Annals of Surgical Oncology

, Volume 15, Issue 4, pp 1183–1192

Cytoreductive Surgery and Intraoperative Hyperthermic Intraperitoneal Chemotherapy with Paclitaxel: A Clinical and Pharmacokinetic Study

  • Eelco de Bree
  • Hilde Rosing
  • Dimitris Filis
  • John Romanos
  • Maria Melisssourgaki
  • Markos Daskalakis
  • Maria Pilatou
  • Elias Sanidas
  • Panagiotis Taflampas
  • Konstantinos Kalbakis
  • Jos H. Beijnen
  • Dimitris D. Tsiftsis
Gynecologic Oncology



Intraperitoneal chemotherapy has been recommended as a treatment option for ovarian cancer with peritoneal dissemination. Although its treatment duration is significantly shorter, intraoperative hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) has several advantages over simple intraperitoneal instillation chemotherapy. While platinum compounds have usually been used, only a few have administered paclitaxel during HIPEC. Its large molecular weight suggests a much more favorable pharmacokinetic profile than that of platinum compounds. The pharmacokinetics of paclitaxel during and after HIPEC have not been studied before.


Thirteen women, mainly with ovarian cancer, underwent cytoreductive surgery and HIPEC with 175 mg/m2 paclitaxel for 2 h. Morbidity was noted. Peritoneal fluid samples and blood samples were harvested during and until 5 days after HIPEC for pharmacokinetic study in ten patients.


No treatment-related mortality was noted. Overall morbidity was 38% (two wound infections, one deep venous thrombosis, two grade 1 thrombopenia, one grade 2 neutropenia, and one grade 3 pancytopenia). Mean maximal intraperitoneal paclitaxel concentration was 101 mg/L, which was an average of 1178 times higher than the peak plasma levels. The peritoneal fluid versus plasma AUC ratio was 1462 for the 2-h HIPEC duration and 366 for the total 5-day study period. Cytotoxic drug concentrations were detected in peritoneal fluid for a mean period of 2.7 days, despite drainage of the drug solution after 2 h of treatment.


HIPEC with paclitaxel following cytoreductive surgery is feasible, relatively safe, and associated with a highly favorable pharmacokinetic profile, despite its short treatment duration. Larger studies with a more homogenous patient cohort and adequate follow-up should be performed to demonstrate its efficacy.


  1. 1.
    Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55:10–30PubMedGoogle Scholar
  2. 2.
    McGuire WP III, Markman M. Primary ovarian cancer chemotherapy: current standards of care. Br J Cancer 2003; 89 suppl 3:S3–8PubMedCrossRefGoogle Scholar
  3. 3.
    Kyrgiou M, Salanti G, Pavlidis N, et al. Survival benefits with diverse chemotherapy regimens for ovarian cancer: a meta-analysis of multiple treatments. J Natl Cancer Inst 2006; 98:1655–63PubMedCrossRefGoogle Scholar
  4. 4.
    Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphomide for stage III ovarian cancer. New Engl J Med 1996; 335:150–5CrossRefGoogle Scholar
  5. 5.
    Markman M, Bundy B, Alberts DS, et al. Phase III study of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: An Intergroup Study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19:1001–7PubMedGoogle Scholar
  6. 6.
    de Bree E, Theodoropoulos PA, Rosing H, et al. Treatment of ovarian cancer using intraperitoneal chemotherapy with taxanes: from laboratory bench to bedside. Cancer Treat Rev 2006; 32:471–82PubMedCrossRefGoogle Scholar
  7. 7.
    Armstrong DK, Bundy BN, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New Eng J Med 2006; 354:34–43PubMedCrossRefGoogle Scholar
  8. 8.
    Trimble EL, Christian MC. Intraperitoneal chemotherapy for women with advanced epithelial ovarian carcinoma. Gynecol Oncol 2006; 100:3–4 PubMedCrossRefGoogle Scholar
  9. 9.
    de Bree E, Tsiftsis DD. Principles of perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis. Recent Results Cancer Res 2007; 169:39–51PubMedGoogle Scholar
  10. 10.
    Dedrick RL, Flessner MF. Pharmacokinetic problems in peritoneal drug administration: Tissue penetration and surface exposure. J Natl Cancer Inst 1997; 89:480–7PubMedCrossRefGoogle Scholar
  11. 11.
    Witkamp AJ, de Bree E, van Goethem AR, et al. Rationale and technique of intraoperative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27:365–74PubMedCrossRefGoogle Scholar
  12. 12.
    Sticca RP, Dach BW. Rationale for hyperthermia with intraoperative intraperitoneal chemotherapy agents. Surg Oncol Clin North Am 2003; 12; 689–701CrossRefGoogle Scholar
  13. 13.
    Markman M. Intraperitoneal Taxol. Cancer Treat Res 1996; 81:1–5PubMedGoogle Scholar
  14. 14.
    Markman M, Rowinsky E, Hakes T, et al. Phase I trial of intraperitoneal taxol: a Gynecologic Oncology Group study. J Clin Oncol 1992; 10:1485–91PubMedGoogle Scholar
  15. 15.
    Fushida S, Furui N, Kinami S, et al. [Pharmacologic study of intraperitoneal paclitaxel in gastric cancer with peritoneal dissemination]. Gan To Kagaku Ryoho 2002; 29:2164–7PubMedGoogle Scholar
  16. 16.
    Hofstra LS, Bos AME, de Vries EGE, et al. Kinetic modelling and efficacy of intraperitoneal paclitaxel combined with intravenous cyclophosphamide and carboplatin as first-line treatment in ovarian cancer. Gynecol Oncol 2002; 85:517–23PubMedCrossRefGoogle Scholar
  17. 17.
    Francis P, Rowinsky E, Schneider J, et al. Phase I feasibility and pharmacologic study of weekly paclitaxel: a Gynecologic Oncology Group pilot study. J Clin Oncol 1995; 13:2961–7PubMedGoogle Scholar
  18. 18.
    Rupniak HY, Whelan RD, Hill BT. Concentration and time-dependent inter-relationships for antitumour drug cytotoxicities against tumour cells in vitro. Int J Cancer 1983; 32:7–12PubMedCrossRefGoogle Scholar
  19. 19.
    Michalakis J, Georgatos SD, de Bree E, et al. Short term exposure of cancer cells to micromolar doses of paclitaxel, with or without hyperthermia, induces long term inhibition of cell proliferation and cell death in vitro. Ann Surg Oncol 2007; 14:1220–8PubMedCrossRefGoogle Scholar
  20. 20.
    Michalakis J, Georgatos SD, Romanos J, et al. Micromolar taxol, with or without hyperthermia, induces mitotic catastrophe and cell necrosis in HeLa cells. Cancer Chemother Pharmacol 2005; 56:615–22PubMedCrossRefGoogle Scholar
  21. 21.
    de Bree E, Rosing H, Beijnen JH, et al. Pharmacokinetic study of docetaxel in intraoperative hyperthermic i.p. chemotherapy for ovarian cancer. Anticancer Drugs 2003; 14:103–10PubMedCrossRefGoogle Scholar
  22. 22.
    de Bree E, Romanos J, Michalakis J, et al. Intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel as second-line treatment for peritoneal carcinomatosis of gynaecological origin. Anticancer Res 2003; 23:3019–28PubMedGoogle Scholar
  23. 23.
    Tsiftsis D, de Bree E, Romanos J, et al. Peritoneal expansion by artificially produced ascites during perfusion chemotherapy. Arch Surg 1999; 134:545–9PubMedCrossRefGoogle Scholar
  24. 24.
    Stokvis E, Ouwehand M, Nan LG, et al. A simple and sensitive assay for the quantificative analysis of paclitaxel in human and mouse plasma and brain tumor tissue using coupled liquid chromatography and tandem mass spectrometry. J Mass Spectrom 2004; 39:1506–12PubMedCrossRefGoogle Scholar
  25. 25.
    Wiernik PH, Schwartz EL, Strauman JJ, et al. Phase I clinical and pharmacokinetic study of taxol. Cancer Res 1987; 47:2486–93PubMedGoogle Scholar
  26. 26.
    Kohn EC, Sarosy G, Bicher A, et al. Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 1994; 86:18–24PubMedCrossRefGoogle Scholar
  27. 27.
    Omura GA, Brady MF, Look KY, et al. Phase III trial of paclitaxel at two dose levels, the higher dose accompanied by filgrastim at two dose levels in platinum-pretreated epithelial ovarian cancer: an Intergroup study. J Clin Oncol 2003; 21:2843–8PubMedCrossRefGoogle Scholar
  28. 28.
    Reed E, Bitton R, Sarosy G, et al. Paclitaxel dose intensity. J Infus Chemother 1996; 6:59–63PubMedGoogle Scholar
  29. 29.
    Takimoto CH, Rowinsky EK. Dose-intense paclitaxel: déjà vu all over again? J Clin Oncol 2003; 21; 2810–4PubMedCrossRefGoogle Scholar
  30. 30.
    Mohamed F, Marchetti P, Stuart OA, et al. Pharmacokinetics and tissue distribution of intraperitoneal paclitaxel with different carrier solutions. Cancer Chemother Pharmacol 2003; 52:405–10PubMedCrossRefGoogle Scholar
  31. 31.
    Innocenti F, Danesi R, Di Paolo A, et al. Plasma and tissue disposition of paclitaxel (taxol) after intraperitoneal administration in mice. Drug Metab Dispos 1995; 23:713–7PubMedGoogle Scholar
  32. 32.
    Ohashi N, Kodera Y, Nakanishi H, et al. Efficacy of intraperitoneal chemotherapy with paclitaxel targeting peritoneal micrometastases as revealed by GFP-tagged human gastric cancer cell lines in nude mice. Int J Oncol 2005; 27:637–44PubMedGoogle Scholar
  33. 33.
    Kuh H-J, Jang S, Wientjes JM, et al. Determinants of paclitaxel penetration and accumulation in human solid tumor. J Pharmacol Exper Ther 1999; 290:871–80Google Scholar
  34. 34.
    Mohamed F, Marchetti P, Stuart OA, et al. A comparison of hetastarch and peritoneal dialysis solution for intraperitoneal chemotherapy delivery. Eur J Surg Oncol 2003; 29:261–5PubMedCrossRefGoogle Scholar
  35. 35.
    de Bree E, Tsiftsis DD. Experimental and pharmacokinetic studies in intraperitoneal chemotherapy: from laboratory bench to bedside. Recent Results Cancer Res 2007; 169:53–73PubMedGoogle Scholar
  36. 36.
    Fushida S, Nao F, Kinami S, et al. [Pharmacologic study of intraperitoneal docetaxel in gastric cancer with peritoneal dissemination]. Gan To Kagaku Ryoho 2002; 29:1759–63PubMedGoogle Scholar
  37. 37.
    Morgan RJ, Doroshow JH, Synold T, et al. Phase I trial of intraperitoneal docetaxel in the treatment of advanced malignancies primarily confined to the peritoneal cavity. Clin Cancer Res 2003; 9:5896–901PubMedGoogle Scholar
  38. 38.
    Yokogawa K, Jin M, Furui N, et al. Disposition kinetics of taxanes after intraperitoneal administration in rats and influence of surfactant vehicles. J Pharm Pharmacol 2004; 56:629–34PubMedCrossRefGoogle Scholar
  39. 39.
    Gelderblom H, Verweij J, van Zomeren DM, et al. Influence of Cremophor EL on the bioavailability of intraperitoneal paclitaxel. Clin Cancer Res 2002; 8:1237–41PubMedGoogle Scholar
  40. 40.
    Mross K, Holländer N, Hauns B, et al. The pharmacokinetics of a 1-h paclitaxel infusion. Cancer Chemother Pharmacol 2000; 45:463–70PubMedCrossRefGoogle Scholar
  41. 41.
    Nannan Panday VR, ten Bokkel Huinink WW, Vermorken JB, et al. Pharmacokinetics of paclitaxel administered as a 3-hour or 96-hour infusion. Pharmacol Res 1999; 40:67–74CrossRefGoogle Scholar
  42. 42.
    Gianni L, Kearns CM, Giani A, et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995; 13:180–90PubMedGoogle Scholar
  43. 43.
    Huizing MT, Keung ACF, Rosing H, et al. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 1993; 11:2127–35PubMedGoogle Scholar
  44. 44.
    Leal BZ, Meltz ML, Mohan N, et al. Interaction of hyperthermia with Taxol in human MCF-7 breast adenocarcinoma cells. Int J Hyperthermia 1999; 15:225–36PubMedCrossRefGoogle Scholar
  45. 45.
    Rietbroek RC, Katschinski DM, Reijers MH, et al. Lack of thermal enhancement for taxanes in vitro. Int J Hyperthermia 1997; 13:525–33PubMedCrossRefGoogle Scholar
  46. 46.
    Knox JD, Mitchel RE, Brown DL. Effects of taxol and taxol/hyperthermia treatments on the functional polarization of cytotoxic T lymphocytes. Cell Motil Cytoskeleton 1993; 24:129–38PubMedCrossRefGoogle Scholar
  47. 47.
    van Bree C, Savoneije JH, Franken NA, et al. The effect of p53-function on the sensitivity to paclitaxel with or without hyperthermia in human colorectal carcinoma cells. Int J Oncol 2000; 16:739–44PubMedGoogle Scholar
  48. 48.
    Othman T, Goto S, Lee JB, et al. Hyperthermic enhancement of the apoptotic and antiproliferative activities of paclitaxel. Pharmacology 2001; 62:208–12PubMedCrossRefGoogle Scholar
  49. 49.
    Cividalli A, Cruciani G, Livdi E, et al. Hyperthermia enhances the response of paclitaxel and radiation in a mouse adenocarcinoma. Int J Radiat Oncol Biol Phys 1999; 44:407–12PubMedGoogle Scholar
  50. 50.
    Cividalli A, Livdi E, Ceciarelli F, et al. Hyperthermia and paclitaxel-epirubicin chemotherapy: enhanced cytotoxic effect in a murine mammary adenocarcinoma. Int J Hyperthermia 2000; 16:61–71PubMedCrossRefGoogle Scholar
  51. 51.
    Sharma D, Chelvi TP, Kaur J, et al. Thermosensitive liposomal taxol formulation: heat-mediated targeted drug delivery in murine melanoma. Melanoma Res 1998; 8:240–4PubMedCrossRefGoogle Scholar
  52. 52.
    Mohamed F, Marchettini P, Stuart OA, et al. Thermal enhancement of new chemotherapeutic agents at moderate hyperthermia. Ann Surg Oncol 2003; 10:463–8PubMedCrossRefGoogle Scholar
  53. 53.
    Hager ED, Dziambor H, Hohmann D, et al. Intraperitoneal hyperthermic perfusion chemotherapy of patients with chemotherapy-resistant peritoneal disseminated ovarian cancer. Int J Gynecol Cancer 2001; 11(suppl. 1):57–63PubMedCrossRefGoogle Scholar
  54. 54.
    Piso P, Dahlke M-H, Loss M, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis. World J Surg Oncol 2004; 2:21–8PubMedCrossRefGoogle Scholar
  55. 55.
    Ryu KS, Kim JH, Ko HS, et al. Effects of intraperitoneal hyperthermic chemotherapy in ovarian cancer. Gynecol Oncol 2004; 94:325–32PubMedCrossRefGoogle Scholar
  56. 56.
    Zanon C, Clara R, Chiappino I, et al. Cytoreductive surgery and intraperitoneal chemohyperthermia for recurrent peritoneal carcinomatosis from ovarian cancer. World J Surg 2004; 28:1040–5PubMedCrossRefGoogle Scholar
  57. 57.
    Gori J, Castano R, Toziano M, et al. Intraperitoneal hyperthermic chemotherapy in ovarian cancer. Int J Gynecol Cancer 2005; 15:233–9PubMedCrossRefGoogle Scholar
  58. 58.
    Raspagliesi F, Kusamara S, Campos, et al. Cytoreduction combined with intraperitoneal hyperthermic perfusion chemotherapy in advanced/recurrent ovarian cancer patients: the experience of National Cancer Institute of Milan. Eur J Surg Oncol 2006; 32:671–5PubMedCrossRefGoogle Scholar
  59. 59.
    Helm CW, Randall-Whites L, Martin RS III, et al. Hyperthermic intraperitoneal chemotherapy in conjunction with surgery for the treatment of recurrent ovarian carcinoma. Gynecol Oncol 2007; 105:90–6PubMedCrossRefGoogle Scholar
  60. 60.
    Rufian S, Munoz-Casares FC, Briceno J, et al. Radical surgery-peritonectomy and intraoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis in recurrent and primary ovarian cancer. J Surg Oncol 2006; 94:316–24PubMedCrossRefGoogle Scholar
  61. 61.
    Bae JH, Lee JM, Ryu KS, et al. Treatment of ovarian cancer with paclitaxel or carboplatin-based intraperitoneal hyperthermic chemotherapy during secondary surgery. Gynecol Oncol 2007; 106:193–209PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2008

Authors and Affiliations

  • Eelco de Bree
    • 1
  • Hilde Rosing
    • 2
  • Dimitris Filis
    • 1
  • John Romanos
    • 1
  • Maria Melisssourgaki
    • 1
  • Markos Daskalakis
    • 1
  • Maria Pilatou
    • 1
  • Elias Sanidas
    • 1
  • Panagiotis Taflampas
    • 1
  • Konstantinos Kalbakis
    • 3
  • Jos H. Beijnen
    • 2
  • Dimitris D. Tsiftsis
    • 1
  1. 1.Department of Surgical OncologyUniversity Hospital, Crete University Medical SchoolHerakleionGreece
  2. 2.Department of Pharmacy and PharmacologySlotervaart Hospital/The Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Department of Medical OncologyUniversity Hospital, Crete University Medical SchoolHerakleionGreece

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