Annals of Surgical Oncology

, Volume 15, Issue 5, pp 1407–1413 | Cite as

Phase I Trial of Pegylated Liposomal Doxorubicin with Hyperthermic Intraperitoneal Chemotherapy in Patients Undergoing Cytoreduction for Advanced Intra-abdominal Malignancy

  • Lawrence E. Harrison
  • Margarette Bryan
  • Lilian Pliner
  • Tracie Saunders
Gastrointestinal Oncology



Cytoreduction coupled with hyperthermic intraperitoneal chemotherapy (HIPEC) is an attractive treatment option for a select group of patients with abdominal-only malignancy. The present phase I study examined the safety and pharmacokinetics of intraperitoneal pegylated liposomal doxorubicin (PLD) used in the context of HIPEC in patients with advanced abdominal-only malignancies.


Patients with advanced abdominal malignancies underwent maximal cytoreduction and HIPEC with escalating doses of PLD (15–100 mg/m2). Perfusate, serum, and tissue doxorubicin levels were measured in five patients undergoing HIPEC at the maximum tolerated dose.


Twenty-one patients were enrolled in this trial. The maximum dose evaluated in this trial was 100 mg/m2 and was well tolerated. The most common grade 3/4 complications were superficial wound infection and prolonged ileus. One patient developed an anastomotic leak in the postoperative period, requiring re-exploration. The median postoperative length of stay was 7 days (range, 4–29 days), three patients required readmissions within 30 days, and there were no operative mortalities The median follow-up time for was 13.7 months (range, 3–38 months). The median overall survival was 30.6 months with a median disease-free survival of 25 months.


We report that HIPEC with PLD following maximal cytoreduction in patients with advanced abdominal-only gastrointestinal or gynecologic malignancies is well tolerated. Encouraging survival after cytoreduction and HIPEC with PLD suggest that a phase II trial to verify activity is indicated.


Phase I Doxorubicin Hyperthermia Cytoreduction Liposomal 


  1. 1.
    Alexander HR BJ, Fraker DL. Rationale and clinical status of continuous hyperthermic peritoneal perfusion for the treatment of peritoneal carcinomatosis. In: DeVita VHS, Rosenberg S (ed.) Principles and Practices of Oncology Updates, Vol. 9. Philadelphia: JB Lippincott, 1995Google Scholar
  2. 2.
    Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737–43PubMedCrossRefGoogle Scholar
  3. 3.
    Reichman TW, Cracchiolo B, Sama J, et al. Cytoreductive surgery and intraoperative hyperthermic chemoperfusion for advanced ovarian carcinoma. J Surg Oncol 2005;90:51–6PubMedCrossRefGoogle Scholar
  4. 4.
    Sugarbaker PH, Chang D. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol 1999;6:727–31PubMedCrossRefGoogle Scholar
  5. 5.
    Loggie BW, Fleming RA, McQuellon RP, et al. Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for disseminated peritoneal cancer of gastrointestinal origin. Am Surg 2000;66:561–8PubMedGoogle Scholar
  6. 6.
    Sugarbaker PH. Management of peritoneal-surface malignancy: the surgeon’s role. Langenbecks Arch Surg 1999;384:576–87PubMedCrossRefGoogle Scholar
  7. 7.
    Rossi CR, Foletto M, Mocellin S, et al. Hyperthermic intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin in patients who undergo cytoreductive surgery for peritoneal carcinomatosis and sarcomatosis: phase I study. Cancer 2002;94:492–9PubMedCrossRefGoogle Scholar
  8. 8.
    Ozols RF, Young RC, Speyer JL, et al. Phase I and pharmacological studies of adriamycin administered intraperitoneally to patients with ovarian cancer. Cancer Res 1982;42:4265–9PubMedGoogle Scholar
  9. 9.
    Cabanes A, Even-Chen S, Zimberoff J, et al. Enhancement of antitumor activity of polyethylene glycol-coated liposomal doxorubicin with soluble and liposomal interleukin 2. Clin Cancer Res 1999;5:687–93PubMedGoogle Scholar
  10. 10.
    Sadzuka Y, Hirota S, Sonobe T. Intraperitoneal administration of doxorubicin encapsulating liposomes against peritoneal dissemination. Toxicol Lett 2000;116:51–9PubMedCrossRefGoogle Scholar
  11. 11.
    Colombo P-E, Boustta M, Poujol S, et al. Biodistribution of doxorubicin-alkylated poly(l-lysine citramide imide) conjugates in an experimental model of peritoneal carcinomatosis after intraperitoneal administration. Eur J Pharm Sci 2007;31:43–52PubMedCrossRefGoogle Scholar
  12. 12.
    Huang SK, Stauffer PR, Hong K, et al. Liposomes and hyperthermia in mice: increased tumor uptake and therapeutic efficacy of doxorubicin in sterically stabilized liposomes. Cancer Res 1994;54:2186–91PubMedGoogle Scholar
  13. 13.
    Esquivel J, Sticca R, Sugarbaker PH, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Ann Surg Oncol 2006;14:128–33PubMedGoogle Scholar
  14. 14.
    Kummerle A, Krueger T, Dusmet M, et al. A validated assay for measuring doxorubicin in biological fluids and tissues in an isolated lung perfusion model: matrix effect and heparin interference strongly influence doxorubicin measurements. J Pharm Biomed Anal 2003;33:475–94PubMedCrossRefGoogle Scholar
  15. 15.
    Hahn GM, Strande DP. Cytotoxic effects of hyperthermia and adriamycin on Chinese hamster cells. J Natl Cancer Inst 1976;57:1063–7PubMedGoogle Scholar
  16. 16.
    Miller RC, Richards M, Baird C, et al. Interaction of hyperthermia and chemotherapy agents; cell lethality and oncogenic potential. Int J Hyperthermia 1994;10:89–99PubMedCrossRefGoogle Scholar
  17. 17.
    Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol-Hematol 2002;43:33–56PubMedCrossRefGoogle Scholar
  18. 18.
    Elias D, Blot F, El Otmany A, et al. Curative treatment of peritoneal carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer 2001;92:71–6PubMedCrossRefGoogle Scholar
  19. 19.
    Shen P, Levine EA, Hall J, et al. Factors predicting survival after intraperitoneal hyperthermic chemotherapy with mitomycin C after cytoreductive surgery for patients with peritoneal carcinomatosis. Arch Surg 2003; 138:26–33PubMedCrossRefGoogle Scholar
  20. 20.
    Markman M. Intraperitoneal antineoplastic drug delivery: rationale and results. Lancet Oncol 2003;4:277–83PubMedCrossRefGoogle Scholar
  21. 21.
    Huang SK, Mayhew E, Gilani S, et al. Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma. Cancer Res 1992;52:6774–81PubMedGoogle Scholar
  22. 22.
    Papahadjopoulos D, Allen TM, Gabizon A, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci U S A 1991;88:11460–4PubMedCrossRefGoogle Scholar
  23. 23.
    Ning S, Macleod K, Abra RM, et al. Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy. Int J Radiat Oncol Biol Phys 1994;29:827–34PubMedGoogle Scholar
  24. 24.
    Kong G, Anyarambhatla G, Petros WP, et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release. Cancer Res 2000;60:6950–7PubMedGoogle Scholar
  25. 25.
    Glehen O, Cotte E, Schreiber V, et al. Intraperitoneal chemohyperthermia and attempted cytoreductive surgery in patients with peritoneal carcinomatosis of colorectal origin. Brit J Surg 2004;91:747–54PubMedCrossRefGoogle Scholar
  26. 26.
    Jacquet P, Stephens AD, Averbach AM, et al. Analysis of morbidity and mortality in 60 patients with peritoneal carcinomatosis treated by cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy. Cancer 1996;77:2622–9PubMedCrossRefGoogle Scholar
  27. 27.
    Lyass O, Uziely B, Ben-Yosef R, et al. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 2000;89:1037–47PubMedCrossRefGoogle Scholar
  28. 28.
    Uziely B, Jeffers S, Isacson R, et al. Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995;13:1777–85PubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2007

Authors and Affiliations

  • Lawrence E. Harrison
    • 1
  • Margarette Bryan
    • 2
  • Lilian Pliner
    • 2
  • Tracie Saunders
    • 2
  1. 1.Division of Surgical OncologyUMDNJ—New Jersey Medical SchoolNewarkUSA
  2. 2.Medical OncologyUMDNJ—New Jersey Medical SchoolNewarkUSA

Personalised recommendations