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A Temperature of 40 °C Appears to be a Critical Threshold for Potentiating Cytotoxic Chemotherapy In Vitro and in Peritoneal Carcinomatosis Patients Undergoing HIPEC

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

Abstract

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) following cytoreductive surgery is a radical but effective treatment option for patients with peritoneal carcinomatosis (PC). Unfortunately, a standardized HIPEC protocol is missing impeding systematic comparisons with regard to minimal effective temperatures.

Objective

The purpose of the present study was to systematically analyse the precise minimal temperature needed for potentiation of chemotherapy effects in vitro and for patient survival.

Methods

We established a cell line-based model to mimic HIPEC conditions used in clinical practice, and evaluated intracellular drug concentrations and long-term survival using different temperatures ranging from 38 to 42 °C combined with cisplatin or doxorubicin. In parallel, we evaluated the temperature reached in the clinical setting by measuring inflow and outflow, as well as in two locations in the peritoneal cavity in 34 patients. Finally, we determined the influence of different HIPEC temperatures on survival.

Results

Long-term survival of cells treated with either cisplatin or doxorubicin was further improved only at temperatures above 40 °C. In patients, during HIPEC, constant temperatures were reached after 10 min in the peritoneal cavity. A temperature above 40 °C for at least 40 min was achieved in 68 % of patients over the 60 min duration of HIPEC. Importantly, we observed a significantly enhanced overall survival (OS) and progression-free survival (PFS) in those patients reaching temperatures above 40 °C.

Conclusions

Hyperthermia significantly potentiated the chemotherapy effects only at temperatures above 40 °C in vitro. Importantly, this temperature threshold was also critical for OS and PFS of PC patients.

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Acknowledgment

This study was supported by Grants from the Robert Bosch Foundation, Stuttgart, Germany.

Disclosure

The authors have no financial interest to disclose.

Author information

Authors and Affiliations

  1. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany

    Lea Schaaf Msc, Heiko van der Kuip PhD, Stefan Winter PhD & Thomas E. Mürdter PhD

  2. Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany

    Waltraud Zopf MD, Marina Münch MD, Klaus-Peter Thon MD, Wolfgang Steurer MD & Christoph Ulmer MD

  3. Department of Oncology, Robert Bosch Hospital, Stuttgart, Germany

    Walter E. Aulitzky MD

Authors
  1. Lea Schaaf Msc
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  2. Heiko van der Kuip PhD
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  3. Waltraud Zopf MD
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  4. Stefan Winter PhD
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Corresponding authors

Correspondence to Lea Schaaf Msc or Christoph Ulmer MD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10434_2015_4853_MOESM1_ESM.tif

Supplementary material 1 (TIFF 6632 kb) Intracellular Doxorubicin concentrations at temperatures below and above 40 °C. Cells were treated for 1 h with 15 µM Doxorubicin at indicated temperatures. Intracellular concentration of Doxorubicin was evaluated by FACS analysis. Values reflect log2 fold changes (treated vs. control) of three independent experiments.

Supplementary material 2 (PDF 16 kb) Patient characteristics and treatment regimens.

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Schaaf, L., van der Kuip, H., Zopf, W. et al. A Temperature of 40 °C Appears to be a Critical Threshold for Potentiating Cytotoxic Chemotherapy In Vitro and in Peritoneal Carcinomatosis Patients Undergoing HIPEC. Ann Surg Oncol 22 (Suppl 3), 758–765 (2015). https://doi.org/10.1245/s10434-015-4853-0

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  • DOI: https://doi.org/10.1245/s10434-015-4853-0

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