Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol

Abstract

PURPOSE We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB). PATIENTS AND METHODS From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease. RESULTS The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis. CONCLUSION The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.

Recent improvement in survival outcomes and reappraisal of prognostic factors in hepatoblastoma

“…However, a recent SIOPEL study showed that the OS rates of PRETEXT IV patients were increased from 61% in SIOPEL‐2 to 88% in SIOPEL‐4 4 . In addition, the JPLT‐2 trial showed an improved OS rate of 67% among patients with PRETEXT IV disease compared with 50.3% in the JPLT‐1 trial 5,22 . In the present study, survival outcomes were significantly associated with the PRETEXT stage in the early cohort but not in the late cohort.…”

“…PRETEXT staging at diagnosis is crucial for the risk stratification of patients with hepatoblastoma. Several trials have confirmed that the PRETEXT stage is a strong predictor of OS for patients with hepatoblastoma 5,10,11 . In the Intergroup CCG/POG study INT‐0098, the OS rates of patients with PRETEXT IV hepatoblastoma were as low as 30.9% 10 .…”

“…Distant metastasis at initial diagnosis has been reported as one of the most important prognostic factors associated with poor outcomes 5,8,13,25 . In the late period, metastasis was significantly associated with poor EFS but not OS.…”

“…Treatment strategies incorporating chemotherapy and surgical resection have evolved over the past two decades, and these advances have significantly improved the survival outcomes, showing overall survival (OS) rates of more than 90% for low‐risk patients 2‐4 . However, there are still considerable differences in outcomes for low‐risk and high‐risk patients 2,5‐7 …”

CHIC Risk Stratification System for Predicting the Survival of Children With Hepatoblastoma: Data From Children With Hepatoblastoma in China

“…Compared to the COG risk stratification system, the CHIC risk stratification system excluded pathologic subtypes and included age at diagnosis to form stratification trees based on four clinically familiar PRETEXT groups. Over the past 10 years, four major organizations have been devoted to exploring effective prognostic factors in children with HB (23,24,(26)(27)(28)(29). In 2013, based on a database involving 1605 HB cases treated between 1988 and 2008 from eight completed HB trials, CHIC identified novel prognostic factors for HB (15).…”