Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular and Clinical Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 2049-9450 Online ISSN: 2049-9469
Journal Cover
June-2016 Volume 4 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
June-2016 Volume 4 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis

  • Authors:
    • Li Lin
    • Lu‑Lu Chen
    • You Wang
    • Xiang‑Yu Meng
    • Chen Liang
    • Fu‑Xiang Zhou
  • View Affiliations / Copyright

    Affiliations: Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China, Center for Evidence‑Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
  • Pages: 1017-1024
    |
    Published online on: March 30, 2016
       https://doi.org/10.3892/mco.2016.836
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The epidermal growth factor receptor (EGFR)‑targeting monoclonal antibody, cetuximab, has been added to standard chemotherapy regimens for treating metastatic colorectal cancer (mCRC). However, the efficacy of adding cetuximab to chemotherapy regimens for patients of differing genetic backgrounds remains controversial. The present study aimed to investigate the efficacy of adding cetuximab to chemotherapeutic regimens in subgroups of patients defined according to the RAS and BRAF mutation status in the first‑line treatment of patients with mCRC. A systematic literature search was performed in databases (including PubMed, Embase, the Cochrane library, the American Society of Clinical Oncology and the European Society For Medical Oncology) up to August 2015. Randomized controlled trials analyzing overall survival (OS) and progression‑free survival (PFS) in mCRC treated with cetuximab, and grouped by RAS and BRAF mutation status, were identified. The major outcome measures were hazard ratios (HRs). Pooled HRs were calculated using fixed‑ or random‑effects models, according to the magnitude of the heterogeneity. A total of nine studies met the inclusion criteria. Use of cetuximab was significantly associated with longer OS in KRAS exon 2 wild‑type tumors [HR=0.87, 95% confidence interval (CI)=0.79‑0.96, Z=2.91, P=0.004] and wild‑type KRAS/RAS (in exons 2, 3 and 4 of KRAS and exons 2, 3 and 4 of an associated gene, NRAS; HR=0.72, 95% CI=0.60‑0.85, Z=3.74, P=0.0002). No significant differences in OS and PFS were identified between KRAS exon 2 mutations and tumors with the other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of an associated gene, NRAS). The meta‑analysis demonstrated that cetuximab‑based chemotherapeutic regimens led to a marked improvement in OS in patients with mCRC who lacked any RAS mutations (either KRAS exon 2 or any other RAS mutation). By contrast, the subgroup analyses revealed no evident PFS or OS benefit in using cetuximab for patients with any RAS mutation. Taken together, the evidence indicates that cetuximab should only be used for mCRC patients with the wild‑type RAS gene. Some benefits were observed in patients with wild‑type KRAS/BRAF who received cetuximab‑based chemotherapy, even though there were insufficient data to perform meta‑analysis with the BRAF mutation status.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, et al: Cetuximab plus irinotecan, fluorouracil and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 29:2011–2019. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M and Koralewski P: Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: The OPUS study. Ann Oncol. 22:1535–1546. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, et al: Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomised phase 3 MRC COIN trial. Lancet. 377:2103–2114. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, et al: Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: The NORDIC-VII study. J Clin Oncol. 30:1755–1762. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, et al: Fluorouracil, leucovorin and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 27:663–671. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Final results from PRIME: Randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 25:1346–1355. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, et al: Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): A randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 15:569–579. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Cancer Genome Atlas Network: Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012. View Article : Google Scholar : PubMed/NCBI

10 

De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, et al: Effects of KRAS, BRAF, NRAS and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis. Lancet Oncol. 11:753–762. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 369:1023–1034. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I and Köhne CH: Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 48:1466–1475. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Higgins JP and Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med. 21:1539–1558. 2002. View Article : Google Scholar : PubMed/NCBI

14 

Higgins JP, Thompson SG, Deeks JJ and Altman DG: Measuring inconsistency in meta-analyses. BMJ. 327:557–560. 2003. View Article : Google Scholar : PubMed/NCBI

15 

Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 360:1408–1417. 2009. View Article : Google Scholar : PubMed/NCBI

16 

Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH and Ciardiello F: Fluorouracil, leucovorin and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 33:692–700. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Stintzing S, von Fischer Weikersthal L, Decker T, Vehling-Kaiser U, Jäger E, Heintges T, Stoll C, Giessen C, Modest DP, Neumann J, et al: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: Mutated tumours in the randomised German AIO study KRK-0306. Ann Oncol. 23:1693–1699. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, et al: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. Lancet Oncol. 15:1065–1075. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY and Xu J: Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 31:1931–1938. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Bokemeyer C, Köhne CH, Ciardiello F, Lenz HJ, Heinemann V, Klinkhardt U, Beier F, Duecker K, van Krieken JH and Tejpar S: FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer. 51:1243–1252. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Mahoney MR, O'Neil BH, Shaw JE, Polite BN, Hochster HS, Atkins AN, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). ASCO Meeting Abstracts. 32:LBA32014.

22 

Tveit K, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Kure E, Ikdahl T, Skovlund T and Christoffersen T: Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: The NORDIC VII study (NCT00145314), by the Nordic colorectal cancer biomodulation group. ASCO Meeting Abstracts. 29:3652011.

23 

Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, Cabiddu M, Iacovelli R, Bossi I, Lonati V, et al: Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis. Eur J Cancer. 51:587–594. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Cui D, Cao D, Yang Y, Qiu M, Huang Y and Yi C: Effect of BRAF V600E mutation on tumor response of anti-EGFR monoclonal antibodies for first-line metastatic colorectal cancer treatment: A meta-analysis of randomized studies. Mol Biol Rep. 41:1291–1298. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Lin L, Chen LL, Wang Y, Meng XY, Liang C and Zhou FX: Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis. Mol Clin Oncol 4: 1017-1024, 2016.
APA
Lin, L., Chen, L., Wang, Y., Meng, X., Liang, C., & Zhou, F. (2016). Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis. Molecular and Clinical Oncology, 4, 1017-1024. https://doi.org/10.3892/mco.2016.836
MLA
Lin, L., Chen, L., Wang, Y., Meng, X., Liang, C., Zhou, F."Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis". Molecular and Clinical Oncology 4.6 (2016): 1017-1024.
Chicago
Lin, L., Chen, L., Wang, Y., Meng, X., Liang, C., Zhou, F."Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis". Molecular and Clinical Oncology 4, no. 6 (2016): 1017-1024. https://doi.org/10.3892/mco.2016.836
Copy and paste a formatted citation
x
Spandidos Publications style
Lin L, Chen LL, Wang Y, Meng XY, Liang C and Zhou FX: Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis. Mol Clin Oncol 4: 1017-1024, 2016.
APA
Lin, L., Chen, L., Wang, Y., Meng, X., Liang, C., & Zhou, F. (2016). Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis. Molecular and Clinical Oncology, 4, 1017-1024. https://doi.org/10.3892/mco.2016.836
MLA
Lin, L., Chen, L., Wang, Y., Meng, X., Liang, C., Zhou, F."Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis". Molecular and Clinical Oncology 4.6 (2016): 1017-1024.
Chicago
Lin, L., Chen, L., Wang, Y., Meng, X., Liang, C., Zhou, F."Efficacy of cetuximab‑based chemotherapy in metastatic colorectal cancer according to RAS and BRAF mutation subgroups: A meta‑analysis". Molecular and Clinical Oncology 4, no. 6 (2016): 1017-1024. https://doi.org/10.3892/mco.2016.836
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team