Pediatric Hepatoblastoma Treatment & Management

Updated: Sep 15, 2017
  • Author: Jennifer Reikes Willert, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Treatment

Medical Care

European groups, such as the International Society for Paediatric Oncology (SIOP), and groups in the United Kingdom and Australia, have been instrumental in demonstrating a role for preoperative adjuvant chemotherapy in improving surgical and overall outcomes. The European cooperative groups have also been very influential in encouraging a role for liver transplantation in patients with tumors deemed nonresectable. They have also developed criteria that can be used to determine which patients will benefit most from preoperative adjuvant chemotherapy as well as which patients should be referred early on for consideration for liver transplantation.

  • Chemotherapy

    • The most important advance in the care of children with hepatoblastoma has been the discovery of effective chemotherapy. Initial reports showed the efficacy of vincristine (VCR), cyclophosphamide (CPM), and doxorubicin with 5-fluorouracil (5-FU). This regimen was based on reports that suggested the efficacy of these agents in children and adults with liver tumors.

    • Cisplatin is the most active single agent used to treat hepatoblastoma. Doxorubicin is active as well. These agents are currently being combined in clinical trials. Attempts to reduce the ototoxic effects of cisplatin have led to the use of carboplatin; however, whether this agent will be as effective as cisplatin against hepatoblastoma remains to be seen. No direct randomized control trial has addressed this question to date.

    • The Intergroup Liver Tumor study showed similar efficacy of the cisplatin/5-FU/VCR regimen and the cisplatin plus doxorubicin regimen. [31] Because the latter regimen was more toxic, the cisplatin/5-FU/VCR combination is regarded as standard in hepatoblastoma. The Intergroup Liver Tumor study demonstrated that intensification of therapy by alternating platinum analogs increased the risk of adverse outcome in children with unresectable or metastatic hepatoblastoma. The cisplatin/5-FU/VCR regimen was shown to be superior in this trial. Early referral for evaluation for liver transplantation is encouraged in these patients.

    • Preoperative chemotherapy can completely eradicate metastatic pulmonary disease and multinodular liver disease. Some authors recommend that all patients undergo preoperative chemotherapy, although patients may present in a setting in which resection occurs first.

    • Chemotherapy is usually started approximately 4 weeks after surgery to allow liver regeneration. A minimum of 2 weeks should pass after surgery before administration of cytotoxic agents.

    • Recent international data continue to support the role of neoadjuvant preoperative chemotherapy with improvements in survival. Data from Italy in a cohort of 13 children with hepatoblastoma also support a role for etoposide and epirubicin when combined with cisplatin, with event-free survival (EFS) and overall survival rates at 5 years of 84% and 88%, respectively. [32]

    • Perilongo et al studied whether preoperative cisplatin alone is as effective as cisplatin plus doxorubicin in standard risk hepatoblastoma. [33] Children younger than 16 years were included in the study (n=126) and randomly assigned to receive cisplatin alone or cisplatin plus doxorubicin. Three-year EFS was 83% for cisplatin and 85% in the cisplatin/doxorubicin group. Overall survival in the cisplatin alone group was 95% compared with 93% in the cisplatin/doxorubicin group. Each treatment arm achieved similar rates of completed resection and survival.

    • Treatment usually consists of 6 cycles of chemotherapy administered every 2-4 weeks; α -fetoprotein (AFP) levels are used as a guide to determine response to therapy.

      • A retrospective study of 20 pediatric patients with grade III and IV surgically unresectable hepatoblastomas by Venkatramani et al found that many cases were resectable after just two cycles of neoadjuvant chemotherapy. [34, 35] At initial diagnosis, 16 of the 20 tumors (80%) were considered unresectable. [35] After two courses of chemotherapy, seven (35%) were considered unresectable, and after four courses of chemotherapy, four (20%) were considered unresectable. All four of the tumors considered unresectable after four cycles of chemotherapy would have qualified for liver transplantation.

    • In addition to the drugs discussed above, carboplatin and etoposide have been used along with liver transplantation for advanced or recurrent disease with some success. Paclitaxel is also used in patients with extremely high-risk disease.

    • Use of neoadjuvant (preoperative) chemotherapy can often render a previously inoperable tumor more easily resectable. Some data from tumor xenografts suggest that these tumors may respond to irinotecan. Irinotecan has indeed shown activity in relapsed or refractory hepatoblastoma but has not yet been used for front-line therapy.

    • Gemcitabine has been used with some partial responses in phase II trials. Combination therapy with other agents may improve outcomes in patients with relapsed/recurrent disease, perhaps providing decreased time to progression.

    • An approach with limited pediatric application is hepatic artery chemoembolization (HACE), which has been used successfully in some liver tumors in adults.

    • Promising studies performed in mice suggest a role for antiangiogenic agents, such as vascular endothelial growth factor (VEGF), in suppressing tumor growth in hepatoblastoma. [36] A considerable amount of preclinical data have also demonstrated a role for multidrug resistance 1 (MDR1) inhibition as potentially leading to an improved response to chemotherapy in tumors that have otherwise become refractory to treatment because of a drug resistance mechanism. [37, 38]

    • A few isolated studies have reported patients receiving only chemotherapy with survival at greater than 5 years. [39]

    • New agents such as ixabepilone, [40] gemcitabine, and bevacizumab (Avastin) have shown efficacy with tolerable side effect and the ability to administer on an outpatient basis. Bevacizumab is associated with side effects such as hypertension, leukoencephalopathy and wound-healing complications that must be taken into consideration. [41]

    • Increasingly, "personalized" oncology evaluations that include assays to evaluate which pathways are most susceptible for relapsed patients are under investigation.

  • Radiotherapy

    • Doses used for treatment of hepatoblastoma are usually 1200-2000 centigray (cGy). These dose limits are based on the liver's limited ability to regenerate after radiation.

    • Radiotherapy may be used when microscopic disease is seen at the resection margins; in general, preoperative chemotherapy should minimize this.

    • Adjuvant radiotherapy may have a role in the treatment of chemoresistant pulmonary metastases.

    • Photodynamic diagnostics and therapy in hepatoblastoma cell lines and animal models are under investigation.

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Surgical Care

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  • Because of the rarity of this disease and to optimize results, children with extensive hepatoblastoma should be managed and treated in centers affiliated with experienced liver transplant teams and with surgeons familiar with this diagnosis and familiar with complex decisions regarding planning for resection. These surgical and liver transplant teams work closely with oncologists, pathologists, and radiologists to provide optimal outcomes.

  • The hepatoblastoma can be completely resected at diagnosis in approximately one third of patients, those who have stage I or II disease. In 60% of patients, hepatoblastomas are localized but are unresectable at diagnosis. Approximately 10% of patients have metastases at diagnosis, most commonly to the lungs. These figures vary depending on the age of the patient at diagnosis, the size of the tumor, and the expertise of the surgical staff available for the procedure. Heroic efforts to resect tumors "up front" should be avoided, and adjuvant chemotherapy should be strongly considered when subtotal resection with microscopic margins is possible or when surgical morbidity is expected to be high.

  • Initial resection of operable primary tumors by lobectomy is the standard of care. Occasionally, pulmonary lesions are resected. This can occur after chemotherapy as well, with the ultimate goal for negative surgical margins for all disease.

  • The following cases warrant early referral to a transplant surgeon:

    • Multifocal or large solitary lesions

    • Tumors involving all 4 sectors of the liver

    • Unifocal, centrally located tumors that involve the main hilar structures or main hepatic veins

  • Second-look laparotomy is warranted if AFP levels remain elevated following resection. Local porta hepatis nodal sampling is performed rather than true nodal dissection because nodal involvement is rare.

  • The most frequent complication of surgery is intraoperative hemorrhage; loss of the entire blood volume is not uncommon.

  • In cases involving a substantial portion of the liver, particularly when diaphragmatic extension precludes complete surgical resection, liver transplantation has been advocated. Liver transplantation has also been considered in the presence of unresectable disease following neoadjuvant (preoperative) or adjuvant (postoperative) chemotherapy. Living related-donor transplantation may be considered in some situations as well. Early involvement of the liver transplant team and the hepatology team is essential because delays can adversely affect outcomes.

  • Results from numerous cooperative international large group studies on hepatoblastoma continue to support a role for preoperative adjuvant chemotherapy in those tumors not easily respectable up front. [4, 42, 43, 44, 27] Some authors advocate using adjuvant chemotherapy preoperatively, even when resection may be successful up front. The controversy over this is considerable, [45] but all are in agreement that complete resection with no residual disease is ultimately the most important prognostic factor for improved survival results in hepatoblastoma. Hence, any treatment, medical or surgical, that leads to an improvement in gross total resection is the goal.

  • Increasing evidence suggests that arterial chemoembolization is feasible in patients with unresectable hepatoblastoma, patients who are not candidates for liver transplant, or both.

  • Liver transplantation has an increasing role in children with nonresectable tumors or in those who show chemotherapy resistance. Overall 5-year survival is as high as 70-89% in some series. Early referral and collaboration with liver transplant centers is encouraged. Whether posttransplant chemotherapy is indicated is controversial.

  • Thoracotomy and resection of pulmonary metastases also have a role, with some patients having long-term disease-free survival when aggressive attempts are made to surgically eradicate all areas of disease.

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Consultations

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  • A multidisciplinary approach in children with malignancy is necessary to ensure that appropriate care is safely administered with minimal toxicity. The team usually consists of specialized pediatric nurses, pediatric surgeons, pharmacologists with expertise in dealing with chemotherapy in children, nutritionists, social workers, child life specialists, and subspecialists in areas such as pediatric gastroenterology, neurology, cardiology, and infectious diseases.

  • Early referral to liver transplant centers is encouraged for nonresectable tumors or those that show chemotherapy resistance.

  • Referral to a radiation oncologist with pediatric experience may also be indicated.

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Diet

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  • Adequate nutrition is necessary for childhood growth and development. Maintaining adequate nutritional status is also important to maximize response to therapy.

  • Many of the treatments may result in compromised nutritional status. Children undergoing radiotherapy or chemotherapy, particularly children younger than 5 years, typically require enteral or parenteral supplementation, often with electrolyte supplementation as well.

  • Occupational therapists and child life specialists may be consulted to help with behavioral issues related to feeding, particularly in infants and toddlers.

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Activity

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  • Specific postoperative limitations on activity may be necessary, and, occasionally, some activities are limited because of central line placement or severe immunosuppression and myelosuppression associated with therapy; otherwise, no specific limitations are placed on activity.

  • Most children are encouraged to attend daycare or school and participate in normal play essential to childhood development. Contact sports should be avoided during therapy, especially during periods of thrombocytopenia.

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