Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Targeted agents for second-line treatment of advanced hepatocellular carcinoma

Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different multikinase inhibitor,was shown to be non-inferior to sorafenib,in terms of survival,while all other agents previously tested failed to prove non-inferiority(or superiority)when compared to sorafenib.Similarly,in the second-line setting,most investigational drugs failed to provide better survival outcomes than placebo.However,in the last 2 years three positive phase III trials have been published in this setting.The RESORCE trial,a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib,showed better outcomes with regorafenib compared to placebo.More recently,the phase III CELESTIAL trial demonstrated the superiority of cabozantinib,a multikinase inhibitor targeting vascular endothelial growth factor receptor,MET,and AXL,vs placebo in the second-and third-line setting in patients progressing on or intolerant to sorafenib.The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels.Overall,the adverse events reported in these trials were in line with the known safety profiles of the tested agents.After nearly a decade of a certain degree of stagnation,we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.

Optimized management of advanced hepatocellular carcinoma:Four long-lasting responses to sorafenib

The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate.Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC.Nevertheless,in clinical practice,some patients are discontinuing this drug because of side effects,and misinterpretation of radiographic response may contribute to this.We highlight the importance of prolonged sorafenib ad-ministration,even at reduced dose,and of qualitative and careful radiographic evaluation.We observed two partial and two complete responses,one histologically confirmed,with progression-free survival ranging from 12 to 62 mo.Three of the responses were achieved following substantial dose reductions,and a gradual change in lesion density preceded or paralleled tumor shrinkage,as seen by computed tomography.This report supports the feasibility of dose adjustments to allow prolonged administration of sorafenib,and highlights the need for new imaging criteria for a more appropriate characterization of response in HCC.

Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Alpha-fetoprotein screening in patients with hepatitis C-induced cirrhosis who achieved a sustained virologic response in the direct-acting antiviral agents era

To the Editor:Hepatocellular carcinoma (HCC) is the most common primary livertumorandthethirdcauseofcancer-relateddeathsworldwide. HCC is the consequence of malignant transformation of hepatocytes and mainly occurs in patients with cirrhosis. Hepatitis C virus (HCV) chronic infection is a leading cause of end-stage liver diseaseandHCCintheWesterncountries[1].Theapprovalof direct-acting antiviral agents (DAAs) for the treatment of HCV has revolutionized the management of the disease, as no absolute contraindication to treatment exists and sustained virological response

The promise of precision medicine:how biomarkers are shaping the future of cholangiocarcinoma treatment

Cholangiocarcinoma(CCA)is the second most frequent primary malignant neoplasm of the hepatobiliary system.Unfortunately,CCA is often diagnosed at an advanced stage,when potentially curative surgical treatments are not recommended.The probability of achieving complete resection in patients who undergo surgery is about 25%(1)and even when complete tumor removal is achieved,the risk of recurrence is greater than 50%.Identification and validation of reliable biomarkers is crucial for the early detection,accurate diagnosis,appropriate staging/prognosis,therapy selection and effective monitoring of patients with biliary tract cancers(BTCs)(Figure 1).Achieving early diagnosis remains a challenge to improve survival and,although many promising biomarkers have been identified(2),to date none have reached clinical practice.

lmmunotherapy in hepatobiliary tumors: search for the missing pieces of the puzzle

In the current era of immunotherapy, the treatment of hepatobiliary cancers is rapidly evolving. The use of immunotherapeutic approaches, which include peptide-based vaccines, checkpoint inhibitors and antibodies, particularly applies to advanced hepatobiliary cancers, for which the availability of limited therapeutic options encourages the adoption of alternative strategies. Thanks to the published/presented, although conflicting, results of some of the clinical trials on this topic together with the incoming results of some other trials, clinicians involved in the cure of hepatobiliary cancer patients need to understand the basic and advanced applications of immunotherapies (1-6).

Hepatocellular carcinoma as the Rose of Jericho:from the desert of sorafenib,to the blossoming of immunotherapy

According to its etymology,the English word“liver”is related to the verb“to live”,and indeed there are few domains of oncology research as lively as liver cancer.The therapeutic landscape of hepatocellular carcinoma(HCC)has been rapidly changing over the last years,after the successful introduction of immune checkpoint inhibitors(ICIs)as standard of care for the treatment of unresectable or metastatic HCC(uHCC).Following more than a decade of tyrosine kinase inhibitors(TKIs)as the only available treatment for advanced HCC,in 2020 the results of the IMbrave150 trial radically changed the therapeutic algorithm(1,2).The combination of the anti-programmed death ligand 1(PD-L1)monoclonal antibody(mAb)atezolizumab and the anti-vascular endothelial growth factor(VEGF)mAb bevacizumab outperformed sorafenib in terms of overall survival(OS)and progression-free survival(PFS),meeting both its co-primary endpoints.The combination has been recognised as the new first-line standard of care by all major scientific societies,and it has been approved by regulatory agencies worldwide(3).

Unravel hepatic artery infusion chemotherapy in patients with resected colorectal liver metastases

Over the past years,important progresses have been made in the treatment of patients with colorectal liver metastases(CLM).Now,5-year overall survival rate may exceed 50%by using the combination of multimodality therapies among which modern systemic chemotherapy,with or without monoclonal antibodies,and hepatic resection are the cornerstones(1,2).In such multimodality,hepatic artery infusion(HAI)has been proposed since many years with the rationale of increasing the concentration of chemotherapy agents in the liver(3).However,HAI still remains infrequently used,in particular in the adjuvant setting mainly because of the requirement of a multidisciplinary team to manage therapy,and the more widespread use of systemic chemotherapy-in particular following the perioperative“sandwich”schema(4).