Abstract
Hypoxia, the state of low oxygenation that often arises in solid tumours due to their high metabolism and irregular vasculature, is a major contributor to the resistance of tumours to radiation therapy (RT) and other treatments. Conventional RT extends treatment over several weeks or more, and nominally allows time for oxygen levels to increase (“reoxygenation”) as cancer cells are killed by RT, mitigating the impact of hypoxia. Recent advances in RT have led to an increase in the use stereotactic body radiotherapy (SBRT), which delivers high doses in five or fewer fractions. For cancers such as pancreatic adenocarcinoma for which hypoxia varies significantly between patients, SBRT might not be optimal, depending on the extent to which reoxygenation occurs during its short duration. We used fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole positron-emission tomography (FAZA-PET) imaging to quantify hypoxia before and after 5-fraction SBRT delivered to patient-derived pancreatic cancer xenografts orthotopically implanted in mice. An imaging technique using only the pre-treatment FAZA-PET scan and repeat dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans throughout treatment was able to predict the change in hypoxia. Our results support the further testing of this technique for imaging of reoxygenation in the clinic.
Highlights
Surgical resection is possible in 15–20% of patients with a new diagnosis of pancreatic cancer and provides the only chance of long-term cure, even though local recurrence or distant metastases occur in the majority of surgically treated patients
Hypoxia varies greatly amongst pancreatic cancer patients[8], meaning that, accounting for the enhanced radio-resistance of hypoxia cells via the oxygen enhancement ratio (OER)—the true effective dose may in some cases be much less than expected, conferring a survival advantage to hypoxic—and possibly more malignant20,24–27—cells
In order to accurately model the response of pancreatic tumours to hypofractionated radiotherapy and hypoxia-activated prodrugs[14,16,17,28], and to develop strategies to improve survival, it will be important to accurately quantify hypoxia and reoxygenation during the short course of SBRT7
Summary
Surgical resection is possible in 15–20% of patients with a new diagnosis of pancreatic cancer and provides the only chance of long-term cure, even though local recurrence or distant metastases occur in the majority of surgically treated patients. Patient-specific optimization of HAP and SBRT dose fractionation schedules to maximize cell-killing in hypoxic tumours requires: 1.) radiobiological modeling of treatment response that incorporates reoxygenation and proliferation kinetics[16,17,18] and 2.), an imaging measurement and analysis framework to characterize treatment response in vivo, including oxygenation status, which can readily be incorporated into a routine clinical workflow. These requirements provided the impetus for us to study the reoxygenation of pancreatic tumours during SBRT, and to develop an imaging technique to measure reoxygenation. The results provide support for further refinement of the imaging technique and modelling of reoxygenation at the clinical scale
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