Skip to main content

Advertisement

Springer Nature Link
Log in

Predictive Value of Early Skin Rash in Cetuximab-Based Therapy of Advanced Biliary Tract Cancer

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Randomized trials in advanced biliary tract cancer (BTC) did not show benefit of cetuximab addition over chemotherapy. This is probably due to the lack of predictive biomarkers. The aim of this study was to explore possible predictive factors. Between 2009 and 2014, 57 patients were treated in 3-week cycles with cetuximab (250 mg/m2/week, loading dose: 400 mg/m2), gemcitabine (1000 mg/m2 on day 1 and 8), and capecitabine (1300 mg/m2/day on days 1–14). The objective response rate (ORR), progression-free (PFS) and overall survival (OS) and the adverse events (AEs) were evaluated. An exploratory analysis was performed to find possible predictive factors on clinicopathological characteristics, routine laboratory parameters and early AEs, which occurred within 2 months from the beginning of treatment. The ORR was 21%. The median PFS and OS were 34 (95% CI: 24–40) and 54 (43–67) weeks, respectively. The most frequent AEs were skin toxicities. In univariate analysis performance status, previous stent implantation, thrombocyte count at the start of therapy, early neutropenia and skin rash statistically significantly influenced the ORR, PFS and/or OS. In multivariate Cox regression analysis only normal thrombocyte count at treatment start and early acneiform rash were independent markers of longer survival. In patients showing early skin rash compared to the others the median PFS was 39 vs. 13 weeks and the median OS was 67 vs. 26 weeks, respectively. It is suggested that early skin rash can be used as a biomarker to select patients who would benefit from the treatment with cetuximab plus chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Randi G, Malvezzi M, Levi F et al (2009) Epidemiology of biliary tract cancers: an update. Ann Oncol 20:146–159. doi:10.1093/annonc/mdn533

    Article  CAS  PubMed  Google Scholar 

  2. Valle J, Wasan H, Palmer DH et al (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281. doi:10.1056/NEJMoa0908721

    Article  CAS  PubMed  Google Scholar 

  3. Noel MS, Hezel AF (2013) New and emerging treatment options for biliary tract cancer. Onco Targets Ther 6:1545–1452. doi:10.2147/OTT.S32545

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sharma A, Chaudhary SP, Shukla NK et al (2014) A randomized controlled trial comparing modified gemcitabine plus oxaliplatin (mGEMOX) to gemcitabine plus cisplatin in management of unresectable gall bladder cancer. J Clin Oncol 32(Suppl):TPS4152

    Google Scholar 

  5. Ulahannan SV, Rahma OE, Duffy AG et al (2015) Identification of active chemotherapy regimens in advanced biliary tract carcinoma: a review of chemotherapy trials in the past two decades. Hepat Oncol 2:39–50. doi:10.2217/hep.14.36

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lee J, Park SH, Chang HM et al (2012) Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 13:181–188. doi:10.1016/S1470-2045(11)70301-1

    Article  CAS  PubMed  Google Scholar 

  7. Malka D, Cervera P, Foulon S et al (2014) Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol 15:819–828. doi:10.1016/S1470-2045(14)70212-8

    Article  CAS  PubMed  Google Scholar 

  8. Chen JS, Hsu C, Chiang NJ et al (2015) A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. Ann Oncol 26:943–949. doi:10.1093/annonc/mdv035

    Article  CAS  PubMed  Google Scholar 

  9. Petrelli F, Borgonovo K, Barni S (2013) The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials. Target Oncol 8:173–181. doi:10.1007/s11523-013-0257-x

    Article  CAS  PubMed  Google Scholar 

  10. Borbath I, Ceratti A, Verslype C et al (2013) Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology. Ann Oncol 24:2824–2829. doi:10.1093/annonc/mdt337

    Article  CAS  PubMed  Google Scholar 

  11. Rubovszky G, Láng I, Ganofszky E et al (2013) Cetuximab, gemcitabine and capecitabine in patients with inoperable biliary tract cancer: a phase 2 study. Eur J Cancer 49:3806–3812. doi:10.1016/j.ejca.2013.07.143

    Article  CAS  PubMed  Google Scholar 

  12. Marcano-Bonilla L, Mohamed EA, Mounajjed T, Roberts LR (2016) Biliary tract cancers: epidemiology, molecular pathogenesis and genetic risk associations. Chin Clin Oncol 5:61. doi:10.21037/cco.2016.10.09

    Article  PubMed  Google Scholar 

  13. Wang RT, Zhang LQ, Mu YP et al (2015) Prognostic significance of preoperative platelet count in patients with gallbladder cancer. World J Gastroenterol 21:5303–5310. doi:10.3748/wjg.v21.i17.5303

    Article  PubMed  PubMed Central  Google Scholar 

  14. Baranyai Z, Jósa V, Tóth A et al (2016) Paraneoplastic thrombocytosis in gastrointestinal cancer. Platelets 27:269–275. doi:10.3109/09537104.2016.1170112

    Article  CAS  PubMed  Google Scholar 

  15. Lee SY, Kim HS, Choi YJ et al (2016) A prognostic index to identify patients with intrahepatic cholangiocarcinoma who could benefit from gemcitabine plus cisplatin. Am J Ther 23:e1449–e1455. doi:10.1097/MJT.0000000000000112

    Article  PubMed  Google Scholar 

  16. Helleday T (2016) PARP inhibitor receives FDA breakthrough therapy designation in castration resistant prostate cancer: beyond germline BRCA mutations. Ann Oncol 27:755–757. doi:10.1093/annonc/mdw048

    Article  CAS  PubMed  Google Scholar 

  17. Cai J, Ma H, Huang F et al (2013) Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis. World J Surg Oncol 11:306. doi:10.1186/1477-7819-11-306

    Article  PubMed  PubMed Central  Google Scholar 

  18. Nagyiványi K, Budai B, Bíró K et al (2016) Synergistic survival: a new phenomenon connected to adverse events of first-line sunitinib treatment in advanced renal cell carcinoma. Clin Genitourin Cancer in press. doi:10.1016/j.clgc.2015.11.016

    PubMed  Google Scholar 

  19. Rini BI, Cohen DP, Lu DR et al (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103:763–773. doi:10.1093/jnci/djr128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hurwitz HI, Douglas PS, Middleton JP et al (2013) Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies. Oncologist 18:273–280. doi:10.1634/theoncologist.2012-0339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huober J, Cole BF, Rabaglio M et al (2014) Symptoms of endocrine treatment and outcome in the BIG 1-98 study. Breast Cancer Res Treat 143:159–169. doi:10.1007/s10549-013-2792-7

    Article  CAS  PubMed  Google Scholar 

  22. Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada clinical trials Group. J Clin Oncol 25:1960–1966. doi:10.1200/JCO.2006.07.9525

    Article  CAS  PubMed  Google Scholar 

  23. Van Cutsem E, Li CP, Nowara E et al (2014) Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study. Br J Cancer 111:2067–2075. doi:10.1038/bjc.2014.494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Havrilesky LJ, Reiner M, Morrow PK et al (2015) A review of relative dose intensity and survival in patients with metastatic solid tumors. Crit Rev Oncol Hematol 93:203–210. doi:10.1016/j.critrevonc.2014.10.006

    Article  PubMed  Google Scholar 

  25. Citron ML (2004) Dose density in adjuvant chemotherapy for breast cancer. Cancer Investig 22:555–568. doi:10.1081/CNV-200027134

    Article  CAS  Google Scholar 

  26. Rudek MA, Connolly RM, Hoskins JM et al (2013) Fixed-dose capecitabine is feasible: results from a pharmacokinetic and pharmacogenetic study in metastatic breast cancer. Breast Cancer Res Treat 139:135–143. doi:10.1007/s10549-013-2516-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lortholary A, Hardy-Bessard AC, de Rauglaudre G et al (2012) A GINECO randomized phase II trial of two capecitabine and weekly paclitaxel schedules in metastatic breast cancer. Breast Cancer Res Treat 131:127–135. doi:10.1007/s10549-011-1776-8

    Article  CAS  PubMed  Google Scholar 

  28. Chan A, McGregor S, Liang W (2014) Utilisation of primary and secondary G-CSF prophylaxis enables maintenance of optimal dose delivery of standard adjuvant chemotherapy for early breast cancer: an analysis of 1655 patients. Breast 23:676–682. doi:10.1016/j.breast.2014.07.004

    Article  PubMed  Google Scholar 

  29. Shimoyama S (2010) Pharmacogenetics of irinotecan: an ethnicity-based prediction of irinotecan adverse events. World J Gastrointest Surg 2:14–21. doi:10.4240/wjgs.v2.i1.14

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bruckner HW, Hirschfeld A, Schwartz M (2016) Targeted therapy for resistant cholangiocharcinoma with bevacizumab or cetuximab added to failed cytotoxic drug cores. Anticancer Res 36:399–402

    CAS  PubMed  Google Scholar 

  31. Valle JW, Wasan H, Lopes A et al (2015) Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol 16:967–978. doi:10.1016/S1470-2045(15)00139-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mizusawa J, Morizane C, Okusaka T et al (2016) Randomized phase III study of gemcitabine plus S-1 versus gemcitabine plus cisplatin in advanced biliary tract cancer: Japan clinical Oncology Group study (JCOG1113, FUGA-BT). Jpn J Clin Oncol 46:385–388. doi:10.1093/jjco/hyv213

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful for all patients to participate in this trial and their families to protect them. We would like to thank deeply for Mónika Nagy for the essential help in data management.

Author information

Authors and Affiliations

  1. Department of Medical Oncology and Clinical Pharmacology “B”, National Institute of Oncology, Ráth Gy. u. 7-9, Budapest, 1122, Hungary

    Gábor Rubovszky, Erna Ganofszky, Éva Juhos, Balázs Madaras, Tünde Nagy, Eszter Szabó, Tamás Pintér, István Láng & Erika Hitre

  2. Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, Hungary

    Barna Budai & Péter Nagy

  3. Institute of Oncology, University of Debrecen, Debrecen, Hungary

    Zsolt Horváth

  4. Surgical and Molecular Tumor Pathology Centre, National Institute of Oncology, Budapest, Hungary

    Erika Tóth

Authors
  1. Gábor Rubovszky
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Barna Budai
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Erna Ganofszky
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Zsolt Horváth
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Éva Juhos
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Balázs Madaras
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Tünde Nagy
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Eszter Szabó
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Tamás Pintér
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Erika Tóth
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Péter Nagy
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. István Láng
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Erika Hitre
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Gábor Rubovszky.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Financial Support

This trial has no funding support.

Electronic supplementary material

ESM 1

(PDF 274 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rubovszky, G., Budai, B., Ganofszky, E. et al. Predictive Value of Early Skin Rash in Cetuximab-Based Therapy of Advanced Biliary Tract Cancer. Pathol. Oncol. Res. 24, 237–244 (2018). https://doi.org/10.1007/s12253-017-0238-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-017-0238-y

Keywords