In the present study bevacizumab was associated with significantly reduced tumour blood flow 1–2 days after chemotherapy. Notably however, follow-up investigation revealed that this effect was associated with rapid tumour regrowth. Patients with only a slight change in blood flow tended to exhibit longer PFS. 15O-water PET was an optimal and non-invasive method for assessing treatment responses to chemotherapy regimens including bevacizumab in patients with NSCLC. The vascular normalization theory proposed by Jain [8] may explain this phenomenon. Unlike physiological angiogenesis processes such as wound healing, tumour angiogenesis continues abnormally while the tumour is growing because the tumour requires a vascular supply to provide essential nutrients and oxygen. Tumour vessels are often tortuous, disorganized and highly permeable, resulting in high interstitial pressure and reduced blood perfusion and oxygenation. Tumour cells can adapt to insufficient blood supply and hypoxia, but drug delivery is inhibited and its efficacy is reduced. Excessive antiangiogenic therapy may lead to reduced tumour blood flow and result in hypoxia and acidosis, which promote tumour progression [9]. Moderate anti-VEGF therapy may lead to ‘vascular normalization’, which is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumour hypoxia and interstitial fluid pressure. As a result drug delivery of cytotoxic anticancer agents is improved, and consequently chemotherapy in combination with anti-VEGF drugs improves survival.
In the current study a decline in tumour blood flow after bevacizumab administration was observed in all patients, but patients with greater reductions in tumour blood flow exhibited tumour regrowth within shorter periods. It may be that greater reduction of tumour perfusion reflects greater pruning of vessels, which leads to hypoxia and acidosis in the tumour. Heist et al. [10] reported that reduced blood perfusion after bevacizumab administration as determined via CT was associated with shorter overall survival in NSCLC patients, which is consistent with the results of the present study. They assessed tumour perfusion before bevacizumab administration and 14 days thereafter. In the current study the assessment of tumour perfusion was performed in 1–2 days after bevacizumab administration. The present study suggests that it may be possible to predict the effects of chemotherapy just days after the administration of bevacizumab using 15O-water PET. If bevacizumab is found to be insufficiently effective at an early stage, switching to another anticancer drug could be considered earlier. In addition, 15Owater PET can be performed at a lower dose than perfusion CT; 0.37 mSv vs. 3.5–6.5 mSv [11].
Tumour blood flow is still not well understood, so it is necessary to clarify how tumour blood flow before treatment and changes in tumour blood flow after treatment affect the efficacy of anticancer therapy, and prognoses. Accordingly, a larger number of cases needs to be examined. Tumour blood flow is associated with tumour hypoxia, which is associated with resistance to chemotherapy. An explanation for why the extent of the reduction in tumour blood flow is associated with the response to chemotherapy may be associated with the altered hypoxic region of the tumour. Further insights may be obtained by combining hypoxic imaging with a radiolabelled tracer such as 18F-fluoromisonidazol [12].
The current study had several limitations. One is the small number of participants, which resulted in low statistical power. It was also conducted at a single facility, which may have resulted in selection bias. Each patient underwent different chemotherapy regimens, which may have influenced blood flow and prognoses. There were also some technical limitations. The parametric images obtained are prone to noise, which slightly reduces the reliability of the quantification. Each VOI was manually placed over the pulmonary nodules, making it as large as possible in an effort to minimize the effects of inhomogeneity. This may have resulted in some variability due to manual measurement.
In conclusion, in the current study mean tumour blood flow diminished within 1–2 days after bevacizumab administration in NSCLC patients, and greater reductions in blood flow were associated with shorter PFS.