Correlation between efficacy and skin rash occurrence following treatment with the epidermal growth factor receptor inhibitor cetuximab: A single institution retrospective analysis

Orditura, Michele; Vita, Ferdinando De; Galizia, Gennaro; Lieto, Eva; Vecchione, Loredana; Vitiello, Fabiana; Martinelli, Erika; Ciardiello, Fortunato

doi:10.3892/or_00000319

Cited by 51 publications

(37 citation statements)

References 18 publications

(26 reference statements)

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“…8,9) Although mechanisms underlying the skin toxicities associated with EGFR inhibitors or MKIs have not been elucidated, positive correlations between severity of these toxicities and efficacy endpoints (including better tumor response, longer time to tumor progression (TTP) and overall survival (OS)) have been demonstrated; thus, it has been suggested that early skin toxicities might be predictive markers for efficacy of these drugs. [10][11][12] Regarding associations between HFS and efficacy after capecitabine therapy, however, few studies, either qualitative or quantitative, have been conducted. A recent report firstly showed a significant positive relationship between capecitabine-related HFS and efficacy, in terms of disease control rate (DCR), progression-free survival (PFS) and OS, after combination therapies with cetuximab and capecitabine (cetuximab+capecitabine+oxaliplatin or cetuximab+capecit abine+irinotecan) in patients with colorectal cancer.…”

Section: -7)mentioning

confidence: 99%

Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

Azuma¹,

Hata

Sai³

et al. 2012

Biological & Pharmaceutical Bulletin

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Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is a promising treatment for colorectal, breast and gastric cancers, but often causes hand-foot syndrome (HFS), the most common dose-limiting toxicity. The current study was conducted to investigate the relationship between HFS and efficacy of capecitabine in 98 patients with metastatic breast cancer. Possible associations between HFS and efficacy endpoints, including time-to-treatment failure (TTF), tumor response in metastatic lesions and changes in tumor markers, were investigated retrospectively using electronic medical records. The TTF of group with HFS of grade 1 and ≥2 was significantly longer than that of group with no HFS, respectively (hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.18-0.87 for group with grade 1; HR, 0.42, 95% CI, 0.19-0.90 for group with grade ≥2). Significantly higher disease control rates for the liver metastasis were observed in patients with HFS (grade 1 and greater) than in those without HFS (92.9 vs. 42.9%, p 0.009). Furthermore, prevention of increases in tumor marker levels (carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA15-3) and National Cancer Center-Stomach-439 (NCC-ST439)) was evident in patients with HFS. This study clearly showed a significant correlation between HFS and some efficacy markers of capecitabine therapy in patients with metastatic breast cancer, and suggests that early dose adjustment based on severity of HFS might improve efficacy. Studies are needed to explore predictive biomarkers for HFS/efficacy, so that capecitabine therapy can be further tailored to patient response.Key words capecitabine; hand-foot syndrome; efficacy; electronic medical record Capecitabine is administered as an oral fluoropyrimidine prodrug in the treatment of a number of cancers, including breast and gastrointestinal cancers. 1) Capecitabine generates 5-fluorouracil (5-FU) preferentially in tumor tissue through a three-step enzymatic process. In the first step, capecitabine is hydrolyzed by carboxylesterase (CES) in the liver to produce the 5′-deoxy-5-fluorocytidine (5′-DFCR). In the second step, 5′-DFCR is converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase (CDA), which is highly active in liver and tumor tissues.2) In the final step, 5′-DFUR is converted to 5-FU by thymidine phosphorylase (TP), a rate-limiting enzyme. Dihydropyrimidine dehydrogenase (DPYD), a ratelimiting catabolic enzyme of the pyrimidines, is also involved in the degradation pathway of capecitabine.1,3) Since TP activity is 3-10 times higher in tumor cells than in the normal tissues, 2,4) selective conversion of capecitabine to 5-FU in tumor tissues minimizes systemic exposure to 5-FU relative to exposures associated with intravenous (i.v.) 5-FU/leukovorin regimens. Thus, capecitabine is associated with a lesser incidence of 5-FU-related severe toxicities, such as diarrhea, stomatitis, nausea, alopecia and neutropenia, while maintaining equivalent or superior efficacy compared with the IV regimens. 5-7)The most com...

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Section: -7)mentioning

confidence: 99%

Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

Azuma¹,

Hata

Sai³

et al. 2012

Biological & Pharmaceutical Bulletin

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“…Therewasanassociationbetweenrashandbettersurvival outcomes in patients treated with erlotinib in the BR.21, TRUST,PA.3andAViTAtrials [11,12,16,25,29,30].Inaddition, patients who experienced rash grade ≥ 2 had better survival outcomes than those with grade 1 rash [25,30]. In studies of cetuximab across different tumor types (CRC, HNSCC,NSCLCandpancreaticcancer),patientswhowere treated with cetuximab and developed rash had better survival outcomes than those who did not develop rash [23,31]. In addition, patients with more severe rash tended to tionofkeratinocytedifferentiationandapoptosis,(3)keratinocytemigrationandadhesioninwoundhealing,and(4)downregulation of immune reactions of the skin by opposing the overactivationofkeratinocytepro-inflammatoryfunctions [2].…”

Section: Potential Of Rash As a Marker For Efficacy Of Egfr Inhibitorsmentioning

confidence: 99%

“…Each subtype has key characteristics and recomsurvive longer than those with less severe rash [23,31]. In comparison with erlotinib and cetuximab, the relationship betweenrashandclinicaloutcomesassociatedwith gefitinib is less clear [4].…”

Section: Egfr Inhibitor-associated Rash: Clinical Characteristics Andmentioning

confidence: 99%

Management of the Cutaneous Side Effects of Therapeutic Epidermal Growth Factor Receptor Inhibition

Reck

Gutzmer

2010

Onkologie

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The epidermal growth factor receptor (EGFR) is expressed in a variety of human tissues and is a key mediator of numerous cellular processes. Dysregulation and overexpression of the EGFR are common features of many tumors; targeted EGFR inhibitors are therefore widely employed as therapeutic agents. Novel mechanisms associated with EGFR inhibitors induce characteristic toxicities, of which cutaneous side effects (generally termed ‘skin rash’) are the most common. Although this rash is generally mild to moderate in severity, it can affect compliance and/or result in dose reductions or treatmentwithdrawal. To ensure that patients can continue to receive active treatment at the optimal dose, effective treatment strategies are required to actively manage rash and aid compliance. This is important as rash is increasingly identified as a predictive marker of benefit with EGFR inhibitors. The incidence and clinical characteristics of rash, in addition to current rash management strategies, are reviewed. Our recommendations based on clinical experience are presented, with two case studies of successful rash management provided to illustrate their success. Active rash management can effectively resolve rash to ensure that patient compliance is maintained, without necessitating dose interruptions or treatment withdrawal.

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“…79,80 A recent retrospective study across patients with several cancer types treated with cetuximab in one centre found that the presence of a skin rash correlated positively with response rate and time to progression and was the only clinical variable to predict response. 81 Similar associations with a skin rash have been noted in other anti-EGFR drugs and linked with multiple clinical end-points, including survival. 82 Other adverse effects include infusion reactions, cytotoxicity, gastrointestinal upset and cardiotoxicity, among others.…”

Section: Adverse Effectsmentioning

confidence: 73%

The epidermal growth factor receptor in squamous cell carcinoma: An emerging drug target

Gaffney

Soyer

Simpson

2013

Australasian Journal of Dermatology

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Squamous cell carcinoma (SCC) of the skin is an increasingly common diagnosis worldwide. Together with precursor lesions, SCC carry a significant morbidity, particularly in regions with high solar UV radiation levels. Advanced lesions are locally or sometimes widely metastatic and may be resistant to treatment. Drugs targeting the epidermal growth factor receptor (EGFR) are currently the only significant non-surgical option for advanced SCC beyond radiotherapy and conventional chemotherapy. The role of the EGFR in skin cancer is described and the outcomes of targeted anti-EGFR therapy published to date are summarised. The future of anti-EGFR targeted therapies in the treatment of skin cancer is discussed. Targeted molecular therapies are becoming increasingly widespread and an understanding of the evidence for their use as well as their side effect profile is important in order to offer patients informed and current advice.

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Correlation between efficacy and skin rash occurrence following treatment with the epidermal growth factor receptor inhibitor cetuximab: A single institution retrospective analysis

Cited by 51 publications

References 18 publications

Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

Management of the Cutaneous Side Effects of Therapeutic Epidermal Growth Factor Receptor Inhibition

The epidermal growth factor receptor in squamous cell carcinoma: An emerging drug target

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