epatocellular carcinoma (HCC) is the most common type of primary liver cancer. Advanced HCC has poor prognosis with short survival rate. According to Barcelona Classification of Liver Cancer (BCLC), systemic therapy is optimal treatment for patients at this stage. In 2007, the targeted therapy with sorafenib was first approved to treat advanced HCC, which helps prolong survival of the patients. This article aims: To update the findings and application of adjuvant regimens for HCC.
Journal of military pharmaco-medicine no5-2020 SYSTEMIC THERAPY FOR HEPATOCELLULAR CARCINOMA: A REVIEW Nguyen Quang Nghia1, Dang Kim Khue1 Ninh Viet Khai1, Ngo Dac Sang2 SUMMARY Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer Advanced HCC has poor prognosis with short survival rate According to Barcelona Classification of Liver Cancer (BCLC), systemic therapy is optimal treatment for patients at this stage In 2007, the targeted therapy with sorafenib was first approved to treat advanced HCC, which helps prolong survival of the patients This article aims: To update the findings and application of adjuvant regimens for HCC * Keywords: Systemic therapy; Hepatocellular carcinoma OVERVIEW Hepatocellular carcinoma is the most frequent liver malignancy, accounting for roughly 80% of primary liver cancer and is the third common cancer in Vietnam [1] HCC is associated with hepatitis B, hepatitis C virus, alcoholic liver cirrhosis and some other toxins: aflatoxin, dioxin Multiple treatment options are available for HCC including curative treatment (hepatectomy, liver transplantation, radiofrequency ablations), trans-arterial chemoembolization, radiation, systemic therapy (chemotherapy, targeted therapy, immunotherapy) and supported therapy Advanced HCC has poor prognosis Most of advanced HCC patients cannot be treated with curative treatments Moreover, the incidence of recurrence after surgical resection is estimated as high as 60% in the first two yeas Advanced HCC occurs in patient with poor underlying liver function, which usually respond poorly to chemotherapy like doxorubicin, cisplatin, 5FU, mitomycin C To date, much attention has been paid to targeted therapy and immunotherapy because of recent advances in treatment of cancer, especially HCC Sorafenib has been approved to extend the survival time of advanced HCC patient since 2007 This advancement represents a breakthrough in the treatment of HCC In recent years, there have been several new agents approved to treat HCC as first line and second line therapy This article aims: To update the findings and application of adjuvant regimens for HCC Organ Transplantation Center, Viet Duc University Hospital Department of Military Science Information, Vietnam Military Medical University Corresponding author: Nguyen Quang Nghia (nghianguyenvduc@gmail.com) Date received: 20/5/2020 Date accepted: 22/06/2020 91 Journal of military pharmaco-medicine no5-2020 BARCELONA CLINIC LIVER CANCER STAGING AND TREATMENT STRATEGIES The Barcelona Clinic Liver Cancer (BCLC) staging system was developed by Llovet et al in the late 1990s to help stratify patients with HCC based on survival outcomes and to direct patients to the best available therapy [2] The classification system combines multiple variables (eg, tumor stage, liver function, performance status, cancer related symptoms) in an algorithm and recognizes stages for the disease The BCLC staging system has been adopted as a standard by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) [3] Patients with very early HCC (stage 0) are candidates for tumor resection or radiofrequency ablation Early-stage HCC (stage A) can be treated with curativeintent radical therapies such as resection, liver transplantation, percuaneous ethanol injection, or radiofrequency ablation Intermediate-stage HCC (stage B) is generally treated with transarterial chemoembolization Advanced HCC (stage C) is treated with systemic agents End-stage HCC (stage D) patients have a survival time of less than months either due to poor liver function or very advanced HCC and may benefit from palliative care According to BCLC, advanced HCC is defined as there are tumors of portal vein invasion and extrahepatic spread The optimal treatment for advanced HCC is systemic therapy Before 2007, the systemic therapy with chemotherapy or interferon 92 was proved ineffective for HCC The phase trial SHARP (Sorafenib in Advanced Hepatocellular Carcinoma) demonstrated that sorafenib could improve longer overall survival time of advanced HCC patients, and became the first approved systemic therapy for advanced HCC [4] Recently, there have been more agents approved to treat advanced HCC such as lenvatinib, regorafenib, nivolumab TARGETED THERAPY Sorafenib Sorafenib is an oral multikinase inhibitor with antiproliferative and antiangiogenic properties by inhibiting vascular endothelial growth factor receptor (VEGFR) -2 and -3 tyrosine kinases, platelet-derived growth factor receptor (PDGFR) -β tyrosine kinases, and rapidly accelerated fibrosarcoma kinases Sorafenib was approved in 2007 by the FDA as first-line therapy for unresectable HCC (BCLC stage C with Child-Pugh class A or BCLC stage B progressing after locoregional therapy) based on OS benefit in the phase SHARP (Sorafenib in Advanced Hepatocellular Carcinoma) trial [4] Compared with placebo in advanced HCC, sorafenib could extend overall survival (OS) by 2.8 months (median OS, 10.7 months vs 7.9 months) and was the first agent to demonstrate survival benefit The side effects of sorafenib includes diarrhea, fatigue, and hand-foot skin reaction Sorafenib was initially approved for patients with well-preserved liver function; however, final results from the GIDEON Journal of military pharmaco-medicine no5-2020 trial-a large prospective, observational, registry study evaluating the efficacy and tolerability of sorafenib in patients with liver dysfunction highlighted a similar safety profile irrespective of Child-Pugh staging There were 3,202 patients with 666 Child B and 74 Child C cirrhosis 676 patients (21%) were indicated an initial dose of 400 mg (half of recommended dose), and 500 patients was given an increase to standard dose 997 patients (31%) received a reduction dose due to adverse effects Median overall survival time were 13.6 months in Child A, 5.2 months in Child B and 2.6 months in Child C [5] STORM studies exploring use of sorafenib as adjuvant therapy after curative-intent local therapy also did not meet their primary endpoints [6] To date, the combinations of sorafenib with other agents have not yielded more positive results than sorafenib alone Sorafenib was the first and only agent that has been shown to significantly improve survival benefit for advanced HCC until 2017 Lenvatinib Lenvatinib is an oral TKI of fibroblast growth factor receptor (FGFR), VEGFR, PDGFR-α, rearranged during transfection (RET), and KIT In a phase noninferiority trial, lenvatinib was found to be noninferior but not statistically superior to sorafenib regarding OS (median OS, 13.6 months vs 12.3 months) Additionally, lenvatinib demonstrated a statistically significant increase in objective response rate (ORR) compared with sorafenib, especially partial response rate (23% vs 9%) [7] Adverse effects including hypertension, diarrhea, low appetite, and weight loss occurred in a third of the patients The results of this study led to the approval of lenvatinib for first-line therapy of unresectable HCC in August 2018 Regorafenib Regorafenib, a potent oral inhibitor of angiopoietin-1 receptor (Tie2), VEGFR, PDGFR, and FGFR is indicated for patients progressing on sorafenib treatment and tolerant to sorafenib The phase RESORCE (Regorafenib for patients with HCC who progressed on sorafenib treatment) trial demonstrated improvement in median OS with regorafenib compared with placebo in a second-line setting (10.6 months vs 7.8 months) [8] Hypertension is the most common adverse effect, found in 15% of patients on regorafenib, followed by handfoot skin reaction Regorafenib is approved by the FDA based on this multinational study in patients who were previously treated with sorafenib Cabozantinib Cabozantinib is a small-molecule TKI with activity against c-Met, VEGFR-2, AXL, and RET Abou-Alfa et al studied the use of cabozantinib vs placebo in patients with advanced HCC who progressed on sorafenib [9, 10] They noted an improvement in median OS (10.2 months vs 8.0 months) Hand-foot syndrome and hypertension were the most common adverse effects in these patients This trial led to the approval of cabozantinib in advanced HCC after progression on sorafenib 93 Journal of military pharmaco-medicine no5-2020 Ramucirumab months vs 4.2 months) Results of the Ramucirumab (Cyramza, Lilly), an confirmatory randomized, controlled intravenous human monoclonal antibody REACH-2 trial were published in 2018 directed against VEGFR-2, was evaluated [12] This study investigated the efficacy in a population of patients with advanced of ramucirumab vs placebo in 292 patients HCC who had progressed on or been with advanced HCC and an α-fetoprotein intolerant to sorafenib Zhu et al initially serum level above 400 ng/mL Findings found no statistically significant change in were similar to previous observations with OS when comparing ramucirumab with ramucirumab, placebo in the REACH (Ramucirumab particular subset of patients (median OS, After Sorafenib in Patients With Advanced 8.5 months vs 7.3 months) Hypertension HCC) trial (median OS, 9.2 months vs and hyponatremia were the only grade 7.6 months) [11] However, a post-hoc adverse effects observed in more than subgroup analysis of the REACH trial 5% of patients Based on the REACH-2 revealed an improvement in survival of trial findings, ramucirumab remains the patients with a baseline α-fetoprotein only serum level above 400 ng/mL compared clinical benefit in a biomarker-selected with less than 400 ng/mL (median OS, 7.8 population in HCC systemic extending agent OS to in this demonstrate Table 1: Systemic therapies currently approved or in advanced development for HCC Agents Mechanism Target(s) Option Sorafenib Oral multikinase inhibitor VEGFR-2,3; PDGFR beta, RAF kinase Lenvatinib Oral multikinase inhibitor FGFR, VEGFR, PDGFR-alpha, RET, KIT Regorafenib Oral multikinase inhibitor Tie2, VEGFR, PDGFR, PGFR Carbozatinib Oral multikinase inhibitor c-met, VEGFR-2, RET, AXL Nivolumab Immune checkpoint inhibitor PD-1 Pembrolizumab Immune checkpoint inhibitor PD-1 Ramucirumab Monoclonal antibody VEGFR-2 94 Journal of military pharmaco-medicine no5-2020 IMMUNOTHERAPY AGENTS CONCLUSION Nivolumab, a PD-1 inhibitor, received a conditional accelerated approval by the FDA in September 2017 for the treatment of HCC in patients who have been previously treated with sorafenib Approval was based on the results of a phase 1/2 dose escalation and expansion trial (CheckMate-040), in which nivolumab was tested in advanced HCC patients with sorafenib-naive or pre-treated patients [13] This study showed an ORR of 15% (95%CI = - 28%) and 20% (95%CI = 15 - 26%) in the escalation and expansion phases, respectively Three complete and many partial responses were noted in each of the phases Median OS of patients with treatment response was 15.6 months (95%CI = 13.2 - 18.9 months Baseline tumor PD-L1 expression did not predict response to therapy The most common treatmentrelated adverse events included rash, pruritus, and fatigue Advanced HCC has poor prognosis, the optimal treatment is systemic therapy The treatment landscape of HCC is changing at a rapid pace Before 2017, there was only sorafenib demonstrated survival benefit for advanced HCC patients But now, there are more new agents to treat HCC in both first-line and second-line treatment Pembrolizumab, another PD-1 inhibitor, has been tested in a global phase trial after progression on or intolerance to sorafenib ORR was similar to nivolumab (17%; 95%CI = 11 - 26%), with complete and 17 partial responses [14] 24% of patients experienced grade Treatment-related adverse effects are transaminitis and fatigue Based on the KEYNOTE-224 trial findings, in November 2018, the FDA approved pembrolizumab as a second-line therapy for patients who have previously received sorafenib REFERENCES International Agency for Research on Cancer GLOBOCAN 2018, 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El-Khoueiry AB, Sangro B, Yau T, et al Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial Lancet... Hepatol 2016; 65(6):1140-1147 Bruix J, Takayama T, Mazzaferro V, et al STORM investigators Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): A phase 3, randomised,... class A or BCLC stage B progressing after locoregional therapy) based on OS benefit in the phase SHARP (Sorafenib in Advanced Hepatocellular Carcinoma) trial [4] Compared with placebo in advanced