Study of the Pharmacokinetics of Mitomycin C in Humans during Intraperitoneal Chemohyperthermia with Special Mention of the Concentration in Local Tissues

Abstract

The aim of this work is to estimate the 24-hour distribution and elimination of mitomycin C (MMC) during and after intraperitoneal chemohyperthermia (IPCH) in 18 patients (13 gastric adenocarcinoma, 3 pancreatic adenocarcinoma, 2 malignant mesothelioma) who received 60 mg MMC during 90-120 min in 6 liters of heating solution HS; (42 °C) or HS flowing at 0.4 liters/ min in a closed circuit. MMC assay in the serum, urine, HS and in local biopsies were performed by high performance liquid chromatography. The amount of MMC in HS decreased by 54.1 ± 13.6% during IPCH. The maximum MMC levels in serum reached 0.4 ± 0.18 mg/l 45 min after the start of IPCH, then rapidly decreased. Only 1.77 ± 0.93 mg were recovered in urine in 24 h. These data are consistent with a large and rapid absorption, mostly in local tissue, demonstrated by the level in 7 post-IPCH biopsies (8.3 ± 7.6 mg/kg).

Heated Intraoperative Intraperitoneal Mitomycin C and Early Postoperative Intraperitoneal 5-Fluorouracil: Pharmacokinetic Studies

“…Despite this important uptake, only low levels were observed simultaneously in the serum. These data, which are similar to those observed previously for both hyperthermic [23][24][25][26][27] and normothermic intraperitoneal MMC, [1,28] demonstrated a clear pharmacologic advantage for heated intraoperative intraperitoneal chemotherapy.…”

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

“…While for many drugs it is difficult to accurately determine tumour tissue concentration and penetration depth after intraperitoneal administration, the penetration depth of some drugs is estimated to be 2-5 mm at maximum, although for other drugs it may be a few cellular layers only [10][11][12][13][14][15][16]. This underlines the need for optimal cytoreductive surgery to precede intraperitoneal chemotherapy.…”

“…Moreover, experimental data indicate that hyperthermia may enhance the penetration depth of intraperitoneally delivered chemotherapeutic drugs into tissues and tumour nodules, without changing the pharmacokinetic profile. The thermal enhancement of the drugs' activity and penetration depth is often already observed at temperatures above 39-40°C [14,54,[61][62][63]. Regardless of these theoretical advantages, to our knowledge, there is no high-level evidence (i. e. a comparative clinical study) that HIPEC is superior to normothermic intraperitoneal chemotherapy.…”

Hyperthermic intraperitoneal chemotherapy: Rationale and technique

“…Additional factors include increased drug penetration in tissue, temperature dependent increases in drug action and inhibition of repair mechanisms. In many cases, this enhancement of activity and penetration depth of drugs is already seen above 3940℃ [16,20,23,24] . The synergism of heat and drugs has been well docu mented, especially for selected chemotherapeutic agents used during HIPEC.…”