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This review explores the dynamic landscape of hepatocellular carcinoma (HCC) treatment, emphasizing on recent developments across various stages and therapeutic approaches. Although curative strategies such as hepatectomy and thermal ablation are standard for early-stage cases, high relapse rates drive investigations into adjuvant and perioperative treatment. Adjuvant therapies face hurdles, but noteworthy advances include IMbrave050 setting a new standard with atezolizumab/bevacizumab. Locoregional treatments gain significance, especially for multifocal HCC, with the integration of innovative combinations with systemic therapies, showing improved outcomes. In the advanced setting, the evolution from sorafenib as the primary first-line option to new standards, such as atezolizumab/bevacizumab and tremelimumab/durvalumab, to other emerging therapies such as tislelizumab and pembrolizumab with lenvatinib, is explored. Additionally, second-line treatments and insights into the interplay between immunotherapies and antiangiogenic agents, as well as novel combination strategies that add complexity to treatment decisions, are discussed.

Background: Diffusion weighted imaging (DWI) with intravoxel incoherent motion (IVIM) modelling can inform on tissue perfusion without exogenous contrast administration. Dynamic-contrast-enhanced (DCE) MRI can also characterise tissue perfusion, but requires a bolus injection of a Gadolinium-based contrast agent. This study compares the use of DCE-MRI and IVIM-DWI methods in assessing response to anti-angiogenic treatment in patients with colorectal liver metastases in a cohort with confirmed treatment response., Methods: This prospective imaging study enrolled 25 participants with colorectal liver metastases to receive Regorafenib treatment. A target metastasis > 2 cm in each patient was imaged before and at 15 days after treatment on a 1.5T MR scanner using slice-matched IVIM-DWI and DCE-MRI protocols. MRI data were motion-corrected and tumour volumes of interest drawn on b=900 s/mm 2 diffusion-weighted images were transferred to DCE-MRI data for further analysis. The median value of four IVIM-DWI parameters [diffusion coefficient D (10 -3 mm 2 /s), perfusion fraction f (ml/ml), pseudodiffusion coefficient D* (10 -3 mm 2 /s), and their product fD* (mm 2 /s)] and three DCE-MRI parameters [volume transfer constant K trans (min -1 ), enhancement fraction EF (%), and their product KEF (min -1 )] were recorded at each visit, before and after treatment. Changes in pre- and post-treatment measurements of all MR parameters were assessed using Wilcoxon signed-rank tests (P<0.05 was considered significant). DCE-MRI and IVIM-DWI parameter correlations were evaluated with Spearman rank tests. Functional MR parameters were also compared against Response Evaluation Criteria In Solid Tumours v.1.1 (RECIST) evaluations., Results: Significant treatment-induced reductions of DCE-MRI parameters across the cohort were observed for EF (91.2 to 50.8%, P<0.001), KEF (0.095 to 0.045 min -1 , P<0.001) and K trans (0.109 to 0.078 min -1 , P=0.002). For IVIM-DWI, only D (a non-perfusion parameter) increased significantly post treatment (0.83 to 0.97 × 10 -3 mm 2 /s, P<0.001), while perfusion-related parameters showed no change. No strong correlations were found between DCE-MRI and IVIM-DWI parameters. A moderate correlation was found, after treatment, between K trans and D* (r=0.60; P=0.002) and fD* (r=0.67; P<0.001). When compared to RECIST v.1.1 evaluations, KEF and D correctly identified most clinical responders, whilst non-responders were incorrectly identified., Conclusion: IVIM-DWI perfusion-related parameters showed limited sensitivity to the anti-angiogenic effects of Regorafenib treatment in colorectal liver metastases and showed low correlation with DCE-MRI parameters, despite profound and significant post-treatment reductions in DCE-MRI measurements., Trial Registration: NCT03010722 clinicaltrials.gov; registration date 6 th January 2015., (© 2021. The Author(s).)

Colorectal cancer is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Despite advances in improving resectability, most patients present with non-resectable colorectal liver metastases requiring palliative systemic therapy and locoregional disease control strategies. There is a growing interest in the use of liver transplantation to treat non-resectable colorectal liver metastases in well selected patients, leading to a surge in the number of studies and prospective trials worldwide, thereby fuelling the emerging field of transplant oncology. The interdisciplinary nature of this field requires domain-specific evidence and expertise to be drawn from multiple clinical specialities and the basic sciences. Importantly, the wider societal implication of liver transplantation for non-resectable colorectal liver metastases, such as the effect on the allocation of resources and national transplant waitlists, should be considered. To address the urgent need for a consensus approach, the International Hepato-Pancreato-Biliary Association commissioned the Liver Transplantation for Colorectal liver Metastases 2021 working group, consisting of international leaders in the areas of hepatobiliary surgery, colorectal oncology, liver transplantation, hepatology, and bioethics. The aim of this study was to standardise nomenclature and define management principles in five key domains: patient selection, evaluation of biological behaviour, graft selection, recipient considerations, and outcomes. An extensive literature review was done within the five domains identified. Between November, 2020, and January, 2021, a three-step modified Delphi consensus process was undertaken by the workgroup, who were further subgrouped into the Scientific Committee, Expert Panel, and Transplant Centre Representatives. A final consensus of 44 statements, standardised nomenclature, and a practical management algorithm is presented. Specific criteria for clinico-patho-radiological assessments with molecular profiling is crucial in this setting. After this, the careful evaluation of biological behaviour with bridging therapy to transplantation with an appropriate assessment of the response is required. The sequencing of treatment in synchronous metastatic disease requires special consideration and is highlighted here. Some ethical dilemmas within organ allocation for malignant indications are discussed and the role for extended criteria grafts, living donor transplantation, and machine perfusion technologies for non-resectable colorectal liver metastases are reviewed. Appropriate immunosuppressive regimens and strategies for the follow-up and treatment of recurrent disease are proposed. This consensus guideline provides a framework by which liver transplantation for non-resectable colorectal liver metastases might be safely instituted and is a meaningful step towards future evidenced-based practice for better patient selection and organ allocation to improve the survival for patients with this disease., Competing Interests: Declaration of interests PT receives honoraria from Astellas Pharma Europe, outside the current study. GS receives research grants from Bayer and Roche, and consulting fees from Astrazeneca, Novartis, and Roche, outside the current study. RA receives honoraria for symposia from Merck Serono and Sanofi, outside the current study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Recurrence is the driving factor for reduced long-term survival in patients following resected hepatocellular carcinoma (HCC). Extensive research efforts have been conducted to understand the molecular processes precipitating disease recurrence. Modern genomic techniques have identified two distinct mechanisms for recurrent HCC (RHCC): Intrahepatic metastasis (IM-HCC); and multicentric origin (MO-HCC). Medline, EMBASE and Cochrane library were methodically searched for primary research articles in English with the aim of appraising existing literature on the identification of clonal origin of RHCC and its potential clinical utility., Areas Covered: Molecular and next-generation sequencing techniques, when applied to clonal origin identification, yield superior accuracy than traditional clinicopathological criteria. Despite various treatment modalities, no optimal therapy has yet been identified for treating clonally differentiated RHCC. Patients with MO-HCC appear to experience improved long-term survival following re-treatment compared to their IM-HCC counterparts (91.7% vs 22.9% 5-year survival, p < 0.001). However, cautious interpretation is advised as heterogeneous classification criteria and small sample sizes restrict the generalizability of such findings., Expert Opinion: Improved identification of clonal origin in RHCC may facilitate further research on RHCC treatment strategies and enable the development of novel therapeutic targets, potentially leading to individualized treatment approaches in the future.

OBJECTIVE. The objective of our study was to compare an abbreviated liver MRI protocol with a standard liver MRI protocol for the posttreatment follow-up of colorectal metastases in assessing disease presence, segmental involvement, and response to chemotherapy and for surgical planning. MATERIALS AND METHODS. This retrospective single-center study reviewed consecutive chemotherapy-naïve patients with colorectal liver metastases (April 1, 2011-August 31, 2017) who underwent gadoxetate disodium-enhanced MRI on a 1.5-T unit before and 8-12 weeks after chemotherapy. Two radiologists blinded to outcomes independently reviewed images obtained using standard MRI sequences at baseline and after treatment. The standard MRI sequences were the following: axial T1-weighted, axial T2-weighted, axial DWI (b values = 0-750 s/mm 2 ), axial multiphase contrast-enhanced T1-weighted, and axial and coronal hepatobiliary phase (HBP) T1-weighted sequences. The standard sequences obtained at baseline and the abbreviated protocol sequences (i.e., HBP gadoxetate disodium-enhanced T1-weighted and DWI sequences) obtained after treatment were reviewed. For each image set, reviewers assessed disease presence and segmental involvement; in addition, for images obtained after therapy, treatment response according to RECIST 1.1 was recorded. RESULTS. One hundred thirteen patients (73 men and 40 women; mean age, 61.6 years) were evaluated. The total number of metastases showed high agreement between the standard protocol and abbreviated protocol (intraclass correlation coefficient = 0.97). There was good agreement between the protocols for segmental involvement (weighted κ = 0.73-0.85), and the weighted kappa was 0.82 for all segments. Discrepancies in segmental involvement did not alter potential surgical planning. Categorization of RECIST 1.1 treatment response using the abbreviated protocol versus the standard protocol showed excellent agreement (weighted κ = 0.92). CONCLUSION. An abbreviated liver MRI protocol (i.e., HBP gadoxetate disodium-enhanced T1-weighted and DWI sequences) allows assessment after chemotherapy similar to a standard liver MRI protocol. Use of the abbreviated protocol can reduce imaging time without sacrificing diagnostic performance for the follow-up of colorectal liver metastases.

Background: Symptoms of advanced hepatocellular carcinoma (HCC) represent a substantial burden for the patient and are important endpoints to assess when evaluating treatment. Patient-reported outcomes were evaluated in subjects with advanced HCC and baseline alpha-fetoprotein (AFP) ≥400 ng/mL treated with second-line ramucirumab., Patients and Methods: Patients with AFP≥400 ng/mL enrolled in the REACH or REACH-2 phase 3 studies were used in this analysis. Eligible patients had advanced HCC, Child-Pugh A, Eastern Cooperative Oncology Group performance status 0/1 and prior sorafenib. Patients received ramucirumab 8 mg/kg or placebo once every 2 weeks. Disease-related symptoms and health-related quality of life (HRQoL) were assessed with the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL-5-Dimensions (EQ-5D) instruments, respectively. Time to deterioration (TTD) (≥3-point decrease in FHSI-8 total score;≥0.06-point decrease in EQ-5D score, from randomisation to first date of deterioration) was determined using Kaplan-Meier estimation and the Cox proportional hazards model. Both separate and pooled analyses for REACH AFP≥400 ng/mL and REACH-2 patients were conducted., Results: In the pooled population with AFP ≥400 ng/mL (n=542; ramucirumab, n=316; placebo, n=226), median TTD in FHSI-8 total score was prolonged with ramucirumab relative to placebo (3.3 vs 1.9 months; HR 0.725; (95% CI 0.559 to 0.941); p=0.0152), including significant differences in back pain (0.668; (0.497 to 0.899); p=0.0044), weight loss (0.699; (0.505 to 0.969); p=0.0231) and pain (0.769; (0.588 to 1.005); p=0.0248) symptoms. TTD in EQ-5D score was not significantly different between ramucirumab and placebo groups (median 2.9 vs 1.9 months). Results in the individual trials were consistent with these findings., Conclusions: Ramucirumab in second-line treatment of advanced HCC demonstrates consistent benefit in the delay of deterioration in disease-related symptoms with no worsening of HRQoL. Taken with previously demonstrated ramucirumab-driven survival benefits in this setting, these data may inform patient-clinician discussions about the benefit-risk profile of this therapy., Trial Registration Number: NCT01140347; NCT02435433, NCT02435433., Competing Interests: Competing interests: AXZ: Consulting or advisory role: Eisai, Bristol-Myers Squibb, Merck, Novartis, Sanofi, AstraZeneca, Bayer, Exelixis, Eli Lilly and Company; Research funding: Eli Lilly and Company, Bayer, Bristol-Myers Squibb, Novartis, Merck. RN: None. PRG: Consulting/advisory boards and personal fees: AstraZeneca, Bayer Schering Pharma, Bristol-Myers Squibb, Ipsen, Eli Lilly and Company MSD, Merck, Novartis, Roche, Sirtex Medical, Sillajen. RSF: Consulting: AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Merck, Novartis, Roche/Genentech. JML: Consulting: Eli Lilly and Company, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai, Celsion Corporation, Exelixis, Merck, Ipsen, Glycotest, Navigant, Leerink Swann, Midatech, Fortress Biotech, Sprink Pharmaceuticals, Nucleix, CanFite. Research funding; Bayer HealthCare Pharmaceuticals, Eisai, Bristol-Myers Squibb, Ipsen. J-FB: Personal and consulting fees: Eli Lilly and Company, Bayer, BMS, Eisai, Ipsen, Onxeo, during the conduct of the study. TO: Advisory role: Eli Lilly and Company, Nippon Boehringer Ingelheim, Dainippon Simitomo Pharma, Ono Pharmaceutical, Nano Carrier, Zeria Pharmaceutical, Daiichi Sankyo. Research grant: Eli Lilly and Company, Novartis Pharma K.K., Kowa K.K., Takeda Bio Development Center Limited, Nippon Boehringer Ingelheim, Dainippon Simitomo Pharma, Pfizer Jana, Bayer Yakuhin, Chugai Pharmaceutical, Yakuruto Honsha, Ono Pharmaceutical, Eisaid, AstraZeneca K.K., Merck Serono, OncoTherapy Science, Kyowa Hakko Kirin, Shizuoka Industry, Baxter, Nano Carrier, Zeria Pharmaceutical, Glaxo Smith Kline K.K., Nobelpharma. Honoraria/personal fees: Eli Lilly and Company, Novartis Pharma K.K., Dainippon Simitomo Pharma, Pfizer Jana, Bayer Yakuhin, Chugai Pharmaceutical, Yakuruto Honsha., Ono Pharmaceutical, Eisai Co, AstraZeneca K.K., Merck Serono, Baxter, Nobelpharma, Bristol-Myers Squibb Company, Nipponchemofa, EA Pharma, FUJIFILM RI Pharma, Astellas Pharma, Nippon Kayaku, Daiichi Sankyo, Celgene, K.K., MSD, K.K., Teijin Pharma. IC: Advisory board: Sanofi Oncology, Eli Lilly and Company, Bristol-Myers Squibb, MSD, Bayer, Roche, Merck Serono, Five Prime Therapeutics; Astra-Zeneca, Oncologie International, Pierre Fabre; Research funding: Eli-Lilly and Company, Janssen-Cilag, Sanofi Oncology, Merck-Serono. Honorarium: Eli Lilly and Company. DC: Consultant for Eli Lilly and Company, during the conduct of the study; outside the submitted work. Consultant for Abbvie; BMS; Pfizer; Novartis; Bioverativ; Ipsen; FACIT.org, president. AG, JG, LB, PBA; CW: Employee and minor shareholder of Eli Lilly and Company. YH is a former employee of Eli Lilly and Company. MK: Consulting or advisory role: Bayer, Bristol-Myers Squibb, Eisai, MSD, Ono Pharmaceutical. Personal fees/Honoraria: Bayer, Eisai, MSD. Research funding: Abbvie, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Gilead, Medico’s Hirata, Otsuka, Takeda, Taiho Pharmaceutical., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Ramucirumab is a fully humanized monoclonal antibody directed selectively at VEGFR-2 - a key player in the VEGF orchestra and angiogenic process. It has demonstrated clinical efficacy and a favorable safety profile in the treatment of a number of malignancies including gastric, lung, urothelial, colorectal and, most recently, advanced liver cancer. This article describes the recent Phase III trial results of ramucirumab in patients with hepatocellular carcinoma, including safety data and patient-reported outcomes, with particular emphasis on efficacy data in the patient population with baseline α-fetoprotein levels ≥400 ng/ml, traditionally considered a poor prognostic group.

Background: Akt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC., Patients and Methods: In this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)-low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway-activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments., Results: In 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7-7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2-8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81-1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway-activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with ≥1 adverse event (AE, 100% versus 98%) and grade ≥3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively., Conclusions: Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed., Trial Registration: ClinicalTrials.gov (NCT01896531)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Loss of ataxia telangiectasia mutated (ATM), a key protein regulating DNA repair signaling, has been suggested to increase sensitivity to DNA damaging agents. We conducted a study analyzing the loss of ATM protein expression in colorectal cancer and correlated this with clinical outcomes., Materials and Methods: The clinical outcomes data and tumor samples from metastatic colorectal cancer patients referred to the Royal Marsden Hospital Drug Development Unit (United Kingdom) from 2012 to 2016 and providing consent for a molecular characterization study were analyzed. Immunohistochemistry (IHC) slides were assessed by a pathologist for nuclear staining intensity of ATM and semiquantitatively scored. ATM loss was defined as a nuclear H-score of ≤ 10., Results: Of 223 colorectal cancer samples, ATM IHC loss was identified in 17 (8%). ATM loss was independent of the RAS and RAF mutational status. ATM loss was associated with superior overall survival after first-line oxaliplatin-based therapy (49 vs. 32 months; hazard ratio [HR], 2.52) but not with irinotecan-based therapy (24 vs. 33 months; HR, 0.72). ATM loss was not prognostic for survival from the diagnosis (50 vs. 44 months; HR, 1.43)., Conclusion: ATM could be considered a biomarker for the development of novel DNA repair targeting agents and treatment of colorectal cancer., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Post-hoc analyses of AFP response and progression and their relationship with objective measures of response and survival were performed in patients from REACH., Methods: Serum AFP was measured at baseline and every 3 cycles (2 weeks/cycle). Associations between AFP and radiographic progression and efficacy end points were analysed., Results: Median percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P < 0.0001) and to radiographic progression (HR 0.613; P < 0.0001) favoured ramucirumab. Association between AFP and radiographic progression was shown at 6 (OR 6.44, 95% CI 4.03, 10.29; P < 0.0001) and 12 weeks (OR 2.28, 95% CI 1.47, 3.53; P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P < 0.0001). More patients in the ramucirumab arm experienced tumour shrinkage and AFP response compared with placebo. Survival was longer in patients with AFP response (13.6 months) than in patients without (6.2 months), irrespective of treatment (HR 0.457, P < 0.0001)., Conclusions: Treatment with ramucirumab prolonged time to AFP progression, slowed AFP increase and was more likely to induce AFP response. Similar benefits in radiographic progression and response correlated with AFP changes.

Purpose: To report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib., Methods: Eligible patients had advanced HCC, Child-Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a ≥3-point decrease from baseline and PS deterioration was defined as a change of ≥2. Both intention-to-treat and pre-specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) ≥400 ng/mL were assessed., Results: There were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP ≥400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab., Conclusions: We report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP ≥400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patient-focused outcome benefits., Clinical Trial Registration: NCT01140347., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib., Methods: In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347., Findings: Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression., Interpretation: Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable., Funding: Eli Lilly and Co., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Multidrug regimens are active against advanced colorectal cancer (ACRC). However, the increased toxicity requires the use of biomarkers to select the patients who will derive the most benefit. We assessed circulating tumor cells (CTCs) as a prognostic biomarker in patients treated with a 4-drug regimen., Patients and Methods: A single-arm phase II trial (Erbitux Study of CPT11, Oxaliplatin, UFToral Targeted-therapy [eSCOUT]) was undertaken in patients with previously untreated KRAS wild-type ACRC using a regimen of irinotecan, oxaliplatin, and tegafur-uracil with leucovorin and cetuximab. Baseline CTCs were enumerated using CellSearch. The endpoints were an objective response rate (ORR) and overall survival (OS). We modeled our results and compared them with those modeled for the capecitabine, oxaliplatin, bevacizumab +/- cetuximab (CAIRO2) trial, stratifying patients a priori into low (< 3) and high (≥ 3) CTC groups., Results: For 48 eligible patients, the best ORR from the 4-drug regimen was 71%, with a disease control rate of 98%. The median OS for patients with a high and low CTC count was 18.7 and 22.3 months (log-rank test, P = .038), respectively. In our modeled data, for patients with a low CTC count, no differences were found between the median OS in the eSCOUT trial and that in the CAIRO2 trial (22.2 vs. 22.0 months). However, for the high CTC group, a clinically relevant improvement was seen in median OS (eSCOUT vs. CAIRO2, 18.7 vs. 13.7 months; P = .001)., Conclusion: These data are hypothesis generating-for patients with ACRC, stratification by CTC count can identify those who might benefit the most from an intensive 4-drug regimen, avoiding high-toxicity regimens in low CTC groups. This hypothesis warrants validation in a phase III biomarker-driven trial., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine the value of SUV-based metabolic parameters derived from pretreatment F-FDG PET/CT of colorectal liver metastases in predicting disease response, progression-free survival (PFS), and overall survival (OS)., Patients and Methods: We retrospectively reviewed 70 colorectal patients with liver metastases who underwent pretreatment F-FDG PET/CT. SUVmean, SUVmax, TLG (total lesion glycolysis), metabolic tumor volume, and metabolic tumor diameter were the metabolic parameters derived from volume of interest analysis of the most FDG-avid liver lesion in each subject. Clinical and laboratory parameters were recorded. Tumor response was assessed by response evaluation criteria in solid tumors 1.1 criteria at 12 weeks after treatment. Associations between tumor response, metabolic parameters, and clinical/laboratory parameters were examined by 1-way analysis of variance. The relationship of the metabolic parameters with PFS and OS was determined by Kaplan-Meier analyses and further confirmed with multivariate Cox regression analyses., Results: SUVmean less than 4.48, SUVmax less than 6.59, TLG less than 75.2, metabolic tumor volume less than 4.49 cm, and hemoglobin level greater than or equal to 11 g/dL were associated with longer PFS (P < 0.05). Prior surgery or radiofrequency ablation to the liver metastases was the only additional factor shown to be associated with longer OS., Conclusions: SUV-based metabolic parameters derived from pretreatment F-FDG PET/CT can predict PFS in colorectal liver metastases.

Aim: The objective of this study was to determine the effect of an upfront primary tumour resection on the progression of synchronous colorectal liver metastases., Materials and Methods: Patients with synchronous colorectal liver metastases referred between 2005 and 2010 were identified. Patients were analysed according to the following two groups: 1) an upfront primary tumour resection and 2) neo-adjuvant chemotherapy. A univariate and multivariate analysis was performed to identify factors significantly contributing to progressive disease. Cox regression analysis was undertaken to determine the effect of management on overall survival (OS) and time to tumour progression (TTP)., Results: A total of 116 patients with synchronous colorectal liver metastases were identified of which 49 patients received an upfront primary tumour resection and 67 received neo-adjuvant chemotherapy. Liver resections were performed in 18 (36.7%) and 14 (20.9%) of the patients in the upfront and neo-adjuvant groups respectively (P 0.06). On multivariate analysis, an upfront primary tumour resection significantly affected progressive disease (p < 0.001, OR 5.67; 95% CI 2.71-11.79). An upfront tumour resection was not a significant predictor of overall survival (P = 0.83; HR 1.10; 95% CI 0.48-2.52)., Conclusion: Our findings suggest that an upfront primary tumour resection in patients with synchronous colorectal liver metastases results in progressive disease. These preliminary findings need to be validated in a future multi-centre independent study., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting., Patients and Methods: OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis., Results: In patients assigned to bevacizumab-FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9-22.3) months and 11·5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively)., Conclusions: Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab-FOLFOXIRI., Clinicaltrialsgov: NCT00778102., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Colorectal cancer (CRC) is one of the commonest cancers with 1.2 million new cases diagnosed each year in the world. It remains the fourth most common cause of cancer-related mortality in the world and accounts for > 600000 cancer-related deaths each year. There have been significant advances in treatment of metastatic CRC in last decade or so, due to availability of new active targeted agents and more aggressive approach towards the management of CRC, particularly with liver-only-metastases; however, these drugs work best when combined with conventional chemotherapy agents. Despite these advances, there is a lack of biomarkers to inform us about the accurate management of the patients with metastatic CRC. It is therefore imperative to carefully select the patients with comprehensive multi-disciplinary team input in order to optimise the management of these patients. In this review we will discuss various treatment options available in management of colorectal liver metastases with potential guidance on how and when to choose these options along with consideration on future directions in management of this disease.

Objective: To determine the prognostic value of pre-treatment apparent diffusion coefficient (ADC) of colorectal liver metastases in predicting disease response, progression-free survival (PFS) and overall survival (OS)., Methods: We retrospectively reviewed 102 patients who underwent pre-treatment diffusion-weighted MRI using a breath-hold (b=0, 150, 500) or a free-breathing (b=0, 50, 100, 250, 500, 750) technique. The mean ADC (b=0-500) and mean flow-insensitive ADC (ADChigh) values (breath-hold: b=150 and 500; free-breathing: b=100 and 500) of up to three hepatic lesions were evaluated in each patient. Clinical and laboratory parameters were recorded. Tumour response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria at 12 weeks after treatment. Associations between tumour response, ADC values and clinical/laboratory parameters were examined by one-way analysis of variance. The relationship of ADC with PFS and OS was determined by Kaplan-Meier analysis., Results: 62 patients responded to chemotherapy at 12 weeks. The pre-treatment mean ADC and mean ADChigh were higher in the non-responding group than in the responding group (1.55 vs 1.36, p=0.033; 1.40 vs 1.16, p=0.024). However, the PFS and OS of the two groups of patients stratified by the median of mean ADC values or threshold derived by receiver operating characteristic analysis were not statistically significant. By multivariate Cox regression analysis, patients with ≤2 metastases and response to chemotherapy showed better PFS; white cell count ≤10 and surgical treatment were associated with better OS., Conclusion: Colorectal liver metastasis with higher pre-treatment mean ADC and mean ADChigh was associated with poorer response to chemotherapy. However, ADC and ADChigh values did not predict the patient outcome in this study cohort., Advances in Knowledge: High mean ADC values of colorectal liver metastases on pre-treatment diffusion-weighted MRI is associated with poorer response to chemotherapy.

Unlabelled: The impact of adding bevacizumab to perioperative chemotherapy in patients with colorectal cancer (CRC) undergoing liver resection is yet to be defined. A retrospective review of our patient records showed that the addition of bevacizumab did not increase morbidity or mortality related to liver resection. Pathologic complete response (CR) is associated with prolonged survival., Background: Patients with colorectal cancer (CRC) and liver metastases benefit from perioperative chemotherapy and liver resection. The potential benefit of adding bevacizumab is yet to be defined. The impact of bevacizumab on liver resection complications has been explored in a small number of retrospective studies., Methods: The records of patients with CRC and liver metastases who underwent liver resection and had received perioperative chemotherapy were reviewed. Complications were reported separately for 2 groups (chemotherapy alone vs chemotherapy and bevacizumab). Survival outcomes (progression-free survival [PFS] and overall survival [OS]) for responders and nonresponders were estimated using the Kaplan-Meier method., Results: Fifty-two patients received chemotherapy alone and 42 patients received chemotherapy and bevacizumab. The median time from the end of systemic treatment to liver resection was 59 days (33-181 days) for the chemotherapy group and 62 days (44-127 days) for the chemotherapy and bevacizumab group. Postoperative complications developed in 54% of the chemotherapy group and in 48% of the chemotherapy and bevacizumab group. Severe complications (grade III-V) occurred in only 13% and 12%, respectively (P = .822). Pathologic complete response (CR) was seen in 11/94 patients. Poor performance status (PS) before starting chemotherapy was associated with higher rates of complications (P = .002), and severe complications led to prolonged hospital admission (P = .001). Patients with pathologic CR had longer OS (P = .0275), but there was no difference in OS between responders and nonresponders (P = .778)., Conclusion: The addition of bevacizumab to chemotherapy does not increase liver resection complication rates. Pathologic CR is associated with prolonged survival., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To compare the diagnostic accuracy of gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MRI, diffusion-weighted MRI (DW-MRI) and a combination of both techniques for the detection of colorectal hepatic metastases., Methods: 72 patients with suspected colorectal liver metastases underwent Gd-EOB-DTPA MRI and DW-MRI. Images were retrospectively reviewed with unenhanced T(1) and T(2) weighted images as Gd-EOB-DTPA image set, DW-MRI image set and combined image set by two independent radiologists. Each lesion detected was scored for size, location and likelihood of metastasis, and compared with surgery and follow-up imaging. Diagnostic accuracy was compared using receiver operating characteristics and interobserver agreement by kappa statistics., Results: 417 lesions (310 metastases, 107 benign) were found in 72 patients. For both readers, diagnostic accuracy using the combined image set was higher [area under the curve (Az)=0.96, 0.97] than Gd-EOB-DTPA image set (Az=0.86, 0.89) or DW-MRI image set (Az=0.93, 0.92). Using combined image set improved identification of liver metastases compared with Gd-EOB-DTPA image set (p<0.001) or DW-MRI image set (p<0.001). There was very good interobserver agreement for lesion classification (κ=0.81-0.88)., Conclusions: Combining DW-MRI with Gd-EOB-DTPA-enhanced T(1) weighted MRI significantly improved the detection of colorectal liver metastases.

Background: Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer, but to date, despite extensive research, no predictive or prognostic biomarkers for bevacizumab have been identified. The development of bevacizumab-induced arterial hypertension has recently been suggested as a potential predictive biomarker., Methods: Blood pressure was recorded during the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection. In this analysis, the development of bevacizumab-induced hypertension was correlated with clinical outcomes., Results: Fifteen percent of patients developed ≥grade 1 hypertension while receiving neoadjuvant chemotherapy, and 4% developed grade 3 hypertension. There was no correlation between the development of hypertension and radiological response rate (P=0.642), progression-free survival (P=0.644) or overall survival (P=0.480) in those who developed hypertension compared with those who did not., Conclusion: Bevacizumab-induced hypertension did not predict radiological response or survival in our study. The results highlight a number of important issues regarding the use of hypertension as a biomarker., (© 2012 Cancer Research UK)

Background: Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection., Patients and Methods: Poor-risk CLM was defined as follows: more than four metastases, diameter >5 cm, R0 resection unlikely, inadequate viable liver function if undergoing upfront resection, inability to retain liver vascular supply, or synchronous colorectal primary presentation. Patients underwent baseline computed tomography, magnetic resonance imaging, and/or positron emission tomography (PET) for staging and received neoadjuvant CAPOX plus bevacizumab, with resectability assessed every four cycles. Primary end point was radiological objective response rate (ORR)., Results: Forty-six patients were recruited, of which 91% underwent PET to ensure metastases confined to liver. Following neoadjuvant CAPOX plus bevacizumab, the ORR was 78% (95% confidence interval 63% to 89%). This allowed 12 of 30 (40%) patients with initial nonsynchronous unresectable CLM to be converted to resectability. In addition, 10 of 15 (67%) patients with synchronous resectable CLM underwent liver resection, with four additional patients being observed alone due to excellent response to neoadjuvant therapy. No grade 3-4 perioperative complications were seen., Conclusion: Neoadjuvant CAPOX plus bevacizumab resulted in a high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability.

Background: Stage IV colorectal cancer encompasses a broad patient population in which both curative and palliative management strategies may be used. In a phase II study primarily designed to assess the efficacy of capecitabine and oxaliplatin, we were able to prospectively examine the outcomes of patients with stage IV colorectal cancer according to the baseline resectability status., Methods: At enrolment, patients were stratified into three subgroups according to the resectability of liver disease and treatment intent: palliative chemotherapy (subgroup A), conversion therapy (subgroup B) or neoadjuvant therapy (subgroup C). All patients received chemotherapy with capecitabine 2000 mg m(-2) on days 1-14 and oxaliplatin 130 mg m(-2) on day 1 repeated every 3 weeks. Imaging was repeated every four cycles where feasible liver resection was undertaken after four or eight cycles of chemotherapy., Results: Of 128 enrolled patients, 74, 22 and 32 were stratified into subgroups A, B and C, respectively. Attempt at curative liver resection was undertaken in 10 (45%) patients in subgroup B and 19 (59%) in subgroup C. The median overall survival was 14.6, 24.5 and 52.9 months in subgroups A, B and C, respectively. For patients in subgroups B and C who underwent an attempt at curative resection, 3-year progression-free survival was 10% in subgroup B and 37% for subgroup C., Conclusions: This prospective study shows the wide variation in outcome according to baseline resectability status and highlights the potential clinical value of a modified staging system to distinguish between these patient subgroups.

To compare the diagnostic accuracy of MnDPDP MR imaging and diffusion-weighted imaging (DWI), alone and in combination, for detecting colorectal liver metastases in patients with suspected metastatic disease. Thirty-three consecutive patients with suspected colorectal liver metastases underwent MR imaging. Three image sets (MnDPDP, DWI and combined MnDPDP and DWI) were reviewed independently by two observers. Lesions were scored on a five-point scale for malignancy and the areas (Az) under the receiver operating characteristic curves were calculated for each observer and image set. The sensitivity and specificity for lesion detection were calculated for each image set and compared. There were 83 metastases, 49 cysts and 1 haemangioma. Using the combined set resulted in the highest diagnostic accuracy for both observers (Az=0.94 and 0.96), with improved averaged sensitivity of lesion detection compared with the DWI set (p=0.01), and a trend towards improved sensitivity compared with the MnDPDP set (p=0.06). There was no difference in the averaged specificity using any of the three image sets (p>0.5). Combination of MnDPDP MR imaging and DWI resulted in the highest diagnostic accuracy and can increase sensitivity without loss in specificity.