Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor

Abstract

The Ras-Raf-MEK-ERK signalling pathway is frequently dysregulated in human malignancies, as is angiogenesis and the vascular endothelial growth factor receptor (VEGF/VEGFR) pathway. These kinases are therefore important anticancer targets. The novel, oral treatment sorafenib (BAY 43-9006), has been shown to be an inhibitor of VEGFR, Raf and platelet-derived growth factor in clinical trials against a variety of cancers, with the greatest activity to date observed in metastatic renal cancer. Although side-effects with this targeted therapy are usually not dose-limiting, they frequently involve the skin, and consist of a maculopapular rash, palmar-plantar dysaesthesia, alopecia and xerosis. In this report, we present two patients in whom treatment with sorafenib resulted in inflammation of actinic keratosis, which in some cases progressed to invasive squamous cell carcinoma. This side-effect is of clinical importance, as early recognition is critical for early treatment and may represent a source of additional morbidity to these patients.

Erlotinib-responsive actinic keratoses

“…Other dermatologic reactions include paronychia and some nail changes, abnormalities in hair growth, xerosis, hypersensitivity reactions, non-specific maculopapular rashes, stomatitis, mucositis and pruritus (9-11). One case report described the incidental development of inflammation of previously undetected actinic keratoses while on sorafenib therapy (12). We presently report the self-limited inflammatory flare-up of actinic keratoses during erlotinib treatment.…”

“…Other conventional chemotherapeutic agents which have been associated with the inflammation of actinic keratosis include docetaxel, doxorubicin, capecitabine, pentostatin, sorafenib and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine and 6-thioguanine (8,12,23,24). The mechanism by which these agents lead to this effect is unknown, although abnormal DNA synthesis and a form of radiation recall have been postulated (12).…”

Evolving Strategies for the Management of Hand–Foot Skin Reaction Associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib

“…The most clinically significant of these toxicities, HFSR, has also been referred to as hand-foot syndrome (HFS) and palmar-plantar erythrodysesthesia [14,32], and has been shown to occur in anywhere from 9% to 62% of patients receiving sorafenib or sunitinib [1,22,[25][26][27]29]. A meta-analysis to study the incidence and risk of HFSR in patients enrolled in prospective clinical trials in which either sorafenib or sunitinib was examined as a single agent was performed using a random-effects or fixed-effects model based on the heterogeneity of the included studies [1,33].…”

Intensified Inflammatory Reaction of Actinic Keratoses after Single Application of Topical 5-Fluorouracil in a Patient Treated with Nilotinib for Chronic Myeloid Leukemia

“…Recently, Lacouture et al [7] described 2 patients in whom treatment with sorafenib, a multitargeted TKI, resulted in inflammation of AKs, which in 1 case progressed to invasive SCC. The authors speculated that sorafenib might target the dysregulated Ras pathway found in SCC and, moreover, might inhibit vascular endothelial growth factor and platelet-derived growth factor receptor-β, both critical to SCC angiogenesis in invasiveness [7].…”

“…Recently, Lacouture et al [7] described 2 patients in whom treatment with sorafenib, a multitargeted TKI, resulted in inflammation of AKs, which in 1 case progressed to invasive SCC. The authors speculated that sorafenib might target the dysregulated Ras pathway found in SCC and, moreover, might inhibit vascular endothelial growth factor and platelet-derived growth factor receptor-β, both critical to SCC angiogenesis in invasiveness [7]. A similar observation was reported by Hong et al [8], who described the development of 3 invasive, well-differentiated SCCs in a female patient treated with a combination of sorafenib and tipifarnib (a farnesyltransferase inhibitor) for metastatic renal cell carcinoma.…”