Cardiotoxicity of immune checkpoint inhibitors: A systematic review and meta-analysis of randomised clinical trials.

BACKGROUND: Immune checkpoint inhibitors (ICIs) may cause potentially life-threatening adverse events (AEs), but the risk of cardiotoxicity has not been fully investigated. It is also unknown whether ICI combinations increase cardiotoxicity compared with single ICI. We aimed to assess the cardiotoxicity of ICI in a range of tumour types. METHODS: This systematic review and meta-analysis was conducted according to PRISMA guidelines (PROSPERO registration number: CRD42020183524). A systematic search of PubMed, MEDLINE, Embase databases, and conference proceedings was performed up to 30 June 2020. All randomised clinical trials comparing ICI with other treatments (primary objective) or dual-agent ICI versus single-agent ICI (secondary objective) in any solid tumour were included. Pooled risk ratios (RRs) with 95% confidence intervals (95% CIs) for cardiotoxicity events were calculated using random effect models. RESULTS: Eighty studies including 35,337 patients were included in the analysis (66 studies with 34,664 patients for the primary endpoint and 14 studies with 673 patients for the secondary endpoint). No significant differences in terms of cardiac AEs were observed between ICI and non-ICI groups (RR 1.14, 95% CI 0.88-1.48, p = 0.326) nor between dual ICI and single ICI groups (RR 1.91, 95% CI 0.52-7.01, p = 0.329). Myocarditis incidence did not significantly differ between ICI and non-ICI groups (RR 1.11, 95% CI 0.64-1.92, p = 0.701) nor between dual ICI and single ICI groups (RR 1.10, 95% CI 0.31-3.87, p = 0.881). No differences were observed in subgroup analyses according to tumour type, setting of disease, treatment line, and type of treatment. CONCLUSION: The use of ICI as single or combination regimens is not associated with increased risk of cardiotoxicity.

Rare side-effects of checkpoint inhibitors.

PURPOSE OF REVIEW: The aim of this review is to draw the attention of the physicians and oncologists on the rare side-effects of checkpoint inhibitors not usually reported in clinical trials to treat them quickly and render their prognosis better. RECENT FINDINGS: Rare side-effects of checkpoint inhibitors are mainly neurologic, haematologic, rheumatologic, renal, and cardiac. The majority of reported side-effects are consequent of the treatment by ipilimumab in patients diagnosed with melanomas. Neurologic side-effects have poorer prognosis compared with other rare side-effects. There is no relationship between developing rare side-effects and the outcome of the disease. SUMMARY: It is important to be aware, when treating patients with checkpoint inhibitors, to detect as early as possible the unpredictable and uncontrollable rare side-effects of these agents. The large spectrum of these rare side-effects should be well documented and reported to assure to the physicians a road map for the diagnosis and the management of these toxicities.

Novel mechanisms and approaches in the medical therapy of solid cancers.

Major advances in cancer research in the last two decades have provided us with a better understanding of the dynamics of the cancer cell and its microenvironment. This has consequently led to the development of new therapies and treatment strategies either targeting the cancer cell or the tumor microenvironment. In this review we will discuss the major existing and promising future treatment approaches in medical oncology. Therapies targeting the cancer cell include hormonal therapies, small molecules, and monoclonal antibodies. They are used mostly in the advanced disease setting. Strategies developed more recently are antibody drug conjugates (trastuzumab emtansine and radioimmunotherapy) and oncolytic viruses. Molecular therapies targeting the tumor microenvironment include angiogenesis inhibitors and the new agents and approaches that interfere with the immune system (immune checkpoint inhibitors and adoptive cell therapy). The development of resistance (primary and acquired) to targeted therapies is unfortunately a common phenomenon that can be overcome or delayed using multiple strategies like the use of second- or third-generation molecular therapies targeting the emerging resistant mutations or genetic abnormalities, multitargeted drugs, and drug combinations targeting the same or different proteins, and/or the use of modern immunotherapy. Molecular targeted therapies have a distinct array of side effects that can be mechanism-based, but can also be unpredictable. Although the progress in research brings a vast amount of new information about cancer and its environment, it renders the field of oncologic research more and more complex with fragmentation of tumor entities. These are important challenges for future research and precision oncology.

Expression, prognostic and predictive impact of VEGF and bFGF in non-small cell lung cancer.

Despite major advances in cancer therapeutics, the prognosis for lung cancer patients is still poor and the median survival for patients presenting with advanced non-small cell lung cancer (NSCLC) is only 8-10 months. Angiogenesis is an important biological process and a relatively early event during lung cancer pathogenesis. Anti-angiogenic agents are used in treating patients with NSCLC, and their molecular biomarkers are also being assessed to predict response. A better understanding of the biology of angiogenesis in NSCLC may reveal new targets for treating this malignancy. In this article, we review the expression and prognostic impact of the angiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in NSCLC.

Is VEGF a predictive biomarker to anti-angiogenic therapy?

Tumor growth and metastasis are dependent on angiogenesis. Inhibiting angiogenesis has therapeutic potentials for treating cancer. Researchers have identified many of the pathways involved in angiogenesis and proposed selective targeted strategies. A high probability of benefit is desirable to justify the choice of anti-angiogenic therapy from an ever-expanding list of expensive new anticancer agents. However, biomarkers of response to anti-angiogenic agents are inconclusive for predicting benefit from these drugs. This paper reviews the most important biomarker of angiogenesis, namely VEGF, in relation to its expression in cancer and the treatment of these cancers through targeting VEGF and its pathways.

Hypoxia-inducible factor in cancer angiogenesis: structure, regulation and clinical perspectives.

Tumor hypoxia is a common feature of many cancers. A master regulator of hypoxic response is the transcription factor hypoxia-inducible factor-1 (HIF-1). It functions as a master regulator of oxygen and undergoes conformational changes in response to varying oxygen concentrations. In this paper, we review what has been described about HIF-1: its structure, its regulation and target genes, its role in cancer, and its implication for cancer therapy.