Prashant Bhangui

Institute of Liver Transplantation and Regenerative Medicine, Medanta -The Medicity, Sector 38, Gurgaon, Delhi NCR 122001, India

Keywords: Hepatocellular carcinoma Portal vein tumour thrombosis Downstaging therapies Living donor liver transplantation and resection Outcomes

ABSTRACT Patients with locally advanced hepatocellular cancer (HCC) and portal vein tumor thrombosis (PVTT) have a dismal prognosis since limited treatment options are available for them.In recent years,effective systemic therapy,and advances in the understanding of technicalities and effectiveness of ablative therapies especially radiotherapy,have given some hope to prolong survival in them.This review summarized recent evidence in literature regarding the possible role of liver resection (LR) and liver transplantation (LT)in patients with locally advanced HCC and PVTT with no extrahepatic disease.Downstaging therapies have helped make curative resection or LT a reality in selected patients.This review emphasizes on the key points to focus on when considering surgery in these patients,who are usually relegated to palliative systemic therapy alone.Meticulous patient selection based on tumor biology,documented downstaging based on imaging and decrease in tumor marker levels,and an adequate waiting period to demonstrate stable disease,may help obtain satisfactory long-term outcomes post LR or LT in an intention to treat strategy in patients with HCC and PVTT.

Introduction

Despite surveillance regimen for early detection of hepatocellular cancer (HCC),unfortunately,10%-40% of high-risk HCC patients present with portal vein tumor thrombosis (PVTT) at the time of diagnosis.If untreated,or in case of palliative treatment only,the outcome of these patients is poor as shown by their short median(between 2 and 6 months),and 3-year survival (5%) [1,2].Surgical treatment,in the form of liver resection (LR) or liver transplantation (LT) is contraindicated as per most published guidelines,such as those from European Association for the Study of Liver (EASL),American Association for the Study of Liver Diseases (AASLD),European Society for Medical Oncology (ESMO) and Barcelona Clinic Liver Cancer (BCLC) [3-6].The BCLC prognosis and treatment strategy algorithm recommends tyrosine kinase inhibitors (TKIs) and immunotherapy for such patients;however,the median overall survival (OS) after TKI use remains poor (5-19 months) according to most published series,and time to tumor progression is short(4.1 months) [6,7].Furthermore,these patients are clubbed with those having extrahepatic spread,thus equating the presence of PVTT in HCC patients to systemic disease.

Grading of PVTT: a guidance for surgical options

PVTT is classified according to the extent and level of involvement of the PV.One of the commonly used classifications is the Cheng’s classification which has five categories: type I0,tumor thrombus formation found under microscopy;type I,tumor thrombus involving segmental or sectoral branches of the PV or above;type II,tumor thrombus involving the right/left PV;type III,tumor thrombus involving the main PV,and finally type IV,tumor thrombus involving the superior mesenteric vein [8].The “Vp classification” proposed by the Liver Cancer Study Group of Japan (LCSGJ)proposes five categories: Vp0 for no PVTT;Vp1 for tumor thrombus involving the segmental PV;Vp2 for tumor thrombus involving the second-order branches of the portal vein;Vp3 for tumor thrombus involving the first-order branches of the portal vein;and Vp4 for tumor thrombus involving the main trunk and/or contralateral branch of the PV [9].Vp1-2 are referred to as segmental PVTT,and Vp3 PVTT as lobar PVTT.This differentiation does have significance,since the outcomes of segmental vs.lobar and main branch PVTT seem to be different after surgical therapy.

The role of LR in patients with HCC and PVTT

LR for HCC with PVTT is not recommended in the European and American HCC guidelines.However,the Asian HCC guidelines (predominantly China and Japan) have expanded the surgical indications to these PVTT patients [10,11].

Short- and long-term outcomes

The 2013 multicenter study by Torzilli et al.was one of the first that challenged the dogma that resection should be contraindicated in HCC-PVTT patients [12].Clinical data of 2046 patients who underwent LR in 10 Eastern and Western expert medical centers were analyzed.Macrovascular invasion was present in 275 patients(13.4%).Five-year OS and recurrence-free survival (RFS) rates were 38% and 18% after LR.A 2015 systematic review including 4389 patients with HCC and macrovascular invasion,showed primarily that there was an improvement in postoperative outcomes of LR over 4 decades,but the long-term outcomes were still poor,albeit better than the outcomes with other palliative therapies [13].The median perioperative mortality was 2.7% (0-24%),the median complication rate was 30.2% (4%-42%),the OS at 1,3,and 5 years were 50%,23%and 18%,and the corresponding RFS rates were 32%,20% and 18%,respectively.

LR compared to local ablative therapy

A 2018 meta-analysis showed that LR resulted in better OS than transarterial chemoembolization (TACE),or other non-resection treatments for patients with HCC and PVTT [14].Two large studies,from Japan and China showed that LR provided benefit in selected HCC-PVTT patients,especially those with PVTT limited to the first order branch of the PV or above [15,16].The benefit over TACE however did not extend to lobar PVTT patients.

Indicators of LR and outcomes

A review analysing 23 articles and 2412 patients revealed a significant difference in 5-year post-resection survival related to PVTT stage: Vp1-2 45% (range 25%-54%),Vp3 19% (range 0-38%),and Vp4 14.5% (range 0-26.4%) [17].Similarly,a systematic review and meta-analysis by Huang et al.including 40 studies involving 8218 HCC-PVTT patients undergoing LR observed a median OS of 14.39 months.The median survival was higher in PVTT with segmental and second order involvement at 20.41 versus 6.41 months if the main PV trunk was involved [18].

Chen et al.analyzed a nationwide database of 1590 HCC-PVTT patients who underwent LR with ‘curative’ intent.The actuarial 3-year survival was 16.6%,while the actual 3-year survival rate was 11.7%.One in nine HCC-PVTT patients reached the long-term survival milestone of 3 years after LR.They concluded that major hepatectomy,controlling intraoperative blood loss,R0 resection,adjuvant TACE,and ‘curative’ treatment for initial recurrence should be considered for patients to achieve better long-term survival outcomes [19].

Kim et al.reported in a recent study of 161 resected HCC-PVTT patients undergoing resection,and that absence of oesophageal varices,maximal tumor size＜5 cm,tumor location in single lobe,anatomical resection,R0 resection,and absence of microvascular invasion were found to be favourable factors for long-term outcomes [20].In another study,maximum tumor size ≥5 cm and PVTT in the main portal trunk were identified as the major prognostic factors influencing HCC recurrence after LR.This study finally concluded that although OS was better in the more recent era,RFS was still unsatisfactory after resection [21].

The Eastern Hepatobiliary Surgery Hospital (EHBH)-PVTT scoring system was established to predict the prognosis of HCC-PVTT patients after R0 LR,and to guide selection of subgroups of patients that could benefit from LR.Total bilirubin,alpha-fetoprotein(AFP),tumor diameter and satellite lesions were included in the score.The EHBH-PVTT score differentiated two groups of patients(≤3 and＞3 points) with distinct long-term prognosis (median OS,17 vs.7.9 months) [22].The Society for Surgery of the Alimentary Tract (SSAT) guidelines suggested that tumor number＞3,Vp4 PVTT,and AFP＞400 ng/mL were independently associated with futile LR in HCC-PVTT patients.A risk-scoring model and a predictive nomogram for futile LR were developed [23].

Consequently,according to LCSGJ,Vp1-3 (especially Vp1 and Vp2) are candidates for resection,conversely Vp4 is a weak indication.Taking into account Cheng’s classification,type I-II could be treated by surgery,while type IV represents a contraindication.

As regards surgical approaches in patients with segmental PVTT anen blochepatectomy could offer radical tumor and PVTT removal,whereasen bloc-resection of PV and thrombus with subsequent portal reconstruction could be used in cases where the bifurcation with or without the main and/or contralateral portal veins is involved.

Neo-adjuvant and adjuvant therapies

Due to the high rate of tumor recurrence after resection,the use of effective adjuvant therapies has been proposed,but the evidence for their use is limited.The effectiveness of postoperative adjuvant TACE to reduce the rate of recurrence is debatable [24,25].Phase III clinical trials exploring the efficacy of adjuvant targeted agents and immune checkpoint inhibitors after LR reported a 28% reduction of recurrence-related death post resection [26],and these results need further substantiation.The EHBH-PVTT scoring system could facilitate the decision between conventional systemic treatment and surgery in patients with advanced HCC because of its accuracy in selecting patients who could be advantaged by LR.

The role of neo-adjuvant as well as downstaging (DS) treatments in patients with unresectable or locally advanced HCC has been explored.Since PVTT has a better radiosensitivity than HCC itself,neo-adjuvant radiotherapy (RT) and transarterial radioembolization (TARE) can be used to achieve tumor DS,allowing surgery and improving disease-free survival and OS [27,28].

In conclusion,individualised decision making based on tumor biology and PVTT grade may be a key in selecting patients with PVTT for resection,with the aim of achieving long-term OS and RFS.

Is there a role for LT in patients with HCC and PVTT?

The BCLC system classifies patients with PVTT and/or extrahepatic disease (EHD) under the same stage (BCLC C,advanced stage).This is not ideal,because better results with newer therapies in patients with HCC and PVTT and no EHD have been obtained with local ablation and systemic therapy as compared to those with EHD with/without PVTT [29-31].

LT vs. LR

Upfront living donor liver transplantation (LDLT) has shown to yield better 3-and 5-year survival rates compared to palliative or systemic therapy alone,especially in patients with segmental PVTT(first and second order PV branches),and those with low levels of AFP,low fluorodeoxy-glucose-18 (FDG-18) avidity on positron emission tomography (PET) scan,and small tumor sizes [32,33].Ma et al.compared the outcomes of resection vs.LT in HCC patients and incidentally detected PVTT on the explant specimen.These would usually represent Vp1 (or very rarely Vp2) PVTT as macrovascular invasion was missed on preoperative imaging,and all these patients had upfront LT.After propensity score matching,they found that LT was associated with significantly better oncological outcomes in HCC patients with both lobar and segmental PVTT [34].Lv et al.also found that LT appeared to afford a better prognosis in patients with type I PVTT,especially in patients with AFP level＞200 ng/mL,as compared to resection [35].This means that,providing the tumor biology is favourable,vascular tumor thrombosis in HCC could be considered essentially as contiguous spread and thus a locally advanced tumor for a period of time,before manifesting as distant spread in a haematogenous fashion.Hence,it may be pertinent to consider LT in a selected cohort of patients.

Downstaging followed by LT

Tumor biology and success of DS strategies have been used to select a cohort of patients with HCC and PVTT who are expected to have a favourable long-term outcome.Complete and partial response of PV tumor thrombi to radiotherapy (SBRT/EBRT/SIRT),TACE,proton beam radiotherapy,or systemic therapy,used alone,or in combination has been well documented and known to improve progression-free survival and OS [36-40].

Some series have also shown that,in patients where the HCC and PVTT have been downstaged successfully within transplant criteria using local ablation with/without systemic therapy,LDLT can yield good long-term outcomes if done after an adequate waiting period ensuring stable disease [41-44].

In our Medanta study [43],SBRT with or without TARE or TACE was used as a part of a DS protocol.This approach allowed to achieve 5-year OS and RFS of 53%,and 52%,respectively.Successful DS was defined as the disappearance of arterial enhancement of PVTT on CT-scan with loss of FDG-18 avidity on PET-scan.Advanced tumor grade (Grade III/IV),and AFP＞400 ng/mL at diagnosis or delta-AFP (initial AFP minus AFP post-DS)＜2000 ng/mL were poor prognostic factors for OS,and RFS,respectively.After excluding two patients who died in the postoperative period due to non-tumor-associated reasons,the 5-year OS was 57%,a number far superior to the expected 3-year survival of 10% according to the BCLC staging and treatment algorithm with systemic therapy,thus demonstrating a significant transplant benefit in these patients,who are usually offered palliative therapy alone [45].Comparing survival rates of post-DS LDLT in our series of HCC-PVTT patients to similar patients who received palliative RT with or without TKI,the transplant benefit was 23 months at 3 years and 34 months at 5 years,respectively [46,47].

In the deceased donor LT (DDLT) setting,a 5-year OS of 60% was reported by Serenari et al.and Assalino et al.in HCC-PVTT patients in case of complete and sustained (6 months) radiological response after DS using yttrium-90 (Y-90) TARE and other locoregional therapies [4 8,4 9].However,in the case series of Serenari et al.,the recurrence rate was very high (3/5 recurred),even in case of sustained response to Y-90 TARE DS,and absence of PVTT enhancement.Yang et al.found that a total tumor diameter＞8 cm,AFP＞100 ng/mL,and maximum standardized uptake values of the tumor[standard uptake value (SUV) max-tumor]＞5 predicted survivals in those with Vp2/Vp3 PVTT undergoing transplantation [50].

Outcomes in relevant series published till date are summarized in Table 1 [32,33,41-45,48-53].

Meerun et al.recently reported 14 patients with PVTT who were downstaged using a single TARE (Y-90) treatment,2 underwent LT and the other 12 had a resection [54].They observed a median OS and progression-free survival of 61.8 and 49.3 months,respectively in their overall cohort of patients with PVTT and/or multifocal or large tumors including 78% of patients with PVTT.This series,as well as others [55,56]showed that achieving complete pathological necrosis after pre-transplant locoregional therapies results in lower recurrence and better survival outcomes after LT compared to those exhibiting partial necrosis.In our study,among the successfully downstaged patients who went on to have LDLT,significant necrosis (＞50%) was seen in the tumor in 32%,and in the PVTT in 82%.A significant proportion (41%) of the vascular tumor thrombi showed complete necrosis,while 59% showed a mixed picture of tumor necrosis and active tumor cells.Detailed assessment of the “tumor thrombus” in these cases showed viable tumor in the body of the thrombus in 35%,and no tumor cells at the tip of the thrombus in 14 of 15 cases.The latter showed only platelet aggregates at the tip.

It is true that the amount and quality of available evidence is limited,and it seems still too early to recommend LT in all HCC patients with PVTT.One needs to be very wary when contemplating LT in patients with very high tumor marker levels or large,infiltrative tumors.Vp4 tumor thrombus is a further relative contraindication (Table 2).Future studies with larger number of patients,and,especially,longer follow-up may pave the way for an elaborate selection algorithm to choose the ideal candidates for such a strategy in patients with locally advanced HCC with PVTT.A multidisciplinary approach combining ablation and a potentially curative LT may offer the best hope of long-term survival in a selected group of patients with favourable tumor biology [57].

Table 2How far is too far in considering LT in patients with PVTT?

Conclusions

LR and LT are two alternative treatments that may offer a chance for prolonged survival in selected patients with HCC and PVTT.There is a need to emphasise that the mere presence of PVTT may not be synonymous with systemic disease as is the case with extrahepatic metastases.Outcomes of both surgical treatments depend on multiple factors,of which tumor biology is most important.

The success of DS therapies depends to a large extent on proper delivery of the planned doses to both the tumor and the PVTT.This is operator dependent and relies on good mapping by the radiologist and the radiation oncologist and on proper delivery of the different agents by the interventional radiologist.The delivery of the correct dosage or the lack of it could result in variable results in terms of DS and long-term outcomes.A waiting time of probably 3 to 4 months after successful DS (preferably off systemic therapy also) is essential to ensure stable disease and test for the tumor natural history and aggressiveness.These conditions can make the difference between long-term survival in Vp4 PVTT patients,and an early recurrence after transplantation even in Vp2 PVTT patients.Hence,use of appropriate DS locoregional therapy and a waiting period are essential.Further studies will be necessary to define the optimal period between successful DS and transplantation to ensure good outcomes.The availability of a living donor,which avoids an interference with the scarce deceased donor pool available to other candidates on the waiting list,and the fact that LDLT allows for a planned transplant are clear benefits in the LDLT setting.

Acknowledgments

None.

CRediT authorship contribution statement

Prashant Bhangui:Conceptualization,Data curation,Methodology,Writing -original draft,Writing -review &editing.

Funding

None

Ethical approval

Not needed.

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.