Abstract
IntroductionTumor hypoxia and angiogenesis are implicated in tumor growth and metastases, and anti-angiogenic therapies have an important role in treating patients with metastatic colorectal cancer. However, the prevalence of hypoxia has not been fully evaluated in colorectal liver metastases, and hypoxic response to anti-angiogenic therapy has not been clearly established. The aims of the study were to evaluate the changes seen on 18F-FMISO and 18F-FDG PET scans in patients treated with anti-angiogenic therapy, and to correlate these measures of hypoxia and metabolism with clinical outcomes, and blood biomarkers of angiogenesis.MethodsPatients with metastatic colorectal carcinoma planned for treatment with bevacizumab and chemotherapy received routine staging investigations prior to any treatment, including a FDG PET scan. A FMISO PET scan was performed within 4 weeks of staging tests, with blood specimens collected at that time for serum VEGF and osteopontin measurement. Follow-up FDG and FMISO scans were performed after 1 cycle of treatment. Results were compared to response (RECIST), progression free survival (PFS), and overall survival (OS).ResultsA total of 15 patients were recruited into this prospective trial, of which 13 patients were evaluable for assessment of treatment follow-up. Baseline FDG uptake was higher than FMISO uptake, and there was a significant decrease in FDG uptake (SUVmax and TGV) but not FMISO uptake (SUVmax and TNR) after treatment. There was a positive correlation between FDG and FMISO SUVmax on both baseline and post-treatment PET scans. Blood biomarkers of serum VEGF and osteopontin were significantly correlated with the FDG and FMISO PET parameters.ConclusionsThis study shows that hypoxia in metastatic colorectal cancer, assessed by FMISO PET, shows minor changes following initial treatment with anti-angiogenic therapy, but is associated with therapeutic response. FDG PET uptake changes (SUVmax, TLG) are also associated with response to anti-angiogenic therapy. These findings demonstrate the interplay between tumor metabolism and hypoxic regulation following anti-angiogenic treatment of metastatic colorectal cancer.
Highlights
Tumor hypoxia and angiogenesis are implicated in tumor growth and metastases, and anti-angiogenic therapies have an important role in treating patients with metastatic colorectal cancer
The concept of vascular “normalization” by anti-Vascular Endothelial Growth Factor (VEGF) agents for improved drug delivery and efficacy is the basis of anti-angiogenic treatments which has been approved for treatment of metastatic colorectal cancer
Our study evaluating FMISO response in patients with metastatic colorectal carcinoma treated with bevacizumab has demonstrated that hypoxia is present at baseline, but there is only minor changes in hypoxia in the tumor following initial treatment
Summary
Tumor hypoxia and angiogenesis are implicated in tumor growth and metastases, and anti-angiogenic therapies have an important role in treating patients with metastatic colorectal cancer. The aims of the study were to evaluate the changes seen on 18F-FMISO and 18F-FDG PET scans in patients treated with anti-angiogenic therapy, and to correlate these measures of hypoxia and metabolism with clinical outcomes, and blood biomarkers of angiogenesis. Most tumors remain restricted in size until the tumor mass expands and overtakes the rate of internal apoptosis by developing blood vessels. This change is the result of a shift in the net balance of stimulators and inhibitors of angiogenesis within the tumor microenvironment [8]. The degree of vascularization is inversely correlated with patient survival, and can predict the development of metastases, and tumor growth
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