Immunotherapy in hepatocellular carcinoma: evaluation and management of adverse events associated with atezolizumab plus bevacizumab

In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.

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Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials

BMC Cancer ◽

10.1186/s12885-021-08977-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hao-chuan Ma ◽

Yi-hong Liu ◽

Kai-lin Ding ◽

Yu-feng Liu ◽

Wen-jie Zhao ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Treatment Options ◽

Small Cell ◽

Efficacy And Safety ◽

Small Cell Lung ◽

First Line ◽

Grade 3

Abstract Background Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC. Methods We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases. Results A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%). Conclusion Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

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An investigation of the safety of continued treatment with sorafenib in patients with unresectable hepatocellular carcinoma after the first disease progression: Multicenter, open-label, phase II safety study.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.462 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 462-462

Author(s):

Noriyuki Akutsu ◽

Shigeru Sasaki ◽

Hideyasu Takagi ◽

Hiroyuki Kaneto ◽

Kazuhiko Yonezawa ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Events ◽

Disease Progression ◽

Treatment Options ◽

Line Treatment ◽

First Line ◽

Open Label ◽

Sorafenib Treatment ◽

First Line Therapy ◽

Unresectable Hepatocellular Carcinoma

462 Background: Randomized studies showed that sorafenib significantly improved outcome in patients with unresectable hepatocellular carcinoma (HCC). However, there is no clear evidence to support the safety and benefit of continued treatment of sorafenib beyond disease progression (PD) in patients with HCC treated with sorafenib. We prospectively evaluated the safety and efficacy of sorafenib beyond PD in patients with HCC whose disease has progressed after first-line treatment with sorafenib. Methods: Unresectable HCC patients with evaluable lesion were treated with sorafenib until 1st PD, followed by soafenib until 2nd PD. The primary endpoint of the study was the safety after 1st PD until 2nd PD. Secondary endpoints of the study were response rate (RR), disease control rate (DCR), time to first PD (TTP1), time to second PD during continued treatment (TTP2), overall survival (OS), and safety throughout the treatment period. Adverse event was evaluated as per The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Tumor response was evaluated as per Modified Response Evaluation in Solid Tumors (mRECIST) criteria. The Kaplan–Meier method was used to determine TTP and OS. Results: Of 30 patients enrolled from 6 sites in Japan, 29 patients received sorafenib treatment, and one patient refused chemotherapy. Twenty patients continued sorafenib beyond PD. Grade 3/4 adverse events occurred less frequently during TTP2 than during TTP1. No critical events related to sorafenib were reported during TTP2. In the first-line therapy, 29 patients treated with sorafenib showed RR of 10.3%, DCR of 60.7% and median TTP1 of 102 days. Twenty patients who received continued sorafenib beyond PD and showed RR of 0%, DCR of 45%, and median TTP2 of 77 days. Median survival time was 306 days. Conclusions: Sorafenib beyond PD had acceptable tolerability and considerable efficacy. In the present conditions without second line treatment, sorafenib beyond PD might be one of the treatment options. Clinical trial information: UMIN000005818.

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Non-immunotherapy options for the first-line management of hepatocellular carcinoma: exploring the evolving role of sorafenib and lenvatinib in advanced disease

Current Oncology ◽

10.3747/co.27.7159 ◽

2020 ◽

Vol 27 (S3) ◽

Author(s):

S. Perera ◽

D. Kelly ◽

G. M. O'Kane

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Treatment Options ◽

Optimal Timing ◽

Advanced Hepatocellular Carcinoma ◽

Line Treatment ◽

First Line ◽

First Line Treatment ◽

Line Management

The results of the sharp trial established sorafenib, a tyrosine kinase inhibitor (TKI), as the sole first-line treatment option in advanced hepatocellular carcinoma (HCC) for more than a decade. In 2020, there has been a surge in new therapies for hcc, including immunotherapeutic strategies and the approval of a number of novel tkis. In addition to sorafenib, lenvatinib and combination atezolizumab–bevacizumab now represent standard first-line treatment options. As those systemic options begin to be better utilized, assurance of adequate liver function and optimal timing are required to improve patient outcomes. Furthermore, sequencing of the agents will have to be carefully tailored, given the increasing armamentarium of choices. Here, we discuss the role of lenvatinib and sorafenib in the first-line management of HCC.

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Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma

Vaccines ◽

10.3390/vaccines8040616 ◽

2020 ◽

Vol 8 (4) ◽

pp. 616

Author(s):

Mohamed A. Abd El Aziz ◽

Antonio Facciorusso ◽

Tarek Nayfeh ◽

Samer Saadi ◽

Mohamed Elnaggar ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Survival Outcomes ◽

Efficacy And Safety ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Despite the advances in screening protocols and treatment options, hepatocellular carcinoma (HCC) is still considered to be the most lethal malignancy in patients with liver cirrhosis. Moreover, the survival outcomes after failure of first-line therapy for unresectable HCC is still poor with limited therapeutic options. One of these options is immune checkpoint inhibitors. The aim of this study is to comprehensively review the efficacy and safety of immune checkpoint inhibitors for patients with HCC.

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Clinical Efficacy and Safety of Apatinib for the Treatment of Patients with Metastatic, Recurrent Cervical Cancer after Failure of Radiotherapy and First-Line Chemotherapy: A Prospective Study

Oncology Research and Treatment ◽

10.1159/000510355 ◽

2020 ◽

Vol 43 (12) ◽

pp. 649-655

Author(s):

Xiaoping Xia ◽

Wenjing Jiang ◽

Wencai Qi ◽

Baoli Hong ◽

Weidong Zhao

Keyword(s):

Cervical Cancer ◽

Adverse Events ◽

Kinase Inhibitor ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

Efficacy And Safety ◽

First Line ◽

Recurrent Cervical Cancer ◽

Line Chemotherapy

Purpose: As a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), apatinib has shown a survival benefit in multiple solid tumors. This study aims to evaluate the efficacy and safety of apatinib in patients with metastatic, recurrent cervical cancer after failure of radiotherapy and first-line chemotherapy. Methods: A total of 42 patients between June 2018 and March 2019 were involved in this study. All patients orally received apatinib once daily in a 4-week cycle until disease progression or adverse events that prohibit further therapy. The primary endpoint was progression-free survival (PFS), the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), health-related quality of life (HRQoL) and adverse events. Results: During a median follow-up of 13 months, 8 patients achieved a partial response and 24 cases achieved stable disease. None of them reported a complete response. The ORR and DCR were 19.0 and 76.2%, respectively. The median PFS was 6.0 months (95% CI 4.9–7.1), and the median OS was 12.0 months (95% CI 10.1–13.9). The global health score/HRQoL improved significantly following 3-cycle treatment (50.4 ± 12.5 vs. 60.1 ± 11.8; p < 0.01). The most frequent grade 3–4 adverse events were hand-foot syndrome, hypertension and fatigue. Conclusion: Apatinib should be an effective and tolerable treatment option for patients with metastatic, recurrent cervical cancer after failure of radiotherapy and first-line chemotherapy.

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Treatment Approaches for Hepatocellular Carcinoma

Clinical medicine Oncology ◽

10.1177/117955490700100002 ◽

2007 ◽

Vol 1 ◽

pp. 117955490700100

Author(s):

Khaldoun Almhanna ◽

Richard Kim ◽

Sujith Kalmadi

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Treatment Options ◽

Tumor Resection ◽

Standard Of Care ◽

The United States ◽

Multidrug Resistant ◽

High Rate ◽

Treatment Modalities ◽

Multiple Risk Factors

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and it is responsible for up to one million deaths annually. Although multiple risk factors for HCC have been identified, and despite preventive measures, the incidence of HCC continues to rise to epidemiologic proportions in the United States. In general, tumor resection and orthotopic liver transplantation are the treatment with the best outcome; however, HCC is generally diagnosed late in its course when patients are not eligible for curative treatment options. HCC is a relatively Chemo-refractory tumor secondary to heterogeneity of the tumor and the high rate of multidrug resistant gene expression. There are no standard treatments for HCC, multiple palliative treatment modalities have been used for patients with unresectable disease. None of these modalities have shown any superiority; and the retrospective nature of these available data has confounded any reasonable conclusions. Different institutions use different treatment schema dependent on the center expertise. Sorafenib, a tyrosine kinase inhibitor, has recently demonstrated a survival advantage in metastatic HCC, and if approved by the FDA, might become the standard of care. In this article we will review the rationale behind the currently available treatment options for HCC.

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Efficacy and safety results from AvaALL: an open-label, randomized phase III trial of standard of care (SOC) with or without continuous bevacizumab (Bev) treatment beyond progression (PD) in patients (pts) with advanced non-small-cell lung cancer (NSCLC) progressing after first-line Bev and chemotherapy (chemo)

Pneumologie ◽

10.1055/s-0037-1619221 ◽

2018 ◽

Vol 72 (S 01) ◽

pp. S39-S40

Author(s):

F Griesinger ◽

J Bennouna ◽

J de Castro Carpeno ◽

AM Dingemans ◽

F Grossi ◽

...

Keyword(s):

Lung Cancer ◽

Standard Of Care ◽

Small Cell ◽

Phase Iii ◽

Efficacy And Safety ◽

Small Cell Lung ◽

First Line ◽

Open Label ◽

Phase Iii Trial ◽

Treatment Beyond Progression

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Radioembolization for Rare Metastatic Disease

Digestive Disease Interventions ◽

10.1055/s-0041-1729875 ◽

2021 ◽

Author(s):

Andrew S. Niekamp ◽

Govindarajan Narayanan ◽

Brian J. Schiro ◽

Constantino Pena ◽

Alex Powell ◽

...

Keyword(s):

Colorectal Cancer ◽

Hepatocellular Carcinoma ◽

Metastatic Colorectal Cancer ◽

Treatment Modality ◽

Treatment Options ◽

Efficacy And Safety ◽

Multiple Tumor ◽

Tumor Types ◽

Hepatic Malignancies ◽

Yttrium 90

AbstractRadioembolization has become a widespread treatment modality for both primary and metastatic hepatic malignancies. Although the majority of data and indication for yttrium-90 radioembolization have been for hepatocellular carcinoma and metastatic colorectal cancer, radioembolization with yttrium-90 has rapidly expanded into the treatment options for multiple tumor types with metastases to the liver. This article reviews the clinical data and expanding utilization of radioembolization for rare metastatic diseases with an emphasis on efficacy and safety.

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Immunohistochemical markers of CYP3A4 and CYP3A7: a new tool towards personalized pharmacotherapy of hepatocellular carcinoma

European Journal of Histochemistry ◽

10.4081/ejh.2016.2614 ◽

2016 ◽

Vol 60 (2) ◽

Cited By ~ 5

Author(s):

D. Fanni ◽

M. Manchia ◽

F. Lai ◽

C. Gerosa ◽

R. Ambu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitor ◽

Standard Of Care ◽

Normal Liver ◽

Individual Variability ◽

Immunohistochemical Markers ◽

Liver Cancers ◽

Individualized Approach ◽

Viral Hepatitis Infection ◽

Global Health Problem

Hepatocellular carcinoma (HCC) represents a major global health problem, since more than 90% of primary liver cancers worldwide are HCC. Most cases of HCC are secondary to viral hepatitis infection (hepatitis B or C), alcoholism and cirrhosis. Sorafenib, an oral tyrosine kinase inhibitor that suppresses tumor proliferation and angiogenesis, emerged as the first effective systemic treatment for HCC after 30 years of research, and is currently the standard-of-care for patients with advanced HCC. Sorafenib is metabolized by cytochrome P450 (CYP450), particularly from the 3A4 isoform, producing two main metabolites: the N-oxide and the N-hydroxymethyl metabolite. We studied 11 HCC sample showing the presence of CYP3A4 and CYP3A7 in most of the samples analyzed. Specifically, the immunoreactivity of CYP3A4 was more strong and widespread than that of CYP3A7. The CYP3A4 immunoreactivity was observed in surrounding hepatocytes in 8 out of 11 cases; while the CYP3A7 immunostaining was found in normal liver cells, in 7 out of 11 cases. These results suggest the existence of a marked inter-individual variability regarding the presence of the isoforms of CYP3A. In addition, since sorafenib is metabolized by CYP3A4, but not by CYP3A7, an overexpression of CYP3A4 may lead to an increase in the degradation of the drug and then to clinical ineffectiveness. These results might implicate the necessity of an individualized approach in the treatment of HCC as positivity to CYP3A4 in HCC liver samples might predict a scarce response to sorafenib.

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