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Pemetrexed and Gemcitabine for Biliary Tract and Gallbladder Carcinomas: a North Central Cancer Treatment Group (NCCTG) Phase I and II Trial, N9943

  • Steven R. AlbertsEmail author
  • Jonathan R. Sande
  • Nathan R. Foster
  • Fernando J. Quevedo
  • Robert R. McWilliams
  • John W. Kugler
  • Tom R. Fitch
  • Anthony J. Jaslowski
Article

Abstract

Purpose

To determine the maximum tolerated dose (MTD) and efficacy of pemetrexed and gemcitabine in patients with either biliary tract or gallbladder carcinoma.

Patients and Methods

Patients with unresectable previously untreated biliary tract cancers were eligible for participation. An initial phase I trial was performed to determine the MTD using an every-2-weeks schedule. The MTD was then used in the phase II portion of the trial. The primary end point for the phase II portion was 6-month survival with a planned accrual of 59 patients.

Results

Overall, 63 eligible patients were enrolled. The MTD was established as pemetrexed 500 mg/m2 IV over 10 min and gemcitabine 800 mg/m2 IV at 10 mg/m2 per minute on days 1 and 15 of an every-4-weeks schedule with vitamin B12 and folate supplementation. Fifty-eight patients were included in the phase II portion. Median age was 61 and median follow-up was 18.2 months. A median of three cycles of treatment was given. Six-month survival was 55% and the median survival was 6.6 months (95% confidence interval 5.4–8.7 months) with a median time to progression of 3.8 months (2.4–5.4). Forty-seven (81%) experienced at least one grade 3+ adverse event, and 28 patients (48%) experienced at least one grade 4 adverse event, most of which were due to grade 4 neutropenia.

Conclusion

The addition of pemetrexed to fixed-dose-rate gemcitabine, in a biweekly schedule, did not enhance the activity of gemcitabine in patients with biliary tract or gallbladder carcinoma.

Keywords

biliary tract cancer gallbladder cancer gemcitabine pemetrexed clinical trial 

References

  1. 1.
    Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer. 1984;54:965–9. doi: 10.1002/1097-0142(19840915)54:6<965::AID-CNCR2820540603>3.0.CO;2-X.PubMedCrossRefGoogle Scholar
  2. 2.
    Takada T, Kato H, Matsushiro T, et al. Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology. 1994;51:396–400.PubMedCrossRefGoogle Scholar
  3. 3.
    Chen JS, Jan YY, Lin YC, et al. Weekly 24 h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract carcinomas. Anticancer Drugs. 1998;9:393–7. doi: 10.1097/00001813-199806000-00004.PubMedCrossRefGoogle Scholar
  4. 4.
    Chen JS, Lin YC, Jan YY, Liau CT. Mitomycin C with weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract and periampullar carcinomas. Anticancer Drugs. 2001;12:339–43. doi: 10.1097/00001813-200104000-00006.PubMedCrossRefGoogle Scholar
  5. 5.
    Harvey JH, Smith FP, Schein PS. 5-Fluorouracil, mitomycin, and doxorubicin (FAM) in carcinoma of the biliary tract. J Clin Oncol. 1984;2:1245–8.PubMedGoogle Scholar
  6. 6.
    Polyzos A, Nikou G, Giannopoulos A, et al. Chemotherapy of biliary tract cancer with mitomycin-C and 5-fluorouracil biologically modulated by folinic acid. A phase II study. Ann Oncol. 1996;7:644–5.PubMedGoogle Scholar
  7. 7.
    Raderer M, Hejna MH, Valencak JB, et al. Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology. 1999;56:177–80. doi: 10.1159/000011961.PubMedCrossRefGoogle Scholar
  8. 8.
    Castro MP. Efficacy of gemcitabine in the treatment of patients with gallbladder carcinoma: a case report [see comment]. Cancer. 1998;82:639–41. doi: 10.1002/(SICI)1097-0142(19980215)82:4<639::AID-CNCR4>3.0.CO;2-G.PubMedCrossRefGoogle Scholar
  9. 9.
    Gallardo J, Fodor M, Gamargo C, Orlandi L. Efficacy of gemcitabine in the treatment of patients with gallbladder carcinoma: a case report. Cancer. 1998;83:2419–21. doi: 10.1002/(SICI)1097-0142(19981201)83:11<2419::AID-CNCR23>3.0.CO;2-9.PubMedCrossRefGoogle Scholar
  10. 10.
    Tsavaris N, Kosmas C, Gouveris P, et al. Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs. 2004;22:193–8. doi: 10.1023/B:DRUG.0000011797.09549.53.PubMedCrossRefGoogle Scholar
  11. 11.
    Kubicka S, Rudolph KL, Tietze MK, et al. Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology. 2001;48:783–9.PubMedGoogle Scholar
  12. 12.
    Fuchs CS, Clark JW, Ryan DP, et al. A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer. 2002;94:3186–91. doi: 10.1002/cncr.10607.PubMedCrossRefGoogle Scholar
  13. 13.
    Penz M, Kornek GV, Raderer M, et al. Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol. 2001;12:183–6. doi: 10.1023/A:1008352123009.PubMedCrossRefGoogle Scholar
  14. 14.
    Valencak J, Kornek GV, Raderer M, et al. Gemcitabine for the treatment of advanced biliary tract carcinomas: evaluation of two different dose regimens. Onkologie. 1999;22:498–501. doi: 10.1159/000027027.CrossRefGoogle Scholar
  15. 15.
    Boxberger F, Jungert B, Brueckl V, et al. Palliative chemotherapy with gemcitabine and weekly high-dose 5-fluorouracil as 24-h infusion in metastatic biliary tract and gall bladder adenocarcinomas. Anticancer Drugs. 2003;14:87–90. doi: 10.1097/00001813-200301000-00012.PubMedCrossRefGoogle Scholar
  16. 16.
    Murad AM, Guimaraes RC, Aragao BC, et al. Phase II trial of the use of gemcitabine and 5-fluorouracil in the treatment of advanced pancreatic and biliary tract cancer. Am J Clin Oncol. 2003;26:151–4. doi: 10.1097/00000421-200304000-00010.PubMedCrossRefGoogle Scholar
  17. 17.
    Malik IA, Aziz Z, Zaidi SH, Sethuraman G. Gemcitabine and cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. Am J Clin Oncol. 2003;26:174–7. doi: 10.1097/00000421-200304000-00015.PubMedCrossRefGoogle Scholar
  18. 18.
    Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol. 2005;23:2332–8. doi: 10.1200/JCO.2005.51.008.PubMedCrossRefGoogle Scholar
  19. 19.
    Adjei AA. Pemetrexed (Alimta): a novel multitargeted antifolate agent. Expert Rev Anticancer Ther. 2003;3:145–56. doi: 10.1586/14737140.3.2.145.PubMedCrossRefGoogle Scholar
  20. 20.
    Giovannetti E, Mey V, Nannizzi S, et al. Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol. 2005;68:110–8.PubMedGoogle Scholar
  21. 21.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. 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. 2000;92:205–16. doi: 10.1093/jnci/92.3.205.PubMedCrossRefGoogle Scholar
  22. 22.
    Storer BE. Design and analysis of phase I clinical trials. Biometrics. 1989;45:925–37. doi: 10.2307/2531693.PubMedCrossRefGoogle Scholar
  23. 23.
    Duffy D, Santner T. Confidence intervals for a binomial parameter based on multistage tests. Biometrics. 1987;43:81–93. doi: 10.2307/2531951.CrossRefGoogle Scholar
  24. 24.
    Kaplan E, Meier P. Nonparametric estimation for incomplete observations. J Am Statistics Assoc. 1958;53:457–81. doi: 10.2307/2281868.CrossRefGoogle Scholar
  25. 25.
    Cox DR. Regression models and life tables. J R Stat Soc (Series B). 1972;34:187–202.Google Scholar
  26. 26.
    Adjei AA, Erlichman C. A phase I trial of MTA and gemcitabine in patients with locally advanced or metastatic cancer. Semin Oncol. 1999;26:94–8.PubMedGoogle Scholar
  27. 27.
    Kalykaki A, Vamvakas L, Agelaki S, et al. A dose escalation study of gemcitabine plus pemetrexed administered biweekly in patients with solid tumors. Oncology. 2006;71:197–203. doi: 10.1159/000106069.PubMedCrossRefGoogle Scholar
  28. 28.
    Dy GK, Suri A, Reid JM, et al. A phase IB study of the pharmacokinetics of gemcitabine and pemetrexed, when administered in rapid sequence to patients with advanced solid tumors. Cancer Chemother Pharmacol. 2005;55:522–30. doi: 10.1007/s00280-004-0950-7.PubMedCrossRefGoogle Scholar
  29. 29.
    Brand R, Capadano M, Tempero M. A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors. Invest New Drugs. 1997;15:331–41. doi: 10.1023/A:1005981317532.PubMedCrossRefGoogle Scholar
  30. 30.
    Tempero M, Plunkett W, Ruiz Van Haperen V, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol. 2003;21:3402–8. doi: 10.1200/JCO.2003.09.140.PubMedCrossRefGoogle Scholar
  31. 31.
    Poplin E, Levy DE, Berlin J, et al. Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion [FDR]) versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201) (Meeting abstract). J Clin Oncol. 2006;24:LBA.Google Scholar
  32. 32.
    Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer [erratum appears in Ann Oncol. 2006 Mar;17(3):535]. Ann Oncol. 2005;16:1639–45. doi: 10.1093/annonc/mdi309.PubMedCrossRefGoogle Scholar
  33. 33.
    von der Maase H, Lehmann J, Gravis G, et al. A phase II trial of pemetrexed plus gemcitabine in locally advanced and/or metastatic transitional cell carcinoma of the urothelium. Ann Oncol. 2006;17:1533–8. doi: 10.1093/annonc/mdl154.CrossRefGoogle Scholar
  34. 34.
    Ma CX, Steen P, Rowland KM, et al. A phase II trial of a combination of pemetrexed and gemcitabine in patients with metastatic breast cancer: an NCCTG study. Ann Oncol. 2006;17:226–31. doi: 10.1093/annonc/mdj054.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • Steven R. Alberts
    • 1
    Email author
  • Jonathan R. Sande
    • 2
  • Nathan R. Foster
    • 1
  • Fernando J. Quevedo
    • 1
  • Robert R. McWilliams
    • 1
  • John W. Kugler
    • 3
  • Tom R. Fitch
    • 4
  • Anthony J. Jaslowski
    • 5
  1. 1.Mayo Clinic and Mayo FoundationRochesterUSA
  2. 2.Duluth CCOPDuluthUSA
  3. 3.Illinois Oncology Research Association CCOPPeoriaUSA
  4. 4.Mayo Clinic ScottsdaleScottsdaleUSA
  5. 5.St. Vincent Regional Cancer Center CCOPGreen BayUSA

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