ABSTRACT: Modern cancer care is characterized by a focus on organ-sparing multi-modal treatments. In the case of non–muscle-invasive bladder cancer this is particularly true; treatment is focused on reducing the frequency of low-risk recurrences and preventing high-risk progression. Deep regional hyperthermia is an oncologic therapeutic modality that can help achieve these two goals. The combination of hyperthermia with chemotherapy and radiotherapy has improved patient outcomes in several tumor types. In this review, we highlight the biology of therapeutic fever-range hyperthermia, discuss how hyperthermia is administered and dosed, demonstrate how heat can be added to other treatment regimens, and summarize the data supporting the role of hyperthermia in the management of bladder cancer.
The recognition of a possible therapeutic benefit of local hyperthermia on the biology of cancer cells dates back for many decades.[1,2] In the time since this discovery, the delivery of hyperthermia has evolved, along with the ability to combine it with other treatment modalities; there has also been continuing elucidation of hyperthermia’s many mechanisms of action. Much of the limitation in the use of therapeutic hyperthermia in the treatment of cancer has been due simply to the inability to effectively deliver locoregional hyperthermia to the target tissue and to monitor temperatures as the treatment is given. The recent development of more sophisticated heat delivery systems and cutting edge thermal dose modeling tools has allowed researchers to better direct the energy required to produce hyperthermia to the sites of desired therapeutic effect. Consequently, phase II and III investigations have been conducted and have demonstrated that hyperthermia can benefit patients with certain types of tumors.
In general, hyperthermia is used as either a radiosensitizer or chemosensitizer and has been part of a combined treatment protocol for tumors in superficial locations (eg, melanoma, head and neck cancer, breast cancer) or in locations where heat monitoring is easier (eg, cervical and rectal cancers, sarcoma).[3] The recognition that urothelial carcinomas demonstrate improved chemosensitivity when heated makes the use of hyperthermia to treat bladder cancer quite appealing.
Effects of Hyperthermia on the Cancer Cell
Mechanisms of Action of Hyperthermia
Hyperthermia-induced Cell Death is Time and Temperature Dependent
The effect of hyperthermia on tumor cells is known to be multifactorial in nature (Table 1). Direct cell kill can occur with temperatures above 40.5°C, but this represents only a part of the benefit. Hyperthermia also cooperates with the myriad cellular, molecular, and metabolic derangements that occur just outside the direct heat kill zone to promote tumor necrosis and apoptosis. Supplemented by multimodal therapies such as chemotherapy or radiotherapy, a synergistic relationship, termed thermosensitization, can be created.
There are two phases of direct cytotoxicty associated with heat exposure.[4] The first phase is one of linear metabolic arrest that represents a period of reversible injury. The second phase is irreversible cytotoxicity and is easier to achieve with increasing temperatures; this more pronounced cytotoxicity is also related to the duration of exposure (Figure). There is a clear dose-response relationship between temperature and cell death, and the transition from the linear to the exponential phase of cytotoxicity occurs more easily at temperatures above 43°C. Although the requisite thermal dose for exponential cell death varies among tumor types, the experimental threshold required for protein denaturation and cell membrane disruption occurs at a dose of 140 kcal/mol.[5,6]
Supplementing this direct cytotoxicity is the observation that nuclear fragility is greatest during the S and M phases of cell life. The G1 and G2 phases are more resistant to cell death, a phenomenon that is thought to be due in part to the expression of adaptive heat-shock proteins.[7] The disruption of cellular transmembrane proteins involved in homeostatic ionic transport combines with architectural damage to ultimately yield cellular blebbing, which is characteristic of apoptosis. In addition, RNA synthesis and DNA synthesis are diminished at temperatures above 42°C. Although RNA synthesis recovers quickly after termination of heat exposure, DNA synthesis remains inhibited for a longer period due to the heat-induced unfolding of hydrophobic segments of protein, rendering them insoluble.[4]
Hyperthermia also has numerous effects on the vascular supply to the tumor. Acidosis leading to intravascular thrombosis, direct corpuscular injury, and the differential response of tumor endothelium are thought to be possible mechanisms of heat-related vascular injury.[8] Postulating that normal cells retain a superior ability to thermoregulate, Manfred von Ardenne proposed that whole-body hyperthermia (WBH) would create a peripheral hyperemia that, when combined with peripheral vasodilatory agents, could create an adjacent tissue vascular steal effect that would result in normal tissues outcompeting tumoral tissues for blood flow, resulting in intratumoral lactic acidosis and enhanced cytotoxicity.[9]
While the study of the tumor microenvironment demonstrates multifactorial vascular injury at temperatures above 43°C, maintaining such temperatures in vivo has proven much more difficult. Several other physiologic processes that are activated at sub-lethal temperatures have subsequently been uncovered; these help explain the clinical benefits of hyperthermia that are observed in the sublethal 41°-43°C range. One of these possible explanations is that the effects of heat can accumulate (ie, a cumulative thermal isoeffect dose effect) and induce cellular mechanisms of cell cycle arrest and apoptosis. Additionally, moderate hyperthermia actually increases tumor blood flow, thereby rendering the cells more susceptible to chemotherapy or radiation therapy.[10]
One mechanism by which the cell attempts to protect itself is thought to be the heat-induced expression of heat shock proteins (HSPs). These are a heterogeneous group of proteins that range in size from 40 to 100 kDa and that are expressed quickly through activation of response elements triggered by heat and other cellular stressors. HSPs are molecular chaperones, whose key duties are to protect cellular proteins from harm, to assist in their proper folding, and to shuttle them to appropriate locations in the cell (such as to sites of degradation). They do this by indiscriminately binding to hydrophobic segments of protein exposed as a result of denaturation; this prevents irreversible interactions between denatured proteins from occurring. HSPs thus protect the cell from heat and contribute to thermotolerance. Although HSP synthesis is induced by moderate degrees of hyperthermia, the production of HSPs is inhibited at higher temperatures; the exact temperature at which inhibition occurs is dependent on the cell type.[11]
