4. Discussion
In this retrospective multicenter study of 130 patients with HB in the
CHIC-HS, the very low- and low-risk groups underwent surgery with
curative intent and were followed up for >5 years. We
investigated the effect of NACT on the 5-year OS and EFS. According to
our results, there was no survival benefit to using NACT before surgery
in terms of EFS and OS. Pathological classification was a risk factor
for adverse events and mortality; three (30%) patients with MEM
pathology experienced tumor recurrence and one (10%) patient died. One
(4%) patient with EMEF pathology had tumor recurrence and remains alive
to date, while two (8%) patients with EMEF pathology died from other
factors. All SCU patients died of progressive disease after relapse, and
no adverse events or deaths were observed in patients with PFH
pathology. Moreover, pathological alterations were observed after NACT.
Because of the rarity of HB and the fact that only 30% of patients had
resectable tumors at the time of diagnosis, it was difficult to perform
a prospective study, and few studies have addressed which patients
benefit the most from upfront surgery. Currently, surgeons mainly judge
whether the tumor is resectable based on subjective evaluation and
experience. For PRETEXT stage III patients, most surgeons usually choose
to receive NACT to make surgery easier, even when tumors are resectable
at the time of diagnosis. Therefore, very few patients with PRETEXT
stage III HB were included in this study. The SIOPEL group reported that
patients with resectable tumors using NACT before surgery had less
surgical complications and better outcomes. Therefore, they recommended
that all patients receive NACT before surgery 4,
resulting in further reduction in the number of patients undergoing
upfront surgery. Establishing objective patient selection criteria for
US is paramount, and the COG argues for decreasing the total cumulative
administered dose of cisplatin to protect patients from hearing loss6,12. The JPLT-2 study showed PRETEXT stage I patients
and some PRETEXT stage II patients without positive annotation factors
who underwent US and had good outcomes (5-year EFS and OS: 74.2% and
89.9%, respectively) 5. The COG study achieved
similar outcomes; the 5-year EFS and OS of patients with PFH pathology
were 100% 12, and in PRETEXT stage I or II patients
without PFH and SCU pathology, the 5-year EFS and OS were 88% and 91%,
respectively 6. However, there was no comparison
between the two approaches in these studies, and differences in the
inclusion criteria made it difficult to compare these results.
To standardize surgical decision-making, an objective and comparable
evaluation method was used to determine the optimal patients for upfront
surgery. We used the risk-stratified staging developed by the CHIC to
explore whether patients with HB in the very low-risk and low-risk
groups benefited from upfront surgery. In this study we verify whether
the CHIC-HS can be used to screen patients with HB for tumors that can
be resected at the time of diagnosis. According to our data, both
patient groups had a relatively favorable prognosis, and there was no
significant difference in the 5-year OS and EFS between the groups. This
suggests that US can achieve long-term disease control in these
patients, which can decrease cisplatin chemoresistance and reduce the
total chemotherapy dose.
NC has some effects on surgical operations, which can lead to tumor
shrinkage and downstaging and the tumor shrinking further away from the
blood vessels 13. This approach can reduce the risk of
intraoperative bleeding and other complications, making surgery easier
to perform. However, after the tumor shrinks, the tissues around the
tumor often show an abnormal shape when relieving compression from the
tumor. Pathological examination showed that these tissues are usually
liver parenchyma, and some surgeons choose to retain this part of the
tissue to obtain a larger residual liver volume. Our results showed that
this did not affect the surgical outcome. There was no statistical
difference in the rate of R1 resection between the groups, and R1
resection had no effect on the 5-year OS and EFS (Table 3), which are
consistent with the findings of previous studies14,15.
Notably, we found that, among the pathologic changes induced by NACT,
some EMEF tumors presented mature mesenchymal tissues (Table S1). This
finding is consistent with those reported by Stephen et al.16, and “maturation” of malignant clones or the
result of selective ablation of immature clones were thought to predict
a better prognosis 17. However, a recent study showed
that patients with MEM pathology were more likely to experience
recurrence and metastasis because they had low sensitivity to
chemotherapy, but no prechemotherapy pathology was available in that
study 18. Consequently, it was difficult to compare
these two studies. In our research, the rate of recurrence and
metastasis in patients with MEM and SCU pathology was higher than that
in other patients, but no conclusion could be drawn due to the small
sample size. The prognostic effect of pathological classification
changes due to NC and effect of pathological classification on prognosis
in different risk groups merit further investigation.
The study limitations include its retrospective nature and small sample
size, that NACT regimens and the number of cycles of NACT varied across
institutions, and our failure to evaluate tumor response to chemotherapy
and acute and long-term toxicities of platinum-based chemotherapy,
especially ototoxicity.
In the future, it will be necessary to explore whether more patients
with HB can benefit from upfront resection, similar to our study, and
the impact of preoperative chemotherapy in altering pathologic type upon
prognosis. Experiments need to be designed to evaluate the chemotherapy
resistance of tumors and the degree of hearing loss in patients. Owing
to the rarity of HB, further studies with a larger sample size and
multicentric samples are needed.
In conclusion, our findings suggested that upfront resection can achieve
long-term disease control in patients with HB and resectable tumors at
diagnosis in the CHIC-HS very low- and low-risk groups. This treatment
approach can reduce the cumulative toxicity of platinum-based
chemotherapy drugs, including in PRETEXT stage III patients. SCU
patients had poorly differentiated tumors and a poor prognosis;
treatment of these patients is controversial, and the optimal therapies
need further investigation. This HB risk stratification system provides
an objective criterion to evaluate whether patients are suitable for
upfront resection. Our findings may help future clinical studies to
explore whether more patients with HB can benefit from upfront
resection.