Treatment-related side effects of EGFr drugs are clinically beneficial

Key Points

International report - Could treatment-related, severe skin toxicity somehow benefit the patient with advanced colorectal cancer? The answer is a resounding yes, according to recent studies.

The studies suggest that the worse the skin toxicity side effects due to anti-epidermal growth-factor receptor (EGFr) therapy, the more encouraging the outlook for most metastatic colorectal patients receiving the treatment.

Dermatologists should, therefore, view the suppurative rashes, pain, itching, inflammation, and other class-specific side effects of EGFr drugs not with apprehension but as "predictors of drug therapy efficacy in the patients, harbingers of shrinking tumors and longer, good-quality life," the authors urge.

First to correlate

Dr. Peeters and his team of Belgian and Italian investigators conducted the first known study to measure the specific correlations of skin toxicity severity to progression-free survival, overall survival, cancer-related symptoms and quality of life following anti-epidermal growth factor receptor therapy.

The EGFr is a naturally occurring protein that plays a major role in cancer cell signaling, particularly in the skin. "Cell function - hence, cell survival - depends on these signals, which are disrupted when EGFr is inhibited. Other studies show that some 85 percent to 100 percent of patients on EGFr inhibitors develop skin side effects," the authors say.

The anti-EGFr class includes widely known biologically targeted cancer treatments such as cetuximab (Erbitux), erlotinib (Tarceva) and - most recently approved - panitumumab (Vectibix), which is the first fully human monoclonal antibody directed against the EGFr. All the other agents are part-mouse, which can potentially make patients more vulnerable to infusion reactions than fully human agents, some experts say.

The paradox

"Paradoxically, we found the more intense the cancer patient's skin discomfort, the longer he or she survived after treatment without progression of the underlying disease," Dr. Peeters tells Dermatology Times.

"Our findings support the role of skin toxicity severity as a surrogate marker of on-target activity associated with clinical benefit. But the discomfort must be alleviated," he says.

The European scientific team revisited data from a previous phase 3 pivotal trial of panitumumab versus best supportive care, showing that the new targeted drug halved the rate of tumor progression compared with best supportive care alone in 463 metastatic colorectal cancer patients refractory to standard chemotherapy. The results of that trial led the Food and Drug Administration (FDA) to approve panitumumab in 2006 for use in advanced colorectal cancer.

"Our current updated analysis of these same patients' biopsies shows not only longer progression-free survival, but also extended overall survival, fewer symptoms of colorectal cancer and improved health-related quality of life. All due to anti-EGFr therapy," Dr. Peeters says.

Importantly, he says, these findings were associated with worsening skin toxicity as measured by standard grading scales, dermatologic life quality indexes and patient-reported outcomes.

Typically, Dr. Peeters notes, at week 24 after treatment began, about four times as many patients on panitumumab plus best supportive care were alive and progression-free, compared to those on best supportive care alone, at a rate of 18 percent to 5 percent, respectively.

The median time to the worst skin toxicity was 15 days, he says, "but an outbreak of extreme skin side effects may occur even beyond 28 days."

Some researchers believe severe skin symptoms are due to high doses of anti-EGFr therapy and look to dose modification for help in some cases. Others, including Dr. Peeters, urge clinicians to try to continue with the original treatment plan until the patient becomes too stressed from the toxic effects.