A Temperature of 40 °C Appears to be a Critical Threshold for Potentiating Cytotoxic Chemotherapy In Vitro and in Peritoneal Carcinomatosis Patients Undergoing HIPEC.
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.
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. lea.schaaf@ikp-stuttgart.de.
Lea
L
Schaaf
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
Heiko
H
van der Kuip
Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany.
Waltraud
W
Zopf
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
Stefan
S
Winter
Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany.
Marina
M
Münch
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
Thomas E
TE
Mürdter
Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany.
Klaus-Peter
KP
Thon
Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany.
Wolfgang
W
Steurer
Department of Oncology, Robert Bosch Hospital, Stuttgart, Germany.
Walter E
WE
Aulitzky
Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany. christoph.ulmer@rbk.de.
Christoph
C
Ulmer
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000556:secondary* / Q000628:therapy; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D010478:Chemotherapy, Cancer, Regional Perfusion; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D004317:Doxorubicin / Q000008:administration & dosage; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D006979:Hyperthermia, Induced; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D009367:Neoplasm Staging; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy; D010534:Peritoneal Neoplasms / Q000556:secondary* / Q000628:therapy; D011379:Prognosis; D012189:Retrospective Studies; D013696:Temperature; D014407:Tumor Cells, Cultured
D004317:Doxorubicin; D002945:Cisplatin