Skip to main content

Advertisement

SpringerLink
Log in

Phase 1a/1b and pharmacogenetic study of docetaxel, oxaliplatin and capecitabine in patients with advanced cancer of the stomach or the gastroesophageal junction

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The prognosis of gastroesophageal cancer is poor, and current regimens are associated with limited efficacy. The purpose of this study was to explore the safety and preliminary efficacy of docetaxel, oxaliplatin plus capecitabine for advanced cancer of the stomach or the gastroesophageal junction (GEJ). Secondary objectives included pharmacokinetic and pharmacogenetic analyses.

Methods

Patients were treated in escalating dose levels with docetaxel and oxaliplatin (both on day 1), plus capecitabine b.i.d. on days 1–14 every 3 weeks, to determine the dose-limiting toxicity and maximum tolerated dose (MTD). An expansion cohort was treated at the MTD. A total of ten polymorphisms in pharmacokinetic and pharmacodynamic candidate genes were analyzed and tested for association with treatment outcome.

Results

A total of 34 evaluable patients were enrolled. The MTD was docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 plus capecitabine 850 mg/m2 b.i.d. The median number of treatment cycles was 6 (range 2–8). Grade ≥ 3 toxicities included neutropenia (24 %), leukocytopenia (15 %), febrile neutropenia (12 %), fatigue (9 %) and diarrhea (6 %). The overall response rate was 45 %; two patients achieved a complete response. Median progression-free survival and overall survival were 6.5 months (95 % CI 5.4–7.6) and 11.0 months (95 % CI 7.9–14.1), respectively. The polymorphisms ERCC1 354C>T, TYMS 1053C>T and rs2612091 in ENOSF1 were associated with severe toxicity; ERCC1 354C>T and ERCC2 2251A>C were associated with poor progression-free survival.

Conclusion

Docetaxel, oxaliplatin plus capecitabine are a well-tolerable, safe and effective treatment regimen for patients with advanced cancer of the stomach or GEJ. Pharmacogenetic markers in pharmacokinetic and pharmacodynamic candidate genes may be predictive for treatment outcome.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. World Health Organization (2014) World cancer report 2014. http://www.who.org

  2. Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE (2010) Chemotherapy for advanced gastric cancer. Cochrane Database Syst 3:CD004064

    Google Scholar 

  3. Sulkes A, Smyth J, Sessa C, Dirix LY, Vermorken JB, Kaye S, Wanders J, Franklin H, LeBail N, Verweij J (1994) Docetaxel (Taxotere) in advanced gastric cancer: results of a phase II clinical trial. EORTC Early Clinical Trials Group. Br J Cancer 70:380–383

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Hejna M, Raderer M, Zacherl J, Ba-Ssalamah A, Puspok A, Schmidinger M, Pluschnig U, Brodowicz T, Zielinski CC (2008) Phase II study of docetaxel in combination with oxaliplatin in patients with metastatic or locally advanced esophagogastric cancer previously untreated with chemotherapy for advanced disease: results of the Central European Cooperative Oncology Group Study ESGAS.1.2.001. Anticancer Drugs 19:535–539

    CAS  PubMed  Google Scholar 

  5. Roth AD, Maibach R, Martinelli G, Fazio N, Aapro MS, Pagani O, Morant R, Borner MM, Herrmann R, Honegger H, Cavalli F, Alberto P, Castiglione M, Goldhirsch A (2000) Docetaxel (Taxotere)-cisplatin (TC): an effective drug combination in gastric carcinoma. Swiss Group for Clinical Cancer Research (SAKK), and the European Institute of Oncology (EIO). Ann Oncol 11:301–306

    Article  CAS  PubMed  Google Scholar 

  6. Roth AD, Maibach R, Fazio N, Sessa C, Stupp R, Morant R, Herrmann R, Borner MM, Goldhirsch A, de Braud F (2004) 5-Fluorouracil as protracted continuous intravenous infusion can be added to full-dose docetaxel (Taxotere)-cisplatin in advanced gastric carcinoma: a phase I–II trial. Ann Oncol 15:759–764

    Article  CAS  PubMed  Google Scholar 

  7. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991–4997

    Article  PubMed  Google Scholar 

  8. Lorenzen S, Hentrich M, Haberl C, Heinemann V, Schuster T, Seroneit T, Roethling N, Peschel C, Lordick F (2007) Split-dose docetaxel, cisplatin and leucovorin/fluorouracil as first-line therapy in advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: results of a phase II trial. Ann Oncol 18:1673–1679

    Article  CAS  PubMed  Google Scholar 

  9. Roth AD, Fazio N, Stupp R, Falk S, Bernhard J, Saletti P, Koberle D, Borner MM, Rufibach K, Maibach R, Wernli M, Leslie M, Glynne-Jones R, Widmer L, Seymour M, de Braud F (2007) Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol 25:3217–3223

    Article  CAS  PubMed  Google Scholar 

  10. Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, Andre T, Gornet JM, Aparicio T, Nguyen S, Azzedine A, Etienne PL, Boucher E, Rebischung C, Hammel P, Rougier P, Bedenne L, Bouche O (2014) Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French Intergroup (Federation Francophone de Cancerologie Digestive, Federation Nationale des Centres de Lutte Contre le Cancer, and Groupe Cooperateur Multidisciplinaire en Oncologie) Study. J Clin Oncol 32:3520–3526

    Article  CAS  PubMed  Google Scholar 

  11. Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O’Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M (1997) Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261–267

    Article  CAS  PubMed  Google Scholar 

  12. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36–46

    Article  CAS  PubMed  Google Scholar 

  13. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4:1013–1019

    CAS  PubMed  Google Scholar 

  14. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  15. Kuppens IE, van Maanen MJ, Rosing H, Schellens JH, Beijnen JH (2005) Quantitative analysis of docetaxel in human plasma using liquid chromatography coupled with tandem mass spectrometry. Biomed Chromatogr 19:355–361

    Article  CAS  PubMed  Google Scholar 

  16. Deenen MJ, Rosing H, Hillebrand MJ, Schellens JH, Beijnen JH (2013) Quantitative determination of capecitabine and its six metabolites in human plasma using liquid chromatography coupled to electrospray tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 913–914:30–40

    Article  PubMed  Google Scholar 

  17. Bruno R, Hille D, Riva A, Vivier N, Bokkel Huinnink WW, van Oosterom AT, Kaye SB, Verweij J, Fossella FV, Valero V, Rigas JR, Seidman AD, Chevallier B, Fumoleau P, Burris HA, Ravdin PM, Sheiner LB (1998) Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187–196

    CAS  PubMed  Google Scholar 

  18. Reigner B, Blesch K, Weidekamm E (2001) Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 40:85–104

    Article  CAS  PubMed  Google Scholar 

  19. Thuss-Patience PC, Kretzschmar A, Repp M, Kingreen D, Hennesser D, Micheel S, Pink D, Scholz C, Dorken B, Reichardt P (2005) Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study. J Clin Oncol 23:494–501

    Article  CAS  PubMed  Google Scholar 

  20. Al-Batran SE, Hartmann JT, Hofheinz R, Homann N, Rethwisch V, Probst S, Stoehlmacher J, Clemens MR, Mahlberg R, Fritz M, Seipelt G, Sievert M, Pauligk C, Atmaca A, Jager E (2008) Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 19:1882–1887

    Article  PubMed  Google Scholar 

  21. Stein A, Arnold D, Thuss-Patience PC, Moehler M, Grothe W, Seufferlein T, Reinacher-Schick A, Geissler M, Hofheinz RD, Schmoll HJ (2014) Docetaxel, oxaliplatin and capecitabine (TEX regimen) in patients with metastatic gastric or gastro-esophageal cancer: results of a multicenter phase I/II study. Acta Oncol 53:392–398

    Article  CAS  PubMed  Google Scholar 

  22. Yu JJ, Lee KB, Mu C, Li Q, Abernathy TV, Bostick-Bruton F, Reed E (2000) Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene. Int J Oncol 16:555–560

    CAS  PubMed  Google Scholar 

  23. Yin M, Yan J, Martinez-Balibrea E, Graziano F, Lenz HJ, Kim HJ, Robert J, Im SA, Wang WS, Etienne-Grimaldi MC, Wei Q (2011) ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clin Cancer Res 17:1632–1640

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Ma SC, Zhao Y, Zhang T, Ling XL, Zhao D (2015) Association between the ERCC1 rs11615 polymorphism and clinical outcomes of oxaliplatin-based chemotherapies in gastrointestinal cancer: a meta-analysis. Onco Targets Ther 8:641–648

    PubMed Central  PubMed  Google Scholar 

  25. Bradbury PA, Kulke MH, Heist RS, Zhou W, Ma C, Xu W, Marshall AL, Zhai R, Hooshmand SM, Asomaning K, Su L, Shepherd FA, Lynch TJ, Wain JC, Christiani DC, Liu G (2009) Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes. Pharmacogn Genom 19:613–625

    Article  CAS  Google Scholar 

  26. Lunn RM, Helzlsouer KJ, Parshad R, Umbach DM, Harris EL, Sanford KK, Bell DA (2000) XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 21:551–555

    Article  CAS  PubMed  Google Scholar 

  27. Qian YY, Liu XY, Pei D, Xu JL, Shen H, Chen XF, Liu YQ, Shen LZ, Shu YQ (2014) The XPD Lys751Gln polymorphism has predictive value in colorectal cancer patients receiving oxaliplatin-based chemotherapy: a systematic review and meta-analysis. Asian Pac J Cancer Prev 15:9699–9706

    Article  PubMed  Google Scholar 

  28. Xue H, Lu Y, Lin B, Chen J, Tang F, Huang G (2012) The effect of XPD/ERCC2 polymorphisms on gastric cancer risk among different ethnicities: a systematic review and meta-analysis. PLoS ONE 7:e43431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Goekkurt E, Hoehn S, Wolschke C, Wittmer C, Stueber C, Hossfeld DK, Stoehlmacher J (2006) Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)—novel predictors for response and survival in gastric cancer patients. Br J Cancer 94:281–286

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Ruzzo A, Graziano F, Kawakami K, Watanabe G, Santini D, Catalano V, Bisonni R, Canestrari E, Ficarelli R, Menichetti ET, Mari D, Testa E, Silva R, Vincenzi B, Giordani P, Cascinu S, Giustini L, Tonini G, Magnani M (2006) Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy. J Clin Oncol 24:1883–1891

    Article  CAS  PubMed  Google Scholar 

  31. Tibaldi C, Giovannetti E, Vasile E, Mey V, Laan AC, Nannizzi S, Di MR, Antonuzzo A, Orlandini C, Ricciardi S, Del TM, Peters GJ, Falcone A, Danesi R (2008) Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 14:1797–1803

    Article  CAS  PubMed  Google Scholar 

  32. Rosmarin D, Palles C, Pagnamenta A, Kaur K, Pita G, Martin M, Domingo E, Jones A, Howarth K, Freeman-Mills L, Johnstone E, Wang H, Love S, Scudder C, Julier P, Fernandez-Rozadilla C, Ruiz-Ponte C, Carracedo A, Castellvi-Bel S, Castells A, Gonzalez-Neira A, Taylor J, Kerr R, Kerr D, Tomlinson I (2015) A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. Gut 64:111–120

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Evans D, Miner T, Akerman P, Millis R, Jean M, Kennedy T, Safran H (2007) A phase I study of docetaxel, oxaliplatin, and capecitabine in patients with metastatic gastroesophageal cancer. Am J Clin Oncol 30:346–349

    Article  CAS  PubMed  Google Scholar 

  34. Sym SJ, Ryu MH, Kang HJ, Lee SS, Chang HM, Lee JL, Kim TW, Yook JH, Oh ST, Kim BS, Kang YK (2010) Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer. Cancer Chemother Pharmacol 66:373–380

    Article  CAS  PubMed  Google Scholar 

  35. Goel G, Jauhri M, Negi A, Aggarwal S (2010) Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma. Hematol Oncol Stem Cell Ther 3:55–59

    Article  CAS  PubMed  Google Scholar 

  36. Andersen M, Schonnemann KR, Yilmaz M, Jensen HA, Vestermark LW, Pfeiffer P (2010) Phase I study of docetaxel, oxaliplatin and capecitabine (TEX) as first line therapy to patients with advanced gastro-oesophageal cancer. Acta Oncol 49:1246–1252

    Article  CAS  PubMed  Google Scholar 

  37. Schonnemann KR, Yilmaz M, Andersen M, Pfeiffer P (2011) New recommendation of doses in an ongoing phase II study of docetaxel, oxaliplatin and capecitabine as first line therapy in advanced gastro-oesophageal cancer. Acta Oncol 50:151–152

    Article  PubMed  Google Scholar 

  38. Malik I, Bernal P, Byrd J (2010) A phase I study of docetaxel, oxaliplatin, & capecitabine (DOC) as first-line therapy of patients with locally advanced or metastatic adenocarcinoma of stomach and GE junction. Cancer Invest 28:833–838

    Article  CAS  PubMed  Google Scholar 

  39. Amarantidis K, Xenidis N, Chelis L, Chamalidou E, Dimopoulos P, Michailidis P, Tentes A, Deftereos S, Karanikas M, Karayiannakis A, Kakolyris S (2011) Docetaxel plus oxaliplatin in combination with capecitabine as first-line treatment for advanced gastric cancer. Oncology 80:359–365

    Article  CAS  PubMed  Google Scholar 

  40. Di Lauro L, Vici P, Belli F, Tomao S, Fattoruso SI, Arena MG, Pizzuti L, Giannarelli D, Paoletti G, Barba M, Sergi D, Maugeri-Sacca M (2014) Docetaxel, oxaliplatin, and capecitabine combination chemotherapy for metastatic gastric cancer. Gastric Cancer 17:718–724

    Article  PubMed  Google Scholar 

  41. Van Cutsem E, Boni C, Tabernero J, Massuti B, Middleton G, Dane F, Reichardt P, Pimentel FL, Cohn A, Follana P, Clemens M, Zaniboni A, Moiseyenko V, Harrison M, Richards DA, Prenen H, Pernot S, Ecstein-Fraisse E, Hitier S, Rougier P (2015) Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: a randomized phase II study. Ann Oncol 26:149–156

    Article  PubMed  Google Scholar 

Download references

Funding

The study was funded by an unrestricted Grant from Sanofi-aventis Netherlands B.V. and by the Netherlands Cancer Institute.

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Maarten J. Deenen, Didier Meulendijks & Jan H. M. Schellens

  2. Department of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Maarten J. Deenen, Didier Meulendijks & Jan H. M. Schellens

  3. Division of Medical Oncology, Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Didier Meulendijks, Henk Boot & Annemieke Cats

  4. Department of Medical Oncology, Medisch Spectrum Twente, Enschede, The Netherlands

    Marie-Cecile J. C. Legdeur

  5. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jos H. Beijnen

  6. Division of Clinical Pharmacology and Pharmaco-epidemiology, Faculty of Science, Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen & Jan H. M. Schellens

Authors
  1. Maarten J. Deenen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Didier Meulendijks
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henk Boot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marie-Cecile J. C. Legdeur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jos H. Beijnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan H. M. Schellens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Annemieke Cats
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Annemieke Cats.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 31 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deenen, M.J., Meulendijks, D., Boot, H. et al. Phase 1a/1b and pharmacogenetic study of docetaxel, oxaliplatin and capecitabine in patients with advanced cancer of the stomach or the gastroesophageal junction. Cancer Chemother Pharmacol 76, 1285–1295 (2015). https://doi.org/10.1007/s00280-015-2872-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2872-y

Keywords

Search

Navigation