Rash from Newer Cancer Agents: Why Do We Still Not Have Effective Therapy for Palliation and/or Prevention?

Commentary on “Dermatologic Toxicities of Targeted Anticancer Therapies”

Yevgeniy Balagula, MD, et al (page 149)

In their paper, “Dermatologic Toxicities of Targeted Anticancer Therapies,” Balagula and others provide a thorough discussion of cutaneous adverse events from newer, targeted anticancer agents. These agents include epidermal growth factor receptor (EGFR) inhibitors, as well as several other multikinase inhibitors. The authors describe the spectrum of skin, hair, and nail changes that arise from several such agents and comprehensively expound upon the psychosocial and physical discomfort of such toxicities.

Although we are unable to predict with accuracy who will develop cutaneous toxicity and to what extent, and though toxicity rates vary greatly depending upon the specific targeted agent, we do know this: for some cancer patients, the development of a rash is almost a foregone conclusion. For example, over 80% of patients treated with cetuximab (Erbitux)—an EGFR inhibitor prescribed for the treatment of cancer of the colorectum, head and neck, and lung—will develop a rash. Almost invariably, this rash will occur on a “cosmetically sensitive area” (namely, the face), as well as on the trunk and extremities. This adverse event also often triggers cutaneous discomfort and emotional distress.

Yet, despite the high likelihood of developing this rash and despite its widespread ramifications, Balagula and others pointedly state that “most of the treatment strategies are still not evidence based.” They also describe how “future analyses are needed to…identify other clinical predictors of severe skin reactions.” Several years have elapsed since EGFR inhibitors were first approved in the United States. But despite the recently published STEPP trial,¹ which provides a valiant effort at rash prevention, to date, effective palliative strategies remain few. Moreover, to our knowledge, next to no studies have been conducted to prevent or palliate rashes from a multitude of other targeted agents. Why has there been a paucity of research to explain the mechanisms of cutaneous toxicities? Why do we today still have no definitive strategies to prevent or effectively palliate these rashes? Below, we briefly speculate on the answers to these questions.

First, a notable literature discusses the association between rash from EGFR inhibitors and improved cancer outcomes. Wacker and others² evaluated data from two phase III studies that were both conducted with erlotinib. Among 444 lung cancer patients who had been prescribed erlotinib and among 254 pancreatic cancer patients treated with erlotinib plus gemcitabine (Gemzar), the development of rash strongly correlated with overall survival. These investigators concluded, “Physicians and patients should view rash development as a positive event indicative of greater likelihood of clinical benefit.”

While true, this statement potentially gives rise to discordant feelings about the rash. This rash can be disfiguring, socially isolating, and painful—and yet, the medical literature describes it as a “positive event.” This reluctance to disengage efficacy of cancer treatment from toxicity of cancer treatment is almost commonplace and appears to provide an impediment to research in cancer symptom palliation, including rash palliation.

Second, if one looks at lists of side effects from cancer therapy, cutaneous toxicity is conspicuously absent. For example, on their Web site, the American Cancer Society states, “The most common side effects of chemo are listed here.” They then go on to list side effects: anemia; fatigue; hair loss; increased chance of bruising, bleeding, and infection; and nausea and vomiting.³ Other than hair loss, no mention is made of cutaneous toxicity. Unless and until rash is recognized as a common and debilitating side effect, there is unlikely to be sufficient willingness to look for palliative strategies.

Finally, a visit to a recent blog⁴ suggests that even among patients prescribed EGFR inhibitors, not all feel adequately prepared by their healthcare providers about the prospect of developing a rash. One patient said, “I also wish that I had been better prepared by my doctor for the cycle of the rash.” A qualitative study from our group similarly reveals that subsets of patients did not recall having been forewarned even about the possibility of developing a rash. Such findings imply that among healthcare providers, some appear to place a lesser concern about rash; as a result, the impetus to look for palliative strategies may again be weakened.

In short, a greater recognition of drug-induced rash and all its ramifications would play an invaluable role in promoting research in drug-induced rash palliation and prevention. The important article from Balagula and colleagues makes a strong case for why this research should be pursued.