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, resection of the primary tumor has been required to cure malignant liver tumors in children.[2-6] Since these tumors occur infrequently, surgeons with experience in pediatric liver resection and transplantation should be involved early in the decision making process concerning the timing and extent of resection. Initial resection versus delayed resection will depend upon the size of the tumor, multifocality, and vascular involvement. 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] 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 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.[9]

In pediatric liver tumors there remain two standard surgical approaches: an attempt at initial surgical resection or a biopsy followed by chemotherapy, or a delayed attempt at surgical resection. If 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 timing of resection as prolonged chemotherapy can lead to unnecessary delays and in rare cases even tumor progression. In COG trials, it is currently recommended that surgery be performed initially if a complete resection can be accomplished. In Europe, using the PRETEXT system, only patients with PRETEXT stage 1 receive resection surgery.

Preoperative chemotherapy can convert a nonresectable tumor to a resectable one. Chemotherapy in some cases is able to eradicate pulmonary metastases completely and eliminate multinodular tumor foci in the liver. Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.[5,6,10-14] 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.[13-15] In an international study, preresection treatment with doxorubicin and cisplatin was given to all children with PRETEXT stage 2, 3, or 4 hepatoblastoma with or without metastases and was well tolerated. PRETEXT stage 1 hepatoblastoma was resected and then treated with the same chemotherapy. Following chemotherapy, and excluding those who received liver transplant (<5% of patients), complete resection was obtained in 87% of children. This strategy resulted in an overall survival of 75% at 5 years after diagnosis for all children entered in the study.[13] Identical overall results were seen in a followup international study.[14] In contrast, an American Intergroup protocol for treatment of children with hepatoblastoma, encourages resection at the time of diagnosis for all tumors amenable to resection without undue risk. The protocol (COG-P9645) 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.

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 [16,17] 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.[18] Tumor rupture at presentation resulting in major hemorrhage which 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.[19]

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,[11,20] though a study of 154 patients with hepatoblastoma did not confirm this finding.[15] Eleven patients had tumor found at the surgical margins following hepatic resection and only 2 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 4 courses of cisplatin and doxorubicin prior to surgery and received 2 courses of postoperative chemotherapy. This study shows 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.

Liver transplantation has recently been associated with significant success in the treatment of children with unresectable hepatic tumors. A review of the world experience has documented a posttransplant survival rate of 82% for children with hepatoblastomas.[9] Intravenous invasion, positive lymph nodes, and contiguous spread did not have a significant adverse effect on outcome. The United Network for Organ Sharing (UNOS) Standard Transplant and Research Files registry reported all children less than 18 years of age 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% and 63%, respectively. The 10-year survival rates were similar to the 5-year rates.[21] In a separate three-institution study for children with hepatocellular carcinoma, the overall 5-year disease-free survival rate was approximately 60%.[22] In hepatocellular carcinoma, vascular invasion, distant metastases, lymph node involvement, tumor size, and male gender were significant risk factors for recurrence. Pretransplant intra-arterial therapy was very effective in patients with hepatoblastoma but less efficacious in children with hepatocellular carcinoma. 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.

References

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