Date of Award
Doctor of Philosophy (PhD)
Hyperthermia (HT), which refers to increasing the temperature of the tumor tissue to 40–45°C for an extended period of time, has been reported to be one of the most effective sensitizers for radiation therapy (RT) and/or chemotherapy. High intensity focused ultrasound (HIFU) has been developed as a non-invasive and non-ionizing tool to induce localized HT. Magnetic resonance thermometry (MR thermometry) is one of the most reliable methods for non-invasively and precisely measuring the in vivo volumetric temperature in real time. The integration of MR thermometry with HIFU has been implemented in commercially available magnetic resonance guided high intensity focused ultrasound (MRgHIFU) systems. MRgHIFU has been previously reported to administer HT to both animals’ muscles and rectal cancer in human patients using MR thermometry and feedback control. Cervical cancer is the fourth most prevalent cancer in women worldwide. Patients with locally advanced cervical cancer (stage IB3-IVA) have worse survival and higher rates of recurrence compared to early stage disease. The addition of HT to RT substantially improves local control and overall survival without affecting treatment-related grade 3–4 toxicity, according to six phase III/IV clinical trials. In previous clinical studies, the HT was induced by microwaves or radiofrequency, which have limitations including superficial penetration or non-localized heating. As a newly-emerged technique, although the feasibility of MRgHIFU induced HT have been evaluated in the thigh muscle in a porcine model, no study has evaluated the feasibility of using MRgHIFU induced HT in various clinically-mimicking pelvic targets. Additionally, no published work has demonstrated successful implementation using the largest volume HT (diameter, Ø=58 mm) for either deep or superficial targets. Furthermore, insufficient assessment has been performed for the targetability of MRgHIFU in primary cervical cancer. However, the above-mentioned evaluations are all necessary steps prior to the clinical translation. Therefore, to address these unmet needs before clinical application, the objectives of this dissertation were (1) to review the available ultrasound-induced HT technology and evaluate published clinical studies combining ultrasound induced HT with RT in the treatment of neoplasms in different human organ systems, (2) to evaluate the feasibility and safety parameters of performing MRgHIFU induced HT to an array of tissue geometries in the pelvis in a porcine model, (3) to characterize the temperature distribution and tissue damage profile of the largest (Ø=58 mm) HT cell in both deep (i.e., 6-cm) and superficial (i.e., 2-cm) targets in vivo with different user-definable parameters, (4) to retrospectively evaluate the percentage of primary lesions and metastatic lymph nodes in late-stage cervical cancer (stage IIIB–IVA) patients that can be targeted by a clinical MRgHIFU device, and to assess optimal patients positioning for the highest targetability rate. In addition, any statistical correlation between the patients’ anatomical geometries/demographics and targetability was also explored. Finally, challenges and future directions are also discussed. The overall goal of the dissertation is to comprehensively evaluate MRgHIFU induced HT, in order to facilitate, accelerate, and serve as an impetus for the clinical translation of MRgHIFU induced HT for the late stage cervical cancer. For the feasibility and safety evaluation, we demonstrated the feasibility of using MRgHIFU to heat a set of clinically mimicking pelvic targets including the muscle adjacent to the ventral and dorsal bladder wall, and the uterus with satisfactory safety parameters. The temperature was maintained within the desired range with reasonable accuracy (1°C within the target range), precision, temperature variation, and heating uniformity for up to 30 minutes. Satisfactory safety parameters were measured by contrast-enhanced MRI, macroscopic tissue observations, and by histological analysis. For the large field HT characterization with the diameter of 58 mm, MRgHIFU-induced large-volume HT is feasible in both deep (i.e., 6-cm) and superficial (i.e., 2-cm) targets with satisfactory (<1°C within the target range) temperature characteristics. Target tissue histology showed some localized tissue damage within the HT volume. No thermal-related skin or subcutaneous tissue damage was observed. We also demonstrated the potential of using feedback control planes to tailor the spatially delivered thermal dose to clinical targets. For the retrospective study, we found that most late-stage cervical cancer patients were targetable by MRgHIFU-induced HT in at least one orientation/angle assuming minimal intervention. No rotation, or a rotation of less than 5°, had the highest chance of anterior targetability, while a rotation of 25°–30° had the highest chance of posterior targetability. Patients’ characteristics and anatomical geometric factors could be used to predict the anterior or posterior targetability and the targeting cross-sectional diameter. Here the results have demonstrated that this technique has the capability to safely heat an array of different pelvic target geometries with mild/reversible tissue damage (with Ø=18 mm), to achieve satisfactory temperature for both deep and superficial (with Ø=58 mm) with heating distributions modifiable by user-definable parameters, as well as to target most late stage cervical cancer primaries with no/minimal potential intervention. These results therefore support proceeding into clinical trials of HT delivered by MRgHIFU for late-stage cervical cancer patients receiving RT.
Michael B. Altman Hong Chen
Michael H. Gach, Dennis E. Hallahan, Zoberi Imran,