Hepatocellular carcinoma (HCC)-closely associated with liver cirrhosis and, in fact, the main cause of death in patients with such disease-is now recognized as one of the most-prevalent and lethal ...neoplasms worldwide. Prognosis and allocation of the multiple available treatment options for patients with HCC are influenced not only by tumour stage, but also by the degree of liver-function impairment. Therefore, accurate assessment and classification of disease is important for patient management. According to the Barcelona Clinic Liver Cancer (BCLC) algorithm, intermediate-stage HCC is defined as extensive multifocal disease without vascular invasion in patients with preserved liver function and absence of cancer-related symptoms; in this context, transarterial chemoembolization (TACE) is considered the standard treatment. The use of drug-eluting beads has enabled standardization of this procedure, resulting in higher reproducibility and tolerability of the treatment. Nevertheless, not all patients with intermediate-stage HCC are good candidates for TACE and, for such patients in whom TACE is not appropriate or has failed, other treatments can be considered, including sorafenib. Radioembolization is a promising alternative that deserves further prospective studies. Herein, we review the current approaches used to accurately stratify patients with intermediate-stage HCC and subsequently allocate the most-appropriate treatments. The key developments in therapeutic strategies are also discussed.
Liver cancer is the fifth most common cancer and the second most frequent cause of cancer-related death globally. Hepatocellular carcinoma represents about 90% of primary liver cancers and ...constitutes a major global health problem. The following Clinical Practice Guidelines will give up-to-date advice for the clinical management of patients with hepatocellular carcinoma, as well as providing an in-depth review of all the relevant data leading to the conclusions herein.
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Reasons for those failures have been discussed previously: poor understanding of drivers of progression, flaws in trial design, underestimation of liver toxicity, marginal antitumour activity, and an ...absence of trial enrichment with adequate biomarkers of benefit.3 Many histology-based, molecular-based or immune-based classifications have now been published to assist that enrichment.4 In The Lancet Oncology, Shukui Qin and colleagues report their evaluation of the safety and activity of camrelizumab, a new immune checkpoint inhibitor developed by Jiangsu Hengrui Medicine. Unfortunately, only 30 (14%) of 217 patients had PD-L1 expression data from liver biopsy, and no relationship between PD-L1 expression and activity has been shown. ...camrelizumab, reproducing the results of other checkpoint inhibitors, might be a good option, but only in a small and unidentified fraction of the hepatocellular carcinoma population. On the basis of their study results, the authors have launched two phase 3 trials: one in June, 2019 comparing sorafenib with camrelizumab plus apatinib (from the same company), and a second involving FOLFOX (leucovorin, fluorouracil, and oxaliplatin; approved in China for the treatment of locally advanced and metastatic liver cancers when surgery and local treatments are unsuitable, and frequently given owing to the lower cost compared with sorafenib, but not considered the standard of care in the rest of the world) versus camrelizumab plus FOLFOX.
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•TACE is the standard-of-care for the treatment of intermediate stage HCC.•DEB-TACE is not superior to conventional TACE in efficacy and safety.•Several studies demonstrated the clinical benefit to ...combine cTACE and RFA.•Outside stage B, TACE can treat lesions/patients not eligible to other treatments.•Further studies are required to state the place of TACE outside intermediate stage.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, representing the sixth leading cause of cancer and the third leading cause of cancer-related mortality. Patient stratification and treatment allocation are based on tumor stage, liver function, and performance status. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is the first-line treatment for patients with intermediate stage HCC, including those with large or multinodular HCC, well-preserved liver function, and no cancer-related symptoms or evidence of vascular invasion or extrahepatic spread. Two TACE techniques have been used since 2004, conventional TACE (cTACE) and TACE with drug-eluting beads (DEB-TACE). cTACE was evidenced first to treat intermediate stage HCC patients. It combines the transcatheter delivery of chemotherapy using Lipiodol-based emulsion plus an embolizing agent to achieve strong cytotoxic and ischemic effects. Drug-eluting beads (DEBs) were developed in order to slowly release chemotherapeutic agents, and to increase ischemia intensity and duration. Recent advances allow TACE treatment of both early stage patients (i.e. those with a solitary nodule or up to 3 nodules under 3 cm) and some advanced stage patients. Here we review recent clinical evidence related to TACE treatment of patients with early, intermediate, and advanced stage HCC. Based on the 2014 TACE algorithm of Raoul et al., this international expert panel proposes an updated TACE algorithm and provides insights into TACE use for patients at any HCC stage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Sorafenib is indicated for advanced and intermediate (post-TACE failure) HCC.•Sorafenib should be given early to ensure patients can benefit from all therapies.•Sorafenib toxicities can be ...effectively prevented and managed for treatment benefit.•Sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab improve survival.•New systemic agents are emerging for the treatment of patients with advanced HCC.
The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can be prevented. Sorafenib-related AEs have been identified as clinical biomarkers for sorafenib efficacy. Healthcare professionals have become more efficient in managing AEs, identifying patients who are likely to benefit from treatment, and assessing response to treatment, resulting in a trend towards increased overall survival in the sorafenib arms of clinical studies. The rapidly changing treatment landscape due to the emergence of new treatment options (sorafenib and lenvatinib equally effective in first line; regorafenib, cabozantinib, and ramucirumab showing OS benefit in second line with nivolumab approved by the FDA based on response rate) underscores the importance of re-assessing the role of the first approved systemic agent in HCC, sorafenib.
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Summary Background Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess ...the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer. Methods We did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I–IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0–2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m2 , leucovorin 200 mg/m2 , bolus fluorouracil 400 mg/m2 , and infusional fluorouracil 1600 mg/m2 (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m2 per day for 4 days and cisplatin 75 mg/m2 on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00861094. Findings 134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25·3 months (IQR 15·9–36·4). Median progression-free survival was 9·7 months (95% CI 8·1–14·5) in the FOLFOX group and 9·4 months (8·1–10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70–1·24; p=0·64). One toxic death occurred in the FOLFOX group and six in the fluorouracil–cisplatin group (p=0·066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 47% events in 131 patients in the FOLFOX group vs three 2% in 128 patients in the cisplatin–fluorouracil group, p<0·0001), sensory neuropathy (24 18% vs one 1%, p<0·0001), increases in aspartate aminotransferase concentrations (14 11% vs two 2%, p=0·002), and increases in alanine aminotransferase concentrations (11 8% vs two 2%, p=0·012) were more common in the FOLFOX group, whereas serum creatinine increases (four 3% vs 15 12%, p=0·007), mucositis (35 27% vs 41 32%, p=0·011), and alopecia (two 2% vs 12 9%, p=0·005) were more common in the fluorouracil and cisplatin group. Interpretation Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery. Funding UNICANCER, French Health Ministry, Sanofi-Aventis, and National League Against Cancer.
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To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether ...pretreatment QoL predicts survival in patients with metastatic pancreatic cancer.
Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m(2); irinotecan, 180 mg/m(2); leucovorin, 400 mg/m(2); and fluorouracil, 400 mg/m(2) bolus followed by 2,400 mg/m(2) 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m(2) weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks.
Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin.
FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.
Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An ...unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib.
In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety.
Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio HR, 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%).
In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.
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