Abstract
Hepatoblastoma is the most common pediatric liver tumor and is usually diagnosed before five years of age. Treatment consists of a combination of chemotherapy and surgery, with the goal being attainment of complete local control by surgical resection and eradication of any extrahepatic disease. Neoadjuvant chemotherapy is utilized and is often beneficial in rendering tumors resectable; however, prolonged chemotherapy administration attempting to render tumors resectable by conventional resection should be avoided. For patients whose tumors are too extensive to be conventionally resected, liver transplantation can be curative and remains the treatment of choice for eligible patients otherwise incurable by conventional resection.
Keywords: Pediatric, liver, transplantation, hepatoblastoma
Hepatoblastoma is the most common pediatric liver tumor and is usually diagnosed before five years of age. It accounts for 1.2% of malignancies in patients less than 15 years of age (1). Recent studies report an increasing incidence of hepatoblastoma in the U.S. from 0.6 to 1.2 per million (2,3). Typically, patients present with an abdominal mass and elevated AFP. Increased risk for development of hepatoblastoma is associated with Beckwith-Wiedemann Syndrome, Familial Adenomatous Polyposis Coli, maternal tobacco exposure and very low birthweight (4-6). Treatment consists of a combination of chemotherapy and surgery, with the goal being attainment of complete local control by surgical resection and eradication of any extrahepatic disease.
Staging
By the surgery based Evans staging system, staging was based upon exploratory surgery at diagnosis for all patients. Stage I and II tumors are those resected at diagnosis with microscopically negative and positive margins, respectively. Stage III and IV tumors are unresectable at diagnosis without and with metastatic disease, respectively. The current COG protocol, AHEP0731, uses a risk stratification scheme that is a hybrid of the old Evans system and PRE-TEXT (Pretreatment Extent of disease) used to define the timing and extent of surgical resection (7). In PRE-TEXT, the tumor group (I, II, III, IV) defines the extent of hepatic parenchymal involvement and the PRE-TEXT annotation factors (V, P, E, F, R, C, N, M denoting hepatic veins or vena cava, portal vein, extrahepatic, multifocal, tumor rupture, caudate lobe, lymph node and metastatic disease, respectively) define unique tumor characteristics and the extent of extrahepatic disease. PRE-TEXT I and II tumors have 3 and 2 adjoining sections free of tumor, respectively, and are usually resectable at diagnosis or after neoadjuvant chemotherapy depending on vascular involvement. For PRE-TEXT III and IV tumors, only one or two nonadjoining sections or none, respectively, are free of tumor and major vessel involvement is common. When the vessels or all sections remain involved after chemotherapy the tumor may not be resectable. Recently, the Childhood Hepatic tumors International Collaboration (CHIC) was formed and developed a new risk stratification and staging system based on PRE-TEXT that will be the basis of the upcoming international liver tumors trial.
Resectability
Complete resection is a critical component for cure in the treatment of hepatoblastoma; however, 60% of tumors are unresectable at the time of diagnosis (8). Neoadjuvant chemotherapy is utilized and is often beneficial in rendering tumors resectable. Commonly, two adjuvant cycles of chemotherapy are reserved for administration post-operatively. Ortega et al. reported 20% of initially unresectable tumors remained unresectable after neoadjuvant chemotherapy. Otte et al. reported a need for liver transplantation for approximately 15% of patients with initially unresectable tumors (9).
Historical perspective: liver transplantation for hepatoblastoma
For patients whose tumors are too extensive to be conventionally resected, liver transplantation can be curative and has become an integral component of current treatment algorithms. In a recent study based on United Network for Organ Sharing (UNOS) registry data, the frequency of liver transplantation for hepatoblastoma increased from five in 1990 to 43 in 2013 (10). A review by Cruz et al. of the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry [1975–2007], UNOS [1988–2010] and Children’s Hospital of Pittsburgh database [1987–2011] revealed a 20-fold increase in liver transplantation for hepatoblastoma over a 32-year period during which the frequency of hepatoblastoma cases increased 4-fold (11). The authors reported an increase in referral rate for liver transplantation for hepatoblastoma from 5% in early 1990s to 20% after 2004.
Indications for liver transplantation for hepatoblastoma
The Children’s Oncology Group (COG) recommends that only tumors where a segmentectomy or hemihepatectomy can be performed with a 1 cm tumor free margin on the middle hepatic vein and portal bifurcation be performed at diagnosis (1). Generally accepted indications for liver transplantation for hepatoblastoma include unifocal POST-TEXT IV (PRE-TEXT classification following chemotherapy) tumors and/or POST-TEXT III or IV with persistent widespread multifocality or major vessel involvement. Ideally, before a transplant there would be some response to chemotherapy. Depending on the surgeon, patients with POST-TEXT III tumors with major vascular involvement may be considered for an extreme conventional resection (conventional resection with major vascular reconstruction) instead of liver transplantation (7). In the nearly completed Childrens Oncology Group study AHEP0731, results are being analyzed for patients with POST-TEXT III with venous involvement and POST-TEXT IV tumors comparing conventional resection versus liver transplantation.
Contraindications to liver transplantation for hepatoblastoma
Transplant is contraindicated in the presence of any active regional or distant metastatic disease not cleared by chemotherapy or surgery (12,13). The treatment strategy for a patient who present with lung metastases with locally advanced tumors where liver transplantation is necessary to achieve tumor extirpation remain the most challenging subset population. Cruz et al. found that in their analysis of the Children’s Hospital of Philadelphia data, extrahepatic disease present prior to liver transplantation (but which had cleared by CT scan prior to transplant) was the main risk factor for recurrent hepatoblastoma post transplantation (11). Other analyses have found that risk of recurrence was similar for those who cleared with chemotherapy versus resection (10,14,15). Recommendations for bilateral lung palpation at the time of thoracotomy for persistent pulmonary disease following neoadjuvant chemotherapy remain controversial (1).
Liver transplantation in multifocal hepatoblastoma
Transplantation versus resection for patients with multifocal disease remains controversial with some recommending transplantation and others advocating for conventional resection when intrahepatic metastases clear with neoadjuvant chemotherapy (7,15-20). For patients with POST-TEXT IV multifocal tumors without metastatic disease after neoadjuvant chemotherapy, liver transplantation is clearly indicated (1).
Timing of liver transplantation
Prolonged chemotherapy administration attempting to render tumors resectable by conventional resection should be avoided. Several studies indicate that continuing to administer chemotherapy after four cycles does not increase the likelihood of conventional resectability of the tumor (21,22). In such patients, where liver transplantation is required to achieve local control, transplantation after four cycles of neoadjuvant chemotherapy is ideal (7).Unfortunately, this is not always possible due to unpredictable factors such as deceased organ donor availability. Héry et al. reviewed their experience with liver transplantation for hepatoblastoma and reported a wait time of 1–50 days for liver transplant (median 16 days); the authors concluded that delays in timing from last chemotherapy to transplant should be kept as short as possible (15). The concept of early referral for consultation (including consultation via telephone, email or other communication) for liver transplantation versus extreme liver resection was introduced by the current COG protocol AHEP0731 and the feasibility and outcome of this approach has been a major objective of that study. The goal is to decrease excessive toxicity due to prolonged chemotherapy and improve survival. In addition, Otte and others have shown that survival is higher (approximately 80% versus 30–40%) for patients who undergo primary liver transplantation (no attempt at conventional resection) as opposed to those in whom liver transplantation is utilized in the salvage setting (13,15,23-25).
Donor source
Utilization of living versus cadaveric donors for liver transplantation is dependent on the provider’s/institution’s approach. Benefits of living donor liver transplantation include control of the timing of transplantation resulting on potentially shorter wait times thereby eliminating dependence on cadaveric liver availability, but engender risk of a major operative procedure to a healthy donor (11,15). Benefits to cadaveric donor transplantation include longer blood vessels from cadaveric donor grafts that allow for easier vascular reconstruction (15). Interestingly, Pham et al. reported increased recurrence rate for those who waited longer on the liver transplantation list for a cadaveric donor liver (mean time of 31 versus 15 days for those with recurrence versus those without, respectively) (10).
Complications of liver transplantation
Peri- and post-operative complications following liver transplantation include primary nonfunction, hepatic artery and portal vein thrombosis, bleeding, bile leak, infection, acute cellular rejection, long term immunosuppressive medication complications, post transplant lymphoproliferative disease and chronic rejection (14). Cruz et al. reported an increased risk of hepatic artery thrombosis in patients with hepatoblastoma undergoing liver transplantation compared to those receiving liver transplants for other conditions (11); however, the PLUTO registry did not find any increase in incidence of this complication (26). Héry et al. reported no post-operative mortality in the month post transplant in 13 pediatric patients receiving liver transplantation for hepatoblastoma (15). Four patients experienced complications (bile leak in one patient, arterial thrombosis followed by re-transplantation in three patients). Of 30 patients undergoing liver transplantation for hepatoblastoma at a single institution, four patients developed hepatic artery and/or portal vein thrombosis with all four requiring retransplantation (10). Second malignancies were infrequently reported with one patient with Burkitt Lymphoma four years after surgery (15).
Survival following liver transplantation for hepatoblastoma
Survival results from different institutional reports of liver transplantation for hepatoblastoma are difficult to compare given the inability to compare by patient specifics such as PRE-TEXT/POST-TEXT grouping, chemotherapy regimens, age, comorbidities, timing of transplant from last chemotherapy, utilization of adjuvant chemotherapy post transplantation and status of metastatic disease at the time of transplant. Upon review of 292 patients (in 29 separate publications) with hepatoblastoma who underwent liver transplantation, 76% of patients were alive at the time of publication (Table 1 and Table S1). Of note, some manuscripts reviewed were not included when patients with hepatoblastoma were unable to be separately identified or when it was unclear if the patients had been previously reported. Of 41 patients (with details reported) with rescue liver transplantation after initial attempt at resection, seventeen were alive (41%) compared with 85% of 175 patients with primary liver transplantation. Post-transplant chemotherapy appeared to have been administered for 140 patients; however, it is difficult to assess any relation to outcome given that details were not reported for many patients and many confounding factors exist (for some patients, chemotherapy was given after transplantation for recurrent disease, whereas others did not include these specifics).
Table 1. Patients with HBL who underwent liver transplantation.
| Reference | Publication date/era | # of patients with hepatoblastoma | Surviving at time of report (%) |
|---|---|---|---|
| Heimann et al. (27) | 1987/NR | 1 | 100 |
| Ringe et al. (28) | 1989/1972–1987 | 2 | 50 |
| Jenkins et al. (29) | 1989/1983–1987 | 3 | 100 |
| Olthoff et al. (30) | 1990/1984–1989 | 1 | 100 |
| Koneru et al. (31) | 1991/Pre-1988 | 12 | 50 |
| Tagge et al. (32) | 1992/1980–1990 | 6 | 83 |
| Lockwood et al. (33) | 1993/NR | 1 | 100 |
| Superina et al. (34) | 1996/ NR | 3 | 67 |
| Bilik et al. (35) | 1997/1986–1997 | 4 | 100 |
| Goss et al. (36) | 1998/1984–1997 | 4 | 75 |
| Al-Qabandi et al. (37) | 1999/1991–1997 | 8 | 63 |
| Dower et al. (38) | 2000/1995 | 1 | 100 |
| Pimpalwar et al. (23) | 2002/1991–2000 | 7 | 86 |
| Srinivasan et al. (39) | 2002/1992–2001 | 13 | 85 |
| Molmenti et al. (40) | 2002/1984–2000 | 9 | 67 |
| Cillo et al. (41) | 2003/1990–2003 | 7 | 71 |
| Otte (13) | 2004/1990–1994 | 61 | 67 |
| Kasahara et al. (42) | 2005/1990–2004 | 14 | 71 |
| Mejia et al. (43) | 2005/1985–2003 | 10 | 70 |
| Chen et al. (44) | 2006/1987–2005 | 7 | 86 |
| Casas-Melley et al. (45) | 2007/2001–2005 | 8 | 75 |
| Faraj et al. (46) | 2008/1993–2007 | 13 | 92 |
| Kosola et al. (47) | 2010/1990–2007 | 6 | 67 |
| Zsíros et al. (48) | 2010/1998–2004 | 31 | 74 |
| Héry et al. (15) | 2011/2001–2009 | 13 | 77 |
| Kim et al. (49) | 2011/1991–2009 | 5 | 100 |
| Ismail et al. (50); Kaliciński et al. (51) | 2012/1990–2010 | 12 | 67 |
| Pham et al. (10) | 2015/1997–2014 | 30 | 87 |
HBL, hepatoblastoma; NR, not reported.
Conclusions
Liver transplantation can be curative in certain patients in whom conventional resection is not possible. Early consultation with pediatric liver transplantation specialists is critical in the management of patients with hepatoblastoma who are most likely to need liver transplantation or extreme liver resection and is important for facilitating timely resection by either conventional resection or liver transplantation (7). Though not without its complications (and lifelong immunosuppression), liver transplantation remains the treatment of choice for eligible patients otherwise incurable by conventional resection.
Acknowledgements
None.
Table S1. Clinical characteristics of patients with HBL who underwent liver transplantation.
| Source/location | Pub. date/era | PRE-TEXT | Mets at dx | Neoadj chemo | Mets prior to LT | LT-primary vs. rescue | LT source | Adjuvant chemo | Outcome | Ref |
|---|---|---|---|---|---|---|---|---|---|---|
| Yale, USA | 1987/NR | NR | No | VCR, CTX, doxo | No | Primary | NR | VCR, CTX, doxo, 5FU, bleo, cis | Pulm met at 7 months post LT, resected. Alive, NED 34 months post LT | (27) |
| Germany | 1989/1972–1987 | NR | NR | NR | NR | NR | NR | NR | Alive NED, 6 years post LT | (28) |
| Germany | 1989/1972–1987 | NR | NR | NR | NR | NR | NR | NR | Died of sepsis early post LT | (28) |
| Boston, USA | 1989/1983–1987 | NR | NR | NR | NR | NR | NR | NR | Alive NED, 9 months | (29) |
| Boston, USA | 1989/1983–1987 | NR | NR | NR | NR | NR | NR | NR | Alive NED, 33 months | (29) |
| Boston, USA | 1989/1983–1987 | NR | NR | NR | NR | NR | NR | NR | Alive NED, 7 years 2 months | (29) |
| UCLA, USA | 1990/1984–1989 | NR | No | NR | No | NR | NR | NR | Alive NED, 5.5 years post LT | (30) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Rescue | NR | No | Died PCP 9 mo post LT | (31) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Rescue | NR | Yes | DOD 23 mo post LT | (31) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Rescue | NR | No | Died of hep art thrombosis 15 days post LT | (31) |
| USA | 1991/Pre-1988 | NR | No | No | No | Primary | NR | No | Died of hep art thrombosis 4 mo post LT | (31) |
| USA | 1991/Pre-1988 | NR | No | No | No | Primary | NR | No | Alive NED, 66 mo | (31) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Rescue | NR | No | DOD 4 mo | (31) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Primary | NR | Yes | Alive NED, 30 mo | (31) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Primary | NR | No | Alive NED, 43 mo | (31) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Primary | NR | Yes | Alive NED, 32 mo | (31) |
| USA | 1991/Pre-1988 | NR | No | No | No | Primary | NR | Yes | Alive NED, 24 mo | (31) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Primary | NR | No | DOD 35 days post LT | (31) |
| USA | 1991/Pre-1988 | NR | No | Yes | No | Primary | NR | Yes | Alive NED, 70 months post LT; (pulm rec @ 7 mo, resected) | (31) |
| Pittsburgh, USA | 1992/1980–1990 | NR | No | NR | NR | NR | NR | NR | Alive | (32) |
| Pittsburgh, USA | 1992/1980–1990 | NR | No | NR | NR | NR | NR | NR | Alive | (32) |
| Pittsburgh, USA | 1992/1980–1990 | NR | No | NR | NR | NR | NR | NR | Alive, 13 months | (32) |
| Pittsburgh, USA | 1992/1980–1990 | NR | No | NR | NR | NR | NR | NR | Alive, 5 months | (32) |
| Pittsburgh, USA | 1992/1980–1990 | NR | Yes | NR | NR | NR | NR | NR | Alive, 36 months | (32) |
| Pittsburgh, USA | 1992/1980–1990 | NR | Yes | NR | NR | NR | NR | NR | Died, 1 month | (32) |
| Leeds, England | 1993/NR | NR | Yes | Cis, doxo, carbo, VP16 | No (radio) | Primary | NR | NR | Alive, NED 35 months post LT | (33) |
| Toronto, Canada | 1996/NR | NR | No | Cis, doxo | No | Primary | NR | No | Alive NED, 2.5 years | (34) |
| Toronto, Canada | 1996/NR | NR | Yes | Cis, doxo | Yes (radio), but resected & neg on repeat scan and surgery | Primary | NR | No | Alive NED, 2.0 years | (34) |
| Toronto, Canada | 1996/NR | NR | Yes | Yes | Yes (radio); No (biopsy) | Rescue | NR | NR | Poor disease control pre-LT; DOD 3 months post LT | (34) |
| Toronto, Canada | 1997/1986–1997 | NR | No | Yes | NR | Primary | NR | No | Alive | (35) |
| Toronto, Canada | 1997/1986–1997 | NR | No | Yes | NR | Primary | NR | No | Alive | (35) |
| Toronto, Canada | 1997/1986–1997 | NR | No | Yes | No | Primary | NR | No | Alive NED, 2.5 years [same pt as above in (34)] | (35) |
| Toronto, Canada | 1997/1986–1997 | NR | Yes | Yes | As above | Primary | NR | No | Alive NED, 2.0 years [same pt as above in (34) Superina] | (35) |
| Toronto, Canada | 1997/1986–1997 | NR | Yes | Yes | As above | Rescue | NR | NR | DOD 3 months post LT [Same pt as above in (34)] | (35) |
| UCLA, USA: 4 pts | 1998/1984–1997 | NR | NR | NR | NR | NR | NR | NR | 75% survival (4 pts) | (36) |
| Birmingham, England | 1999/1991–1997 | IV | NR | Cis, doxo | No | Primary | Cad | NR | Alive, 82 months; retransplant @ 6 years related to hep art thrombosis | (37) |
| Birmingham, England | 1999/1991–1997 | II | NR | Cis, doxo | No | Primary | Cad | NR | Died with pulm met (+ FAP), unclear if 2nd neoplasm, 70 months | (37) |
| Birmingham, England | 1999/1991–1997 | III | NR | Cis, doxo + other | No | Rescue | Cad | NR | AFP elevated at LT; DOD, 23 months | (37) |
| Birmingham, England | 1999/1991–1997 | IV | NR | Cis, doxo | No | Primary | Cad | NR | Alive, 36 months | (37) |
| Birmingham, England | 1999/1991–1997 | IV | NR | Cis, doxo + other | No | Primary | Cad | NR | Alive, 9 months | (37) |
| Birmingham, England | 1999/1991–1997 | IV | NR | Cis, doxo, carbo | No | Primary | Cad | NR | Alive, 22 months | (37) |
| Birmingham, England | 1999/1991–1997 | IV | NR | Ciis, doxo + other | No | Rescue | Cad | NR | Alive, 12 months | (37) |
| Birmingham, England | 1999/1991–1997 | IV | NR | Cis, doxo, carbo | No | Primary | Cad | NR | Died of infection, 1 month | (37) |
| Edmonton, Canada | 2000/1995 | NR | Yes | Carbo, VCR, 5FU, cis, VP16, doxo, ifos | No (radio) | Rescue | Living | Cis, doxo | Alive NED, 38 months | (38) |
| Birmingham, England | 2002/1991–2000 | III | No | Yes | No | Primary | NR | NR | Alive NED | (23) [new patients not previously reported in (37)] |
| Birmingham, England | 2002/1991–2000 | IV | No | Yes | No | Primary | NR | NR | Alive NED | (23) |
| Birmingham, England | 2002/1991–2000 | IV | No | Yes | No | Primary | NR | NR | Alive NED | (23) |
| Birmingham, England | 2002/1991–2000 | IV | No | Yes | No | Primary | NR | NR | Alive NED | (23) |
| Birmingham, England | 2002/1991–2000 | IV | No | Yes | No | Primary | NR | NR | Alive NED | (23) |
| Birmingham, England | 2002/1991–2000 | NR | Yes (relapse) | Yes | No (cleared by surgeray) | Rescue | NR | NR | Alive NED, 3 years post LT | (23) |
| Birmingham, England | 2002/1991–2000 | NR | NR | Yes | No | Rescue | NR | NR | DOD 23 months post LT | (23) |
| UK | 2002/1992–2001 | III | No | VCR, cis, 5FU | No | Primary | Cad | No | Alive NED, 9 years | (39,46) |
| UK | 2002/1992–2001 | IV | No | Cis, carbo, doxo | No | Primary | LRLT | Cis, carbo, doxo | Alive NED, 3.8 years | (39,46) |
| UK | 2002/1992–2001 | III | No | Cis, carbo, doxo | No | Rescue | Cad | No | Died of respiratory failure 3 weeks post LT | (39,46) |
| UK | 2002/1992–2001 | IV | No | Cis, carbo, doxo | No | Primary | LRLT | Cis, carbo, doxo | Alive NED, 3.5 years | (39,46) |
| UK | 2002/1992–2001 | III | No | Cis, doxo | No | Primary | Cad | No | Alive NED, 7.5 years | (39,46) |
| UK | 2002/1992–2001 | IV | No | Cis, carbo, doxo | No | Primary | Cad | Cis, carbo, doxo | Alive NED, 4.8 years | (39,46) |
| UK | 2002/1992–2001 | III | No | Cis, doxo | No | Primary | Cad | Carbo, doxo | Alive NED, 2.4 years | (39,46) |
| UK | 2002/1992–2001 | III | No | Cis, carbo, doxo | No | Primary | Living | No | Alive NED, 1.2 years | (39,46) |
| UK | 2002/1992–2001 | III | No | Cis, carbo, doxo | No | Primary | Cad | Cis | Alive NED, 1.9 years | (39,46) |
| UK | 2002/1992–2001 | III | No | Cis, carbo, doxo | No | Primary | Living | Cis, carbo, doxo | Alive NED, 2 years | (39,46) |
| UK | 2002/1992–2001 | III | No | Cis, carbo, doxo | No | Primary | Cad | Cis, carbo, doxo | Alive NED, 2.3 years | (39,46) |
| UK | 2002/1992–2001 | IV | Yes | Cis, carbo, doxo | No (radio) | Primary | Cad | Cis, CTX,VP16 | Alive with pulm mets, 8 months post LT | (39,46) |
| UK | 2002/1992–2001 | IV | No | Cis, carbo, doxo | No | Primary | Cad | Cis, carbo, doxo | Alive NED, 1 month post LT | (39,46) |
| Dallas, USA | 2002/1984–2000 | NR | NR | CTX, doxo | No | Rescue | NR | No | Alive NED | (40) |
| Dallas, USA | 2002/1984–2000 | NR | NR | Cis, VCR, 5FU, MTX | No | Rescue | NR | No | Died of PCP 2.5 years post LT | (40) |
| Dallas, USA | 2002/1984–2000 | NR | NR | Cis, VCR, 5FU | No | Primary | NR | No | Died early post LT due to hep art thrombosis | (40) |
| Dallas, USA | 2002/1984–2000 | NR | NR | Cis, VCR, 5FU | No | Rescue | NR | Cis, VCR, VP16 | Alive NED | (40) |
| Dallas, USA | 2002/1984–2000 | NR | NR | Cis, doxo | No | Primary | NR | Cis, VCR, 5FU | Alive NED | (40) |
| Dallas, USA | 2002/1984–2000 | NR | NR | Carbo, VCR, 5FU, cis, VP16 | No | Primary | NR | No | Died due to sepsis 8 days post LT | (40) |
| Dallas, USA | 2002/1984–2000 | NR | NR | Cis, VCR, 5FU, VP16 | No | Primary | NR | Cis, VCR, 5FU | Alive NED | (40) |
| Dallas, USA | 2002/1984–2000 | NR | NR | Cis, VCR, 5FU, carbo | No | Primary | NR | Carbo, VCR, 5FU | Alive NED | (40) |
| Dallas, USA | 2002/1984–2000 | NR | NR | Cis, VCR, 5FU, doxo, MTX, irino, CTX, topo | No | Primary | NR | Doxo, irino | Alive 1 year post LT; + margins, elevated AFP at LT; dev’d pulm met | (40) |
| Padua, Italy | 2003/1990–2003 | NR | No | SIOPEL-1 | No | Rescue | Cad | NR | Died 6 mos post LT | (41) |
| Padua, Italy | 2003/1990–2003 | NR | No | SIOPEL-1 | No | Primary | LR | NR | DOD 60 mos post LT | (41) |
| Padua, Italy | 2003/1990–2003 | NR | No | SIOPEL-1 | No | Primary | Cad | NR | Local recurrence @ 100 mos post LT, s/p resection, chemo & brachytherapy; survived @ 108 mos post LT. | (41) |
| Padua, Italy | 2003/1990–2003 | NR | No | SIOPEL-1 | No | Primary | Cad | NR | Alive, NED | (41) |
| Padua, Italy | 2003/1990–2003 | NR | No | SIOPEL-1 | No | Primary | Cad | NR | Alive, NED | (41) |
| Padua, Italy | 2003/1990–2003 | NR | No | SIOPEL-1 | No | Primary | Cad | NR | Alive, NED | (41) |
| Padua, Italy | 2003/1990–2003 | NR | No | SIOPEL-1 | No | Primary | Cad | NR | Alive, NED | (41) |
| SIOPEL-1 | 2004/1990–1994 | IV | Yes | Cis, doxo | No | Rescue | Cad | NR | Alive NED 115 months post LT; colon carcinoma at 9 years post LT, alive at last contact | (13) |
| SIOPEL-1 | 2004/1990–1994 | II | No | Cis, doxo | No | Rescue | Cad | NR | DOD, 24 months post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | IV | Yes | Cis, doxo | No | Primary | Cad | NR | Alive NED, 120 months post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | IV | No | Cis, doxo | No | Primary | Cad | NR | Alive NED, 122 months post LT; Retransplanted 6 years post LT related to art thrombosis. | (13) |
| SIOPEL-1 | 2004/1990–1994 | IV | No | Cis, doxo | No | Primary | Cad | NR | Alive NED, 125 months post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | IV | No | Cis, doxo | No | Primary | Cad | NR | Alive NED, 119 months post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | II | Yes | Cis, doxo | No | Rescue | Cad | NR | Died related to art thrombosis at 6 days post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | IV | Yes | Cis, doxo | No | Rescue | Cad | NR | Alive NED, 52 months post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | III | No | Cis, doxo | No | Primary | Cad | NR | DOD, 70 mo post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | IV | No | Cis, doxo | No | Primary | Cad | NR | Alive, NED 98 months post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | III | No | Cis, doxo | No | Rescue | Cad | NR | Died of sepsis, 48 months post LT | (13) |
| SIOPEL-1 | 2004/1990–1994 | IV | Yes | Cis, doxo | No | Primary | Cad | NR | Alive, NED 92 months post LT | (13) |
| Omaha: 10 pts | 2004/1986–1999 | NR | NR | NR | NR | Primary (6 pts), rescue [4] | Cad [8], Living [2] | 3 of 10 pts | 70% OS | (13) |
| Madrid: 8 pts | 2004/1986–2001 | NR | NR | NR | NR | Primary (7 pts), rescue [1] | Cad [7], Living [1] | 7 of 8 pts | 75% OS | (13) |
| Bergamo: 4 pts | 2004/1988–2000 | NR | NR | NR | NR | Primary (3 pts), rescue [1] | Cad [4] | No | 25% OS | (13) |
| Coop. German group: 4 pts | 2004/1989–2001 | NR | NR | NR | NR | Primary (4 pts) | Cad [4] | No | 100% OS | (13) |
| Kyoto: 8 pts | 2004/1990–2001 | NR | NR | NR | NR | Primary (4 pts), rescue [4] | Living [8] | 6 of 8 pts | 62% OS | (13) |
| Padova: 5 pts | 2004/1994–1999 | NR | NR | NR | NR | Primary (5 pts) | Cad [4], Living [1] | 3 of 5 pts | 80% OS | (13) |
| Paris: 3 pts | 2004/1996–2001 | NR | NR | NR | NR | Primary (1 pt), rescue [2] | Cad [3] | No | 33% OS | (13) |
| Torino: 1 pt | 2004/1999 | NR | NR | NR | NR | Primary (1 pt) | Cad [1] | No | 100% OS | (13) |
| Chicago: 2 pts | 2004/1999–2001 | NR | NR | NR | NR | Primary (1 pt), rescue [1] | Cad [2] | No | 50% OS | (13) |
| Brisbane: 3 pts | 2004/1999–2001 | NR | NR | NR | NR | Primary (1 pt), rescue [2] | Cad [3] | No | 66% OS | (13) |
| Boston: 1 pt | 2004/2001 | NR | NR | NR | NR | Primary [1] | Living [1] | Yes | 100% OS | (13) |
| Kyoto, Japan | 2005/1990–2004 | III | NR | Cis/doxo | NR | Primary | Living | CTX, 5FU | DOD 280 days post LT | (42) |
| Kyoto, Japan | 2005/1990–2004 | IV | NR | Cis/doxo | NR | Rescue | Living | CTX, carbo, VP16, mel | DOD 960 days post LT | (42) |
| Kyoto, Japan | 2005/1990–2004 | IV | NR | Cis/doxo | NR | Primary | Living | Carbo, VP16, 5FU | DOD 330 days post LT | (42) |
| Kyoto, Japan | 2005/1990–2004 | III | NR | None | NR | Primary/post Kasai | Living | Carbo, doxo | Alive NED 81 months | (42) |
| Kyoto, Japan | 2005/1990-2004 | IV | NR | Cis/doxo | NR | Rescue | Living | Carbo, doxo | Alive NED 794 months | (42) |
| Kyoto, Japan | 2005/1990–2004 | IV | NR | Cis/doxo | NR | Primary | Living | Cis, doxo | Alive NED 67 months | (42) |
| Kyoto, Japan | 2005/1990–2004 | III | NR | Cis/doxo, VP16 | NR | Rescue | Living | CTX | Alive NED 55 months | (42) |
| Kyoto, Japan | 2005/1990–2004 | IV | NR | Cis/doxo | NR | Rescue | Living | No | Alive NED 42 months | (42) |
| Kyoto, Japan | 2005/1990–2004 | IV | NR | Cis/doxo | NR | Primary | Living | Cis, doxo | Alive NED 36 months | (42) |
| Kyoto, Japan | 2005/1990–2004 | III | NR | Cis/doxo | NR | Rescue | Living | Carbo, VP16 | Alive NED 21 months | (42) |
| Kyoto, Japan | 2005/1990–2004 | IV | NR | Cis/doxo | NR | Rescue | Living | Irino | DOD 202 days post LT | (42) |
| Kyoto, Japan | 2005/1990–2004 | III | NR | Cis/doxo, VP16 | NR | Rescue | Living | Irino | Alive NED 17 months | (42) |
| Kyoto, Japan | 2005/1990–2004 | III | NR | Cis/doxo | NR | Primary | Living | Irino | Alive NED 8 months | (42) |
| Kyoto, Japan | 2005/1990–2004 | III | NR | Cis/doxo | NR | Primary | Living | Irino | Alive NED 6 months | (42) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, 5FU, VCR | No | Primary | Cad | No | Alive NED | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | No | No | Primary | Cad | No | Alive NED | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, doxo, bleo, 5FU, VCR | No | Rescue | Cad | Cis, 5FU, VCR (for rec) | DOD 14 months | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, doxo | No | Primary | Cad | Cis, doxo | Alive NED | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, doxo | No | Rescue | Cad | Cis, doxo (for rec) | DOD 38 months | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, doxo | No | Primary | LRLT | Cis, doxo (for rec) | Alive at 480 months; pulm mets resected ×3 & chemo | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, doxo, mito | No | Rescue | Cad | No | Alive NED | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, doxo | No | Rescue | Cad | Cis, doxo (for rec) | DOD 4 months | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, doxo | No | Primary | Cad | Cis, doxo | Alive NED | (43) |
| San Antonio, USA | 2005/1985–2003 | NR | NR | Cis, 5FU, VCR | No | Primary | Living | Cis, doxo | Alive NED | (43) |
| St. Louis, USA | 2006/1987–2005 | NR | NR | Cis, 5FU, VCR | NR | Primary | Cad | NR | Alive | (44) |
| St. Louis, USA | 2006/1987–2005 | NR | NR | Cis, 5FU, VCR | NR | Primary | Cad | For rec | DOD 1 year post LT | (44) |
| St. Louis, USA | 2006/1987–2005 | NR | NR | Cis, 5FU, VCR, ifos, doxo, CTX, VP16, carbo | NR | Rescue | Cad | NR | Alive | (44) |
| St. Louis, USA | 2006/1987–2005 | NR | NR | Cis, 5FU, VCR, ifos | NR | Primary | Living | NR | Alive | (44) |
| St. Louis, USA | 2006/1987–2005 | NR | NR | Carbo, 5FU, VCR | NR | Primary | Cad | NR | Alive | (44) |
| St. Louis, USA | 2006/1987–2005 | NR | NR | Cis, 5FU, VCR | NR | Primary | Cad | NR | Alive | (44) |
| St. Louis, USA | 2006/1987–2005 | NR | NR | Cis, 5FU, VCR | NR | Primary | Living | NR | Alive | (44) |
| Delaware, USA | 2007/2001–2005 | NR | No | Cis, 5FU, VCR, irino | No | Rescue | Living | Yes | Alive NED 53 months | (45) |
| Delaware, USA | 2007/2001–2005 | NR | No | Cis, 5FU, VCR, carbo, doxo | No | Rescue | Living | Yes | DOD 8 months | (45) |
| Delaware, USA | 2007/2001–2005 | NR | No | Cis, 5FU, VCR | No | Primary | Living | Yes | Alive NED 23 months | (45) |
| Delaware, USA | 2007/2001–2005 | NR | No | Cis, 5FU, VCR | No | Primary | Living | Yes | Alive NED 23 months | (45) |
| Delaware, USA | 2007/2001–2005 | NR | No | Cis, 5FU, VCR | No | Primary | Living | Yes | Alive NED 22 months | (45) |
| Delaware, USA | 2007/2001–2005 | NR | No | Cis, 5FU, VCR | No | Primary | Living | Yes | Alive NED 8 months | (45) |
| Delaware, USA | 2007/2001–2005 | NR | Yes | Carbo, cis, VCR, CTX, doxo, topo | No (radio) | Primary | Living | Yes | Alive NED 48 months | (45) |
| Delaware, USA | 2007/2001–2005 | NR | Yes | Cis, 5FU, VCR, CTX, doxo, ifos, VP16 | No (radio) | Primary | Living | Yes | DOD | (45) |
| London, UK | 2008/1993–2007 | III | NR | Cis, 5FU, VCR | No | NR | Cad | No | Alive | (46) [without pts reported in (39)] |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | III | NR | Cis, carbo, doxo | No | NR | Cad | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Living | Yes | Died | (46) |
| London, UK | 2008/1993–2007 | II | NR | Cis, carbo, doxo | No | NR | Living | Yes | Alive | (46) |
| London, UK | 2008/1993–2007 | IV | NR | Cis, carbo, doxo | No | NR | Living | Yes | Alive | (46) |
| Poland: 6 pts | 2008/1990–2007 | NR | NR | NR | NR | Primary (4 pts) Rescue [2] | NR | NR | DOD (2 pts, both post rescue LT), Alive post pulm rec (1 pt), Alive NED (3 pts) | (50,51) |
| Finland | 2010/1990–2007 | III | Yes | Cis, doxo, CTX, VCR, 5FU | No | Primary | Cad | No | Died 15.9 years, awaiting heart transplant for cardiomyopathy | (47) |
| Finland | 2010/1990–2007 | III | No | Cis, doxo | No | Primary | Cad | No | Alive 18.1 years | (47) |
| Finland | 2010/1990–2007 | III | No | Cis, doxo, carbo, CTX | No | Rescue | Cad | No | DOD | (47) |
| Finland | 2010/1990–2007 | IV | No | Cis, doxo, CTX, VP16, VCR | No | Primary | Cad | No | Alive 18.5 years | (47) |
| Finland | 2010/1990–2007 | III | No | Cis, doxo | No | Primary | Cad | No | Alive 14.5 years | (47) |
| Finland | 2010/1990–2007 | IV | Yes | Cis, doxo, carbo | No | Primary | Cad | No | Alive 2.3 years | (47) |
| SIOPEL-3HR: 31 pts | 2010/1998–2004 | PRE-TEXT IV in 26 pts | Yes (6 pts) | Cis, carbo, doxo | Yes (5 pts) | Primary | NR | Yes (23 pts) | 8 of 31 pts DOD; 74% 3 yr EFS | (48) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | Yes | DOD, 1.9 years | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | Yes | DOD, 1.5 years | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | Yes | Alive, 2.5 years | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | No | Died cardiac failure, 1.4 years | (15) |
| France | 2011/2001–2009 | II | No | Yes | No | Primary | NR | Yes | Alive, 2.9 years | (15) |
| France | 2011/2001–2009 | IV | Yes | Yes | No | Primary | NR | Yes | Alive, 4.4 years | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | Yes | Alive, 4.6 years | (15) |
| France | 2011/2001–2009 | IV | Yes | Yes | No | Primary | NR | Yes | Alive, 4.8 years | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | No | Alive, 4.9 years | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | Yes | Alive, 4.6 years | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | No | Alive, 1 year | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | No | Alive, 1.5 years | (15) |
| France | 2011/2001–2009 | IV | No | Yes | No | Primary | NR | Yes | Alive, 3.7 years | (15) |
| Seoul, Korea | 2011/1991–2009 | III | NR | Cis/doxo | NR | NR | NR | NR | Alive NED | (49) |
| Seoul, Korea | 2011/1991–2009 | III | NR | Cis/doxo | NR | NR | NR | NR | Alive NED | (49) |
| Seoul, Korea | 2011/1991–2009 | IV | NR | Cis/doxo | NR | NR | NR | NR | Alive NED | (49) |
| Seoul, Korea | 2011/1991–2009 | IV | NR | Cis/doxo | NR | NR | NR | NR | Alive NED | (49) |
| Seoul, Korea | 2011/1991–2009 | IV | NR | Cis/doxo | NR | NR | NR | NR | Alive NED | (49) |
| Poland: 12 pts | 2012/1990–2010 | II (1 pt); III (6 pts); IV (5 pts); | Yes (2 pts) | Yes, at least cis/doxo | No | Primary (10 pts) rescue [2] | NR | NR | ● 2 of 2 pts with rescue LT DOD 5 & 14 months post LT ● 8 of 10 survived post primary LT |
(50) [6 in (51)] |
| Stanford, USA | 2015/1997–2014 | IV | No | Cis, 5FU, VCR | No | Primary | Cad | Yes | Died of sepsis | (10) |
| Stanford, USA | 2015/1997–2014 | IV | No | Cis, 5FU, VCR | No | Primary | Cad | Yes | DOD | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | Cis, doxo | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | Cis, doxo | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | Yes | Cis, doxo | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | Yes | Cis, 5FU, VCR | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | No | NR | No | Primary | Cad | NR | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | No | Cis, doxo | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | Yes | Cis, doxo | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | No | Cis, doxo | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | Cis, doxo | No | Rescue | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | No | Cis, 5FU, VCR | No | Primary | Cad | Yes | Died of primary nonfunction | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | NR | No | Primary | Cad | NR | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | No | Cis, 5FU, VCR | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | Cis, doxo | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | Yes | Cis, 5FU, VCR | No | Primary | Cad | Yes | Died of sepsis | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | SIOPEL 4 | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | Cis, 5FU, VCR | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | Cis, 5FU, VCR | No | Primary | Living | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | Cis, 5FU, VCR | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | Yes | Cis, 5FU, VCR | No | Primary | Living | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | Cis, 5FU, VCR | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | SIOPEL 4 | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | No | Cis, 5FU, VCR | No | Primary | Living | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | IV | Yes | COG AHEP0731 | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | II | No | NR | No | Rescue | Living | NR | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | COG AHEP0731 | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | COG AHEP0731 | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | No | COG AHEP0731 | No | Primary | Cad | Yes | Alive | (10) |
| Stanford, USA | 2015/1997–2014 | III | Yes | COG AHEP0731 | No | Primary | Cad | Yes | Alive | (10) |
Pub., publication; mets, metastatic; dx, diagnosis; neoadj, neoadjuvant; chemo, chemotherapy; LT, liver transplantation; ref, reference; NR, not reported; VCR, vincristine; CTX, cyclophosphamide; doxo, doxorubicin; 5FU, 5-fluorouracil; bleo, bleomycin; cis, cisplatin; pulm, pulmonary; met, metastasis; NED, no evidence of disease; PCP, pneumocystis carinii pneumonia; hep, hepatic; art, artery; DOD, died of disease; rec, recurrence; carbo, carboplatin; VP16, etoposide; radio, radiologically; cad, cadaveric; FAP, familial adenomatous polyposis; AFP, alphafetoprotein; ifos, ifosfamide; MTX, methotrexate; irino, irinotecan; topo, topotecan; SIOPEL, International Childhood Liver Tumors Strategy Group; OS, overall survival; Mel, melphalan; mito, mitomycin.
Footnotes
Conflicts of Interest: The authors have no conflicts of interest to declare.
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