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In Reply

Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, United Kingdom

The Letter to the Editor by Dr Gerber et al is very interesting, as although their patient had an epidermal growth factor receptor inhibitor (EGFRI)–induced skin rash, and this had spared the previously irradiated field, the sparing appeared to be transient. This is the first documented case of the development of an EGFRI-induced rash in an initially spared preirradiated field. However, I think it is premature and incorrect to conclude that radiation-induced prevention of erlotinib-induced skin rash is transient. A careful study of the photograph of their patient reveals that the central sparing of the rash is still very marked over a significant area. The area of progression of the rash in the irradiated area surrounds the edge of the radiotherapy field, which is in the penumbra of the beam. We know that the radiation dose falls off significantly in the penumbra of the beam at the edge of the field, and with slight variations in the position of the patient during radiotherapy treatment. It is conceivable that the edge of the radiotherapy field had a lesser dose that the central part of the field. Experimental data suggest that erlotinib rash is due to inhibition of the epidermal growth factor receptor (EGFR) in basal epidermal keratinocytes and the outer root sheath of the hair follicle, leading to growth arrest and subsequent inflammation.¹ One can hypothesize that a certain threshold dose of radiotherapy is required to cause sufficient depletion of basal-layer stem cells to block the subsequent development of the pathological process of inflammation on erlotinib, and consequent rash. I can confirm that in the patient discussed in my original article,² the absence of the rash appears to be permanent, because he has since been rechallenged with erlotinib after a long break due to toxicity, and redeveloped the rash with the characteristic sparing (Fig 1). Since then, I have documented the absence of the rash in the irradiated field in several patients on different tyrosine kinase inhibitors, and in all of these patients, the absence of the rash appears to be permanent. The second photograph is of a patient with HER-2–positive breast cancer who had a left mastectomy and adjuvant radiotherapy to the left chest wall several years ago and developed the characteristic papulopustular rash on lapatinib, on the right anterior chest wall and right breast. The left chest wall skin was completely and permanently spared (Fig 2).

View larger version (97K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Photograph of the back of a patient with lung cancer who was rechallenged with erlotinib and developed the rash with characteristic sparing, which appears to be permanent.

View larger version (100K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Photograph of the left chest wall of a patient with HER-2–positive breast cancer showing permanent sparing of the rash that developed during treatment of lapatinib. The patient had adjuvant radiotherapy several years ago.

We know that EGFRI rash is exacerbated in the radiotherapy field if the EGFRI and radiotherapy are given concurrently.³ It is also known that radiotherapy upregulates EGFR.⁴ It is logical to hypothesize that increased EGFR-expressing stem cells during radiotherapy and their inhibition by an EGFRI, concurrently gives rise to more growth arrest and more inflammation. However, Gerber et al have offered no explanation for the mechanism for radiosensitization based on their hypothesis. In fact, their hypothesis is fundamentally incompatible with the concept of radiosensitization. Lastly, I do not discount their suggestion that immunological processes may have played a part in the progression of the rash at the edge of the radiotherapy field in their patient, where possibly, a subthreshold dose of radiotherapy was delivered. We agree that further studies are needed to investigate these aspects at the molecular and cellular level.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Lacouture ME: Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803-812, 2006[CrossRef][Medline]

2. Mitra SS, Simcock R: Erlotinib induced skin rash spares skin in previous radiotherapy field. J Clin Oncol 24:e28-e29, 2006[Free Full Text]

3. Lacouture ME, Hwang C, Marymont MH, et al: Temporal dependence of the effect of radiation on erlotinib-induced skin rash. J Clin Oncol 25:2140,2007[Free Full Text]

4. Huang SM, Li J, Armstrong EA, et al: Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res 62:4300-4306, 2002[Abstract/Free Full Text]

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Related Correspondence

• Radiation-Induced Prevention of Erlotinib-Induced Skin Rash Is Transient: A New Aspect Toward the Understanding of Epidermal Growth Factor Receptor Inhibitor–Associated Cutaneous Adverse Effects
  Peter Arne Gerber, Elaine Enderlein, Bernhard Homey, Anja Muller, Edwin Boelke, and Wilfried Budach
  JCO 2007 25: 4697-4698 [Full Text]

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