Treatment Option Overview

Surgical Approaches
        Orthotopic liver transplantation
        Special considerations for surgical resection
Chemotherapy
        Presurgical chemotherapy
        Postsurgical chemotherapy
        Chemotherapy and metastatic disease
Limited Role for Radiation Therapy
Other Treatment Approaches

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ¹ for more information.)

Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment, comparing the results with those previously obtained with standard therapy.

Because of the relative rarity of cancer in children, all children with liver cancer should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimum treatment.[1]

Historically, complete surgical resection of the primary tumor has been required to cure malignant liver tumors in children.[2-5]; [6][Level of evidence: 3iiA] Complete surgical resection of the primary tumor continues to be the goal of definitive surgical procedures, but surgical resection is often combined with other treatment modalities (e.g., chemotherapy) to achieve this goal.

Surgical Approaches

There are three ways in which surgery is used to treat primary pediatric liver cancer:

• Initial surgical resection (alone or followed by chemotherapy).
• Delayed surgical resection (chemotherapy followed by surgery).
• Orthotopic liver transplantation.

The timing of the surgical approach is critical. For this reason, surgeons with experience in pediatric liver resection and transplantation should be involved early in the decision-making process for determining optimal timing and extent of resection.

If the tumor can be completely excised by an experienced surgical team, less postoperative chemotherapy may be needed. If preoperative chemotherapy is to be administered, it is very important to consult frequently with the surgical team concerning the timing of resection, as prolonged chemotherapy can lead to unnecessary delays and in rare cases, tumor progression.

Early involvement with an experienced pediatric liver surgeon is especially important in patients with PRETEXT stage 3 or 4 disease, patients with involvement of major liver vessels, and patients with low alpha-fetoprotein (AFP) levels.[7] While vascular involvement was initially thought to be a contraindication to resection, experienced liver surgeons are able to perform aggressive approaches avoiding transplantation.[7,8]; [9][Level of evidence: 3iiA] In a group of adult patients that were initially thought to be nonresectable, 85% of the patients were resected using an aggressive approach to the tumor with a mortality rate of 6%.[8] The resection margins were clear in over 90% of the patients. Accomplishing a complete resection is imperative since rescue transplant of incompletely resected patients has an inferior outcome compared to patients who are transplanted as the primary surgical therapy.[10]

The decision as to which surgical approach to use depends on many factors including the following:

• PRETEXT stage.
• Size of the primary tumor.
• Presence of multifocal hepatic disease.
• Vascular involvement.
• AFP levels.
• Whether preoperative chemotherapy may convert an unresectable tumor into a potentially resectable tumor.
• Whether hepatic disease meets surgical and histopathologic criteria for orthotopic liver transplantation.

In North American clinical trials, the Children's Oncology Group (COG) has recommended that surgery be performed initially if a complete resection can be accomplished (see the Postsurgical Staging for Childhood Liver Cancer ² section for more information). In European clinical trials, using the Presurgical Staging system (see Presurgical Staging for Hepatoblastoma and Hepatocellular Carcinoma ³ section for more information), only patients with PRETEXT stage 1 receive resection surgery and all other patients are biopsied. COG is investigating the use of PRETEXT stage at diagnosis and after chemotherapy to determine the optimal surgical approach and its timing (COG-AHEP0731 ⁴).

It is difficult to compare the North American and European approaches. However, somewhat comparable results for children with PRETEXT stage 1 and 2 tumors were obtained in two international studies in which children with stage 2 disease were treated with delayed surgery (chemotherapy with doxorubicin/cisplatin or cisplatin alone prior to attempted surgical resection of the primary liver tumor). Patients with PRETEXT stage 1 tumors were treated with initial surgery (chemotherapy was given following complete resection).[11,12] Patients with PRETEXT stage 3 tumors were treated with neoadjuvant chemotherapy (four cycles of cisplatin/doxorubicin or cisplatin/vincristine/fluorouracil) with reassessment of resectability and resection if possible, followed by two more cycles of chemotherapy. The overall survival (OS) was 75% at 5 years. The 5-year survival of PRETEXT stage 1 and 2 patients is 90% to 100% on the European studies and seems to be similar to that of children treated on North American studies where surgery was performed before chemotherapy. In comparison, a survey of children with liver tumors who were treated prior to the consistent use of combination chemotherapy found that 45 of 78 patients (57%) with hepatoblastoma who had complete excision of the tumor survived while no children with positive margins or gross disease following resection survived.[3]

Orthotopic liver transplantation

Liver transplantation has recently been associated with significant success in the treatment of children with unresectable hepatic tumors.[13-15][Level of evidence: 3iiA] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas.[10,16,17] Intravenous invasion, positive lymph nodes, and contiguous spread did not have a significant adverse effect on outcome. It has been suggested that adjuvant chemotherapy following transplant may decrease the risk of tumor recurrence.[18]

There are discrepant results on the outcomes for patients with lung metastases at diagnosis who undergo orthotopic liver transplantation following complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for this group of patients,[10] while others have noted high rates of hepatoblastoma recurrence.[17,19] All of these studies are limited by small patient numbers; further study is needed to better define outcomes for this subset of patients.

The United Network for Organ Sharing (UNOS) Standard Transplant and Research Files registry reported all children younger than 18 years listed for a liver transplant in the United States from October 1987 through July 2004. Of these children, 135 had hepatoblastoma and 41 had hepatocellular carcinoma and both groups received liver transplant with 5-year survival rates of 69% for hepatoblastoma and 63% for hepatocellular carcinoma. The 10-year survival rates were similar to the 5-year rates.[20,21] In a separate three-institution study for children with hepatocellular carcinoma, the overall 5-year disease-free survival rate was approximately 60%.[22] Application of the Milan criteria for UNOS selection of recipients of deceased donor livers is controversial.[23] However, living donor liver transplants are more common with children and the outcome is similar.[19,24] In hepatocellular carcinoma, vascular invasion, distant metastases, lymph node involvement, tumor size, and male gender were significant risk factors for recurrence. Because of the poor prognosis in patients with hepatocellular carcinoma, liver transplant should be considered for disorders such as tyrosinemia and familial intrahepatic cholestasis early in the course, prior to the development of liver failure and malignancy.

Special considerations for surgical resection

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.[25]

Microscopic residual disease after resection

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.[17,26] In a European study conducted between 1990 and 1994, 11 patients had tumor found at the surgical margins following hepatic resection and only 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 prior to surgery and received two courses of postoperative chemotherapy. 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.[17]

Surgical resection for metastatic disease

Surgical resection of distant disease has also contributed to the cure of children with hepatoblastoma. Resection of pulmonary metastases is recommended when the number of metastases is limited [27,28] and is often performed at the same time as resection of the primary tumor. When possible, resection of areas of locally invasive disease, such as in the diaphragm, and of isolated brain metastasis is recommended.[29]

Chemotherapy

In recent years, virtually all children with hepatoblastoma have been treated with chemotherapy, and in some centers, even children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[11,12,26]

Presurgical chemotherapy

In an international study, pre-resection neoadjuvant chemotherapy (doxorubicin and cisplatin) was given to all children with PRETEXT stage 2, 3, or 4 hepatoblastoma with or without metastases. The chemotherapy was well tolerated. PRETEXT stage 1 hepatoblastoma was resected and treated with the same chemotherapy. Following chemotherapy, and excluding those who received liver transplant (less than 5% of patients), complete resection was obtained in 87% of children. This strategy resulted in an OS of 75% at 5 years after diagnosis for all children entered in the study.[11] Identical overall results were seen in a follow-up international study.[12] The Childhood Liver Tumour Strategy Group (SIOPEL) compared cisplatin 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. The rates of resection were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups, as were OS (95% and 93%), respectively.[30][Level of evidence:1iiA] Another SIOPEL study of high-risk hepatoblastoma treated patients with cisplatin alternating with carboplatin/doxorubicin in a dose intensive fashion. In 74 patients with PRETEXT stage 4 tumors, 22 of whom also had metastases, 31 became resectable and 26 underwent transplant. The 3-year OS of this group was 69% ± 11%. The 3-year OS of all patients with metastases was 62% ± 12%.[17]

Postsurgical chemotherapy

In contrast, an American Intergroup protocol for treatment of children with hepatoblastoma, encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The protocol (COG-P9645 ⁵) did not treat children with stage I tumors of purely fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease. Further study will be needed to determine whether presurgical chemotherapy is preferable to resection followed by chemotherapy for children with PRETEXT stage 2, 3, and 4 hepatoblastoma.

Chemotherapy and metastatic disease

In rare cases, chemotherapy has eradicated pulmonary metastases and eliminated multinodular tumor foci in the liver. Intensive platinum- and doxorubicin-based multidrug chemotherapy can induce complete regressions in approximately 50% of patients, with subsequent 3-year event-free survival of 56%.[17] Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.[4,5,11,12,31-33]

Limited Role for Radiation Therapy

The utility of radiation therapy is questioned because the liver cannot tolerate high doses of radiation.[32,34]

Radiation therapy, even in combination with chemotherapy, has not cured children with nonresectable tumors. There may be a role for radiation therapy in the management of incompletely resected hepatoblastoma,[32,34] although a study of 154 patients with hepatoblastoma did not confirm this finding.[26] This study showed that second resection of positive margins and/or radiation therapy may not be necessary in patients with incompletely resected hepatoblastoma whose residual tumor is microscopic.[26]

For patients with stage IV disease in which extrahepatic disease is controlled, but the primary tumor remains unresectable following standard chemotherapy, radiation therapy has been used as an interim treatment measure prior to surgical re-exploration.

Other Treatment Approaches

Other treatment approaches such as transarterial chemoembolization, have been used for patients with postsurgically-staged stage III hepatoblastoma.[35,36]

Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[37-39] Some local approaches such as cryosurgery, radiofrequency ablation, and transarterial chemoembolization that suppress hepatocellular carcinoma tumor progression are used as bridging therapy in adults to delay tumor growth while on a waiting list for cadaveric liver transplant.[40] Transarterial chemoembolization has been used in a few children to successfully shrink tumor size to permit resection.[36] (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment ⁶ for more information.)

References

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