Accurate Three-Dimensional Thermal Dosimetry and Assessment of Physiologic Response Are Essential for Optimizing Thermoradiotherapy

Abstract

Numerous randomized trials have revealed that hyperthermia (HT) + radiotherapy or chemotherapy improves local tumor control, progression free and overall survival vs. radiotherapy or chemotherapy alone. Despite these successes, however, some individuals fail combination therapy; not every patient will obtain maximal benefit from HT. There are many potential reasons for failure. In this paper, we focus on how HT influences tumor hypoxia, since hypoxia negatively influences radiotherapy and chemotherapy response as well as immune surveillance. Pre-clinically, it is well established that reoxygenation of tumors in response to HT is related to the time and temperature of exposure. In most pre-clinical studies, reoxygenation occurs only during or shortly after a HT treatment. If this were the case clinically, then it would be challenging to take advantage of HT induced reoxygenation. An important question, therefore, is whether HT induced reoxygenation occurs in the clinic that is of radiobiological significance. In this review, we will discuss the influence of thermal history on reoxygenation in both human and canine cancers treated with thermoradiotherapy. Results of several clinical series show that reoxygenation is observed and persists for 24–48 h after HT. Further, reoxygenation is associated with treatment outcome in thermoradiotherapy trials as assessed by: (1) a doubling of pathologic complete response (pCR) in human soft tissue sarcomas, (2) a 14 mmHg increase in pO2 of locally advanced breast cancers achieving a clinical response vs. a 9 mmHg decrease in pO2 of locally advanced breast cancers that did not respond and (3) a significant correlation between extent of reoxygenation (as assessed by pO2 probes and hypoxia marker drug immunohistochemistry) and duration of local tumor control in canine soft tissue sarcomas. The persistence of reoxygenation out to 24–48 h post HT is distinctly different from most reported rodent studies. In these clinical series, comparison of thermal data with physiologic response shows that within the same tumor, temperatures at the higher end of the temperature distribution likely kill cells, resulting in reduced oxygen consumption rate, while lower temperatures in the same tumor improve perfusion. However, reoxygenation does not occur in all subjects, leading to significant uncertainty about the thermal–physiologic relationship. This uncertainty stems from limited knowledge about the spatiotemporal characteristics of temperature and physiologic response. We conclude with recommendations for future research with emphasis on retrieving co-registered thermal and physiologic data before and after HT in order to begin to unravel complex thermophysiologic interactions that appear to occur with thermoradiotherapy.

Biological modeling in thermoradiotherapy: present status and ongoing developments toward routine clinical use

“…In addition, reoxygenation is also caused indirectly by hyperthermia by a reduced oxygen consumption rate due to the killing of (chronic) hypoxic cells at somewhat higher temperatures [35]. The improved tumor oxygenation and decreased IFP may last for at least 24h [30,31,34].…”

“…Several studies suggest that re-oxygenation after hyperthermia, which lasts up to 24-48 h, is not only caused by increased blood flow but also by a decrease in oxygen consumption, possibly due to heat-induced tumor cell death or a heat-induced change in tumor metabolism [30,35,[95][96][97]. These dual effects are likely caused by the generally heterogeneous temperature distributions achieved in clinical hyperthermia.…”

Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation

“…The review by Szasz [5] discusses whether heterogenous heating is beneficial over homogenous heating. On the other hand, the review by Dewhirst et al [6] emphasizes the importance of hyperthermia to improve perfusion and long duration reoxygenation (i.e., 24-48 h post hyperthermia).…”

“…The papers by Schemm et al [1] and Nakahara et al [2] are new support of the existence of a thermal dose effect relationship and is another confirmation for the need to always strive for the highest quality assurance and control for optimal treatment outcome. As reported by various papers improved efficiency can be achieved by innovating the heating and improved patient selection to fit with the correct level (complexity) of technology (Kroesen et al [11], Poni et al [12], Androulakis et al [13]) enhanced understanding of the biological principles, either by experimental or clinical research (Dewhirst et al [6], Sengedorj et al [7]) or through building new more advanced biological models (Scheidegger et al [14]) and supported by adequate computer modelling to predict the temperature distribution in the tissue (Kok et al [15]). At the same time the contribution of Ademaj et al [9] makes it crystal clear that to better understand which mechanisms are dominant to maximize treatment outcome during the clinical application of thermoradiotherapy, we still have a world to gain in accurate and complete documentation of the quality of the thermal therapy delivered to the patient.…”

Avoiding Pitfalls in Thermal Dose Effect Relationship Studies: A Review and Guide Forward

“…Although CEM43 and its variants CEM43Tx account for the dominant biological effect at high temperatures, i.e., cytotoxicity, in most clinical studies, the measured tumour temperatures reported were lower than the intended 43 • C. Since biological mechanisms vary according to the achieved temperatures, at this lower temperature, apart from cytotoxicity, other biological effects, such as perfusion and enhanced oxygenation, are presumably dominant [10,11]. Detailed explanations of the dependence of the biological mechanisms in relation to temperature were reported in [4,5,12].…”