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Track 1

DR LOVE: Can you discuss the evolution of the SERIES (Skin and Eye Reactions to Inhibitors of EGFR and kinaseS) Clinic?

DR LACOUTURE: Our interest in the dermatological toxicities of novel anticancer drugs began with the knowledge that many of these agents are otherwise largely devoid of systemic or hematopoietic side effects and, therefore, the high frequency of complaints affecting the skin, hair and nails make these side effects of the utmost importance.

We had to take into consideration that these could be life-saving or life-prolonging treatments. Our goals were to better understand and manage these dermatological side effects and to try to maintain patients on therapy for as long as possible.

Fortunately, we were able to fulfill these goals by providing rapid access for patients. We try to see patients the same day or the next day and treat them for side effects to be able to maintain them on anticancer therapy (Lacouture 2006).

Tracks 2, 4

DR LOVE: What are the skin toxicities you have observed with sorafenib and sunitinib?

DR LACOUTURE: Dermatological side effects are seen with high frequency. Data from Phase III randomized studies indicated that sorafenib led to a hand-foot skin reaction in 30 percent of patients, with Grade III to Grade IV severity in only five percent (Escudier 2007).

With sunitinib, the development of the hand-foot skin reaction occurred in 20 percent of patients, and of those cases only five percent were Grade III to IV in severity (Motzer 2007).

Hand-foot syndrome also occurs with other agents, such as fluorouracil or pegylated doxorubicin. However, these seem to be clinically and histologically distinct from the hand-foot skin reaction occurring with sorafenib and sunitinib.

With more conventional agents, you have swelling, redness and pain diffusely through the palms and soles. With sorafenib and sunitinib, you have a thickening of the skin. This thickening, when it is subject to pressure, leads to bleeding underneath the thickened areas, causing significant pain for the patient.

DR LOVE: What’s the typical time course of these symptoms and signs, and how do you manage them?

DR LACOUTURE: The hand-foot skin reaction tends to develop after the first month of therapy. With sorafenib, for which an administration of 400 milligrams twice daily is uninterrupted, you tend to see it earlier than with sunitinib, as the sunitinib regimen allows for a two-week drug holiday.

Patients are able to recover from the tenderness and pain during that two-week drug holiday.

Flushing — the red face and the seborrheic dermatitis-like reaction — occurs within the first two to four weeks. Hand-foot skin reactions usually occur later, and they tend to become worse over time if the symptoms are not managed.

For management, we have used high-concentration urea-containing preparations, such as urea 40 percent creams.

These are keratolytics, so they disrupt the outer layer of the skin, the stratum corneum. They seem to thin out that thickened skin layer that may be responsible for the increased pressure leading to the pain.

We also prescribe high-potency topical steroids, such as clobetasol ointment, as this will minimize the proliferation or the division of those skin cells. It will also decrease the underlying inflammation.

Track 16

DR LOVE: What are some common questions you receive from medical oncologists about these syndromes?

DR LACOUTURE: One question is whether the rash that occurs secondary to sorafenib correlates with response. Some evidence suggests that sorafenib-induced rash may correlate with survival, perhaps indicating greater bioavailability.

Another question is whether the rash secondary to the TKIs is similar to that occurring secondary to the EGFR inhibitors. However, the in vitro inhibitory profiles of these agents are completely different.

Therefore, the rash secondary to EGFR inhibitors should not be confused with the rash secondary to TKIs. It is completely different, both in its clinical presentation and in its response to therapy with doxycycline or with tetracycline antibiotics, which are ineffective against the rash associated with the TKIs.

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Neil Love, MD

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David I Quinn, MBBS, PhD
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Mario Lacouture, MD
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Bernard J Escudier, MD
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