Cancer Chemotherapy and Pharmacology

, Volume 63, Issue 5, pp 799–805 | Cite as

A pharmacologic analysis of intraoperative intracavitary cancer chemotherapy with doxorubicin

  • Kurt Van der Speeten
  • O. A. Stuart
  • H. Mahteme
  • P. H. Sugarbaker
Original Article

Abstract

Purpose

A pharmacologic analysis of intracavitary doxorubicin in the treatment of patients with intracavitary cancer dissemination was performed to further evaluate the possible benefits of this treatment modality.

Methods

Twenty appendiceal malignancy patients with peritoneal carcinomatosis (PC), three appendiceal malignancy patients with direct extension into the pleural cavity, 20 patients with peritoneal mesothelioma and one patient with pleural mesothelioma were available for pharmacologic monitoring. After intraperitoneal or intrapleural administration of doxorubicin, plasma and peritoneal fluid samples were obtained at 15, 30, 45, 60 and 90 min in all patients. After intrapleural administration, plasma and pleural fluid samples were collected at similar intervals. Tumor and normal tissues were obtained when available. Doxorubicin concentrations were determined by high-performance liquid chromatography (HPLC).

Results

Intraperitoneal doxorubicin showed a prolonged retention in the peritoneal cavity. Doxorubicin concentrations in tumor tissue were consistently elevated above intraperitoneal concentrations from 30 through 90 min. For appendiceal malignancy, the concentrations of doxorubicin were significantly higher in minimally aggressive mucinous tumors. Pleural chemotherapy solutions retained doxorubicin to a greater extent than peritoneal fluid.

Conclusions

Doxorubicin shows characteristics favorable for intracavitary administration with sequestration of doxorubicin in cancer nodules.

Keywords

Intraperitoneal chemotherapy Intrapleural chemotherapy Doxorubicin Pharmacokinetics Pharmacodynamics Appendiceal cancer Peritoneal mesothelioma Pleural mesothelioma 

Notes

Conflict of Interest

None.

References

  1. 1.
    Zoetmulder FA (1982) Modelstudies over het colorectale carcinoom. Amsterdam, RodopiGoogle Scholar
  2. 2.
    Sugarbaker PH, Cunliffe WJ, Belliveau J et al (1989) Rationale for integrating early postoperative intraperitoneal chemotherapy into the surgical treatment of gastrointestinal cancer. Semin Oncol 16(4):83–97PubMedGoogle Scholar
  3. 3.
    Weiss L (1990) Metastatic inefficiency. Adv Cancer Res 54:159–211PubMedCrossRefGoogle Scholar
  4. 4.
    Sugarbaker PH (2003) Peritonectomy procedures. Surg Oncol Clin N Am 12(3):703–727PubMedCrossRefGoogle Scholar
  5. 5.
    Alberts DS, Liu PY, Hannigan EV et al (1996) Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335(6):1950–1955PubMedCrossRefGoogle Scholar
  6. 6.
    Markman M, Bundy BN, Alberts DS et al (2001) Phase III trial 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 Oncology Group. J Clin Oncol 19(4):1001–1007PubMedGoogle Scholar
  7. 7.
    Armstrong DK, Bundy B, Wenzel L et al (2006) Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354(1):34–43PubMedCrossRefGoogle Scholar
  8. 8.
    Verwaal VJ, Van Ruth S, De Bree E et al (2003) 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 21(20):3737–3743PubMedCrossRefGoogle Scholar
  9. 9.
    Sugarbaker PH (2005) An instrument to provide containment of intraoperative intraperitoneal chemotherapy with optimized distribution. J Surg Oncol 92(2):142–146PubMedCrossRefGoogle Scholar
  10. 10.
    Cummings J, Stuart JFB, Calman KC (1984) Determination of adriamycin, adriamycinol and their 7-deoxyaclycones in human serum by high-performance liquid chromatography. J Chromatogr 311:125–133PubMedCrossRefGoogle Scholar
  11. 11.
    Ronnett BM, Zahn CM, Kurman RJ et al (1995) Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis: a clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 19(12):1390–1408PubMedCrossRefGoogle Scholar
  12. 12.
    Cerruto CA, Brun EA, Chang D, Sugarbaker PH (2006) Prognostic significance of histomorphologic parameters in diffuse malignant peritoneal mesothelioma. Arch Pathol Lab Med 130(11):1654–1661PubMedGoogle Scholar
  13. 13.
    Tritton TR (1991) Cell surface actions of adriamycin. Pharmacol Ther 49:293–309PubMedCrossRefGoogle Scholar
  14. 14.
    Hahn GM, Braun J, Har-Kedar I (1975) Thermochemotherapy: synergism between hyperthermia (42–43°) and adriamycin (or bleomycin) in mammalian cell inactivation. Proc Nat Acad Sci 72(3):937–940PubMedCrossRefGoogle Scholar
  15. 15.
    Lane P, Vichi P, Bain DL et al (1987) Temperature dependence studies of adriamycin uptake and cytotoxocity. Cancer Res 42:4038–4042Google Scholar
  16. 16.
    Carter SK (1981) Adriamycin—a review. J Natl Cancer Inst 55:1265–1274Google Scholar
  17. 17.
    Johansen PB (1981) Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse. Cancer Chemother Pharmacol 5:267–270PubMedCrossRefGoogle Scholar
  18. 18.
    Ozols RF, Young RC, Speyer JL et al (1982) Phase I and pharmacological studies of adriamycin administered intraperitoneally to patients with ovarian cancer. Cancer Res 42:4265–4269PubMedGoogle Scholar
  19. 19.
    Ozols RF, Grotzinger KR, Fisher RI et al (1979) Kinetic characterization and response to chemotherapy in a transplantable murine ovarian cancer. Cancer Res 39:3202–3208PubMedGoogle Scholar
  20. 20.
    Ozols RF, Locker GY, Doroshow JH et al (1979) Pharmacokinetics and tissue penetration in murine ovarian cancer. Cancer Res 39:3209–3214PubMedGoogle Scholar
  21. 21.
    Ozols RF, Willson JKV, Weltz MD et al (1980) Inhibition of human ovarian cancer colony formation by adriamycin and its major metabolites. Cancer Res 40:4109–4112PubMedGoogle Scholar
  22. 22.
    Sugarbaker PH, Mora JT, Carmignani P, Stuart OA, Yoo D (2005) Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist 10(2):112–122PubMedCrossRefGoogle Scholar
  23. 23.
    Roboz J, Jacobs AJ, Holland JF et al (1981) Intraperitoneal infusion of doxorubicin in the treatment of gynecologic carcinomas. Med Pediatr Oncol 9:245–250PubMedCrossRefGoogle Scholar
  24. 24.
    Yan TD, Welch L, Black D et al (2007) A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. Ann Oncol 18(5):827–834PubMedCrossRefGoogle Scholar
  25. 25.
    Raspagliesi F, Kusamura S, Campos Torres JC et al (2006) 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 32(6):671–675PubMedCrossRefGoogle Scholar
  26. 26.
    Yan TD, Black D, Savady R et al (2007) A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Ann Surg Oncol 14(2):484–492PubMedCrossRefGoogle Scholar
  27. 27.
    Stelin G, Rippe B (1990) A phenomenological interpretation of the variation in dialysate volume with dwell time in CAPD. Kidney Int 38(3):465–472PubMedCrossRefGoogle Scholar
  28. 28.
    Ceelen WP, Påhlman L, Mahteme H (2006) Pharmacodynamic aspects of intraperitoneal cytotoxic therapy. In Peritoneal carcinomatosis: a multidisciplinary approach. Cancer Treat Res, Springer, 195–214Google Scholar
  29. 29.
    Dedrick RL, Flessner MF (1997) Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure. J Natl Cancer Inst 89(7):480–487PubMedCrossRefGoogle Scholar
  30. 30.
    Sugarbaker PH, Stuart OA (2007) Pharmacokinetic and phase II study of heated intraoperative intraperitoneal melphalan. Cancer Chemother Pharmacol 59(2):151–155PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Kurt Van der Speeten
    • 1
  • O. A. Stuart
    • 2
  • H. Mahteme
    • 3
  • P. H. Sugarbaker
    • 2
  1. 1.Department of Surgical OncologyZiekenhuis Oost-LimburgGenkBelgium
  2. 2.Washington Cancer Institute, Washington Hospital CenterWashington, DCUSA
  3. 3.Department of Surgical Sciences, Section of SurgeryAkademiska Sjukhuset, Uppsala University HospitalUppsalaSweden

Personalised recommendations