martes, 12 de marzo de 2019

Childhood Liver Cancer Treatment (PDQ®) 1/3 —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

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General Information About Childhood Liver Cancer

Liver cancer is a rare malignancy in children and adolescents and is divided into the following two major histologic subgroups:
Other, less common, histologies include the following:

Cellular Classification of Childhood Liver Cancer

Liver tumors are rare in children. Their diagnoses may be challenging, in part, because of the lack of consensus regarding a classification system. Systematic central histopathological review of these tumors performed as part of pediatric collaborative therapeutic protocols has allowed the identification of histologic subtypes with distinct clinical associations. As a result, histopathology has been incorporated within the Children’s Oncology Group (COG) protocols and, in the United States, as a risk-stratification parameter used for patient management.
The COG Liver Tumor Committee sponsored an International Pathology Symposium in 2011 to discuss the histopathology and classification of pediatric liver tumors (hepatoblastoma, in particular) to develop an International Pediatric Liver Tumors Consensus Classification that would be required for international collaborative projects. The results of this international classification for pediatric liver tumors have been published.[1] This standardized, clinically meaningful classification will allow the integration of new biological parameters and tumor genetics within a common pathologic language in order to help improve future patient management and outcome.
For information on the histology of each childhood liver cancer subtype, refer to the following sections of this summary:
References
  1. López-Terrada D, Alaggio R, de Dávila MT, et al.: Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol 27 (3): 472-91, 2014. [PUBMED Abstract]

Tumor Stratification by Imaging and Evans Surgical Staging for Childhood Liver Cancer

Historically, the four major study groups (International Childhood Liver Tumors Strategy Group [previously known as Société Internationale d’Oncologie Pédiatrique–Epithelial Liver Tumor Study Group (SIOPEL)], Children's Oncology Group [COG], Gesellschaft für Pädiatrische Onkologie und Hämatologie [Society for Paediatric Oncology and Haematology], and Japanese Study Group for Pediatric Liver Tumors) have had disparate risk stratification categories, making it difficult to compare outcomes across continents. All groups are now using the PRE-Treatment EXTent of tumor (PRETEXT) grouping system as part of the risk stratification.

Tumor Stratification by Imaging

The primary treatment goal for patients with liver cancer is surgical extirpation of the primary tumor. Therefore, the risk grouping designed depends heavily on factors determined by imaging that are related to safe surgical resection of the tumor, as well as the PRETEXT grouping. These imaging findings are termed annotation factors.
The use of high-quality, cross-sectional imaging to evaluate children with hepatoblastoma is of paramount importance because the risk stratification that defines treatment is very dependent on imaging analysis. Three-phase computed tomography scanning (noncontrast, arterial, and venous) or magnetic resonance imaging (MRI) with contrast agents are used for imaging. MRI with gadoxetate disodium, a gadolinium-based agent that is preferentially taken up and excreted by hepatocytes, is being used with increased frequency and may improve detection of multifocal disease.[1]
The imaging grouping systems used to radiologically define the extent of liver involvement by the tumor is designated as:
  • PRETEXT (PRE-Treatment EXTent of disease): The extent of liver involvement is defined before therapy.
  • POSTTEXT (POST-Treatment EXTent of disease): The extent of liver involvement is defined in response to therapy.

PRETEXT and POSTTEXT Group Definitions

PRETEXT is used by the major multicenter trial groups as a central component of risk stratification schemes that define treatment of hepatoblastoma. PRETEXT is based on the Couinaud eight-segment anatomic structure of the liver using cross-sectional imaging. The PRETEXT system divides the liver into four parts, called sections. The left lobe of the liver consists of a lateral section (Couinaud segments I, II, and III) and a medial section (segment IV), whereas the right lobe consists of an anterior section (segments V and VIII) and a posterior section (segments VI and VII) (refer to Figure 1). PRETEXT groups were devised by the SIOPEL for their first trial, SIOPEL-1 [2] and revised for SIOPEL-3 in 2007.[3]
ENLARGEFigure showing 4 sections of the liver: the right posterior section, the right anterior section, the left medial section, and the left lateral section. The boundaries of each section are defined by the right hepatic vein, the middle hepatic vein, and the umbilical fissure/ligamentum teres. Also shown are 8 anatomic segments (I-VIII), each corresponding to a specific section of the liver.
Figure 1. PRETEXT is distinct from Couinaud 8-segment (I–VIII) anatomic division of the liver. PRETEXT defines 4 'Sections'. Boundaries of each section defined by the right and middle hepatic veins, and umbilical fissure. Reprinted by permission from Copyright Clearance Center: Springer Nature, Modern Pathology, Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium, Dolores López-Terrada, Rita Alaggio, Maria T de Dávila, et al., Copyright © 2013.
PRETEXT group assignment I, II, III, or IV is determined by the number of contiguous uninvolved sections of the liver. PRETEXT is further described by annotation factors, defined as V, P, E, M, C, F, N, or R, depending on extension of tumor beyond the hepatic parenchyma of the major sections (refer to Table 1 for detailed descriptions of the PRETEXT groups and Table 2 for descriptions of the annotation factors).
Annotation factors identify the extent of tumor involvement of the major vessels and its effect on venous inflow and outflow, which is critical knowledge for the surgeon and can affect surgical outcomes. There were differences in the definitions of gross vascular involvement used by the COG and major liver surgery centers in the United States compared with SIOPEL definitions used in Europe; these differences have been resolved in the definitions to be used in an international trial that begins in 2018.[4]
Although PRETEXT can be used to predict tumor resectability, there are limitations. The distinction between real invasion beyond the anatomic border of a given hepatic section and the compression and displacement by the tumor can be very difficult, especially at diagnosis. Additionally, distinguishing between vessel encroachment and involvement can be difficult, particularly if inadequate imaging is obtained. The PRETEXT group assignment has a moderate degree of interobserver variability, and in a report published in 2005 using data from the SIOPEL-1 study, the preoperative PRETEXT group agreed with postoperative pathologic findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.[5]
Because distinguishing PRETEXT group assignment is difficult, central review of imaging is critical and is generally performed in all major clinical trials. For patients not enrolled on clinical trials, expert radiologic review should be considered in questionable cases in which the PRETEXT group assignment affects choice of treatment.
The POSTTEXT is determined after chemotherapy. It has been shown that the greatest chemotherapy response, measured as decreases in tumor size and alpha-fetoprotein (AFP) level, occurs after the first two cycles of chemotherapy.[6,7] Also, a study that evaluated surgical resectability after two versus four cycles of chemotherapy showed that many tumors may be resectable after two cycles.[6]
Table 1. Definitions of PRETEXT and POSTTEXT Groupsa
PRETEXT and POSTTEXT GroupsDefinitionImage
aAdapted from Roebuck et al.[3]
IOne section involved; three adjoining sections are tumor free.
ENLARGELiver PRETEXT I; drawing shows two livers. Dotted lines divide each liver into four vertical sections of about the same size. In the first liver, cancer is shown in the section on the far left. In the second liver, cancer is shown in the section on the far right.
IIOne or two sections involved; two adjoining sections are tumor free.
ENLARGELiver PRETEXT II; drawing shows five livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown in the two sections on the left. In the second liver, cancer is shown in the two sections on the right. In the third liver, cancer is shown in the far left and far right sections. In the fourth liver, cancer is shown in the second section from the left. In the fifth liver, cancer is shown in the second section from the right.
IIITwo or three sections involved; one adjoining section is tumor free.
ENLARGELiver PRETEXT III; drawing shows seven livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown in three sections on the left. In the second liver, cancer is shown in the two sections on the left and the section on the far right. In the third liver, cancer is shown in the section on the far left and the two sections on the right. In the fourth liver, cancer is shown in three sections on the right. In the fifth liver, cancer is shown in the two middle sections. In the sixth liver, cancer is shown in the section on the far left and the second section from the right. In the seventh liver, cancer is shown in the section on the far right and the second section from the left.
IVFour sections involved.
ENLARGELiver PRETEXT IV; drawing shows two livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown across all four sections. In the second liver, cancer is shown in the two sections on the left and spots of cancer are shown in the two sections on the right.
Table 2. Annotation Factors For Describing PRETEXT and POSTTEXT Groupsa
Annotation FactorsDefinition
aAdapted from Roebuck et al.[3]
bAdditional details describing the annotation factors have been published.[4]
VbVenous involvement: Vascular involvement of the retrohepatic vena cava or involvement of all three major hepatic veins (right, middle, and left).
V0 Tumor within 1 cm.
V1 Tumor touching.
V2 Tumor compressing or distorting.
V3 Tumor ingrowth, encasement, or thrombus.
PbPortal involvement: Vascular involvement of the main portal vein and/or both right and left portal veins.
P0 Tumor within 1 cm.
P1 Tumor touching.
 P2 Tumor compressing or distorting.
P3 Tumor ingrowth, encasement, or thrombus.
EbExtrahepatic involvement of a contiguous structure such as the diaphragm, abdominal wall, stomach, colon, etc.
E1 Direct extension of tumor in adjacent organs or diaphragm.
E2 Peritoneal nodules (add a suffix to E if any tumor ascites).
MbDistant metastatic disease (usually lungs, occasionally bone or brain).
CCaudate lobe involvement.
 C1 Tumor involving the caudate lobe (all C1 patients are at least PRETEXT II).
FMultifocal tumor nodules.
 F1 Two or more discrete tumors (multifocal).
NbLymph node involvement.
 N1 Abdominal lymph node metastasis only.
 N2 Extra-abdominal lymph node metastasis (with or without abdominal nodes).
RbTumor rupture.
H1Imaging and clinical findings of intraperitoneal hemorrhage.
M1Any metastasis other than E or N.

Hepatoblastoma prognosis by PRETEXT group and annotation factor

The Children’s Hepatic tumor International Collaboration (CHIC) analyzed survival in a collaborative database of 1,605 patients with hepatoblastoma treated on eight separate multicenter clinical trials, with central review of all tumor imaging and histologic details.[8] Patients who underwent orthotopic liver transplant are included in all of the international study results.[9]
Survival at 5 years, unrelated to annotation factors, was found to be the following:
  • 90% for PRETEXT I.
  • 83% for PRETEXT II.
  • 73% for PRETEXT III.
  • 52% for PRETEXT IV.
When each annotation factor was examined separately, regardless of the PRETEXT group or other annotation factors present in each patient, the 5-year overall survival (OS) was found to be the following:
  • 51% for positive V (involvement all three hepatic veins and/or inferior vena cava).
  • 49% for positive P (involvement both right and left portal veins).
  • 53% for positive E (contiguous extrahepatic tumor).
  • 52% for positive F (multifocal).
  • 51% for positive R (tumor rupture).
  • 41% for positive M (distant metastasis).

Hepatocellular carcinoma prognosis by PRETEXT group and annotation factor

The 5-year OS by PRETEXT group for hepatocellular carcinoma in SIOPEL-1 was found to be the following:[10]
  • 44% for PRETEXT I.
  • 44% for PRETEXT II.
  • 22% for PRETEXT III.
  • 8% for PRETEXT IV.

Evans Surgical Staging for Childhood Liver Cancer (Historical)

The COG/Evans staging system is based on operative findings and surgical resectability and has been used for many years in the United States to group children with liver cancer. This staging system was used to determine treatment in past years (refer to Table 3).[11-13] Currently, other risk stratification systems are used to classify patients and determine treatment strategy (refer to Table 5 for more information).
Table 3. Definition of Evans Surgical Staging
Evans Surgical StageDefinition
Stage IThe tumor is completely resected.
Stage IIMicroscopic residual tumor remains after resection.
Stage IIIThere are no distant metastases and at least one of the following is true: (1) the tumor is either unresectable or the tumor is resected with gross residual tumor; (2) there are positive extrahepatic lymph nodes.
Stage IVThere is distant metastasis, regardless of the extent of liver involvement.

Hepatoblastoma prognosis by Evans surgical stage

Stages I and II
Approximately 20% to 30% of children with hepatoblastoma are stage I or II. Prognosis varies depending on the subtype of hepatoblastoma:
  • Patients with well-differentiated fetal (previously termed pure fetal) histology tumors (4% of hepatoblastomas) have a 3- to 5-year OS rate of 100% with minimal or no chemotherapy, whether PRETEXT I, II, or III.[13-15]
  • Patients with non–well-differentiated fetal histology, non–small cell undifferentiated stage I and II hepatoblastomas have a 3- to 4-year OS rate of 90% to 100% with adjuvant chemotherapy.[13,14]
  • If any small cell undifferentiated elements are present in patients with stage I or II hepatoblastoma, the 3-year survival rate is 40% to 70%.[14,16]
Stage III
Approximately 50% to 70% of children with hepatoblastoma are stage III. The 3- to 5-year OS rate for children with stage III hepatoblastoma is less than 70%.[13,14]
Stage IV
Approximately 10% to 20% of children with hepatoblastoma are stage IV. The 3- to 5-year OS rate for children with stage IV hepatoblastoma varies widely, from 20% to approximately 60%, based on published reports.[13,14,17-20] Postsurgical stage IV is equivalent to any PRETEXT group with annotation factor M.[8,21,22]

Hepatocellular carcinoma prognosis by Evans surgical stage

Stage I
Children with stage I hepatocellular carcinoma have a good outcome.[23]
Stage II
Stage II is too rarely seen to predict outcome.
Stages III and IV
Stages III and IV are usually fatal.[10,24]
References
  1. Meyers AB, Towbin AJ, Geller JI, et al.: Hepatoblastoma imaging with gadoxetate disodium-enhanced MRI--typical, atypical, pre- and post-treatment evaluation. Pediatr Radiol 42 (7): 859-66, 2012. [PUBMED Abstract]
  2. Brown J, Perilongo G, Shafford E, et al.: Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 36 (11): 1418-25, 2000. [PUBMED Abstract]
  3. Roebuck DJ, Aronson D, Clapuyt P, et al.: 2005 PRETEXT: a revised staging system for primary malignant liver tumours of childhood developed by the SIOPEL group. Pediatr Radiol 37 (2): 123-32; quiz 249-50, 2007. [PUBMED Abstract]
  4. Towbin AJ, Meyers RL, Woodley H, et al.: 2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT). Pediatr Radiol 48 (4): 536-554, 2018. [PUBMED Abstract]
  5. Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005. [PUBMED Abstract]
  6. Lovvorn HN 3rd, Ayers D, Zhao Z, et al.: Defining hepatoblastoma responsiveness to induction therapy as measured by tumor volume and serum alpha-fetoprotein kinetics. J Pediatr Surg 45 (1): 121-8; discussion 129, 2010. [PUBMED Abstract]
  7. Venkatramani R, Stein JE, Sapra A, et al.: Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma. Br J Surg 102 (1): 108-13, 2015. [PUBMED Abstract]
  8. Czauderna P, Haeberle B, Hiyama E, et al.: The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer 52: 92-101, 2016. [PUBMED Abstract]
  9. Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004. [PUBMED Abstract]
  10. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002. [PUBMED Abstract]
  11. Ortega JA, Krailo MD, Haas JE, et al.: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (12): 2167-76, 1991. [PUBMED Abstract]
  12. Douglass EC, Reynolds M, Finegold M, et al.: Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 11 (1): 96-9, 1993. [PUBMED Abstract]
  13. Ortega JA, Douglass EC, Feusner JH, et al.: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 18 (14): 2665-75, 2000. [PUBMED Abstract]
  14. Meyers RL, Rowland JR, Krailo M, et al.: Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 53 (6): 1016-22, 2009. [PUBMED Abstract]
  15. Malogolowkin MH, Katzenstein HM, Meyers RL, et al.: Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children's Oncology Group. J Clin Oncol 29 (24): 3301-6, 2011. [PUBMED Abstract]
  16. De Ioris M, Brugieres L, Zimmermann A, et al.: Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer 44 (4): 545-50, 2008. [PUBMED Abstract]
  17. Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000. [PUBMED Abstract]
  18. Perilongo G, Brown J, Shafford E, et al.: Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors. Cancer 89 (8): 1845-53, 2000. [PUBMED Abstract]
  19. Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004. [PUBMED Abstract]
  20. Zsíros J, Maibach R, Shafford E, et al.: Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol 28 (15): 2584-90, 2010. [PUBMED Abstract]
  21. Katzenstein HM, Furman WL, Malogolowkin MH, et al.: Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee. Cancer 123 (12): 2360-2367, 2017. [PUBMED Abstract]
  22. O'Neill AF, Towbin AJ, Krailo MD, et al.: Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children's Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children's Oncology Group. J Clin Oncol 35 (30): 3465-3473, 2017. [PUBMED Abstract]
  23. Douglass E, Ortega J, Feusner J, et al.: Hepatocellular carcinoma (HCA) in children and adolescents: results from the Pediatric Intergroup Hepatoma Study (CCG 8881/POG 8945). [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-1439, 420, 1994.
  24. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study. J Clin Oncol 20 (12): 2789-97, 2002. [PUBMED Abstract]

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):
  1. 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.
  2. 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.
  3. 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]
  4. 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]

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.[6,26,36]
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.[37] 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.[38] 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.[39] 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.[40] 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.[41-43] It has been used in a few children to successfully shrink the tumor to permit resection.[42] 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.[44]
  • Transarterial radioembolization. Transarterial radioembolization with yttrium Y 90-resin beads has been used to palliate children with hepatocellular carcinoma.[45] (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.[46] 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.[47] 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%.[46] 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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