Cutaneous side effects of colorectal cancer tx may predict efficacy

October 1, 2007

Studies suggest that the worse the skin toxicity side effects due to anti-epidermal growth-factor receptor (EGFr) therapy, the more encouraging the outlook will be for most metastatic colorectal patients receiving the treatment. The EGFr is a naturally occurring protein that plays a major role in cancer cell signaling, particularly in the skin.

Chicago-Could treatment-related severe skin toxicity somehow benefit the patient with advanced colorectal cancer? The answer is a resounding "yes," according to new studies reported recently at the American Society of Clinical Oncology (ASCO) meeting.

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, goodquality life," the authors urge.

First to correlate

Dr. Peeters and his team of Belgian and Italian investigators presented their analysis called "Association of Skin Toxicity Severity with Clinical Outcomes and Quality of Life with Panitumumab" at a special ASCO poster discussion. It is 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, the scientists explain to Dermatology Times.

"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 anti-EGFr class includes such widely known biologically targeted cancer treatments as cetuximab (Erbitux), erlotinib (Tarceva) and - most recently approved - panitumumab (Vectibix), the first fully human monoclonal antibody directed against the EGFr.

All the other agents are part murine, which potentially can make patients more vulnerable to infusion reactions than fully human agents, according to some experts.

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 says.

"Our findings support the role of skin toxicity severity as a surrogate marker of on-target activity associatedwith clinical benefit. But the discomfort must be alleviated," Dr. Peeters continues.

The European scientific team revisited data from a previous phase 3 pivotal trial of panitumumab vs. 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," says Dr. Peeters.

Importantly, Dr. Peeters emphasized, 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 noted, 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 (18 percent vs. 5 percent).

The median time to the worst skin toxicity was 15 days, Dr. Peeters noted, "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.

"Dermatologists should be very careful about appropriate treatment. They should know that official U.S. prescribing information for anti-EGFr therapy includes boxed warnings as part of the evolving FDA labeling for this class," Dr. Peeters points out.

"Some recent studies show that severe toxicities - leading to dose modification, stopping EGFr treatment altogether, or (rarely) even death - occurred in 8 percent to 17 percent of patients receiving EGFr inhibitors," Dr. Peeters notes.

Looking at panitumumab separately in a pooled analysis of 966 metastatic colorectal patients receiving EGFr treatment, Dr. Peeters concluded," This drug as monotherapy is well-tolerated by most patients. While some may be very distressed by the side effects, they still can see a real clinical benefit (in reduced cancer symptoms) which they wouldn't have without the drug."