Doctor of Philosophy
The current standard of breast conserving therapy is lumpectomy followed by whole breast radiotherapy which is prohibitively long for many patients (4-6 weeks). In addition, the need for treating the whole breast has been questioned. The London Regional Cancer Program is enrolling early stage breast cancer patients in a prospective Phase I/II clinical trial (SIGNAL) to assess the safety/efficacy of neoadjuvant stereotactic ablative radiotherapy (SABR) to the tumour alone to reduce treatment times. This provides a unique opportunity to assess tumour response to SABR using non-invasive imaging. Patients received a pre-SABR dynamic contrast-enhanced (DCE)-MRI to guide target volume delineation. A subset also received post-SABR DCE-MRI to facilitate response assessment.
Recent safety concerns of long-term retention of gadolinium-based contrast agents (GBCA) in brain and bone led us to reduce the dose of GBCA to half the clinical dose part way through SIGNAL. Chapter 2 presents an investigation of the impact of this reduction on the inter- and intra-observer variability for target volume delineation and we found no significant decreases. These results are important for any context that requires repeated administrations of GBCAs to patients.
Chapter 3 presents an investigation of the impact of intra-session image registration on the voxel-by-voxel application of the Tofts model. Image registration led to significant reductions in the uncertainty in model parameter estimates and unphysical parameter estimates. Also, we showed that computation time could be reduced by a factor of two without affecting these results.
Chapter 4 presents an investigation of DCE-MRI based assessment of treatment response to SABR in early stage breast cancer. The analysis included two time delays post-SABR (6-7 or 16-19 days) and two SABR fractionation schemes (21Gy/1fraction or 30Gy/3fractions). DCE-MRI response assessment one-week post-SABR was confounded by acute inflammatory effects whereas 2.5 weeks appeared sufficiently long to minimize these effects. Kinetic parameters measured 2.5 weeks post-SABR in both fractionation groups were indicative of response, but only the single fraction led to enhancement in tissue surrounding the tumour. Such metrics will be valuable in adapting treatment to patients and in future studies that will investigate higher ablative doses with the potential to eliminate surgery.
Summary for Lay Audience
The current standard of treatment for low-risk early stage breast cancer patients is a lumpectomy followed by 4-7 weeks of whole breast radiotherapy. This treatment time length has been shown to be prohibitively long for many patients, particularly elderly or rural patients. The London Regional Cancer Program is conducting a clinical trial with the aim of assessing the safety and efficacy of treating low-risk early stage breast cancer with 1-3 treatments of radiation therapy 1-3 weeks prior to surgery. This new treatment approach may significantly improve the quality of life for many patients but also provides a unique opportunity to assess treatment response to the high dose radiation using non-invasive imaging, which may allow for the development of prognostic biomarkers of tumour response. The main objective of this thesis was to explore the role of an imaging technique called dynamic contrast enhanced (DCE) MRI in non-invasively assessing tumour response in patients receiving high dose radiotherapy.
Recent findings have shown long-term retention of contrast agents used in DCE-MRI in brain and bone which led us to reduce the dose of these contrast agents part-way through the clinical trial. Chapter 2 presents an investigation of the impact that this reduction has on patient care, specifically the effect on the radiotherapy delivery process. We found that we could lower the contrast dose used without compromising patient care.
Chapter 3 investigates the role that motion correction strategies play in the analysis of DCE-MRI and was an important step in the analysis of DCE-MRI. Building off these results, Chapter 4 presents the results that address the original objective of investigating DCE-MRI in assessing tumour response to high dose radiation therapy. This work presents novel insights into the vascular response to high dose radiotherapy and shows that DCE-MRI may be a good candidate to assess tumour response – so long as the imaging time post-radiotherapy is sufficiently long to avoid confounding acute inflammatory effects due to the radiation. The work presented in this thesis sets the stage for future studies that will investigate even higher doses of radiotherapy with the potential to eliminate surgery altogether.
Mouawad, Matthew, "Neoadjuvant Stereotactic Ablative Radiotherapy To Treat Early Stage Breast Cancer Patients: The Role Of DCE-MRI" (2019). Electronic Thesis and Dissertation Repository. 6264.
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