Editorial Manager(tm) for Cutis Manuscript Draft
Manuscript Number: 10--8R1
Title: Painful annular pustular drug eruption induced by erlotinib in a case of non-small-cell lung cancer
Article Type: Letter to the Editor
Corresponding Author: Dr. Po-Yuan Wu, M.D.
Corresponding Author's Institution: China Medical University/Hospital First Author: Tzu-Chun Lin, M.D.
Dear editors and reviewers:
We acknowledge that our manuscript has been reviewed. We agree that this is an important area that requires more detailed revisions. I am detailing the changes I have made in response to the reviewers' comments point-by-point, using track changes mode in Word where I have made those changes in the revised manuscript.
Comment 1: Important features to highlight would include the latency after initiation of the drug, and the clinical mimicry to inflammatory tinea, both of which have been reported with gefinitib in the following reference (Rare cutaneous side-effect of gefitinib masquerading as superficial dermatophytosis. Lin SS, Tsai TH, Yang HH. Clin Exp Dermatol. 2009 Jun;34(4):528-530)
Response to Comment 1: We agree with the referee that this is an important point. We insert several sentences and cite two references to discuss the important features, including latency after initiation of the drug, and the clinical mimicry to inflammatory tinea by using track changes mode in the revised manuscript. The referee is right and thank for this comment. Comment 2: Page 1, line 3 is unclearly written.
Response to Comment 2: We agree with the referee that this is an important point. We descript it more clearly with two revised sentences added by using track changes mode in the revised manuscript. The referee is right and thank for this comment.
Comment 3: page 2, line 27 - define Akt; and would this be more clearly noted as a negative predictor?
Response to Comment 3: We agree with the referee that this is an important point. We supplement one paragraph and cite two references to define Akt and descript it as a negative predictor from previous study by using track changes mode in the revised manuscript. The referee is right and thank for this comment.
In accordance with the referees’ wishes, we have made changes and supplements in the revised manuscript. We thank the referees for these comments.
Yours sincerely,
Po-Yuan Wu, MD
Department of Dermatology
China Medical University/ Hospital 2 Yude Road, Taichung 40447, Taiwan
Tel: +886(0)422052121 ext. 4497, Fax: +886(0)422064561 E-mail: [email protected]
Financial Disclosure
Title page:
Title: Painful annular pustular drug eruption induced by erlotinib in a case of non-small-cell lung
cancer
Tzu-Chun Lin, MD; Po-Yuan Wu, MD
Dr. Lin is a dermatologist, China Medical University Hospital, Taiwan. Dr. Wu is Instructor,
Department of Dermatology, China Medical University/Hospital, Taiwan.
Correspondence to: Po-Yuan Wu, Department of Dermatology, China Medical University/Hospital,
2 Yude Road, Taichung 404, Taiwan
Tel: +886(0)422052121 ext. 4497, Fax: +886(0)422064561
E-mail: [email protected]
Funding sources: None.
Key words: erlotinib; bevacizumab; annular pustular drug eruption; epidermal growth factor
receptor; non-small-cell lung cancer
Conflicts of interest: The authors report no conflict of interest. *Title Page
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Erlotinib, like gefitinib, is an oral low molecular—weight inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Both reversibly inhibit the activation of EGFR tyrosine kinase through competitive binding of the adenosine triphosphate binding domain of the receptor. ErlotinibErlotinib, a relatively new class of cancer agents, as early gefitinib, is an oral low molecular—weight active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase through competitive binding of the adenosine triphosphate binding domain of the receptors. It has been approved for prolonging survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy.
A 54-year-old female visited our Dermatology Department with a generalized painful pustular drug reaction of four weeks’ duration. She was suffering from advanced non-small-cell lung cancer (NSCLC; T4N0M1), which had been diagnosed 12 months prior to this visit. She commenced chemotherapy with first-line chemotherapeutic agents on a three-week schedule [including cisplatin 80 mg/m2 intravenously on day 1 plus gemcitabine 1200 mg/m2 on days 1 and 8 of a 21-day cycle,
combined with bevacizumab, 15 mg/kg every 3 weeks]. Later, after four courses of conventional chemotherapy, she experienced poor control of her malignancy because of frequently missing scheduled chemotherapy for hematological toxicity, such as leukopenia, thrombocytopenia, bleeding tendency and nasal bleeding. She started a new target therapy with erlotinib, oral daily dose at 150 mg, and continued with bevacizumab at the initially prescribed dose, 15 mg/kg every 3 weeks. The first-line chemotherapy agents, cisplatin and gemcitabine, were stopped. However, seven months later after persist therapy with erlotinib and bevacizumab, severe painful erythematous rash, desquamation with annular pustular eruption presented on the trunk and four limbs, more seriously on both lower extremities (Figures 1A,B), as well as some follicular papules on the upper trunk and both shoulders (Figure 1C).
A skin biopsy from the annular pustular eruption demonstrated patchy subcorneal neutrophilic pustules with a background of spongiosis and neutrophilic/eosinophilic exocytosis. Basal cell vacuolar *Manuscript (should not include ANY author information)
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change and keratinocyte apoptosis were present with a perivascular infiltrate of mixed lymphohistiocytic cells and neutrophils in the superficial dermis (Figure 2). According to the above histopathological features and a literature review, severe annular pustular drug eruption induced by erlotinib, grade III skin toxicity (>50% body surface), was confirmed. The patient ceased erlotinib usage temporarily and received treatment with corticosteroids, moisture protection cream combined with analgesics. The skin lesions improved four weeks later. Thereafter, she restarted erlotinib from low dose and tolerated it well.
The most common side-effects of erlotinib are cutaneous adverse effects (acneiform eruption, xerosis, fissures of the palms and soles and paronychia, nasal or oral ulcers, urticariform rash and seborrhoeic dermatitis) and diarrhea, in 75% and 56% of patients, respectively.1 However, as these
secondary effects respond well to treatment, few patients discontinue these kinds of therapy. In the presence of skin rash, dose reductions to "subtherapeutic" levels are claimed to remain effective and prevent unnecessary early treatment termination.2 In general, the skin rash manifests within one to three
weeks after initiation of the anti-EGFR drugs, and is maximal by the third to fifth week. A dose-related adverse reaction is generally observed, with higher incidence and more severe rash encountered at higher dose levels.3 However, in our case, the painful annular pustular rash appearing after long-term
administratio of seven months with the erlotinib is uncommon. This unusual presentation of late-onset cutaneous adverse reaction mimicking superficial dermatophytosis has rarely been reported and should not be misdiagnosed as fungal infections. The periodic-acid–Schiff staining and tissue cultures can be undertaken to help in the differential diagnosis.4
Akt protein family, which members are also called protein kinases B, is a predominantly cytoplasmic serine/threonine protein kinase that is activated by phosporylation in response to growth factors or insulin. In humans, there are three isoforms in the Akt protein family: Akt1, Akt2, and Akt3. Akt1 is involved in cellular survival pathways by inhibiting apoptotic processes, and has been implicated as a major factor in many types of cancer. It is also able to induce protein synthesis pathways, and plays a
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major role in cell metabolism and growth. Akt1 has been known to provide an essential survival signal required for differentiation and stratification of primary human keratinocytes.5 Tan AR et al.6 have
identified that higher baseline Akt activity in normal keratinocytes is significantly correlated with not developing a rash. Low skin Akt activity, as a negative predictor, may help to identify the patients who are more likely to develop skin toxicity from erlotinib and possibly from other anti-EGFR agents.
Phosphorylated Akt activity, which may be a predictive utility for skin toxicity in patients treated with erlotinib, is significantly higher in patients who do not develop skin toxicity.3 However, cutaneous
toxicity seems to be a surrogate marker of clinical benefit, and patients who present with more severe skin rash have a better response to treatment and long survival.1 Several studies found a positive
correlation between the degree of rash and the months of survival in patients treated with cetuximab.47
In a recent study, erlotinib, like cetuximab, was suggested a better response to treatment in patients with more severe cutaneous toxicity.1
In a study of EGRF target therapy with cetuximab, the skin toxicity significantly increases when added to the first-line chemotherapy and bevacizumab, a kind of VEGFR inhibitor. The increase of skin toxicity in the cetuximab-containing treatment group could be fully attributed to cetuximab-related skin toxicity.5 8 Erlotinib resistance may be associated with a rise in host stromal and tumor cell vascular
endothelial growth factor. The multitargeted agent approach, including a combination of single-targeted therapies, is the next generation of targeted therapies in solid tumors. Our patient concomitantly used bevacizumab, which is a vascular endothelial growth factor-targeted agent and widely used in general oncology practice, every 3 weeks. The combined inhibition of both vascular endothelial growth factor receptor (VEGFR) and EGFR signaling pathways has the clinical potential to offer additional benefits in preclinical and early clinical data for treatment of NSCLC. It is well tolerated and has demonstrated encouraging efficacy and safety in early clinical studies.69
We present a rare case of a painful annular pustular drug eruption after receiving administration of erlotinib in the therapy of NSCLC. This severe annular pustular eruption is linked to erlotinib
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administration. This late-onset cutaneous side-effect of anti-EGFR drugs mimicking superficial dermatophytosis should not be misdiagnosed as fungal infections. Erlotinib resistance and multitargeted agent therapy are concerned topics, which merit further investigations. Bevacizumab, which is a kind of vascular endothelial growth factor receptor inhibitor and may delay wound healing, would play an important role. Whether bevacizumab deteriorates the skin toxicity of erlotinib in a case of non-small-cell lung cancer has to be determined. Even though the multitargeted agent therapy becomes popular, the severe cutaneous adverse effects are still the most concerned side-effects and need to be much cautious.
Sincerely,
Tzu-Chun Lin, MD Po-Yuan Wu, MD Taichung, Taiwan
The authors report no conflict of interest.
REFERENCES
1. Pérez-Soler R, Chachoua A, Hammond LA et al. Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. J Clin Oncol. 2004;22:3238-47.
2. Lind JS, Postmus PE, Heideman DA et al. Dramatic Response to Low-Dose Erlotinib of Epidermal Growth Factor Receptor Mutation-Positive Recurrent Non-small Cell Lung Cancer After Severe Cutaneous Toxicity. J Thorac Oncol. 2009;4:1585-6.
3. Eilers RE Jr, Gandhi M, Patel JD et al. AKT1 Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy. J Natl Cancer Inst. 2010;102:47-53.
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4. Lin SS, Tsai TH, Yang HH. Rare cutaneous side-effect of gefitinib masquerading as superficial dermatophytosis. Clin Exp Dermatol. 2009;34:528-30.
5. Thrash BR, Menges CW, Pierce RH et al. AKT1 provides an essential survival signal required for differentiation and stratification of primary human keratinocytes. J Biol Chem. 2006;281:12155-62. 36. Tan AR, Steinberg SM, Parr AL et al. Markers in the epidermal growth factor receptor pathway and skin toxicity during erlotinib treatment. Ann Oncol. 2008;19:185-90.
47. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-45. 58. Tol J, Koopman M, Rodenburg CJ et al. A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann
Oncol. 2008;19:734-8.
69. Pennell NA, Lynch TJ Jr. Combined inhibition of the VEGFR and EGFR signaling pathways in the treatment of NSCLC. Oncologist. 2009;14:399-411.
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Figure 1 (A) Painful erythematous maculopapular skin rash with confluence on both lower legs. (B) Close-up view of the annular pustular eruption. (C) Follicular papules on the upper trunk and shoulders. Figure 2 Pustular erythroderma demonstrated interface dermatitis and subcorneal neutrophilic-rich pustules, numerous neutrophils/eosinophils exocytosis with some keratinocyte apoptosis, perivascular lymphohistiocytic cells and neutrophil infiltrations (H&E, original magnification x200).
Figure 1
Figure 2
