Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040.

BACKGROUND: Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. PATIENTS AND METHODS: Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). RESULTS: Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION: With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.

Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.

Totally laparoscopic right-lobe hepatectomy for adult living donor liver transplantation: useful strategies to enhance safety.

The overriding concern in living donor liver transplantation is donor safety. A totally laparoscopic right hepatectomy without middle hepatic vein for adult living donor liver transplantation is presented. The surgical procedure is described in detail, focusing on relevant technical aspects to enhance donor safety, specifically the hanging maneuver and dynamic fluoroscopy-controlled bile duct division.

The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 24th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2022.

This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.

No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors.

Farnesoid X receptor (FXR) has been recently reported to enhance chemoresistance through bile acid-independent mechanisms. Thus, FXR transfection plus activation with GW4064 resulted in reduced sensitivity to cisplatin-induced toxicity. This is interesting because primary tumors of the liver, an organ where FXR is expressed, exhibit marked refractoriness to pharmacological treatment. Here we have determined whether FXR is upregulated in hepatocellular carcinoma (HCC), cholangiocarcinoma (CGC) and hepatoblastoma (HPB) and whether this is related with the expression of genes involved in mechanisms of chemoresistance. Using RT-QPCR and Taqman low density arrays we have analyzed biopsies from healthy livers or surgically removed tumors from naive patients and cell lines derived from HCC (SK-HEP-1, Alexander and Huh7), CGC (TFK1) and HPB (HepG2), before and after exposure to cisplatin at IC50 for 72 h. In liver tumors FXR expression was not enhanced but significantly decreased (healthy liver > HCC > HPB ≈ CGC). Except for CGC, this was not accompanied by changes in the proportions of FXR isoforms. Changes in 36 genes involved in drug uptake/efflux and metabolism, expression/function of molecular targets, and survival/apoptosis balance were found. Changes affecting SLC22A1, CYP2A1 and BIRC5 were shared by HCC, CGC and HPB. Similarity in gene expression profiles between cell lines and parent tumors was found. Pharmacological challenge with cisplatin induced changes that increased this resemblance. This was not dependent upon FXR expression. Thus, although FXR may play a role in inducing chemoresistance under certain circumstances, its upregulation does not seem to be involved in the multidrug resistance phenotype characteristic of HCC, CGC and HPB.

Hepatic Flow Redistribution is Feasible in Patients with Hepatic Malignancies Undergoing Same-Day Work-Up Angiography and Yttrium-90 Microsphere Radioembolization.

PURPOSE: To assess the feasibility of performing same-day vascular flow redistribution and Yttrium-90 radioembolization (90Y-RE) for hepatic malignancies. MATERIALS AND METHODS: From November 2015 to February 2019, patients undergoing same-day hepatic flow redistribution during work-up angiography, 99mTechnetium-labeled macroaggregated albumin (99mTc-MAA) SPECT/CT and 90Y microsphere-RE, were recruited. Within 18 h following the delivery of 90Y resin microspheres, an 90Y-PET/CT study was performed. According to patients' vascular anatomy, flow redistribution was performed by microcoil embolization of extrahepatic branches (group A), intrahepatic non-tumoral vessels (group B) and intrahepatic tumoral arteries (group C). The accumulation of 99mTc-MAA particles and microspheres in the redistributed areas was qualitatively evaluated using a 5-point visual scale (grade 1 = < 25% accumulation; grade 5 = 100% accumulation). Differences in the distribution of microspheres among groups were assessed with Mann-Whitney U test. RESULTS: Twenty-two patients were treated for primary (n = 17) and secondary (n = 5) hepatic malignancies. The MAA-SPECT/CT showed uptake in all the redistributed areas. Regarding the accumulation of microspheres within the redistributed segments in all the groups, perfusion patterns were classified as 2 in 1 case, 4 in 6 cases and 5 in 15 cases. No statistically significant differences were observed between groups A and B-C (U value = 34, p = 0.32) and between groups B and C (U value = 26, p = 0.7). Mean predicted absorbed doses by the tumoral and normal hepatic tissues were 163.5 ± 131.2 Gy and 60.4 ± 69.3 Gy, respectively. Mean total procedure time (from work-up angiography to 90Y delivery) was 401 ± 0.055 min. CONCLUSION: Performing same-day redistribution of the arterial hepatic flow to the target and 90Y-microsphere delivery is feasible in the treatment of liver tumors. Clinical Trials Registry NCT03380130.

Intensified neoadjuvant multimodal approach in synchronous liver metastases from gastric cancer: a single institutional experience.

BACKGROUND: Synchronous liver metastases (LM) from gastric (GC) or esophagogastric junction (EGJ) adenocarcinoma are a rare events. Several trials have evaluated the role of liver surgery in this setting, but the impact of preoperative therapy remains undetermined. METHODS: Patients with synchronous LM from GC/EGJ adenocarcinoma who achieved disease control after induction chemotherapy (ICT) and were subsequently scheduled to chemoradiotherapy (CRT) to the primary tumor and surgery assessment were retrospectively analyzed. Pathological response, patterns of relapse, progression-free survival (PFS), and overall survival (OS) were calculated. From July 2002 to September 2012, 16 patients fulfilling the inclusion criteria were identified. RESULTS: Primary tumor site was GC (nine patients) or EGJ (seven patients). LM were considered technically unresectable in nine patients. Radiological response to the whole neoadjuvant program was achieved in 13 patients. Eight patients underwent surgical resection of the primary tumor; in five of these LM were resected. A complete pathological response in the primary or in the LM was found in four and three patients, respectively. The most frequent site of relapse/progression was systemic (eight patients). Local and liver-only relapses were observed in two patients each. After a median follow-up of 91 months, the median OS and PFS were 23.0 (95% CI 13.2-32.8) and 17.0 months (95% CI 11.7-22.3). 5-year actuarial PFS is 17.6%. CONCLUSION: Our results suggest that an intensified approach using ICT followed by CRT in synchronous LM from GC/EGJ adenocarcinoma is feasible and may translate into prolonged survival times in selected patients.

New therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is often diagnosed at an advanced stage when most potentially curative therapies such as resection, transplantation or percutaneous and transarterial interventions are of limited efficacy. The fact that HCC is resistant to conventional chemotherapy, and is rarely amenable to radiotherapy, leaves this disease with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools and strategies is much needed. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of chronic liver disease. However, in spite of this heterogeneity recent insights into the biology of HCC suggest that certain signaling pathways and molecular alterations are likely to play essential roles in HCC development by promoting cell growth and survival. The identification of such mechanisms may open new avenues for the prevention and treatment of HCC through the development of targeted therapies. In this review we will describe the new potential therapeutic targets and clinical developments that have emerged from progress in the knowledge of HCC biology, In addition, recent advances in gene therapy and combined cell and gene therapy, together with new radiotherapy techniques and immunotherapy in patients with HCC will be discussed.

[Gene therapy: what is it and what is its use?]. / Terapia génica: qué es y para qué sirve?

Gene therapy has developed as a method of approach to the treatment of human diseases based on the transfer of genetic material to the cells of an individual. Normally, the aim of this transfer of genetic material is to re-establish a cellular function that has been abolished or is defective, to introduce a new function or to interfere with an existing function. Thus, the different gene therapy strategies are based on the combination of three key elements: the genetic material to be transferred, the method of transfer and the cellular type that will incorporate this genetic material. Attention was initially centred on the treatment of monogenic hereditary diseases, but subsequently the majority of clinical trials (over four hundred) have concerned the treatment of cancer. In China a genetic product has been approved for commercialisation: an adenovirus that transfers the correct version of the tumour suppressor gene p53. And, in the late 1990s, a group of children with severe combined immunodeficiency were successfully treated through the ex vivo transfer of the correct version of the altered gene to their bone marrow, although some of these children later developed lymphoproliferative syndromes due to the activation of an oncogen in the corrected cells. Human gene therapy is feasible and can be useful, but the tools need improving for it to become part of the therapeutic arsenal.

Cost-effectiveness of selective internal radiation therapy using yttrium-90 resin microspheres in treating patients with inoperable colorectal liver metastases in the UK.

OBJECTIVE: Selective internal radiation therapy (SIRT) using SIR-Spheres(®) (90)Y-labeled resin microspheres has been shown to be a well-tolerated, effective treatment in patients with inoperable liver-dominant chemotherapy-refractory metastatic colorectal cancer (mCRC). This study estimated the cost-effectiveness of (90)Y-resin microspheres compared to best supportive care (BSC) from a UK perspective. METHODS: Survival data from a comparative retrospective cohort study was analyzed and used in a state-transition cost-effectiveness model, using quality-adjusted life years (QALYs) gained as the measure of effectiveness. The model incorporated costs for the SIRT procedure, monitoring, further treatment, adverse events, and death. Utility values, reflecting patient quality-of-life, were taken from a published source. RESULTS: SIRT using (90)Y-resin microspheres compared to BSC improved overall survival by a mean of 1.12 life years and resulted in a cost per QALY gained of £28,216. In sensitivity analysis, this varied between £25,015-£28,817. CONCLUSION: In an area of large unmet need, treatment with (90)Y-resin microspheres offers a clinically effective and cost-effective treatment option.

Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma.

In rats with diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC), we studied in vivo gene transfer efficiency using intraportal injections of recombinant adenovirus carrying the lacZ reporter gene (AdCMVlacZ) and the therapeutic efficacy of adenovirus-mediated transfer of the thymidine kinase gene of the herpes simplex virus (HSV-tk) followed by ganciclovir (GCV) administration. DENA was very effective in inducing HCC but also stimulated nontumor cell replication, as shown by proliferating cell nuclear antigen (PCNA) staining. The study of in vivo gene transfer efficiency in tumor-bearing rats showed that nontumor tissue and small tumor nodules were transduced effectively whereas a poor transduction rate was noted in large tumor nodules. Concerning therapeutic efficacy, three groups of rats with established HCC were studied: group A and B received intraportally recombinant adenovirus carrying HSV-tk (AdCMVtk) or AdCMVlacZ, respectively, and 2 days after GCV was given intraperitoneally for 9 days; group C received only saline. Of the rats from groups B and C, 100% and 93% respectively, exhibited multiple HCC tumor nodules at end of the study. In contrast, a complete regression of tumor was observed in 63% of animals from group A. This group showed significant elevation of serum transaminases and a diffuse hepatotoxic lesion in liver tissue; histological signs of regeneration were observed in surviving animals. Nine out of 19 rats from group A died during the treatment period. We conclude that (i) in the DENA model of HCC, tumoral cells can be destroyed in vivo by the HSV-tk/GCV system despite poor transduction of large tumor nodules, suggesting that toxic metabolites generated by nontumor cells may exert a bystander effect on tumor tissue; (ii) significant hepatoxicity and a high mortality rate occurred in HSV-tk/GCV-treated rats; these side effects appear to be due to the fact that in DENA-treated livers enhanced cell proliferation was present not only in tumor nodules but also in nontumor parenchyma, leading to GCV sensitization of both tissues; (iii) our results have implications concerning the efficacy and potential risks of the HSV-tk/GCV system in the treatment of human HCC.

Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application.

Gene-directed enzyme prodrug therapy (GDEPT) is a two step therapeutic approach for cancer gene therapy. In the first step, the transgene is delivered into the tumor and expressed. In the second step a prodrug is administered and is selectively activated by the expressed enzyme. The first GDEPT system described was the thymidine kinase gene of the Herpes Simplex virus (HSVtk) in combination with the prodrug Ganciclovir (GCV). A large number of experiments have been performed with this system, in different types of tumors and initial studies in animal models were very promising. This encouraged investigators to move into clinical trials although poor results have been obtained so far. A large effort has been made with numerous different strategies to enhance HSVtk/GCV efficacy in cellular and in vivo models and very strong cytotoxic effects have been obtained. The present review describes the current state of preclinical research and summarizes the results of the clinical trials undertaken.

Prognosis of hepatocellular carcinoma in relation to treatment: a multivariate analysis of 178 patients from a single European institution.

BACKGROUND: Because the prognosis of patients with hepatocellular carcinoma is not fully understood, particularly regarding therapy, we have evaluated it in a series of patients with a homogeneous diagnostic and therapeutic work-up. METHODS: From 1985 to 1996, 42 variables were recorded prospectively in 178 constructive patients who had a diagnosis of hepatocellular carcinoma. Treatment consisted of liver transplantation ( n = 22), partial hepatectomy (n = 11), arterial, chemoembolization ( n = 52), systemic or regional chemotherapy (n = 51), and other therapies (n = 5); 37 patients received no specific therapy. Statistical analysis was performed according to a Cox model. RESULTS: There were no differences between the survival of patients receiving chemotherapy, other therapies, or no treatment (control group n = 93). survival rates a 1,3, and 5 years were 81%, 74%, and 74% for liver transplantation, 72%, 58%, and 58% for hepatectomy, 55%, 26%, and 13% for chemoembolization, and 13%, 3%, and 0% for the control group. Cirrhosis, systemic syndrome, bilobar involvement, Child's stage C disease, and treatment were independent predictors of survival. CONCLUSIONS: This series shows that certain easily accessible parameters may help establish individual prognosis and stratify patients in clinical trials and indicates that chemoembolization, partial resection, and liver transplantation can prolong life expectancy of patients with hepatocellular carcinoma.

Aortic valve replacement with bioprostheses in liver transplant recipients.

Three cases of aortic valve replacement with porcine bioprostheses are reported in liver transplant recipients at two to six years after transplantation. Indications for aortic valve replacement (AVR) were aortic stenosis (n = 2) and aortic regurgitation (n = 1). The use of bioprostheses was recommended because of patient age, the need for multiple liver biopsies, and contraindication to the use of anticoagulation therapy. The patient who underwent AVR because of aortic regurgitation developed structural valve deterioration (SVD) during the next five years after surgery, and thus replacement of the bioprosthetic valve was required. Recipients of liver transplant who undergo valve replacement with tissue valves should be carefully followed up because of the risk of early SVD. AVR may be performed safely after liver transplantation.

Splenic embolization prior to myelosuppressive treatment in hepatocarcinoma and active chronic hepatitis.

In the treatment of active chronic hepatitis and hepatocellular carcinoma some effective drugs can produce myelosuppression. Hypersplenism may considerably limit the dosage of such drugs. Splenectomy is an effective treatment for hypersplenism, although it is not without complications. Partial splenic embolization is a good and safe procedure; 15 patients were treated in order to achieve higher platelet and leukocyte counts. Embolization has been performed with gelfoam with local and systemic antibiotics (Spigos' protocol) and 50-75% of the splenic parenchyma was infarcted. All patients could be treated for the underlying hepatopathy with adequate dosages of interferon or chemotherapeutic drugs.

Conversion from calcineurin inhibitors to mycophenolate mofetil in liver transplant recipients with diabetes mellitus.

Diabetes mellitus, a frequent metabolic complication in liver transplant recipients, may be produced by the diabetogenic effect of calcineurin inhibitors cyclosporine and tacrolimus. The aim of this study was to investigate the safety and metabolic effects of a gradual switch from cyclosporine or tacrolimus to mycophenolate mofetil among 12 diabetic liver transplant recipients. One patient was withdrawn from the study due to gastrointestinal side effects. Of the 11 remaining patients, cyclosporine or tacrolimus was completely withdrawn in five patients. Two patients developed suspected acute rejection episodes that were controlled by increasing the tacrolimus dosage. Glycosylated hemoglobin A1C and C-peptide levels were significantly lower at 3 and 6 months after the initiation of mycophenolate mofetil (P<.03 in all cases). Furthermore, urea and uric acid levels were significantly reduced after the change of treatment. In conclusion, a switch from cyclosporine/tacrolimus to mycophenolate mofetil may produce beneficial metabolic effects in diabetic liver transplant recipients, but poses a risk of graft rejection.