Recommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review

Department of Clinical Oncology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
Cancer Treatment Reviews (Impact Factor: 7.59). 11/2011; 38(5):505-14. DOI: 10.1016/j.ctrv.2011.09.004
Source: PubMed


Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient's quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity.

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    • "Wild-type KRAS and skin toxicity are generally known to correlate with greater chemosensitivity and survival in cetuximab regimens, and this was also evident in the current study (Bass et al, 2012; Bokemeyer et al, 2012; Peeters and Price, 2012; Custidio and Feliu, 2013). At present, KRAS mutation is considered the most specific biomarker of poor chemosensitivity, allowing patients to avoid unnecessary and expensive therapy, but its positive predictive value is somewhat limited. "
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    ABSTRACT: Background: Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy. Methods: A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway. Results: For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively. Conclusion: LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.
    Full-text · Article · Apr 2013 · British Journal of Cancer
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    • "Thus, a therapy designed to target activating and mutated resistant forms of EGFR, but avoiding inhibition of native EGFR would be a promising molecular target for cancer therapy allowing a better efficacy associated with no or more manageable toxicity. Furthermore , an appropriate screening and identification of side effects at early-stage of EGFR therapy will undoubtedly allow for best management of toxicity by matching patients to the best treatment (personnalized medecine) [139] [140] [141]. "
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    ABSTRACT: The tyrosine kinase epidermal growth factor receptor (EGFR) has emerged in recent years as a key and validated target of targeted therapies for solid tumors. It plays a central role in oncology since it is involved in many steps of tumor progression such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Recent advances in targeted therapies have demonstrated that tyrosine kinase inhibitors (TKIs), have provided a marked benefit to subsets of patients whose tumors harbor specific genetic abnormalities. However, resistance phenomenon appears rapidly and patients with EGFR mutations acquire resistance to TKI inhibitors decreasing therefore the median time to disease progression to few months. Several strategies were envisioned to overcome this resistance, such as dual-target inhibitors, multitarget and combined therapy. This review summarizes recent advances in TKIs development with special focus on rational strategies for the design of potent EGFR inhibitors including molecular modeling studies based on crystallographic data. Such advances open the way for new research possibilities in modern medicinal chemistry combined to structure-based drug design.
    Full-text · Article · Feb 2013 · Current Medicinal Chemistry
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    ABSTRACT: Chemotherapeutic agents used in colorectal cancer are frequently associated with severe adverse reactions that compromise the efficacy of treatment. Predicting toxicity could enable therapy to be tailored. Genetic variations have been associated with toxicity in patients treated with fluoropyrimidines (5-fluorouracil, capecitabine and tegafur), oxaliplatin, irinotecan and cetuximab. Complexity of treatment and variability in toxicity classifications make it difficult to compare studies. This article analyzes the association between toxicity and polymorphisms in DPYD, TYMS, MTHFR, ABCB1, UGT1A1, ERCC1, ERCC2, XRCC1, GSTT1 and GSTM1. In addition, the state-of-the-art and future perspectives are discussed.
    No preview · Article · Jul 2012 · Pharmacogenomics
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