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Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface malignancies with application of cytostatic drugs such as oxaliplatin (OX) after cytoreductive surgery. Despite its increased use, evidence for optimal drug dosage, and notably duration of HIPEC, is scarce.

Methods

In this study, OX distribution was comprehensively assessed in nine patients during HIPEC (300 mg OX/m2 body surface area in Physioneal solution for 30 min). Oxaliplatin and its derivatives were measured in peritoneal perfusates over time by liquid chromatography coupled with mass spectrometry (LC-MS), and the resulting total platinum concentration in tissue was analyzed by atomic absorption spectrometry. Additionally, a novel impedance-based real-time cytotoxicity assay was used to evaluate the bioactivity of perfusates ex vivo.

Results

Compared with amounts of OX expected in peritoneal perfusates by calculation, only 10–15% of the parent drug could be detected by LC-MS during HIPEC. Notably, the study additionally detected platinum compounds consistent with OX transformation, accounting for a further fraction of the applied drug. The cytotoxic properties of perfusates remained unchanged during HIPEC, with only a slight but significant attenuation evidenced after 30 min.

Conclusions

The bioactivity of peritoneal perfusates ex vivo is a useful parameter for evaluating the actual cytotoxic potential of OX and its derivatives used in HIPEC over time, overcoming important limitations and disadvantages associated with respective drug monitoring only. Ex vivo cytotoxicity assays may be a promising tool to aid guiding future standardization and harmonization of HIPEC protocols based on drug-mediated effects.

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References

  1. Lambert LA. Looking up: recent advances in understanding and treating peritoneal carcinomatosis. CA Cancer J Clin. 2015;65:283–98.

    Article  Google Scholar 

  2. Chua TC, Moran BJ, Sugarbaker PH, et al. Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol. 2012;30:2449–56.

    Article  PubMed  Google Scholar 

  3. 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;21:3737–43.

    Article  PubMed  Google Scholar 

  4. Chua TC, Yan TD, Morris DL. Outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma: the Australian experience. J Surg Oncol. 2009;99:109–13.

    Article  PubMed  Google Scholar 

  5. Elias D, Bedard V, Bouzid T, et al. Malignant peritoneal mesothelioma: treatment with maximal cytoreductive surgery plus intraperitoneal chemotherapy. Gastroenterol Clin Biol. 2007;31:784–8.

    Article  PubMed  Google Scholar 

  6. Helm JH, Miura JT, Glenn JA, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis. Ann Surg Oncol. 2015;22:1686–93.

    Article  PubMed  Google Scholar 

  7. Magge D, Zenati MS, Austin F, et al. Malignant peritoneal mesothelioma: prognostic factors and oncologic outcome analysis. Ann Surg Oncol. 2014;21:1159–65.

    Article  PubMed  Google Scholar 

  8. Carteni G, Manegold C, Garcia GM, et al. Malignant peritoneal mesothelioma: results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. Lung Cancer. 2009;64:211–8.

    Article  CAS  PubMed  Google Scholar 

  9. Simon GR, Verschraegen CF, Janne PA, et al. Pemetrexed plus gemcitabine as first-line chemotherapy for patients with peritoneal mesothelioma: final report of a phase II trial. J Clin Oncol. 2008;26:3567–72.

    Article  CAS  PubMed  Google Scholar 

  10. Spratt JS, Adcock RA, Muskovin M, Sherrill W, McKeown J. Clinical delivery system for intraperitoneal hyperthermic chemotherapy. Cancer Res. 1980;40:256–60.

    CAS  PubMed  Google Scholar 

  11. Goodman MD, McPartland S, Detelich D, Saif MW. Chemotherapy for intraperitoneal use: a review of hyperthermic intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. J Gastrointest Oncol. 2016;7:45–57.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Elias D, Bonnay M, Puizillou JM, et al. Heated intraoperative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution. Ann Oncol. 2002;13:267–72.

    Article  CAS  PubMed  Google Scholar 

  13. Extra JM, Espie M, Calvo F, Ferme C, Mignot L, Marty M. Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol. 1990;25:299–303.

    Article  CAS  PubMed  Google Scholar 

  14. Diaz-Rubio E, Sastre J, Zaniboni A, et al. Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: a phase II multicentric study. Ann Oncol. 1998;9:105–8.

    Article  CAS  PubMed  Google Scholar 

  15. Alcindor T, Beauger N. Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol. 2011;18:18–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Raymond E, Faivre S, Chaney S, Woynarowski J, Cvitkovic E. Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther. 2002;1:227–35.

    CAS  PubMed  Google Scholar 

  17. Tesniere A, Schlemmer F, Boige V, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29:482–91.

    Article  CAS  PubMed  Google Scholar 

  18. Hills CA, Kelland LR, Abel G, Siracky J, Wilson AP, Harrap KR. Biological properties of ten human ovarian carcinoma cell lines: calibration in vitro against four platinum complexes. Br J Cancer. 1989;59:527–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Roberts D, Schick J, Conway S, et al. Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells. Br J Cancer. 2005;92:1149–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hill SM, Rodgers CS, Hulten MA, Wilson AP. Cytogenetics of a cell line derived from an ovarian papillary serous cystadenocarcinoma. Cancer Genet Cytogenet. 1984;12:321–7.

    Article  CAS  PubMed  Google Scholar 

  21. Peper JK, Schuster H, Löffler MW, Schmid-Horch B, Rammensee HG, Stevanovic S. An impedance-based cytotoxicity assay for real-time and label-free assessment of T-cell-mediated killing of adherent cells. J Immunol Methods. 2014;405:192–8.

    Article  CAS  PubMed  Google Scholar 

  22. Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M, Gamelin E. Clinical pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res. 2000;6:1205–18.

    CAS  PubMed  Google Scholar 

  23. Ehrsson H, Wallin I, Yachnin J. Pharmacokinetics of oxaliplatin in humans. Med Oncol. 2002;19:261–5.

    Article  CAS  PubMed  Google Scholar 

  24. Ceelen WP, Pahlman L, Mahteme H. Pharmacodynamic aspects of intraperitoneal cytotoxic therapy. Cancer Treat Res. 2007;134:195–214.

    CAS  PubMed  Google Scholar 

  25. Thomas F, Ferron G, Gesson-Paute A, Hristova M, Lochon I, Chatelut E. Increased tissue diffusion of oxaliplatin during laparoscopically assisted versus open heated intraoperative intraperitoneal chemotherapy (HIPEC). Ann Surg Oncol. 2008;15:3623–4.

    Article  PubMed  Google Scholar 

  26. Carlier C, Laforce B, Van Malderen SJ, et al. Nanoscopic tumor tissue distribution of platinum after intraperitoneal administration in a xenograft model of ovarian cancer. J Pharm Biomed Anal. 2016;131:256–62.

    Article  CAS  PubMed  Google Scholar 

  27. Ried M, Lehle K, Neu R, et al. Assessment of cisplatin concentration and depth of penetration in human lung tissue after hyperthermic exposure. Eur J Cardiothorac Surg. 2015;47:563–6.

    Article  PubMed  Google Scholar 

  28. Facy O, Al Samman S, Magnin G, et al. High pressure enhances the effect of hyperthermia in intraperitoneal chemotherapy with oxaliplatin: an experimental study. Ann Surg. 2012;256:1084–8.

    Article  PubMed  Google Scholar 

  29. Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag. 2005;1:249–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mahteme H, Wallin I, Glimelius B, Pahlman L, Ehrsson H. Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion. Eur J Clin Pharmacol. 2008;64:907–11.

    Article  CAS  PubMed  Google Scholar 

  31. Mehta AM, Van den Hoven JM, Rosing H, et al. Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy. Int J Pharm. 2015;479:23–7.

    Article  CAS  PubMed  Google Scholar 

  32. Jerremalm E, Hedeland M, Wallin I, Bondesson U, Ehrsson H. Oxaliplatin degradation in the presence of chloride: identification and cytotoxicity of the monochloro monooxalato complex. Pharm Res. 2004;21:891–4.

    Article  CAS  PubMed  Google Scholar 

  33. Mehta AM, Huitema AD, Burger JW, Brandt-Kerkhof AR, van den Heuvel SF, Verwaal VJ. Standard clinical protocol for bidirectional hyperthermic intraperitoneal chemotherapy (HIPEC): systemic leucovorin, 5-fluorouracil, and heated intraperitoneal oxaliplatin in a chloride-containing carrier solution. Ann. Surg. Oncol. 2016. Doi:10.1245/s10434-016-5665-6

    Google Scholar 

  34. Dubois D, Dubois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916;17:863–71.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the German Research Foundation - DFG (CRC 685 “Immunotherapy” project C09 to Alfred Königsrainer, and Stefan Löb, and by a research grant from RanD S.r.l, to Markus W. Löffler, and Alfred Königsrainer. We thank Miriam Petersen and Heinz Bussemas (Labmed Dortmund, Dr. Eberhard & Partner, Dortmund, Germany) for expert analysis of samples by AAS and helpful collaboration. We also thank Anita Hack for productive discussions and expert advice as well as RanD S.r.l for financial support. Ultimately, we express our gratitude to the patients who participated in this study, without whom this project would not have been possible.

Disclosure

Markus W. Löffler and Alfred Königsrainer received grant support by RanD S.r.l for this work, a manufacturer of devices and consumables for HIPEC. The other authors declare no conflicts of interest.

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Correspondence to Markus W. Löffler MD.

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Löffler, M.W., Schuster, H., Zeck, A. et al. Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols. Ann Surg Oncol 24, 1650–1657 (2017). https://doi.org/10.1245/s10434-017-5790-x

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