Search

Xin Zhao,1 Chenhao Zhang,2 Yi An,3 Zixuan Zhang,3 Jiahe Zhao,3 Xinwen Zhang,3 Yue Yang,4 Wei Cao4 1Department of Rheumatology, Guang’anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 2Department of Emergency, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, 100102, People’s Republic of China; 3Department of School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Department of Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, 100102, People’s Republic of ChinaCorrespondence: Wei Cao, Department of Wangjing Hospital of China Academy of Chinese Medical Sciences, No. 6 Zhonghuan South Road, Chaoyang District, Beijing, 100102, People’s Republic of China, Tel +86 10-84739099, Email caoweicw0@126.comAbstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by polyarticular, symmetric, and aggressive inflammation of the small joints in the hands and feet, resulting in dysfunction. With progress and development in medicine, treatment of RA is constantly evolving, making several drugs available for the treatment of RA. From the nonsteroidal anti-inflammatory drugs (NSAIDs) at the start of illness to glucocorticoids and then to conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), therapeutic-use drugs for RA have been keeping pace with scientific research. However, various types of drugs have additional side effects when used over the long-term. New and emerging biological and targeted agents have been widely applied in recent years; however, the side effects have not been thoroughly investigated. In this paper, we review the research progress on liver damage caused by novel biological and targeted agents available for RA treatment. The aim is to provide a reference for rational clinical administration of such drugs.Keywords: liver damage, novel biological agents, research progress, rheumatoid arthritis, targeted agents

Marta Peri,1 Nicola Fazio2 1Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy; 2Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, ItalyCorrespondence: Nicola Fazio via Ripamonti 435, Milan 20141, ItalyTel +390257489439Fax +390294379224Email nicola.fazio@ieo.itAbstract: Neuroendocrine tumors (NETs) of the lung are well-differentiated neuroendocrine neoplasms (NENs) with a heterogeneous clinical behaviour. Unlike gastroenteropancreatic NENs where therapeutic armamentarium clearly increased over the last decade, everolimus represented the only clinical practical innovation for lung NET patients over the last years. Therefore, for lung NETs, a multidisciplinary discussion within a dedicated team remains critical for an adequate decision-making. Although the main regulatory authorities considered the everolimus-related evidence is enough to approve the drug in advanced lung NETs, several clinical features deserve to be discussed. In this review, we systemically and critically analysed the main clinical studies including patients with advanced lung NETs receiving everolimus. Furthermore, we reported the biological and clinical background of everolimus in lung NET setting. The purpose of this review is to help clinical community to contextualize evidence and experience for a personalised use of this drug in clinical practice in the context of advanced lung NET patients.Keywords: lung NET, typical carcinoid, atypical carcinoid, everolimus, mammalian target of rapamycin (mTOR) inhibitor, targeted agents

Jing Qi, 1 Xiuzhi Guo, 1 Aihua Li 2 1Department of Respiration Medicine, Tai’an Central Hospital, Tai’an; 2Department of Respiration Medicine, Yankuang Group General Hospital, Jining, ChinaCorrespondence: Aihua LiDepartment of Respiration Medicine, Yankuang Group General Hospital, 560 Kuangjian East Road, Jining, Shandong 273500, ChinaTel +86 537 536 7018Fax +86 537 536 7017Email lahykjtzyy@sohu.comBackground: Several published meta-analyses have confirmed that single-agent maintenance therapy in advanced non-small-cell lung cancer (NSCLC) can prolong time to disease progression and potentially increase overall survival (OS) in comparison to placebo. However, whether doublet maintenance therapy can improve the survival of advanced NSCLC remains undetermined.Methods: We searched several databases for relevant trials. Prospective randomized controlled trials comparing doublet vs single-agent maintenance therapy in NSCLC patients were included for analysis. Outcomes of interest were OS, progression-free survival (PFS), and incidence of grade 3/4 toxicities.Results: A total of 1,950 advanced-NSCLC patients from six trials were included for analysis. Our results showed that doublet maintenance therapy in NSCLC patients significantly improved PFS (HR 0.74, 95% CI 0.59– 0.93; P=0.010), but not for OS (HR 0.95, 95% CI 0.85– 1.07; P=0.40) in comparison with single-agent maintenance therapy. Subgroup analysis by maintenance regimen showed that pemetrexed plus bevacizumab maintenance therapy significantly improved PFS, but not OS. In addition, there was no significant risk difference between doublet and single-agent maintenance therapy in terms of grade 3/4 hematologic and nonhematologic toxicities.Conclusion: Our study suggests that doublet maintenance therapy in advanced-NSCLC patients demonstrates PFS benefits, but not OS benefits, in comparison with single-agent maintenance therapy. Future trials are suggested to assess the long-term clinical benefit of doublet maintenance treatment in NSCLC patients and its impact on health-related quality of life.Keywords: targeted agents, maintenance therapy, doublet, single agent, meta-analysis

Yanyang Pang,1 Zhen Shen,2 Jiancheng Sun,3 Wu Wang4 1Department of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan 571101, China; 2Division of Liver Disease, Huangshi City Hospital of Traditional Chinese Medicine (Infectious Disease Hospital), Edong Healthcare Group, Huangshi, Hubei 435000, China; 3Department of General Surgery, The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; 4Laboratory of Tropical Biomedicine and Biotechnology, School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571101, China Purpose: We aimed to investigate whether the use of targeted agents (TAs) in advanced gastroesophageal cancer (GEC) increased the complete response (CR) and to assess the surrogate endpoints for survival in the targeted treatment of GEC by using a meta-analysis of randomized controlled trials (RCTs).Methods: Eligible studies were identified using Medline, PubMed, and meeting abstracts. Searches were last updated on April 30, 2018. We calculated the incidence and Peto odds ratio (Peto OR) of CR events in patients assigned to TAs compared with controls. Simple linear regression models were fitted for median overall survival (OS) and each surrogate [median progression-free survival (PFS), CRs, objective response rate (ORR), and disease control rate (DCR), respectively].Results: A total of 7,892 GEC patients from 18 RCTs were included for analysis. The incidence of CR in GEC patients treated with TAs was 2.0% (95% CI, 1.3%–3.0%) compared with 1.7% (95% CI, 1.0%–2.7%) in the control arms. The use of TAs in advanced GEC had a tendency to improve the possibility of archiving CR (Peto OR 1.42; 95% CI, 0.98–2.04; P=0.064) compared with controls. Subgroup analysis according to treatment TAs showed that the addition of antiepidermal growth factor receptor (EGFR) agents to chemotherapy in GEC significantly improved the CR rate in comparison with control (Peto OR 1.77; 95% CI, 1.02–3.09; P=0.044), but not for other molecular TAs (P=0.49 for angiogenesis inhibitors, P=0.66 for mesenchymal-epithelial transition inhibitors). We also found that the addition of TAs to first-line therapy (Peto OR 1.41; 95% CI, 0.94–2.11; P=0.098) had a tendency to increase the chance of obtaining a CR, but not for second-line therapy (Peto OR 1.47; 95% CI, 0.60–3.55; P=0.40). In addition, correlation analysis indicates that PFS, ORR, and DCR were strongly correlated with OS for GEC patients receiving TAs (r=0.85 for PFS; r=0.86 for ORR; r=0.81 for DCR). No marked correlation was found between OS and CRs (r=0.43; P=0.18).Conclusion: Although the CR is a rate event in advanced GEC patients, adding the TAs to therapies, especially for anti-EGFR agents, increases the chance of archiving CR in comparison with the controls. PFS, ORR, and DCR are significantly correlated with OS and could be used as surrogate endpoints in patients with GEC who have received TA therapy, but not for CR. Keywords: gastroesophageal carcinoma, systematic review, novel molecular agents

Xiaofei Li,1 Jia Wan,2 Zhenping Wu,3 Juncai Tu,1 Yongtao Hu,1 Shuang Wu,1 Lianqing Lou1 1Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China; 2The First Hospital of Nanchang, Nanchang, China; 3Gastroenterology Department, Jinhua Central Hospital, Jinhua, China Aims: Concerns have increased about the risk of fatal adverse events (FAEs) associated with molecular targeted agents (MTAs) in the treatment of advanced hepatocellular carcinoma (HCC). The purpose of this study is to investigate the overall incidence and risk of FAEs in advanced HCC with administration of MTAs by using a meta-analysis of available clinical trials.Materials and methods: Electronic databases were searched for relevant articles before March 2017. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Pooled incidence, Peto ORs and 95% CIs were calculated according to the heterogeneity of selected studies.Results: A total of 4,716 HCC participants from 10 randomized controlled trials (RCTs) were finally considered for this meta-analysis. The pooled incidence of death due to MTAs was 2.1% (95% CI 1.6%–2.8%) with a Peto OR of 1.79 (95% CI 1.07–3.01; p=0.027) in comparison with controlled groups. Subgroup analysis according to biological agents showed that brivanib treatment in HCC patients significantly increased the risk of developing FAEs (Peto OR 3.97; 95% CI 1.17–13.51; p=0.028) but not for sorafenib (Peto OR 1.78; 95% CI 0.54–5.89; p=0.34) and other MTAs (Peto OR 1.43; 95% CI 0.75–2.76; p=0.28). Sensitive analysis showed that the pooled results were influenced by removing each single trial. The most common causes of FAEs were hepatic failure (22.2%) and hemorrhage (13.3%), respectively.Conclusion: Clinicians should be aware of the risks of FAEs during the administration of MTAs in advanced HCC patients, especially for patients with abnormal liver function. However, the use of sorafenib remains justified in its approved indications due to their potential survival benefits and limited toxicities. Keywords: liver cancer, clinical trials, novel molecular agents

Jiamin Jin, Chunbo Teng, Tao Li College of Life Science, Northeast Forestry University, Harbin, China Purpose: We aimed to compare the efficacy of combination therapy versus gemcitabine monotherapy in the treatment of elderly pancreatic cancer (PC) by using a meta-analysis.Materials and methods: Databases were searched to identify relevant clinical trials. Hazard ratios (HRs) were used to estimate overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted by using Comprehensive Meta Analysis software (version 2.0).Results: A total of 3,401 elderly PC patients from six randomized controlled trials were included for analysis. In comparison with gemcitabine alone, combination therapy in elderly PC patients did not significantly improve OS (HR 0.93, 95% CI: 0.82–1.06, p=0.29). Sub-group analysis according to treatment regimens showed that combined chemotherapy significantly improved OS in comparison with gemcitabine alone (HR 0.73, 95% CI: 0.56–0.94, p=0.016), while gemcitabine plus targeted agents did not improve OS (HR 1.02, 95% CI: 0.87–1.19, p=0.83). Additionally, gemcitabine plus nab-paclitaxel significantly improved PFS in elderly PC patients (HR 0.69, 95% CI: 0.52–0.91, p=0.009) in comparison with gemcitabine alone. No publication bias was detected by Begg’s and Egger’s tests for OS.Conclusion: The findings of this study suggest that combined chemotherapy, but not for gemcitabine plus targeted agents, could be recommended for elderly PC patients due to its survival benefits. Further studies are still needed to assess the treatment tolerance of combination chemotherapy in these patient populations. Keywords: pancreatic cancer, elderly, randomized controlled trials, meta-analysis, targeted agents

Triple-negative breast cancer (TNBC) represents a very heterogeneous group of breast diseases. Currently, the backbone of therapy for TNBC is mainly chemotherapy as there are no effective specific targeted agents approved to treat TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. Therefore, new targeted strategies are, accordingly, urgently needed. This article discusses the recent developments in targeted agents explored for TNBC, aiming to offer novel therapeutic strategies that can potentially assist in designing personalized therapeutics in the future as well as provide the basis for further research in an attempt to target TNBC., Competing Interests: The authors report no conflicts of interest in this work.

Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of "central dogma" of simplified reductionist transcription and single gene-phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.

Lung cancer is the leading cause of cancer-related death in the United States. Though incremental advances have been made in the treatment of this devastating disease during the past decade, new therapies are urgently needed. Traditional cytotoxic agents have been combined with other modalities with improved survival for early-stage patients. Newer cytotoxic agents targeting the same or different mechanisms have been developed at different stages. Optimization of various chemotherapy regimens in different settings is one of the aims of current clinical trials. Some predictive biomarkers (eg, excision repair cross-complementing 1, ERCC1) and histotypes (eg, adenocarcinoma) are found to be associated with resistance/response to some cytotoxic drugs. Another notable advance is the addition of targeted therapy to lung cancer treatment. Targeted agents such as erlotinib and bevacizumab have demonstrated clinical benefits and gained Food and Drug Administration approval for lung cancer. More agents targeting various signaling pathways critical to lung cancer are at different stages of development. Along with the effort of new targeted drug discovery, biomarkers such as epidermal growth factor receptor and anaplastic lymphoma kinase mutations have proven useful for patient selection, and more predictive biomarkers have been actively evaluated in non-small cell lung cancer. The paradigm of lung cancer treatment has shifted towards biomarker-based personalized medicine.

With the recent approval of pazopanib, an oral multitargeted tyrosine kinase inhibitor which potently targets vascular endothelial growth factor receptors 1-3, platelet-derived growth factor, and c-kit, six agents are now available for use in the management of metastatic renal cell carcinoma (RCC). Pazopanib has shown improved progression-free survival compared with placebo in treatment-naïve or cytokine-treated patients with metastatic RCC in large Phase II and Phase III clinical trials. Pazopanib has demonstrated a tolerable side effect profile and is currently being compared with sunitinib in a Phase III noninferiority trial. In this review, the outcomes of the clinical testing of pazopanib are discussed, as well as a perspective on the placement of pazopanib among other approved agents.