Elsevier

The Lancet Oncology

Volume 6, Issue 7, July 2005, Pages 491-500
The Lancet Oncology

Review
Cutaneous side-effects of kinase inhibitors and blocking antibodies

https://doi.org/10.1016/S1470-2045(05)70243-6Get rights and content

Summary

Although kinase inhibitors raise hope for people with cancer, patients and their clinicians are commonly confronted with the cutaneous side-effects that are associated with the use of these drugs. This review is the result of collaborations between dermatologists, medical oncologists, and pathologists, and discusses the cutaneous side-effects seen after treatment with the inhibitors of epidermal-growth-factor receptor (EGFR), imatinib, sorafenib, and sunitinib. Some of the side-effects caused by these agents are very distressing, partly because they are chronic owing to the long duration of treatment. Therefore, patients need early and appropriate dermatological management. Moreover, several studies have reported a link between the antitumour efficacy of EGFR inhibitors and cutaneous side-effects. Elucidation of this connection could lead to the identification of crucial predictive factors for tumour response.

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

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.

References (76)

  • AM O'Farrell et al.

    SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo

    Blood

    (2003)
  • AA Sharov et al.

    Fas and c-kit are involved in the control of hair follicle melanocyte apoptosis and migration in chemotherapy-induced hair loss

    J Invest Dermatol

    (2003)
  • L Valeyrie et al.

    Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients

    J Am Acad Dermatol

    (2003)
  • ML Hensley et al.

    Imatinib treatment: Specific issues related to safety, fertility, and pregnancy

    Semin Hematol

    (2003)
  • M Ebnoether et al.

    Cerebral oedema as a possible complication of treatment with imatinib

    Lancet

    (2002)
  • GD Demetri et al.

    Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors

    N Engl J Med

    (2002)
  • R Perez-Soler

    Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome?

    Oncology (Huntingt)

    (2003)
  • RS Herbst et al.

    Gefitinib: a novel targeted approach to treating cancer

    Nat Rev Cancer

    (2004)
  • J Mendelsohn et al.

    Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer

    J Clin Oncol

    (2003)
  • DR Spigel et al.

    Bevacizumab and erlotinib in the treatment of patients with metastatic renal carcinoma (RCC): update of a phase II multicenter trial

    Proc Am Soc Clin Oncol

    (2005)
  • P Pautier et al.

    Preliminary results of a phase II study to evaluate gefitinib (ZD1839) combined with paclitaxel (P) and carboplatin (C) as second-line therapy in patients (pts) with ovarian carcinoma (OC)

    Proc Am Soc Clin Oncol

    (2004)
  • D Cunningham et al.

    Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer

    N Engl J Med

    (2004)
  • KJ Busam et al.

    Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225

    Br J Dermatol

    (2001)
  • W Jacot et al.

    Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours

    Br J Dermatol

    (2004)
  • R Van Doorn et al.

    Follicular and epidermal alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor

    Br J Dermatol

    (2002)
  • J Albanell et al.

    Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition

    J Clin Oncol

    (2002)
  • R Murillas et al.

    Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure

    EMBO J

    (1995)
  • C Robert et al.

    Inflammatory skin diseases, T cells, and immune surveillance

    N Engl J Med

    (1999)
  • R Perez-Soler et al.

    Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer

    J Clin Oncol

    (2004)
  • EE Cohen et al.

    Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck

    J Clin Oncol

    (2003)
  • SA Chrysogelos

    Chromatin structure of the EGFR gene suggests a role for intron 1 sequences in its regulation in breast cancer cells

    Nucleic Acids Res

    (1993)
  • H Buerger et al.

    Length and loss of heterozygosity of an intron 1 polymorphic sequence of EGFR is related to cytogenetic alterations and epithelial growth factor receptor expression

    Cancer Res

    (2000)
  • ML Amador et al.

    An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors

    Cancer Res

    (2004)
  • NT Shah et al.

    Practical management of patients with non-small-cell lung cancer treated with gefitinib

    J Clin Oncol

    (2005)
  • J Koistinaho et al.

    Tetracycline derivatives as anti-inflammatory agents and potential agents in stroke treatment

    Ernst Schering Res Found Workshop

    (2004)
  • T Krakauer et al.

    Doxycycline is anti-inflammatory and inhibits staphylococcal exotoxin-induced cytokines and chemokines

    Antimicrob Agents Chemother

    (2003)
  • GW Amsden

    Anti-inflammatory effects of macrolides—an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions?

    J Antimicrob Chemother

    (2005)
  • S Dueland et al.

    Epidermal growth factor receptor inhibition induces trichomegaly

    Acta Oncol

    (2003)
  • Cited by (492)

    • Commonly prescribed medications associated with alopecia

      2023, Journal of the American Academy of Dermatology
    View all citing articles on Scopus
    View full text