Cardiovascular Toxicities Secondary to Biotherapy and Molecular Targeted Therapies in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

Abstract

A broad spectrum of novel targeted therapies with prime antitumor activity and/or ample control of hormonal symptoms together with an overall acceptable safety profile have emerged for patients with metastatic neuroendocrine neoplasms (NENs). In this systematic review and quantitative meta-analysis, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases were searched to assess and compare the safety profile of NEN treatments with special focus on the cardiovascular adverse effects of biotherapy and molecular targeted therapies (MTTs). Quality/risk of bias were assessed using GRADE criteria. Placebo-controlled randomized clinical trials (RCTs) in patients with metastatic NENs, including medullary thyroid cancer (MTC) were included. A total of 3695 articles and 122 clinical trials registered in clinicaltrials.gov were screened. We included sixteen relevant RCTs comprising 3408 unique patients assigned to different treatments compared with placebo. All the included studies had a low risk of bias. We identified four drug therapies for NENs with eligible placebo-controlled RCTs: somatostatin analogs (SSAs), tryptophan hydroxylase (TPH) inhibitors, mTOR inhibitors and tyrosine kinase inhibitors (TKI). Grade 3 and 4 adverse effects (AE) were more often encountered in patients treated with mTOR inhibitors and TKI (odds ratio [OR]: 2.42, 95% CI: 1.87–3.12 and OR: 3.41, 95% CI: 1.46–7.96, respectively) as compared to SSAs (OR:0.77, 95% CI: 0.47–1.27) and TPH inhibitors (OR:0.77, 95% CI: 0.35–1.69). MTOR inhibitors had the highest risk for serious cardiac AE (OR:3.28, 95% CI: 1.66–6.48) followed by TKIs (OR:1.51, 95% CI: 0.59–3.83). Serious vascular AE were more often encountered in NEN patients treated with mTOR inhibitors (OR: 1.72, 95% CI: 0.64–4.64) and TKIs (OR:1.64, 95% CI: 0.35–7.78). Finally, patients on TKIs were at higher risk for new-onset or exacerbation of pre-existing hypertension (OR:3.31, 95% CI: 1.87–5.86). In conclusion, SSAs and TPH inhibitors appear to be safer as compared to mTOR inhibitors and TKIs with regards to their overall toxicity profile, and cardiovascular toxicities in particular. Special consideration should be given to a patient-tailored approach with anticipated toxicities of targeted NEN treatments together with assessment of cardiovascular comorbidities, assisting clinicians in treatment selection and early recognition/management of cardiovascular toxicities. This approach could improve patient compliance and preserve cardiovascular health and overall quality of life.

Role of Endomyocardial Biopsy in Diagnostics of Myocarditis

“…Review of cardiotoxic effects of biotherapy and molecular targeted therapy in treatment of neuroendocrine neoplasms with somatostatin analogues, tryptophan hydroxylase, mTOR and tyrosine kinase inhibitors found that biotherapy has a significantly lower incidence of adverse cardiac events and exacerbations of pre-existing conditions. EMB confirmed myocarditis has been reported in only one patient so far [ 118 ].…”

Endothelial Dysfunction in Childhood Cancer Survivors: A Narrative Review

“…The administration of vascular endothelial growth factor (VEGF) inhibitors and multi-target tyrosine kinase inhibitors can inhibit proliferation and migration of neighboring endothelial cells [103]. Inflammation may be stimulated by increased cytokine levels, for example, as a result of immune checkpoint inhibitor therapy on leukocytic cells or an increase in proinflammatory cytokines with chimeric antigen receptor T-cell [6,104].…”

Nursing Management and Adverse Events in Thyroid Cancer Treatments with Tyrosine Kinase Inhibitors. A Narrative Review

“…In conclusion, adverse events during therapy with sorafenib, lenvatinib, cabozantinib and vandetanib are common to the four compounds, are frequently experienced by all patients at least once during treatment and are generally not life-threatening, excluding cardiovascular AEs [ 74 ]. A proactive educational nursing approach aimed at the prevention and correct management of toxicities during therapy, together with a contribution of a multidisciplinary healthcare team, is essential in optimizing therapeutic adherence, satisfying a patients’ need for information [ 39 , 75 ], maximizing benefits, reducing risks and medication errors [ 76 ], and positively impacting the QoL of both patient and their family.…”