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      A review of the treatment options for skin rash induced by EGFR-targeted therapies: Evidence from randomized clinical trials and a meta-analysis

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          Abstract

          Background

          Agents targeting the epidermal growth factor receptor (EGFR) are amongst the most extensively used of the targeted agents in the therapy of some of the most common solid tumors. Although they avoid many of the classic side effects associated with cytotoxic chemotherapy, they are associated with unpleasant cutaneous toxicities which can affect treatment compliance and impinge on patient quality of life. To date, despite a plethora of consensus recommendations, expert opinions and reviews, there is a paucity of evidence-based guidance for the management of the skin rash that occurs in the treatment of patients receiving EGFR-targeted therapies.

          Methods

          A literature search was conducted as a first step towards investigating not only an evidence-based approach to the management of skin rash, but also with a view to designing future randomized trials.

          Results

          The literature search identified seven randomized trials and a meta-analysis was conducted using the data from four of these trials involving oral antibiotics. The meta-analysis of the data from these four trials suggests that prophylactic antibiotics might reduce the relative risk of severe rash associated with EGFR-targeted agents by 42–77%. Vitamin K cream was also identified as having a potential role in the management EGFR-targeted agent induced rash.

          Conclusions

          This review and meta-analysis clearly identify the need for further randomized studies of the role of oral antibiotics in this setting. The results of the ongoing randomized trials of the topical application of vitamin K cream plus or minus doxycycline and employing prophylactic versus reactive strategies are eagerly awaited.

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          Most cited references69

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          Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.

          Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
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            Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.

            This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated. Patients received cetuximab (400 mg/m(2) initial dose followed by 250 mg/m(2)/wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1, plus leucovorin 200 mg/m(2) and fluorouracil as a 400 mg/m(2) bolus followed by a 600 mg/m(2) infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233). The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated. KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.
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              Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer.

              Panitumumab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status. Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status. From June 2006 to March 2008, 1,186 patients were randomly assigned 1:1 and received treatment. KRAS status was available for 91% of patients: 597 (55%) with wild-type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio [HR] = 0.73; 95% CI, 0.59 to 0.90; P = .004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR = 0.85, 95% CI, 0.70 to 1.04; P = .12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse event rates were generally comparable across arms with the exception of known toxicities associated with anti-EGFR therapy. Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.
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                Author and article information

                Journal
                Radiol Oncol
                Radiol Oncol
                RADO
                Radiology and Oncology
                Versita, Warsaw
                1318-2099
                1581-3207
                June 2013
                21 May 2013
                : 47
                : 2
                : 166-175
                Affiliations
                [1 ]Institute of Oncology, Ljubljana, Slovenia
                [2 ]Merck KGaA, Darmstadt, Germany
                [3 ]McCloud Consulting Group, Sydney, Australia
                [4 ]Universitätsmedizin Mannheim, University of Heidelberg, Germany
                Author notes
                Correspondence to: Assist. Prof. Janja Ocvirk, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 1 5879 220; Fax: +386 1 5879 305; E-mail: jocvirk@ 123456onko-i.si .
                Article
                rado-47-02-166
                10.2478/raon-2013-0014
                3691090
                23801914
                9ec1e4ba-e42a-4cb1-91cd-9db3060f08a8
                Copyright © by Association of Radiology & Oncology

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 15 November 2012
                : 15 December 2012
                Categories
                Research Article

                Oncology & Radiotherapy
                acne-like skin rash,cetuximab,antibiotics,erlotinib,gefitinib,panitumumab,vitamin k

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