Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 4, pp 647–653 | Cite as

Intraperitoneal gemcitabine pharmacokinetics: a pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas

  • T. Clark Gamblin
  • Merrill J. Egorin
  • Eleanor G. Zuhowski
  • Theodore F. Lagattuta
  • Laurie L. Herscher
  • Angelo Russo
  • Steven K. Libutti
  • H. Richard Alexander
  • Robert L. Dedrick
  • David L. Bartlett
Original Article



The pyrimidine analogue gemcitabine (2′, 2′-difluorodeoxycitidine, dFdC) is active against pancreatic cancer, and its high clearance (CLtb) and low incidence of local toxicity make it an excellent candidate for evaluation as intraperitoneal (IP) therapy. We designed a dosing schema that used multiple sequential exchanges of a peritoneal dialysate containing dFdC in an effort to produce prolonged IP dFdC exposure.


As part of a study involving multi-modality therapy for advanced pancreatic adenocarcinoma, patients were treated with four 6-h IP dwells of dFdC (50 mg/m2 in 2 l) over a 24-h period. A second 24-h cycle of IP dFdC therapy was repeated 1 week later. Each exchange of dialysate contained 50 mg/m2 dFdC in 2 l of commercial 1.5% dextrose dialysis solution. Plasma and peritoneal fluid were analyzed by HPLC to determine concentrations of dFdC and its inactive metabolite 2′, 2′ difluorodeoxyuridine (dFdU). Clinical data were recorded to note drug toxicity and response.


Nine patients underwent IP dFdC therapy, and eight were able to receive two cycles. There were no recorded significant toxicities. Low plasma dFdC concentrations (<1 μg/ml) were present transiently in seven of nine patients, and dFdC was not detectable in the plasma of the other two. Plasma dFdU concentrations were low but increased gradually until 12 h and then declined little if any. IP dFdC concentrations declined rapidly, and dFdC was seldom measurable prior to administration of the next scheduled 6-h dwell. dFdU concentrations in peritoneal fluid were very low (<0.5 μg/ml) throughout treatment. The mean area under the concentration versus time curve (AUC) for dFdC in peritoneal fluid was 182 μg/ml × h, which was approximately 70× the AUC of dFdC reported in the ascites of a patient undergoing systemic dFdC therapy.


IP dFdC was well tolerated, and no significant toxicities were noted. The rapid decrease in peritoneal dFdC concentrations and low concentrations of IP dFdU imply almost total absorption of IP-administered dFdC. Little, if any, dFdC could be detected in plasma, but the steady-state plasma dFdU concentrations also imply absorption and inactivation of virtually all IP-administered dFdC. These findings are consistent with the known high CLtb and low incidence of local toxicity of dFdC and argue for its further evaluation as a drug for IP therapy.


Intraperitoneal chemotherapy Pharmacokinetics Gemcitabine Pancreatic cancer 



We thank the University of Pittsburgh Cancer Institute Hematology/Oncology Writing Group for helpful suggestions regarding the manuscript and Mr. Jeremy A. Hedges for excellent secretarial assistance.


  1. 1.
    Burris HA, Moore MJ, Andersen J et al (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
  2. 2.
    Dedrick RL (1986) Interspecies scaling of regional drug delivery. J Pharm Sci 75(11):1047–1052PubMedCrossRefGoogle Scholar
  3. 3.
    Dedrick RL (1985) Theoretical and experimental bases of intraperitoneal chemotherapy. Semin Oncol 12(3):1–6PubMedGoogle Scholar
  4. 4.
    Dedrick RL, Myers CE, Bungay PM, DeVita VT (1978) Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 62(1):1–11PubMedGoogle Scholar
  5. 5.
    Delauter BJ, Ramanathan RK, Egorin MJ, Stover LL, Zuhowski EG, Plunkett W, Zamboni WC (2000) Pharmacokinetics of gemcitabine and 2′, 2′-difluorodexoyrindine in patient with ascites. Pharmacotherapy 20(10):1204–1207PubMedCrossRefGoogle Scholar
  6. 6.
    Fossella FV, Lippman SM, Shin DM et al. (1997) Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naïve patients with advanced non-small cell lung cancer. J Clin Oncol 15(1):310–316PubMedGoogle Scholar
  7. 7.
    Gastointestinal Tumor Study Group (1988) Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group. J Natl Cancer Inst 80(10):751–755CrossRefGoogle Scholar
  8. 8.
    Green MR (1996) Gemcitabine safety overview. Semin Oncol 23(5):32–35PubMedGoogle Scholar
  9. 9.
    Grunewald R, Kantarjian H, Du M, Faucher K, Tarassoff P, Plunkett W (1992) Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol 10:406–413PubMedGoogle Scholar
  10. 10.
    Heinemann V, Hertel LW, Grindey GB, Plunkett W (1988) Comparison of the cellular pharmacokinetics and toxicity of 2′, 2′- difluorodeoxycytidine and 1-beta-d-arabinofuranosylcytosine. Cancer Res 48(14):4024–4031PubMedGoogle Scholar
  11. 11.
    Heinemann V, Xu Y, Chubb S, Sen A, Hertel LW, Grindley GB, Plunkett W (1990) Inhibition of ribonucleotide reductase in CCRF-CEM cells by 2′, 2′-difluorodeoxy-cytidine. Mol Pharmacol 38(4):567–572PubMedGoogle Scholar
  12. 12.
    Hertel LW, Boder GB, Kroin JS, Rinzel SM et al (1990) Evaluation of the antitumor activity of gemcitabine (2′, 2′-difluoro-2′-deoxyctidine). Cancer Res 50(14):4417–4422PubMedGoogle Scholar
  13. 13.
    Jemal A, Tiwari RC, Ghafoor A et al. (2004) Cancer statistics, 2004. CA Cancer J Clin 54:8–29PubMedCrossRefGoogle Scholar
  14. 14.
    Klaassen DJ, MacIntyre JM, Catton GE, Engstrom PF, Moertel CG (1985) Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintence 5-fluoruracil––an Eastern Cooperative Oncology Study Group. J Clin Oncol 3:373–378PubMedGoogle Scholar
  15. 15.
    Lund B, Kristjansen PE, Hansen HH (1993) Clinical and preclinical activity of 2′, 2′-difuorodeoxycytidine (gemcitabine). Cancer Treat Rev 19(1):45–55PubMedCrossRefGoogle Scholar
  16. 16.
    Macchia G, Valentini V, Mattiucci GC et al. (2007) Preoperative chemoradiation and intra-operative radiotherapy for pancreatic carcinoma. Tumori 93(1):53–60PubMedGoogle Scholar
  17. 17.
    Moertel CG, Frytak S, Hahn RG et al. (1981) Therapy of locally resectable pancreatic carcinoma: a randomized comparison of high dose (6,000 rads) radiation alone, moderate dose radiation (4,000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 48:1705–1710PubMedCrossRefGoogle Scholar
  18. 18.
    Moore MJ, Tannock IF, Ernst DS et al. (1997) Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 15(12):3441–3445PubMedGoogle Scholar
  19. 19.
    Murphy JD, Adusumilli S, Griffith KA et al. (2007) Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 68(3):801–808PubMedGoogle Scholar
  20. 20.
    Pestieau SR, Stuart OA, Chang D et al. (1998) Pharmacokinetics of intraperitoneal gemcitabine in a rat model. Tumori 84(6):706–711PubMedGoogle Scholar
  21. 21.
    Regine WF, Abrams RA (2006) Adjuvant therapy for pancreatic cancer: current status, future directions. Semin Oncol 33(6):S10–S13PubMedCrossRefGoogle Scholar
  22. 22.
    Ridwelski K, Meyer F, Hribaschek A et al. (2002) Intraoperative and early postoperative chemotherapy into the abdominal cavity using gemcitabine may prevent postoperative occurrence of peritoneal carcinomatosis. J Surg Oncol 79:10–16PubMedCrossRefGoogle Scholar
  23. 23.
    Ries LAG, Eisner MP, Kosary CL, et al. SEER cancer statistic review 1975–2002. Available at
  24. 24.
    Sabbatini P, Aghajanian C, Leitao M et al. (2004) Intraperitoneal cisplatin with intraperitoneal gemcitabine in patients with epithelial ovarian cancer: results of a phase I/II trial. Clin Cancer Res 10(9):2962–2967PubMedCrossRefGoogle Scholar
  25. 25.
    Schultz RM, Merriman RL, Toth JE, Zimmermann JE et al. (1993) Evaluation of new anticancer agents against the MIA PaCa-2 and PANC-1 human pancreatic carcinoma xenografts. Oncol Res 5(6–7):223–228PubMedGoogle Scholar
  26. 26.
    Shaib YH, Davila JA, Naumann C, El-Serag H (2007) The impact of curative intent surgery on the survival of pancreatic cancer patients: A US population-based study. Am J Gastroenterol 102:1–6CrossRefGoogle Scholar
  27. 27.
    Sohn TA, Yeo CJ, Cameron JL et al (2000) Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 4:567–579PubMedCrossRefGoogle Scholar
  28. 28.
    Stadler WM, Kuzel T, Roth B et al. (1997) Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15(11):3394–3398PubMedGoogle Scholar
  29. 29.
    Storniolo AM, Allerheiligen SR, Pearce HL (1997) Preclinical, pharmacologic, and phase I studies of gemcitabine. Semin Oncol 24:S7-2–S7-7Google Scholar
  30. 30.
    Sultana A, Tudur Smith C, Cunningham D et al. (2007) Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy. Br J Cancer 96(8):1183–1190PubMedCrossRefGoogle Scholar
  31. 31.
    Toschi L, Finocchiaro G, Bartolini S et al. (2005) Role of gemcitabine in cancer therapy. Future Oncol 1(1):7–17PubMedCrossRefGoogle Scholar
  32. 32.
    Vennok AP, Egorin MJ, Rosner GL et al. (2000) Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol 18(14):2780–2787Google Scholar
  33. 33.
    Vyas VP, Rubin EH, Zamek R et al. (2000) Intraperitoneal gemcitabine: phase I study. Proc AACR 41:612 (Abstract)Google Scholar
  34. 34.
    Yeo TP, Hruban RH, Leach SD et al. (2002) Pancreatic cancer. Curr Probl Cancer 26:176PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • T. Clark Gamblin
    • 1
    • 2
    • 9
  • Merrill J. Egorin
    • 3
    • 4
    • 5
  • Eleanor G. Zuhowski
    • 5
  • Theodore F. Lagattuta
    • 5
  • Laurie L. Herscher
    • 6
  • Angelo Russo
    • 6
  • Steven K. Libutti
    • 7
  • H. Richard Alexander
    • 7
  • Robert L. Dedrick
    • 8
  • David L. Bartlett
    • 2
    • 7
  1. 1.Division of Surgical Oncology, Department of SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Division of Transplantation, Department of SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Division of Hematology/Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of PharmacologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  5. 5.Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  6. 6.Radiation Oncology BranchNational Cancer Institute, National Institutes of HealthBethesdaUSA
  7. 7.Surgery BranchNational Cancer Institute, National Institutes of HealthBethesdaUSA
  8. 8.Division of Bioengineering and Physical Science, Office of Research ServicesNational Institutes of HealthBethesdaUSA
  9. 9.Liver Cancer Center, UPMC Montefiore HospitalPittsburghUSA

Personalised recommendations