromosomal abnormalities. These abnormalities in rhabdoid tumors include translocations involving a breakpoint on chromosome 22q11 and homozygous deletion at the chromosome 22q12 region that harbors the SMARCB1/INI1 gene.[70,72]
  • Lack of INI1 expression. Lack of detection of INI1 by immunohistochemistry is characteristic of malignant rhabdoid tumors.[70]
  • Poor prognosis. A characteristic thought to be shared by small cell undifferentiated hepatoblastomas and malignant rhabdoid tumors is the poor prognosis associated with each.[61,70,73]
The ongoing international Pediatric Hepatic Malignancy International Treatment Trial (PHITT) designates any childhood liver tumor as rhabdoid tumor of the liver if it contains cells that lack INI1 expression. (Refer to the AHEP1531 trial in the Treatment options under clinical evaluation for hepatoblastoma section of this summary for more information.) Patients with INI1-negative tumors, which are presumed to be related to rhabdoid tumors, may not be entered on the international trial, which addresses treatment of hepatoblastoma that includes small cell undifferentiated histology, hepatocellular carcinoma, and hepatic malignancy of childhood NOS, but not rhabdoid tumor of the liver. In this trial, all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated hepatoblastoma are required to have testing for INI1/SMARCB1 by immunohistochemistry according to the practices at the institution.
If INI1 is maintained but small cell undifferentiated histology is present, the current literature suggests a worse outcome for these patients. However, because small cell undifferentiated hepatoblastoma and rhabdoid tumor of the liver have not been discriminated in past studies, some of the prognostic features attributed to the former may have been contributed in part by the latter. Published studies of prognostic features related to small cell undifferentiated histology include the following:
  • In 2009, the results of a study of 11 young children with low AFP levels and small cell morphology were reported. Ten children died of disease progression, and one child died of complications. Six of six children tested were INI1 negative, but only one child had any rhabdoid morphology. This finding suggests that many or all liver tumors with small cell morphology and very low AFP levels in young children may be rhabdoid tumors of the liver. These tumors have a poor prognosis that is associated with the driver mutation.[70]
  • A single-institution study of seven children with small cell morphology liver tumors found that all retained expression of INI1. Six children survived, and one child died of complications from liver transplant.[74]
  • A study of 23 liver tumors from the Kiel tumor bank found 12 tumors with small cell morphology. Nine tumors had malignant rhabdoid tumor classic histology, and two tumors had mixed small cell and rhabdoid histologies. Outcomes were not provided, but it was noted that rhabdoid brain tumors had small cell, not classic, rhabdoid histology.[75]
  • In a single-institution study of six children with INI1-negative liver tumors, two children with small cell morphology died. The remaining four children with classic rhabdoid histology were not treated with cisplatin-based therapy; three children survived, and one child died from complications of transplant.[76]
The outcomes of the CHIC trial of childhood liver tumors may clarify some of the questions regarding these different histologic and genetic findings.
Patients with small cell undifferentiated hepatoblastoma whose tumors are unresectable have an especially poor prognosis.[70] Patients with stage I tumors appear to have increased risk of treatment failure when small cell elements are present.[77] For this reason, completely resected tumors composed of well-differentiated fetal histology or of mixed fetal and embryonal cells must have a thorough histologic examination as small foci of undifferentiated small cell histology indicates a need for aggressive chemotherapy.[77] Aggressive treatment for this histology was investigated in the completed COG AHEP0731 [NCT00980460] study, and all tumors were tested for INI1 expression by immunohistochemistry. In this study, hepatoblastoma that would otherwise be considered very low or low risk was upgraded to intermediate risk if any small cell undifferentiated elements were found (refer to Table 5 for more information).

Risk Stratification

There are significant differences among childhood cancer study groups in risk stratification used to determine treatment, making it difficult to compare results of the different treatments administered. Table 5 demonstrates the variability in the definitions of risk groups.
Table 5. A Comparison of the Use of PRETEXT in Risk Stratification Schemes for Hepatoblastomaa,b
COG (AHEP-0731)SIOPEL (SIOPEL-3, -3HR, -4, -6)GPOHJPLT (JPLT-2 and -3)
AFP = alpha-fetoprotein; COG = Children's Oncology Group; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); JPLT = Japanese Study Group for Pediatric Liver Tumor; PRETEXT = PRE-Treatment EXTent of disease; SCU = small cell undifferentiated; SIOPEL = International Childhood Liver Tumors Strategy Group.
aAdapted from Czauderna et al.[65]
bRefer to Table 2 for more information about the annotations used in PRETEXT.
cThe COG and PRETEXT definitions of vascular involvement differ.
Very low riskPRETEXT I or II; well-differentiated fetal histology; primary resection at diagnosis
Low risk/standard riskPRETEXT I or II of any histology with primary resection at diagnosisPRETEXT I, II, or IIIPRETEXT I, II, or IIIPRETEXT I, II, or III
Intermediate riskbPRETEXT II, III, or IV unresectable at diagnosis; or V+c, P+, E+; SCU histologyPRETEXT IV or any PRETEXT with rupture; or N1, P2, P2a, V3, V3a; or multifocal
High riskbAny PRETEXT with M+; AFP level <100 ng/mLAny PRETEXT; V+, P+, E+, M+; SCU histology; AFP level <100 ng/mL; tumor ruptureAny PRETEXT with V+, E+, P+, M+ or multifocalAny PRETEXT with M1 or N2; or AFP level <100 ng/mL

International risk classification model

The Children's Hepatic tumors International Collaboration (CHIC) developed a novel risk stratification system for use in international clinical trials on the basis of prognostic features present at diagnosis. CHIC unified the disparate definitions and staging systems used by pediatric cooperative multicenter trial groups, enabling the comparison of studies conducted by heterogeneous groups in different countries.[43] Original detailed clinical patient data were extracted from eight published clinical trials using central review of imaging and histology, and prognostic factors were identified by univariate analysis.[42]
Based on the initial univariate analysis of the data combined with historical clinical treatment patterns and data from previous large clinical trials, five backbone groups were selected, which allowed for further risk stratification. Subsequent multivariate analysis was performed on the basis of these backbone groups; the groups were defined according to the following clinical prognostic factors: AFP (≤100 ng/mL), PRETEXT group (I, II, III, or IV), and presence of metastasis (yes or no). The backbone groups are as follows:[43]
  • Backbone 1: PRETEXT I/II, not metastatic, AFP greater than 100 ng/mL.
  • Backbone 2: PRETEXT III, not metastatic, AFP greater than 100 ng/mL.
  • Backbone 3: PRETEXT IV, not metastatic, AFP greater than 100 ng/mL.
  • Backbone 4: Any PRETEXT group, metastatic disease at diagnosis, AFP greater than 100 ng/mL.
  • Backbone 5: Any PRETEXT group, metastatic or not, AFP less than or equal to 100 ng/mL at diagnosis.
Other diagnostic factors (e.g., age) were queried for each of the backbone categories, including the presence of at least one of the following PRETEXT annotations (defined as VPEFR+, refer to Table 2) or AFP less than or equal to 100 ng/mL:[43]
  • V: Involvement of vena cava or all three hepatic veins, or both.
  • P: Involvement of portal bifurcation or both right and left portal veins, or both.
  • E: Extrahepatic contiguous tumor extension.
  • F: Multifocal liver tumor.
  • R: Tumor rupture at diagnosis.
An assessment of surgical resectability at diagnosis was added for PRETEXT I and II patients. Patients in each of the five backbone categories were stratified on the basis of backwards stepwise elimination multivariable analysis of additional patient characteristics, including age and presence or absence of PRETEXT annotation factors (V, P, E, F, and R). Each of these subcategories received one of four risk designations (very low, low, intermediate, or high). The result of the multivariate analysis was used to assign patients to very low-, low-, intermediate-, and high-risk categories, as shown in Figure 3. For example, the finding of an AFP level of 100 to 1,000 ng/mL was significant only among patients younger than 8 years in the backbone PRETEXT III group. The analysis enables prognostically similar risk groups to be assigned to the appropriate treatment groups on upcoming international protocols.[43]
ENLARGEDiagram showing risk stratification trees for the Children’s Hepatic tumors International Collaboration—Hepatoblastoma Stratification (CHIC-HS).
Figure 3. Risk stratification trees for the Children’s Hepatic tumors International Collaboration—Hepatoblastoma Stratification (CHIC-HS). Very low-risk group and low-risk group are separated only by their resectability at diagnosis, which has been defined by international consensus as part of the surgical guidelines for the upcoming collaborative trial, Paediatric Hepatic International Tumour Trial (PHITT). Separate risk stratification trees are used for each of the four PRETEXT groups. AFP = alpha-fetoprotein. M = metastatic disease. PRETEXT = PRETreatment EXTent of disease.[43] Reprinted from The Lancet Oncology, Volume 18, Meyers RL, Maibach R, Hiyama E, Häberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P, Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration, Pages 122–131, Copyright (2017), with permission from Elsevier.

Treatment of Hepatoblastoma

Treatment options for newly diagnosed hepatoblastoma depend on the following:
  • Whether the cancer is resectable at diagnosis.
  • The tumor histology.
  • How the cancer responds to chemotherapy.
  • Whether the cancer has metastasized.
Cisplatin-based chemotherapy has resulted in a survival rate of more than 90% for children with PRETEXT and POST-Treatment EXTent (POSTTEXT) I and II resectable disease before or after chemotherapy.[46,48,58]
Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 6. (Refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for information describing each stage.)
Table 6. Outcomes for Hepatoblastoma Multicenter Trialsa
StudyChemotherapy RegimenNumber of PatientsOutcomes
AFP = alpha-fetoprotein; C5V = cisplatin, 5-fluorouracil (5FU), and vincristine; CARBO = carboplatin; CCG = Children’s Cancer Group; CDDP = cisplatin; CITA = pirarubicin-cisplatin; COG = Children's Oncology Group; DOXO = doxorubicin; EFS = event-free survival; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); HR = high risk; IFOS = ifosfamide; IPA = ifosfamide, cisplatin, and doxorubicin; JPLT = Japanese Study Group for Pediatric Liver Tumor; NR = not reported; OS = overall survival; PLADO = cisplatin and doxorubicin; POG = Pediatric Oncology Group; PRETEXT = PRE-Treatment EXTent of disease; SIOPEL = International Childhood Liver Tumors Strategy Group; SR = standard risk; SUPERPLADO = cisplatin, doxorubicin, and carboplatin; THP = tetrahydropyranyl-adriamycin (pirarubicin); VP = vinorelbine and cisplatin; VPE+ = venous, portal, and extrahepatic involvement; VP16 = etoposide.
aAdapted from Czauderna et al.[65] and Meyers et al.[78]
bStudy closed early because of inferior results in the CDDP/CARBO arm.
INT0098 (CCG/POG) 1989–1992C5V vs. CDDP/DOXOStage I/II: 504-Year EFS/OS:
I/II = 88%/100% vs. 96%/96%
Stage III: 83III = 60%/68% vs. 68%/71%
Stage IV: 40IV = 14%/33% vs. 37%/42%
P9645 (COG) b1999–2002C5V vs. CDDP/CARBOStage I/II: Pending publication1-Year EFS:
I/II: Pending publication
Stage III: 38III/IV: C5V = 51%; CDDP/CARBO = 37%
Stage IV: 50
HB 94 (GPOH)1994–1997I/II: IFOS/CDDP/DOXOStage I: 274-Year EFS/OS:
I = 89%/96%
Stage II: 3II = 100%/100%
III/IV: IFOS/CDDP/DOXO + VP/CARBOStage III: 25III = 68%/76%
Stage IV: 14IV = 21%/36%
HB 99 (GPOH)1999–2004SR: IPASR: 583-Year EFS/OS:
SR = 90%/88%
HR: CARBO/VP16HR: 42HR = 52%/55%
SIOPEL-2 1994–1998SR: PLADOPRETEXT I: 63-Year EFS/OS:
SR: 73%/91%
PRETEXT II: 36
PRETEXT III: 25
HR: CDDP/CARBO/DOXOPRETEXT IV: 21HR: IV = 48%/61%
Metastases: 25HR: metastases = 36%/44%
SIOPEL-3 1998–2006SR: CDDP vs. PLADOSR: PRETEXT I: 183-Year EFS/OS:
SR: CDDP = 83%/95%; PLADO = 85%/93%
PRETEXT II: 133
PRETEXT III: 104
HR: SUPERPLADOHR: PRETEXT IV: 74HR: Overall = 65%/69%
VPE+: 70
Metastases: 70Metastases = 57%/63%
AFP <100 ng/mL: 12
SIOPEL-4 2005–2009HR: Block A: Weekly; CDDP/3 weekly DOXO; Block B: CARBO/DOXOPRETEXT I: 23-Year EFS/OS:
All HR = 76%/83%
PRETEXT II: 17
PRETEXT III: 27
PRETEXT IV: 16HR: IV = 75%/88%
Metastases: 39HR: Metastases = 77%/79%
JPLT-1 1991–1999I/II: CDDP(30)/THP-DOXOStage I: 95-Year EFS/OS:
I = NR/100%
Stage II: 32II = NR/76%
III/IV: CDDP(60)/THP-DOXOStage IIIa: 48IIIa = NR/50%
Stage IIIb: 25IIIb = NR/64%
Stage IV: 20IV = NR/77%
JPLT-2 1999–2010I: Low-dose CDDP-pirarubicinPRETEXT I–IV: 2125-Year EFS/OS:
I = NR/100%
II–IV: CITAII = NR/89%
III = NR/93%
IV = NR/63%
Metastases: High dose chemotherapy + stem cell transplantMetastases = 32%

Treatment options for hepatoblastoma that is resectable at diagnosis

Approximately 20% to 30% of children with hepatoblastoma have resectable disease at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRETEXT I tumors and PRETEXT II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins.
Prognosis varies depending on the histologic subtype, as follows:
  • Patients with well-differentiated fetal histology (4% of hepatoblastomas) have a 3- to 5-year OS rate of 100% with minimal or no adjuvant chemotherapy.[47,61,69]
  • Patients with non–well-differentiated fetal histology, non–small cell undifferentiated hepatoblastomas have a 3- to 4-year OS rate of 90% to 100% with adjuvant chemotherapy.[47,48,58,61,79]
  • If any small cell undifferentiated elements are present, the 3-year survival rate is 40% to 70%.[60,61]
Treatment options for hepatoblastoma resectable at diagnosis showing non–well-differentiated fetal histology include the following:
  1. Resection followed by two to four cycles of chemotherapy.
Re-resection of positive microscopic margins may not be necessary. Conclusive evidence is lacking for tumors with resection at diagnosis compared with those with positive microscopic margins resected after preoperative chemotherapy.
Evidence (gross surgical resection [with or without microscopic margins] and postoperative chemotherapy):
  1. Gross surgical excision with or without microscopic margins is followed by four courses of combination chemotherapy with cisplatin, vincristine, and fluorouracil or cisplatin and doxorubicin or cisplatin alone.[46-48,58]
    Second resection of positive margins and/or radiation therapy may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic and who receive subsequent chemotherapy.[54,62]
  2. There is no reliable data for local recurrence risk in patients with a positive microscopic margin status who were resected at diagnosis.[49] SIOPEL studies suggest that in patients who received preoperative chemotherapy, positive microscopic margin did not increase risk of local recurrence.[54,58,62]
    • In a European study conducted between 1990 and 1994, 11 patients had tumor found at the surgical margins after hepatic resection and two patients died, neither of whom had a local recurrence. None of the 11 patients underwent a second resection and only one patient received radiation therapy postoperatively. All of the patients were treated with four courses of cisplatin and doxorubicin before surgery and received two courses of postoperative chemotherapy.[54]
    • In another European study of high-risk hepatoblastoma, 11 patients had microscopic residual tumor remaining after initial surgery and received two to four postoperative cycles of chemotherapy with no additional surgery. Of these 11 patients, 9 survived.[62]
    • In the SIOPEL-2 study, 13 of 13 patients with microscopic positive resection margins survived.[58]
  3. A randomized clinical trial demonstrated comparable efficacy with postoperative cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma.[47]
    • Although outcome was nominally higher for the children who received cisplatin/doxorubicin, this difference was not statistically significant.
    • The combination of cisplatin/vincristine/fluorouracil was significantly less toxic than the doses of cisplatin/doxorubicin, to which it was compared.
Results of chemotherapy clinical trials are described in Table 6.
Treatment options for hepatoblastoma of well-differentiated fetal (pure fetal) histology resectable at diagnosis include the following:
  1. Complete surgical resection followed by watchful waiting or chemotherapy.[69]
Evidence (complete surgical resection followed by watchful waiting or chemotherapy):
  1. In the COG prospective clinical trial (INT0098), nine children with stage I (completely resected) well-differentiated fetal histology and fewer than two mitoses per high-power field were treated with adjuvant doxorubicin for four cycles.[47]
    • At a median follow-up of 5.1 years, the EFS and OS were 100% for all nine children.
  2. In the COG P9645 (NCT00003994) study, 16 patients with stage I (completely resected) tumor had well-differentiated fetal histology and received no adjuvant chemotherapy. In a retrospective PRETEXT classification of 21 of these 25 patients with adequate data, PRETEXT I, II, and III were found in 7, 10, and 4 patients, respectively.[69]
    • The EFS and OS were 100% for patients with stage I well-differentiated fetal histology, including one patient who had a second surgery to address a positive tumor margin.
  3. Treatment of a small focus of undifferentiated small cell histology within an otherwise well-differentiated fetal histology tumor with aggressive chemotherapy has been reported in the following small series suggesting the importance of a thorough histologic examination of apparent well-differentiated fetal histology.[77]
    A retrospective study of 16 patients with well-differentiated fetal histology treated at multiple institutions had complete surgical resections, but also had elements of (or, in some case, predominance of) small cell histology found in the resected tumor.[77]
    • Despite receiving postoperative chemotherapy, 10 of 16 patients recurred, and 5 of these patients died of hepatoblastoma.

Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis

Approximately 70% to 80% of children with hepatoblastoma have tumors that are not resected at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend biopsy without an attempt to resect the tumor at diagnosis in children with PRETEXT II tumors with less than 1 cm radiographic margin on the vena cava and middle hepatic vein and in all children with PRETEXT III and IV tumors.
Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery.[80]
Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:
  1. Chemotherapy followed by reassessment of surgical resectability and complete surgical resection.
  2. Chemotherapy followed by reassessment of surgical resectability and orthotopic liver transplant.[48,52,81-86]
  3. Transarterial chemoembolization (TACE). TACE may be used to improve resectability before definitive surgical approaches.[87,88]
In recent years, almost all children with hepatoblastoma have been treated with chemotherapy, and in European centers, children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[48,54,58] Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of well-differentiated fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease.[69] In this study, most patients with PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.
Patients whose tumors remain unresectable after chemotherapy should be considered for liver transplant.[48,52,81-85] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical.[59] In the COG AHEP0731 (NCT00980460) study, early referral (i.e., based on imaging done after the second cycle of chemotherapy) to a liver specialty center with liver transplant capability was recommended for patients with POSTTEXT III tumors with positive V or P and POSTTEXT IV tumors with positive F.
Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection):
  1. In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed.[48]
    • The chemotherapy was well tolerated.
    • Complete resection was obtained in 87% of children.
    • This strategy resulted in an OS rate of 75% at 5 years after diagnosis.
  2. Identical results were seen in a follow-up international study (SIOPEL-2).[58]
  3. The SIOPEL-3 study compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard risk was defined as tumor confined to the liver and not involving more than three sectors.[79][Level of evidence:1iiA]
    • The rates of resection were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
    • The OS rates were also similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
  4. In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma.[62]
    • In 74 patients with PRETEXT IV tumors, 22 of whom also had metastases, 31 became resectable and 26 underwent transplant. The 3-year OS of this group was 69% (± 11%).
    • Of the 70 patients with metastases enrolled in the trial, the 3-year EFS rate was 56% and the OS rate was 62%. Of patients with lung metastases, 50% were able to achieve complete remission of metastases with chemotherapy alone (without lung surgery).
  5. SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients whose tumors were resected or whose livers were transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT II (27%), III (44%), and IV (26%).[55][Level of evidence: 2Dii]
    • Ninety-seven percent of patients (60 of 61) had a partial response with chemotherapy.
    • Eighty-five percent of patients (53) underwent complete macroscopic resection; tumor was microscopically present in five patients, all of whom are disease-free survivors.
    • Two patients died postoperatively.
    • There were 37 partial hepatectomies and 16 liver transplants.
    • The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection. The 3-year disease-free survival (DFS) was 76% (95% CI, 65%–87%), and the 3-year OS was 83% (95% CI, 73%–93%).
    • Of the 16 PRETEXT IV patients, 11 were downstaged after chemotherapy—6 patients to PRETEXT III, 4 patients to PRETEXT II, and 1 patient to PRETEXT I. Twelve tumors became resectable; of these, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease, the 3-year DFS was 73% (95% CI, 51%–96%), and the 3-year OS was 80% (95% CI, 60%–100%).
  6. In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% will survive disease-free.[89]
  7. A combination of ifosfamide, cisplatin, and doxorubicin followed by postinduction resection has also been used in the treatment of advanced-stage disease.[90]
In the United States, unresectable tumors have been treated with chemotherapy before resection or transplant.[45-47,69] On the basis of radiographic imaging, most stage III and IV hepatoblastomas are rendered resectable after two cycles of chemotherapy.[91] Some European centers have also used extended resection of selected POSTTEXT III and IV tumors rather than liver transplant.[59,92-94]
Chemotherapy followed by TACE followed by high-intensity focused ultrasound showed promising results in China for PRETEXT III and IV patients with hepatoblastoma, some of whom were resectable but did not undergo surgical resection because of parent refusal.[95]

Treatment options for hepatoblastoma with metastases at diagnosis

The outcomes of patients with metastatic hepatoblastoma at diagnosis are poor, but long-term survival and cure is possible.[45-47] Survival rates at 3 to 5 years range from 20% to 79%.[55,62,96,97] To date, the best outcomes for children with metastatic hepatoblastoma resulted from treatment with dose-dense cisplatin and doxorubicin, although significant toxicity was also noted (SIOPEL-4 [NCT00077389] trial).[55][Level of evidence: 2Dii]
Treatment options for hepatoblastoma with metastases at diagnosis include the following:
  1. Chemotherapy followed by reassessment of surgical resectability.
    • If the primary tumor and extrahepatic disease (usually pulmonary nodules) are resectable after chemotherapy, surgical resection followed by additional chemotherapy.
    • If extrahepatic metastatic disease is in complete remission after chemotherapy and/or surgical resection of lung nodule but the primary tumor remains unresectable, orthotopic liver transplant.
    • If extrahepatic metastatic disease is not resectable or the patient is not a transplant candidate, additional chemotherapy, TACE, or radiation therapy.
The standard combination chemotherapy regimen in North America is four courses of cisplatin/vincristine/fluorouracil [47] or doxorubicin/cisplatin [48,69,96] followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy are usually given. Study results for different chemotherapy regimens have been reported (refer to Table 6 for more information).
High-dose chemotherapy with stem cell rescue does not appear to be more effective than standard multiagent chemotherapy.[98]
Evidence (chemotherapy to treat metastatic disease at diagnosis):
  1. A subset of 39 patients presenting with metastases were entered on the SIOPEL-4 (NCT00077389) trial, a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Patients whose tumors were resected or livers transplanted after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors were unresectable after three cycles of chemotherapy received two additional cycles of very intensive carboplatin and doxorubicin before surgery.[55][Level of evidence: 2Dii]
    • After three cycles of chemotherapy, there was a complete response (only in the metastases) in 20 of 39 patients and a partial response in 18 of 39 patients. Nineteen of the patients who achieved a complete response were alive without disease 3 years after diagnosis.
    • Of the patients who achieved a partial response, seven patients underwent metastasectomy near the time of resection or liver transplant, with an OS of 100%. An additional seven patients with residual small pulmonary nodules underwent resection without metastasectomy; of those, six patients did well and one patient recurred.
    • Two patients with initial metastases eventually recurred.
    • Liver transplant, rather than resection alone, was needed to treat 7 of the 39 patients who presented with metastases.
    • For the subset of 39 patients presenting with metastases, the 3-year DFS was 77% (95% CI, 63%–90%), and the OS was 79% (95% CI, 66%–92%).
In patients with resected primary tumors, any remaining pulmonary metastasis is surgically removed, if possible.[96] A review of patients treated on a U.S. intergroup trial suggested that resection of metastasis may be done at the time of resection of the primary tumor.[97][Level of evidence: 3iiA]
If extrahepatic disease is in complete remission after chemotherapy, and the primary tumor remains unresectable, an orthotopic liver transplant may be performed.[55,62,69,90]
The outcome results are discrepant for patients with lung metastases at diagnosis who undergo orthotopic liver transplant after complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for these groups,[55,62,85,90] while others have noted high rates of hepatoblastoma recurrence.[52,81,84,87] All of these studies are limited by small patient numbers; additional study is needed to better define outcomes for this subset of patients. Recent clinical trials have resulted in few pulmonary recurrences in children who underwent liver transplants and presented with metastatic disease.[55,62,99]
If extrahepatic disease is not resectable after chemotherapy or the patient is not a transplant candidate, alternative treatment approaches include the following:
  • Nonstandard chemotherapy agents. Nonstandard chemotherapy agents such as irinotecan, high-dose cisplatin/etoposide, or continuous-infusion doxorubicin have been used.[100-102]; [103][Level of evidence: 3iiA]
  • TACE.[88,104]
  • Radiation therapy.[105]

Treatment options for progressive or recurrent hepatoblastoma

The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following:[106]
  • Site of recurrence.
  • Previous treatment.
  • Individual patient considerations.
Treatment options for progressive or recurrent hepatoblastoma include the following:
  1. Surgical resection. In patients with hepatoblastoma that is completely resected at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease, in conjunction with an overall strategy that includes appropriate chemotherapy, may make extended disease-free survival possible.[97,106,107]
    If possible, isolated metastases are resected completely in patients whose primary tumor is controlled.[108] A retrospective study of patients in SIOPEL studies 1, 2, and 3 showed a 12% incidence of recurrence after complete remission by imaging and AFP. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, the 3-year EFS was 34%, and the OS was 43%.[106][Level of evidence: 3iiA] Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma.[109][Level of evidence: 3iiiB]
    Enrollment in a clinical trial should be considered if all of the recurrent disease cannot be surgically removed. Phase I and phase II clinical trials may be appropriate and should be considered.
  2. Chemotherapy. Analysis of survival after recurrence demonstrated that some patients treated with cisplatin/vincristine/fluorouracil could be salvaged with doxorubicin-containing regimens, but patients treated with doxorubicin/cisplatin could not be salvaged with vincristine/fluorouracil.[110] Addition of doxorubicin to vincristine/fluorouracil/cisplatin is under clinical evaluation in the COG study AHEP0731 [NCT00980460]. Combined vincristine/irinotecan and single-agent irinotecan have been used with some success.[103]; [102][Level of evidence: 3iiiA]
    A review of COG phase I and II studies found no promising agents for relapsed hepatoblastoma.[111]
  3. Liver transplant. Liver transplant should be considered for patients with nonmetastatic disease recurrence in the liver that is not amenable to resection.[52,81,84]
  4. Percutaneous ablation. Percutaneous ablation techniques may also be considered for palliation [112] or, in some cases, for curative therapy of oligometastatic disease.[109][Level of evidence: 3iiiB]

Treatment options under clinical evaluation for hepatoblastoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
  • AHEP1531 (NCT03533582) (Cisplatin and Combination Chemotherapy in Treating Children and Young Adults with Hepatoblastoma or Liver Cancer After Surgery):
    This is the COG's participation in a large international trial (PHITT) of treatment of all stages of hepatoblastoma and hepatocellular carcinoma in children.
    • Very low-risk hepatoblastoma is defined as either: 1) a well differentiated fetal mass completely resected at diagnosis, and these patients are treated with no chemotherapy; or 2) a non–well differentiated fetal mass or incompletely resected well differentiated fetal mass, and these patients are treated with two cycles of cisplatin chemotherapy.
    • Low-risk hepatoblastoma is defined as a PRETEXT I to III tumor without any positive VPEFR annotation factors (venous involvement, portal involvement, extrahepatic spread, multifocality, and tumor rupture). These patients are treated with two cycles of cisplatin chemotherapy and then undergo resection (if possible) followed by randomization between two and four more cycles of cisplatin. If the tumor is unresectable, the patient receives two more cycles of cisplatin chemotherapy, and the tumor's resectability is reassessed. If it is still unresectable, patients undergo liver transplant.
    • Intermediate-risk hepatoblastoma is defined as a PRETEXT I to III primary tumor with a positive VPEFR annotation factor but without metastasis. Patients are randomly assigned to either four 14-day cycles of cisplatin or four 21-day cycles of C5VD (cisplatin, fluorouracil, vincristine, and doxorubicin). Transplant teams are consulted early as needed. Patients in both arms then undergo resection and receive two more cycles of their assigned chemotherapy.
    • High-risk hepatoblastoma is defined as presence of distant metastasis or AFP less than 100 or age 8 years and older. All patients are treated with three cycles of induction chemotherapy per the SIOPEL-4 trial (dose-intensive cisplatin, doxorubicin, and carboplatin). The patients aged 8 years and older or with AFP less than 100 and those whose metastases have cleared receive three cycles of carboplatin and doxorubicin. Patients with metastases that have not cleared by end of induction are randomly assigned to receive either carboplatin/doxorubicin cycles alternating with carboplatin/etoposide for six cycles or carboplatin/doxorubicin alternating with vincristine/irinotecan for six cycles.
    • Hepatocellular carcinoma that is potentially resectable is treated with complete resection without any chemotherapy if the mass appears to derive from underlying liver disease. If the hepatocellular carcinoma appears to be de novo without underlying disease, it is treated with resection followed by four cycles of cisplatin/doxorubicin.
    • Patients with hepatocellular carcinoma that is metastatic or appears unresectable at diagnosis undergo consultation with interventional radiology and liver transplant services. Patients are then randomly assigned to receive either cisplatin/doxorubicin/sorafenib for three 21-day cycles or cisplatin/doxorubicin/sorafenib alternating with gemcitabine/oxaliplatin/sorafenib for four 14-day cycles. Responding patients continue chemotherapy for the same number of cycles (3 or 4); they receive the same chemotherapy regimen to which they were originally assigned.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

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Childhood Liver Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute
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