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

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

Treatment Option Overview for Childhood Liver Cancer

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 and 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 onto a clinical trial when one is available. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimal treatment.[1]

Surgery

Historically, complete surgical resection of the primary tumor has been required to cure malignant liver tumors in children.[2-6]; [7][Level of evidence: 3iiiA] This approach continues to be the goal of definitive surgical procedures, which are often combined with chemotherapy. In patients with advanced hepatoblastoma, postoperative complications are associated with worsened overall survival.[8]

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 (preceded by chemotherapy).
Orthotopic liver (cadaveric and living donor) transplant (most often preceded by chemotherapy).

The timing of the surgical approach is critical. For this reason, surgeons who have experience performing pediatric liver resections and transplants are involved early in the decision-making process for determining optimal timing and extent of resection. Also, the rarity of liver tumors in children has resulted in limited experience and exposure of surgeons to these procedures. In some cases, the patient may need to be referred to another institution for surgery or, more commonly, for liver transplant. Consultation with the surgeon should occur shortly after diagnosis.

In children and adolescents with primary liver tumors, the surgeon has to be prepared to perform a highly sophisticated liver resection after confirmation of the diagnosis by pathological investigation of intraoperative frozen sections. While complete surgical resection is important for all liver tumors, it is especially true for hepatocellular carcinoma because curative chemotherapy is not available. Intraoperative ultrasonography may result in further delineation of tumor extent and location and can affect intraoperative management.[9]

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

Early involvement with an experienced pediatric liver surgeon is especially important in patients with PRE-Treatment EXTent of disease (PRETEXT) group III or IV or involvement of major liver vessels (positive annotation factors V [venous] or P [portal]).[10] Although vascular involvement was initially thought to be a contraindication to resection, experienced liver surgeons are sometimes able to successfully resect the tumor and avoid performing a transplant.[11-13]; [14][Level of evidence: 3iiA] Accomplishing the appropriate surgery at resection is critical. Margin-negative resection is imperative because patients who undergo rescue transplants of incompletely resected tumors have an inferior outcome compared with patients who undergo transplant as the primary surgical therapy.[15][Level of evidence: 3iiiA]

The decision as to which surgical approach to use (e.g., partial hepatectomy, extended resection, or transplant) depends on many factors, including the following:

PRETEXT group and POST-Treatment EXTent of disease (POSTTEXT) group.
Size of the primary tumor.
Presence of multifocal hepatic disease.
Gross vascular involvement.
Alpha-fetoprotein (AFP) levels.
Whether preoperative chemotherapy is potentially likely to convert an unresectable tumor into a resectable tumor.
Whether hepatic disease meets surgical and histopathologic criteria for orthotopic liver transplantation.

The approach taken by the Children's Oncology Group (COG) in North American clinical trials is to perform surgery initially when a complete resection can be accomplished with a simple, negative-margin hemihepatectomy. The COG study AHEP0731 (NCT00980460) has studied the use of PRETEXT and POSTTEXT to determine the optimal approach and timing of surgery. POSTTEXT imaging grouping is performed after two and four cycles of chemotherapy to determine the optimal time for definitive surgery (refer to the Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer section of this summary for more information).[6,16]

Orthotopic liver transplant

Liver transplants have been associated with significant success in the treatment of children with unresectable hepatic tumors.[17]; [18-20][Level of evidence: 3iiA] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas.[15,21-23] Intravenous vascular invasion, positive lymph nodes, and contiguous extrahepatic spread did not have a significant adverse effect on outcome. It has been suggested that adjuvant chemotherapy after transplant may decrease the risk of tumor recurrence but its use has not been studied definitively in a randomized clinical trial.[24]

Evidence (orthotopic liver transplant):

The United Network for Organ Sharing (UNOS) database was queried for all patients younger than 18 years old with a primary malignant liver tumor who underwent an orthotopic liver transplant between 1987 and 2012 (N = 544). The patients were diagnosed with hepatoblastoma (n = 376, 70%), hepatocellular carcinoma (n = 84, 15%), and other (n = 84, 15%). Patients with hepatocellular carcinoma were older, more often hospitalized at the time of transplant, and more likely to receive a cadaveric organ than were patients with hepatoblastoma.
1. Five-year patient survival was 73% and graft survival was 74% for the entire cohort, with most deaths resulting from malignancy. On multivariate analysis, independent predictors of 5-year patient and graft survival included the following:[25]
  1. Diagnosis.
    
    For the study period of 1987 to 2012, the 5-year patient survival rate was 76% and the graft survival was 77% for hepatoblastoma; the survival rate was 63% and graft survival rate was 63% for hepatocellular carcinoma.
    
    For the study period of 2009 to 2012, the 3-year patient survival rate was 84% and the graft survival rate was 84% for hepatoblastoma; the survival rate was 85% and graft survival rate was 85% for hepatocellular carcinoma.
  2. Transplant era.
    
    The death rate by hazard ratio was 1.0 for the period before 2002, 0.72 for the period of 2002 to 2009, and 0.54 for the period of 2009 to 2012.
  3. Medical condition at transplant.
    
    For hepatoblastoma patients, the survival rate by hazard ratio was 1.0 for hospitalized patients versus 1.81 for not hospitalized patients at the time of transplant. For hepatocellular carcinoma patients, the survival rate by hazard ratio was 1.0 for hospitalized patients versus 1.92 for not hospitalized patients.
    
    Patients hospitalized in the intensive care unit did not fare worse.
A report of 149 patients with hepatocellular carcinoma younger than 21 years who underwent transplants between 1987 and 2015 utilized detailed data collected at all U.S. pediatric transplant centers by the U.S. Scientific Registry of Transplant Recipients.[17]
- One-year graft survival was about 85%, which did not differ from the survival for hepatoblastoma or biliary atresia. Survival continued to decline over time, from 85% at 1 year, 52% at 5 years, and 43% at 10 years, which was a more dramatic decline than what was seen for hepatoblastoma or biliary atresia.
- The survival after transplant did not differ from that of adults who underwent transplant for hepatocellular carcinoma.
- Of the hepatocellular carcinoma patients, 22 had hepatocellular carcinoma diagnosed after transplant for medical cirrhotic disease such as tyrosinemia. They had a superior outcome, but it was not statistically significant compared with the rest of the 149 patients.
A review of the Surveillance, Epidemiology, and End Results (SEER) database and numerous single-institution series have reported results similar to the UNOS database study described above.[12,18-20,26]; [23][Level of evidence: 3iiA]
In a three-institution study of children with hepatocellular carcinoma, the overall 5-year disease-free survival rate was approximately 60%.[27]

Application of the Milan criteria for UNOS selection of recipients of deceased donor livers is controversial.[28,29] The Milan criteria for liver transplantation are directed toward adults with cirrhosis and hepatocellular carcinoma. The criteria do not apply to children and adolescents with hepatocellular carcinoma, especially those without cirrhosis. Living-donor liver transplant is more common in children and the outcome is similar to those undergoing cadaveric liver transplant.[30,31] In hepatocellular carcinoma, gross vascular invasion, distant metastases, lymph node involvement, tumor size, and male sex 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, before the development of liver failure and malignancy.

Surgical resection for metastatic disease

Surgical resection is often recommended, but the rate of cure in children with hepatoblastoma has not been fully determined. Resection of metastases, when possible, is often recommended, including the areas of locally invasive disease (e.g., diaphragm) and isolated brain metastases. Resection of pulmonary metastases should be considered if the number of metastases is limited.[32-35] In an American study of 20 patients who presented with pulmonary metastases, only nine patients underwent surgical resection. The timing of pulmonary resection in relation to definitive resection of the primary tumor varied (two patients before, five patients simultaneously, and two patients after primary resection). Eight of the nine patients survived. Of 20 children with relapse restricted to the lungs, all patients received salvage chemotherapy, 13 had pulmonary surgery, 8 had metastasectomy, and 5 had biopsy only. Of these patients, only 4 of 13 were long-term survivors, two of whom presented with stage I disease and two of whom presented with stage IV disease.[34] Radiofrequency ablation has also been used to treat oligometastatic hepatoblastoma when patients prefer to avoid surgical metastasectomy.[36][Level of evidence: 3iiiB]

Chemotherapy

Chemotherapy regimens used in the treatment of hepatoblastoma and hepatocellular carcinoma are described in their respective sections (refer to the Treatment of Hepatoblastoma and the Treatment of Hepatocellular Carcinoma sections of this summary for more information). Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.[6,26,37]

The standard of care in the United States is preoperative chemotherapy when the tumor is unresectable and postoperative chemotherapy after complete resection, even if preoperative chemotherapy has already been given.[38] Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma; however, the use of postoperative chemotherapy after definitive surgical resection or liver transplant has not been investigated in a randomized fashion.

Radiation Therapy

Radiation therapy, even in combination with chemotherapy, has not cured children with unresectable hepatic tumors. Although there is no standard indication, radiation therapy may have a role in the management of incompletely resected hepatoblastoma.[39] However, a study of 154 patients with hepatoblastoma showed that radiation therapy and/or second resection of positive margins may not be necessary in some patients with incompletely resected hepatoblastoma and microscopic residual tumor.[40] Stereotactic body radiation therapy is a safe and effective alternative treatment that has been successfully used in hepatocellular carcinoma in adults who are unable to undergo liver ablation/resection.[41] This highly conformal radiotherapeutic technique, when available, may be considered on an individual basis in children with hepatocellular carcinoma.

Other Treatment Approaches

Other treatment approaches include the following:

Transarterial chemoembolization (TACE). TACE has been used for patients with inoperable hepatoblastoma.[42-44] It has been used in a few children to successfully shrink the tumor to permit resection.[43] Chemotherapy followed by TACE and high-intensity focused ultrasonography showed promising results in China for PRETEXT III and IV patients, some of whom were resectable but did not undergo surgery because of parent refusal.[45]
Transarterial radioembolization. Transarterial radioembolization with yttrium Y 90-resin beads has been used to palliate children with hepatocellular carcinoma.[46] (Refer to the PDQ summary on Adult Primary Liver Cancer Treatment for more information.)

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[47] Children and adolescents with cancer should be referred to medical centers that have multidisciplinary teams of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

Primary care physicians.
Pediatric surgeons and transplant surgeons.
Radiation oncologists.
Pediatric medical oncologists/hematologists.
Rehabilitation specialists.
Pediatric nurse specialists.
Social workers.
Child life professionals.
Psychologists.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer have been outlined by the American Academy of Pediatrics.[48] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[47] Childhood and adolescent cancer survivors require close monitoring because late effects of therapy may persist or develop months or years after treatment. (Refer to Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

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