Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management

Abstract

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities, including malignant melanoma, thyroid, colonic and ovarian carcinomas, and some sarcomas. Thus, a number of inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Up to now one drug of this category (vemurafenib) has been approved by the FDA and the European Commission for late-stage melanoma. Although these new targeted anticancer therapies are generally considered to be safe and well tolerated, certain toxicities have been attributed to them, with cutaneous side effects being perhaps the most frequent amongst them. Based on results of clinical trials and on case series, a distinct profile of cutaneous toxicity has been observed, which is similar to that of EGFR and multikinase inhibitors. As exanthema, palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity, and paronychia, can be controlled in most cases with common conservative modalities, special attention should be given to the early detection of epithelial skin tumors (mainly keratoakanthomas) that can be induced during therapy with these agents. This report reviews all current published data on cutaneous side effects of RAS-RAF-MEK-ERK pathway inhibitors, and attempts to provide the clinician with clear hints for their management.

The use of vemurafenib in Australian patients with unresectable or metastatic melanoma containing the V600 BRAF gene mutation

“…Importantly, metastases from cSCCs have not been reported. All such lesions are simply excised 33 and do not require dose modification. 34 The cSCCs typically consisted of only one or two lesions with a median time to development of the first lesion of 8 weeks (range, 2-36) after vemurafenib commencement.…”

“…with urea or lactic acid); • avoidance of alcoholic lotions or gels; • use of bath oils or non-soap cleansers instead of soap; and • use of a high-factor sunscreen (at least 30+). 33 Patients should be referred to a dermatologist for an appointment 8-12 weeks after commencement of vemurafenib as this is the median time for development of cSCC and hyperkeratosis, which may require specialist management. The treating medical oncologist should ask about the appearance of new skin lesions and subsequent referrals to a dermatologist can be made as clinically indicated.…”

“…If bacterial superinfection is detected, then oral antibiotics should be administered together with local antiseptics. 33 Direct microscopic examination of scales in eczema or other skin rashes prepared with potassium hydroxide should be undertaken to identify any fungi, such as pityrosporum. If present, then additional therapy with ciclopiroxol amine, ketoconazole or clotrimazole is recommended, mostly in an oil-in-water emulsion.…”

“…If present, then additional therapy with ciclopiroxol amine, ketoconazole or clotrimazole is recommended, mostly in an oil-in-water emulsion. 33 Dose interruption may be required until severe photosensitivity resolves but with appropriate sun avoidance measures, treatment should be able to be resumed at the previous dose. While some cutaneous AEs such as panniculitis may resolve spontaneously, a short course of low-dose prednisolone may be required to bring symptoms under control.…”

Assessment of Augmented Immune Surveillance and Tumor Cell Death by Cytoplasmic Stabilization of p53 as a Chemopreventive Strategy of 3 Promising Medicinal Herbs in Murine 2-Stage Skin Carcinogenesis

“…Furthermore, the burden of side effects associated with the existing therapies makes their use further questionable. 2 Carcinogenesis in the skin can be induced by the application of a subthreshold dose of a carcinogen (initiation phase), followed by repetitive treatment with a noncarcinogenic tumor promoter. The initiation phase requires only a single application of either a direct-acting carcinogen or a procarcinogen (which has to be metabolized before being active) and is essentially irreversible; the promotion phase, however, is initially reversible but later becomes irreversible.…”