Zhe Yng , Jing-Qi Sun , Shuo Wng , Li Zhung , Shu-Sen Zheng , ,*

a Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China

b Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310 0 03, China

To the Editor:

Downstaging therapy has been confirmed to help patients whose tumors are beyond the liver transplantation (LT) criteria to gain the opportunity for LT with long-term survival. Zhan et al. [1] recently demonstrated that patients with hepatocellular carcinoma (HCC) beyond the Hangzhou criteria on initial diagnosis without extrahepatic metastasis or vascular invasion have comparative outcomes with those matching Milan criteria after LT if these patients are successfully downstaged to the Hangzhou criteria [1] . However, whether the downstaging therapy prolongs the survival time of those with portal vein tumor thrombosis (PVTT) is not clear. Our study was to add some data in this field.

Some single center or multicenter studies have proven that a considerable number of patients with successful pre-LT downstaging therapy can achieve a similar long-term survival. For example, a recent study in South Korea reported that patients with locally advanced HCC and PVTT achieved acceptable oncologic outcomes after combined transarterial chemoembolization (TACE) and 3-dimensional conformal radiotherapy, with a 3-year overall survival (OS) rate of 60.5% [2] . With these encouraging results, some surgeons advocated that PVTT should no longer be a contraindication for LT.

All our included liver recipients were patients with PVTT exceeding the Milan criteria or even the Hangzhou criteria. We enrolled 107 HCC patients with PVTT transplanted between April 2016 and October 2019. Treatment modalities for HCC downstaging consisted of locoregional and systematic therapy. Patients were categorized into three groups: patients with well radiographic response, patients with poor radiographic response and non-downstaged patients. Well radiographic response was defined as more than 50% necrosis or nonviable tumor according to abdominal computed tomography (CT) or magnetic resonance imaging (MRI) scan. Poor radiographic response was less than 50%necrosis or nonviable tumor on radiology. Non-downstaged patients included those who accepted liver transplantation without local regional therapy (LRT) or systemic therapy. The imaging examination of tumor necrosis in patients with effective downstaging therapy matched completely with the pathological results obtained after LT. OS and recurrence-free survival (RFS) rates were analyzed by the Kaplan-Meier method and log-rank test. Independent prognostic indicators were assessed by using Cox’s proportional hazard model. A logistic regression model was used to assess the candidate predictors on the odds of achieving well radiographic response. APvalue of＜0.05 was considered statistically significant.

The median time from downstaging therapy to LT was 3.0 months (range 1.1-10.4 months). Among the 107 HCC patients, 48 received pre-LT downstaging therapy, 15 (15/48, 31%) had well radiographic response and 33 (69%) had poor radiographic response.Predictors of well response to downstaging are shown in Table 1 .In summary, patients were less likely to achieve well response to downstaging with pre-LT alpha fetoprotein (AFP) ≥10 0 0 ng/mL(P= 0.021), pre-LT platelet to lymphocyte (PLR) ≥120 (P= 0.022),total tumor size＞8 cm (P= 0.046), or poorly differentiated HCC(P= 0.044). Patients who received multiple combined downstaging therapies [TACE, thermal ablation, tyrosine kinase inhibitors or programmed cell death protein 1 (PD-1) antibody] were more likely to achieve well response (P= 0.009). Poorly differentiated HCC (P= 0.024) was an independent risk factor, and multiple combined downstaging therapies (P= 0.007) was an independent favorable factor associated with well response to downstaging therapy.

Compared with poor radiographic response or non-downstaged patients, those who achieved well radiographic response to downstaging therapy had significantly superior 1-, 2-, and 3-year RFS(72.0% vs. 30.4%, 72.0% vs. 22.6%, and 72.0% vs. 22.6%;P= 0.002;Fig. 1 A) and OS (100% vs. 66.3%, 90.9% vs. 47.7%, and 90.9% vs.47.7%;P= 0.008; Fig. 1 B). As shown in Table 2 , in the univariate analysis, pre-LT AFP ≥10 0 0 ng/mL, pre-LT neutrophil to lymphocyte ratio (NLR) ≥7, pre-LT PLR ≥120, pre-LT C-reactive protein(CRP) ≥10 mg/L, maximum or total tumor size＞8 cm, poorly differentiated tumor and Vp4-PVTT were risk factors for both RFS and OS. In addition, tumor necrosis＞50% after downstaging andmultiple combined downstaging therapies were both favorable factors for RFS and OS. In the multivariate analysis, pre-LT AFP ≥10 0 0 ng/mL was an independent risk factor for post-LT HCC recurrence (HR = 3.032;P= 0.010) and OS (HR = 3.287;P= 0.026).In addition, tumor necrosis＞50% after downstaging favored RFS(HR = 0.311;P= 0.041) and OS (HR = 0.116;P= 0.038).

Table 1 Univariate and multivariate analysis evaluating predictors of well response to downstaging therapy.

Fig. 1. Outcomes of HCC patients with PVTT who underwent LT. Kaplan-Meier RFS ( A ) and overall survival ( B ) after LT for HCC with PVTT stratified by radiographic response after pretransplant downstaging therapy. HCC: hepatocellular carcinoma; PVTT: portal vein tumor thrombus; LT: liver transplantation; RFS: recurrence-free survival; OS:overall survival.

Pretransplant neoadjuvant therapy for advanced HCC patients is recommended to improve patient outcome in recent studies.In an Indian study [3] , protocol downstaging of HCC with PVTT consisted of stereotactic body radiotherapy (SBRT) for major PVTT and chemoembolization or radioembolization for advanced HCC.These patients had acceptable survival after successful downstaging following living donor liver transplant (LDLT). Initial AFP＜400 ng/mL and AFP fall＞20 0 0 ng/mL favorably influenced survival in these patients.

Besides the serological biomarkers, pathological change on explant was one of the most important surrogates to evaluate the efficacy of LRT. According to a multicenter study from the United States, for LT recipients with HCC receiving pre-LT LRT, achieving complete pathologic response portended significantly lower post-LT recurrence and superior survival [4] . However, pathological response on explant was unable to be detected after pre-LT LRT.In the present study, preoperative assessment on radiology was introduced, and well radiographic response was defined as more than 50% necrosis or nonviable tumor according to abdominal CT or MRI scan. Compared with poor radiographic response or nondownstaged patients, those achieved well radiographic response to downstaging therapy had significantly superior 1-, 2-, and 3-year RFS and OS. In our patients, 31% HBV background HCC patients with PVTT could achieve well radiographic response to pre-LT therapy (radiographic tumor necrosis＞50%).

A previous study has demonstrated that TACE was associated with significant survival benefits when compared with best supportive care [5] . With the introduction of multikinase inhibitors for HCC, TACE combined with sorafenib could significantly improve OS compared with TACE monotherapy alone [6] . In addition, combination strategy of radiotherapy plus TACE or sorafenib surpassed monotherapy as well [ 7 , 8 ]. However, for patients with advanced HCC with PVTT, there was no significant difference between patients treated with TACE plus radiotherapy and TACE plus sorafenib in terms of progression-free survival and OS [9] . Since the emerging of immunotherapy for HCC, a recent study on the combination of immune checkpoint inhibitor and anti-angiogenic agent has shown synergic antitumor benefits [10] . In our study, most patients(89.6%) received TACE, with 22.9% receiving TACE and systematic therapies (sorafenib, lenvatinib or PD-1 antibody). Patients who received multiple combined downstaging therapies (TACE, thermal ablation, tyrosine kinase inhibitors or PD-1 antibody) were more likely to achieve well response and better outcomes.

Table 2 Univariate and multivariate analysis of tumor recurrence and overall survival.

In conclusion, for HCC patients with PVTT, well response to pre-LT downstaging therapy is a predictor of better outcomes and patients can have acceptable survival with LT after successful downstaging. Combined locoregional and systematic therapies may help to improve the responsiveness to downstaging therapy.

Acknowledgments

We would like to thank Chang Kai Wun for correcting this paper.

CRediT authorship contribution statement

Zhe Yang: Conceptualiazation, Data curation, Funding acquisition, Writing - original draft. Jing-Qi Sun: Formal analysis, Data curation. Shuo Wang: Investigation, Writing - original draft. Li Zhuang: Investigation, Writing - review & editing. Shu-Sen Zheng:Conceptualiazation, Supervision, Writing - review & editing.

Funding

This study was supported by grants from the National S&T Major Project ( 2017ZX10203205 ), the Medical Science and Technology Project of Zhejiang Province ( 2014KYA082 ) and the Natural Science Foundation of Zhejiang Province ( Y21H160259 ).

Ethical approval

This study was approved by the Ethics Committee of Shulan(Hangzhou) Hospital, and informed consents were obtained from all of the patients.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.