Continuing medical education
Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane

https://doi.org/10.1016/j.jaad.2014.07.032Get rights and content

There has been a rapid emergence of numerous targeted agents in the oncology community in the last decade. This exciting paradigm shift in drug development lends promise for the future of individualized medicine. Given the pace of development and clinical deployment of targeted agents with novel mechanisms of action, dermatology providers may not be familiar with the full spectrum of associated skin-related toxicities. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents, and their intensity can be dose-limiting or lead to therapy discontinuation. In light of the often life-saving nature of emerging oncotherapeutics, it is critical that dermatologists both understand the mechanisms and recognize clinical signs and symptoms of such toxicities in order to provide effective clinical management. Part I of this continuing medical education article will review in detail the potential skin-related adverse sequelae, the frequency of occurrence, and the implications associated with on- and off-target cutaneous toxicities of inhibitors acting at the cell membrane level, chiefly inhibitors of epidermal growth factor receptor, KIT, and BCR-ABL, angiogenesis, and multikinase inhibitors.

Introduction

Key points

  1. Targeted therapies offer more precise oncologic treatment options; however, they are not free of adverse effects

  2. Cutaneous adverse effects are among the most frequently encountered, and significantly impact both quality of life and health care economics

  3. Dermatologists can provide key input in treatment of patients with targeted cancer therapies

Virtually all cancers are driven by molecular aberrations that ultimately lead to uncontrolled proliferation. This notion has spurred the development of a spectrum of therapies specifically aimed at the molecular mechanisms contributing to cancer development and progression. The emergence of this class of agents, often referred to as “targeted therapies,” offers a promise of more effective treatments tailored to a specific disease and possibly even to an individual patient's cancer.

Although designed to be significantly more “precise” than traditional chemotherapies, targeted therapies frequently induce adverse effects (AEs). Cutaneous toxicities are among the most frequently observed AEs1 and, when severe or protracted, can result in significant morbidity, requiring dose modification or drug discontinuation.2 The morbidity can affect patient's quality of life, including patient's physical,3 emotional,4 and psychological well-being.5 In addition, AEs can affect medication adherence, risk of infection, and cancer therapy dosing6, 7 and result in a substantial economic burden5 and potentially time-exhaustive clinic visits for cancer patients. In one analysis, management of dermatologic toxicities of targeted therapies was estimated at a median of $1920 per patient.8

Given the increasing use of targeted therapies, dermatology providers are encountering growing numbers of oncology patients who are experiencing cutaneous side effects of varied pathogeneses and complexity. The resulting need for a dual clinical expertise has led to collaborative efforts between dermatologists and oncologists, including the introduction of supportive oncodermatology fellowship programs.5 To allow for uniform reporting and proper cataloging of side effects between specialists caring for cancer patients, a standardized grading system has been established,9 and dermatologic AEs have been stratified accordingly.10

In this 2-part review, we address the key skin and skin appendage–related toxicities of the most prominent targeted anticancer therapies and discuss the incidence, pathogenesis, clinical presentations, and management strategies by drug category (Table I). Part I will focus on inhibitors of membrane-associated therapeutic targets (Fig 1), while part II details inhibitors of intracellular signaling pathways and immunotherapies.

Section snippets

Epidermal growth factor receptor inhibitors

Key points

  1. Epidermal growth factor receptor inhibitors generate a unique constellation of skin toxicities, including papulopustular eruption, hair and nail changes, mucositis, and photosensitivity

  2. The severity of papulopustular eruption directly correlates with epidermal growth factor receptor inhibitor efficacy and patient outcomes

  3. Prophylaxis and the early management of cutaneous toxicities may prevent dose reduction or dose discontinuation

Epidermal growth factor receptor (EGFR) inhibitors are among the

KIT and BCR-ABL inhibitors

Key points

  1. Among the oldest targeted inhibitors, blocking agents of KIT and BCR-ABL have been described to cause a series of cutaneous toxicities, including a broad spectrum of inflammatory eruptions

  2. Most adverse effects in this class are dose-related and reversible after drug discontinuation

Imatinib, nilotinib, and dasatinib are inhibitors of tyrosine kinases generated from the bcr-abl fusion protein, c-Kit, and platelet-derived growth factor receptors (PDGFRs). The bcr-abl protein is the result of

Antiangiogenesis agents

Key point

  1. The inhibition of angiogenesis also affects normal skin homeostasis, leading to mucocutaneous hemorrhage and poor wound healing

While endothelial cells in normal tissue are typically not mitotically active,123 neoplastic tissue features high cellular turnover and rapid growth capacity. Neovascularization is an important element to maintaining oxygen supply to the rapidly proliferating neoplastic cells. More than 30 growth factors involved in the promotion and inhibition of angiogenesis have been

Multikinase inhibitors

Key points

  1. Multikinase inhibitors affect many tyrosine kinase systems and result in a vast array of skin-related adverse effects

  2. Hand–foot skin reaction is a poorly understood painful complication that often negatively affects drug dosing; treatments for hand–foot skin reaction are limited

  3. Inflammatory, appendageal, and neoplastic skin toxicities overlap with other drug categories

Sorafenib, sunitinib, pazopanib, and vandetanib are small molecule inhibitors of the tyrosine kinase activity of the

Conclusion

Cutaneous adverse effects are among the most frequently observed, with many targeted therapies. Dermatologists can provide a useful role in early recognition and mitigation of skin-related toxicities, thereby influencing the need for dose-reduction or drug discontinuation. With continued expansion of the family of targeted therapies, providers caring for those with cutaneous conditions will become integral components to the multidisciplinary team approach of oncologic care.

We thank Lisa

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    Funding sources: None.

    Conflicts of interest: None declared.

    Date of release: February 2015

    Expiration date: February 2018

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