WAILEA, HAWAII – Oral capecitabine shows considerable early promise for the secondary prevention of nonmelanoma skin cancers in solid organ transplant recipients and other immunosuppressed individuals, according to Dr. Paul Nghiem.

Organ transplant recipients are at sharply increased risk of nonmelanoma skin cancer (NMSC). Many transplant recipients develop dozens of squamous cell carcinomas and/or basal cell carcinomas per year, and these tumors often behave very aggressively.

Dermatologists are sorely in need of additional tools to protect organ transplant recipients from NMSC – and capecitabine could fill the bill, he said at the SDEF Hawaii Dermatology Seminar.

Capecitabine (Xeloda) is a 5-fluorouracil (5-FU) precursor widely used for the treatment of colorectal cancer and metastatic breast cancer. Dr. Nghiem, a dermatologist at the University of Washington and the Fred Hutchinson Cancer Center in Seattle, credits University of Minnesota dermatologists with doing the pioneering work in developing capecitabine as a novel means of secondary prevention of NMSCs in the transplant population.

In a recent observational study, the Minnesota group reported on 15 solid organ transplant recipients, mean age 57 years, with recurrent NMSCs who were placed on low-dose capecitabine for the off-label purpose of preventing further NMSCs. The regimen was 1 g/m² daily on days 1-14 of a 21-day cycle.

Comparing cumulative incidence rates for NMSC during the first year on capecitabine to those the year before, the investigators found the mean number of squamous cell carcinomas per month declined by 0.33, the mean number of actinic keratoses fell by 2.45 per month, and the mean number of basal cell carcinomas dropped by 0.04 per month. All these reductions were statistically significant.

Toxicities were deemed manageable. Grade 3/4 toxicities consisted of fatigue in 40% of patients, hand-foot syndrome in 20%, and diarrhea in 20%. One-third of subjects discontinued capecitabine by 1 year (Clin. Transplant. 2010 Nov. 2 [doi:10.1111/j.1399-0012.2010.01348.x]).

There are no definitive data yet, but Dr. Ngheim predicted there will not be a major rebound in NMSCs upon discontinuation of capecitabine, as occurs when systemic retinoids given for the treatment of multiple NMSCs are stopped. That’s because capecitabine is actually killing cancer cells.

"After all, we don’t see a rebound after we treat squamous cell carcinomas with topical 5-FU. I would suspect there is going to be a longer-lasting benefit than with retinoids, and that capecitabine really might be a boon to these folks," he said.

While studies of capecitabine for the secondary prevention of NMSCs continue, physicians can use several other means to protect transplant and other immunosuppressed patients. Dermatologic examinations at intervals of every 3 months or less are important to detect these cutaneous tumors before they metastasize. In addition, regular use of a broad-spectrum sunscreen has been shown to prevent the development of actinic keratoses and invasive squamous cell carcinomas in a randomized trial involving 120 immunocompromised organ transplant recipients (Br. J. Dermatol. 2009;161[suppl. 3]:78-84).

Also, Dr. Nghiem said, it has become clear in the last several years that the calcineurin inhibitors prescribed by transplant physicians to improve graft survival have a highly unwelcome ancillary effect: "They act directly on keratinocytes as a second-level fertilizer to make squamous cell carcinomas grow and become more aggressive."

Unlike the calcineurin inhibitors, sirolimus does not have a direct carcinogenic effect on keratinocytes. In animal studies, substituting sirolimus for calcineurin inhibitors in order to prevent graft rejection results in a striking reduction in NMSCs. Whether the same holds true in humans is now under formal study.

03/15/11  

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EXPERT ANALYSIS FROM SDEF HAWAII DERMATOLOGY SEMINAR

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