Surgical approach to achieve R0 resections in primary and metastatic liver tumors: a literature review

Introduction

Liver cancer is one of the most common cancers around the globe and has the second-highest cancer mortality rate in the world (1). Primary liver tumors, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), represents the majority (>95%) of all primary malignant liver tumors (2). On the other hand, metastatic liver tumors originate in other organs and spread to the liver, generally through hematogenous routes due to the rich vascularization of the liver. According to the origin site, tumor biology and behavior, liver metastasis can be divided amongst others in colorectal liver metastases (CRLM), metastases from endocrine tumors, and nonendocrine/noncolorectal liver metastasis (3). Although, each subtype differs in pathogenesis, tumor behavior, and prognosis, surgical treatment modalities have become the gold standard for curative treatment for liver malignancies (3). Characterization of surgical treatment available for liver malignancies can be discussed by liver tumor etiology/disease, or by technique. As the scope of this review, we find it best to present the current discussion by technique, with a particular focus in current strategies to achieve R0 resections in challenging surgical procedures. Anatomical and non-anatomical liver resections are vastly discussed elsewhere (4-7). Therefore, are not included in the present review.

Regardless of the etiology of the tumor, and following the principles of surgical oncology, achieving macro- and microscopically clear margins (R0), while preserving adequate function of the remaining organ, are the main goal after liver resections (2,7). However, in order to achieve R0 resections very often technically challenging approaches are required. Alternatively, R1 resections-defined as those with clear macroscopic margins, but with evidence of microscopic positive margins (8) have been reported (9). In addition, advances in different systemic treatments have allowed for an expanded patient population with more advanced and complex disease to be offered aggressive surgical treatment (2). Hence, pushing the safety limits to a higher extent and imposing an even higher challenge for the hepato-pancreato-biliary (HPB) surgeon.

Nevertheless, there is no consensus of which should be the ideal minimal safety margin for liver tumor resections (3), with contrasting reports in regards of safety, tumor recurrence and overall outcomes following R0 resections. Therefore, we aim to review current worldwide surgical practices to achieve R0 resections for primary and metastatic liver tumors and their subsequent reported outcomes in particularly challenging surgical techniques (Table 1). We present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-778/rc).

Methods

PubMed database, Google Scholar, and OVID Medline were searched during June 1^st to July 20^th, 2022 for peer-reviewed original articles related to surgical techniques performed to achieve R0 resections in the setting of primary and/or metastatic liver tumors. In order to present an up-to-date review, articles published between 2015 to July 2022 were preferentially included. The following search terms were used: Resection margin primary liver tumor, R0 resection primary liver tumor, R0 resection metastatic liver tumor, vascular control, In situ liver resection, ante-situm liver resection, vascular involvement liver tumor R0 resection, surgical technique liver tumor resection. English-language literature including retrospective/prospective studies, clinical trials, single/multicenter cohorts, case reports, as well as systematic reviews and meta-analysis were reviewed. The search strategy summary is described in Table 2.

Tumors involving vascular inflow/outflow

Hepatic resection can be complicated by tumors involving the major vascular structures of the liver affecting the inflow (hilar structures: portal vein, hepatic artery), outflow [inferior vena cava (IVC) and/or hepatic veins], or in some cases, both. The degree of invasion of vascular structures varies according to tumor microenvironment, histologic and clinicopathological characteristics, and can involve the vascular wall or present as intravascular extension (tumor thrombosis) (10). Therefore, achieving an R0 resection becomes even more technically challenging. This requires a careful balance between aggressive surgical techniques and consideration of patient safety to minimize risks of bleeding and embolic complications (11-13). Although previously considered unresectable, advances in the surgical field have allowed surgical management of liver tumors with vascular invasion. Vascular reconstructions are crucial in these cases as they allow for preservation of adequate liver function postoperatively and reduction of postoperative complications. Such procedures require careful preoperative planning, including volumetric assessments ensuing a future liver remnant (FLR) volume of ~40% when possible (14). Techniques achieving R0 resection and acceptable postoperative outcomes have been described for hepatectomies with vascular reconstructions including the portal vein (PV), hepatic artery, IVC, and hepatic veins, and are described below.

Inflow: vascular resection and reconstruction of hilar structures

PV system involvement can be seen with primary and metastatic liver tumors. If involvement is present and resection and reconstruction is needed, PV reconstructions are usually performed using end-to-end anastomosis with continuous suture and oblique cut of the vein to minimize size discrepancy or the standard main-to-left PV reconstruction with or without an interposed graft (15,16). The long extrahepatic course of the left PV allows for an easier resection and reconstruction when compared to the right PV shorter length (16). The use of graft interposition is usually not necessary unless the resected portion of the PV is significant (exceeding ~6 cm). In such cases, grafts using autologous (internal jugular, left renal, splenic, iliac or saphenous vein) or synthetic materials [ringed/not-ringed 10 mm polytetrafluoroethylene (PTFE) or polyethylenterephthalat (PTE)] can be used for reconstruction (16). Recently, Conticchio et al. reported the use of Rex-shunt for reconstruction of the left PV in patients with hepatic malignancies requiring right or extended right hepatectomies and resection of the bifurcation or main PV. The authors found the procedure to be feasible and reproducible, and conclude that it can be used to achieve R0 resections or in cases where the standard main-to-left PV reconstruction is not a suitable option (15).

In the presence of tumor thrombosis, consideration for surgical resection is usually based on its extension. Currently, Cheng’s classification of PV tumor thrombosis and The Japanese Vp—PV invasion—classification of PV tumor thrombosis classification are widely used to determine the best surgical approach (17,18). For primary tumors, tumor thrombosis of the PV is usually seen in ~40% of HCC patients (17). Thrombectomy is usually the preferred treatment option, unless the tumor thrombus is strongly attached to the vessel’s wall, in which PV resection is then required (17). When the PV tumor thrombus is located in the main PV, the bifurcation or the contralateral PV, performing a thrombectomy first, followed by liver resection has shown improved survival outcomes in patients with Cheng’s III and IV classification (17). On the other hand, PV involvement with metastatic liver tumors, including CRLM and CCA, present mostly with microscopic tumor invasion affecting the intrahepatic PV, while macroscopic tumor thrombus in the portal branch are rarely seen (19,20). In these cases, vascular resection and reconstruction are needed to achieve R0 resections. Nevertheless, reports of outcomes after this challenging procedure in metastatic liver tumors are scarce.

Surgical techniques for hepatic artery resection and reconstruction due to tumor involvement are complex and their use is controversial (16). In order to maintain arterial blood flow to the remnant liver, and avoid derangement of the anastomosis, hepatic artery resection and reconstruction is preferably performed when liver parenchyma transection is completed (16). Nevertheless, this procedure can be performed prior or after transection based on a case-by-case level (16). Most commonly, strategies for arterial reconstruction include direct end-to-end anastomosis if possible, and vascular interposition grafts (saphenous vein, gonadal vein, splenic artery, radial artery or inferior mesenteric artery). Additional techniques include transposition of another artery by end-to-end anastomosis between a reversed splenic artery, left gastric or gastroduodenal artery and the hepatic artery stump (16). Lastly, in cases where all possible reconstruction techniques are not feasible, PV arterialization can be performed as a salvage procedure for dearterialized grafts (16,21). This technique has been particularly useful in cases where there is hepatic artery encasement by the tumor as well as CCA involving the bile duct and biliary confluence. Successful PV arterialization with achievement of R0 resection was recently reported as salvage inflow surgical technique in a 78-year-old woman with CCA originating from the cysto-choledocal junction (21). The group performed surgical resection of segments 4b/5 en-bloc with the gallbladder, biliary confluence and common bile duct. For PV arterialization, the right hepatic artery stump was mobilized to reach the portal plane and the anastomosis between the right hepatic artery and the right PV was completed using a termino-lateral interrupted suture. The patient recovered uneventfully and was discharged at postoperative day 10 (21). Nevertheless, available reports following this technique are scarce and more studies reporting short- and long-term outcomes after this approach are needed.

Outflow: vascular resection and reconstruction of IVC and/or hepatic veins

The adequate surgical approach for tumors invading the IVC will mostly depend on the degree and location of the obstruction by the tumor. Tumors involving the hepatocaval confluence require a more technically challenging procedure when compared to tumors with tangential infiltration of the IVC (16). Nonetheless, when facing these challenging cases, three important surgical steps must take place: (I) control of suprahepatic IVC, (II) control of infrahepatic IVC and (III) vascular clamping + vascular resection and reconstruction.

Generally, when the IVC segment affected by the tumor is below the hepatic veins, an abdominal incision will allow for control of the supra e infrahepatic IVC in a sufficient and safe manner. Control of the infrahepatic IVC is achieved above the confluence of the left renal vein. For suprahepatic IVC control a number of techniques have been described. Broadly, methods to expose the suprahepatic IVC include those in where the IVC is clamped in the abdominal cavity at the infradiaphragmatic/infrapericardial region, and those with IVC clamping performed in the thorax at the supradiaphragmatic region/intrapericardial IVC level (22,23). However, there is no current consensus on which technique ensures the safest approach to expose and clamp the suprahepatic IVC and that will probably depend on the location and size of the tumor. Full liver mobilization and ligation of the diaphragmatic veins bilaterally is generally adequate for less complex cases, with resection of the retrohepatic IVC usually performed en-bloc with the liver tumor (16). On the other hand, the thoracic approach is usually the preferred technique in cases with large tumors with a short intraabdominal suprahepatic IVC, tumor thrombosis of the retrohepatic IVC and/or hepatic veins, or when the tumor encase the hepatocaval confluence (22). In these cases, total hepatic vascular exclusion (THVE) with preserved liver remnant perfusion and standard THVE with or without venovenous bypasss and in-situ cold perfusion represents the only way to achieve total tumor resection (16,22,24-26). Despite being a challenging approach, available reports show evidence of its safety and feasibility when carefully performed (22,23,26,27). Although reports have shown feasibility of the procedure, THVE should be performed in cases with a detailed preoperative planning, interdisciplinary pre-operative assessment and availability of cardiovascular and thoracic surgeons if the supradiaphragmatic region/intrapericardial technique is being considered.

Recently, Tohyama et al. (22) described a transmediastinal, intrapericardial IVC approach for hepatectomy and resection of the hepatic confluence or tumor thrombectomy of the suprahepatic IVC performed in five patients. Indications for this procedure included an expected R0/R1 status after hepatectomy and tumor thrombectomy in HCC patients with tumor thrombus in the supra-hepatic IVC and in patients with liver tumors invading the hepatic vein confluence, or anticipation of an adequate residual liver volume to achieve appropriate liver function. In order to secure the supra-diaphragmatic intrapericardial IVC, the authors performed a vertical incision in the diaphragmatic pericardium towards the ventral side of the intrapericardial IVC. Adjacent vasculature was excluded when possible, and clamping of the preserved hepatic veins to prevent backflow from the residual liver was also performed. Optimal resection site was confirmed by transesophageal echocardiography, and after hemodynamic stability was confirmed, the ICV wall was resected. The nine-step detailed procedure is reported by the authors (22).

Reconstruction of the IVC can be performed by primary closure by a running suture in cases where the wall defect is ≤30% of the IVC circumference (16). Patch repair with autologous patches can be used as a measure to prevent stenosis, or in cases with larger defects and involvement up to 30% (16). Recent studies suggest that peritoneal patch represent a safe and effective option for venous reconstruction during hepatectomy for liver tumors, even allowing for reconstruction of cases deemed to be unresectable (28). Alternatives reconstruction options include the use of prosthetic replacement, particularly in cases with segmental resection of the IVC distant to the hepatocaval confluence or as an alternative to patch repair in extensive resections (>60% of IVC diameter) (16). PTFE grafts and 18–20-mm ringed Gore-Tex grafts are usually recommended (16). In addition, performing a caval shift procedure is suggested to avoid infection of the synthetic graft when performing these particular cases (16).

Hepatic veins can be infiltrated by tumors located medially and in the posterior portion of the liver, as seen in intrahepatic CCA (29,30). In these cases, an approach of suprahepatic and/or infrahepatic IVC control as described above are also usually required. If collateral circulation is present, reconstruction is not necessary for hepatic vein tributaries that demonstrated limited contribution to venous drainage during preoperative evaluation. However, in cases where no collateral circulation—large inferior hepatic vein draining segment VI—reconstruction of the right hepatic vein is crucial to avoid congestion in segments VI and VII and prevent detrimental postoperative complications (30). As observed during living donor liver transplantation (LDLT), it is recommended to perform reconstruction of vascular outflow when large tributaries (>4 mm) are present (31). Commonly used grafts for hepatic vein reconstruction include autologous grafts, cryopreserved or prosthetic vascular grafts (30).

In particular cases, primary or metastatic tumors involving outflow and/or inflow structures present with such complexity that the abovementioned techniques become unfeasible. However, surgical advances and the possibility to merge techniques across surgical disciplines have open the door to provide alternative treatment options for these complex patients. Such is the case of ex-vivo, in-situ and ante-situ liver resections.

Ex-vivo liver resections

Ex-vivo liver resection is a complex procedure that involves complete hepatectomy, liver resection outside of the body, and auto-transplantation of the remnant liver. This procedure merges transplant techniques with oncology principles in order to access anatomically difficult tumors and improve treatment options for complex patients (32). Currently, there are no guidelines for indications and technical considerations for these techniques. Therefore, its use is based on a case-by-case strict approach, and include patients with malignant and non-malignant tumors (33). A recent meta-analysis evaluated outcomes after ex-vivo resections in 29 studies with reports of 215 patients (33). As expected, R0 resections rate was 100%. Overall mortality rate at 90-day was 11.6%, and mean overall survival was 55.8%, with both parameters being lower in patients undergoing ex-vivo resections for malignant tumors that those with non-malignant tumors, in alignment with previous reports (34). Importantly, in patients undergoing ex-vivo resections for malignant tumors, there was a significant relationship between the maximum tumor size and postoperative liver failure and 90-day mortality rate (33). Feasibility of the technique has been also reported in smaller series including its use for advanced CCA (35) and sarcoma-like tumors (36) with acceptable immediate liver function. However, high rate of tumor recurrence, morbidity and mortality have been reported (32-36).

In-situ liver resections with hypothermic perfusion

When prolonged operative time is expected due to complex vascular outflow reconstruction, the use of hypothermic perfusion appears as a promising technique to reduce the risk of ischemia and reperfusion injury (37). The procedure includes adequate tumor location by direct ultrasound and hepatic transection; preparation of the graft to be use for reconstruction; total hepatic vascular occlusion, tumor resection, graft placement, and hepatic reperfusion (37). Organo-protective and cell-protective solutions such as the histidine-tryptophan-ketoglutarate-Brettschneider or University of Wisconsin solution are the preferred solutions for perfusion of the liver (16). Feasibility of this procedure have been reported previously in cases requiring vascular reconstruction and resection of tumors with complete invasion of the hepatic veins (37), as well in even more complex cases including tumor invasion of the IVC and hepatic veins with concomitant use of extracorporeal membrane oxygenation (38).

Ante-situ liver resections

This complex procedure involves complete dissection of the hepatic venous confluence from the IVC, as well as complete detachment of the liver from the IVC in order to rotate the liver ante-situm allowing for better access and exposure to the tumor (16). The liver is then packed in sterile ice ante-situm followed by perfusion of the PV with cold preservation solutions (16). Ante-situm liver resections are performed with or without venovenous bypass, with the latter being the preferred method if the patient’s hemodynamic status allows it. Ye et al. (39) published a case series of 23 patients with unresectable HCC who underwent ante-situm resections and reported 1-, 3-, 5-, and 10-year survival rates of 65.2%, 56.5%, 50.9%, and 20.3%, respectively. Nevertheless, reports of poor outcomes including high rate of tumor recurrence and high mortality rate have been also reported, particularly in patients with malignant tumors (36). Similarly, Oldhafer et al. (11) reported the use of a modified ante-situm resection technique using total vascular occlusion (median time of 23 minutes) without cold perfusion or veno-venous bypass to treat eight patients with tumors invading the hepatocaval confluence. Vascular replacement was performed using allogeneic donor veins or PTFE grafts. An R0 resection was achieved in 6 cases (75%) with a median overall survival of 33.5 months (11). However, the authors noted the technically challenging nature of the procedure that limits it to experienced surgeons and high-volume surgical centers.

The overall promising results highlight the fact that although ex-vivo, in-situ and ante-situ liver resections are extremely challenging procedures, the different technical variants allow the execution of potential curative resections in patients with lesions deemed unresectable otherwise. As there is no current consensus on recommendations for which technique to apply, knowledge of interdisciplinary techniques, in conjunction with a detailed pre-surgical planning and availability of a multidisciplinary surgical team is crucial for successful performance of these types of complex resections.

Additional techniques

Staged resections

A relatively established procedure in the field of hepatic resection is the two-stage hepatectomy, which helps increase resectability of complex tumors. In this procedure, the tumors in each hepatic lobe (if both lobes involved) are resected in distinct stages, with an interval to reduce the risk of liver failure (40). This procedure takes advantage of the liver’s unique ability to regenerate following PV ligation or portal vein embolization (PVE). Generally, the PV branch ipsilateral to the tumor is embolized, either through percutaneous, transhepatic, or transileocolic routes, allowing for atrophy of the diseased liver (41). Various embolic materials, including absolute ethanol, fibrin glue, and N-butyl cyanoacrylate, have been used for PVE. However, no material has demonstrated a significant advantage clinically (41). Regeneration of the contralateral lobe generally takes place 4–8 weeks following PVE due to the release of growth factors and hormones from the atrophied lobe (2). Because PVE is performed before planned hepatic resection, its indications can vary based on the extent of liver disease and the planned operation. Current guidelines state the FLR should be anticipated to be 25% for patients with healthy livers, >30% in patients with liver disease, and >40% in cirrhotic livers (41). On the other hand, a study by Dueland et al. (42) involving 103 patients found that LT was more effective than PVE and hepatic resection for patients with extensive CRLM. These findings suggest that transplantation should be prioritized over two-stage hepatectomy when possible due to increased chance of cure and lower complication rates.

Feasibility of staged resections for CRLM is a topic of increased research interest with promising results. A recent multicenter study across the United States evaluated outcomes of 196 patients who underwent a two-stage hepatectomy for bilateral CRLM (40). R0 resections were achieved in 157 patients (84.4%) in the first stage and 174 patients (92.1%) in the second stage. Reported overall morbidity rate was 47.4% after the second stage, and 90-day mortality rate was 4.5%. The authors demonstrated the safety and feasibility of two staged hepatectomies in complex patients when carefully selected, as the group only proceeded with a second stage in patients with favorable biology (40). Importantly, it was observed that overall survival was negatively affected by positive surgical margins after the second procedure as well as increased estimated blood loss (40). When compared to simultaneous resections, staged CRLM have shown improved long-term survival, comparative peri-operative mortality and reduced mortality rates (43,44). In a recent population-based cohort study including and 776 (62%) staged and 442 (38%) simultaneous resections, the reported median overall survival was 78 (95% CI: 59–86) vs. 40 (95% CI: 35–46) months, respectively (43). Nitsche et al. reported their single center experience of 72 patients following staged resection vs. 68 following simultaneous resection. The authors found longer cumulative operation time in patients with staged resections vs. those undergoing simultaneous resections (460 vs. 299 minutes, respectively; P=0.003). Nonetheless, similar perioperative mortality was found between groups [2 (3%) vs. 1 (2%), respectively; P=0.25)]. In addition, liver-related morbidity rates and liver-related complications according to Clavien-Dindo classification were similar between groups. When exploring colorectal-related morbidity rates, the authors found significantly lower rates of complications grade 2 in patients following staged vs. simultaneous resections [2 (7%) vs. 11 (19%), respectively; P=0.001] (44). Nevertheless, further studies are needed in order to fully elucidate the benefits of a staged resection for CRLM when compared to simultaneous resections.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure

ALPPS is a relatively new technique that aims to increase the potential for hepatic resection by stimulating FLR augmentation (45). First performed by Dr. Hans Schlitt in 2007, the idea for this technique is derived from the concept of PV occlusion, in which portal venous blood flow is redistributed to the liver in order to promote FLR hypertrophy (45). As hepatic resection is limited by the amount of liver parenchyma left behind, ALPPS helps expand treatment options for patients. ALPPS has been used to treat primary and metastatic liver tumors, with improved outcomes after prudent patient selection and technical experience (46).

The first step of the ALPPS procedure involves liver mobilization with clearance of disease from the FLR (if any). The structures within the porta hepatis are skeletonized and the right PV is ligated and divided while preserving the right hepatic duct and right hepatic artery. After a brief 1–2 week interval to allow for FLR hypertrophy, the right bile duct, hepatic artery, and the right hepatic vein with or without the middle hepatic vein (depending on the type of resection—right hepatectomy or extended right hepatectomy) are ligated and divided (46). Various alterations have been made to this original procedure, including tourniquet, radiofrequency-assisted liver partition, and segmental modifications. Thus far, no particular technique has emerged as the standard of care, and outcomes still have room for improvement (45). Currently, the use of ALPPS is limited to two-stage hepatectomy and is not recommended for elderly patients and those with poor functional status due to high complication rates (45). In a recent publication by Chan et al. (46), ALPPS demonstrated comparable outcomes, with no significant differences in morbidity or mortality when compared to PVE for hepatitis-related HCC. Furthermore, only 1 out of 46 patients (resection rate: 97.8%) who underwent ALPPS failed to proceed to resection, as compared to 33 out of 102 patients (resection rate: 67.7%) who underwent PVE. This suggests improved outcomes using current surgical practices and carefully selected patients. Although ALPPS stimulates increased FLR hypertrophy compared to PVE, higher morbidity and mortality rates have limited its feasibility at the beginning of its implementation (45). A better understanding of such complex procedure, in alignment with improved and adequate surgical training have allowed for improved outcomes in present times. In addition, current strategies involving minimally invasive techniques are being implemented to improve postoperative outcomes following ALPPS (47,48). Similarly, ALPPS modifications have led to improved R0 resection rates up to 100% (49), including feasibility when combined with techniques such as ex-vivo resections (32,50).

Resection and partial liver segment transplantation with delayed total hepatectomy (RAPID) procedure

The principle of the RAPID procedure is to transplant the patient with a small auxiliary left liver graft (left lateral segment or left lobe) and ligation of right PV, followed by transplanted graft hypertrophy and subsequent second stage hepatectomy (51). This approach basically combines principles of the ALPPS procedure, two stage hepatectomies, liver transplantation (LT) and LDLT. For example, the RAPID technique allows for an expanded donor pool for patients with CRLM through the use of small segmental auxiliary grafts and more recently for cirrhotic patients with unresectable HCC (51,52). The small graft used in the RAPID technique may be more susceptible to small-for-size syndrome, in which portal hyperperfusion leads to microvascular damage and subsequent liver failure (51,52). Outcomes may yet be improved by predictive models such as the one designed by Golse et al. (53). The RAPID procedure, while still experimental in nature, represents an exciting new option of expanding the donor pool for LT. In addition, refinement of the technique and surgical advances have allowed to implement RAPID in even more complex cases as seen in the first report of a successful RAPID procedure with a graft from a living liver donor performed in a patient with liver cirrhosis and HCC (54) and the first report of a successful RAPID procedure in a patient with non-resectable CRLM (55). Further studies, especially prospective clinical trials, are needed to optimize its effectiveness and reduce complication rates.

Liver transplant and oncology—“transplant oncology”

Hepatic resection is often considered a second-line treatment if transplantation is possible, as patients generally have underlying liver disease which limits the feasibility of long-term remission. LT is the only solid organ transplant that has been able to effectively cure cancer. This unique potential led to the development of transplant oncology, a new interdisciplinary field that combines surgical oncology and transplantation medicine to improve outcomes and quality of life for cancer patients (56). Currently, LT represents one of the most effective treatments for early-stage HCC, and current efforts are aimed at expanding the potential pool of patients who are eligible for transplant (57). The acceptable survival rate has been a matter of debate. Some have suggested a 5-year-survival rate of 50%, while others advocated for a more stringent 10-year-survival rate of 50%. Estimates of risk have greatly improved and there is now a risk estimation of tumor recurrence after transplant (RETREAT) score which has been validated by the United Network for Organ Sharing (UNOS) database (56).

LT is also an option for early-stage intrahepatic CCA, although resection is more common as the disease often presents late and consequently carries a poor prognosis (58). In addition, it has been used with varying degrees of success for HCC, CRLM, and metastatic neuroendocrine tumors (59). Recently, efforts have been towards implementation of LT in patients with advanced HCC and unresectable CRLM (18,60-63). The SECA-II arm D study evaluated survival of 10 patients with unresectable CRLM after LT using extended criteria for patients and donors. Although, a relative short disease-free and overall survival (4 and 18 months, respectively) was found, the authors conclude that using extended criteria donors could allow LT to be an option for selected patients and with it, improve long-term overall survival after LT (62,63). In addition, improvements in patient selection have led to improved outcomes for hilar CCA and early-stage intrahepatic CCA transplantation (64). Further research is needed to better understand tumor immunology and its impact on transplantation outcomes (65), as well as additional ways to take advantage of merging such interesting fields in medicine. Such advantages will subsequently translate into improve long and short term outcomes for liver-related oncology patients, with an improved recurrence free time and better quality of life for these patients.

Important considerations

Currently, there is no definite tool to assess tumor prognosis after liver resections. Kim et al. (66) found that the 2019 World Health Organization classification was not associated with post-resection prognosis of combined HCC and CCA. Nevertheless, clinical assessment and strict follow-up aid in clinical decision and prognosis assessment. A recent study by Zhang et al. (67) investigated 2,509 HCC patients who underwent R0 hepatic resection in 1,104 (44.0%) patients had microvascular invasion on the resection biopsy. The study found that preoperative hypercoagulability was associated with a poor prognosis in HCC patients with microvascular invasion after resection as the international normalized ratio level independently affected overall survival and recurrence-free survival. In addition, extremely high preoperative α-fetoprotein level was associated with increased rates of R1 resection and vascular invasion (67). In another report, preoperative model of end-stage liver disease, grade of post hepatectomy liver failure and HCC recurrence were independent predictors for patient survival (68).

A better understanding of the factors that influence prognosis following R0 hepatic resection for primary and metastatic liver tumors will allow for better preoperative planning and postoperative outcomes and should be a focus of future research efforts. It is important to highlight, that most of these complex patients are deemed unresectable, limiting the therapeutic options to palliative chemotherapy. Under this premise, these challenging procedures represents an alternative therapeutic option and therefore, attempting R0 resections in complex cases would be a justifiable approach.

Conclusions

Regardless of the surgical approach used to treat primary and metastatic liver tumors, the common end goal is achieving an R0 resection. Safety and feasibility of R0 resections have been reported for multiple techniques. However, success and postoperative outcomes are determined by a detailed preoperative assessment, taking into account tumor biology, disease burden, patient status, surgeons’ proficiency and multidisciplinary care. Technical complexity should not be a limitation to achieve or pursue R0 tumor resection. Development of new systemic treatments, complemented with aggressive surgery offers the possibility of prolonged patient survival. However, there has to be a balance between patient risk/benefit in attempting R0 resections. Adequate training of surgeons on implementation of transplant oncology techniques, as well as minimally invasive techniques applied to HPB surgery represents as a promising path to improve short and long-term outcomes for liver-related oncology patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Francisco Schlottmann and Marco G. Patti) for the series “Current Management of Upper Gastrointestinal Malignancies” published in Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-778/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-778/coif). The series “Current Management of Upper Gastrointestinal Malignancies” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Zamora-Valdes D, Taner T, Nagorney DM. Surgical Treatment of Hepatocellular Carcinoma. Cancer Control 2017;24:1073274817729258. [Crossref] [PubMed]
2. Orcutt ST, Anaya DA. Liver Resection and Surgical Strategies for Management of Primary Liver Cancer. Cancer Control 2018;25:1073274817744621. [Crossref] [PubMed]
3. Heinrich S, Lang H. Hepatic resection for primary and secondary liver malignancies. Innov Surg Sci 2017;2:1-8. [Crossref] [PubMed]
4. Dong S, Wang Z, Wu L, et al. Effect of surgical margin in R0 hepatectomy on recurrence-free survival of patients with solitary hepatocellular carcinomas without macroscopic vascular invasion. Medicine (Baltimore) 2016;95:e5251. [Crossref] [PubMed]
5. Tsilimigras DI, Sahara K, Moris D, et al. Effect of Surgical Margin Width on Patterns of Recurrence among Patients Undergoing R0 Hepatectomy for T1 Hepatocellular Carcinoma: An International Multi-Institutional Analysis. J Gastrointest Surg 2020;24:1552-60. [Crossref] [PubMed]
6. Qi LN, Ma L, Chen YY, et al. Outcomes of anatomical versus non-anatomical resection for hepatocellular carcinoma according to circulating tumour-cell status. Ann Med 2020;52:21-31. [Crossref] [PubMed]
7. Joechle K, Vreeland TJ, Vega EA, et al. Anatomic Resection Is Not Required for Colorectal Liver Metastases with RAS Mutation. J Gastrointest Surg 2020;24:1033-9. [Crossref] [PubMed]
8. Whalen GF. Principles of Surgical Oncology. In: Pieters RS, Liebmann J. editors. Cancer Concepts: A Guidebook for the Non-Oncologist. Worcester, MA, USA: University of Massachusetts Medical School, 2016.
9. Bari H, Thiyagarajan UM, Brown R, et al. Liver Resection and role of Extended Histology (LiREcH study) in patients with multifocal colorectal cancer liver metastases. HPB (Oxford) 2021;23:1615-22. [Crossref] [PubMed]
10. Chen S, Wang C, Gu Y, et al. Prediction of Microvascular Invasion and Its M2 Classification in Hepatocellular Carcinoma Based on Nomogram Analyses. Front Oncol 2022;11:774800. Erratum in: Front Oncol 2022;12:888008. [Crossref] [PubMed]
11. Oldhafer F, Ringe KI, Timrott K, et al. Modified ante situm liver resection without use of cold perfusion nor veno-venous bypass for treatment of hepatic lesions infiltrating the hepatocaval confluence. Langenbecks Arch Surg 2018;403:379-86. [Crossref] [PubMed]
12. Huang Y, Liao A, Pu X, et al. A randomized controlled trial of effect of 15- or 25-minute intermittent Pringle maneuver on hepatectomy for hepatocellular carcinoma. Surgery 2022;171:1596-604. [Crossref] [PubMed]
13. Mobarak S, Stott MC, Tarazi M, et al. Selective Hepatic Vascular Exclusion versus Pringle Maneuver in Major Hepatectomy: A Systematic Review and Meta-Analysis. Front Surg 2022;9:860721. [Crossref] [PubMed]
14. Berumen J, Hemming A. Vascular Reconstruction in Hepatic Malignancy. Surg Clin North Am 2016;96:283-98. [Crossref] [PubMed]
15. Conticchio M, Salloum C, Allard MA, et al. The rex shunt for left portal vein reconstruction during hepatectomy for malignancy using of rex-shunt in adults for oncoliver surgery. Surg Endosc 2022;36:8249-54. [Crossref] [PubMed]
16. Radulova-Mauersberger O, Weitz J, Riediger C. Vascular surgery in liver resection. Langenbecks Arch Surg 2021;406:2217-48. [Crossref] [PubMed]
17. Peng SY, Wang XA, Huang CY, et al. Better surgical treatment method for hepatocellular carcinoma with portal vein tumor thrombus. World J Gastroenterol 2018;24:4527-35. [Crossref] [PubMed]
18. Cullen JM, Vargas P, Goldaracena N. Living donor liver transplantation for patients with advanced hepatocellular carcinoma. Hepatoma Res 2020;6:76. [Crossref]
19. Yamamoto N, Sugano N, Morinaga S, et al. Massive portal vein tumor thrombus from colorectal cancer without any metastatic nodules in the liver parenchyma. Rare Tumors 2011;3:e47. [Crossref] [PubMed]
20. Vaghiri S, Alaghmand Nejad S, Kasprowski L, et al. A single center comparative retrospective study of in situ split plus portal vein ligation versus conventional two-stage hepatectomy for cholangiocellular carcinoma. Acta Chir Belg 2022; Epub ahead of print. [Crossref] [PubMed]
21. Marino R, Ratti F, Catena M, et al. Portal vein arterialization: a possibility in cholangiocarcinomas infiltrating the right hepatic artery? Updates Surg 2022;74:1781-6. [Crossref] [PubMed]
22. Tohyama T, Tamura K, Takai A, et al. Transmediastinal, intrapericardial inferior vena cava approach based on anatomical landmarks for hepatectomy using total hepatic vascular exclusion. Langenbecks Arch Surg 2022;407:391-400. [Crossref] [PubMed]
23. Bacalbasa N, Balescu I, Dima S, et al. Left Hepatectomy Through Double Approach and Total Vascular Exclusion for Giant Left Lobe Hepatocarcinoma. In Vivo 2021;35:1191-5. [Crossref] [PubMed]
24. Azoulay D, Lim C, Salloum C, et al. Complex Liver Resection Using Standard Total Vascular Exclusion, Venovenous Bypass, and In Situ Hypothermic Portal Perfusion: An Audit of 77 Consecutive Cases. Ann Surg 2015;262:93-104. [Crossref] [PubMed]
25. Dokmak S, Aussilhou B, Marchese T, et al. Right Trisectionectomy and Caval Reconstruction with Peritoneal Patch Under Short Total Vascular Exclusion for Hepatocellular Carcinoma with Tumoral Thrombus in Suprahepatic Vena Cava. Ann Surg Oncol 2018;25:1152. [Crossref] [PubMed]
26. Kim SM, Hwang S, Moon DB, et al. Patch venoplasty for resecting tumor invading the retrohepatic inferior vena cava using total and selective hepatic vascular exclusion. Ann Hepatobiliary Pancreat Surg 2021;25:536-43. [Crossref] [PubMed]
27. Ko S, Kirihataya Y, Matsumoto Y, et al. Retrocaval liver lifting maneuver and modifications of total hepatic vascular exclusion for liver tumor resection. World J Hepatol 2016;8:411-20. [Crossref] [PubMed]
28. Langella S, Menonna F, Casella M, et al. Vascular Resection During Hepatectomy for Liver Malignancies. Results from a Tertiary Center using Autologous Peritoneal Patch for Venous Reconstruction. World J Surg 2020;44:3100-7. [Crossref] [PubMed]
29. Yang S, Han D, Wang L, et al. Reconstruction of the middle hepatic vein using a vein graft from the resected portion of the liver. Surg Case Rep 2020;6:277. [Crossref] [PubMed]
30. Li A, Wu B, Yin L, et al. Right hepatic vein reconstruction in middle hepatectomy: A case report. Int J Surg Case Rep 2022;95:107188. [Crossref] [PubMed]
31. Jeng LB, Thorat A, Yang HR, et al. Venous outflow reconstruction in living donor liver transplantation: Dealing with venous anomalies. World J Transplant 2015;5:145-53. [Crossref] [PubMed]
32. Baimas-George MR, Levi DM, Eskind LB, et al. Ex vivo liver resection coupled with associated liver partition and portal vein ligation: Combining existing techniques to achieve surgical resectability. J Surg Oncol 2019;119:771-6. [Crossref] [PubMed]
33. Serrablo A, Giménez-Maurel T, Utrilla Fornals A, et al. Current indications of ex-situ liver resection: A systematic review. Surgery 2022;172:933-42. [Crossref] [PubMed]
34. Zawistowski M, Nowaczyk J, Jakubczyk M, et al. Outcomes of ex vivo liver resection and autotransplantation: A systematic review and meta-analysis. Surgery 2020;168:631-42. [Crossref] [PubMed]
35. Ozsoy M, Ozsoy Z, Yilmaz S, et al. Ex situ Liver Resection and Partial Liver Autotransplantation for Advanced Cholangiocarcinoma. Niger J Surg 2019;25:97-100. [Crossref] [PubMed]
36. Schlegel A, Sakuraoka Y, Motwani K, et al. Outcome after ex situ or ante situm liver resection with hypothermic perfusion and auto-transplantation: A single-centre experience in adult and paediatric patients. J Surg Oncol 2020;122:1122-31. [Crossref] [PubMed]
37. Lopez-Lopez V, Garcia-Lopez J, Eshmuminov D, et al. Left renal vein graft and in situ hepatic perfusion in hepatectomy for complete tumor invasion of hepatic veins: hemodynamic optimization and surgical technique. Langenbecks Arch Surg 2022;407:1-7. [Crossref] [PubMed]
38. Balci D, Ozcelik M, Kirimker EO, et al. Extended left hepatectomy for intrahepatic cholangiocarcinoma: hepatic vein reconstruction with in-situ hypothermic perfusion and extracorporeal membrane oxygenation. BMC Surg 2018;18:7. [Crossref] [PubMed]
39. Ye Q, Zeng C, Wang Y, et al. Long-Term Outcomes of Ante-Situm Resection and Auto-Transplantation in Conventionally Unresectable Hepatocellular Carcinoma: A Single-Center Experience. Ann Transplant 2018;23:81-8. [Crossref] [PubMed]
40. Chavez MI, Gholami S, Kim BJ, et al. Two-Stage Hepatectomy for Bilateral Colorectal Liver Metastases: A Multi-institutional Analysis. Ann Surg Oncol 2021;28:1457-65. [Crossref] [PubMed]
41. Orcutt ST, Kobayashi K, Sultenfuss M, et al. Portal Vein Embolization as an Oncosurgical Strategy Prior to Major Hepatic Resection: Anatomic, Surgical, and Technical Considerations. Front Surg 2016;3:14. [Crossref] [PubMed]
42. Dueland S, Yaqub S, Syversveen T, et al. Survival Outcomes After Portal Vein Embolization and Liver Resection Compared With Liver Transplant for Patients With Extensive Colorectal Cancer Liver Metastases. JAMA Surg 2021;156:550-7. [Crossref] [PubMed]
43. Bogach J, Wang J, Griffiths C, et al. Simultaneous versus staged resection for synchronous colorectal liver metastases: A population-based cohort study. Int J Surg 2020;74:68-75. [Crossref] [PubMed]
44. Nitsche U, Weber C, Kaufmann B, et al. Simultaneous Versus Staged Resection of Colorectal Cancer Liver Metastasis: A Retrospective Single-Center Study. J Surg Res 2020;255:346-54. [Crossref] [PubMed]
45. Bertens KA, Hawel J, Lung K, et al. ALPPS: challenging the concept of unresectability--a systematic review. Int J Surg 2015;13:280-7. [Crossref] [PubMed]
46. Chan A, Zhang WY, Chok K, et al. ALPPS Versus Portal Vein Embolization for Hepatitis-related Hepatocellular Carcinoma: A Changing Paradigm in Modulation of Future Liver Remnant Before Major Hepatectomy. Ann Surg 2021;273:957-65. [Crossref] [PubMed]
47. Michal K, Sau M, Tamara GMH, et al. A better route to ALPPS: minimally invasive vs open ALPPS. Surg Endosc 2020;34:2379-89. [Crossref] [PubMed]
48. Fernandes ESM, de Barros F, Magistri P, et al. Total robotic ALPPS approach for hepatocellular carcinoma in cirrhotic liver. Int J Med Robot 2021;17:e2238. [Crossref] [PubMed]
49. Baili E, Tsilimigras DI, Moris D, et al. Technical modifications and outcomes after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) for primary liver malignancies: A systematic review. Surg Oncol 2020;33:70-80. [Crossref] [PubMed]
50. Baili E, Tsilimigras DI, Filippou D, et al. Associating liver partition and portal vein ligation for staged hepatectomy in patients with primary liver malignancies: A systematic review of the literature. J BUON 2019;24:1371-81. [PubMed]
51. Nadalin S, Settmacher U, Rauchfuß F, et al. RAPID procedure for colorectal cancer liver metastasis. Int J Surg 2020;82S:93-6. [Crossref] [PubMed]
52. Line PD, Hagness M, Berstad AE, et al. A Novel Concept for Partial Liver Transplantation in Nonresectable Colorectal Liver Metastases: The RAPID Concept. Ann Surg 2015;262:e5-9. [Crossref] [PubMed]
53. Golse N, Joly F, Nicolas Q, et al. Partial orthotopic liver transplantation in combination with two-stage hepatectomy: A proof-of-concept explained by mathematical modeling. Clin Biomech (Bristol, Avon) 2020;73:195-200. Erratum in: Clin Biomech (Bristol, Avon) 2020;77:105047. [Crossref] [PubMed]
54. Balci D, Kirimker EO, Kologlu MB, et al. Left Lobe Living Donor Liver Transplantation Using Rapid Procedure in a Cirrhotic Patient With Portal Vein Thrombosis. Ann Surg 2022;275:e538-9. [Crossref] [PubMed]
55. Königsrainer A, Templin S, Capobianco I, et al. Paradigm Shift in the Management of Irresectable Colorectal Liver Metastases: Living Donor Auxiliary Partial Orthotopic Liver Transplantation in Combination With Two-stage Hepatectomy (LD-RAPID). Ann Surg 2019;270:327-32. [Crossref] [PubMed]
56. Hibi T, Sapisochin G. What is transplant oncology? Surgery 2019;165:281-5. [Crossref] [PubMed]
57. Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017;14:203-17. [Crossref] [PubMed]
58. Mazzaferro V, Gorgen A, Roayaie S, et al. Liver resection and transplantation for intrahepatic cholangiocarcinoma. J Hepatol 2020;72:364-77. [Crossref] [PubMed]
59. Moeckli B, Ivanics T, Claasen M, et al. Recent developments and ongoing trials in transplant oncology. Liver Int 2020;40:2326-44. [Crossref] [PubMed]
60. Sapisochin G, Goldaracena N, Laurence JM, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study. Hepatology 2016;64:2077-88. [Crossref] [PubMed]
61. Uchiyama H, Itoh S, Yoshizumi T, et al. Living donor liver transplantation for hepatocellular carcinoma: results of prospective patient selection by Kyushu University Criteria in 7 years. HPB (Oxford) 2017;19:1082-90. [Crossref] [PubMed]
62. Smedman TM, Line PD, Hagness M, et al. Liver transplantation for unresectable colorectal liver metastases in patients and donors with extended criteria (SECA-II arm D study). BJS Open 2020;4:467-77. [Crossref] [PubMed]
63. Gorgen A, Ivanics T, Sapisochin G. Liver transplantation for unresectable colorectal metastasis: a new hope. Hepatobiliary Surg Nutr 2020;9:665-8. [Crossref] [PubMed]
64. Goldaracena N, Gorgen A, Sapisochin G. Current status of liver transplantation for cholangiocarcinoma. Liver Transpl 2018;24:294-303. [Crossref] [PubMed]
65. Sapisochin G, Hibi T, Toso C, et al. Transplant Oncology in Primary and Metastatic Liver Tumors: Principles, Evidence, and Opportunities. Ann Surg 2021;273:483-93. [Crossref] [PubMed]
66. Kim M, Hwang S, Ahn CS, et al. Post-resection prognosis of combined hepatocellular carcinoma-cholangiocarcinoma cannot be predicted by the 2019 World Health Organization classification. Asian J Surg 2021;44:1389-95. [Crossref] [PubMed]
67. Zhang XP, Zhou TF, Wang ZH, et al. Association of Preoperative Hypercoagulability with Poor Prognosis in Hepatocellular Carcinoma Patients with Microvascular Invasion After Liver Resection: A Multicenter Study. Ann Surg Oncol 2019;26:4117-25. [Crossref] [PubMed]
68. Elshaarawy O, Aman A, Zakaria HM, et al. Outcomes of curative liver resection for hepatocellular carcinoma in patients with cirrhosis. World J Gastrointest Oncol 2021;13:424-39. [Crossref] [PubMed]