Published online Jan 27, 2023. doi: 10.4240/wjgs.v15.i1.19
Peer-review started: September 21, 2022
First decision: October 18, 2022
Revised: October 29, 2022
Accepted: December 21, 2022
Article in press: December 21, 2022
Published online: January 27, 2023
Processing time: 118 Days and 21.4 Hours
Hepatocellular carcinoma (HCC) is one of the most lethal tumors in the world. Liver resection (LR) and liver transplantation (LT) are widely considered as radical treatments for early HCC. However, the recurrence rates after curative treatment are still high and overall survival is unsatisfactory. Microvascular invasion (MVI) is considered to be one of the important prognostic factors affecting postoperative recurrence and long-term survival. Unfortunately, whether HCC patients with MVI should receive postoperative adjuvant therapy remains unknown. In this review, we summarize the therapeutic effects of transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, tyrosine protein kinase inhibitor-based targeted therapy, and immune checkpoint inhibitors in patients with MVI after LR or LT, aiming to provide a reference for the best adjuvant treatment strategy for HCC patients with MVI after LT or LR.
Core Tip: Microvascular invasion (MVI) is considered to be one of the important prognostic factors affecting postoperative recurrence and long-term survival. Unfortunately, whether hepatocellular carcinoma (HCC) patients with MVI should receive postoperative adjuvant therapy remains unknown. In this review, we summarize the therapeutic effects of transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, tyrosine protein kinase inhibitor-based targeted therapy, and immune checkpoint inhibitors in patients with MVI after liver resection (LR) or liver transplantation (LT), aiming to provide a reference for the best adjuvant treatment strategy for HCC patients with MVI after LT or LR.
- Citation: Li J, Yang F, Li J, Huang ZY, Cheng Q, Zhang EL. Postoperative adjuvant therapy for hepatocellular carcinoma with microvascular invasion. World J Gastrointest Surg 2023; 15(1): 19-31
- URL: https://www.wjgnet.com/1948-9366/full/v15/i1/19.htm
- DOI: https://dx.doi.org/10.4240/wjgs.v15.i1.19
Hepatocellular carcinoma (HCC) is the seventh most common cancer and the second leading cause of cancer-related deaths in the world, with unsatisfactory long-term outcomes[1]. Nowadays, hepatectomy liver resection (LR) and liver transplantation (LT) are still the most efficient strategies for HCC with relatively preserved liver function[2]. Unfortunately, the surgical resection rate of HCC is still low in clinical practice due to untimely diagnosis and delayed treatment in most HCC patients. Even with radical surgery, the 5-year recurrence rate is still 70%-80%[3]. Accordingly, decreasing the recurrence rate after surgical resection is of utmost importance to improve the clinical outcomes for early-stage HCC patients.
Various risk factors are associated with the recurrence of HCC. Malignant biological characteristics of the tumor and the condition of the underlying liver disease, such as hepatitis and liver cirrhosis, were found to be more significant prognostic factors than tumor size and warrant closer attention in clinical practice[4]. Among malignant biological characteristics of HCC, microvascular invasion (MVI) is considered a risk factor for intrahepatic microscopic metastatic disease and one of the crucial factors for early HCC recurrence after LR or LT. As a consequence, In the 8th edition of the American Joint Co
Advances in systemic therapy for advanced HCC, as well as promising strategies for perioperative management of LR, have led to a substantial improvement of surgical outcomes in recent years. Transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), as well as targeted therapies based on tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs), are the current state-of-the-art strategies, which have shown great promise in the treatment of advanced HCC[8-12]. However, whether TACE/HAIC, TKIs (such as sorafenib and lenvatinib), and ICIs [such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors] are beneficial for decreasing tumor recurrence rates in HCC patients with MVI remains controversial. In view of this, results derived from all the studies were analyzed, aiming to outline the optimal treatment strategy for HCC with MVI after LR. For patients with early-stage HCC, LR, LT, and local ablation (LA) are considered as first-line treatments. However, MVI cannot be precisely evaluated in HCC patients who underwent LA. Therefore, we mainly discuss the effect of postoperative treatments on the surgical outcomes after LT and LR. This review article aims to provide updated information on the recent developments in postoperative adjuvant therapy in HCC patients with MVI.
MVI has been widely identified as a crucial risk factor for intrahepatic recurrence after R0 surgical resection, which was evidenced by increased local recurrence rates and reduced recurrence-free survival (RFS) after LR compared to HCC patients without MVI. Whether postoperative adjuvant therapy could improve the surgical outcomes for HCC with MVI remains unclear. There is an urgent need to discuss several postoperative adjuvant treatments such as TACE/HAIC and TKI and ICI therapy, aiming to shed a new light on ways to improve the prognosis for such HCC patients.
The main purpose of TACE after LR is to eliminate the tumor cells released due to compression during operation and destroy the existing microscopic foci in the remnant liver that cannot be found by preoperative imaging examination. It delivers specific drugs, along with iodized oil, mainly to su
The pro-tumor environment that induces immunosuppression, such as myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages in the liver immune cell population, may play a major role in the limited effectiveness of chemotherapy drugs. Moreover, chemotherapy drugs themselves may change the composition of the inflammatory cell population[29]. In addition to the interaction of immune cells, hepatocirrhosis microenvironment composes a physical barrier that stimulates tumor growth by altering biomechanical properties, cytokine secretion, and activation of multiple signaling pathways, preventing drugs from reaching targets in the tumor parenchyma and thus reducing drug availability.
Moreover, high-dose TACE can damage liver cells, leading to the deterioration of liver function, reduced immunity against tumor cells, and increased risk of hepatitis B virus reactivation. In TACE, the combined use of multiple drugs may increase the burden on the liver leading to drug-induced liver injury, and ultimately adversely affect the therapeutic effect. Therefore, factors such as liver function and operation time should be considered in postoperative combined TACE treatment[19]. In addition, tumor load, tumor invasion, and postoperative recovery may be factors affecting the efficacy. The relevant studies on the postoperative application of TACE or HAIC as adjuvant therapy are listed in Table 1. However, these results need to be further verified by high-quality RCTs.
Ref. | Study type | Adjuvant therapy | Number | 2-yr DFS (%) | P value | 2-yr OS (%) | P value | PMID |
Li et al[17] | RCT | HAIC | 63 | 58.7 | 0.023 | 97.7 | 0.037 | 32418078 |
NAT | 64 | 38.6 | 78.5 | |||||
Sun et al[72] | Retrospective | TACE | 137 | 55.5 | 0.012 | 78.8 | 0.006 | 26714945 |
NAT | 185 | 36.2 | 62.2 | |||||
Wei et al[73] | RCT | TACE | 125 | 44.7 | 0.02 | 64.3 | 0.029 | 30305149 |
NAT | 125 | 30.6 | 49.8 | |||||
Ye et al[13] | Retrospective | TACE | 86 | 58.3 | 0.002 | 86.5 | 0.019 | 29151695 |
NAT | 174 | 41.1 | 65.7 | |||||
Liu et al[74] | Retrospective | TACE | 24 | 26.9 | 0.03 | NA | NA | 27038790 |
NAT | 26 | 4.2 | NA | |||||
Wang et al[75] | Retrospective | TACE | 57 | 66 | 0.008 | 94 | 0.04 | 30249510 |
NAT | 57 | 50 | 83 | |||||
Cai et al[76] | Retrospective | TACE | 25 | 39.1 | 0.06 | NA | NA | 34926296 |
TACE + T cell self | 23 | 58.2 | NA | |||||
Kim et al[27] | RCT | HAIC | 31 | 9.1 | 0.324 | 87.1 | 0.561 | 22067673 |
NAT | 62 | 4.2 | 78.3 | |||||
Nitta et al[77] | Retrospective | HAIC | 38 | 33.1 | 56.2 | 0.318 | 23435678 |
Intrahepatic tumor recurrence after LR can be divided into early recurrence and late recurrence. Early recurrence is related to intrahepatic metastasis of primary tumors that cannot be detected clinically, which may be related to the spread and metastasis of tumor cells in portal vein circulation caused by the shedding of cancer cells before surgery or the pressure exerted on tumors during LR. As liver cancer cells gradually infiltrate the tumor capsule surrounding matrix, and vascular wall, they further invade blood vessels to form MVI. The multi-kinase inhibitors that target tumor cells and tumor blood vessels act on a variety of kinases and pro-angiogenic receptors, blocking downstream signaling pathways, inhibiting the proliferation and promoting apoptosis of tumor cells, as well as inhibiting tumor cell angiogenesis, and migration, with a wide range of anti-tumor effects that promote the prevention and treatment of tumor recurrence[30].
Sorafenib is a multi-kinase inhibitor that blocks multiple molecular pathways through its anti-angiogenic and anti-proliferative effects. A RCT revealed that sorafenib could effectively improve the survival time with advanced HCC patients[31]. In addition, sorafenib has been reported to inhibit postoperative intrahepatic recurrence and abdominal metastasis, thereby extending postoperative survival time[32,33].
Sorafenib can improve the prognosis of MVI in HCC patients after R0 LR. A meta-analysis investigated the preventive effect of sorafenib against tumor recurrence in HCC with MVI, and the results showed that LR plus sorafenib significantly improves the prognosis of HCC with MVI compared to LR alone. However, this meta-analysis has some shortcomings. First, it only included retrospective studies, which may cause selection bias. Second, the patients in these four studies were all Chinese, which also weakens the universality of the conclusion[34].
Recent studies have demonstrated the efficacy of sorafenib in preventing recurrence of HCC after LR[35]. Li et al[36] as well as Xia et al[37] found that the OS and DFS of Barcelona Clinic Liver Cancer stage C HCC patients treated with oral sorafenib after LR was significantly longer than those of patients only treated by LR. Wang et al[38] proved that sorafenib as an adjuvant therapy for HCC can prevent early recurrence after LR. Huang et al[39] evaluated the impact of sorafenib as an adjuvant therapy on the clinical outcomes in HCC with MVI. The results indicated that adjuvant sorafenib significantly prolonged both OS and RFS of patients with HCC after radical resection.
However, a RCT revealed that sorafenib treatment after LR did not improve the DFS of HCC patients, but increased the incidence of side effects, such as hand-foot skin reaction, diarrhea, and fatigue[40]. Similarly, it was found that postoperative sorafenib adjuvant therapy cannot improve RFS in HCC patients with MVI[41]. The relevant studies on postoperative application of TKIs as adjuvant therapy are listed in Table 2. There are differences in the results from different centers. In addition to the sample size and research methods that may affect the results, these differences may also be caused by different definitions and classifications of MVI. It may be necessary to conduct systematic research under uniform definitions and standards to make the results more comparable.
NCT number | Title | Interventions | Characteristics | n | Date | Current status |
NCT02678806 | Radiotherapy in Hepatocellular Carcinomas After Hepatectomy With Narrow Margin (< 1 cm) and/or Microvascular Invasion (RHCC:BCLC-A) | Radiation: Postoperative radiotherapy. Drug: Postoperative TACE | Phase: Not applicable. Allocation: Randomized. Intervention model: Parallel. Outcome measures: Overall survival | 620 | November 1, 2017 to November 1, 2022 | Recruiting |
NCT04053972 | The Impact on Recurrence Risk of Adjuvant Lenvatinib for Patients With Hepatocellular Carcinoma And Microvascular Invasion (MVI) After Hepatectomy: A Random, Controlled, Stage III Clinical Trial | Drug: Lenvatinib | Phase: 3. Allocation: Randomized. Intervention model: Parallel. Outcome measures: RFS and OS recurrence rate | 377 | January 31, 2018 to December 31, 2022 | Recruiting |
NCT02867280 | Sorafenib Treatment in Patients With Hepatocellular Carcinoma With Microvascular Invasion After Radical Resection | Drug: Sorafenib | Phase: 3. Allocation: Non_x005f randomized. Outcome measures: Recurrence free survival; time to recurrence; recurrence rate; overall survival; incidence of treatment related; adverse events; incidence of dose modification of sorafenib due to adverse events | 154 | June 1, 2016 to January 31, 2020 | Terminated |
NCT03192618 | The Impact on Recurrence Risk of Adjuvant Transarterial Chemoinfusion (TAI) for Patients With Hepatocellular Carcinoma And Microvascular Invasion (MVI) After Hepatectomy: A Random, Controlled, Stage III Clinical Trial | Procedure: Adjuvant transarterial chemoinfusion. Drug: mFOLFOX6 (oxaliplatin, calcium folinate, and 5-fluorouracil) | Phase: 3. Allocation: Randomized. Outcome measures: DFS; recurrence rate; OS | 290 | July 1, 2017 to December 31, 2024 | Recruiting |
NCT02436902 | Adjuvant Therapies for Patients With HCC and MVI | Procedure: TACE. Drug: Sorafenib, TACE plus sorafenib and empty control | Phase: 3. Allocation: Non_x005f randomized. Outcome measures: Overall survivals; hospital mortality; recurrence rates | 240 | February 1, 2019 to August 30, 2022 | Recruiting |
NCT03732105 | Radiotherapy/Apatinib for Adjuvant Treatment of HCC Patients receIved Curative resection With Microvascular Invasion | Radiotherapy. Drug: Apatinib and radiotherapy + apatinib | Phase: 2. Allocation: Randomized. Outcome measures: RFS; time to recurrence; overall survival; safety events; health related quality of life | 160 | November 1, 2018 to December 31, 2023 | Not yet recruiting |
NCT03575806 | Combine TACE and Autologous Tcm Immunotherapy Versus TACE Alone for HCC With MVI After Radical Resection | Combination product: TACE plus autologous Tcm immunotherapy. Procedure: TACE | Phase: 2. Allocation: Non_x005f randomized. Outcome measures: RFS time; OS rate at 24 mo | 52 | January 9, 2017 to October 31, 2019 | Completed |
Should we apply sorafenib in hepatocellular carcinoma patients with microvascular invasion after curative hepatectomy? | Drug: Sorafenib | Phase: Not applicable. Allocation: Retrospective study. Outcome measures: DFS; recurrence rate; OS | 49 | January, 2009 to December, 2016 | Completed | |
Microvascular Invasion as a Predictor of Response to Treatment with Sorafenib and Transarterial Chemoembolization for Recurrent Intermediate-Stage Hepatocellular Carcinoma | Procedure: TACE. Drug: Sorafenib, TACE plus sorafenib, and TACE | Phase: Not applicable. Allocation: Retrospective study. Outcome measures: DFS; recurrence rate; OS | 127 | January, 2010 to December, 2016 | Completed | |
Postoperative adjuvant sorafenib improves survival outcomes in hepatocellular carcinoma patients with microvascular invasion after R0 liver resection: a propensity score matching analysis | Drug: Sorafenib | Phase: Not applicable. Allocation: Retrospective study. Outcome measures: DFS; recurrence rate; OS | 728 | January, 2009 to December, 2016 | Completed | |
NCT00692770 | Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial | Drug: Sorafenib | Phase: 3. Allocation: Randomized. Outcome measures: DFS; recurrence rate; OS | 1114 | August 15, 2008 to November 17, 2010 | Completed |
Although targeted drugs have greatly improved the prognosis of patients with advanced liver cancer, the efficacy of single drugs is still limited, and drug resistance may occur during treatment due to tumor heterogeneity and changes in the immune microenvironment. In addition, the side effects of drugs and the tolerance of patients also affect the therapeutic effect. In the future, it may be necessary to standardize the population suitable for targeted therapy, and consider combined therapy to improve the efficacy when single drugs are insufficient. In view of the above results, the role of targeted drugs as adjuvant therapy may still be controversial, and a large number of prospective RCTs are needed to further verify their efficacy in the future.
ICIs are a new class of anti-tumor drugs that target regulatory signals between T cells, target cells, and other immune cells. T cells can recognize specific antigens presented on target cells by major histocompatibility complex proteins through their T cell receptors, and can induce apoptosis of target cells. T-cell activity is precisely regulated by co-stimulatory and co-inhibitory molecules to maintain an appropriate immune response without harmful overactivation. Therefore, adjuvant application of ICI after LR, may activate T cells to destroy circulating tumor cells and prevent recurrence.
At present, the main immune checkpoint molecules targeted by immunotherapy are PD-1, PD-L1, and cytotoxic T lymphocyte-associated protein 4. Cancer immunotherapy may have a significant impact in adjuvant settings, as it can immediately induce tumor cell killing and potentially produce durable immune responses that eliminate residual micrometastases that are thought to lead to early recurrence. Anti-PD-1/PD-L1 antibody, either alone or in combination, has shown successful induction of pathological reactions in a variety of tumor types, while also inducing tumor-specific T cell amp
At present, no large-scale clinical datasets have confirmed the role of ICIs in preventing postoperative recurrence and improving long-term survival in HCC. CheckMate-9DX is an ongoing trial investigating whether nivolumab can improve RFS compared with placebo in HCC patients who have a high risk of recurrence after LR or ablation, which includes patients with MVI.
Prevention of postoperative recurrence is an important part of the treatment of HCC, which is still an unsolved clinical problem. For early operable HCC with MVI, optimal liver function reserve, good physical condition, and increased tolerance to immune-related toxicity may improve the curative opportunity of the patients. However, the response of such patients to immunotherapy or drug resistance is still a challenge that cannot be ignored.
Considering the potential adverse reactions to combined administration, it is particularly important to select specific patients that most likely benefit from such therapies. Therefore, it is necessary to establish an effective predictive model, and a large number of prospective clinical studies are still needed to provide reliable guidance. In addition, there are studies on targeted drugs combined with immunotherapy for postoperative assistance, as shown in Table 3. We expect these effective research results to provide a reference for clinical decision-making. Since MVI is one of the critically important risk factors for relapse and metastasis, surgical resection alone may not completely eliminate the adverse effects of MVI and improve the prognosis of patients. Although there is no uniform standard for adjuvant therapy after LR, it may be one of the most promising strategies to improve the efficacy HCC therapy in patients with MVI.
NCT number | Title | Interventions | Characteristics | n | Date | Current status |
NCT04682210 | Sintilimab Plus Bevacizumab as Adjuvant Therapy in HCC Patients at High Risk of Recurrence After Curative Resection | Drug: Sintilimab. Drug: Bevacizumab | Phase: 3. Allocation: Randomized. Intervention model: Parallel | 246 | December, 2020 to December, 2024 | Not yet recruiting |
NCT04981665 | A Study to Evaluate TACE Sequential Tislelizumab as Adjuvant Therapy in Participants With HCC at High Risk of Recurrence After Curative Resection | Drug: Tislelizumab. Drug: TACE | Phase: 2. Allocation: N/A. Intervention model: Single group assignment | 50 | November 8, 2021 to December, 2024 | Recruiting |
NCT05407519 | A Study to Evaluate Tislelizumab Combined With Sitravatinib as Adjuvant Therapy in Participants With HCC at High Risk of Recurrence After Curative Resection | Drug: Tislelizumab. Drug: Sitravatinib | Phase: 2. Allocation: N/A. Intervention model: Single group assignment | 52 | July 25, 2022 to June 30, 2026 | Recruiting |
NCT04639180 | A Study to Evaluate Camrelizumab Plus Rivoceranib (Apatinib) as Adjuvant Therapy in Patients With Hepatocellular Carcinoma (HCC) at High Risk of Recurrence After Curative Resection or Ablation | Drug: Camrelizumab.Drug: Rivoceranib (apatinib) | Phase: 3. Allocation: Randomized. Intervention model: Crossover assignment | 674 | April 1, 2021 to July 31, 2024 | Recruiting |
NCT03839550 | Combine Apatinib Mesylate With PD-1 Antibody SHR-1210 for HCC With High Risk of Recurrence After Radical Resection | Drug: Apatinib Mesylate. Drug: SHR-1210 | Phase: 2. Allocation: Randomized. Intervention model: Parallel | 200 | February 15, 2019 to February 28, 2023 | Not yet recruiting |
NCT03847428 | Assess Efficacy and Safety of Durvalumab Alone or Combined With Bevacizumab in High Risk of Recurrence HCC Patients After Curative Treatment (EMERALD-2) | Drug: Durvalumab. Drug: Bevacizumab. Other: Placebo | Phase: 3. Allocation: Randomized. Intervention model: Parallel | 908 | April 29, 2019 to May 31, 2024 | Not yet recruiting |
NCT04102098 | A Study of Atezolizumab Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation (IMbrave050) | Drug: Atezolizumab. Drug: Bevacizumab | Phase: 3. Allocation: Randomized. Intervention model: Parallel | 668 | December 31, 2019 to July 16, 2027 | Not yet recruiting |
LT is suitable for patients with early HCC[46], but unfortunately, many patients are diagnosed at an advanced stage. Although many centers have expanded the indications beyond the Milan criteria and achieved promising results, there is still a high risk of relapse after transplantation, with HCC recurrence peaking about 2-3 years after LT[47-50].
Theoretically, LT completely eliminates tumors and potential lesions in the liver. However, MVI or undetected extrahepatic lesions can lead to HCC recurrence after transplantation. MVI was reported to be a major risk factor for HCC recurrence after LT[51]. Milan and other similar criteria are based on tumor size according to imaging, which does not provide sufficient information about pathological features and tumor biology, such as MVI and differentiation/grade. Therefore, these criteria cannot fully predict the recurrence of HCC after LT. MVI in the liver can predict tumor recurrence and indicate a poor prognosis. However, although MVI is an important predictor of tumor recurrence, without pathological examination, it is almost impossible to detect MVI before LT. Therefore, MVI largely determines the long-term prognosis of patients after resection and transplantation[52]. Theoretically, adjuvant therapy after LT may eradicate residual tumor cells in the blood. Therefore, it is very important to explore adjuvant therapy to improve the survival rate after transplantation.
At present, there is no systematic adjuvant therapy for HCC patients with MVI after transplantation, and most of the related studies focused on the treatment of recurrence after transplantation. Only some studies investigated adjuvant treatments for patients with a high risk of recurrence after transplantation beyond the Milan criteria. Nevertheless, patients with MVI were included in these studies, as summarized below and listed in Table 4.
Ref. | Interventions | Characteristics | n | Result | PMID |
Rodríguez-Perálvarez et al[53] | Drug: mTOR inhibitors | Multicenter retrospective study | 219 | Effective | 23867318 |
Vivarelli et al[54] | Drug: Cyclosporine | Retrospective study | 70 | Effective | 15838913 |
Vivarelli et al[55] | Drug: Tacrolimus | Retrospective study | 139 | Ineffective | 18948815 |
Geissler et al[56] | Drug: Sirolimus | Phase: 3. Allocation: Randomized. Intervention model: Parallel | 525 | Ineffective | 26555945 |
Friend et al[78] | Drug: Nivolumab | Retrospective study | 2 | Ineffective | 28643391 |
Biondani et al[60] | Drug: Nivolumab | Case report | 1 | Ineffective | 29293878 |
DeLeon et al[61] | Drug: PD-1/PD-L1 inhibitors | Retrospective study | 7 | Partly effective | 30603124 |
Gassmann et al[63] | Drug: Nivolumab | Case report | 1 | Ineffective | 30255136 |
Varkaris et al[65] | Drug: Pembrolizumab | Case report | 1 | Ineffective | 29215617 |
Iavarone et al[79] | Drug: Sorafenib | Multicenter retrospective study | 28 | Ineffective | 31365177 |
There is a high burden of early immunosuppression, especially in the case of calcineurin inhibitors such as cyclosporine and tacrolimus, which are usually the basic drugs against organ rejection after transplantation and may also increase the risk of HCC recurrence[53-55]. By contrast, immunosuppressive regimens based on mammalian target of rapamycin inhibitors, such as sirolimus and everolimus, have antitumor properties in vitro and in vivo and may reduce the HCC recurrence rates. Unfortunately, a prospective phase III multicenter RCT showed no significant improvement of the recurrence rate in HCC transplant recipients treated with sirolimus[56].
Some small studies have shown that sorafenib can improve the survival rate of LT patients with a high risk of recurrence after transplantation[33], but there is also evidence against chemotherapy or sorafenib adjuvant therapy after LT[57]. Whether targeted drugs are suitable for LT patients with MVI therefore remains to be verified in the future. Overall, there is no evidence that systemic adjuvant chemotherapy after LT can prevent HCC recurrence[58].
Although ICIs have demonstrated a certain level of efficacy in advanced liver cancer, based on the characteristics of ICIs and the special physical condition of patients after LT, balancing graft-protective immunosuppression and anti-tumor immune enhancement is still an unresolved issue. The use of ICIs as adjuvant therapy in transplant recipients has been the subject of several case reports[58-62], but ICIs may promote allograft injury[63], leading to severe rejection and even death. When systematically evaluating the data of cancer transplant recipients receiving ICIs, 37.5% of the recipients experienced liver allograft rejection, resulting in a 75% incidence of end-stage organ failure[64]. PD-1 inhibitor therapy after LT was reported in eight cases, including two cases of graft rejection[58,60,65]. Even if the treatment strategy of combined ICIs has great prospects, clinicians should be extremely cautious in practical application.
Tumor cell invasion of microscopic blood vessels in the surrounding liver tissue adjacent to the tumor is a histological feature of HCC. In recent years, several studies have intended to classify MVI based on different features[66-68], indicating that MVI can be further classified as MI and microscopic portal vein invasion (MPVI)[69,70], where tumor cells may invade the microvessels at the initial stage of invasion, while the newly formed microvascular structure due to the interaction of liver tissue around the tumor is defined as MI. Subsequently, as tumor invasion accelerates, tumor cells float and settle in the portal vein branches farther away from the original tumor, which is defined as MPVI. Unfortunately, MVI can only be definitively diagnosed by examining surgical specimens, limiting its role in guiding individualized treatment. The two types of MVI have different foundations and mechanisms. MPVI is a more advanced form of tumor invasion than MI. Patients with MPVI have more aggressive tumor characteristics, and the two different risk factors for recurrence suggest that the goals should be different when designing adjuvant therapy for each type. For MI, the main strategy should be targeted at disseminated tumor cells that spread from the primary tumor[7]. For MPVI, a potentially systemic treatment strategy is more appropriate. Our preliminary study indicated that postoperative adjuvant therapy could improve long-term outcomes after curative LR in HCC patients with MPVI, but the effect was weaker in MI. At the same time, our studies have shown that in MI, a wider surgical margin can eliminate peripheral intrahepatic micrometastasis, thereby preventing early tumor recurrence. By contrast, the surgical results of MPVI patients are similar regardless of the width of the surgical margin[71].
Therefore, it may not be wise to classify the two types of vascular invasion into one group for research and analysis, while more appropriate treatment strategies should be developed based on different biological and histological characteristics. Several limitations exist in this study. First, the prognosis of HCC is affected by a variety of factors including tumor markers, tumor size, tumor differentiation, and liver cancer staging, here, we only give a systematic review of the prognosis of patients with MVI, not considering other factors. Second, since adjuvant therapy after LT with MVI is relatively limited, the results obtained may not objectively reflect its efficacy. Third, we did not categorize all studies using meta-analysis, so there may still be valid treatment outcomes missed. Thus, more clinical studies may be needed to analyze the postoperative adjuvant therapy for such populations in order to obtain the best treatment strategy.
Adjuvant therapy for preventing tumor recurrence after radical resection in HCC patients with MVI is the key to improving the long-term survival rate. Although there is still controversy, after LR, TACE may be an effective choice to improve DFS and OS. As targeted therapy and immunotherapy have been effective in improving the prognosis of patients with advanced liver cancer in many retrospective studies, adjuvant therapy based on molecular targeted drugs needs further study. Many RCT studies evaluating adjuvant ICI after LR are ongoing, and their results may provide additional references for adjuvant therapy. In the future, prospective studies should be carried out to clarify the improvement of prognosis in the MVI subgroup by these two treatments. Moreover, in consideration of the actual drug efficacy, adverse reactions, and patient tolerance, the relationship between efficacy and safety should be balanced in clinical practice. It may be necessary to distinguish potential populations benefiting from each combination therapy, and to assess whether patients have the preconditions to receive effective combination therapy using novel biomarkers and biological characteristics.
Provenance and peer review: Invited article; Externally peer reviewed.
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Specialty type: Gastroenterology and hepatology
Country/Territory of origin: China
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P-Reviewer: Nath L, India; Ullah K, Pakistan S-Editor: Wang JJ L-Editor: Wang TQ P-Editor: Wang JJ
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