Antiangiogenic Agents and the Skin: Cutaneous Adverse Effects of Sorafenib, Sunitinib, and Bevacizumab

Abstract

As new antiangiogenic therapies have been introduced and added to the therapeutic arsenal against various types of cancer, previously unknown adverse effects have been detected. These effects negatively impact patients' quality of life and can even make it necessary to suspend treatment. Adverse skin reactions occur in 90% of patients treated with angiogenesis inhibitors. In some cases, a correlation has been observed between the severity of reactions and treatment efficacy and tumor response. It is therefore extremely important that dermatologists be able to recognize and manage these reactions. Moreover, in order to avoid the unjustified withdrawal of potentially life-extending treatments, dermatologists must be able to differentiate between non-life-threatening reactions and life-threatening reactions that necessitate the suspension of treatment. In this review article, we analyze the main cutaneous adverse effects of the most common antiangiogenic agents.

Keratoacanthoma of the Nasal Septum Secondary to Ranibizumab Use

“…There has also been report of lichenoid keratosis with ranibizumab use [22]. Although ranibizumab has not been specifically linked to precancerous and cancerous skin lesions, other antiangiogenesis agents have been [20, 23]. Sorafenib, a multikinase inhibitor (including VEGF receptors), has been associated with actinic keratosis, focal squamous atypia, keratoacanthoma, and squamous cell carcinoma [23–25].…”

“…Although ranibizumab has not been specifically linked to precancerous and cancerous skin lesions, other antiangiogenesis agents have been [20, 23]. Sorafenib, a multikinase inhibitor (including VEGF receptors), has been associated with actinic keratosis, focal squamous atypia, keratoacanthoma, and squamous cell carcinoma [23–25]. The mechanism is thought to be inhibition of the RAF kinase signaling pathway which results in keratinocyte differentiation and proliferation.…”

“…Interestingly, these lesions have mostly been seen in men and have occurred in non-sun-exposed regions. Typically, skin lesions will arise between 2 weeks and 3 years after starting sorafenib [23]. The patient presented in the case report indicated that he began taking ranibizumab approximately several weeks to months prior to him noticing the lesion.…”

Melanonychia and Blue lunulae with the Multikinase Inhibitor Sorafenib

“…Sometimes they require dose modifications and/or treatment interruptions [11]. Increased awareness by dermatologists who work with oncologists, of the diversity, frequency, and treatment of sorafenib-induced cutaneous adverse reactions will be helpful for patients who require long-term therapy with this medication for their cancers.…”

Yellowish nail pigmentation caused by sunitinib

“…Sunitinib is a multikinase inhibitor administered by mouth that selectively targets vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, platelet‐derived growth factor receptor (PDGFR), colony‐stimulating factor 1 receptor (CSF1R), the stem cell factor receptor c‐KIT (CD117), glial cell line‐derived neurotrophic factor receptor (RET), and Fms‐like tyrosine kinase‐3 (FLT3) receptor . It has been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST) with intolerance or resistance to treatment with imatinib mesylate, advanced and/or metastatic renal cell carcinoma, and unresectable or metastatic pancreatic neuroendocrine tumors …”