Hyperthermia, Tissue Microcirculation, and Temporarily Increased Thermosensitivity in VX2 Carcinoma in Rabbit Liver

The role of microcirculatory factors within and around liver tumors after heat treatment was investigated in a rabbit model of liver cancer (VX2 carcinoma). As a physiological factor of the microenvironment, regional blood flow (RBF) was measured by the hydrogen clearance method, and a histopathological study was done. Local hyperthermia was administered directly to the liver tumor via a 915-MHz microwave. Hyperthermia produced a temporary reduction of RBF in both the tumor and the surrounding normal liver tissues, and the histopathology revealed congestion, petechiae, and thrombosis. After hyperthermia at 43.0°C for 20 min, RBF in the tumor rapidly decreased to a minimum of 40% of the control level during 0–12 h after the treatment and increased gradually to the pretreatment level at 2 days. RBF in the normal liver also decreased rapidly after hyperthermia, to a minimum of 30% of the pretreatment level, 1–12 h after treatment. In the case of treatment at 42.5°C for 20 min, RBF in the tumor also rapidly decreased to a minimum of 40% of the control level, at 4 h after the treatment, and recovery was within 2 days. However, RBF in the surrounding normal liver decreased to 80% of the control level, at 2 h after the treatment, and then increased more rapidly to reach levels seen in the controls. Thus, the latter condition of heat treatment was considered to be favorable for therapeutic gain. Based on the results of these sequential microcirculatory changes, the effects of continuous and intermittent hyperthermia were studied in groups given various treatments. In a group treated with intermittent hyperthermia at 4-h intervals, the antitumor effects determined by tumor growth retardation were significantly greater, as compared with findings in the group given treatment without an interval and that given at a 24-h interval (P < 0.001). In the tumor at 4 h after hyperthermia, the increased thermosensitivity was considered to surpass the developing thermotolerance. Thus, the antitumor effect of hyperthermia in vivo greatly depends on the microcirculation. The most efficacious mode for application of hyperthermia must be vigorously examined if a clinical relevance is to be gained.