Download Treatment of Cutaneous Reactions to Epidermal Growth Factor

Treatment of Cutaneous Reactions to Epidermal
Growth Factor Receptor Inhibitors
Rebecca G. Pomerantz
Mentor: Larisa J. Geskin, MD – Department of Dermatology
Co-Authors: Ezra D. Mirvish; Larisa J. Geskin, MD
Background: Cutaneous toxicity is the most common adverse effect of anticancer therapy
with epidermal growth factor receptor (EGFR) inhibiting agents. In some cases the drug-induced
skin rash is severe, interfering with activities of daily living and requiring dose reduction or
cessation of EGFR inhibitor therapy. EGFR inhibitor-induced rash is a relatively new clinical
entity without established, evidence-based treatment paradigms to inform its management.
Methods: We have treated skin toxicity in EGFR inhibitor-treated patients with the retinoid
acitretin, with excellent responses.1 In order to formally evaluate the utility of this management
approach, we designed a pilot trial utilizing acitretin to treat cutaneous reactions to the EGFR
inhibitor erlotinib. In this trial, patients with National Cancer Institute Common Terminology
Criteria for Adverse Events (CTCAE) Grade 2 rash are treated with low-dose (10 mg/day)
acitretin and followed for 12 weeks; we evaluate clinical response (primary outcome) and effect
on skin-related quality of life (secondary outcome). In addition, we published a review of EGFR
inhibitor-induced cutaneous toxicities, focusing on clinical features, histopathological
characteristics, and management of these toxicities, including our own novel treatment
algorithm.2
Results: Numerous patients have been treated in our clinic with acitretin for EGFR
inhibitor-induced skin toxicity. The severity of these cutaneous reactions has ranged from
moderate to severe, painful, dose-limiting eruptions. Nearly all of these patients have benefited
from acitretin therapy, and more than half have had complete or near-complete responses;
management of cutaneous toxicity in these patients has enabled continuation of EGFR inhibitor
therapy at full dose. Collectively, our anecdotal experiences suggest a potential role for acitretin
in the treatment of cutaneous eruptions associated with EGFR inhibitor therapy. A clinical trial
was designed to formally evaluate this hypothesis, and is currently ongoing.
Conclusions: Cutaneous toxicity to erlotinib therapy is extremely common and in severe
cases, may limit the clinical utility of a potentially life-sustaining therapy. Most of the current
treatment options for EGFR inhibitor-associated skin toxicity have significant limitations,
including lack of efficacy and unfavorable side effect profiles. In order to avoid dose reduction,
interruption, or discontinuation of antineoplastic therapy in patients experiencing significant
cutaneous toxicities to EGFR inhibitors, improved treatment paradigms for management of
these cutaneous toxicities are needed. Acitretin may be helpful for management of moderate to
severe skin reactions to EGFR inhbitors.
References:
1. Pomerantz RG, Chirinos RE, Falo LD Jr, Geskin LJ. Acitretin for treatment of EGFR
inhibitor-induced cutaneous toxicity. Archives of Dermatology, 2008 July; 144(7): 949-50.
2 . Pomerantz RG, Mirvish ED, Geskin LJ. Cutaneous reactions to epidermal growth factor
receptor inhibitors. Journal of Drugs in Dermatology, 2010 October; 9(10): 1229-34.
Bibliography
Published abstracts

Pomerantz RG, Mirvish ED, Erdos G, Falo LD Jr, Geskin LJ. Novel approach to gene
expression profiling in Sezary Syndrome. Journal of Investigative Dermatology, Apr
2010; 130 (Suppl 1): S29.

Mirvish ED, Pomerantz RG, Geskin LJ. Lack of novel Merkel Cell Polyomavirus in
Mycosis Fungoides tumors. Journal of Investigative Dermatology, Apr 2010; 130 (Suppl
1): S29.

Pomerantz RG, Patton TJ Jr, Mirvish ED, Falo LD Jr, Geskin LJ. Disease stage-related
changes in T cell receptor-VB profile in cutaneous T cell lymphoma. Journal of
Immunology, Apr 2009; 182: 88.10.

Chirinos RE, Pomerantz RG, Jukic DM, Geskin LJ. Systemic antineoplastic and/or
immune modulating drugs induce high CD30 expression in skin lesions. Journal of
Investigative Dermatology, 2007; 127 (Suppl 1): S14.
Poster presentations

Pomerantz RG, Mirvish ED, Erdos G, Falo LD Jr, Geskin LJ. Novel approach to gene
expression profiling in Sezary Syndrome. Poster presentation at the Society for
Investigative Dermatology Annual Meeting, Atlanta, GA, May 7, 2010.

Mirvish ED, Pomerantz RG, Geskin LJ. Lack of novel Merkel Cell Polyomavirus in
Mycosis Fungoides tumors. Poster presentation at the Society for Investigative
Dermatology Annual Meeting, Atlanta, GA, May 7, 2010.

Pomerantz RG, Patton TJ Jr, Mirvish ED, Falo LD Jr, Geskin LJ. Disease stage-related
changes in T cell receptor-VB profile in cutaneous T cell lymphoma. Poster presentation
at the American Association of Immunologists 96th Annual Meeting, Seattle, WA, May
10, 2009.

Pomerantz RG, Mirvish ED, Moore PS, Chang Y, Swerdlow SH, Geskin LJ. Lack of
association of novel polyomavirus with Mycosis Fungoides tumors. Poster presentation
at the International Society for Cutaneous Lymphomas annual meeting, San Francisco,
CA, March 5, 2009.

Mirvish ED, Pomerantz RG, Watkins SC, Geskin LJ. FOXP3 and CD30 expression in
drug-induced cutaneous lymphoproliferative lesions. Poster presentation at the
International Society for Cutaneous Lymphomas annual meeting, San Francisco, CA,
March 5, 2009.
Oral presentation

Pomerantz RG, Mody E, Qureshi AA. Follow-up of psoriatic arthritis mutilans patients
treated with anti-TNF-a therapy. Podium presentation at the Medical Dermatology
Society Annual Meeting, Washington D.C., February 2, 2007.
Published manuscripts in peer-reviewed journals

Pomerantz RG, Mirvish ED, Erdos G, Falo LD Jr, Geskin LJ. Novel approach to
gene expression profiling in Sezary Syndrome. British Journal of Dermatology, 2010
November; 163(5): 1090-4.

Pomerantz RG, Mirvish ED, Geskin LJ. Cutaneous reactions to epidermal growth
factor receptor inhibitors. Journal of Drugs in Dermatology, 2010 October; 9(10):
1229-34.

Mirvish ED, Pomerantz RG, Geskin LJ. Infectious agents in cutaneous T cell
lymphoma. Journal of the American Academy of Dermatology, 2011 February; 64(2):
423-31.

Pomerantz RG, Campbell LS, Jukic DM, Geskin LJ. Posttransplant Cutaneous T-cell
Lymphoma. Archives of Dermatology, 2010 May; 146(5): 513-6.

Pomerantz RG, Mody E, Husni ME, Qureshi AA. Follow-up of psoriatic arthritis
mutilans patients treated with anti-TNF-alpha therapy. Journal of Drugs in
Dermatology, 2009 April; 8(4): 406-12.

Pomerantz RG, Chirinos RE, Falo LD Jr, Geskin LJ. Acitretin for treatment of EGFR
inhibitor-induced cutaneous toxicity. Archives of Dermatology, 2008 July; 144(7):
949-50.

Pomerantz RG, Husni ME, Mody E, Qureshi AA. Adalimumab for treatment of
pyoderma gangrenosum. British Journal of Dermatology, 2007 December; 157(6):
1274-5.

Pomerantz RG and Grandis JR. The epidermal growth factor receptor signaling
network in head and neck carcinogenesis and implications for targeted therapy.
Seminars in Oncology, 2004 December; 31(6): 734-43.
Manuscript in press

Pomerantz RG, Lee DA, Siegel DM. Risk Assessment in Surgical Patients:
Balancing Risks and Benefits. Clinics in Dermatology, in press.
Book Chapters

Pomerantz RG, Kupper TS, Qureshi AA. “Immunomodulation in Dermatology.”
Therapy of Skin Diseases, Krieg T, Bickers D, Miyachi Y, eds., New York: Springer,
2009.

Mirvish ED, Pomerantz RG, Falo LD, Geskin LJ. “Dendritic cell vaccines in cancer:
obstacles to overcome.” Dendritic Cells in Cancer, Shurin MR and Salter RD, eds.,
New York: Springer, 2009.
Research Grants

Howard Hughes Medical Institute Research Training Fellowship for Medical
Students, 2008-2009 (support for full-time research between second and third years
of medical school)

Binational Science Foundation Travel Grant for Young Scientists, 2011

American Medical Association Seed Grant, 2008-2009

American Dermatological Association Medical Student Fellowship Grant, 2009

OSI Pharmaceuticals Research Grant, 2008-present
Summary of Scholarly Activity
Significance of the project
EGFR inhibitors are an important new class of molecular targeting agents for the
treatment of a variety of advanced neoplastic diseases. Cutaneous toxicity to EGFR inhibitor
agents is extremely common and in severe cases, may limit the clinical utility of a potentially
life-sustaining therapy. Clinical trials such as this one are needed to enable the development of
evidence-based paradigms for the treatment of EGFR inhibitor-associated skin rashes.
Approaches to project goals
Larisa Geskin, MD, my faculty mentor for this project, has experience treating skin
toxicity in EGFR inhibitor-treated patients with acitretin, with excellent responses. I wrote a short
manuscript describing one such patient, who developed a severe, painful pustular eruption upon
beginning erlotinib therapy for pancreatic cancer; the rash resolved completely with low dose
(10 mg/day) acitretin. This was the first reported case of acitretin for treatment of EGFR
inhibitor-induced skin toxicity. Subsequently, we designed a prospective study utilizing acitretin
to treat cutaneous reactions to the EGFR inhibitor erlotinib, in order to formally evaluate the
utility of this management approach. Additionally, I wrote a review of EGFR inhibitor-induced
cutaneous toxicities, incorporating the novel management algorithm that is utilized in Dr.
Geskin's clinic.
Independence of the student
The novel concept of utilizing acitretin to treat EGFR inhibitor-induced skin reactions was
Dr. Geskin's. I wrote the manuscript for our initial case report described above, and worked with
Dr. Geskin to design the clinical trial. I wrote the protocol for the trial and subsequently
incorporated the modifications requested by the IRB. I also successfully sought funding for this
study from the American Medical Association (AMA Seed Grant for Medical Students) and from
OSI Pharmaceuticals (grant for investigator-initiated trial), and wrote the grants to both
organizations. Additionally, I was the primary author of our review article describing the clinical
characteristics and management of EGFR inhibitor-induced cutaneous toxicities.
Project originality
This is the first prospective study to evaluate acitretin, or any oral retinoid agent, for
treatment of cutaneous reactions to EGFR inhibitor therapy. The results of this study are
expected to provide a new evidence-based treatment option for the management of EGFR
inhbitor-associated skin rashes.
Project limitations and possible future directions
This is a pilot study designed to evaluate acitretin in a small number of patients with
erlotinib-induced skin rash. Future studies evaluating the efficacy of this approach may be
designed as randomized, controlled prospective trials. Additionally, future studies may evaluate
patients with skin reactions to EGFR inhibitors other than erlotinib.
Contribution to analytical skills
This work has provided extensive and valuable experience in study design, writing and
revising a protocol, the IRB submission process, writing and revising manuscripts, submitting to
peer-reviewed journals, identifying appropriate funding sources, and grant writing. I hope that
the skills developed through this work will provide grounding for a career in academic medicine
and research.
Scholarly Project Paper
Published manuscripts relevant to this work have been uploaded to the Scholarly Project
site. In addition, I have attached selected publications related to my work on other concurrent
projects.
Addendum
In addition to this study, I have also been working on multiple projects related to
Cutaneous T Cell Lymphoma, during my CSTP/Howard Hughes fellowship year and on an
ongoing basis throughout medical school. Those projects which led to manuscripts and/or
presentations are noted in the bibliography above. Additionally, I have uploaded some of these
manuscripts to the Scholarly Project site.