Modern therapeutic approaches for hepatic tumors: progress, limitations, and future directions

Abstract

Hepatic tumors, such as hepatocellular carcinoma (HCC) and metastatic liver malignancies, represent a substantial worldwide health concern due to elevated mortality rates and unfavorable prognoses. Notwithstanding progress in surgical, locoregional, and systemic therapy, significant obstacles like as late-stage diagnosis, treatment resistance, and discrepancies in healthcare access still hinder patient outcomes. This study thoroughly analyzes recent breakthroughs in hepatic tumor treatment, including surgical improvements, immunotherapy, targeted medicines, and nanotechnology-based drug delivery systems. The discourse emphasizes minimally invasive methods including laparoscopic and robotic-assisted hepatectomies, the function of immune checkpoint inhibitors, and the promise of nanoparticle-based therapeutics to improve drug administration while reducing systemic toxicity. This study aims to critically assess current hepatic tumor treatments, examining their effectiveness, constraints, and prospective developments. Critical concerns, such as drug resistance, post-treatment recurrence, and the accessibility of innovative medicines in resource-constrained environments, are addressed. The review underscores the significance of personalized medicine, biomarker-guided treatment approaches, and interdisciplinary teamwork in enhancing therapeutic results. Future research seeks to enhance patient survival and quality of life through the integration of developing technology and the refinement of present treatment approaches.

Introduction

Because of their high rates of morbidity and mortality, hepatic tumors which include both primary and secondary malignancies present a major concern for world health. Nearly three quarters of all instances of liver cancer are cholangiocarcinoma, hepatoblastoma, or hepatocellular carcinoma (HCC). Because the liver is responsible for both filtering blood and supplying it, it is common for tumors to spread to other parts of the body and cause secondary liver cancers [1]. With 8.3% of all cancer-related deaths attributable to HCC alone, these malignancies rank as the second most common cancer killers globally. There were 905,677 new cases of liver cancer in 2020, but the fact that it was responsible for 830,000 fatalities highlights the disease's disproportionate deadly impact [2]. In addition, the prevalence of risk factors such as alcoholism, non-alcoholic fatty liver disease (NAFLD), and viral hepatitis has been on the rise worldwide, making liver cancer the only one of the five deadliest cancers to exhibit an annual percentage increase in incidence. There are significant regional differences in hepatic tumors [3]. Chronic hepatitis B virus (HBV) infections are the main cause of hepatocellular carcinoma (HCC), which is most common in East Asia and China. In China, the incidence rate is above 50% of all cases worldwide. Due to insufficient healthcare infrastructure and the high prevalence of HBV, Sub-Saharan Africa also has a substantial burden [4]. On the other hand, the obesity pandemic has been associated with an increase in liver cancer cases in industrialized nations like the US, where NAFLD and metabolic syndromes are major risk factors. Liver cancer, for instance, has climbed 3% to 4% per year in occurrence over the last several decades, and it now ranks as the fifth leading cause of cancer-related deaths in the US [5, 6]. There is a large disparity in five-year survival rates depending on tumor stage at diagnosis, but overall, it is around 18% in the US. Just 5–15% of patients are able to undergo curative treatments like liver transplantation or surgical resection when their disease is in an early stage. The median survival time for individuals with advanced disease without therapy is fewer than 12 months, which is significantly worse than the overall survival rate [7–9]. The purpose of this review article is to survey recent developments in liver cancer treatment, discuss new approaches to treatment, and draw attention to the obstacles that still need to be overcome. Our goals are to provide a comprehensive overview of the current state of liver cancer research, including its worldwide prevalence and epidemiological trends, the various treatment options available (including surgical, loco-regional, and systemic approaches), the impact of nanotechnology and immunotherapy on the field, the challenges posed by drug resistance, toxicity, and accessibility, and finally, to suggest areas for future research that emphasize personalized medicine, biomarker-driven therapies, and interdisciplinary collaborations.

The mainstay of liver cancer curative treatment is surgical removal of the cancerous tissue and subsequent liver transplantation. Laparoscopic and robot-assisted hepatectomies are two examples of how surgical innovations have made resections safer and more feasible, especially for malignancies that were previously thought to be inoperable [7]. By enhancing liver regeneration, two-stage hepatectomy (TSH) and portal vein embolization (PVE) have made resection possible even in patients with large tumor loads. Due to the lower regenerating ability of cirrhotic livers, the risk of post-operative morbidity is 20% to 30% higher with right hepatectomy compared to left hepatectomy. Advanced HCC, perihilar cholangiocarcinoma, metastatic colorectal cancer, and other malignancies have rekindled interest in liver transplantation, which was first offered in the 1980 s. Recurrence rates of 15% to 30% during the first two years are concerning, despite the survival advantage that transplantation affords. Using the Milan and UCSF criteria as a guide, advances in immunosuppressive regimens and donor organ allocation have led to better results for certain patients [10, 11]. Researchers found that compared to conservative therapy, trans-arterial chemoembolization (TACE) improved two-year survival by 23% for patients with intermediate-stage HCC. But response rates are still all over the place, with barely 10% to 20% of instances reaching a full response. Improvements to TACE's effectiveness and safety profile have been made possible by the creation of drug-eluting beads. As a result of substantial advancements in systemic therapy, the multi-kinase inhibitor sorafenib is now the gold standard for treating advanced HCC. The median survival time for patients using sorafenib is 10.7 months, compared to 7.9 months for those taking a placebo, a difference of around three months in overall survival tie. Unfortunately, the treatment only helps only a third of patients, and resistance usually appears within six months. The therapy options have grown with the introduction of second-line drugs such as regorafenib, lenvatinib, and immune checkpoint inhibitors like pembrolizumab; nevertheless, their effectiveness is still limited [12, 13]. The development of immunotherapy has opened up fresh possibilities for combating medication resistance and the immune evasion that tumors exhibit. Clinical trials have demonstrated encouraging results for checkpoint inhibitors targeting PD-1/PD-L1 pathways, including nivolumab and atezolizumab, which achieved objective response rates ranging from 15 to 20%. Researchers are looking into potential combinations of checkpoint inhibitors, kinase inhibitors, and anti-angiogenic medicines to see if they can improve treatment outcomes [14]. The use of drug delivery systems based on nanoparticles could revolutionize the way liver cancer is treated. Chemotherapeutic drugs'bioavailability and therapeutic index can be enhanced by nanotechnology by adjusting drug size, surface characteristics, and targeting mechanisms. Doxorubicin and paclitaxel, for example, have demonstrated improved tumor targeting and decreased systemic toxicity in liposomal formulations. To further tackle the complex nature of tumor biology, nanoparticles can be designed to administer combination therapy [15–18].

These improvements have not eliminated the substantial obstacles that have long plagued liver cancer treatment. Some important issues to consider are the following: the need for earlier detection of liver cancers (since most cases are diagnosed at advanced stages), the fact that drug resistance is driven by cancer stem-like cells and genetic mutations, which reduces the effectiveness of systemic therapies over the long term, the toxicity of current treatments (such as sorafenib and TACE), which limits their use in patients with poor performance status, and the fact that low- and middle-income countries have unequal access to advanced treatments, which worsens global health inequities [19]. In order to personalize treatments for each patient, future studies should investigate ways to combine personalized medicine with molecular diagnostics and biomarker-driven therapeutics. Liver cancer patients have reason to be hopeful about their prognosis, thanks to recent advancements in immunotherapy, medication delivery, and the discovery of new medicines that target tumor-specific pathways. In conclusion, there have been tremendous strides in liver cancer treatment over the last 20 years, but there are still huge gaps in terms of accessibility, long-term results, and effectiveness. To improve the prognosis for this terrible disease, it is essential to address these issues through patient-centered research, technological innovation, and interdisciplinary collaboration [20, 21].

This review aims to deliver a thorough analysis of current breakthroughs in hepatic tumor treatment, assessing the efficacy, limitations, and developing techniques in surgical, locoregional, and systemic therapies. This article aims to: (1) examine contemporary surgical methodologies, including minimally invasive and robotic-assisted hepatectomies, and their effects on patient outcomes; (2) evaluate the contribution of targeted therapies, immunotherapy, and nanotechnology-based drug delivery systems in improving treatment accuracy and minimizing systemic toxicity; (3) identify significant challenges such as drug resistance, post-treatment recurrence, and healthcare disparities that impede optimal patient care; and (4) emphasize future trajectories in personalized medicine, biomarker-driven treatment strategies, and interdisciplinary collaborations. This review synthesizes recent accomplishments and ongoing problems to offer significant insights for guiding future research and clinical decision-making in hepatic tumor care.

Current challenges in hepatic tumor management

The intricate interaction of elements pertaining to early detection, treatment accessibility, therapeutic effectiveness, and systemic resistance mechanisms is the root cause of the current difficulties in managing hepatic tumors. Hepatocellular carcinoma (HCC) screening adherence and diagnostic accuracy are major issues, despite the fact that early diagnosis is crucial for curative treatment [22]. Although Spanish guidelines suggest routine abdominal ultrasound screening for those with liver cirrhosis, studies show that only 47% of patients with HCC in Spain were diagnosed as part of a surveillance program, and even fewer were detected at an early stage [23, 24]. In the US, comparable problems have been brought to light; for example, out of 1,005 patients enrolled in the HALT-C study, 70% of patients with advanced-stage HCC were diagnosed as a result of missed detections during surveillance, mostly because of patients'lack of adherence or the insensitivity of ultrasonography. Ultrasonography has limited sensitivity for lesions less than 2 cm, with reported sensitivity rates of 50–60%, and operator dependence and subjective interpretation further exacerbate its limitations for early-stage identification. Despite their frequent recommendation as supplementary tools, tumor markers have failed to significantly enhance diagnosis accuracy or decrease associated expenses. Combining ultrasonography with tumor markers, for instance, did not improve detection but did raise screening program costs [25, 26]. New biomarkers, including microRNA panels, have demonstrated potential in pilot studies, but they still need to be independently validated to be sure they work. In order to overcome these obstacles and improve early detection, especially in populations at high risk, standardized screening programs that are both effective and affordable are necessary. Another important concern is the efficiency of monitoring programs in terms of cost. A yearly incidence of HCC more than 1.5% in cirrhotic individuals or 0.2% in people with chronic liver disease who do not have cirrhosis is considered the threshold at which screening becomes cost-effective. The social and emotional effects of false-positive results, the financial burden of confirmatory tests, and the unpredictability in life expectancy among cirrhotic patients make it difficult to determine cost-effectiveness. In settings with limited resources, where specialists and powerful imaging technology are not readily available, these difficulties become much more apparent [27, 28]. Variations in illness etiology and lack of consensus on screening intervals add another layer of complexity to the already heavy load of surveillance. The management of HCC is further complicated by the variability of risk factors linked to its development. Case in point: elastography-based assessments of liver stiffness have proven useful for risk stratification in the context of chronic hepatitis C virus (HCV) infection. Nevertheless, it is necessary to have lifelong monitoring due to the residual risk of HCC, even when antiviral medication achieves sustained virologic response (SVR). Hepatocellular carcinoma (HCC) is more likely to occur in patients with chronic hepatitis B virus (HBV) infection if they are older, male, have a high viral load, and drink alcohol regularly. These dangers are amplified for patients with alcohol-related cirrhosis, especially those with low platelet counts and those over the age of 55 [29, 30]. Screening and management efforts for non-alcoholic fatty liver disease (NAFLD) are further complicated by a lack of data, imaging problems caused by obesity, and co-morbid illnesses that restrict therapy options. There are also substantial therapeutic hurdles to overcome when managing hepatic tumors. A poor prognosis and strong resistance to systemic treatments are hallmarks of advanced-stage HCC. Drugs such as sorafenib do improve results, but only slightly; without treatment, the median survival is under 12 months. Compared to placebo, sorafenib increased overall survival in the SHARP trial from 7.9 to 10.7 months; nevertheless, objective response rates stayed modest, at only 2%. Improved progression-free survival (PFS) does not necessarily translate into large overall survival (OS) advantages; same pattern is seen with other targeted medicines such ramucirumab, lenvatinib, regorafenib, and cabozantinib. The association between tumor shrinkage and overall survival (OS) is modest, while lenvatinib showed non-inferiority to sorafenib with a median OS of 13.6 months. Immunotherapy has brought exciting new possibilities, but there are still obstacles. Nivolumab and pembrolizumab are examples of checkpoint inhibitors that have demonstrated response rates of 15–20%. In certain cases, these patients have achieved long-lasting tumor control. The findings of the phase III trials, however, have been inconsistent [31, 32]. As an example, pembrolizumab was not shown to have a statistically significant advantage over placebo in an OS trial. Additional validation is required, as early trials using combination therapy, like atezolizumab and bevacizumab, demonstrated response rates as high as 65%. In low-income locations, where the burden of liver cancer is disproportionately high, the high cost of immunotherapy further limits accessibility. Hepatic tumors are complicated, adding to the difficulties in diagnosis and treatment. Both medication resistance and tumor recurrence are influenced by tumor heterogeneity and the existence of cancer stem-like cells. As is the case with sorafenib, multidrug resistance mechanisms typically manifest themselves after six months of starting systemic treatment [33, 34]. Part of the reason for this resistance is the tumor microenvironment, which encourages angiogenesis and immune evasion, which in turn reduces the effectiveness of treatments. The creation of delivery methods based on nanotechnology to enhance medication targeting and decrease systemic toxicity is one example of an effort to circumvent these obstacles. Although there has been promise in preclinical research, clinical translation is still in its infancy [35–39]. Researchers have looked into non-invasive diagnostic innovations to increase the sensitivity of HCC detection, such as diffusion-weighted imaging and MRI with organ-specific contrast medium. Nevertheless, there has been no confirmation of substantial diagnostic benefits compared to traditional MRI methods from prospective investigations[40]. Hypointensity in venous phases, pseudocapsules, and intralesional fat are some of the other criteria that have been studied, although their practical utility has been little. Some have questioned the usefulness of using response rate and time to progression as surrogate endpoints in clinical trials [41, 42]. Although these metrics are helpful for gauging the efficacy of treatments, they have not reliably indicated improvements in overall survival. For instance, sorafenib's phase II studies were thought to have been unsuccessful because of poor response rates. However, improvements in overall survival and progression-free survival allowed for the development of phase III trials, which were ultimately successful. Concerns over the reliability of these endpoints were raised when certain medications, including FOLFOX, which had better response rates, failed to show advantages in OS. Lastly, unequal access to care based on socioeconomic status is still a major problem. There is frequently a dearth of diagnostic and treatment facilities in areas where HCC is prevalent. Low- and middle-income patients often lack access to screening programs, modern imaging technology, and systemic medicines [43–47]. There is a significant disparity in the global results for liver cancer due to the restricted treatment options, the emotional and financial burden of false-positive diagnoses, and other factors. A concerted effort incorporating innovations in early detection, risk classification driven by biomarkers, enhanced systemic medicines, and fair healthcare delivery is necessary to tackle these complex difficulties. To improve outcomes for patients with hepatic malignancies internationally, future research should focus on validating novel diagnostic tools, developing resistance-breaking therapeutic techniques, and establishing cost-effective, scalable interventions [48–50].

Modern and emerging therapeutic modalities

Surgical interventions

Thanks to developments in surgical methods and a better knowledge of the liver's special regenerative ability, modern liver surgery has evolved substantially throughout the years. Surprisingly, the liver has the remarkable ability to regenerate a significant portion of its functional tissue—up to 80%—in a matter of weeks following a large hepatectomies, as long as the remaining parenchyma is in good health. This extraordinary quality allows for curative surgery for primary and secondary liver cancers, as it enables substantial liver resections [51, 52]. Improvements in transection techniques, low central venous pressure anesthetic, and inflow occlusion approaches like the Pringle maneuver helped overcome early difficulties in liver surgery, which were mostly associated with uncontrolled bleeding during resection. Resections of the liver have become safer and more accurate thanks to detailed mapping of its segmental structure. Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PHC), colorectal liver metastases (CRLM), and neuroendocrine tumors (NETs) are the hepatic malignancies that are best treated by removing the liver [53, 54]. The usual course of treatment for NETs is full tumor resection, but cytoreductive surgery may be necessary to reduce symptoms or treat hormone-secreting tumors that have not responded to medicinal treatment. In cases where liver function is intact and substantial portal hypertension is absent, defined by a portal pressure of less than 20 mmHg, surgical resection is preferred over transplantation for HCC. But for patients with recurrent HCC or those with worsening underlying liver disease, liver transplantation is still a viable salvage option. Before surgery, patients with HCC that is just barely resectable may undergo transarterial chemoembolization (TACE). Another way that TACE and PVE can get the future liver remnant (FLR) ready for surgery is by making the non-tumorous segments swell to compensate for the tumors [55, 56]. A less intrusive method that aims to preserve as much good liver tissue as possible and reduce the risk of postoperative liver failure, parenchyma-sparing liver surgery is becoming more popular. People who already have liver disease or multifocal tumors benefit greatly from this procedure. To effectively manage tumors, close to important blood vessels, parenchyma-sparing resections frequently employ ablative therapies such irreversible electroporation (IRE), leading to a high rate of local tumor control [57, 58]. Patients with HCC and CRLM had similar five-year survival rates after parenchyma-sparing surgery as they do after conventional anatomic resections, according to multiple studies. But this method isn't great for patients with widespread disease, and it only manages to treat a couple of tumors per patient on average [59, 60].

Two-stage hepatectomy (TSH) is a game-changing method for individuals with bilobar CRLM or inadequate FLR. As part of TSH, patients undergo liver regeneration after the first surgery to remove operable tumors, and then another surgery to remove any residual lesions [61]. According to several studies, the three-year survival rate for TSH can reach 84%, while the completion rates vary between 72 and 87%. Up to 30% of patients may develop disease progression during the waiting period between phases, which is usually 4–8 weeks. This raises complications. In response to these restrictions, ALPPS was developed to facilitate liver partitioning and portal vein ligation during staged hepatectomy. The second surgery can be done in just 7–14 days because to ALPPS, which speeds up the liver's regeneration process. With ALPPS, FLR hypertrophy rates are far higher than with traditional TSH; in as little as nine days, patients might see median volume increases of 74% [62]. Partial ALPPS and laparoscopic techniques have helped allay initial fears about ALPPS's high morbidity and mortality rates, although the technique is still hotly debated among liver surgeons. In order to make liver tumors more amenable to removal, percutaneous venoendothelial grafting (PVE) is an essential procedure that causes the contralateral lobe to enlarge. Although the surgery is effective in more than 90% of cases, a small percentage of patients may have tumor progression due to delayed liver expansion. More randomized controlled studies are needed to confirm this method, however sequential embolization of the portal and hepatic veins is being considered as a way to achieve quicker hypertrophy [63]. Liver partitioning in conjunction with portal vein ligation (ALPPS) is one example of a novel approach that has been developed in response to the persistent problem of inadequate liver expansion. The discipline has been transformed by minimally invasive liver surgery, which includes robotic-assisted and laparoscopic methods. This type of surgery reduces postoperative recovery times while still being effective against cancer [64, 65]. With the use of cutting-edge devices like the da Vinci Surgical System, robotic liver surgery offers improved precision thanks to 3D vision and more instrument versatility. Research comparing robotic and laparoscopic liver resections has revealed comparable results; however, robotic surgery provides benefits in intricate situations necessitating meticulous dissections or extensive suturing. The benefits of robotic-assisted liver surgery aren't without their drawbacks. The procedure isn't cheap, and doctors need to do 40 instances before they're competent doing big hepatectomies, according to research [66, 67].

Liver surgery now routinely incorporates ablative procedures like IRE and microwave ablation (MWA), especially for patients who do not do well with substantial resections. To accomplish full tumor clearance or as a bridge therapy before transplantation, these treatments are frequently administered in conjunction with surgery. The use of ablative therapies in conjunction with parenchyma-sparing resections has been associated with local control rates higher than 80% in studies [68]. When intrusive procedures like excision or ablation aren't an option, new non-invasive methods like stereotactic body radiation (SBRT) can control cancers close to vital organs and tissues. Patients receiving ALPPS for CRLM had a 46% long-term survival rate, compared to 26% for conventional TSH, demonstrating the significant improvement in outcomes of modern liver surgery. Up to 60% of cases can be resected, especially with parenchyma-sparing procedures. Research shows that over 25% of cases that were initially unresectable can become surgical candidates after undergoing neoadjuvant chemotherapy, thanks to the expansion of resectable tumors made possible by systemic therapy integration. The advancements in liver cancer management can be attributed to the multidisciplinary strategy that blends surgical breakthroughs with systemic and ablative medications [69, 70]. Problems still exist, even with these improvements. The ongoing problem of tumor progression during the time between staged procedures highlights the importance of finding ways to speed up liver regeneration without sacrificing safety. New possibilities for better patient selection and treatment results include biomarker-guided techniques and precision medicine. Improving these methods and incorporating new treatments to further broaden the scope of liver surgery will probably be the focus of future studies. The ability to overcome seemingly insurmountable obstacles and create new therapeutic options is demonstrated by modern liver surgery, which makes use of technical advancements and a multidisciplinary approach [71, 72]. The sector is well-positioned to provide better outcomes for patients with complex hepatic illnesses as long as research and collaboration continue. This highlights the necessity of continuous improvement (Table 1).

Table 1.

This table provides a detailed comparison of various modern liver surgery techniques, including key metrics, outcomes, and challenges, offering a comprehensive overview for expert audiences

Technique/approach	Indications	Success rate (%)	Survival outcomes	Hypertrophy/regeneration metrics	Complication rate (%)	Learning curve	Oncological efficacy	Cost implications	Notable advantages	Key challenges	Combination therapies	Patient selection criteria	Refs.
Major Hepatectomy	HCC, ICC, PHC, CRLM, NETs	90–95	5-year survival: ~ 50%	N/A	~ 15	Moderate	High	Moderate to High	Effective for large tumor burden	Risk of postoperative liver failure	Neoadjuvant chemotherapy	Adequate liver function	[73]
Parenchyma-Sparing Surgery	HCC, multifocal CRLM	80–90	Comparable to anatomic resection	N/A	~ 10	High	Comparable long-term survival	Moderate to High	Preserves healthy liver parenchyma	Not suitable for extensive disease	Ablation therapies (e.g., IRE)	Underlying liver disease	[74]
Two-Stage Hepatectomy (TSH)	Bilobar CRLM, insufficient FLR	72–87	3-year survival: 59–84%	Hypertrophy: 20–40%	~ 30	High	Moderate	High	Allows resection in bilobar disease	Tumor progression during interval	Systemic therapy in between stages	Bilobar disease	[75]
ALPPS	Extensive CRLM, small FLR	92	3-year survival: ~ 46%	Hypertrophy: 74% (median in 9 days)	30–40	Very High	Promising	High	Rapid hypertrophy of FLR	High morbidity and early mortality rates	Partial ALPPS for safety	High regenerative capacity	[76]
Portal Vein Embolization (PVE)	Small FLR	> 90	Enables subsequent surgery	Induces 20–40% hypertrophy	~ 10	Moderate	Moderate	Low to Moderate	Simple, well-tolerated procedure	Delayed growth in 10–15% of cases	Sequential embolization of veins	Sufficient FLR post-embolization	[77]
Robotic-Assisted Surgery	HCC, ICC, complex resections	~ 90	Similar to laparoscopic outcomes	N/A	~ 10	Steep	High	Very High	3D vision, precision, flexibility	High cost, steep learning curve	Combination with laparoscopic surgery	Complex cases requiring precision	[78]
Microwave Ablation (MWA)	Small tumors (< 3 cm), inoperable cases	~ 85	Local control: > 80%	N/A	1–3	Low	Moderate	Low	Effective near vascular structures	Heat sink effect near large vessels	Combined with surgery	Small tumor burden	[79]
Irreversible Electroporation (IRE)	Tumors near major vessels	~ 79	Local recurrence: ~ 10–50%	N/A	2–5	Moderate	Moderate	Moderate	Preserves bile ducts and vessels	Requires precise needle placement	Bridge to surgery/transplantation	Tumors near critical structures	[80]
Stereotactic Body Radiotherapy (SBRT)	Tumors near central structures	~ 80	Local control: 67–90%	N/A	~ 5	Moderate	Moderate	Moderate	Non-invasive, precise targeting	Proximity to bowel/stomach limiting doses	Combined with systemic therapies	Contraindication to surgery	[81]
Neoadjuvant Chemotherapy	Initially unresectable tumors	~ 25 converted	Variable	N/A	Drug-specific	N/A	Moderate	High	Converts unresectable cases to resectable	Chemotherapy-induced liver toxicity	Integrated into multimodal plans	Tumor downstaging response	[82]
Sequential Embolization	Insufficient hypertrophy with PVE	~ 85	N/A	Faster hypertrophy than PVE alone	~ 10	Moderate	Moderate	Moderate	Accelerates regeneration	Limited randomized data supporting outcomes	Experimental in some centers	Sufficient baseline FLR	[83]
Combination Systemic Therapies	Advanced or borderline resectable HCC	Varies	Survival improved in select cases	N/A	Drug-specific	N/A	Moderate	Moderate to High	Synergistic effect with local therapies	Risk of additive toxicities	Integrated with ICIs or TKIs	Molecular and tumor characteristics	[84]

Ablative therapies

With the advent of less invasive ablation techniques, which use energy to kill tumor tissue while sparing good liver tissue around it, these procedures have become standard practice in the treatment of liver tumors. Irreversible electroporation (IRE) and electrochemotherapy are examples of non-thermal methods, while thermal techniques like radiofrequency ablation (RFA) and microwave ablation (MWA) are examples of thermal procedures. The versatility of these approaches allows for their usage in a variety of clinical contexts, since they can be applied percutaneously, laparoscopically, or even during open surgery [85, 86]. The two ablation methods that continue to see the greatest utilization are RFA and MWA. While they both use heat to kill tumor cells, the ways in which they do it and the results they get are different. In comparison to RFA, which utilizes alternating current, MWA, which generates heat through electromagnetic waves, results in larger and faster necrosis zones. Because of its greater efficiency, MWA is frequently chosen as the treatment of choice for tumors bigger than 3 cm or for many lesions [87]. Both methods are quite effective for tumors that are less than 3 cm in size, with full ablation achieved in as many as 95% of cases. Complicating issues affect just 1–3 percent of patients, further reducing their morbidity rates. On the other hand, the heat sink effect, in which blood flow dissipates thermal energy, makes both approaches ineffective when aiming at tumors close to large blood arteries or the biliary tract [88]. For tumors near the portal vein, for instance, up to 20% of the time, incomplete ablation is found. When used properly, thermal ablation techniques can be quite useful. Patients with bilobar metastases often need surgical excision in addition to their use of these. To provide a full example, in two-stage hepatectomy (TSH), lesions in the liver lobe that were not initially resected can be treated with RFA or MWA, allowing for better disease control overall. Ablation therapies in conjunction with systemic chemotherapy considerably increased overall survival in instances of recurrent intrahepatic cholangiocarcinoma (ICC) following resection, in comparison to chemotherapy alone. These methods emphasize the significance of thermal ablation in removing heavy tumors while keeping the liver healthy [88]. When administered independently, RFA and MWA do not offer the full benefit of their potential. Surgical excision has far lower recurrence rates than ablation for tumors bigger than 3 cm in patients with colorectal liver metastases (CRLM), which can reach 66%. However, in a few number of cases, thermal ablation has been a lifesaver for HCC. As an example, ablation is frequently used as the initial treatment for tiny HCC (< 2 cm) with compensated liver function. Patients on liver transplant waiting lists can also benefit from thermal ablation since it stops tumor progression. Research shows that ablation can improve long-term results and decrease dropout rates in 90–95% of transplant candidates by controlling illness [89].

For tumors close to important structures, non-thermal modalities such as IRE provide a good option. IRE causes apoptosis by sparing the extracellular matrix with brief, high-voltage electrical pulses that puncture the cell membrane. For malignancies near the portal vein or biliary system, IRE is the best option since it preserves blood arteries and bile ducts [90]. With tumor control rates ranging from 55 to 79 percent and recurrence rates of 10 percent at 6 months and 50 percent at 12 months, IRE has been proven beneficial in retrospective investigations. On the other hand, IRE isn't without its drawbacks; for example, it takes a lot of time and requires general anesthesia and exact needle insertion. Also, between 30 and 40 percent of patients experience cardiovascular issues including arrhythmias, and 2 percent of patients report rare but serious symptoms like hemorrhage and portal vein thrombosis. Patients with HCC may also benefit from IRE as a transitional treatment before liver transplantation. For instance, bile ducts within the treated zones stayed intact, and five of the six patients who received IRE before transplantation had total tumor necrosis, while the sixth had fewer than 5% viable cancer cells. It is evident that IRE has the ability to manage malignancies in difficult areas without endangering important structures [91]. In addition, surgical resection is being more and more integrated with IRE in staged operations for complicated situations, including multiple CRLM. Another non-thermal approach that is just starting to gain traction is electrochemotherapy. This method improves medication delivery into tumor cells by combining chemotherapeutic agent injection with reversible electroporation. Without major side effects, preliminary CRLM investigations have shown total necrosis in more than 85 percent of treated lesions. Larger clinical trials are necessary to validate the effectiveness of electrochemotherapy, which is still in its experimental phase but shows promise for controlling liver cancers that have not responded to previous treatments. Patients at high risk or those who cannot have surgery because of co-morbidities are also effectively managed with ablation therapy [92]. In well-selected individuals, ablation offers survival rates comparable to resection for small HCC because it provides local control with no impact on liver function. Patients with small HCC who receive RFA or MWA have a five-year survival rate that varies between 40 and 70% based on tumor features and liver condition. For patients who aren't good candidates for more invasive procedures, ablation is a great choice because of these results [93].

In most cases, ablation therapies have good safety records. A common complication of thermal modalities is temporary post-ablation syndrome, which often goes away on its own. This syndrome is marked by inflammation and fever. Injuries to the bile ducts or blood vessels, which are considered severe consequences, happen in fewer than 2% of instances [94]. The increased procedural risks associated with non-thermal methods, such as IRE, especially cardiovascular events, highlight the importance of meticulous patient selection and close perioperative monitoring. For patients with complicated or high-risk malignancies, these medicines have extended therapy options (Fig. 1).

Fig. 1.

Procedural technique encompassing the four phases of SMWA. A The planning phase involves using the navigation system's planning module to choose the skin entry point and the intrahepatic target location. This is done to plan the ideal ablation probe trajectory. The manufacturer's predicted simulated ablation zone is green, the intended ablation margin is orange, and the target tumor is red. B During the navigation phase, the cross-hair viewer is used to indicate the direction of the projected trajectory, and the aiming device is guided along that trajectory. Millimeters denote the trajectory depth for successive ablation probe positions. C Following ablation probe insertion, the positional accuracy of the probe is measured in millimeters and confirmed in the validation scan in relation to the anticipated trajectory. If the results are good, the procedure is called microwave ablation. D The validation of the ablation zone: Direct overlay of pre- and post-ablation pictures with the validation module allows for fast calculation of the completeness of ablation, ensuring that a sufficient ablation zone has been validated [95]

Systemic medicines, such neoadjuvant or adjuvant chemotherapy, combined with ablation therapies increase their effectiveness even further. For instance, in about 20–25% of cases, tumors that were previously unresectable can be made resectable by combining ablation with chemotherapy. Similarly, patients undergoing phased resections had better outcomes when ablation is combined with portal vein embolization to enhance liver regeneration. The adaptability of ablation therapy in tackling various clinical issues is demonstrated by these multimodal approaches [96]. Tumor size, location, and patient characteristics all play a role in the long-term results of ablation treatments. Ablation has survival rates that are on par with surgical options for tiny, circumscribed cancers. Surgical excision, however, is still the best option for larger or more complicated lesions. Surgery improves survival and decreases recurrence rates, according to studies. This is especially true for individuals with CRLM bigger than 3 cm or HCC that has difficult anatomical characteristics [97]. Improving local tumor control and using sophisticated imaging techniques are the future prospects of ablation therapy. Example: ablation guided by ultrasound or real-time MRI increases accuracy, decreases complications, and guarantees total tumor removal. Furthermore, there is ongoing study into the possibility of improving outcomes for high-risk patients by combining ablation with immuno-modulating therapy or localized medication delivery [98]. To sum up, ablation therapies provide individualized answers to many different clinical problems, and they have quickly become an integral aspect of liver cancer treatment. For larger or more architecturally advantageous tumors, surgical resection is still the way to go. However, ablation offers excellent alternatives for individuals with tiny, localized lesions or those who are not surgical candidates. The importance of ablation therapies in the overall management of liver cancers is expected to grow as techniques advance.

Liver transplantation

In carefully selected situations when total hepatectomy is required to attain full tumor clearance, liver transplantation offers long-term survival as a curative treatment for some hepatic cancers (Fig. 2).

Fig. 2.

Liver transplant milestones. Abbreviations: DCD—Cardiac death; DAA—Direct-acting antiviral agent [99]

The high rates of tumor recurrence and the quick disease progression experienced by many early transplant recipients after liver transplantation made for unsatisfactory results when the procedure was first launched in the 1980 s. Since then, liver transplantation has become the go-to treatment for some types of liver cancer, including hepatocellular carcinoma (HCC), thanks to improvements in patient selection criteria, neoadjuvant medications, and surgical protocols. Improvements in recurrence-free survival and the promise of multimodal therapies for a wider variety of liver cancers have resulted from stricter qualifying requirements [100]. The most prevalent malignant reason for liver transplantation is HCC, which accounts for 25% of all U.S. transplants and up to 40% in Europe. Since its introduction in 1996, the Milan criteria have been the gold standard for determining whether patients are good candidates for liver transplantation. As long as there is no macrovascular invasion or extrahepatic illness, patients meeting these criteria can have either one tumor that is 5 cm or smaller, or up to three tumors that are 3 cm or less. Recurrence rates < 20% and 5-year survival rates of 70–80% are demonstrated in patients matching Milan criteria. The University of California San Francisco (UCSF) standards and other modifications to the Milan criteria raise the maximum tumor size to 8 cm, with a maximum diameter of 4.5 cm for each tumor, or 6.5 cm for a single tumor. Careful patient selection can preserve outcomes even with greater tumor loads, as demonstrated by similar survival rates achieved with these enlarged criteria. To enhance predictive accuracy, numerous selection processes now use AFP levels, a biomarker of tumor aggressiveness [101]. As an illustration, the Metroticket 2.0 model achieves 5-year survival rates surpassing 75% in patients with AFP < 400 ng/mL by combining AFP levels with total tumor volume (≤ 115 cm³) as predictors. Patients with an elevated AFP (> 1,000 ng/mL) are not eligible for transplantation because they have poor differentiation, microvascular invasion, and an increased risk of recurrence [99]. To manage tumor growth while waiting for transplant, neoadjuvant therapies are often used, including thermal ablation, selective internal radiation therapy (SIRT), and transcutaneous acupuncture for cervical cancer (TACE). By halting tumor progression in 90–95% of cases, these medicines lower dropout rates and provide light on tumor biology, letting doctors reevaluate eligibility when patients exhibit severe disease behavior [102]. Another cancer for which liver transplantation has been successful under strict protocols is perihilar cholangiocarcinoma (PHC). Neoadjuvant chemoradiotherapy with SBRT, 5-fluorouracil, and maintenance capecitabine was a groundbreaking technique developed in 2002 by the Mayo Clinic. Compared to 20–30% for resection alone, patients who met strict criteria, such as tumor size < 3 cm, lack of nodal or distant metastases, and negative biopsy results, had 5-year survival rates of 60–70%. Compared to the 27.4 months attained with resection (p = 0.049), the median overall survival for patients treated with transplantation was 32.5 months in a multicenter study including 304 participants. At 5 years, 41% of transplant recipients had avoided recurrence, compared to 27% of resection patients [103]. Based on these results, liver transplantation has replaced surgical resection as the treatment of choice for unresectable PHC in many hospitals, and randomized trials are still looking at whether or not it is better than surgical resection in resectable instances. Still up for debate, nonetheless, is the function of liver transplantation in cases of intrahepatic cholangiocarcinoma (ICC). Over the years, ICC has been linked to dismal survival rates and recurrence rates that topped 60%. Newer research, however, indicates that some patient subgroups may have better results. An instance of this is the astounding survival rate of 73% after 5 years and 100% after 1 year in individuals with cirrhosis who had one “very early” ICC lesion (≤ 2 cm). After achieving disease stability by gemcitabine-based chemotherapy for at least six months, non-cirrhotic individuals with advanced ICC can benefit from liver transplantation [104, 105]. Liver transplantation may be an option for ICC in certain circumstances, as these patients show a recurrence-free survival rate of about 50% after 5 years. The high recurrence rates of colorectal liver metastases (CRLM) made liver transplantation an unfavorable option in the past. On the other hand, new research has shown that it can work in some situations. To be strictly selected, a tumor must have a diameter of 5.5 cm or less, CEA levels must be less than 80 µg/L, BRAF mutations must not be present, and the patient must have maintained disease stability for over 6 months after chemotherapy. Even though recurrence-free survival at 1 year is still below 40%, 5-year survival rates exceed 60% under these conditions [106]. In order to further assess the effectiveness of liver transplantation in comparison to chemotherapy for unresectable CRLM, three randomized trials are under underway: two in Norway and one in France (TRANSMET). The RAPID method is one example of an innovative surgical strategy that combines partial liver transplantation with delayed removal of residual metastatic liver tissue, giving patients more options [107]. A potential strategy for increasing indications, this technology takes advantage of partially transplanted liver cells, which can regenerate and restore liver function, while avoiding competition for fully transplanted cells. Another, more limited, use for liver transplantation is in the case of neuroendocrine liver metastases (NELM). Early transplantation is usually unnecessary for these benign tumors because of how slowly they develop. Nevertheless, liver transplantation provides remarkable results in specific circumstances, such as patients younger than 60 years old with tumors that are well-differentiated (Ki-67 < 10%) and in which less than 50% of the liver is involved. The 5-year survival rates were more than 90% in one research, which is comparable to the rates seen in early-stage HCC. Somatostatin analogs and other neoadjuvant medications do not significantly improve post-transplant results, highlighting the need for careful selection [108]. Expanding liver transplantation for malignancies is hindered mostly by tumor recurrence. Surgical tumor seeding, microscopic illness remnants, and immunosuppression-induced tumor promotion are the mechanisms of recurrence[109]. Overly strict immunosuppression after transplant can increase the likelihood of cancer recurrence, while inadequate suppression increases the likelihood of graft rejection. In an effort to decrease recurrence while maintaining graft function, efforts are underway to incorporate immune checkpoint inhibitors into post-transplant regimens. It is becoming more usual to employ multimodal techniques that integrate systemic treatments with liver transplantation [110]. Around 20–25% of the time, tumors can be shrunk to a size where they match transplant requirements by the use of downstaging therapies like chemotherapy and transdermal brachytherapy. Patients with ICC and CRLM who were not previously transplantable have been able to see tumor response rates of 50–70% after receiving a combination of systemic chemotherapy and SIRT. These holistic methods bring attention to how liver transplantation fits into the bigger picture of oncology. The long-term effects of liver transplantation differ greatly depending on the type of malignancy. Patients with HCC who match the Milan or UCSF criteria usually have a recurrence rate < 20% and a 5-year survival rate of 70–80%. Compared to 20–30% for excision, 5-year survival with PHC approaches 60–70% with pre-transplant procedures. The results of ICC are still unpredictable, but in certain patients the 5-year survival rate is between 50 and 70%. Five-year survival rates for CRLM patients who meet strict criteria are 60%, whereas NELM provides the best prognosis, with cases that are well chosen having survival rates surpassing 90%. Finally, in cases when surgical resection is not enough to cure some hepatic cancers, liver transplantation is a game-changing possibility. Its indications are being expanded by advances in patient selection, neoadjuvant treatments, and surgical procedures, which are improving results for tumors that were previously untreatable [111]. Transplant oncology faces ongoing challenges such tumor recurrence and organ scarcity. However, new developments in immunotherapy, precision medicine, and innovative surgical techniques hold great potential for reshaping this field in the future (Table 2).

Table 2.

Comprehensive comparison of liver cancer therapies, highlighting indications, effectiveness, challenges, and advancements across ablation techniques, liver transplantation, and innovative surgical approaches

Aspect	Thermal ablation (RFA/MWA)	Non-thermal ablation (IRE, Electrochemotherapy)	Liver transplantation	Two-Stage Hepatectomy (TSH)	ALPPS	Portal Vein Embolization (PVE)	Combination therapies	Innovative techniques	References
Primary indications	Small HCC (< 3 cm), ICC, CRLM	Tumors near critical structures (bile ducts, veins)	HCC, ICC, CRLM, NELM, PHC	Bilobar CRLM	Extensive CRLM, small FLR	Insufficient FLR	Advanced or borderline resectable HCC	High-risk or unresectable tumors	[112]
Energy source/mechanism	Heat via alternating current (RFA) or EM waves (MWA)	High-voltage electrical pulses (IRE), chemotherapeutic delivery	Full organ removal and replacement	Sequential resections	Rapid hypertrophy through partition	Induces FLR hypertrophy	Chemotherapy, SIRT, TACE	MRI/US-guided ablation, robotic surgery	[113]
Tumor Size	Effective up to 3 cm	Effective near sensitive structures, size-dependent	Dependent on criteria	No size limit if FLR regenerates	No size limit if FLR regenerates	N/A	Variable	Size-dependent	[114]
Effectiveness	Full ablation in ~ 95% (< 3 cm tumors)	Tumor control 55–79%, recurrence 10–50% at 12 months	5-year survival: 70–80% (HCC under Milan criteria)	3-year survival: 59–84%	5-year survival: ~ 46%	Hypertrophy success: ~ 90%	Converts 20–25% unresectable cases	Enhances precision and safety	[115]
Challenges	Heat sink effect, incomplete ablation near large vessels	Requires precise needle placement, time-intensive	Organ scarcity, immunosuppression risks	Progression during interval (up to 30%)	High morbidity/mortality in early studies	Tumor progression (10–15%)	Toxicity, efficacy variability	Expensive, steep learning curves	[116]
Complication Rate	~ 1–3% (minor), < 2% (severe)	30–40% cardiovascular issues, 2% severe events	< 20% recurrence under Milan/UCSF	~ 30%	~ 40%	~ 10%	Drug- and modality-specific	Minimal with advanced monitoring	[117]
Combined modalities	With surgery for bilobar metastases	Pre- or post-surgery, transplantation bridging	TACE, SIRT, ablation for downstaging	PVE, systemic chemotherapy	Systemic therapy during interval	Sequential embolization trials	Immunotherapy, targeted therapies	Immuno-modulating therapies	[118]
Survival outcomes	5-year: 40–70% (small HCC)	Variable (specific to study)	5-year: 70–80% (HCC), ~ 60% (PHC)	3-year: ~ 84%	5-year: ~ 46%	Enables subsequent surgery	Improved with multimodal approaches	Enhances overall survival rates	[119]
Advantages	Minimally invasive, spares liver tissue	Preserves critical structures	Curative for selected tumors	Enables staged removal of bilobar disease	Accelerated second surgery (7–14 days)	Safe and effective hypertrophy	Tumor downstaging, better outcomes	Synergistic tumor control	[120, 121]
Limitations	Ineffective near vessels, limited for > 3 cm tumors	General anesthesia required, complex setup	High recurrence for poorly selected cases	Disease progression during wait	High costs, limited availability	Delayed hypertrophy in 10–15% cases	Drug resistance, additive toxicity	Expensive, long training periods	[122]
Innovation	Ultrasound/MRI-guided ablation	Electrochemotherapy for chemo-resistant tumors	Improved patient selection criteria	Hybrid approaches with ablation	Partial ALPPS for reduced risks	Sequential portal/hepatic vein embolization	Biomarker-guided therapies	Nanotechnology, localized delivery	[123–126]
Learning curve	Moderate	High	Moderate	High	Very high	Moderate	Moderate to high	Very high	[127]
Future research directions	Enhanced imaging for real-time precision	Clinical validation of electrochemotherapy	Immune checkpoint inhibitors post-transplant	Improved tumor biology evaluation	Minimizing risks in ALPPS	Faster, safer hypertrophy methods	Biomarker-guided therapy decisions	Immuno-modulating agent trials	[128, 129]

Chemotherapy and combination therapies

Management of liver cancers relies heavily on chemotherapy and combination therapies, which provide ways to lessen the likelihood of recurrence, make previously unresectable tumors resectable, and increase the likelihood of long-term survival. To reduce the likelihood of intrahepatic and extrahepatic recurrence, perioperative chemotherapy for resectable tumors aims to target micrometastatic illness. In cases where tumors cannot be surgically removed, systemic treatments in conjunction with locoregional techniques try to reduce tumor size, enhance disease control, and pave the way for further surgical removal. The incorporation of immune checkpoint inhibitors, biomarker-guided treatments, and developments in molecular profiling have transformed these approaches [130–133].

A large body of literature describes perioperative chemotherapy as it pertains to CRLM (resectable colorectal liver metastases). For six months, divided evenly between pre- and post-operative periods, the EPOC study recommended either FOLFOX or CAPOX (capecitabine plus oxaliplatin) as the standard regimens. By comparing these methods to surgery alone, progression-free survival was increased by 8% after three years. Molecularly targeted medicines have been a mixed bag so far [134]. In the New EPOC study, for example, it was discovered that combining FOLFOX with cetuximab, an anti-EGFR drug, surprisingly led to worse results in KRAS wild-type tumors, including higher rates of recurrence. Therefore, anti-VEFG therapies such as cetuximab or bevacizumab should not be administered during the perioperative period. The use of adjuvant chemotherapy to treat ICC and PHC after surgical resection is still in its early stages, although it is becoming more common and effective. In biliary tract malignancies, the randomized phase III BILCAP study found that capecitabine, when given for six months, enhanced three-year overall survival (63% vs. 53%, HR 0.81, p = 0.028) [135]. Capecitabine and gemcitabine-cisplatin are being compared in the ongoing ACTICCA-1 trial to determine the best adjuvant approach. Individuals exhibiting high-risk characteristics, like nodal illness or margin positive, may benefit from perioperative systemic treatments that incorporate molecularly targeted medications. Previous attempts to treat hepatocellular carcinoma (HCC) using a combination of systemic and locoregional therapy were unsuccessful. As an example, recurrence-free survival was not improved in adjuvant circumstances by the multikinase inhibitor sorafenib after liver resection or ablation [136]. Similarly, randomized trials which combined sorafenib with locoregional therapies such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) failed to show a substantial improvement in survival. But things have altered because of new immune checkpoint inhibitors. Phase III trials are currently investigating the use of anti-PD-1 drugs, such as nivolumab and pembrolizumab, as adjuvant therapy after surgery or ablation (e.g., NCT03383458, NCT03867084). When used in conjunction with locoregional therapy, these medicines have the potential to greatly decrease recurrence rates and increase overall survival, according to preliminary studies. There has been outstanding success in CRLM using conversion therapy, which tries to reduce tumor sizes to a point where curative surgery is possible [137]. Based on the treatment plan and individual patient factors, the rate of secondary resection might be anywhere from 26 to 70%. Folic acid, 5-fluorouracil, and irinotecan, or FOLFOX or FOLFIRI, in conjunction with anti-EGFR drugs such as cetuximab or panitumumab, is the most effective strategy for KRAS wild-type cancers. In 60–70% of cases, these regimens cause tumors to shrink completely or partially. When anti-EGFR drugs fail to shrink tumors with a KRAS or NRAS mutation, the gold standard treatment is chemotherapy plus bevacizumab, which results in a secondary resection rate of 30–40%. It is important to carefully limit the duration of preoperative chemotherapy, nevertheless [138]. The likelihood of perioperative problems, such as oxaliplatin-induced sinusoidal obstruction syndrome and irinotecan-associated steatohepatitis, increases when chemotherapy is administered for more than 12–16 weeks. Because molecular profiling allows for individualized approaches based on modifiable genetic variations, it has revolutionized the therapy landscape. As an example, combining BRAF and MEK inhibition can overcome resistance to anti-EGFR treatment; however, BRAF-V600E mutations are found in 5–10% of mCRC. In a similar vein, HER2/neu amplification predicts resistance to anti-EGFR medicines but responds well to HER2-directed treatments; it is observed in 3–5% of mCRC. Three to five percent of patients with stage IV colorectal cancer have tumors that are either mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H). These patients show remarkable sensitivity to immune checkpoint inhibitors, with sustained response rates that surpass fifty percent. Especially for difficult cases with bad prognoses, these findings are changing the game for perioperative and conversion therapy approaches [139, 140]. Additionally, targeted medicines are revolutionizing the way ICC is treated. Highly actionable targets include FGFR2 fusions (10–20% of ICC cases) and IDH1 mutations (15–20% of ICC cases). FGFR inhibitors are suitable for conversion therapy since they produce objective response rates of 35–40%. While IDH1 inhibitors do not cause tumors to shrink as much, they do provide long-term disease management, which makes them a good candidate for multimodal approaches. New targets are being studied as well, including dMMR/MSI-H subtypes and BRAF-V600E mutations; preliminary data suggests that targeted therapy enhance outcomes. To treat symptoms in functional tumors, systemic medications are mostly employed for neuroendocrine tumors (NETs) of the liver, a distinct subtype of NETs. In hormonally active NETs, somatostatin analogs such as lanreotide and octreotide successfully inhibit hormone release and forestall carcinoid crises [141]. In pancreatic NETs, peptide receptor radionuclide treatment (PRRT) using ~ 177Lu-DOTATATE has shown to be more effective than molecularly targeted medicines in obtaining response rates for non-functional or advanced NETs. An increasing number of curative perioperative techniques are considering PRRT, especially for instances that cannot be resected. Due to low response rates with standard therapy, unresectable HCC has historically been tough to manage. But now, in some patients, downstaging and conversion to resectability are possible thanks to new medication combinations. A phase Ib trial found that a total response rate of 36.7% was attained by combining pembrolizumab with lenvatinib, a multikinase inhibitor. Similarly, a phase III trial showed that the combination of atezolizumab (anti-PD-L1) with bevacizumab significantly improved overall survival, with a response rate of 27% [142]. As a new gold standard for conversion therapy in cases of unresectable HCC, these combinations show great promise. Unresectable cancers can be effectively down staged using locoregional therapies like SIRT and hepatic artery infusion chemotherapy (HAIC)[143, 144]. Secondary resection was possible in as many as half of the cases when HAIC with floxuridine had tumor control rates higher than 70% in CRLM. Similarly, SIRT has been shown to be effective in reducing the progression of ICC and HCC, however there is a lack of strong data from randomized trials. Patients whose cancer is either borderline or unresectable have important new treatment choices thanks to these medicines. Treatment techniques are being further refined with the help of biomarkers and innovative prognostic technologies. A non-invasive method for guiding perioperative therapy, tumor-derived cell-free DNA has recently become a strong predictor of recurrence risk in CRLM. As a potential biomarker for immunotherapy response, immune cell infiltration inside the tumor microenvironment is also being investigated; preliminary research suggests it may be able to predict treatment results and recurrence risk [145, 146]. The door is opening for more targeted and individualized methods of treating liver cancer thanks to these developments. Finally, when it comes to treating liver cancer, both resectable and nonresectable tumors can be effectively addressed with the use of chemotherapy and combination therapies. New therapeutic options, made possible by developments in immunotherapy, targeted treatments, and molecular profiling, have opened the door to curative solutions for situations that are getting more complicated [147]. The prognosis for patients with liver tumors will be transformed as these modalities continue to evolve and are integrated into multimodal methods, which will further improve results (Table 3).

Table 3.

Comprehensive comparison of chemotherapy and combination therapies in liver cancer management, detailing strategies, outcomes, and advancements across perioperative, conversion, and systemic treatment modalities

Parameter	Details	CRLM	HCC	ICC	PHC	NETs	Targeted therapies	Conversion therapy	Locoregional therapies	Challenges	Future directions	References
Standard regimens	Chemotherapy options for perioperative and adjuvant settings	FOLFOX, CAPOX	Sorafenib, Lenvatinib	Gemcitabine-cisplatin	Capecitabine	PRRT, Lanreotide	Anti-EGFR, VEGF inhibitors	FOLFOX/FOLFIRI + EGFR inhibitors	TACE, SIRT, HAIC	High toxicity in systemic therapies	Molecular profiling-based personalization	[148]
Outcomes (3-year survival)	Survival improvement with perioperative therapy	8% increase	Under evaluation	63% (Capecitabine)	60–70% (Neoadjuvant)	> 90% (Selected NETs)	27–36% response rates (Atezolizumab + Bevacizumab)	30–70% resection success rates	~ 70% tumor control rates	High recurrence rates in larger tumors	Novel biomarkers for better selection	[149]
Adjuvant Therapy effectiveness	Progression-free survival enhancement	Yes, proven	Limited	Emerging	Confirmed	Limited evidence	BRAF/MEK inhibitors for BRAF mutations	Conversion success rates depend on duration	Tumor necrosis achieved in 70–80% cases	Long-term effects uncertain	Integration with systemic approaches	[150]
Combination approaches	Integrated use of locoregional and systemic therapies	Chemotherapy + ablation	ICIs + TACE/SIRT	Conversion + systemic	Chemoradiation	Somatostatin analogs + PRRT	HER2-directed therapies for HER2 amplifications	Immune checkpoint inhibitors + chemotherapy	Ablation + chemotherapy	Increased perioperative complications	Immunotherapy combinations	[151]
Molecular subtypes	Predictive biomarkers for treatment selection	KRAS/NRAS mutations	PD-L1 expression	FGFR2, IDH1 mutations	Molecular profiles emerging	Ki-67 < 10% in NETs	Resistance observed in mutated subsets	High-response in MSI-H/dMMR subtypes	Biomarker-guided therapeutic choices	Limited data for certain targets	Expanded biomarker integration	[152]
Secondary resection rates	Conversion therapy to enable surgical removal	26–70%	36.7% (Lenvatinib + Pembrolizumab)	35–40% (FGFR2 fusions)	50–60% (Chemo + Neoadjuvant)	Rare	HER2/neu amplifications	> 50% success in certain populations	Limited for larger tumors	Tumor growth during chemotherapy	Acceleration of response for better outcomes	[153]
Progression-free survival (PFS)	Improved control of tumor progression	Extended ~ 12 months	Limited evidence	Improved with conversion	Comparable	Effective for functional NETs	High for anti-PD-L1 combinations	Time-dependent outcomes	Promising in resistant cases	Toxicity of multi-agent regimens	Safer multimodal strategies	[154]
Locoregional techniques	Integration of systemic and targeted methods	Ablation + chemotherapy	TACE, SIRT	SIRT	Chemoradiotherapy	Rare	Emerging for high-risk ICC cases	Tumor size reduction success	Effective for smaller lesions	Challenges in vascular structures	Real-time imaging for precision	[155, 156]
Toxicity rates	Safety and tolerability concerns in treatment regimens	10–20% perioperative complications	ICI-related toxicities	Chemo-limited hepatic issues	Manageable	Minimal	Manageable in advanced cases	Moderate to high	Cardiovascular risks in IRE	Higher in prolonged regimens	Safer delivery systems	[157]
5-Year Survival rates	Long-term efficacy of multimodal approaches	60–70%	27% (Atezolizumab + Bevacizumab)	50–60%	50–70%	> 90% (Selected)	Up to 80% in biomarker-selected cases	Improved in > 40% cases	Comparable to surgical resection	High variability by tumor type	Precision medicine focus	[158]
Emerging techniques	Innovations improving existing therapies	HAIC, Dual-blockade strategies	Immune checkpoint inhibitors	Conversion therapy emerging	Sequential embolization	PRRT	Combining ICIs with molecular targets	Novel systemic-regional integrations	Enhanced ablation accuracy	Limited patient access to new trials	Nanotechnology for localized delivery	[159–161]
Limitations	Barriers and ongoing challenges in implementation	Recurrence in larger CRLM	Low response in certain HCC	Slow conversion in advanced ICC	Strict criteria required	Low rates of systemic use	Cost and toxicity of new agents	Few randomized trials for strategies	Inconsistent data for advanced stages	High recurrence in advanced cases	Research gaps in resistant tumors	[162]

Immunotherapy for hepatic tumors

Hepatic cancers, particularly hepatocellular carcinoma (HCC), can now be effectively treated with immunotherapy, which harnesses the body's immune system to provide long-lasting anticancer effects. The recurrence incidence of HCC after resection is substantial, at 70% within five years and as high as 50% in the first two years [163]. However, there are promising adjuvant and neoadjuvant immunotherapeutic methods. Immune checkpoint inhibitors (ICIs) are leading the way in this development, especially those that target PD-1, PD-L1, and CTLA-4 (Fig. 3).

Fig. 3.

Hierarchical cancer immunological microenvironment (HCC) schematic. Specific immune response in HCC is mediated by the invasion of different subpopulations of immune cells, regulatory cytokines, and some inhibitory signals. A number of substances are produced by HCC tumor cells that inhibit the tumoricidal capacity of CTL and NK cells, including hypoxia, IDO, VEFG, IL-10, and TGF-β, IL-10, and inhibitory receptors NKG2 A. Furthermore, in order to entice TANs into the tumor stroma, HCC tumor cells release CXC chemokines, particularly CXCL8. B cell PD-1 signaling activation enhances IL-10 production, which in turn suppresses effector T cell anti-tumor immunity. The cytotoxicity of CTL and NK cells is impaired due to an increase in IL-10 secretion and a decrease in IL-6 and IL-12 secretion caused by the interaction between MDSCs and TAMs. Several cytokines, including VEFG, IL-β, and IL-6, which are produced by CAFs and HSCs, and VEFG and GM-CSF, which are produced by HCC tumor cells, promote the aggregation of MDSCs in the tumor stroma. By interacting with PD-L1 on KCs, which in turn interacts with PD-1 on T cells, MDSCs and KCs facilitate immune evasion. Inducing T cell apoptosis can be achieved by binding Galectin-9 on MDSCs to TIM-3 on T cells. By reducing the production of TNF-α and IFN-γ, Tregs can hinder CTL activation. They can also diminish the anti-tumor activity of NK cells by producing IL-2, IL-8, and TGF-β. In order to inhibit the antitumor response of CTL, DCs can mediate the synthesis of IL-10 and the decrease of IL-12. TAN stands for tumor-associated neutrophil; CAF for cancer-associated fibroblast; NK for natural killer cells; TAM for tumor-associated macrophage; MDSC for myeloid-derived suppressor cell; and CTL for cytotoxic T lymphocyte. The acronyms IDO, KC, DC, IL-10, NKG2 A, TGF-β, GM-CSF, and ICI stand for hepatic stellate cell, kupffer cell, dendritic cell, transforming growth factor β, interleukin-10, vascular endothelial growth factor, granulocyte–macrophage colony-stimulating factor, and immune checkpoint inhibitor, respectively [164]

Despite obstacles including variable trial performance, combination treatments are showing great promise for better results in advanced and adjuvant settings. Things like big tumor size, venous or microvascular invasion, and insufficient tumor capsule development are the main factors that determine whether a tumor will return after HCC resection. All of these things highlight how important adjuvant therapies are. There is a lack of information regarding post-resection care due to the phase III STORM trial's evaluation of sorafenib as an adjuvant treatment, which did not show a substantial benefit [165]. Nevertheless, a key factor in the likelihood of recurrence is the tumor immune microenvironment. Favorable results are linked to high densities of CD3+ and CD8+ T cells in the tumor and its margins, while aggressive behavior and increased recurrence are connected with high PD-L1 expression by tumor or immune cells. These results strongly support the need to investigate adjuvant immunotherapy for HCC. The efficacy of ICIs in adjuvant and neoadjuvant cancer treatment is being studied in ongoing trials. A number of phase III trials are currently evaluating the effectiveness of ICIs in preventing recurrence following curative resection or ablation. These trials include IMbrave 050 (atezolizumab with bevacizumab, NCT04102098) and KEYNOTE-937 (pembrolizumab, NCT03867084) [166]. Combining atezolizumab and bevacizumab appears to increase antitumor immune responses via blocking the PD-L1 and VEFG pathways, providing a dual effect that decreases the likelihood of recurrence, according to preliminary evidence. Results are expected to shed light on the utility of durvalumab paired with bevacizumab (EMERALD-2, NCT03847428) as an adjuvant strategy for recurrence prevention [167, 168].

Research on the efficacy of ICIs in neoadjuvant settings is focused on tumor shrinkage and secondary resectability. Research studies like PRIME-HCC (NCT03682226) are looking into neoadjuvant therapy combinations of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4). By increasing T-cell response activation and decreasing regulatory T-cell repression, this regimen has shown synergistic effects that increase tumor shrinking [169]. Overall response rates (ORRs) in early-phase trials were more than 30%, and some patients even achieved complete pathological responses (CPRs). Patients with potentially resectable HCC are also being studied for the efficacy of nivolumab in combination with cabozantinib, a multikinase inhibitor (NCT03299946). Immunotherapy for advanced HCC has encountered obstacles, despite promising initial outcomes [170]. Patients'reactions varied widely, as shown in the phase III trial of pembrolizumab in a second-line context (NCT02702401), which aimed to enhance overall survival (OS) compared to placebo but failed to do so. Similarly, in first-line treatment, nivolumab was not found to be better than sorafenib (NCT01658878) [171]. The necessity for combination techniques to improve efficacy is highlighted by these undesirable results. An example of this is the IMbrave150 study (NCT03434379), which established a new benchmark for first-line treatment in advanced HCC with its combination of atezolizumab and bevacizumab, which significantly improved overall survival (median 19.2 months vs. 13.4 months with sorafenib, HR 0.66, p < 0.001). Further investigation into combination medicines is being pursued in ongoing trials. Combinations of ICIs with other ICIs, locoregional treatments, or multikinase inhibitors are becoming more common in order to take advantage of their synergistic effects [172]. As an example, the CheckMate 040 trial found that a combination of nivolumab and ipilimumab produced long-lasting responses in patients with advanced HCC, with overall response rates (ORRs) of 33%. Furthermore, there is ongoing research into the possibility of boosting immune activation through combinations of ICIs with locoregional therapies like as TACE or SIRT. These therapies increase tumor antigen release, which could be further enhanced by checkpoint inhibition. These multimodal techniques are being tested in trials with the identifiers NCT03033446 and NCT02837029 [173]. Immunotherapy strategy refinement relies on emerging biomarkers[174]. A high PD-L1 expression is a predictor of responsiveness to ICIs, especially in combination regimens, and is linked to aggressive illness. Likewise, enhanced responses are correlated with tumor mutational burden (TMB) and infiltrating CD8 + T cell presence. Research into non-invasive liquid biopsy methods, such as circulating tumor DNA (ctDNA) analysis, is ongoing; these tools have the potential to further enable individualized treatment approaches by monitoring tumor dynamics and predicting recurrence risk [175]. One issue with immunotherapy is the possibility of immune-related adverse events (irAEs). Up to 10% of patients treated with anti-PD-1 or anti-PD-L1 drugs have liver toxicity, which is one of the inflammation-inducing effects of ICIs. Maintaining a balance between treatment efficacy and patient safety requires early diagnosis and management of irAEs. When treating irAEs of grade 2 or above, the guidelines suggest using corticosteroids first, and only in cases where other treatments have failed should immune-modulating drugs be considered [176]. To address the unfulfilled demand for curative treatments in HCC, neoadjuvant and adjuvant immunotherapies also show potential. For instance, nivolumab and ipilimumab are being evaluated as perioperative treatments in trials like NCT03222076 and NCT03510871 with the goals of improving OS and increasing resectability. Initial data suggests that these regimens have the potential to reduce tumor size in 20–40% of patients, opening up new avenues for surgical intervention. Immunotherapy is still in its early phases of investigation for different types of hepatic cancers, including intrahepatic cholangiocarcinoma (ICC) and metastatic colorectal cancer (mCRC) [177]. However, preliminary research suggests that ICIs could be useful for subgroups identified by genetic markers, such as cancers with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) characteristics. Further research in hepatic settings should focus on these malignancies because they show ORRs over 40% with PD-1 inhibitors like pembrolizumab [178].

Finally, immunotherapy is changing the game when it comes to treating liver malignancies, especially HCC. Despite ongoing issues like inconsistent trial results and immune-related toxicities, there is great potential in combination tactics, biomarker-guided therapy, and perioperative techniques [179]. As more and more data become available, immunotherapy has the potential to significantly impact liver cancer patients'chances of recurrence, resectability, and long-term survival (Table 4).

Table 4.

Comprehensive immunotherapy strategies for hepatic cancers, highlighting advances in adjuvant, neoadjuvant, and advanced-stage settings, combination approaches, biomarker innovations, and trial outcomes

Parameter	HCC adjuvant setting	HCC neoadjuvant setting	HCC advanced stage	Combination strategies	Emerging biomarkers	Adverse events (irAEs)	ICC applications	mCRC applications	Trials and evidence	Outcomes	Challenges	Future directions	References
Immunotherapy agents	Anti-PD-1 (pembrolizumab), anti-PD-L1 (atezolizumab), durvalumab	Nivolumab + ipilimumab, nivolumab + cabozantinib	Atezolizumab + bevacizumab, nivolumab, pembrolizumab	ICIs + locoregional therapies (TACE/SIRT), ICIs + multikinase inhibitors	High PD-L1 expression, tumor mutational burden (TMB), CD8 + T cells	Circulating tumor DNA (ctDNA), liquid biopsy methods	Corticosteroid-responsive liver toxicity	PD-L1 positive tumors	MSI-H/dMMR subsets	IMbrave050, KEYNOTE-937, CheckMate 040, IMbrave150	Improved OS (19.2 months with atezolizumab + bevacizumab)	Variable trial responses	[180]
Pathological response rates	~ 30% ORR in early-phase trials	~ 20–40% tumor size reduction, 10–20% complete pathological response	~ 33% ORR (nivolumab + ipilimumab), > 50% sustained responses	Combination ORR exceeds monotherapy rates	PD-L1 predicts higher responsiveness, TMB correlates with outcomes	Infiltrating CD8 + T cells linked to positive outcomes	Liver irAEs in ~ 10% patients, 2–5% severe reactions	Genetic markers under investigation	MSI-H shows ORR > 40% with ICIs	Enhanced secondary resectability in neoadjuvant setting	High toxicity in combination therapies	Development of robust biomarkers	[181]
Survival metrics	3-year recurrence reduction expected in trials	OS benefit in ongoing studies	Median OS: 19.2 months (IMbrave150)	Synergistic benefits in dual checkpoint blockade	Tumor immune microenvironment critical to outcomes	Tumor-derived DNA for recurrence risk monitoring	Grade 2 + irAEs require corticosteroids	Early data indicates promise	dMMR patients show significant survival improvements	Long-lasting responses; improved resectability	Immune heterogeneity impacts efficacy	Novel combination therapies for better safety profiles	[182]
Trial examples	IMbrave050, KEYNOTE-937	PRIME-HCC, CheckMate trials	IMbrave150 (Atezolizumab + Bevacizumab), Pembrolizumab trials	NCT02837029 (ICIs + SIRT), NCT03033446 (ICIs + TACE)	Ongoing studies in PD-L1 and TMB biomarkers	Research into ctDNA and other non-invasive biomarkers	Monitoring guidelines for irAEs emerging	Need randomized trials	Promising in subsets defined by MSI-H, dMMR	Evidence of reduced recurrence rates in early trials	Long-term follow-up data lacking	Integration of novel biomarkers with ICIs	[183]
Combination efficacy	Expected synergy with ICIs + bevacizumab	Synergistic effects seen with nivolumab + ipilimumab	Combination ORR (e.g., ICIs + multikinase inhibitors) > 30%	TACE/SIRT enhances antigen release for checkpoint inhibition	Biomarkers enable individualized treatment plans	Personalized approaches emerging	irAEs require early intervention	Potential role of ICIs	Ongoing combination trials (ICIs + chemotherapy)	Tumor control through immune checkpoint + local therapies	Drug-related toxicities add complexity	Address immune resistance mechanisms	[184, 185]
Tumor control	Improved local recurrence control	Higher rates of downstaging and secondary resectability	Superior tumor antigen release with TACE/SIRT	ICIs show durable control when paired with regional therapies	Favorable immune profiles linked to improved control	ctDNA for dynamic treatment adjustment	Toxicity management guidelines established	Potential downstaging through ICIs	Biomarker-based strategies in clinical trials	Enhanced antigen release enables better checkpoint outcomes	Limited for advanced cases	Improved delivery systems for ICIs	[186]
Challenges	Limited data for adjuvant settings	Variability in neoadjuvant responses	Heterogeneous trial outcomes with monotherapy	Balancing efficacy and toxicity	Lack of standard biomarkers for every patient	High false-negative rates in current liquid biopsies	Balancing immune control and liver safety	Variable results in ICC	Few MSI-H/dMMR patients for robust data	Translating early response rates into long-term survival	Significant irAEs in combination regimens	Building large-scale biomarker databases	[187]
Emerging approaches	Focus on perioperative ICIs	Combinations that increase OS, resectability	Refining first-line therapies	Focus on locoregional + ICIs for synergy	Multi-omics for predictive profiling	Liquid biopsies integrated into routine clinical settings	Integration with systemic therapies	Further ICC trials needed	Expanding eligibility for biomarker-defined groups	Combining ICIs with nanotechnology for better delivery	High trial dropout due to adverse events	Biomarker-driven patient stratification	[188, 189]

Clinical translation

There have been major successes and major setbacks in the hepatocellular carcinoma (HCC) clinical trial landscape. There have been several phase III trials that have not been able to repeat the success of the SHARP study, which made sorafenib the standard therapy. The intrinsic problems of treating advanced HCC, the difficulty of finding appropriate patient populations, and the complexity of planning effective studies are all highlighted by these setbacks [190]. The trial results provide important lessons that can be used to improve future medication development and patient outcomes by identifying areas that need modification. A lack of knowledge about HCC biology, prospective medications'weak antitumor activity, liver toxicity, and inefficient trial design are all reasons why several phase III trials failed. Sunitinib, for instance, had better results than sorafenib in a head-to-head phase III trial, even though it was effective in renal cell carcinoma. Sunitinib had a median overall survival (OS) of 7.9 months compared to sorafenib's 10.2 months (HR 1.30, p = 0.0014), and the study was terminated early because of toxicity concerns. Sunitinib had a considerably higher treatment-related fatality rate (3.2% vs.0.3%), highlighting the need for phase II trials to assess liver-specific toxicity [191]. One such example is linifanib, an inhibitor of both VEGFR and PDGFR that has shown encouraging results in preclinical studies. Linifanib did not achieve the non-inferiority criterion in a phase III study included 1,035 patients; sorafenib had an OS of 9.8 months and linifanib 9.1 months (HR1.04, 95% CI 0.89–1.22). Level 3–4 hypertension (20% vs. 10%) and liver-related problems (20% vs. 10%) were also shown to be more common with linifanib in the experiment. In a population with underlying cirrhosis, these data highlight the need of balancing potency with tolerability [192].

Another multikinase inhibitor that could not achieve non-inferiority in both first-line and second-line scenarios was brivanib, which targets the VEGFR and FGFR pathways. Median overall survival (OS) for brivanib was 9.5 months compared to 9.9 months for sorafenib in a phase III trial conducted in the first-line scenario (p = 0.3). Brivanib does not significantly improve overall survival compared to placebo in a phase III trial evaluating second-line treatment (OS: 9.4 vs. 8.2 months, p = 0.3). The difficulties in competing with sorafenib's proven effectiveness while dealing with the diverse and ever-changing character of HCC may be reflected in these failures [193]. There has also been little success with trials of erlotinib and other EGFR inhibitors. Median overall survival (OS) was 9.5 months for the sorafenib/erlotinib group and 8.5 months for the sorafenib group, respectively; no statistically significant difference was seen between the two groups in the SEARCH study. Adding erlotinib shortened the median treatment duration from four months to three months and increased cumulative toxicity. Findings like this show how dangerous combo regimens can be and how ineffective EGFR-targeted treatments are [194]. There have been substantial challenges in the studies of adjuvant therapy as well. Patients who had undergone resection or ablation were part of the STORM trial, which aimed to assess sorafenib in an adjuvant context to decrease recurrence. The experiment did not show a substantial improvement in recurrence-free survival, despite enrolling 1114 participants. One possible reason sorafenib didn't work was because it couldn't stop the development of new liver cancers or slow down the spread of micrometastatic illness. According to these results, adjuvant methods that work in advanced disease must target different biological processes [195].

The significance of meticulous trial design has emerged as a recurrent theme in these trials. To ensure balanced comparison groups, stratification by portal invasion, metastasis, and disease progression type is crucial. In addition, OS, the benchmark for effectiveness in HCC trials, seldom correlates with endpoints like time-to-progression (TTP) and objective response rate (ORR). Overall survival is still the most reliable endpoint, even though modified response criteria like mRECIST have been used to evaluate tumor response in HCC. The use of biomarkers into the design of trials is another critical area that needs development. Despite indications that distinct molecular subtypes of HCC respond differently to targeted therapy, none of the failed trials included biomarker-based patient selection [196]. In the SHARP trial, for example, biomarker analysis suggested that low HGF levels and high c-KIT levels would reflect sorafenib's beneficial effects; however, these results were not confirmed. Trials utilizing biomarker-enrichment techniques, such as refametinib in RAS-mutant HCC (NCT01915602) and tivantinib in high-MET-expressing tumors (NCT01755767), show promise for future studies. Time and again, the difficulties of treating liver-specific toxicity have been brought to light. The IGF-1R inhibitor cixutumumab, for instance, was linked to hyponatremia in 25% of patients and grade 3–4 hyperglycemia in 46% of patients in a phase II study. We need phase II trials that focus on liver-related safety profiles since these toxicities could mask the anticancer advantages of potential drugs [197]. One potential way to tackle these difficulties is by using combination methods. As an illustration, the IMbrave150 study demonstrated that atezolizumab plus bevacizumab was more effective than sorafenib in enhancing overall survival (19.2 vs. 13.4 months, HR 0.58, p < 0.001). The necessity of addressing immunological checkpoints and the tumor microenvironment was demonstrated by this trial's positive results. To improve effectiveness while reducing resistance, future trials should keep investigating combo regimens [198–200]. Last but not least, research in this area should center on developing high-throughput biomarkers through the examination of tissues. Tumor plasticity and escape mechanisms are two of the components that contribute to HCC's heterogeneity, which in turn calls for tailored treatment plans. To maximize the use of resources and the quality of results, it is possible to conduct companion diagnostic studies and use stratified trial designs to determine which patient subgroups might benefit most from certain treatments. Finally, it is crucial to conduct safety evaluations tailored to the liver, use biomarkers to select patients, and use a rigorous trial design, as shown in HCC clinical trials. Even if a lot of trials didn't reach their main goals, they still gave us great information that can help with HCC treatments in the future [201]. Researchers are well-positioned to make significant strides in the treatment of this difficult disease as molecular profiling, novel trial designs, and combination medicines are integrated (Table 5).

Table 5.

Key insights and outcomes from HCC clinical trials, highlighting successes, failures, and lessons for future study designs

Trial/study	Drug(s)/regimen	Mechanism of action	Phase	Primary endpoint	Median OS (months)	HR	Significance (p-value)	Key challenges	Toxicity profile	Biomarker insights	Combination potential	Trial design insights	Key takeaways	References
SHARP	Sorafenib	Multikinase inhibitor (VEGFR, PDGFR)	III	OS	10.7 vs. 7.9 (placebo)	0.69	< 0.001	First successful phase III trial	Hand-foot syndrome, fatigue	High c-KIT, low HGF linked to positive outcomes	Established as standard-of-care	Stratification crucial for meaningful subgroup analysis	Demonstrated the feasibility of OS as a robust endpoint	[202]
Sunitinib versus sorafenib	Sunitinib	Multikinase inhibitor	III	OS	7.9 vs. 10.2 (sorafenib)	1.30	0.0014	High fatality rate with sunitinib (3.2% vs. 0.3%)	Grade 3–4 hypertension, liver toxicity	No biomarker-based patient selection	None identified	Insufficient phase II safety data on liver-specific toxicity	Emphasized tolerability and balanced trial arms	[203]
Linifanib	Linifanib	VEGFR, PDGFR inhibitor	III	Non-inferiority (OS)	9.1 vs. 9.8 (sorafenib)	1.04	0.3	Higher toxicity (hypertension 20% vs. 10%)	Grade 3–4 liver-related events in 20%	Biomarker-based enrichment absent	Potential for combinatorial trials	Lack of adaptive endpoints	Highlighted importance of balancing efficacy with safety	[204]
Brivanib (first-line)	Brivanib	VEGFR, FGFR inhibitor	III	OS	9.5 vs. 9.9 (sorafenib)	NS	0.3	Non-inferiority not achieved	Fatigue, liver-related events	Inadequate stratification for molecular subtypes	Limited utility as monotherapy	High dropout rates	Underlined complexity of targeting angiogenesis pathways	[205]
Brivanib (second-line)	Brivanib	VEGFR, FGFR inhibitor	III	OS	9.4 vs. 8.2 (placebo)	NS	0.3	Poor patient selection (less aggressive HCC in placebo group)	Tolerable overall	No biomarker-driven selection	Promising as part of combinations	Poor correlation between TTP and OS	Validated the need for enriched trials	[206]
SEARCH	Sorafenib + Erlotinib	VEGFR, EGFR inhibitor	III	OS	9.5 vs. 8.5	NS	NS	Increased cumulative toxicity with combination therapy	Shortened treatment duration (4 vs. 3 months)	EGFR not a strong target in HCC	None identified	Higher toxicity without added benefit	Showcased risks of unvalidated combinations	[207]
STORM	Sorafenib (adjuvant)	Multikinase inhibitor	III	Recurrence-free survival (RFS)	No significant benefit	NA	NA	Failed to prevent recurrence or new tumor formation	Consistent with sorafenib safety profile	Inability to target micrometastatic disease	None identified	Need for alternative adjuvant approaches	Highlighted challenges of translating systemic therapy	[208]
IMbrave150	Atezolizumab + Bevacizumab	PD-L1 + VEGF inhibition	III	OS	19.2 vs. 13.4 (sorafenib)	0.58	< 0.001	Marked improvement in OS with combination therapy	Hypertension, proteinuria	PD-L1 expression predictive of response	Set new standard for first-line treatment	Combination trials require safety monitoring	Validated dual pathway targeting	[209]
Tivantinib	Tivantinib	MET inhibitor	III	OS	Ongoing	NA	NA	Biomarker-enrichment for MET-positive tumors needed	Tolerable overall	MET-positive tumors showed promise	Promising for biomarker-defined subgroups	Enrichment needed for MET expression	Underlined importance of molecular stratification	[210]
Refametinib	Refametinib	MEK inhibitor	II	ORR	Ongoing	NA	NA	Need for RAS mutation stratification	Well-tolerated	RAS mutations may predict response	Promising for molecularly targeted approaches	Evidence for personalized trials	Importance of biomarker-guided therapy design	[211]
CheckMate 040	Nivolumab (anti-PD-1)	Immune checkpoint inhibition	I/II	ORR	ORR: ~ 20%	NA	NA	Variable responses, need for predictive biomarkers	Immune-related adverse events	Tumor immune microenvironment critical	Combinations with ipilimumab promising	Challenges in understanding immune resistance	Demonstrated checkpoint inhibitors'role in HCC treatment	[212]

Challenges and future perspectives

New developments in precision medicine, systemic treatments, and surgical procedures are fast changing the face of cancer treatment for the liver. Even though we've come a long way, there are still obstacles that need constant improvement in treatment methods and individualized approaches to healthcare. The evolution of technology, the identification of biomarkers, the development of combination medicines, and the results of translational research all interact to form these difficulties and the potential future paths for the treatment of liver cancer. Hepatocellular carcinoma (HCC) is characterized by great variability in both its genetic causes and the way it manifests in individual patients, which makes disease management very difficult [213]. Although sorafenib and lenvatinib, two current systemic treatments, have increased survival rates overall, they are only partially effective in some populations. In clinical studies, median overall survival remained low at 10.7 months, even though sorafenib enhances survival by about three months. This underscores the necessity for medicines that are tailored to individual tumor biology and patient characteristics. The IMbrave150 trial demonstrated that immune checkpoint inhibitors (ICIs) such atezolizumab and bevacizumab achieved median overall survival rates of 19.2 months, establishing immunotherapy as a game-changing method for HCC [214]. The response rates to immunotherapy vary greatly, though, and it only helps some individuals. Only around 20–30% of individuals get long-term improvements from treatment, meaning that many more are resistant. There is an immediate need for immunological biomarkers since studies like CheckMate 040 and CheckMate 459 failed to find a connection between PD-L1 expression and response rates. Managing toxicity is still a major challenge, particularly for individuals who have cirrhosis. Although there is an increase in efficacy, the probability of immune-related adverse events (irAEs) is higher when the CTLA-4 and PD-1/PD-L1 pathways are both blocked at once. Grade 3–4 toxicities are more common when nivolumab and ipilimumab are used together, necessitating careful monitoring and the knowledge of hepatologists. Similarly, ICIs increase the risk of toxicities when combined with anti-VEFG treatments or tyrosine kinase inhibitors (TKIs), hence patient selection and classification are crucial [215, 216].

Precision targeting and less systemic toxicity are two benefits of nanotechnology that are transforming the delivery of drugs for liver cancer. In one study, researchers found that luminous core–shell nanoparticles could specifically target HepG2 cells, resulting in an 85% reduction in medication dosage and a 15% improvement in tumor inhibition. Using just 7% of the normal dose, another study shown that animals with tumors were significantly inhibited by docetaxel-loaded mesoporous silica nanoparticles [217–220]. These results demonstrate the therapeutic index optimization and side effect reduction capabilities of nanotechnology. One potential way to tackle resistance and increase effectiveness is through combination therapy. Synergistic effects were observed in lipid nanoparticles co-delivering doxorubicin and curcumin, which included prolonged drug release (lasting 48 h), increased apoptosis, and decreased cytotoxicity in normal liver cells. More encouraging news comes from clinical trials investigating the effects of NBTXR3 nanoparticles activated by SBRT [221]. Preliminary findings point to safety, anti-tumor activity, and the absence of dose-limiting toxicity. Incorporating biomarkers into treatment decision-making should be a top priority for future research. While biomarkers like cell-free DNA, miRNAs, and circulating tumor DNA have demonstrated promise in predicting therapy response and monitoring disease progression, they are still not utilized routinely in clinical practice. A start towards biomarker-enriched study designs has been made by trials such as those studying MET expression in tivantinib or RAS mutations in refametinib, but further validation is needed. As a tool for finding therapeutically relevant mutations and creating personalized treatments, molecular profiling is playing an increasingly important role. One example of a drug that shows promise for precision oncology is an inhibitor of FGFR for ICCs with changed FGFR2 or IDH1 for ICCs with modified IDH1. Molecular stratification is crucial in clinical trials, as these medicines reach response rates of 30–40% in subgroups characterized by biomarkers [222]. Recent developments like SBRT and radiation-enhanced nanoparticles have revived radiotherapy, which has been underused in HCC in the past. Recent developments, such as NBTXR3 nanoparticles, have great potential for improving radiation effects while protecting normal tissues, and SBRT has shown local tumor control rates surpassing 80% in specific trials. The foundation of treatment must continue to be patient-centric care. Thorough conversations with patients and their families are necessary due to the complicated and frequently lengthy nature of liver cancer treatments. The possible for lifelong monitoring and interventions, as well as the hazards and long-term effects of therapies, should be covered in these conversations. Optimal treatment sequencing is going to be critical when combination medicines and tailored approaches become the norm. One way to achieve this goal would be to optimize the sequence of locoregional treatments, ICIs, and TKIs so that they have the most impact with the least amount of side effects. We can anticipate useful direction from ongoing trials that examine combination regimens, such as ICIs with anti-VEFG drugs or SBRT. There are possibilities to improve combination regimens through nanotechnology as well. In order to restore tumor suppressor activity and improve liver health, lipid-based nanoparticles targeting the CCAAT/enhancer binding protein alpha (CEBPA) gene have demonstrated promise. These nanoparticles may supplement current systemic therapy [223]. The dual difficulty of treating cancer and protecting liver function could be tackled by such developments. Finally, precision, innovation, and complexity are defining a new era in liver cancer management. Nanotechnology, immunotherapy, and systemic medicines are improving results but creating new obstacles in patient classification, biomarker integration, and toxicity management. Realizing the full potential of these developments requires collaboration among researchers, physicians, and patients. The goal of developing targeted treatments that can cure liver cancer is moving closer with every new dollar spent on clinical trials and translational research [224, 225].

Conclusion

Notable progress in hepatic tumor treatment has been realized through surgical advances, targeted systemic medicines, and the development of nanotechnology-based drug delivery systems. Minimally invasive methods, including laparoscopic and robotic-assisted hepatectomies, have enhanced surgical results, whilst immunotherapy and targeted medicines have introduced novel therapeutic options, especially for advanced hepatocellular carcinoma (HCC). Moreover, nanotechnology and innovative drug delivery methods have demonstrated promise in improving treatment accuracy and reducing systemic toxicity. Notwithstanding these advancements, significant obstacles persist, such as late-stage diagnosis, treatment resistance, post-therapy recurrence, and inequities in access to modern treatments. The intricacy of hepatic malignancies, influenced by tumor heterogeneity and the tumor microenvironment, persists in restricting the long-term effectiveness of existing therapies. Furthermore, the elevated expenses and infrastructural demands linked to contemporary treatments provide obstacles, especially in resource-constrained environments. Future research should concentrate on the integration of personalized medicine, biomarker-driven medicines, and interdisciplinary treatment strategies to enhance patient outcomes. Progress in precision medicine, including molecular profiling and tailored immunotherapy, offers potential for improving treatment effectiveness and reducing side effects. Furthermore, initiatives to enhance worldwide access to advanced medicines and early detection methods will be essential in decreasing liver cancer mortality. By tackling these issues through new research and collaborative clinical initiatives, the field can progress towards more effective, accessible, and patient-centered care of hepatic tumors.

Abbreviations

HCC

Hepatocellular Carcinoma

ICC

Intrahepatic Cholangiocarcinoma

CRLM

Colorectal Liver Metastases

PHC

Perihilar Cholangiocarcinoma

NETs

Neuroendocrine Tumors

PVE

Portal Vein Embolization

ALPPS

Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy

TACE

Transarterial Chemoembolization

MWA

Microwave Ablation

RFA

Radiofrequency Ablation

IRE

Irreversible Electroporation

SBRT

Stereotactic Body Radiation Therapy

FLR

Future Liver Remnant

CTLA-4

Cytotoxic T-Lymphocyte Associated Protein 4

PD-1

Programmed Cell Death Protein 1

PD-L1

Programmed Death-Ligand 1

TMB

Tumor Mutational Burden

OS

Overall Survival

PFS

Progression-Free Survival

ICIs

Immune Checkpoint Inhibitors

Author contributions

Shayan Sadrinasab: Conceptualization, Methodology, Data curation, Writing—review & editing; Sadaf Saket: Investigation, Formal analysis, Writing—original draft, Writing—review & editing; Nadia Pourmohammadi: Data curation, Visualization, Writing—original draft, Writing—review & editing; Fatemeh Khosravi: Validation, Formal analysis, Writing—review & editing; Masoud Saadat Fakhr: Supervision, Project administration, Conceptualization, Writing—review & editing.

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Data availability 

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.