Is CEM43 still a relevant thermal dose parameter for hyperthermia treatment monitoring?

CEM43 has its roots in the direct cytotoxic effect of heat, whereby the amount of cell death depends on the temperature and exposure time. CEM43 is a normalising method to convert the various time-temperature exposures applied into an equivalent exposure time expressed as minutes at the reference temperature of 43 °C. The CEM43 concept also holds a number of weaknesses, however. When used to predict treatment efficacy of combined radiotherapy plus hyperthermia, CEM43 does not include the effect of sensitisation by enhanced oxygenation, variation in interval time and the effect of multiple fractions. Further, it does not include the effect of increased perfusion at the lower thermal dose - and the occurrence of stasis at the higher thermal dose. Overall, studies towards a thermal dose-effect relationship in radiotherapy plus hyperthermia present a diffuse message without a definitive conclusion. However, prospective studies and studies with large patient numbers did report significant thermal dose-effect relationships and provide a good reason to continue research in the CEM43 model. Such research would be best performed in homogeneous patient groups with a single pathology and a low variation in tumour size and heterogeneity. Further, high quality thermometry, strict treatment schedules with fixed intervals and preferably homogenous heating are important requirements to enhance the probability of detecting a thermal dose-effect relationship. The slowly growing availability of hybrid MR hyperthermia systems should be a strong stimulus to expand these studies with the inclusion of measuring thermal dose-dependent blood flow and oxygen changes in the tumour and normal tissues.