We searched PubMed by crossing the drug names “sorafenib” etc with the following search terms: “hair”, “skin rash”, “skin toxicity”, “acne”, “folliculitis”, “acral erythema”, and “oedema”. We searched the reference lists of articles identified by these strategies and selected those we judged relevant. Review articles were included as well. There were no language restrictions.
ReviewCutaneous side-effects of kinase inhibitors and blocking antibodies
Introduction
Treatments that target receptors with kinase activity, which are involved in the transmission of pleiotropic proliferation signals, could revolutionise cancer treatment. Many small molecules or monoclonal antibodies that can block the activity of distinct sets of kinases are now available, and some of them have already shown survival benefits in patients with cancer, such as imatinib in patients with gastrointestinal stromal tumours.1
However, the range of activity of these agents is not simply directed at tumour cells. These agents are associated with various adverse events, with cutaneous side-effects being the most commonly reported. A systematic dermatological survey of patients receiving these treatments is important for several reasons. First, adapted management of cutaneous side-effects and prompt prescription of symptomatic measures improves the patient's quality of life and could affect adherence with treatment. These treatments are commonly given over long periods and some patients find the chronic cutaneous side-effects associated with them difficult to accept. Second, any association between clinical findings and the range of targeted kinases could lead to ideas about the specific role of a distinct kinase in the emergence of a particular cutaneous symptom, and might help to elucidate the pathogenetic mechanisms about skin or hair physiology. Finally, some of these skin events seem to be related to clinical outcomes and survival and could potentially be useful as surrogate markers for treatment efficacy.2 Several of the adverse skin events, such as acute folliculitis, multiple subungual splinter haemorrhages, or hair depigmentation,3 are not recognised as classic drug-associated manifestations.
Clinical and pathological descriptions of these disorders are given here, along with mechanistic hypotheses and symptomatic treatments. This review is about the cutaneous side-effects recorded with inhibitors of epidermal growth-factor receptor (EGFR) and three other inhibitors that block various kinase combinations: imatinib (c-KIT, BCR-ABL, and platelet-derived-growth-factor receptor [PDGFRβ]), sorafenib (Raf proteins, vascular-endothelial-growth-factor receptor [VEGFR] 2 and 3, PDGFRβ, and FLT3), and sunitinib (c-KIT, VEGFR2, PDGFRβ, and FLT3), on the basis of our personal experience and on previously reported data.
Section snippets
EGFR inhibitors and blocking antibodies
Several cancers are associated with an aberrant or overexpressed EGFR. This receptor is a transmembrane protein encoded by the c-erb-B proto-oncogene that dimerises on ligand binding, causing the initiation of mitogenic intracellular signal cascades through its tyrosine-kinase activity. Its main endogenous ligands include epidermal growth factor and transforming growth factor α. Overexpression of EGFR has been associated with chemoresistance and a poor prognosis in various tumours, and it is
Combinations of kinase inhibitors
Several other inhibitors of various combinations of kinases are being tested in patients with various cancers. Imatinib inhibits the tyrosine kinase functions of BCR-ABL, PDGFRβ, and c-KIT, and is now established as first-line treatment in patients with chronic myelogenous leukaemia and gastrointestinal stromal tumours.1, 46 Imatinib induces non-specific rashes in 30–40% of patients with chronic myelogenous leukaemia that are generally self-limiting and easily managed. Rare and classic
Conclusion
The inhibition of tyrosine-kinase receptors widely expressed in the skin structures results in a wide range of chronic cutaneous side-effects. Many of these adverse skin events, such as acute folliculitis, multiple subungual splinter haemorrhages, and hair depigmentation are not known as classic drug-related manifestations. The study of these hitherto unknown side-effects will provide useful information on skin, hair, and pigment-cell physiology. Most importantly, however, physicians will need
Search strategy and selection criteria
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