Abstract
Background: We aimed to retrospectively investigate the role of
neoadjuvant chemotherapy in low-risk patients with hepatoblastoma (HB)
who underwent curative resection between February 2009 and December
2017. We also verified the feasibility of the risk stratification system
to select the optimal patients for upfront resection.
Procedure: We compared 5-year overall survival (OS) and
event-free survival (EFS) between the upfront surgery (US) (n=26) and
neoadjuvant chemotherapy (NC) (n=104) groups at three oncology centers
in Beijing, China. To reduce the effect of covariate imbalances,
propensity score matching (PSM) was used. We explored whether
preoperative chemotherapy affected surgical outcomes and identified the
risk factors for events and death, including resection margin status,
PRETreatment EXTent of disease stages, age, sex, pathology
classification, and α-fetoprotein levels.
Results: The median follow-up period was 64 months
(interquartile range 60–72). After PSM, 22 pairs of patients were
identified and the patient characteristics were similar for all
variables included in propensity score matching. In the US group, the
5-year EFS and OS rates were 81.8% and 86.3%, respectively. In the NC
group, 5-year EFS and OS rates were 81.8% and 90.9%, respectively. No
significant differences in EFS or OS were observed between the groups.
Pathological classification was the only risk factor for death and
disease progression, tumor recurrence, diagnosis of other malignant
neoplasms, and death from any cause (p =0.007 and p =0.032,
respectively).
Conclusion: Upfront resection can achieve long-term disease
control in low-risk patients with resectable HB, thus reducing the
cumulative toxicity of platinum-based chemotherapy drugs.
Introduction
Hepatoblastoma (HB) is a rare disease with an incidence of 1.6/million
children. However, it is the most common malignant pediatric liver
cancer, which usually develops in patients aged <3 years, and
its incidence has increased by >5% annually1,2. With improvements in surgical techniques and the
use of adjuvant chemotherapy, the 5-year survival rate of HB has
increased from approximately 35% (50 years ago) to 80%–90%
(currently) 3.
The primary treatment modality for HB is complete surgical resection;
however, 60%–70% patients are inoperable during diagnosis because of
a high tumor bulk volume or major blood vessel invasion4. Systemic cisplatin-based chemotherapy is effective
for reducing tumor volume in patients with HB and can convert most
unresectable tumors into resectable tumors. Therefore, the International
Childhood Liver Tumors Strategy Group (SIOPEL) prefers the use of
neoadjuvant chemotherapy (NACT) and delayed resection to facilitate
tumor resection 4. However, the Children’s Oncology
Group (COG) trial AHEP0731 and Japanese Study Group for Pediatric Liver
Tumors (JPLT) study indicated that upfront resection in selected HB
cases achieved excellent outcomes 5,6. Unnecessary
NACT may result in potential exposure to chemotherapy and
treatment-related toxicity, and an increased number of chemotherapy
cycles are associated with chemotherapy resistance7-9. However, the value of upfront resection has not
been established, and there is no clear consensus regarding which
patients with HB benefit the most from this form of treatment.
Due to the lack of a uniform staging system, it is difficult to
interpret and compare the results reported by different research groups,
and it creates difficulties in terms of optimal patient selection. Four
major cooperative trial groups (SIOPEL, COG, the German Society for
Pediatric Oncology and Hematology, and JPLT) formed the Children’s
Hepatic Tumors International Collaboration (CHIC) to define a common
hepatoblastoma stratification (CHIC-HS), which makes the heterogenous
results of prior research more comparable 10.
In this retrospective, multicenter study, we compared event-free
survival (EFS) and overall survival (OS) in CHIC-HS low-risk patients
with HB who underwent surgical resection and NACT and verified the
feasibility of the risk stratification systems used to select the
optimal treatment for patients with HB.
Methods
The study was performed in accordance with the Strengthening the
Reporting of Observational Studies in Epidemiology guidelines. This
study complied with the tenets of the Declaration of Helsinki and the
Capital Institute of Pediatrics’ (CIP) ethics committee approved this
study (SHERLL2022047). Due to the
retrospective nature of the study, the need for informed consent was
waived.
Patient selection
The medical records of patients with HB who underwent curative resection
with or without NACT at CIP (Beijing, China) and two other centers
between February 2009 and December 2017 were collected. We classified
patients into upfront surgery (US) and NACT (NC) groups, based on
whether they had received NACT or not. The CHIC-HS system assigned
patients to four risk groups based on age, serum α-fetoprotein (AFP)
levels, and PRETreatment EXTent of disease stages (PRETEXT) stage and
its annotation factors 11. Eligible patients were
stratified into a very low- or low-risk group (Table 1), were
<8 years old, and had a histopathologic diagnosis of HB. The
tumors were estimated to be resectable at the time of diagnosis,
patients had complete clinical and follow-up data, and liver and kidney
function were normal. Patients with other tumors or serious medical
diseases, who refused surgery, and who refused postoperative
chemotherapy were excluded.
Outcomes
The primary outcomes were 5-year OS and EFS. We defined EFS as the time
from surgery to tumor recurrence, diagnosis of other tumors, death from
any cause, or last follow-up without the occurrence of any of these
events.
The secondary objectives were to 1) explore whether preoperative
chemotherapy affected surgical outcomes and 2) identify risk factors for
events and death, e.g., resection margin status,
PRETEXT stages, age, sex,
pathology classification, and AFP level at diagnosis. R0 resection was
defined as a microscopically negative margin, and R1 resection as
macroscopically complete resection with positive microscopic margins.
Statistical analysis
The non-parametric Mann–Whitney U test was used to compare
non-normal data between groups. All tests were two-sided, and ap -value of <0.05 was considered statistically
significant.
To reduce the confounding
effects of imbalances in the study covariates, propensity score matching
(PSM) was performed. The propensity score (PS) was estimated using a
logistic regression model, in which the treatment modality was regressed
onto sex, age at surgery, AFP levels at diagnosis, and PRETEXT stage as
potential covariates. The US group was PS-matched to the NC group in a
1:1 ratio, using maximum distance (caliper) of 0.15 between matched
participants based on their propensity score. The balance in covariates
between the groups before and after PSM was evaluated using standardized
mean differences (SMDs). SMD <0.2 was deemed to be the ideal
balance.
The Kaplan–Meier method was performed to estimate OS and EFS, and a
log-rank test was conducted to compare these results among the patient
groups.
The relationships between
resection margin status, PRETEXT
stages, age, sex, pathology classification, AFP levels, and outcome
events (events and deaths) were analyzed using logistic regression,
since we only studied the effects of variables on death and events, but
not on the length of survival. Statistical significance was set at
two-sided p -value <0.05.