Tumor physiological changes during hypofractionated stereotactic body radiation therapy assessed using multi-parametric magnetic resonance imaging

Abstract

Radiation therapy is a primary treatment for non-resectable lung cancer and hypoxia is thought to influence tumor response. Hypoxia is expected to be particularly relevant to the evolving new radiation treatment scheme of hypofractionated stereotactic body radiation therapy (SBRT). As such, we sought to develop non-invasive tools to assess tumor pathophysiology and response to irradiation. We applied blood oxygen level dependent (BOLD) and tissue oxygen level dependent (TOLD) MRI, together with dynamic contrast enhanced (DCE) MRI to explore the longitudinal effects of SBRT on tumor oxygenation and vascular perfusion using A549 human lung cancer xenografts in a subcutaneous rat model. Intra-tumor heterogeneity was seen on multi-parametric maps, especially in BOLD, T2* and DCE. At baseline, most tumors showed a positive BOLD signal response (%ΔSI) and increased T2* in response to oxygen breathing challenge, indicating increased vascular oxygenation. Control tumors showed similar response 24 hours and 1 week later. Twenty-four hours after a single dose of 12 Gy, the irradiated tumors showed a significantly decreased T2* (-2.9±4.2 ms) and further decrease was observed (-4.0±6.0 ms) after 1 week, suggesting impaired vascular oxygenation. DCE revealed tumor heterogeneity, but showed minimal changes following irradiation. Rats were cured of the primary tumors by 3×12 Gy, providing long term survival, though with ultimate metastatic recurrence.

The effect of flow on blood oxygen level dependent (R*2) MRI of orthotopic lung tumors

“…We previously reported a typical BOLD signal response of 2% to 3% for subcutaneous A549 compared with the 8% to 10% observed in the orthotopic setting using the same pulse sequence, though with the different TE required to match the observed . A more rigorous comparison is , which indicated ~120 s –1 for orthotopic A549 tumors here versus 58 s –1 for subcutaneous tumors . We note that some values are greater than typically reported for tumors previously, but previous studies of subcutaneous tumors reported a mean value of 101.4 s –1 for G3H prolactinomas (with a range of 75–140 s –1 ) and values as high as 110 s –1 for DU‐145 tumors and 130 s –1 for PC3 tumors at 4.7T .…”

“…We note that some values are greater than typically reported for tumors previously, but previous studies of subcutaneous tumors reported a mean value of 101.4 s –1 for G3H prolactinomas (with a range of 75–140 s –1 ) and values as high as 110 s –1 for DU‐145 tumors and 130 s –1 for PC3 tumors at 4.7T . We are unaware of other studies of orthotopic lung tumors using oxygen‐sensitive MRI, although other studies have examined human lung tumor xenografts growing subcutaneously in rats and mice …”

“…H460 were sparsely vascularized, whereas the A549 had extensive capillaries (Figure ). Architecture of A549 tumors was also different in the orthotopic setting compared to the subcutaneous site, where a multinodular structure was observed with very sparse vasculature generally limited to the stromal bed around the nodules . This is also distinct from the vasculature reported for A549 growing subcutaneously in nude mice .…”

“…A constant k was included as a precaution for possible long T 2 component in the voxel, but was ultimately found to be close to 0 most of the time or at maximum around 2% of S 0 . Starting values of S 0 and for curve fitting were calculated by first solving Equation 1 based on SI at the first 2 TE values . R 2 > 0.8 was set as a threshold to ensure curve fitting reliability.…”

Translating preclinical MRI methods to clinical oncology

“…Hyperoxic gas breathing interventions are generally reversible and studies have shown that repeated challenges resulted in similar responses, allowing effective comparison of hypoxia‐modulating interventions . Successive imaging on sequential days or over several days showed no significant differences in responses in some tumor types . A change in longitudinal relaxation in response to an oxygen‐breathing challenge has been shown to discriminate tumor tissue from radiation‐induced necrosis .…”