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Cutaneous Adverse Events in Patients on Chemotherapy

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Julia Ernst, MS, Assistant Editor

It is estimated that more than 1.6 million people will be diagnosed with cancer in the United States by the end of 2012.1 Chemotherapy is a common, widely-used treatment for cancer, and there are many types of chemotherapeutic agents and delivery systems available.2 In addition to gastrointestinal and hematopoietic toxicity, cutaneous adverse events (AEs) are also commonly seen in patients being treated with chemotherapy.2 These cutaneous AEs can vary significantly in terms of the gravity of the AE (ie, mild, moderate, severe, life-threatening, fatal) and in regard to the impact on the patient’s quality of life.2,3,4

Just as the spectrum of chemotherapy-associated cutaneous toxicities are broad, so are the chemotherapeutic agents available. Cytotoxic therapies represent the oldest class of these drugs; the newest agents are targeted therapies, which include, primarily, small-molecule drugs and monoclonal antibodies.5,6,7 As the number of chemotherapeutic agents increase, so does the range of skin-related toxicities.

Chemotherapy-Induced Cutaneous Toxicities

As with many classes of drugs, there are many different types of chemotherapy and many distinct medications within those broader classes, explains Milan J. Anadkat, MD, assistant professor, division of dermatology, Washington University School of Medicine, St. Louis, MO. The first step in understanding the cutaneous toxicities of chemotherapy is to better understand the distinct classes of drugs available, according to Dr. Anadkat, because some of the reactions are very drug-specific; an increased understanding of chemotherapy agents can decrease the time needed to diagnose the problem and, as a result, the time needed to treat it.

“It depends on what types of drugs are used to determine the incidence at which dermatologic adverse events will occur,” explains Mario Lacouture, MD, dermatology service, department of medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.

The broad class of “chemotherapy drugs” can be broken down into five subgroups: cytotoxic agents, steroids, differentiating agents, targeted agents and immunotherapy.8 There are then many different types of each agent. Some cutaneous AEs appear across the spectrum of these drugs; others are more commonly seen with one agent compared to another, and some agents cause more severe reactions than others. As Dr. Lacouture explains, the specific reactions will depend on the patient’s drug regimen. For the purposes of this article, because the cytotoxic and targeted agents are more likely to cause cutaneous AEs, these are the drugs that will be covered in detail.

Cytotoxic Agents. Cytotoxic agents represent the oldest class of chemotherapy drugs.5,8 These agents disrupt the replication of rapidly-dividing malignant and non-malignant cells by interfering with DNA replication.5 Specific agents include alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors and mitotic inhibitors.8 As the oldest class of drugs, the cutaneous side effects that may appear in patients on these therapies are the most well understood; reactions are non-specific (mucositis, alopecia) and specific (toxic erythema of chemotherapy, serpentine supravenous hyperpigmentation).5

According to Dr. Anadkat, the side effects of cytotoxic therapy are widely viewed as the standard types of adverse events that occur with chemotherapy.

“When people think of chemotherapy, they think of these therapies that are going to make you lose your hair, make you get sores in your mouth — what we call mucositis — and are going to give you nail changes. That’s what people think of when they think of chemotherapy,” explains Dr. Anadkat. “So, as cutaneous side effects go, the biggest thing for years that was consistent was alopecia, which, as a side effect, people hate, but is not dangerous.”

Targeted Therapies. This class of chemotherapy drugs is one of the newest, and one of the most likely to cause cutaneous AEs.9 These agents work by influencing the growth, division and spread of cancer cells, as well as the signals that cause cancer cells to die naturally.9 Examples of targeted chemotherapeutic agents include growth signal inhibitors (trastuzumab [Herceptin], imatinib [Gleevec], others); angiogenesis inhibitors (sorafenib [Nexavar], sunitinib [Sutent], others); and more.6,8,9

“What we saw, with the targeted therapies, is, because they’re so specific toward a certain protein, or toward a certain molecular pathway, they also had more specific side effects,” explains Dr. Anadkat. “And, again, cutaneous toxicity started becoming one of the most common side effects. What was different with the targeted therapies (versus the older cytotoxic agents) is that, this time, the skin side effects were sometimes the most significant toxicities.”

According to Dr. Lacouture, as many as 90% of patients treated with these newer targeted therapies will experience cutaneous AEs. Commonly seen AEs include rash, dry skin, pruritus, nail changes, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) and hair changes.3,10 In addition to these AEs, which have, for the most part, previously been observed with chemotherapeutic agents, the targeted therapies have also introduced novel toxicities.

“Some of the unique — but still dose-limiting — side effects that are coming with the targeted chemotherapies are things like pyoderma gangrenosum, which are large, ulcerative rashes, essentially — they look like infection, but they’re really not,” explains Dr. Anadkat. “There are drugs that cause this very odd but profound edema of the limbs — we’ve seen it with mTOR inhibitors, the newest of those things being drugs like everolimus [Afinitor].”

The Multi-faceted Impact of Cutaneous Toxicities

The Common Terminology Criteria for Adverse Events, Version 4, which was developed by Drs. Anadkat and Lacouture and colleagues, provides a comprehensive list of dermatologic adverse events that are associated with chemotherapy.3 The list is subdivided into two categories: (1) Skin and Subcutaneous Tissue Disorder Adverse Events and (2) Dermatologic Adverse Events Listed Under Other System Organ Classes.3 Adverse events are graded on a scale of 1-5 (1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=fatal) and symptoms are described in the context of severity.3 In other words, for example, “dry skin” is categorized as Grade 1 (“covering <10% BSA [body surface area] and no associated erythema or pruritus”), Grade 2 (“covering 10%-30% BSA and associated with erythema or pruritus; limiting instrumental ADL [activities of daily living]”) and Grade 3 (“covering >30% BSA and associated with pruritus; limiting self-care ADL”).3

According to Dr. Anadkat, the CTCAEv4 was designed for oncologists, but it is useful for dermatologists to understand in terms of knowing “how the oncologists think.” The CTCAEv4 can also serve as a resource for dermatology professionals who are not as familiar with the cutaneous AEs of chemotherapy who want to learn more.3

These cutaneous AEs can have a significant, varied effect on the patient.

“The consequences of these side effects are four-fold,” says Dr. Lacouture. “They affect a patient emotionally, of course, so there’s a psychosocial impact. They impact a patient financially — they have to pay significant out-of-pocket costs. They also have an effect on the patient’s health — it’s not only the way they look, in some patients, because they can lead to skin infections. For example, we showed that, in some patients treated with the targeted therapies, up to a third of them can develop skin infections that need to be treated, because they can become systemic and obviously cause many more problems. The fourth problem is that they lead to dose modifications of the anti-cancer therapy.”

Of these four concerns, the quality-of-life and dosing issues seem to be the most prevalent, and also the most problematic.

“We only tend to worry about severe side effects, but we have to come to the understanding that these patients are going to be on these drugs for, hopefully, many months, and a moderate side effect may not be a problem when chemotherapy was delivered through an infusion in the vein — the patient would develop side effects for 3 or 4 days, like nausea and vomiting — but now patients take these pills every day,” explains Dr. Lacouture. “When you’re talking about a moderate side effect, for months, it’s going to be difficult to deal with. So even moderate side effects have to be taken into consideration.”

A majority of the events discussed in the CTCAEv4 include a measurement of the impact of the AE on quality of life in determining severity; in many cases, the AE grade increases in conjunction with the quality-of-life impact of the side effect.3 Numerous studies have demonstrated the side effect’s impact on quality of life. Some of the most frequent issues include a decreased ability to care for oneself, pain and embarrassment.2,4-5,7,11-13

The Role Of The Dermatologist

When it comes to care of patients who experience cutaneous AEs from chemotherapy, the oncology team is on the front line to treat these toxicities, according to Dr. Anadkat; this may be one of the reasons that only 8% of patients who experience cutaneous AEs are referred to a dermatologist, according to Dr. Lacouture. However, the emergence of novel cutaneous AEs, which can be more complicated or severe than typical reactions, may demonstrate a need for dermatologic consultation.

“Treating skin disease is something that most non-dermatologists have a very limited understanding of, arising from a very limited focus on dermatologic education in medical school,” explains Dr. Anadkat. “If they understand the simple stuff, they’ll try simple remedies for simple problems.  For someone with itching, they’ll say: Moisturize more, here’s some Benadryl, maybe I’ll put you on a short course of oral steroids, or give you a steroid cream, but that’s that.”

It is at this juncture — when it becomes apparent that first-line measures are not alleviating skin toxicities, or when a cutaneous AE that is novel or difficult to diagnose — that dermatologists can play a role in managing chemotherapy-induced cutaneous AEs. However, for dermatologists to have a role in treating these events, they must become more familiar with the various chemotherapeutic agents and have a specific understanding of which agents cause which toxicities.

“As a dermatologist, you can’t simply see these patients and say they’re on quote-unquote chemotherapy and they have quote-unquote a rash. You need to be far more specific,” Dr. Anadkat explains. “It’s, rather, understanding that many of these patients will come to you on two or three or four chemotherapeutic agents, and it’s our job to say: You have this rash, and, despite the fact that you’re on four chemotherapies, and you’re on four or five other drugs, this specific rash is seen with this specific chemotherapy.”

This understanding, according to Dr. Anadkat, will enable the dermatologist to better consult with the oncologist and determine which drug is causing which toxicity; such a specific understanding will then allow reduction or cessation of the causative agent, rather than several of the drugs all at once.

Prophylactic and Palliative Care

The most significant role dermatologists can play in the care of these patients  is two-fold. Prophylactic treatment can be effective in two sects of patients: individuals who are prescribed chemotherapeutic agents that are known to cause certain cutaneous AEs can benefit from preemptive treatment, and individuals with a known propensity for, or history of, a certain illness can take measures to prevent a recurrence that may occur with chemotherapy.

Mucositis, which has, in some studies, been identified by patients as the most severe side effect of chemotherapy, is one very common cutaneous AE for which the latter strategy can be helpful.14 There are other oral complications of chemotherapy for which preventive treatment is beneficial, according to Andrei Barasch, DMD, MDSc, chairman of the department of dental medicine at Winthrop University Hospital in Mineola, NY.

“The prevalence of some [oral] complications can be minimized by prophylactic measures,” explains Dr. Barasch. “For example, patients with known herpetic carrier status receive antiviral therapy during their cancer treatment, which prevents acute reactivation. Similarly, prevalence of bacterial infectious episodes can be reduced by a thorough oral examination for detection of possible problematic spots and/or occult sores… The incidence of mucositis may be significantly reduced by palifermin (Kepivance) (recombinant human keratinocyte growth factor), which remains the only FDA-approved agent for this purpose.”

Chemotherapeutic drugs known to cause oral complications include some targeted agents (epidermal growth factor receptor [EGFR] inhibitors, antimetabolites and alkylating agents) and some cytotoxic drugs.12,13

EGFR inhibitors have become a widely used targeted agent for many types of cancer, including colorectal, breast and lung cancers, non-small cell lung cancer and squamous cell carcinoma (SCC) of the head and neck.15,16 Because EGFR is expressed by basal keratinocytes, sebocytes, the outer root sheath and some endothelial cells, EGFR inhibitors have long been associated with cutaneous AEs, appearing as early as clinical trials.15 According to Dr. Lacouture, dermatologic AEs from the EGFR inhibitors will be experienced by as many as 90% of patients, but they can be effectively managed with prophylaxis.

A 2010 study by Dr. Lacouture and colleagues in the Journal of Clinical Oncology (JCO) compared rates of EGFR-induced cutaneous toxicities in patients who had been prophylactically treated with a combination of a skin moisturizer, sunscreen and doxycycline, and controls.16 All participants were treated with the EGFR inhibitor panitumumab (Vectibix).

The primary endpoint was the difference in incidence rates of specific skin toxicities greater than Grade 2 in patients vs. controls. Patients taking panitumumab who were treated with the skincare regimen prior to initiation of therapy had an incidence rate of skin toxicities of 29%; participants who did not receive the prophylactic treatment had a 62% incidence rate of skin toxicities.16 Importantly, no differences were observed in disease control or progression; 1% of patients in the preemptive arm experienced dose delays compared to 6% of controls.16

While these examples are only a few of the numerous preventive strategies that can be implemented, they are representative of the beneficial ways in which dermatologists can be involved in the care of these patients.

“Dermatologists can greatly impact patients’ quality of life and decrease the need for interruptions in cancer treatment,” explains Beth N. McLellan MD, an instructor in the department of dermatology at New York University’s Langone Medical Center. “Several studies have shown successful prophylactic approaches to treating these side effects, so dermatologists may be able to help more if they are included in a patient’s care from the beginning, but this is not currently routinely done.”

An Interesting Paradox

While the prevalence of cutaneous AEs from chemotherapy have increased with the emergence of newer therapies like the targeted agents, these novel treatments have also presented a unique challenge.

“With some of the targeted agents, what we’ve seen is that some people who have skin toxicity are the ones who were most likely to benefit from the chemotherapy,” explains Dr. Anadkat. “So, herein lies the big paradox: You want to see a skin side effect, or, at least, getting the skin side effect is a good prognostic sign. With certain targeted therapies, if the patient gets a skin side effect, you don’t want to have the knee-jerk reaction of stopping the therapy, or of decreasing the dose, because, if anything, the skin side effect tells you: Good. This means I’m doing something.”

An increasing number of studies are beginning to provide in-depth analysis of this correlation, particularly in regard to improved treatment outcomes and the prevalence of skin toxicity in patients treated with some of the targeted agents, like EGFR inhibitors.17,18 As more details are understood about this connection, the healthcare professionals who study it are hopeful that dermatology providers can be more involved in the management – and prevention – of these events.

“As newer chemotherapy agents have emerged, some of which show a link between severity of skin toxicity and improved outcomes, the role of dermatologists in this area is growing,” explains Dr. McLellan.

Increasing Understanding to Improve Outcomes

Dr. Anadkat calls the role of the dermatologist in the prevention and management of these cutaneous AEs “crucial.”

“The goal and the challenge here is to be selective about which toxicity does really require the recommendation of decreasing the dosage of the drug, or trying temporary discontinuation based on the toxicity, versus determining which of these are rashes are not-life threatening, not dangerous, or, if anything, necessary and likely a good prognostic sign, in which cases we need to treat through it,” he explains. “Dermatologists can be a little more specific in the modality that we would choose for a skin toxicity and little more specific in the treatments we would encourage, and that’s where, I think, we have a role.”

SIDEBAR: Emerging Cutaneous Toxicities with the New Melanoma Drugs

In the second and third quarters of 2011, the FDA approved two new drugs for metastatic melanoma: ipilimumab (Yervoy) and vemurafenib (Zelboraf).19,20 Both drugs demonstrated significant improvements in overall survival for melanoma patients.19,20 Recently, patients have begun developing adverse cutaneous reactions to the drugs that were not seen in clinical trials.
Patients on ipilimumab have experienced autoimmune-mediated inflammation in many parts of the body, including the skin, according to Dr. McLellan, which can, in turn, result in dermatitis or vitiligo.

Vemurafenib has been shown to cause secondary skin cancers, according to Dr. McLellan, most commonly squamous cell carcinoma (SCC), and verruca. She recommends that all verrocous-appearing lesions be biopsied or treated, as they sometimes turn out to be squamous cell carcinomas. Patients on vemurafenib may also experience drug eruptions similar to common dermatoses, including keratosis pilaris and seborrheic dermatitis. Dr. Lacouture puts the incidence of SCC that develops in response to vemurafenib at up to 20%; he also notes that 1% to 5% of patients taking vemurafenib may develop secondary primary melanoma.

“This, of course, is paradoxic, that we’re seeing a therapy that’s causing multiple skin cancers while being effective for another type of skin cancer,” says Dr. Anadkat.

In terms of emerging chemotherapy-induced cutaneous AEs, Dr. Lacouture notes that these reactions are the most novel. He also suggests that these new AEs may represent another way for dermatologists to become more involved in the care of patients who experience chemotherapy-induced cutaneous toxicities, because the emerging reactions are dermatologically specific.

Dr. McLellan concurs.

“With each new chemotherapy agent, there are new toxicities that emerge,” she explains. “Including dermatologists in early-phase chemotherapy clinical trials can help these toxicities to be identified earlier so that we can figure out how to best treat them.”

ADDITIONAL RESOURCES

For dermatology professionals who are interested in learning more about this topic, the following resources may be of particular interest.

Dr. Lacouture’s Skin Care Guide for People Living with Cancer

This paperback guide, written by Dr. Lacouture, was published this year. It provides a detailed discussion about skin care specifically for patients who are currently being treated for cancer and cancer survivors. It can also serve as an in-office guide for starting conversations with patients and providing more information. It can be purchased on Amazon.

For more information, please visit www.drlacoutureskincare.com.

The Multinational Association of Supportive Care in Cancer

This organization is dedicated to providing information on the prevention and management of adverse events from cancer treatment, including cutaneous toxicities. The MASCC offers symposia, CME and CNE, guidelines and tools, and more.

For more information, please visit www.mascc.org.