Rash from EGFR inhibitors: Opportunities and challenges for palliation

Solomon, Benjamin; Jatoi, Aminah

doi:10.1007/s11912-008-0048-1

Cited by 17 publications

(20 citation statements)

References 21 publications

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“…Epidermal growth factor receptor inhibitors are being used more often in cancer therapy; rash is their most common side effect [1]. This rash typically occurs on the face, trunk, and upper extremities within 1 week of starting cancer therapy; it can be severe in 5–10% of patients, reaching rates as high as 12% in patients receiving cetuximab and other chemotherapy [1, 2].…”

Section: Introductionmentioning

confidence: 99%

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Clinical Predictors of Severe Cetuximab-Induced Rash: Observations from 933 Patients Enrolled in North Central Cancer Treatment Group Study N0147

Jatoi

Green

Rowland³

et al. 2009

Oncology

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Objective: Epidermal growth factor receptor inhibitors can result in a severe rash in 5–10% of patients and can detract from quality of life. The objective of this study was to identify clinical predictors of severe rash in the hope of utilizing such factors in the design of future rash palliative and prevention trials. Methods: 933 cetuximab-treated patients enrolled on N0147, an adjuvant chemotherapy trial for colon cancer, were evaluated for clinical risk factors of severe rash. Results: Within this cohort, 50 patients (5%) developed a severe rash (grade 3). More men compared to women developed such a rash: 34 (7%) versus 16 (3%) (multivariate odds ratio = 2.12; 95% confidence interval: 1.14–3.88; p = 0.017). A greater number of younger patients (<70 years of age) also developed a rash: 48 (6%) versus 2 (1%) (multivariate odds ratio = 0.21; 95% confidence interval: 0.05–0.88; p = 0.032). Race and performance score were not predictive. Conclusion: Men and younger patients are at greater risk for a severe cetuximab-induced rash although overall the risk is low. These observations are particularly important in designing future rash prevention and palliation trials.

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Section: Introductionmentioning

confidence: 99%

“…This rash typically occurs on the face, trunk, and upper extremities within 1 week of starting cancer therapy; it can be severe in 5–10% of patients, reaching rates as high as 12% in patients receiving cetuximab and other chemotherapy [1, 2]. Almost never fatal, this skin toxicity does, nonetheless, spawn considerable morbidity [3, 4].…”

Section: Introductionmentioning

confidence: 99%

Clinical Predictors of Severe Cetuximab-Induced Rash: Observations from 933 Patients Enrolled in North Central Cancer Treatment Group Study N0147

Jatoi

Green

Rowland³

et al. 2009

Oncology

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“…Both classes of agents display significant anti-tumor activity in a range of EGFR-dependent mouse xenograft models, and both have been approved for clinical use in selected cancer patients, including lung, head and neck, and colon cancers, where they display modest activity (3,(6)(7)(8). Although these therapeutics show promise, their use is restricted by antibody clearance by wtEGFR in the liver and dose-limiting toxicities, such as skin rash that results from significant uptake of these agents in normal skin where EGFR is expressed (9).…”

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confidence: 99%

Antibodies specifically targeting a locally misfolded region of tumor associated EGFR

Garrett

Burgess

Gan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal Growth Factor Receptor (EGFR) is involved in stimulating the growth of many human tumors, but the success of therapeutic agents has been limited in part by interference from the EGFR on normal tissues. Previously, we reported an antibody (mab806) against a truncated form of EGFR found commonly in gliomas. Remarkably, it also recognizes full-length EGFR on tumor cells but not on normal cells. However, the mechanism for this activity was unclear. Crystallographic structures for Fab:EGFR 287-302 complexes of mAb806 (and a second, related antibody, mAb175) show that this peptide epitope adopts conformations similar to those found in the wtEGFR. However, in both conformations observed for wtEGFR, tethered and untethered, antibody binding would be prohibited by significant steric clashes with the CR1 domain. Thus, these antibodies must recognize a cryptic epitope in EGFR. Structurally, it appeared that breaking the disulfide bond preceding the epitope might allow the CR1 domain to open up sufficiently for antibody binding. The EGFR C271A/C283A mutant not only binds mAb806, but binds with 1:1 stoichiometry, which is significantly greater than wtEGFR binding. Although mAb806 and mAb175 decrease tumor growth in xenografts displaying mutant, overexpressed, or autocrine stimulated EGFR, neither antibody inhibits the in vitro growth of cells expressing wtEGFR. In contrast, mAb806 completely inhibits the ligand-associated stimulation of cells expressing EGFR C271A/C283A. Clearly, the binding of mAb806 and mAb175 to the wtEGFR requires the epitope to be exposed either during receptor activation, mutation, or overexpression. This mechanism suggests the possibility of generating antibodies to target other wild-type receptors on tumor cells.cancer ͉ cryptic ͉ epitope ͉ therapeutic antibody ͉ structure

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“…The type and number of regression variables were formulated a priori based on prior reports of rash risk, the distribution of each candidate variable within the patient group, and constraints related to the size of the patient group. 10,11 A deliberate decision was made to include a contained number of variables and to forego the examination of certain other variables such as concomitant chemotherapy in order not to exceed this limit and report potentially spurious findings. Odds ratios and p-values were derived.…”

Section: Statistical Analysesmentioning

confidence: 99%

Epidermal Growth Factor Receptor (EGFR) Inhibitor-Induced Rash: A Consecutive Patient Series that Illustrates the Need for Rigorous Palliative Trials

Solomon

Jatoi

2011

Journal of Palliative Medicine

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Purpose: Rash is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors and negatively impacts quality of life. This single-institution study sought to explore how rash is currently managed outside a clinical trial setting and to further characterize general clinical aspects of this rash. Methods/Results: Among 4101 consecutive patients with cancer of the lung, colorectum, pancreas, and head and neck, 138 had received an EGFR inhibitor. Within this group, 96 (69%) developed a rash. Forty-nine of these patients were prescribed rash therapy, and a total of 26 different palliative regimens were used. Surprisingly, most patients, with the exception of 2, appear to have manifested evidence of rash improvement-even when unproven or disproved therapies had been prescribed. Fourteen patients stopped their EGFR inhibitor because of rash, and 11 were then able to restart. No demographic variables were able to predict rash development. Conclusion: The observation that multiple, largely unproven, anecdotal therapies are being prescribed to palliate EGFR inhibitor-induced rashes underscores the need for more rigorous, prospective palliative trials.

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Rash from EGFR inhibitors: Opportunities and challenges for palliation

Cited by 17 publications

References 21 publications

Clinical Predictors of Severe Cetuximab-Induced Rash: Observations from 933 Patients Enrolled in North Central Cancer Treatment Group Study N0147

Clinical Predictors of Severe Cetuximab-Induced Rash: Observations from 933 Patients Enrolled in North Central Cancer Treatment Group Study N0147

Antibodies specifically targeting a locally misfolded region of tumor associated EGFR

Epidermal Growth Factor Receptor (EGFR) Inhibitor-Induced Rash: A Consecutive Patient Series that Illustrates the Need for Rigorous Palliative Trials

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