Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a high mortality neoplasm which usually appears on a cirrhotic liver.The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis.Notwithstanding the current deployment of treatments with curative intent(liver resection/local ablation and liver transplantation)in early and intermediate stages,a high rate of HCC recurrence persists,underscoring a pivotal clinical challenge.Emergent systemic therapies(ST),particularly immunotherapy,have demonstrate promising outcomes in terms of increase overall survival,but they are currently bound to the advanced stage of HCC.This review provides a comprehensive analysis of the literature,encompassing studies up to March 10,2024,evaluating the impact of novel ST in the early and intermediate HCC stages,specially focusing on the findings of neoadjuvant and adjuvant regimens,aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent.We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent.Finally,we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Selection of first-line systemic therapies for advanced hepatocellular carcinoma:A network meta-analysis of randomized controlled trials

BACKGROUND The majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma(HCC)used placebo or sorafenib as comparators,and there are limited data providing a cross comparison of treatments in this setting,especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.AIM To systematically review and compare response rates,survival outcomes,and safety of first-line systemic therapies for advanced hepatocellular carcinoma.METHODS We searched PubMed,Science Direct,the Cochrane Database,Excerpta Medica Database,and abstracts from the American Society of Clinical Oncology 2020 annual congress.Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC.Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials.A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments.P value,a frequentist analog to the surface under the cumulative ranking curve,was used to rank treatments.RESULTS In total,1398 articles were screened and 27 included.Treatments compared were atezolizumab plus bevacizumab,brivanib,donafenib,dovitinib,FOLFOX4,lenvatinib,linifanib,nintedanib,nivolumab,sorafenib,sunitinib,vandetanib,11 sorafenib combination therapies,and three other combination therapies.For overall response rate,lenvatinib ranked 1/19,followed by atezolizumab plus bevacizumab and nivolumab.For progression-free survival(PFS),atezolizumab+bevacizumab was ranked 1/15,followed by lenvatinib.With the exception of atezolizumab+bevacizumab[hazard ratios(HR)PFS=0.90;95%confidence interval(CI):0.64-1.25],the estimated HRs for PFS for all included treatments vs lenvatinib were>1;however,the associated 95%CI passed through unity for bevacizumab plus erlotinib,linifanib,and FOLFOX4.For overall survival,atezolizumab plus bevacizumab was ranked 1/25,followed by vandetanib 100 mg/d and donafinib,with lenvatinib ranked 6/25.Atezolizumab+bevacizumab was associated with a lower risk of death vs lenvatinib(HRos=0.63;95%CI:0.44-0.89),while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity.Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13,respectively,for the lowest incidence of treatment terminations due to adverse events,followed by sorafenib(5/13),lenvatinib(10/13),and atezolizumab+bevacizumab(13/13).CONCLUSION There is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements.Therefore,first-line systemic treatment should be selected based on individualized treatment goals.

Systemic oncological therapy in breast cancer patients on dialysis

The advancement of renal replacement therapy has significantly enhanced the survival rates of patients with end-stage renal disease(ESRD)over time.How-ever,this prolonged survival has also been associated with a higher likelihood of cancer diagnoses among these patients including breast cancer.Breast cancer treatment typically involves surgery,radiation,and systemic therapies,with ap-proaches tailored to cancer type,stage,and patient preferences.However,renal replacement therapy complicates systemic therapy due to altered drug clearance and the necessity for dialysis sessions.This review emphasizes the need for opti-mized dosing and administration strategies for systemic breast cancer treatments in dialysis patients,aiming to ensure both efficacy and safety.Additionally,ch-allenges in breast cancer screening and diagnosis in this population,including soft-tissue calcifications,are highlighted.

Optimizing care for gastric cancer with overt bleeding:Is systemic therapy a valid option?

Gastric cancer(GC)and gastroesophageal junction cancer(GEJC)represent a significant burden globally,with complications such as overt bleeding(OB)further exacerbating patient outcomes.A recent study by Yao et al evaluated the effectiveness and safety of systematic treatment in GC/GEJC patients presenting with OB.Using propensity score matching,the study balanced the comparison groups to investigate overall survival and treatment-related adverse events.The study's findings emphasize that systematic therapy can be safe and effective and contribute to the ongoing debate about the management of advanced GC/GEJC with OB,highlighting the complexities of treatment decisions in these high-risk patients.

Re-evaluating the role of pelvic radiation in the age of modern precision medicine and systemic therapy

The efficacy of pelvic radiation in the management of locally advanced stage rectal cancer has come under scrutiny in the context of modern precision medicine and systemic therapy as evidenced by recent clinical trials such as FOWARC(J Clin Oncol 2019;37:3223-3233),NCT04165772(N Engl J Med 2022;386:2363-2376),and PROSPECT(N Engl J Med 2023;389:322-334).In this review,we comprehensively assess these pivotal trials and offer additional insights into the evolving role of pelvic radiation in contemporary oncology.

Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

Systemic treatment of hepatocellular carcinoma secondary to nonalcoholic fatty liver disease

Hepatocellular carcinoma(HCC)is the third leading cause of cancer death globally,with 15%of cases arising on a background of non-alcoholic fatty liver disease(NAFLD).NAFLD is a heterogenous condition ranging from fatty liver to cirrhosis and is itself a growing global problem,with estimated worldwide prevalence of 50%in 2040.Pathophysiology of NAFLD-HCC is not well understood,there are no dedicated screening programs,and there have been no clinical studies of anticancer treatments in this population specifically.However,the NAFLD-HCC population appears different than other aetiologies-patients tend to be older,diagnosed at more advanced stages,have more comorbidities,and overall worse prognosis.Understanding of best treatment options for this group of patients is an urgent unmet clinical need.This narrative review discusses NAFLD-HCC pathophysiology and systemic treatment,and offers suggestions for future directions in this therapy area.

Is there still a role for the hepatic locoregional treatment of metastatic neuroendocrine tumors in the era of systemic targeted therapies?

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs) frequently present with distant metastases at the time of diagnosis and the liver is the most frequent site of spreading. The early identification of metastatic disease represents a major prognostic factor for GEP-NENs patients. Radical surgical resection, which is feasible for a minority of patients, is considered the only curative option, while the best management for patients with unresectable liver metastases is still being debated. In the last few years, a number of locoregional and systemic treatments has become available for GEP-NEN patients metastatic to the liver. However, to date only a few prospective studies have compared those therapies and the optimal management option is based on clinical judgement. Additionally, locoregional treatments appear feasible and safe for disease control for patients with limited liver involvement and effective in symptoms control for patients with diffuse liver metastases. Considering the lack of randomized controlled trials comparing the locoregional treatments of liver metastatic NEN patients, clinical judgment remains key to set the most appropriate therapeutic pathway. Prospective data may ultimately lead to more personalized and optimized treatments. The present review analyzes all the locoregional therapy modalities(i.e., surgery, ablative treatments and transarterial approach) and aims to provide clinicians with a useful algorithm to best treat GEP-NEN patients metastatic to the liver.

Management of bone metastases in renal cell carcinoma: bone-targeted treatments, systemic therapies, and radiotherapy

Metastatic renal cell carcinoma(mRCC)presents with bone metastases in around 20%-30%of patients enrolled in the most recent first-line clinical trials.Emergence of several new agents in first line,in both monotherapy and combination,has significantly improved patient outcomes.However,the activity of such agents on bone metastases is unclear and management of these patients is complex,due to potential complications that can significantly impair quality of life.This review addresses mRCC diagnosis and monitoring and summarizes the current evidence on systemic therapy,ablative therapies such as stereotactic ablative radiotherapy and surgery,and supportive therapy with bone-targeting agents for these patients,with the goal of improving their outcomes.

Combining local regional therapy and systemic therapy:Expected changes in the treatment landscape of recurrent hepatocellular carcinoma

Improvements in early screening,new diagnostic techniques,and surgical treatment have led to continuous downward trends in hepatocellular carcinoma(HCC)morbidity and mortality rates.However,high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC.The clinical characteristics and prognosis of recurrent HCC are heterogeneous,and guidelines on treatment strategies for recurrent HCC are lacking.Therapies such as surgical resection,radiofrequency ablation,and transhepatic arterial chemoembolization are effective for tumors confined to the liver,and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis.With the deepening of the understanding of the immune microenvironment of HCC,blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC.In addition,improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment.Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC.This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment,demonstrates the basis for combining local treatment and systemic treatment,and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.

Clinical and pathological portraits of axillary presentation breast cancer and effects of preoperative systemic therapy

There is a lack of investigation into the biological characteristics and preoperative systemic therapy （PST） for occult breast cancer （OBC）. For this study, departmental records in Breast Disease Center of Peking University First Hospital from January 2008 to December 2015 were retrospectively reviewed to identify cases of OBC. Eleven cases were included, and all patients were female, with a median age of 56 （range： 29-75） years. The sensitivity of magnetic resonance imaging （MRD was I00%, and the false positive rate was 33.3%. Based on histologic analysis of the axillary node, 9 （81.8%） cases were grade 3, and 2 （18.2%） cases were grade 2; 4 （36.4%） cases were 〉10% estrogen receptor （ER） positive and 6 （54.5%） human epidermal growth receptor 2 （HER2） positive. Nine cases （81.8%） exhibited over 30% Ki67 expression. PST was performed in 5 of the 11 cases. The lymph node response rate was 100% （5/5）, but no complete remission was achieved. In conclusion, aggressive subtypes were predominant among the included cases, and PST should be considered for OBC treatment options.

Combination approaches in hepatocellular carcinoma:How systemic treatment can benefit candidates to locoregional modalities

The management of hepatocellular carcinoma(HCC)is challenging because most patients have underlying cirrhosis,and the treatment provides,historically,a limited impact on the natural history of patients with advanced-stage disease.Additionally,recurrence rates are high for those patients who receive local and locoregional modalities,such as surgical(resection and transplantation)or imageguided(ablation and intra-arterial)therapies.Translational research has led to new concepts that are reshaping the current clinical practice.Substantial advancements were achieved in the understanding of the hallmarks that drive hepatocarcinogenesis.This has primed a successful incorporation of novel agents with different targets,such as anti-angiogenic drugs,targeted-therapies,and immune-checkpoint inhibitors.Although clinical trials have proven efficacy of systemic agents in advanced stage disease,there is no conclusive evidence to support their use in combination with loco-regional therapy.While novel local modalities are being incorporated(e.g.,radioembolization,microwave ablation,and irreversible electroporation),emerging data indicate that locoregional treatments may induce tumor microenvironment changes,such as hyperexpression of growth factors,release of tumor antigens,infiltration of cytotoxic lymphocytes,and modulation of adaptative and innate immune response.Past trials that evaluated the use of antiangiogenic drugs in the adjuvant setting after ablation or chemoembolization fail to demonstrate a substantial improvement.Current efforts are directed to investigate the role of immunotherapy-based regimens in this context.The present review aims to describe the current landscape of systemic and locoregional treatments for HCC,present evidence to support combination approaches,and address future perspectives.

Treatment Patterns and Economic Assessment of Systemic Therapy for Metastatic Colorectal Cancer

Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer deaths in the United States. The goal of this study was to understand treatment patterns, biomarker testing practices, treatment adherence, and the clinical and economic outcomes associated with chemotherapy for metastatic disease. Methods and Materials: We retrospectively examined electronic health records of patients with metastatic CRC who initiated chemotherapy between 01 January 2007 and 30 June 2011, with follow-up to 30 June 2012. Parameters analyzed included demographics and clinical characteristics, treatment patterns, clinical outcomes, and health care resource utilization. Results: In the analysis, 756 patients were included;median age was 61 years (55% male) at start of first line therapy. The most commonly used regimens in the first, second, and third line were FOLFOX + bevacizumab (46%), FOLFIRI + bevacizumab (23%), and irinotecan + cetuximab (23%) respectively. Adherence to guidelines decreased with increasing line of therapy. When assessed by treatment backbone categories in the third line, outcome measures including overall survival (OS), and time to treatment discontinuation (TTD) were not statistically different between groups. In the multivariable model, body mass index (BMI), performance status, and KRAS were significant predictors of survival. Conclusions: This study provides insight into patterns of care and outcomes of mCRC patients for the aforementioned time period. As treatment options for mCRC evolve, it is valuable to understand the continuum of care to help inform future treatment among candidates for continued therapy.

Past,present and future of primary systemic treatment in breast cancer

Primary systemic treatment is a fundamental part of breast cancer therapy, and it is applied to non-surgical and locally advanced tumours as well as surgical tumours to increase the likelihood of conservative treatment. Its aim is to achieve the best possible survival with better cosmetic results and with the lowest number of treatment-related secondary effects. Before treatment is started, it is necessary to attain the best knowledge of the biological features and locoregional extension of the tumour. To do so, it is necessary to obtain a biopsy of the lesion with a wide bore needle,as well as good radiological knowledge of the disease.Therefore, currently, the use of a dynamic magnetic resonance imaging(MRI) of the breast should be included in all cases. In addition, before it is started,especially in those tumours in which conservative treatment is considered, one or several radiopaque markers should be put into place to make it possible to locate the area to be treated if there is a considerable or complete response. Systemic treatment is mainly based on combined chemotherapy with anthracyclins and taxanes, in addition to some biological agents with demonstrated efficiency for increasing the likelihood of complete disease response(trastuzumab in patients with Her-2/neu overexpression). However, there is room for neoadjuvant hormone treatment, in patients with hormone receptor overexpression, especially in those cases in which chemotherapy is contraindicated as well as in elderly patients with a relatively short life expectancy. The assessment of preoperative treatment should be based on adequate radiological tests, and nowad these should include MRI before taking decisions about adequate surgical treatment. The objective of primary treatment is to be able to increase survival and improve the chances of local treatment in the case of locally advanced treatment, achieving results that are at least equal to those of adjuvant treatment in the case of surgical tumours, but with greater chances of conservative surgery. Although the objective is survival, achieving complete pathological response seems to be a reasonable related objective, although these are more closely linked in some tumour subtypes.

Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is one of the most lethal malignant tumours worldwide.The mortality-to-incidence ratio is up to 91.6%in many countries,representing the third leading cause of cancer-related deaths.Systemic drugs,including the multikinase inhibitors sorafenib and lenvatinib,are first-line drugs used in HCC treatment.Unfortunately,these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance.Thus,novel pharmacological alternatives are urgently needed.For instance,immune checkpoint inhibitors have provided new approaches targeting cells of the immune system.Furthermore,monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients.In addition,drug combinations,including first-line treatment and immunotherapy,as well as drug repurposing,are promising novel therapeutic alternatives.Here,we review the current and novel pharmacological approaches to fight HCC.Preclinical studies,as well as approved and ongoing clinical trials for liver cancer treatment,are discussed.The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.

Systematic sequential therapy for ex vivo liver resection and autotransplantation: A case report and review of literature

BACKGROUND Perihilar cholangiocarcinoma(pCCA)is a highly malignant tumor arising from the biliary tree.Radical surgery is the only treatment offering a chance of long-term survival.However,limited by the tumor’s anatomic location and peri-vascular invasion,most patients lose the chance for curative treatment.Therefore,more methods to increase the resectability of tumors as well as to improve outcomes are needed.CASE SUMMARY A 68-year-old female patient had a hepatic hilar mass without obvious symptoms.Laboratory results showed hepatitis B positivity.Magnetic resonance imaging indicated that the mass(maximum diameter:41 mm)invaded the left and right branches of the main portal vein,as well as the middle,left and right hepatic veins;enlarged lymph nodes were also detected in the hilum.The patient was diagnosed with pCCA,and the clinical stage was determined to be T4N1M0(stage IIIC).Considering the tumor’s anatomic location and vascular invasion,systematic conversion therapy followed by ex vivo liver resection and autotrans-plantation(ELRA)was determined as personalized treatment for this patient.Our original systemic sequential therapeutic strategy(lenvatinib and tislelizumab in combination with gemcitabine and cisplatin)was successfully adopted as conversion therapy because she achieved partial response after three cycles of treatment,without severe toxicity.ELRA,anastomotic reconstruction of the middle hepatic vein,right hepatic vein,root of portal vein,inferior vena cava and right hepatic artery,and lymph node dissection were performed at one month after systemic therapy.Pathological and immunohistochemical examination confirmed the diagnosis of pCCA with lymph node metastasis.Although the middle hepatic vein was partially obstructed four months later,hepatic vein stent implantation successfully addressed this problem.The patient has survived for 22 mo after the diagnosis,with no evidence of recurrence or metastasis.CONCLUSION An effective therapeutic strategy for conversion therapy greatly increases the feasibility and efficiency of ELRA.

Cohort study to assess geographical variation in cholangiocarcinoma treatment in England

BACKGROUND Outcomes for cholangiocarcinoma(CCA)are extremely poor owing to the complexities in diagnosing and managing a rare disease with heterogenous sub-types.Beyond curative surgery,which is only an option for a minority of patients diagnosed at an early stage,few systemic therapy options are currently recommended to relieve symptoms and prolong life.Stent insertion to manage disease complications requires highly specialised expertise.Evidence is lacking as to how CCA patients are managed in a real-world setting and whether there is any variation in treatments received by CCA patients.AIM To assess geographic variation in treatments received amongst CCA patients in England.METHODS Data used in this cohort study were drawn from the National Cancer Registration Dataset(NCRD),Hospital Episode Statistics and the Systemic Anti-Cancer Therapy Dataset.A cohort of 8853 CCA patients diagnosed between 2014-2017 in the National Health Service in England was identified from the NCRD.Potentially curative surgery for all patients and systemic therapy and stent insertion for 7751 individuals who did not receive surgery were identified as three end-points of interest.Linear probability models assessed variation in each of the three treatment modalities according to Cancer Alliance of residence at diagnosis,and for socio-demographic and clinical characteristics at diagnosis.RESULTS Of 8853 CCA patients,1102(12.4%)received potentially curative surgery.The mean[95%confidence interval(CI)]percentage-point difference from the population average ranged from-3.96(-6.34 to-1.59)%to 3.77(0.54 to 6.99)%across Cancer Alliances in England after adjustment for patient sociodemographic and clinical characteristics,showing statistically significant variation.Amongst 7751 who did not receive surgery,1542(19.9%)received systemic therapy,with mean[95%CI]percentage-point difference from the population average between-3.84(-8.04 to 0.35)%to 9.28(1.76 to 16.80)%across Cancer Alliances after adjustment,again showing the presence of statistically significant variation for some regions.Stent insertion was received by 2156(27.8%),with mean[95%CI]percentage-point difference from the population average between-10.54(-12.88 to-8.20)%to 13.64(9.22 to 18.06)%across Cancer Alliances after adjustment,showing wide and statistically significant variation from the population average.Half of 8853 patients(n=4468)received no treatment with either surgery,systemic therapy or stent insertion.CONCLUSION Substantial regional variation in treatments received by CCA patients was observed in England.Such variation could be due to differences in case-mix,clinical practice or access to specialist expertise.

Acute respiratory distress syndrome and severe pneumonitis after atezolizumab plus bevacizumab for hepatocellular carcinoma treatment:A case report

BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common cancers worldwide and has a high mortality.However,the treatment options for advanced HCC are limited to tyrosine kinase inhibitors,such as sorafenib and lenvatinib.Since previous regimens have an insufficient efficacy,the combination therapy of atezolizumab and bevacizumab(Ate/Bev)has been investigated,which showed an improvement in progression-free and overall survival.However,the adverse events of this combination therapy in advanced HCC have not been established.Herein,we report a novel case of an unresectable HCC and acute respiratory distress syndrome(ARDS)after a combination therapy of Ate/Bev.CASE SUMMARY An 82-year-old male visited our outpatient clinic for an incidentally detected liver mass.Liver magnetic resonance imaging and enhanced chest computed tomography(CT)were performed,which showed arterial hyperenhancement with washout in delayed phase suggesting HCC,and a well-defined metastatic solid nodule,respectively.F-18 fluorodeoxyglucose positron emission tomography(PET)-CT exhibited multiple hypermetabolic lesions in the iliac bone,lumbar vertebrae,and femur.Because of the high burden of the intrahepatic tumor,transarterial radioembolization was initially performed;after 37 d,a combination therapy of Ate/Bev was administered.The patient visited the emergency department three days after Ate/Bev treatment complaining of dyspnea.He was diagnosed with severe pneumonitis based on CT.Despite administering oxygen via a high-flow nasal cannula,the P/F ratio was only 74;therefore,the patient was diagnosed with ARDS based on the overall examination results.Low tidal volume with high positive end-expiratory pressure,sedative agents combined with a neuromuscular blocker,and a systemic steroid were promptly applied to manage the ARDS.However,the patient did not recover from the hypoxia and expired 31 h after being admitted.CONCLUSION Clinicians should be aware of severe pneumonitis due to the immune-related adverse events of this combination therapy,and patients should be closely monitored after therapy.

New First-line Immunotherapy-based Therapies for Unresectable Hepatocellular Carcinoma: A Living Network Meta-analysis

Background and Aims:Several first-line immune checkpoint inhibitor(ICI)-based combination therapies have been identified for unresectable hepatocellular carcinoma(uHCC).This network meta-analysis(NMA)aimed to provide the most updated evidence about the preferred first-line ICI-based regimens for uHCC.Methods:A comprehensive literature search was performed in various databases from database inception to May 2022.The phase 3 trials evaluating first-line single-agent ICIs,molecular-target agents(MTAs),or their combinations in uHCC were included.The main endpoints were overall survival(OS)and progression-free survival(PFS).Pooled effect estimates were calculated using a random effects model within the frequentist framework.Subgroup analyses based on etiology were also conducted.Results:Twelve trials at low risk of bias with 8,275 patients comparing 13 treatments were included.OS with atezolizumab plus bevacizumab was comparable to sintilimab plus IBI305[hazard ratio(HR):1.16;95%confidence interval(CI):0.80–1.68]and camrelizumab plus apatinib(HR:1.06;95%CI:0.75–1.51).The combination therapies,apart from atezolizumab plus cabozantinib in OS and durvalumab plus tremelimumab in PFS,had higher P-score than single-agent MTAs or ICIs.The survival benefits were associated with a high risk of adverse events leading to treatment discontinuation.The proportion of patients with hepatitis B virus-related HCC receiving ICIs combinations might positively correlate with survival advantages(R2=0.8039,p=0.0155).Conclusion:This NMA demonstrated that atezolizumab plus bevacizumab remains the stand of care and confers comparable survival benefits to sintilimab plus IBI305 and camrelizumab plus apatinib in first-line therapy for uHCC.The optimal treatment algorithms should consider efficacy,safety,and etiology.

Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment

BACKGROUND： Hepatocellular carcinoma （HCC） is a com- plex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple con- founding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortal- ity globally with a rising trend of incidence in some of the de- veloped countries, which indicates the need for better surgical and nonsurgical management strategies.