Effect of Local Hyperthermia on Blood Flow and Microenvironment: A Review

Abstract The blood flow in tumors varies considerably among different tumor types. Even in the same tumor, the distribution of vasculature and blood flow is quite heterogeneous. The tumor blood flow generally decreases as the tumors grow larger, owing partially to progressive deterioration of vascular beds and to the rapid growth of tumor cell population relative to vascular beds. Contrary to the general notion that blood flow is less in tumors than in normal tissues, blood flow in many tumors, particularly in small tumors, is actually greater than that in surrounding normal tissues at normothermic conditions. Compared to the normal tissue blood flow, however, the capacity of tumor blood flow to increase upon heating appears to be rather limited. Consequently, the heat dissipation by blood flow in tumors is slower than that in normal tissues, and thus the temperature of tumor rises higher than that in normal tissue during heating. Preferential heating of tumors, however, may not be achieved all the time because the relative blood perfusion in some tumors remains greater than that in the surrounding normal tissues despite the profound increase in normal tissue blood flow during heating. The vasculature in tumor can be significantly damaged at temperatures which may alter but do not damage the vasculature of normal tissue. Upon heating, the intratumor environment becomes acidic, hypoxic, and nutritionally deprived due probably to vascular damage. Such a suboptimal environment in the heated tumors potentiates the response of tumor cells to hyperthermia, inhibits the repair of thermal damage, and also interferes with the development of thermal tolerance. The acidic environment also appears to potentiate the response of tumor cells to certain drugs at elevated temperatures. The changes in oxygenation of tumors and normal tissues caused by the changes in blood flow may have significant implications in the effectiveness of different sequences of hyperthermia and radiotherapy in the combined use of these two modalities. Changes in the distribution of drugs in tumors and normal tissues due to changes in blood flow will also determine the optimal use of hyperthermia in conjunction with chemotherapy.