Upfront or delayed surgery in resectable hepatoblastoma: analysis from the children's hepatic tumors international collaboration database

Eiso Hiyama; Tomoro Hishiki; Kenichi Yoshimura; Mark Krailo; Rudolf Maibach; Beate Haeberle; Arun Rangaswami; Dolores Lopez-Terrada; Marcio H Malogolowkin; Marc Ansari; Rita Alaggio; Allison F O'Neill; Angela D Trobaugh-Lotrario; Kenichiro Watanabe; Irene Schmid; Sarangarajan Ranganathan; Yukichi Tanaka; Takeshi Inoue; Jin Piao; Jason Lin; Piotr Czauderna; Rebecka L Meyers; Daniel C Aronson

doi:10.1016/j.eclinm.2024.102811

Upfront or delayed surgery in resectable hepatoblastoma: analysis from the children's hepatic tumors international collaboration database

EClinicalMedicine. 2024 Sep 9:76:102811. doi: 10.1016/j.eclinm.2024.102811. eCollection 2024 Oct.

Authors

Eiso Hiyama¹, Tomoro Hishiki², Kenichi Yoshimura³, Mark Krailo⁴, Rudolf Maibach⁵, Beate Haeberle⁶, Arun Rangaswami⁷, Dolores Lopez-Terrada⁸, Marcio H Malogolowkin⁹, Marc Ansari^{10

11}, Rita Alaggio^{12

13}, Allison F O'Neill¹⁴, Angela D Trobaugh-Lotrario¹⁵, Kenichiro Watanabe¹⁶, Irene Schmid¹⁷, Sarangarajan Ranganathan¹⁸, Yukichi Tanaka¹⁹, Takeshi Inoue²⁰, Jin Piao⁴, Jason Lin²¹, Piotr Czauderna²², Rebecka L Meyers²³, Daniel C Aronson²⁴

Affiliations

¹ Natural Science for Basic Research and Development, Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima University, Hiroshima, Japan.
² Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
³ Department of Biostatistics and Health Data Science, Nagoya City University, Japan.
⁴ Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ ETOP IBCSG Partners Foundation, Bern, Switzerland.
⁶ Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany.
⁷ Division of Pediatric Hematology and Oncology, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
⁹ Division of Pediatric Hematology Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
¹⁰ Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.
¹¹ Division of Pediatric Oncology and Hematology, Department of Women, Child and Adolescent, University Geneva Hospitals, Geneva, Switzerland.
¹² Pathology Unit, IRCCS Ospedale Pediatrico Bambino Gesu Pediatric Hospital, Roma, Italy.
¹³ Department of Medical and Surgical Biotechnology Sciences, Sapienza University, Roma, Italy.
¹⁴ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Pediatric Hematology/Oncology, Providence Sacred Heart Children's Hospital, Spokane, WA, USA.
¹⁶ Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, Japan.
¹⁷ Department of Pediatric Hematology and Oncology, Dr. von Hauner Children`s Hospital, University Hospital, LMU Munich, Munich, Germany.
¹⁸ Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁹ Department of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan.
²⁰ Department of Pathology, Osaka City General Hospital, Osaka, Japan.
²¹ Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan.
²² Department of Surgery and Urology, for Children and Adolescents, Medical University of Gdansk, Poland.
²³ Division of Pediatric Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.
²⁴ Department of Pediatric Surgery, University Children's Hospital Zurich, Zurich, Switzerland.

Abstract

Background: In the treatment of resectable hepatoblastoma (HB), it has not been established whether upfront surgery (UF) at diagnosis or neoadjuvant chemotherapy and delayed surgery (DL) is preferred. We compared patients with localized HB who underwent either UF, or DL after neoadjuvant chemotherapy in the Children's Hepatic tumors International Collaboration (CHIC) database of 1605 cases enrolled in eight multicenter hepatoblastoma trials between 1988 and 2010.

Methods: Among the 512 resectable HB patients who had PRETEXT (PRETreament EXTent of disease) I or II unruptured tumors at diagnosis without extrahepatic invasion, distant metastases, or massive vascular invasion, 172 underwent UF and 340 underwent DL. The primary outcomes were event-free and overall survivals after start of treatment in these two groups. Survival analysis was performed using the Kaplan-Maier analysis with long-rank tests and multivariable Cox regression models.

Findings: Complete resection rates were comparable (93.6% in UF and 89.7% in DL). The total cycles of chemotherapy of DL (median:6) were significantly more than those of UF (median:4) (P < 0.01). The 5-year event-free survival (EFS) was 90.6% and 86.6% (P = 0.89) in the UF and DL cohorts, respectively. The surgical complications, recurrence rates, and late complications were not significantly different between the cohorts but the EFS rates of DL patients with a low alpha-fetoprotein (AFP) level (100-999 ng/mL) or older age at diagnosis (≥3 years old) were significantly worse than others.

Interpretation: The outcomes, surgical resectability, and complications were not significantly different between the UF and DL groups. Eligible patients with a low AFP level (<1000 ng/mL) or older age (≥3 years old) showed better outcomes in the UF group and might be considered for initial resection.

Funding: European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission; Children's Oncology Group Cure Search grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research and Development; Japan Society for the Promotion of Science; and Swiss Cancer Research grant.

Keywords: Age at diagnosis; Alpha-fetoprotein; Hepatoblastoma; Outcome; Resectable; Up-front surgery.