Tumour perfusion and associated physiology: Characterization and significance for hyperthermia

There is a clear association between the vascular and pathophysiological characteristics of solid tumours and hyperthermia. Such an association involves both an effect of the tumour vasculature and pathophysiology on heating and the influence of heat on these tumour characteristics. Of the parameters involved in this interaction it is probably blood flow/perfusion that plays the most critical role. The vascular supply is one of the major vehicles by which heat is dissipated, and as such it will significantly influence the ability to heat tumours. Typically, the lower the blood flow rate the easier it becomes to heat. It is also important in determining the microenvironment that exists within tumours; a poor microvascular blood supply results in the development of large areas that are nutrient deprived, low in oxygen (hypoxic) and highly acidic, and cells exposed to such adverse conditions, especially low pH, are more sensitive to the killing effect of heat. When tumours are heated the tumour pathophysiology and vascularity change, and do so in a temperature-dependent fashion. At mild clinically relevant tumour temperatures blood flow transiently increases. There is also a corresponding improvement in oxyhaemoglobin saturation of the individual red blood cells within tumour microvessels, and these changes combine to increase overall oxygen availability with a subsequent improvement in tumour oxygenation status. With higher tissue temperatures one may see a transient increase in tumour blood flow during the heating period, but vascular damage soon occurs leading to a rapid decrease in flow. There are again corresponding changes in other pathophysiological factors including oxyhaemoglobin saturation, energy status, and pH, which ultimately lead to ischemia and cell death.

Historically there have been a number of reviews dealing with the significance of the tumour vasculature and pathophysiology for hyperthermia 1–4. However, in recent years it has become clear that the issue is far more complex than was earlier thought. In order to expand and update our knowledge it was suggested that a volume of the International Journal of Hyperthermia be dedicated to this aspect. The eight papers included in this special issue under the general title of ‘Tumour perfusion and associated physiology: Characterization and significance for hyperthermia’ were the result.

The first article in this issue is a comprehensive updated overview by Vaupel and Kelleher on how tumour pathophysiology and vasculature are important for hyperthermia. They show that there are controversial experimental and clinical data which substantially deviate with respect to the extent, the time course, and even the direction of changes in pathophysiological parameters upon (mild) hyperthermia. These effects probably reflect the heterogeneity that exists in tumours, making it difficult to actually predict how tumours will respond to heating. Thus, several of the ‘consensus’ opinions regarding the tumour vascular and pathophysiological effects of heat may not be true with heating in the clinical situation, and that this is a critical issue requiring further clarification. One characteristic feature of most solid tumours is hypoxia. Its presence in tumours is known to have a negative impact on local tumour control and overall survival in patients due to a decrease in the efficacy of radiation and chemotherapy, as well as driving malignant progression. The next paper in this issue, by Sun et al., concentrates on the use of mild temperature hyperthermia to increase tumour blood perfusion and thus decrease the level of tumour hypoxia. They summarise the various studies that show these effects and further demonstrate it using results from their own studies with dual marker immunohistochemistry. The kinetics of these mild temperature hyperthermia-induced changes and how this approach can be exploited to enhance radiation and chemotherapy are also discussed. They also briefly review how mild temperature hyperthermia can be further exploited to improve radiation sensitivity by combining it with drugs that induce damage to the tumour vasculature, and which are currently undergoing clinical testing.

Apart from the effect of hypoxia on tumour response to conventional therapies and malignancy, there is now evidence that hypoxia suppresses anti-tumour effector cells and can enhance tumour escape from immune surveillance. This aspect is the basis of the review by Lee et al. These authors further suggest that by using mild temperature hyperthermia to alter tumour vascular perfusion and oxygenation status one should be able to overcome this hypoxia induced resistance to immune-based therapy. The significance of hyperthermia on tumour infiltrating host cells theme is continued in the next paper by Muthana et al. They review the current knowledge relating to the effects of hyperthermia treatment on aspects of the induction and manifestation of immunological responses that are most pertinent to the development and maintenance of protective anti-tumour immunity.

One more paper in this special issue deals specifically with mild temperature hyperthermia. Griffin and colleagues review the physiological changes induced by mild temperature hyperthermia and how that can affect radiation response, but do so from a more clinically relevant aspect in which multiple treatments are given. They suggest that in such treatments, scheduling and frequency become critical issues, with mild temperature heating given every 2–3 days being optimal to maximally enhance radiation response.

The final three papers in this special issue concern the imaging methods that can be used to monitor the tumour vascular and pathophysiological parameters important for hyperthermia. In the first of these, Hokland and co-workers review all the approaches that can and have been used, whether invasive or non-invasive. They conclude that of all the procedures available the non-invasive approaches would certainly seem preferable especially those based on MRI and PET. Both these techniques are already well established clinical procedures used routinely in hospitals. They have also been used to some limited extent in connection with hyperthermia, but the full potential in this context has never been achieved, and additional effort here is clearly required. The paper by Lüdermann and colleagues takes another approach with the MR methods. Here they discuss the potential to exploit various MR parameters to produce temperature maps within tumours. The pros and cons of the different approaches are considered, but the overall conclusion is that MR temperature thermometry is superior to other techniques because it allows for non-invasive mapping of the entire treatment area during heat application, which is definitely what is required clinically. Dewhirst et al., in the final paper, examine the role that functional imaging parameters which reflect the tumour microenvironment may have in predicting outcome and overall survival in patients treated with hyperthermia and conventional therapies. MR, PET and optical methods are discussed and the authors conclude that although all these techniques have the potential to be utilised in this context, optical methods may prove superior because it is easier and cheaper to perform such measurements, especially where multiple observations are required. However, whatever technique is chosen, functional imaging in general has the ability to help identify those patients most likely to benefit from hyperthermia as well as define the optimal hyperthermia treatment.