CORONADO, CALIF. The side effects associated with epidermal growth factor receptor inhibitors can be so awful that several cancer patients have told Dr. Jonathan Cotliar that they would rather die than continue taking them.
"That's significant when you hear that from many people," Dr. Cotliar said at the annual meeting of the Pacific Dermatologic Association.
One side effect that occurs in 60%80% of cancer patients who take epidermal growth factor receptor inhibitors (EGFRIs) is skin toxicity, mostly in the form of papulopustular lesions. Paronychia, fissures, xerosis, alopecia, eyelash trichomegaly, telangiectasias, and photosensitivity also can occur.
"I think the companies that developed these drugs underestimated the significance of cutaneous toxicity," said Dr. Cotliar, director of inpatient dermatology services in the division of dermatology at the University of California, Los Angeles.
The incidence of skin toxicity among patients who take the monoclonal antibodies cetuximab (Erbitux) or panitumumab (Vectibix) is somewhat higher compared with those who take the tyrosine kinase inhibitors erlotinib (Tarceva) or gefitinib (Iressa). All of the agents cause apoptosis of keratinocytes. "That's probably the major event that allows for what we see clinically in these patients," he said.
"We also know that there is early initiation of keratinocyte differentiation. In theory, that allows the stratum corneum to become impaired, which leads to many of these toxicities. We also know that inhibition of epidermal growth factor leads to epithelial cell production of proinflammatory mediators. That allows for the adaptive immune response to take hold," he explained.
Papulopustular lesions commonly occur on the face, chest, back, and scalp. The palms and soles are spared.
Histology reveals a thinned stratum corneum, dilated follicular infundibula, necrotic keratinocytes, and mixed inflammation in the upper dermis. "In addition, you may see acantholysis of the follicular epithelium," Dr. Cotliar said.
Ironically, skin toxicityspecifically the papulopustular lesionsis a surrogate marker for treatment efficacy of EGFRIs. "We know that this eruption is more severe and incidence is greater in responders to these medications than in those who don't respond," said Dr. Cotliar, who disclosed that he is a consultant for Amgen Inc., which manufactures panitumumab, and has received honoraria from the company.
"We also know that there is a nice correlation between survival, both overall and progression free, [and] severity of the rash. We don't know if this is an epiphenomenon or if there's something about the cutaneous toxicity that's allowing the immune response to percolate and fight the underlying cancer," he noted.
The severity of papulopustular lesions seems to be linked to the EGFRI dose. "We also know that patients typically develop these lesions 13 weeks after their first infusion or their first pills," he said. "The maximal toxicity occurs by weeks 35."
Once patients stop taking the EGFRI, the cutaneous side effects usually resolve within a couple of weeks.
There is no current standard for treating skin toxicity associated with EGFRI use. A proposed treatment algorithm was recently published (Oncologist 2007;12:61021), but "everything we know about treating these patients is based on case reports," Dr. Cotliar said.
A first approach might involve modifying the dose of the EGFRI by following package insert instructions. Most patients referred to Dr. Cotliar and his associates are started on 1% or 2% hydrocortisone or sometimes tetracycline or doxycycline.
"A lot of times I will start patients on doxycycline 100 mg b.i.d.," he said. "I also typically startfor the first week or twowith a mid- to high-potency topical corticosteroid."
One "black hole" among possible treatment options is isotretinoin. "Nobody's sure what effect it has on tumor biology," he said. "We're also not sure of its effect on EGFRIs. We need to know more about that. We do know from case reports that 2030 mg/day is successful in helping resolve some of these lesions."
Other potential treatments for papulopustular lesions include colloidal oatmeal lotion, topical erythromycin, clindamycin, metronidazole, and topical retinoids.
Potential treatments for xerosis and pruritus triggered by the use of EGFRIs include bland emollients and antihistamines.
Potential treatments for paronychia and fissures include aluminum acetate soaks, 4% thymol, emollients, topical corticosteroids, intralesional steroids, systemic antibiotics, electrodesiccation, cryosurgery, surgical debridement, and nail plate avulsion, Dr. Cotliar said.
Lastly, pulsed dye lasers can be used to treat telangiectasias.
Papulopustular lesions are commonly seen in patients who are taking epidermal growth factor inhibitors. Courtesy Dr. Jonathan Cotliar