In the last decade, angiogenesis and anti-angiogenic therapies have gained a lot of interest for the treatment of patients with advanced colorectal cancer. Since the introduction of bevacizumab and, more recently, of aflibercept, overall survival of this patient setting has improved.
Many experimental data have shown that anti-neoangiogenic compounds act on arterial vessels, reducing tumor blood flow and normalizing vessel structure, thus inhibiting tumor growth and progression. These findings need dynamic observations, that can be easily obtained from experimental models, but are very difficult to achieve from humans. Dynamic Contrast Enhanced Magnetic Resonance is an easy-to-perform technique which can be helpful in this sense, especially when exploring liver blood flow. Dynamic parameters can be obtained from a continuous image acquisition, in a breath-free condition. This condition, however, does not allow a morphological evaluation of hepatic metastases. Thus, in clinical practice, patients should undergo an experimental dynamic NMR in addition to the standard CT scan that provides the morphological description of lesions. We then tried to identify an alternative technique suitable for every institution. We demonstrated that our method allows to obtain morphological and dynamic information, and thus could be applied in future studies.
The majority of clinical researches studied the variation of liver blood flow before and after the administration of an antiangiogenic compound, often combined with chemotherapy; the reduction of liver flow was interpreted by the authors as the activity of the antiangiogenic drug. Interestingly, our study shows that liver perfusion is reduced in patients responding to chemotherapy alone, raising some doubts on the interpretation of the previously mentioned studies. This is not surprising as chemotherapy itself has demonstrated to have an antiangiogenic effect, especially when administered with a metronomic schedule.
Furthermore, whilst neo-angiogenesis is supposed to be active only in tumor tissue or in its neighborhood, where new vessels are needed to supply cancer cells, no neo-angiogenic activity is expected in healthy tissue. It was then unexpected the reduction that we observed in total perfusion of healthy liver in those patients responding to chemotherapy. While variation in perfusion can be easily explained by a reduction of neo-angiogenesis in tumor areas of the liver, this mechanism hardly explains the reduction of perfusion in areas where there is no new vessels formation. The unique explanation is an indirect control of blood flow even in healthy liver by tumor cells. This could be possible as liver blood flow is controlled by very complex, and not completely elucidated, mechanisms that are independent from extrinsic innervation or vasoactive agents. This further complicates the interpretation of those studies trying to explore the effect of anti-neoangiogenic compounds on liver blood flow.
Even though the primary end-point of our study was not reached, we believe that it brings to attention some aspects that have never been described before, and that must be taken into account when projecting new researches on liver blood flow.
Written by: Marco Tampellini and Chiara Baratelli
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