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1.
Targeted therapy for hepatocellular carcinoma.
Huang, A, Yang, XR, Chung, WY, Dennison, AR, Zhou, J
Signal transduction and targeted therapy. 2020;(1):146
Abstract
The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.
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Lenvatinib complementary with radioiodine therapy for patients with advanced differentiated thyroid carcinoma: case reports and literature review.
Sheu, NW, Jiang, HJ, Wu, CW, Chiang, FY, Chiou, HC, Hsiao, PJ
World journal of surgical oncology. 2019;(1):84
Abstract
BACKGROUND The prognosis for patients with advanced differentiated thyroid carcinoma (ADTC) with disseminated distant metastases is very poor. Tyrosine kinase inhibitors targeting tumor angiogenesis have been shown to improve progression-free survival in patients with advanced thyroid carcinoma and progressive radioiodine-refractory thyroid carcinoma. Tyrosine kinase inhibitor has been reported as a successful neoadjuvant for total thyroidectomy to reduce tumor burden. However, the special indications for prompt treatment with lenvatinib as a rescue therapy to reduce tumor burden and prolong a durable response to radioiodine therapy have not been explored. CASE PRESENTATION Here, we present two ADTC cases with distant metastases who were effectively treated by total thyroidectomy combined with lenvatinib to prolong a durable response to radioiodine therapy. Case 1 was a 66-year-old male diagnosed with ADTC and disseminated brain, lung, and bone metastases. Lenvatinib was initiated via compassionate access because of rapidly progressive tumor growth even after second doses of radioiodine therapy and external beam radiation therapy for his brain metastases. The result was a durable response to lenvatinib, slowing progressive tumor growth for 3 years and allowing a third course of radioiodine therapy to treat the bone metastases. Case 2 was a 45-year-old male diagnosed with ADTC and diffuse disseminated lung metastases. Respiratory failure ensued after total thyroidectomy, requiring mandatory support by respirator. Lenvatinib was started as a rescue therapy to reduce tumor burden rapidly. The patient was successfully weaned off the respirator only 1 week after using lenvatinib. The patient was then maintained on a low dose of lenvatinib, allowing three subsequent courses of radioiodine therapy. Currently, his lung metastasis remains well controlled with decreased lung infiltrating nodules and the patient can tolerate exercise well. CONCLUSION Our case experience indicated that lenvatinib has significant value as salvage therapy, reducing tumor burden, producing a durable response and maintaining quality of life. For ADTC patients with progressive life-threatening metastases, our experience suggests that lenvatinib treatment can be used as an urgent rescue therapy as well as a complement to radioiodine therapy to improve tumor eradication.
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3.
Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers.
Fondevila, F, Méndez-Blanco, C, Fernández-Palanca, P, González-Gallego, J, Mauriz, JL
Experimental & molecular medicine. 2019;(9):1-15
Abstract
Regorafenib is a sorafenib-derived chemotherapy drug belonging to the multikinase inhibitor family. This agent effectively targets a wide range of tyrosine kinases involved in cancer biology, such as those implicated in oncogenesis, angiogenesis, and tumor microenvironment control. The beneficial effects of regorafenib in clinical trials of patients who suffer from advanced hepatocellular carcinoma (HCC), colorectal cancer (CRC) or gastrointestinal stromal tumors (GISTs) refractory to standard treatments led to regorafenib monotherapy approval as a second-line treatment for advanced HCC and as a third-line treatment for advanced CRC and GISTs. Multiple in vitro and in vivo studies have been performed over the last decade to reveal the molecular mechanisms of the favorable actions exerted by regorafenib in patients. Given the hypothetical loss of sensitivity to regorafenib in tumor cells, preclinical research is also searching for novel therapeutic approaches consisting of co-administration of this drug plus other agents as a strategy to improve regorafenib effectiveness. This review summarizes the anti-tumor effects of regorafenib in single or combined treatment in preclinical models of HCC, CRC and GISTs and discusses both the global and molecular effects that account for its anti-cancer properties in the clinical setting.
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Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature.
Denaro, N, Latina, A, Cesario, F, Bramardi, F, Corrado, L, Borretta, G, Merlano, MC
Oncology. 2019;(4):206-210
Abstract
Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs.
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5.
Efficacy of sequential therapies with sorafenib-sunitinib versus sunitinib-sorafenib in metastatic renal cell carcinoma: A systematic review and meta-analysis.
Wen, T, Xiao, H, Luo, C, Huang, L, Xiong, M
Oncotarget. 2017;(12):20441-20451
Abstract
The most efficient sequence of targeted agents for metastatic renal cell carcinoma patients has yet to be identified. Whether the sequence of sorafenib and sunitinib really matters is controversial and not answered clearly until now. This meta-analysis aims to estimate the efficacy of receptor tyrosine kinase inhibitors sorafenib-sunitinib and sunitinib-sorafenib for metastatic renal cell carcinoma, on the outcome of first-line progression-free survival, second-line progression-free survival, total progression-free survival and overall survival.We searched PubMed, Embase, Cochrane Library and ClinicalTrails.gov for eligible studies. Data were analyzed using random or fixed effects model depending on the heterogeneity of the eligible studies. Heterogeneity across studies were analyzed using Q and I2 statistics.Of 902 identified studies, ten were qualified in our analysis (N = 1732 patients). Sorafenib-sunitinib yielded no statistically significant benefit in first-line progression-free survival (fixed effects; HR = 0.95; 95%CI 0.75-1.21; p = 0.702), total progression-free survival (random effects; HR = 0.92; 95%CI 0.71-1.19; p = 0.531) and overall survival (fixed effects; HR = 0.89; 95%CI 0.72-1.09; p = 0.257), compared with sunitinib-sorafenib. Second-line progression-free survival was longer for sorafenib-sunitinib than sunitinib-sorafenib (fixed effects; HR = 0.55; 95%CI 0.44-0.68; p = 0.000).Sequential therapies with sorafenib and sunitinib is well tolerated and efficient in mRCC. However, there are no evidence supported that sorafenib-sunitinib has the superiority to sunitinib-sorafenib in sequence. The ideal sequence of targeted agents requires further elucidation.
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6.
Exceptional serological and radiological response to sorafenib in 2 patients with advanced hepatocellular carcinoma and chronic hepatitis C viral infection: case report and review of the literature.
Atkin, C, Earwaker, P, Pallan, A, Shetty, S, Punia, P, Ma, YT
BMC gastroenterology. 2017;(1):30
Abstract
BACKGROUND In patients with advanced hepatocellular carcinoma (HCC), the multikinase inhibitor sorafenib is the only systemic treatment that has been shown to increase overall survival. However, similar to other tyrosine kinase inhibitors, most patients achieve disease stabilisation radiologically, and only 2-3% of patients achieve a partial response. Recent exploratory subgroup analyses of the large phase 3 trials have demonstrated that patients with chronic hepatitis C virus (HCV) infection associated HCC survive longer than those who are negative for HCV. The mechanism underlying this currently remains unknown. A small number of cases of complete response to sorafenib treatment have now been reported worldwide, however a prolonged response has only been reported in 2 cases, both of whom had HCV-related HCC. CASE PRESENTATION A 55 year old gentleman was diagnosed with hepatocellular carcinoma and concomitant chronic hepatitis C viral infection. He progressed following transarterial chemoemoblisation treatment and was commenced on sorafenib treatment. His serum alphafetoprotein level normalised within 2 months of treatment and he achieved an almost complete radiological response. This response was maintained for 20 months before the patient progressed. A 75 year old lady was diagnosed with advanced hepatocellular carcinoma and concomitant chronic hepatitis C viral infection. She was commenced on sorafenib treatment but required early dose reductions due to palmar plantar erythrodysesthesia, and liver decompensation. Despite this she achieved an excellent serological and radiological response that was maintained for 24 months. CONCLUSIONS Our two cases show that patients with HCV-associated HCC can attain excellent responses to sorafenib treatment that is durable. Furthermore, such exceptional responses can be achieved even with dose reductions and treatment breaks.
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Management of people with intermediate-stage hepatocellular carcinoma: an attempted network meta-analysis.
Roccarina, D, Majumdar, A, Thorburn, D, Davidson, BR, Tsochatzis, E, Gurusamy, KS
The Cochrane database of systematic reviews. 2017;(3):CD011649
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Abstract
BACKGROUND There is significant uncertainty in the treatment of intermediate-stage hepatocellular carcinoma which is defined by the Barcelona Clinic Liver Cancer (BCLC) as hepatocellular carcinoma stage B with large, multi-nodular, Child-Pugh status A to B, performance status 0 to 2, and without vascular occlusion or extrahepatic disease. OBJECTIVES To assess the comparative benefits and harms of different interventions used in the treatment of intermediate-stage hepatocellular carcinoma (BCLC stage B) through a network meta-analysis and to generate rankings of the available interventions according to their safety and efficacy. However, we found only one comparison. Therefore, we did not perform the network meta-analysis, and we assessed the comparative benefits and harms of different interventions versus each other, or versus placebo, sham, or no intervention (supportive treatment only) using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised clinical trials registers to September 2016 to identify randomised clinical trials on hepatocellular carcinoma. SELECTION CRITERIA We included only randomised clinical trials, irrespective of language, blinding, or publication status, in participants with intermediate-stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, size, or number of the tumours (provided they met the criteria of intermediate-stage hepatocellular carcinoma), of presence or absence of portal hypertension, of aetiology of hepatocellular carcinoma, and of the future remnant liver volume. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various interventions compared with each other or with no active intervention (supportive treatment only). We excluded trials which compared variations of the same intervention: for example, different methods of performing transarterial chemoembolisation. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We calculated the hazard ratio (HR) with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and assessed the quality of the evidence using GRADE. MAIN RESULTS Three randomised clinical trials, including 430 participants, met the inclusion criteria for this review; however, data from two trials with 412 participants could be included in only one primary outcome (i.e. mortality). All three trials were at high risk of bias. All three trials included supportive care as cointervention. The comparisons included in the two trials reporting on mortality were: systemic chemotherapy with sorafenib versus no active intervention; and transarterial chemoembolisation plus systemic chemotherapy with sorafenib versus transarterial chemoembolisation alone. The trials did not report the duration of follow-up; however, it appeared that the participants were followed up for a period of about 18 to 30 months. The majority of the participants in the trials had cirrhotic livers. The trials included participants with intermediate-stage hepatocellular carcinoma arising from viral and non-viral aetiologies. The trials did not report the portal hypertension status of the participants. The mortality was 50% to 70% over a median follow-up period of 18 to 30 months. There was no evidence of difference in mortality at maximal follow-up between systemic chemotherapy versus no chemotherapy (hazard ratio 0.85, 95% CI 0.60 to 1.18; participants = 412; studies = 2; I2 = 0%; very low quality evidence). A subgroup analysis performed by stratifying the analysis by the presence or absence of transarterial chemoembolisation as cointervention did not alter the results. None of the trials reported on serious adverse events other than mortality, health-related quality of life, recurrence of hepatocellular carcinoma, or length of hospital stay. One of the trials providing data was funded by the pharmaceutical industry, the other did not report the source of funding, and the trial with no data for the review was also funded by the pharmaceutical industry. We found two ongoing trials. AUTHORS' CONCLUSIONS Currently, there is no evidence from randomised clinical trials that people with intermediate-stage hepatocellular carcinoma would benefit from systemic chemotherapy with sorafenib either alone or when transarterial chemoembolisation was used as a cointervention (very low quality evidence). We need high-quality randomised clinical trials designed to measure differences in clinically important outcomes (e.g. all-cause mortality or health-related quality of life).
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Sorafenib in combination with transarterial chemoembolization for hepatocellular carcinoma: a meta-analysis.
Hu, MD, Jia, LH, Liu, HB, Zhang, KH, Guo, GH
European review for medical and pharmacological sciences. 2016;(1):64-74
Abstract
OBJECTIVE This meta-analysis aimed to analyze the efficacy of sorafenib in combination with transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS Electronic data bases were searched for studies (1) enrolled HCC patients undergoing TACE; (2) with sorafenib therapy and control arm of no sorafenib therapy were included for meta-analysis and meta-regression; (3) studies without control arm were included for data review and (4) had time to progression (TTP) and overall survival (OS) or relative outcome of HCC as the endpoint. Meta-analysis and meta-regression were performed according to Cochrane guidelines. RESULTS Five studies (3 randomized trials, 1 cohort study and 1 prospective non- randomized controlled trial, totally 899 patients) were eligible for meta-analysis. The hazard ratio (HR) for TTP was 0.75 (95% CI: 0.48-1.03, p = 0.003) with significant heterogeneity (I2 = 82.7%) and for OS was 0.76 (95% CI: 0.47-1.05, p = 0.147) with slight heterogeneity (I2 = 47.9%). However, no covariate was found as independent predictor for better treatment efficacy. Hand-foot skin reaction, alopecia, rash/desquamation, diarrhea, hypertension, fatigue, anorexia, nausea and vomiting were common adverse events. CONCLUSIONS TACE combined with sorafenib has potential efficacy for HCC.
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Selective use of sorafenib in the treatment of thyroid cancer.
Pitoia, F, Jerkovich, F
Drug design, development and therapy. 2016;:1119-31
Abstract
Sorafenib is a multiple kinase inhibitor (MKI) approved for the treatment of primary advanced renal cell carcinoma and advanced primary liver cancer. It was recently approved by several health agencies around the world as the first available MKI treatment for radioactive iodine-refractory advanced and progressive differentiated thyroid cancer. Sorafenib targets C-RAF, B-RAF, VEGF receptor-1, -2, -3, PDGF receptor-β, RET, c-kit, and Flt-3. As a multifunctional inhibitor, sorafenib has the potential of inhibiting tumor growth, progression, metastasis, and angiogenesis and downregulating mechanisms that protect tumors from apoptosis and has shown to increase the progression-free survival in several Phase II trials. This led to the Phase III trial (DECISION) which showed that there was an improvement in progression-free survival of 5 months for patients on sorafenib when compared to those on placebo. Adverse events with this drug are common but usually manageable. The development of resistance after 1 or 2 years is almost a rule in most patients who showed partial response or stabilization of the disease while on sorafenib, which makes it necessary to think of a plan for subsequent therapies. These may include the use of another MKI, such as lenvatinib, the second approved MKI for advanced differentiated thyroid cancer, or include patients in clinical trials or the off-label use of other MKIs. Given sorafenib's earlier approval, most centers now have access to its prescription. The goal of this review was to improve the care of these patients by describing key aspects that all prescribers will need to master in order to optimize outcomes.
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Short-term and long-term efficacy of 7 targeted therapies for the treatment of advanced hepatocellular carcinoma: a network meta-analysis: Efficacy of 7 targeted therapies for AHCC.
Niu, M, Hong, D, Ma, TC, Chen, XW, Han, JH, Sun, J, Xu, K
Medicine. 2016;(49):e5591
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Abstract
BACKGROUND A variety of targeted drug therapies in clinical trials have been proven to be effective for the treatment of hepatocellular carcinoma (HCC). Our study aims to compare the short-term and long-term efficacies of different targeted drugs in advanced hepatocellular carcinoma (AHCC) treatment using a network meta-analysis approach. METHODS PubMed, Embase, Ovid, EBSCO, and Cochrane central register of controlled trials were searched for randomized controlled trials (RCTs) of different targeted therapies implemented to patients with AHCC. And the retrieval resulted in 7 targeted drugs, namely, sorafenib, ramucirumab, everolimus, brivanib, tivantinib, sunitinib, and sorafenib+erlotinib. Direct and indirect evidence were combined to evaluate stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR), overall response ratio (ORR), overall survival (OS), and surface under the cumulative ranking curve (SUCRA) of patients with AHCC. RESULTS A total of 11 RCTs were incorporated into our analysis, including 6594 patients with AHCC, among which 1619 patients received placebo treatment and 4975 cases had targeted therapies. The results revealed that in comparison with placebo, sorafenib, and ramucirumab displayed better short-term efficacy in terms of PR and ORR, and brivanib was better in ORR. Regarding long-term efficacy, sorafenib and sorafenib+erlotinib treatments exhibited longer OS. The data of cluster analysis showed that ramucirumab or sorafenib+erlotinib presented relatively better short-term efficacy for the treatment of AHCC. CONCLUSION This network meta-analysis shows that ramucirumab and sorafenib+erlotinib may be the better targeted drugs for AHCC patients, and sorafenib+erlotinib achieved a better long-term efficacy.