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\begin{document}

\title{Outcomes of Extended Hepatic Resection for POST-TEXT III and IV
Hepatoblastoma: a single center experience}



\author[1]{Wei Yao}%
\author[2]{kuiran dong}%
\author[1]{Kai Li}%
\author[1]{Gongbao Liu}%
\author[1]{Chenghao Bai}%
\author[1]{Xianmin Xiao}%
\author[1]{Shan Zheng}%
\affil[1]{Children's Hospital of Fudan University}%
\affil[2]{Children\'s Hospital of Fudan University}%


\vspace{-1em}



  
  \date{June 16, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Objective: To investigate the long-term outcomes of extended hepatectomy
for POST-TEXT III and IV hepatoblastoma. Methods: The clinical data of
35 patients with POST-TEXT III and IV hepatoblastoma from January 2009
to June 2019 were analyzed retrospectively. Results: There were 34 cases
of POST-TEXT III and 1 cases of POST-TEXT IV, respectively. All 35 cases
underwent hepatic resection, including 7 cases of hepatic
trisectionectomy, 8 cases of extended hemihepatectomy, 4 cases of
irregular hepatectomy, 12 cases of mesohepatectomy and 4 cases of ALPPS
procedure. Pringle maneuver and Glissonean approach was used in 4 and 22
patients, respectively. The average blood loss of patients with
Glissonean approach (147.73 \selectlanguage{ngerman}± 137.46ml) was significantly less than that
of patients without the approach (387.69 ± 235.69ml; P = 0.001). The
5-year overall survival rate and event-free survival rate was 79.2\% and
73.7\%, respectively. According to the classification of tumor margin
distance, the 5-year overall survival rates of the tumors with margin
\textgreater{} 1cm, 0.5-1cm, \textless{} 0.5cm and close to the tumor
margin were 100\%, 78.0\%, 83.3\% and 53.3\%, respectively (P=0.371).
Seven patients developed recurrence which occurred within 1 year after
tumor resection. Conclusion: Non-transplant extended hepatic resection
is a feasible approach for POST-TEXT III and IV hepatoblastomas. On the
basis of mastering the Glisson approach and ensuring a certain resection
margin, it is possible to achieve a similar oncological outcome to liver
transplantation.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Instruction}

Hepatoblastoma is the most common primary tumor of the liver in
children, accounting for nearly 80\% of pediatric malignant liver
tumor\textsuperscript{{[}1{]}}. With the development of multimodal
treatment approaches combining platinum based (neo-)adjuvant
chemotherapy and surgery, the overall survival (OS) rates have now
reached over 80\% for patients advanced
disease\textsuperscript{{[}2-4{]}}, but complete resection is crucial
for cure in the treatment of hepatoblastoma\textsuperscript{{[}5, 6{]}}.
The post-treatment extent of disease (POST-TEXT) staging was commonly
used for assessing the tumor extension after neoadjuvant chemotherapy
and evaluating tumor resectability\textsuperscript{{[}7{]}.} It was a
great challenge in the treatment of POST-TEXT III and IV hepatoblastoma
and primary liver transplantation was recommended as surgical option for
these patients because of the excellent outcomes\textsuperscript{{[}8,
9{]}}. In recent years, a few studies results had showed that
non-transplant hepatic resections can achieve similar outcomes with
liver transplantation in some selected POST-TEXT III and IV
patients\textsuperscript{{[}10-13{]}}.

The purpose of this study is to evaluate the results of extended hepatic
resection in POST-TEXT III and IV hepatoblastoma patients at a Chinese
National Children's Medical Center with long-term follow-up.

\textbf{Methods}

\textbf{Clinical data}

The medical records of POST-TEXT III and IV hepatoblastoma patients
admitted to Children's Hospital of Fudan University from January 2009 to
June 2019 were analyzed retrospectively. The study was approved by the
institution scientific and ethics committee of our hospital. Informed
consent was obtained from all legal guardians of the children who agreed
to participate in this study. The staging of hepatoblastoma is based on
the pretreatment extent of disease (PRETEXT) system. Tumor extensions
before and after neoadjuvant chemotherapy were referred to as PRETEXT
and POST-TEXT, respectively. Variables studied included age at
diagnosis, gender, neoadjuvant and adjuvant chemotherapy regimens,
a-fetoprotein (AFP) levels, type of operation, operative time, amount of
blood loss, histology, and clinical outcomes.

\textbf{Treatment algorithm}

All patients received neoadjuvant chemotherapy of C5V regimen (cisplatin
+ vincristine + 5-fluorouracil) according to the treatment protocol of
Children Oncology Group (COG). Tumor response and the possibility of
resection were evaluated every 2 cycles after chemotherapy with a
maximum of 6 cycles. The choice of surgical procedures was performed
according to the number of sectors and the hepatic vessels involved.
Standard hepatic trisectionectomy was performed for patients with three
lobes involved; extended hepatectomy was performed for patients with
half liver and one liver segment involved; mesohepatectomy was performed
for patients with central hepatoblastoma; irregular hepatectomy was
performed for patients with multiple liver segments involved;
associating liver partition and portal vein ligation for staged
hepatectomy (ALPPS) was performed for patients with less than 40\%
residual liver after hepatic trisectionectomy or irregular hepatectomy;
if the above-mentioned operation is still unable to remove the tumor,
liver transplantation would be recommended. Adjuvant chemotherapy was
started 3 weeks after operation and stopped after 2 times of normal AFP.

Follow up and statistics

The end point of follow-up was January 2020. Those who have died are
complete data, and those who are still alive or lost are censored data.
Data analysis was performed by using SPSS18.0 software. The survival
rate was analyzed by Kaplan Meier method and the estimates of both the
5-year EFS and OS are given with 95\% confidence intervals (CIs). The
continuous data are summarized with the median and range or the
interquartile range. P \textless{} 0.05 was considered as statistically
significant.

\textbf{Results}

\textbf{Clinical characteristics}

From January 2009 to June 2019, a total of 35 children with POST-TEXT
III and IV hepatoblastoma were treated, including 24 males and 11
females, with an average age of 23.89 \selectlanguage{ngerman}± 22.87 months (2-91 months).
Serum AFP was significantly higher than normal in all cases, of which
only 1 (2.9\%) case was \textless{}1000ug/L, 8 (22.8\%) cases
were1000-100,000 ug/L, and 26 (74.3\%) cases were \textgreater{}
100000ug/L. There were 1, 31, and 3 cases of PRETEXT II, III, and IV,
including 5 cases of lung metastasis. Tumor biopsy was performed in 27
patients (77.1\%). The tumor volume before treatment was 105.23-1235.06
cm\textsuperscript{3}, with an average volume of 568.99 ± 285.56
cm\textsuperscript{3}.

There were 34 and 1 cases of POST-TEXT III and IV, respectively. One
case of PRETEXT II was upgraded to POST-TEXT IV, and 3 cases of PRETEXT
IV were downgraded to POST-TEXT III (Table 1). Neoadjuvant chemotherapy
was performed in 8 patients (22.9\%) within 2 cycles; 22 patients
(62.9\%) within 4 cycles; 5 patients (14.3\%) within 6 cycles. The
relationship between tumor preoperative cycles and stage is shown in
Table 1. The tumor volume after chemotherapy was 20.66-1235.77
cm\textsuperscript{3}, with an average volume of 272.64 ± 2569.19
cm\textsuperscript{3}, of which the volume was reduced by 30 cases
(85.7\%), and the average size was reduced by 67.45\% ± 14.98\%; the
volume was increased by 5 cases (14.3\%), and the average size was
increased by 92.14 \% ± 74.71\%. The relationship between tumor volume
change and stage is shown in Table 1.

\textbf{Surgical Results}

All 35 cases underwent hepatic resection, including 7 cases of hepatic
trisectionectomy (4 right, 3 left), 8 cases of extended hemihepatectomy
(4 right hemihepatectomy with additional segment IV, 4 left
hemihepatectomy with additional segment V), 4 cases of irregular
hepatectomy, 12 cases of mesohepatectomy and 4 cases of ALPPS procedure
(Table 2). The average operation time was 262.29 ± 107.16 minutes
(range, 120-520 minutes), and the average blood loss was 236.86 ± 212.41
ml (range, 20-700 ml). Pringle maneuver and Glissonean approach was used
in 4 and 22 patients, respectively. The average blood loss of patients
with Glissonean approach (147.73 ± 137.46ml) was significantly less than
that of patients without the approach (387.69 ± 235.69ml; P = 0.001).

Because of the injury of the bile duct, additional hepaticojejunostomy
was performed in 3 patients who did use Glissonean pedicle approach.
Postoperative complications occurred in 10 patients: bile leak in 9
patients, of which 4 patients were resolved by drainage and the rest
were absorbed spontaneously; Budd Chiari syndrome in 1 patient, of whom
was died of the emergency surgery. The incidence of bile leak was 27.3\%
in 6 cases who used Glissonean pedicle approach and 23.1\% in 3 cases
without the approach (P = 0.784). The postoperative liver function of
all patients, including 4 patients undergoing ALPPS procedure, recovered
gradually within one month. The relationship between POST-TEXT
classification, operation time, blood loss, bile leakage and the type of
surgery was listed in Table 2.

Histological analysis revealed mixed epithelial/mesenchymal
hepatoblastoma in 20 patients, embryonal hepatoblastoma in 6 patients
and fetal hepatoblastoma in 9 patients. Microscopically positive
resection margin was confirmed by pathology in one patient, the
resection margins of rest 34 patients were negative. According to the
classification of tumor margin distance, there were 7 cases (20.0\%)
with margin \textgreater{} 1 cm, 15 cases (42.9\%) with margin 0.5-1 cm,
7 cases (18.9\%) with margin \textless{} 0.5 cm, and 6 cases (16.2\%)
with close to tumor margin. AFP returned to normal after surgery in 30
cases. The average time of AFP recovery was 11.8 ± 10.5 weeks (4-60
weeks), 90\% of them recovered within 12 weeks. Further adjuvant
chemotherapy was given in all patients and the average cycle was 4.76 ±
2.36 (2-15 cycles) after operation.

\textbf{Follow-up}

Thirty-four patients were followed up successfully, with a follow-up
rate of 97.1\%. After average follow up of 37.26 ± 29.84 months (range,
4-124 months), 28/35 patients were still alive, and 26 of them were
disease free. The 5-year overall survival (OS) rate was79.2\%; the
5-year event-free survival (EFS) rate was 73.7\% (Fig. 1). According to
the classification of tumor margin distance, the 5-year overall survival
rates of the tumors with margin \textgreater{} 1cm, 0.5-1cm, \textless{}
0.5cm and close to the tumor margin were 100\%, 78.0\%, 83.3\% and
53.3\%, respectively (P=0.371; Fig 2).

Seven patients developed recurrence, of whom 3 had hepatic local
recurrence, 3 had multiple pulmonary metastases and 1 had bone
metastases. All recurrence occurred within 1 year after tumor resection
and 5 patients died due to disease progression. The average time to
recurrence was 6±3.96 months (range, 1--12 months). Of the all
recurrence patients, 3 had tumor margin within 0.5-1 cm, 1had tumor
margin \textless{} 0.5 cm and 3 cases had close to tumor margin (Table
3). There was no statistical difference in the recurrence rate of
different tumor margin (P=0.932). In addition to irregular hepatectomy,
other surgical procedures have tumor recurrence (Table 3), but there is
no significant difference in the recurrence rate of different surgical
procedures (P=0.352).

\textbf{Discussion}

Complete resection of hepatoblastoma is one of the most important
factors that affect the prognosis of hepatoblastoma. Although COG and
SIOP Epithelial Liver Tumor Study Group (SIOPEL\selectlanguage{english})are controversial about
whether early hepatoblastoma need neoadjuvant chemotherapy or primary
resection, the treatment strategy of neoadjuvant chemotherapy followed
by surgery has become a consensus for unresectable
cases\textsuperscript{{[}14, 15{]}}. At present, neoadjuvant
chemotherapy based on platinum can reduce the tumor volume, avoid the
risk of tumor rupture and allow many initially unresectable tumors to be
safely removed \textsuperscript{{[}14{]}}. The SIOPEL trials have
revealed that more than half of PRETEXT IV tumors can be completely
resected after intensified neoadjuvant
chemotherapy\textsuperscript{{[}16{]}}. Therefore, neoadjuvant
chemotherapy was used in all the advanced cases in this study. And tumor
size was regressed in 85.7\% patients, with an average reduction of
67.45\%. Despite tumor volumes regressed significantly with increasing
neoadjuvant chemotherapy cycles, SIOPEL evaluated tumor resectability
after four cycles of neoadjuvant chemotherapy\textsuperscript{{[}17{]}},
while COG evaluated every two cycles, with a maximum of six
cycles\textsuperscript{{[}18{]}}. In our study, the COG treatment
strategy was adopted, and 81.1\% of tumor can be resected within four
cycles of neoadjuvant chemotherapy. Therefore, the majority of advanced
hepatoblastoma became resectable through neoadjuvant chemotherapy.

Primary liver transplantation was recommended as surgical treatment
option for advanced hepatoblastoma presenting as POST-TEXT IV or central
POST-TEXT III stages after neoadjuvant chemotherapy. The long-term
survival rates could reach up to 80\% to 90\% for these patients
undergoing primary transplant\textsuperscript{{[}19-21{]}}. In recent
years, with the optimization of neoadjuvant chemotherapy, the progress
of image evaluation and the improvement of surgical techniques, more and
more studies reveal that non-transplant resection techniques in selected
POST-TEXT III and IV hepatoblastoma achieved a similar survival rate to
primary liver transplantation\textsuperscript{{[}10, 11, 13, 22{]}}.
What type of hepatic resection is used for POST-TEXT III and IV
hepatoblastoma depends on the relationship between the tumor edge and
the major liver vessels; on the other hand, it also depends on whether
the tumor can be completely removed to ensure a negative margin. In this
study, in addition to trilobectomy, expanded hemihepatectomy,
mesohepatectomy or irregular hepatectomy were selected according to the
number of hepatic segments involved and the relationship with the liver
vessels. By choosing different types of hepatic resection, we can ensure
that the residual liver can be preserved as much as possible on the
basis of complete resection of tumor. In cases where liver tumor
resection cannot be performed due to insufficient residual liver, ALPPS
procedure will be of great usefulness for rapidly increasing the volume
of residual liver in a short period\textsuperscript{{[}23, 24{]}}. In
this study, 4 patients underwent ALPPS due to insufficient residual
liver. All patients had a rapid increase in residual liver volume within
2 weeks, and all tumors were successfully removed without liver
dysfunction. Therefore, we believe that ALPPS could be reserved for
those patients who would not have sufficient future liver remnant.

The tumors of POST-TEXT III and IV are very large or critically
positioned and impinge on essential vascular structures, or tumors that
are multicentric and present in three or four sectors, often requiring
non-anatomical liver resection. Glissonean approach can be used to
selectively block secondary Glisson pedicle according to the sectors
involved, make a decrease in the amount of intraoperative bleeding,
reduce the incidence of bile duct injury, and avoid intraoperative
pringle maneuver\textsuperscript{{[}25, 26{]}}. In this study, pringle
maneuver was used only in 4 cases, while Glissonean approach was used in
majority of cases (22/35). And the average blood loss of patients with
Glissonean approach was significantly less than that of patients without
the approach. Although the incidence of bile leak using the Glissonean
approach is similar to that without the technique, and the incidence
rate of ALPPS is the highest in all procedures, the incidence of biliary
tract injury is significantly reduced, which reflects the advantages of
this approach.

In recent years, reports of non-transplanted hepatic resection for
POST-TEXT III and IV hepatoblastoma have increasingly been reported. The
5-year overall survival rate and 5-year tumor-free survival rate of
these patients is 80.7\% -88\% and 62.2\%\textasciitilde{}75\%,
respectively, which is similar to that of liver
transplantation\textsuperscript{{[}10, 11, 13{]}}. Our results are
similar to those reported in the literature, indicating that it is
feasible to perform hepatic resection for POST-TEXT III and IV
hepatoblastoma. When hepatic resection for POST-TEXT III and IV
hepatoblastoma is performed, it is sometimes difficult to guarantee a
margin of resection greater than 1 cm. Although macroscopic residual
tumor is an important factor affecting the prognosis of hepatoblastoma,
there is still a debate about the prognostic impact of this
microscopically positive resection margin\textsuperscript{{[}27, 28{]}}.
Recently, SIOPEL analyzed 431 cases of hepatoblastoma in its 2 and 3
trials and found that the tumor recurrence rate (6\%) and 5-year
survival rate (91\%) of the microscopically residual cases were similar
to those of the negative cases (recurrence rate: 5\%, 5-year survival
rate: 92\%). Therefore, it is concluded that the presence of a
microscopically positive resection margin did not in\selectlanguage{english}fluence the outcome
even without additional local treatment\textsuperscript{{[}29{]}}. In
this study, we found that the recurrence rate of the patients whose
tumor were resected close to the edge was higher than that of the
patients who had resection margin, but the 5-year survival rate of was
lower than that of the patients who had resection margin. In addition,
we also observed that there was no significant correlation between the
different distance of resection margin and the recurrence rate and
survival rate. Therefore, our results indicate that when hepatic
resection is performed on POST-TEXT III and IV hepatoblastoma, as long
as a certain margin distance is ensured, tumor recurrence rate could be
reduced and long-term survival rate could be improved.

In summary, non-transplant extended hepatic resection is a feasible
approach for POST-TEXT III and IV hepatoblastomas. Different hepatectomy
can be selected according to the different sectors of liver involved. On
the basis of mastering the Glisson approach and ensuring a certain
resection margin, it is possible to achieve a similar oncological
outcome to liver transplantation.

Acknowledgments: We thank Professor Kai Li for her assistance with
language editing and proofreading.

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Conflict of Interest statement: All authors have no conflicts of
interest.

Funding: There is no fund support for this study.

Figure Legend

Fig 1. Kaplan-Meier estimates for overall survival (OS) and event-free
survival (EFS). 5-year OS was 79.2\%; 5-year EFS was 73.7\%.

Fig 2. Kaplan-Meier estimates for overall survival (OS) of different
tumor margin. 5-year OS of margin \textgreater{} 1cm, 0.5-1cm,
\textless{} 0.5cm and close to the tumor margin were 100\%, 78.0\%,
83.3\% and 53.3\%, respectively.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

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