Pediatric hepatocellular carcinoma

Table 3 Changing outcome of children with hepatocellular carcinoma over last 4 decades

Study (yr)Ref.	Number of patients	Factors governingoutcome	Intervention (s)done	Survival
Conservative treatment (Observation and resection)
Lack et al[31] (1983)	32 (5FLHCC)	Higher resectability and overall survival with FLHCC	Observation Resection	5 yr 7% MST of HCC 4.2 mo and FLHCC 28.5 mo
Wu et al[96] (1987)	20	-	-	5 yr 0; MST 4.7 mo
Hsu et al[28] (1987)	51	Early HBeAg seroconversion with severe liver injury predispose to HCC	Observation Resection	1 yr 10.5%
Chen et al[29] (1988)	44	No difference in survival with chemotherapy	Observation Resection	5 yr 7%
Ni et al[97] (1991)	71	Favorable prognosis with resectability and absence of icterus	Observation Resection	1 yr 10%, 5 yr 4%
Lee et al[6] (1998)	28	-	-	5 yr 17%
Hsiao et al[98] (2009)	13	-	-	DFS 30%
Allan et al[8] (2014) SEER database	218	Reduced mortality associated with resectability (OR = 0.18), non-Hispanic (OR = 0.52), local disease (OR = 0.46)	-	5 yr 24%, 10 yr 23%, 20 yr 8%
Mixed treatments (chemotherapy/TACE/liver transplantation)
Tagge et al[99] (1992)	21	Total hepatectomy and LT improved survival in those with unresectable disease	Surgery in 15 (6 PH, 7 LT, 2 Exenteration and MOT) Pre-operative CT in 2 Observation in 6	1 yr 29%
Chen et al[10] (1998)	55	Good outcome with resection, poor with unsatisfactory resection & metastases Distant metastases carries worst prognosis	Resection CT Observation	MST with resection 23 mo, CT 3 mo and no treatment 2 mo
Moore et al[7] (2004)	68	-	Resection ± CT TACE Observation	> 5y 11% MST 4 mo
Pham et al[17] (2007)	22	-	Surgery ± CT	OS 5 yr 30% MST 23 mo
Zhang et al[12] (2013)	45	Low overall survival with metastases & non-resectability, but unrelated to HBsAg positivity Large tumor size, early metastasis, bilateral involvement, and PV invasion precluded resection	Resection TACE Observation	1 yr 34%, 3 yr 4%, 5 yr 4% MST 6 mo (Resection 28.6 mo, TACE 4 mo, None 5 mo, presence of metastases 4 mo)
McAteer et al[15] (2013) SEER database	238	Lower hazard of death with surgery (HR = 0.23) and lymphadenectomy (HR = 0.26) More hazard of death with female gender (HR = 2.07), older age (> 5 yr, HR > 5) and distant metastases (HR = 3.4)	Surgery in 112 No surgery in 118 Unknown in 8	OS 5 yr for 0-4 yr age 53%, 5-19 yr age 32% OS 5 yr for males 40%, females 26% DFS 5 yr for localized 61%, regional 39% and metastatic 9% DFS 5 yr 70% with lymphadenectomy vs 57% without
McAteer et al[30] (2013) SEER database	80	Lower hazard of death with LT as compared to resection (HR = 0.05)	Surgery (LT 20, resection 60)	OS 5 y with LT 85%, Resection 53%
Wang et al[38] (2017)	65	Initial treatment allocation predicted OS (TACE HR = 0.298, Resection HR = 0.105 with No treatment as reference)	Resection TACE No treatment	For moderate stage disease: Median OS longer with resection (38 mo) vs TACE (13.6 mo) vs No treatment (1.8 mo). For advanced disease: Median OS longer with TACE (7.1 mo) vs no treatment (2.3 mo)
Chemotherapy
Czauderna et al[27] (2002) SIOPEL 1	39	Poor outcome related to metastases and higher PRETEXT stage	CT in 37, followed by resection	OS 5 yr 28% EFS 5 yr 17% 93% deaths due to tumour progression
Katzenstein et al[16] (2002) CCG/POG	46	Poor outcome with recurrent disease Favourable prognosis with stage I and normal AFP Comparable survival between 2 regimens	CT (CDDP + Vincristine + 5-FU vs CDDP + Doxo)	EFS 5 yr 19% (Stage I 88%, III 8%, IV 0) OS 5 yr 19% (Stage I 88%, III 23%, IV 10%)
Murawski et al[100] (2016) SIOPEL 2 and 3	85	Complete tumor resection and tumor free margins predict OS	Primary surgery (if feasible) à Super-PLADO (CDDP, Doxo and Carbo) à Assessment for LT	Response to CT in 40% OS at 5 yr 22% 5-yr OS with complete resection 63% vs 59% with LT 5-yr OS with macroscopically involved margins 14%
Liver transplantation
Reyes et al[101] (2000)	19	Risk for recurrence with vascular and LN invasion, distant metastases, size of tumor and male gender	LT ± Systemic or intra-arterial neoadjuvant CT	1 yr 79% 3 yr 68% 5 yr 63%
Austin et al[24] (2006) UNOS database	41	Primary cause of death: Metastatic or recurrent disease Pretransplant medical disease and era of LT associated with graft and patient survival	All LT	1 yr 86% 3 yr 63% 5 yr 58%
Arikan et al[13] (2006)	13	-	LT in 7 Observation in 6	Overall 1 yr 53%, 4 yr 27% (With LT 1 yr 72%, 4 yr 72%) No recurrence at 36 mo with LT
Beaunoyer et al[23] (2007)	10	1 out of 7 outside MC had recurrence, died	LT in all Pre-LT CT in 5	OS 1 yR 100%, 5 yR 83% RFS 5 yr 89%
Sevmis et al[14] (2008)	9	1 out of 4 outside MC had recurrence, excised	LT in all Pre-LT CT in 3	100% survival at 19.8 ± 10.6 (7-32) mo Recurrence in 1 out of 4 outside MC, excised
Ismail et al[22] (2009)	21	Mortality related to recurrence and PRETEXT stage in the non-LT group, but not in the LT group	LT 11 Non-LT 10 (Resection in 8 - 4 after CT)	OS with LT 72% at median 43 mo and Non-LT 40% at median 66 mo Recurrence after LT in 1/11 and after resection in 6/8
Romano et al[18] (2011)	10	-	All primary LT No CT / resection	80% RFS at median FU of 4 y (1-11 y)
Palaniappan et al[26] (2016)	12	1 Multifocal + 2 with microvascular invasion 2 underwent TACE before LT	All primary LT (8 diagnosed incidentally in explant livers)	92% OS at a median of 5 (1-27) mo
Baumann et al[25] (2018) ELTR data	175	Survival better in children with inherited liver disease than without (HR = 0.29) and vs adults with HCC with inherited liver disease (HR = 0.27) Survival rate increased with increasing age in non-inherited group	All LT	OS at 5 yr: Patient 58% and Graft 56% Patient survival at 5 yr and 10 yr Inherited: 81% and 81% Non-inherited: 53% and 45%

AFP: Alpha-fetoprotein; Carbo: Carboplatin; CDDP: Cisplatin; CCG: Children’s cancer group; CT: Chemotherapy; DFS: Disease free survival; EFS: Event-free survival; ELTR: European Liver Transplant Registry; FLHCC: Fibrolamellar variant of HCC; FU: Follow-up; 5-FU: 5-Fluorouracil; HR: Hazard ratio; LN: Lymph-node; LT: Liver transplantation; MC: Milan criteria; MOT: Multi-organ transplantation; MST: Median survival time; OR: Odd’s ratio; OS: Overall survival; PH: Partial hepatectomy; POG: Pediatric Oncology group; PRETEXT: Pretreatment tumor extent evaluation; RFS: Recurrence free survival; SEER: Surveillance epidemiology and end-results; SIOPEL: Group for epithelial liver tumors of the international society of pediatric oncology; TACE: Trans-arterial chemoembolization.