In the present study, the survival rate of the POCR(+) group was better than that of the POCR(-) group (p = 0.0041), suggesting that achieving POCR after reduction hepatectomy could have an important impact on survival in patients with unresectable HCC. Moreover, even in the cases in which POCR was not achieved the administration of TKIs resulted in an improvement in survival outcomes; i.e., the survival rates of the POCR(-)TKI(+) group were better than those of the POCR(-)TKI(-) group (p = 0.0473). Thus, reduction hepatectomy could be effective against unresectable advHCC, especially when POCR is achieved via postoperative multidisciplinary therapy. Even in cases in which POCR is not achieved, the administration of TKIs should be considered in the postoperative period.
In ovarian carcinoma, the maximal resection of any primary or metastatic carcinoma followed by postoperative chemotherapy has become the standard treatment strategy . However, there are only a limited number of reports about reduction hepatectomy for HCC [10–13]. In the latter studies, it was reported that the OS rate after reduction hepatectomy for HCC ranged from 52–67.7% at 1 year, from 20.0–40.6% at 3 years, and from 10–21.7% at 5 years [11–13]. As different patients were selected and different treatment options were employed in different eras, it is hard to simply compare OS rates, although the OS rates described in previous reports were similar to those obtained in the present study.
The potential prognostic factors identified in the univariate analyses in the current study were tumor size, vascular invasion, the number of tumors in the remnant liver, and whether POCR was achieved. Vascular invasion, which was diagnosed based on pathological examinations, was the only independent prognostic factor that exhibited significance in the multivariate analysis. However, pathological vascular invasion cannot be detected preoperatively. Thus, we decided to focus on POCR, which can be set as an aim of multidisciplinary therapy after reduction hepatectomy.
Achieving POCR using postoperative multidisciplinary treatment had an important impact on survival in the current cases. When the cases were limited to those in which POCR was achieved, the 1-year, 3-year, and 5-year OS rates after reduction hepatectomy were 100%, 75.0%, and 37.5%, respectively, and the MST was 56.55 months. This suggests that reduction hepatectomy followed by postoperative treatment that aims to achieve POCR could be an effective treatment strategy for advHCC.
The postoperative treatments employed after reduction surgery for HCC are different from those used to treat other malignancies. Firstly, the recovery of the remnant liver after hepatectomy enables further treatment for tumors in the remnant liver, which is considered to affect prognosis in most cases of HCC . In fact, tumors were detected in the remnant liver after reduction hepatectomy in all of the present cases, but extrahepatic metastases were only detected in 3 cases. Secondly, there are established additional non-surgical treatments for HCC localized in the liver, such as LAT and TAI therapy. RFA is indicated for cases of HCC involving ≤ 3 tumors and a maximum tumor size of ≤ 3 cm and is sometimes employed as an alternative to hepatectomy . TACE is indicated for cases of unresectable HCC involving large or multifocal tumors without vascular invasion or extrahepatic metastases . R0 resection is the first-choice treatment for some advanced malignancies, even in cases involving distant metastases. For distant metastases from HCC, there are not enough data supporting the validity of this approach, and the efficacy of surgical resection for lung metastases [15, 16], adrenal gland metastases , and brain metastases  is disputed.
In the present study, the number of tumors in the remnant liver after the reduction hepatectomy was the only factor that differed significantly between the POCR(+) and POCR(-) groups. This indicates that it is important that reduction hepatectomy is performed with the aim of reducing the number of tumors in the remnant liver to ≤ 3, which agrees with the conclusion of the study by Hai et al. .
In the current study, there were only 6 cases in which TKIs were orally administered. Two reasons are considered as possible explanations for the low frequency of TKI treatment. The first reason is the small number of cases included in the present study; i.e., only 30. Second, the treatment options for HCC changed during the study period. The most important change was the introduction of TKIs as a treatment option. Sorafenib, a TKI, was reported to improve the prognosis of HCC in 2008 , and it started to be used in the clinical setting in Japan in 2009. Moreover, lenvatinib, another TKI, was reported to be non-inferior to sorafenib in the REFLECT trial in 2018 .
In the present study, TKIs were only administered in the cases in which POCR was not achieved. This might have been due to the fact that TKIs were mainly administered when surgery, LAT, and TAI therapy were not indicated; i.e., TKIs were used when the abovementioned treatments were not expected to be effective, although concomitant TKI and TAI therapy has been suggested to be effective in some studies [20, 21]. The MST of the POCR(-)TKI(+) group was 33.52 months, which is superior to the outcomes described in other studies in which unresectable HCC was treated with TKIs [6, 19].
According to the present study, POCR might not need to be achieved via surgery alone, and even patients in whom POCR is achieved using LAT or TAI therapy can be good candidates for reduction surgery. Furthermore, the findings of the current study suggest that some patients would benefit from reduction hepatectomy even if POCR is not achieved. Patients that are likely to benefit from TKI treatment can also be good candidates for reduction hepatectomy.
This study had several limitations. The first is the inevitable selection bias caused by the study’s retrospective and single-center design. One of the most important processes in reduction hepatectomy for advHCC is the selection of cases that would benefit from such treatment. Of course, the safety of surgery should be considered to be the most important factor from an ethical viewpoint. There were no surgery-related deaths in the present study. At the same time, surgical safety also has an important impact on whether postoperative multidisciplinary treatment can be performed. Other limitations of this study include the small number of cases and the short follow-up periods in some of the cases.