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Purpose: Transarterial chemoembolization (TACE) may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy., Patients and Methods: Patients with liver-confined hepatocellular carcinoma (HCC) were planned to receive up to two rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30 days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, with assessment window of 21 days from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumor and host determinants of response., Results: Fifteen patients were included in the safety and efficacy population: 73% had nonviral cirrhosis; median age was 72 years. Child-Pugh class was A in 14 patients. Median tumor size was 4 cm. Ten patients (67%) received pembrolizumab after one TACE; 5 patients after two (33%). Pembrolizumab yielded no synergistic toxicity nor dose-limiting toxicities post-TACE. Treatment-related adverse events occurred in 93% of patients, most commonly skin rash (40%), fatigue, and diarrhea (27%). After a median follow-up of 38.5 months, objective response rate 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months [95% confidence interval (CI): 7.30-NE (not estimable)]. Median duration of response was 7.3 months (95% CI: 6.3-8.3). Median overall survival was 33.5 months (95% CI: 11.6-NE). Dynamic changes in peripheral T-cell subsets, circulating tumor DNA, serum metabolites, and in stool bacterial profiles highlight potential mechanisms of action of multimodal therapy., Conclusions: TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE., (©2024 The Authors; Published by the American Association for Cancer Research.)

Transarterial chemoembolization (TACE) is the treatment of choice for intermediate-stage hepatocellular carcinoma (HCC). Recent data suggest that TACE may boost the efficacy of anti-PD-1 immunotherapy. The authors present the trial protocol for PETAL, a phase Ib study, which will assess the safety and bioactivity of pembrolizumab, an anti-PD-1 antibody, following TACE in HCC. After a run-in phase evaluating six patients to establish preliminary safety, up to 26 additional participants will be enrolled. Pembrolizumab will be administered three-times weekly for 1 year or until progression, starting 30-45 days after TACE. The primary objective is to determine safety and the secondary objective is to preliminarily evaluate efficacy. Radiological responses will be evaluated every four cycles. Clinical Trial Registration : NCT03397654 (ClinicalTrials.gov).

Background: After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209-040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3-4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC., Methods: The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC., Discussion: The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population., Trial Registration: EudraCT Number: 2018-000987-27 Clinical trial registry & ID: ClinicalTrials.gov : NCT03682276 .

Accurate disease monitoring is essential after transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) because of the potential for profound adverse events and large variations in survival outcome. Posttreatment changes on conventional imaging can confound determination of residual or recurrent disease, magnifying the clinical challenge. On the basis of increased expression of thymidylate synthase ( TYMS ), thymidine kinase 1 ( TK-1 ), and equilibrative nucleoside transporter 1 ( SLC29A1 ) in HCC compared with liver tissue, we conducted a proof-of-concept study evaluating the efficacy of 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) PET to assess response to TACE. Because previous PET studies in HCC have been hampered by high background liver signal, we investigated whether a temporal-intensity voxel clustering (kinetic spatial filtering, or KSF) improved lesion detection. Methods: A tissue microarray was built from 36 HCC samples and from matching surrounding cirrhotic tissue and was stained for TK-1 A prospective study was conducted; 18 patients with a diagnosis of HCC by the criteria of the American Association for the Study of Liver Diseases who were eligible for treatment with TACE were enrolled. The patients underwent baseline conventional imaging and dynamic 18 F-FLT PET with KSF followed by TACE. Imaging was repeated 6-8 wk after TACE. The PET parameters were compared with modified enhancement-based RECIST. Results: Cancer Genome Atlas analysis revealed increased RNA expression of TYMS, TK-1, and SLC29A1 in HCC. TK-1 protein expression was significantly higher in HCC ( P < 0.05). The sensitivity of 18 F-FLT PET for baseline HCC detection was 73% (SUV max , 9.7 ± 3.0; tumor to liver ratio, 1.2 ± 0.3). Application of KSF did not improve lesion detection. Lesion response after TACE by modified RECIST was 58% (14 patients with 24 lesions). A 30% reduction in mean 18 F-FLT PET uptake was observed after TACE, correlating with an observed PET response of 60% (15/25). A significant and profound reduction in the radiotracer delivery parameter K 1 after TACE was observed. Conclusion: 18 F-FLT PET can differentiate HCC from surrounding cirrhotic tissue, with PET parameters correlating with TACE response. KSF did not improve visualization of tumor lesions. These findings warrant further investigation., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Neuroendocrine liver metastases are clinically challenging due to their frequent disseminated distribution. This study aims to present a British experience with an emerging modality, radioembolisation with yttrium-90 labelled microspheres, and embed this within a meta-analysis of response and survival outcomes., Methods: A retrospective case series of patients treated with SIR-Spheres (radiolabelled resin microspheres) was performed. Results were included in a systematic review and meta-analysis of published results with glass or resin microspheres. Objective response rate (ORR) was defined as complete or partial response. Disease control rate (DCR) was defined as complete/partial response or stable disease., Results: Twenty-four patients were identified. ORR and DCR in the institutional series was 14/24 and 21/24 at 3 months. Overall survival and progression-free survival at 3-years was 77.6% and 50.4%, respectively. There were no grade 3/4 toxicities post-procedure. A fixed-effects pooled estimate of ORR of 51% (95% CI: 47%-54%) was identified from meta-analysis of 27 studies. The fixed-effects weighted average DCR was 88% (95% CI: 85%-90%, 27 studies)., Conclusion: Current data demonstrate evidence of the clinical effectiveness and safety of radioembolisation for neuroendocrine liver metastases. Prospective randomised studies to compare radioembolisation with other liver directed treatment modalities are needed., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Survival advantage following trans-arterial chemoembolization (TACE) is variable in patients with hepatocellular carcinoma (HCC). We combined pre-TACE radiologic features to derive a novel prognostic signature in HCC., Methods: A multi-institutional dataset of 98 patients was generated from two retrospective cohorts from United Kingdom (65%) and Italy (36%). The prognostic impact of a number baseline imaging parameters was assessed and factors significant on univariate analysis were combined to create a novel radiologic signature on multivariable analyses predictive of overall survival (OS) following TACE., Results: Median OS was 15.4 months. Tumour size > 7 cm (p < 0.001), intra-tumour necrosis (ITN) (p = 0.02) and arterial ectatic neovascularisation (AEN) (p = 0.03) emerged as individual prognostic factors together with radiologic response (p < 0.001) and elevated alpha-fetoprotein (AFP) (p = 0.01). Combination of tumour size > 7 cm, ITN and AEN identified patients with poor prognosis (p < 0.001)., Conclusions: We identified a coherent signature based on commonly available imaging biomarkers likely to be reflective of differential patterns of relative hypoxia and neovascularisation. Large tumours displaying AEN and ITN are characterised by a shorter survival after TACE.

Background: Preoperative portal vein occlusion with either percutaneous portal vein embolization (PVE) or portal vein ligation is routinely used to induce liver hypertrophy prior to major liver resection in patients with hepatic malignancy. While this increases the future liver remnant, and hence the number of patients suitable for resection, recent evidence suggests that induction of liver hypertrophy preoperatively may promote tumor growth and increase recurrence rates. The aims of this current study were to evaluate the impact of PVE on hepatic recurrence rate and survival in patients with colorectal liver metastases (CRLM)., Methods: The MEDLINE, EMBASE and Web of Science databases were searched to identify studies assessing the oncological outcomes of patients undergoing major liver resection for CRLM following PVE. Studies comparing patients undergoing one-stage liver resection with or without preoperative PVE were included. The primary outcome was postoperative hepatic recurrence (PHR), while secondary outcomes were 3- and 5-year overall survival (OS)., Results: Of the 2131 studies identified, six non-randomized studies (n = 668) met the eligibility criteria, comparing outcomes of patients undergoing major liver resection with or without PVE (n = 182 and n = 486, respectively). No significant difference was observed in PHR (odds ratio [OR] 0.78; 95 % confidence interval [CI] 0.42-1.44), 3-year OS (OR 0.80; 95 % CI 0.56-1.14) or 5-year OS (OR 1.12; 95 % CI 0.40-3.11)., Conclusions: PVE does not have any adverse effect on PHR or OS in patients undergoing major liver resection for CRLM. Further studies based on individual patient data are needed to provide definitive answers.

Background: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is variable, despite a myriad of prognostic markers. We compared and integrated the established prognostic models, HAP and ART scores, for their accuracy of overall survival (OS) prediction., Results: In both training and validation sets, HAP and ART scores emerged as independent predictors of OS (p<0.01) with HAP achieving better prognostic accuracy (c-index: 0.68) over ART (0.57). We tested both scores in combination to evaluate their combined ability to predict OS. Subgroup analysis of BCLC-C patients revealed favorable HAP stage (p<0.001) and radiological response after initial TACE (p<0.001) as positive prognostic factors., Patients and Methods: Prognostic scores were studied using multivariable Cox regression and c-index analysis in 83 subjects with Barcelona Clinic Liver Cancer (BCLC) A/B stage from UK and Italy (training set), and 660 from Korea and Japan (validation set), all treated with conventional TACE. Scores were further validated in an separate analysis of patients with BCLC-C stage disease (n=63) receiving initial TACE., Conclusion: ART and HAP scores are validated indices in patients with intermediate stage HCC undergoing TACE. The HAP score is best suited for screening patients prior to initial TACE, whilst sequential ART assessment improves early detection of chemoembolization failure. BCLC-C patients with low HAP stage may be a subgroup where TACE should be explored in clinical studies., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Two-stage liver resection (2-SLR) is used clinically in conjunction with portal vein embolization for bilobar disease to increase the number of patients suitable for liver resection. The long-term outcomes after 2-SLR for multiple bilobar colorectal liver metastases (CLM) was examined., Methods: Patients who sought care between November 2003 and April 2006 with multiple CLM considered suitable for 2-SLR were prospectively followed. Clinicopathological data were collected. Surgical outcomes were defined as complete clearance of tumor (R0/R1/R2), postoperative morbidity (within 3 months), 30 day mortality, disease-free survival (DFS), and overall survival (OS)., Results: A total of 131 patients with CLM underwent liver resection during the study period, 38 of whom were planned for a 2-SLR for multiple bilobar disease. Only 33 (87%) completed the 2-SLR with a curative intent. Five patients did not undergo stage II resection because of disease progression. The postoperative morbidity was 11 and 33% after stage I and stage II liver resections, respectively. Five patients (13%) encountered postoperative complications specific to liver surgery. The median interval from stage II resection to disease recurrence in the R0 group was 18 months versus 3 months in the R1/R2 group (P < 0.001). R0 resection with curative intent versus R1/R2 noncurative resection has a significantly longer period of DFS (P < 0.001) and OS (P = 0.04)., Conclusions: The 2-SLR combined with portal vein embolization is an effective and safe method for resecting previously unresectable multiple bilobar CLM. However, a positive resection margin leads to poor DFS and OS.

Liver metastases and hepatocellular carcinomas are two of the most common causes of cancer deaths in the world. Radiofrequency ablation (RFA) is a well recognized, effective and minimally invasive means of treating malignant hepatic tumors. This article describes the use of contrast-enhanced 3D ultrasound (CE-3DUS) in the staging, targeting and follow-up of patients with liver tumors undergoing RFA. In particular, its value in the management of large hepatic lesions will be illustrated. Current limitations of CE-3DUS and future developments in the technique will also be discussed. In summary, CE-3DUS is useful in the RFA of liver tumors with improved detection and display of occult lesions and recurrence, in the assessment of lesional geometry and orientation for a more accurate planning and guidance of multiple RFA needle electrodes in large tumors and in the evaluation of residual or recurrent disease within the immediate and/or subsequent follow-up periods.

Introduction: Preoperative portal vein embolization (PVE) is used clinically to prevent postoperative liver insufficiency. The current study examined the impact of portal vein embolization on liver resection., Method: A comprehensive Medline search to identify all registered literature in the English language on portal vein embolization. Meta-analysis was performed to assess the result of PVE and its impact on major liver resection., Result: A total of 75 publications met the search criteria but only 37 provided data sufficiently enough for analysis involving 1088 patients. The overall morbidity rate for PVE was 2.2% without mortality. Four weeks following PVE, 85% patients underwent the planned hepatectomy (n = 930). Twenty-three patients had transient liver failure following resection after PVE (2.5%) but 7 patients developed acute liver failure and died (0.8%). The reason for nonresection following PVE (n = 158, 15%) included inadequate hypertrophy of remnant liver (n = 18), severe progression of liver metastasis (n = 43), extrahepatic spread (n = 35), refusal to surgery (n = 1), poor general condition (n = 1), altered treatment to transcatheter artery embolization or chemotherapy (n = 24), complete remission after treatment with 3 cycles of fluoracil and interferon alpha in a patient with hepatocellular carcinoma (n = 1), incomplete pre- or postembolization scanning (n = 8). Of those who underwent laparotomy without resection, (n = 27) reasons included intraoperative finding of peritoneal dissemination (n = 15), portal node metastasis (n = 2), severe invasion of the tumor to the hepatic artery and portal vein (n = 1), and gross tumoral extension precluding curative resection (n = 9). Two techniques were used for portal vein embolization: percutaneous transhepatic portal embolization, (PTPE) and transileocolic portal embolization, (TIPE). The increase in remnant liver volume was much greater in PTPE than TIPE group (11.9% vs. 9.7%; P = 0.00001). However, the proportion of patients who underwent resection following PVE was 97% in TIPE and 88% PTPE, respectively (P = <0.00001). Although there was no significant difference in patients who had major complications post-PVE, the rate for minor complications was significantly higher among patients who had PTPE (53.6% vs. 0%, P = <0.0001)., Conclusion: PVE is a safe and effective procedure in inducing liver hypertrophy to prevent postresection liver failure due to insufficient liver remnant.

Primary and secondary liver tumours are common malignancies that are being treated more aggressively nowadays than decades ago. Surgery is the most effective method of treatment but is only suitable for a minority of patients with well-defined and easily accessible tumours. Surgical resection is contraindicated in patients with massive involvement of the liver or in cases where the disease involves the confluence of vessels at the porta hepatis. These patients may benefit from a variety of ablative and embolic therapies including selective internal radiation therapy (SIRT) with Yttrium-90 microspheres. SIRT has been introduced in the 1980's but the technology has been refined and made more available only recently. The microspheres are injected directly into the hepatic arteries, through a trans-femoral angiographic approach, and are delivered selectively to tumours due to their preferential blood supply by hepatic arteries. SIRT can therefore target small volumes disease with a higher dose of radiation compared with external-beam radiation and is associated the relatively low toxicity and a good response irrespective of tumor origin. Assessment of response to therapy is best performed with metabolic imaging using (18)F-FDG PET scanning. Although it is not considered as a cure, it has been shown to improve quality of life and prolong survival, with the main cause of death being extra-hepatic spread. The technical and clinical demands of patient selection, treatment planning, administration, and clinical follow-up require an interdisciplinary team willing to work cooperatively to achieve the best result for the patient.

Selective Internal Radiation Therapy using yttrium-90 (Y-90) microspheres is a novel method for the treatment of advanced liver cancer. The procedure involves intrahepatic arterial delivery of the Y-90 microspheres. Since hepatic tumors derive their blood supply mainly from the hepatic arteries, it is assumed that the microspheres will be preferentially delivered to tumor cells. However, this has not been confirmed at histology. We report a case of hepatic metastasis from an unknown primary, where treatment with Y-90 microspheres was the only available option due to inoperability and low tolerance to chemotherapy. Pretherapy F-18 FDG-PET scan defined the distribution of the active tumor within the liver. Following the injection of Y-90 microspheres, Bremsstrahlung imaging showed uptake only in the F-18 FDG-PET-defined tumor area. Post therapy debulking surgery was performed and histopathology of tumor samples confirmed the preferential distribution of the injected microspheres in the hepatic tumor circulation with very little in the healthy liver tissue. The case confirms the preferential blood flow to hepatic tumors as depicted by the distribution of Y-90 microspheres injected directly in the hepatic arteries. It also demonstrates that concordance between F-18 FDG-PET and Y-90 Bremsstrahlung scans can be a useful clue to the in vivo distribution of microspheres.

Introduction: Selective internal radiation therapy (SIRT) with SIR spheres (90Y microspheres) is a treatment option for liver tumours in patients in whom other therapies are inappropriate or have failed. This study aims to assess the value of FDG PET in assessing the response to SIRT as compared to computed tomography (CT)., Material and Methods: Twenty-one patients (11 F, 10 M; age range 40-75 years, mean, 58 years) received SIR spheres at the Hammersmith Hospital. One patient received two treatments. Most patients had colorectal metastases (n=10), while the others (n=11) had liver metastasis from different primaries. The mean administered dose was 1.9 GBq (range, 1.2-2.5 GBq). Follow-up was done with FDG PET and CT at 6 weeks, and 6-monthly thereafter. Pre-therapy and post-therapy CT and PET scans were assessed visually (RECIST criteria for CT) and semi-quantitative for PET using the standardized uptake value (SUV)., Result: Eighty-six percent of patients showed decreased PET activity at 6 weeks while only 13% showed a partial response in the size of tumour on CT scan. The mean pre-treatment SUV was 12.2+/-3.7 and the mean post-treatment SUV was 9.3+/-3.7 (P=0.01). CT imaging showed progressive disease in 27% patients and stable liver disease in 60% patients. Based on FDG PET results one patient had surgery for down-staged tumour., Conclusion: FDG PET imaging is more sensitive than CT in the assessment of early response to SIR spheres, allowing clinicians to proceed with further therapeutic options.

Background and Aim: Selective internal radiation therapy with 90Y microspheres (SIR spheres) is increasingly used in the treatment of extensive liver tumours. Careful selection and preparation of patients are necessary to avoid possible adverse effects. We aimed to evaluate the incidence and severity of adverse effects resulting from the administration of SIR spheres during therapy., Materials and Methods: Between June 2004 and August 2006, 21 patients (11 women and 10 men; age range 40-75 years; mean, 58 years) with a wide range of extensive liver tumours were treated with SIR spheres. The mean administered dose was 1.87 GBq (range 1.2-2.5 GBq). During the follow-up period of 26 months, all adverse effects were monitored and classified according to the National Cancer Institute criteria., Results: Four patients had adverse effects: one case of cholecystitis followed by fibrosis and portal hypertension, one case of peptic ulceration and two cases of radiation hepatitis. All cases responded to appropriate therapy., Conclusion: Proper selection of patients and accurate interpretation of pre-treatment investigations are vital for minimizing adverse effects following therapy with SIR spheres. In our experience, all adverse effects were moderate with no life-threatening consequences.