Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 3, pp 511–517

A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas

  • Marisa E. Hill
  • Xiaobai Li
  • Sharon Kim
  • Angela Campbell
  • Kristy Culler
  • Mark Bloomston
  • Mark Zalupski
  • Gwen Hejna
  • Tanios Bekaii-Saab
Original Article

Abstract

Background

Pancreas cancer remains a formidable challenge. We report the first prospective analysis of the 3-drug combination of gemcitabine (G), docetaxel (T) and capecitabine (X) (mGTX) with schedule modification to maximize biomodulation of X.

Methods

We conducted a dose escalation study of mGTX in first-line treatment of metastatic pancreas cancer using three dose levels (DL 1-3). Patients received docetaxel on days 1 and 8, gemcitabine on days 8 and 15, and capecitabine on days 8 through 21. Gemcitabine dose was fixed at 750 mg/m2 over 75 min, capecitabine was given twice daily and escalated from 500 to 650 mg/m2 at DL2 and docetaxel increased from 30 to 36 mg/m2 at DL3.

Results

Twenty-one patients (18 evaluable) were enrolled in the study. MTD was reached at DL3 and one DLT was observed at DL2 (prolonged neutropenia). The most common grade 3/4 toxicities were leukopenia (29%) and neutropenia (29%) and fatigue (25%). Tumor growth control rate was 80% (11% PR; 69% SD lasting at least 3 months). Median progression-free-survival was 5.8 months (95% CI 2.7, 10.6) and median overall survival was 7.4 months (95% CI 3.8 16.8). CA 19-9 decreased by at least 50% from baseline in half the patients.

Conclusion

mGTX demonstrates acceptable tolerability with interesting activity in patients with pancreatic cancer. The recommended doses for phase II studies are docetaxel 36 mg/m2 days 1 and 8, gemcitabine 750 mg/m2 over 75 min days 8 and 15, and capecitabine 625 mg/m2 twice daily days 8 through 21.

Keywords

Pancreas Adenocarcinoma Gemcitabine Capecitabine Docetaxel 

References

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics. CA Cancer J Clin 59(4):225–249CrossRefPubMedGoogle Scholar
  2. 2.
    Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413PubMedGoogle Scholar
  3. 3.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Ding K, Ptaszynski M, Parulekar W (2005) Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). In: Proceedings of ASCO 2005Google Scholar
  4. 4.
    Kosuri K, Muscarella P, Bekaii-Saab TS (2006) Updates and controversies in the treatment of pancreatic cancer. Clin Adv Hematol Oncol 4(1):47–54PubMedGoogle Scholar
  5. 5.
    Pliarchopoulou K, Pectasides D (2009) Pancreatic cancer: current and future treatment strategies. Cancer Treat Rev 35(5):431–436CrossRefPubMedGoogle Scholar
  6. 6.
    Lopes G, Lima CMR (2005) Docetaxel in the management of advanced pancreatic cancer. Semin Oncol 32(2 Suppl 4):S10–S23CrossRefPubMedGoogle Scholar
  7. 7.
    Ducreux M, Boige V, Malka D (2004) Emerging drugs in pancreatic cancer. Expert Opin Emerg Drugs 9(1):73–78CrossRefPubMedGoogle Scholar
  8. 8.
    Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ (2002) Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 20(1):160–164CrossRefPubMedGoogle Scholar
  9. 9.
    Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP (2009) Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27(33):5513–5518CrossRefPubMedGoogle Scholar
  10. 10.
    Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J (2008) The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol 61(1):167–175CrossRefPubMedGoogle Scholar
  11. 11.
    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(4):1013–1019PubMedGoogle Scholar
  12. 12.
    Kindwall-Keller T, Otterson GA, Young D, Neki A, Criswell T, Nuovo G, Soong R, Diasio R, Villalona-Calero MA (2005) Phase II evaluation of docetaxel-modulated capecitabine in previously treated patients with non-small cell lung cancer. Clin Cancer Res 11(5):1870–1876CrossRefPubMedGoogle Scholar
  13. 13.
    Nadell P, Shapiro C, Otterson GA, Hauger M, Erdal S, Kraut E, Clinton S, Shah M, Stanek M, Monk P, Villalona-Calero MA (2002) Pharmacobiologically based scheduling of capecitabine and docetaxel results in antitumor activity in resistant human malignancies. J Clin Oncol 20(11):2616–2623CrossRefGoogle Scholar
  14. 14.
    Ren Q, Kao V, Grem JL (1998) Cytotoxicity and DNA fragmentation associated with sequential gemcitabine and 5-fluoro-2’-deoxyuridine in HT-29 colon cancer cells. Clin Cancer Res 4(11):2811–2818PubMedGoogle Scholar
  15. 15.
    Tempero M, Plunkett W, Ruiz Van Haperen V, Hainsworth J, Hochster H, Lenzi R, Abbruzzese J (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21(18):3402–3408CrossRefPubMedGoogle Scholar
  16. 16.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216CrossRefPubMedGoogle Scholar
  17. 17.
    Stathopoulos GP, Syrigos K, Polyzos A, Fountzilas G, Rigatos SK, Ziras N, Potamiannou A, Tsiakopoulos I, Androulakis N, Aravantinos G, Athanasiadis A, Papakotoulas P, Georgoulias V (2004) Front-line treatment of inoperable or metastatic pancreatic cancer with gemcitabine and capecitabine: an intergroup, multicenter, phase II study. Ann Oncol 15(2):224–229CrossRefPubMedGoogle Scholar
  18. 18.
    Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, Saletti P, Bauer J, Figer A, Pestalozzi B, Köhne CH, Mingrone W, Stemmer S, Tàmas K, Kornek V, Koeberle D, Cina S, Bernhard J, Dietrich D, Scheithauer W (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 25(16):2212–2217CrossRefPubMedGoogle Scholar
  19. 19.
    Ko AH, Hwang J, Venook AP, Abbruzzese JL, Bergsland EK, Tempero MA (2005) Serum CA19–9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer. Br J Cancer 93(2):195–199CrossRefPubMedGoogle Scholar
  20. 20.
    Allendorf JD, Lauerman M, Bill A, DiGiorgi M, Goetz N, Vakiani E, Remotti H, Schrope B, Sherman W, Hall M, Fine RL, Chabot JA (2008) Neoadjuvant chemotherapy and radiation for patients with locally unresectable pancreatic adenocarcinoma: feasibility, efficacy, and survival. J Gastrointest Surg 12(1):91–100CrossRefPubMedGoogle Scholar
  21. 21.
    Adams RB, Allen PJ (2009) Surgical treatment of resectable and borderline resectable pancreatic cancer: expert consensus statement by Evans et al. Ann Surg Oncol 16(7):1745–1750CrossRefPubMedGoogle Scholar
  22. 22.
    Furukawa T (2008) Molecular targeting therapy for pancreatic cancer: current knowledge and perspectives from bench to bedside. J Gastroenterol 43(12):905–911CrossRefPubMedGoogle Scholar
  23. 23.
    Wong HH, Lemoine NR (2009) Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol 6(7):412–422CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Marisa E. Hill
    • 1
  • Xiaobai Li
    • 1
  • Sharon Kim
    • 1
  • Angela Campbell
    • 1
  • Kristy Culler
    • 1
  • Mark Bloomston
    • 1
  • Mark Zalupski
    • 2
  • Gwen Hejna
    • 2
  • Tanios Bekaii-Saab
    • 1
    • 3
  1. 1.Ohio State University Comprehensive Cancer Center, Arthur James Cancer HospitalColumbusUSA
  2. 2.University of MichiganAnn ArborUSA
  3. 3.Department of PharmacologyThe Ohio State UniversityColumbusUSA

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