Summary

With Focused Ultrasound Surgery (FUS) it has become possible to destroy diseased tissues (for example tumours) inside the body without surgical incision and without insertion of instruments into the body. This non-invasive technology has the potential to reduce side-effects and hospitalization times for treatments and it is already in clinical use for the treatment of, among others, uterine fibroids, bone metastases and prostate cancer.

MRI-guided Focused Ultrasound Surgery (MRgFUS) combines high intensity focused ultrasound with magnetic resonance imaging (MRI) to visualise the tumour and surrounding anatomy and to provide thermal monitoring, which allows the physician to safely control the procedure. However, for abdominal organs, for example to treat liver metastases, several technological challenges have to be solved before MRgFUS can become a competitive alternative to surgery and other image guided ablation techniques. Particular problems are posed by the complexity of the liver anatomy, the shielding of the target by the rib cage and its three-dimensional deformation due to respiratory motion. To tackle these challenges, the VPH (Virtual Physiological Human) project TRANS-FUSIMO has developed a prototypical real-time control system for MRgFUS treatments in moving abdominal organs. This system is called TRANS-FUSIMO treatment system or TTS in short.

The TRANS-FUSIMO project (January 2014 to December 2018) was conducted by twelve partners from seven countries. Its outcome is a validated and quality assured prototype of a system for conducting FUS treatments in moving abdominal organs. It integrates models for the motion of the relevant abdominal organs, models for the monitoring and prediction of the target location during the treatment, models for the thermal monitoring, models for transcostal sonications, virtual transducer models, and also models for the outcome prediction of the therapy which have been used as part of the validation of TTS.

All these models shall lead to optimized FUS treatments in moving abdominal organs and thus to safer, more efficient and more effective procedures of the future.

In order to validate the TRANS-FUSIMO treatment prototype and its constituting models and to assess the feasibility of the treatment of organs under respiratory motion, the TRANS-FUSIMO project has performed the following validation studies:

• In-silico validation: Extensive validation of TTS using numerical simulations in the PC.
• In-vitro validation: Extensive validation of TTS in phantoms.
• Animal study: Validation of TTS in living animals under ventilated breathing.
• Imaging studies on human volunteers: Preparatory studies for clinical study.

The validations show that the TRANS-FUSIMO system prototype as a whole, and the algorithms for motion compensation in particular, are working properly. The consortium had also planned to perform a first-in-human study. This, however, would need more pre-clinical experiments to reach statistical significance of safety and effectiveness, which could not be performed within the project duration .

Project Context and Objectives

In recent years, High-Intensity Focused Ultrasound (FUS) under guidance of magnetic resonance imaging (MRgFUS) has been clinically established for non-invasive tumour surgery, e.g. in the treatment of fibromyoma of uterus, palliation of bone metastases, treatment of functional neurological disorders (such as essential tremor, idiopathic tremor dominant Parkinson disease, neuropathic pain) and also prostate tumours. However, treating tumours in moving organs such as the liver is still a great challenge due to several complexities.

These complexities include technological as well as physiological challenges like organ motion due to breathing and shielding of the target by the rib cage. The preceding VPH project FUSIMO (2011-2014) aimed at the development of a planning system for MRgFUS that is capable of dealing with these challenges in the treatment of the liver.

TRANS-FUSIMO had the aim to translate the knowledge gained during FUSIMO into a clinically applicable prototype system spanning the full clinical workflow of planning, executing, and assessing, as well as learning from the procedure. With such an integrated system, MRgFUS could in the future become a commercially and clinically competitive alternative to current surgical and minimally-invasive oncological interventions, thus providing a non-invasive treatment, reducing side effects and healthcare costs. The particular objectives of the TRANS-FUSIMO project were:

1. To develop a prototypical MRgFUS treatment system to support executing and assessing the intervention under breathing motion;
2. To interface state-of-the-art FUS hardware, imaging devices, and MR compatible robot to build an integrated real-time-capable system for liver FUS;
3. To improve model based software components for optimized clinical workflow, real-time applicability and validated outcome prediction;
4. To conduct pre-clinical (phantoms, animal) experiments with the TRANS-FUSIMO system to show safety and effectiveness of the system;
5. To conduct a first-in-human trial to investigate neoadjuvant MRgFUS therapy to achieve prolonged survival of liver cancer patients;
6. To build a case and results database that allows for training and learning to use the prototypical TRANS-FUSIMO treatment system.

The central component of the prototypical TRANS-FUSIMO treatment system (objectives 1-3) was planned to be a real-time control that interfaces to the following hardware devices:

• MRI hardware for acquisition of anatomical and thermometry data,
• FUS hardware for generating and focusing high intensity ultrasound waves,
• Ultrasound (US) imaging and MR imaging for tracking the movement of liver and ribs,
• MR compatible robot arm for placing the ultrasound transducer on supine patients.

With the real-time interfacing of the MR hardware, the TRANS-FUSIMO treatment system prototype would be able to receive images from the MR device: planning images, transducer calibration images, and most importantly, the monitoring images, which are needed in real-time. On the one hand, these real-time images show the motion of the breathing patient and thus give information about the moving target. On the other hand, they are needed to get real-time information about the rising temperature in the body during the treatment. Another possibility to track the target area would be to use a diagnostic US device with real-time capability.

Also, the prototypical TRANS-FUSIMO treatment system would need the ability to communicate real-time motion information to the FUS hardware that generates the acoustic high intensity focused ultrasound waves. This real-time steering of the FUS hardware was supposed to be achieved using the US or MR imaging information and a motion model. Finally, a MR compatible robot arm was supposed to place the transducer hardware on the abdomen of the patient at the beginning of the procedure.

Pre-clinical tests in-vitro, ex-vivo and on animals were planned to validate the prototypical system against its specifications and in order to show safety and effectiveness before doing a first-in-human treatment (objective 4).

In the final phase of the project a first-in-human clinical trial with patients that are treated with MRgFUS under breathing motion was planned to be conducted (objective 5) in order to show the clinical applicability of the TRANS-FUSIMO prototypical treatment system.

Finally, to enable clinical personnel to train and learn the MRgFUS therapy of the liver, a training and learning system was planned to be implemented. The training and learning system was planned to use emulated hardware devices and data recorded during interventions, including the TRANS-FUSIMO pre-clinical and clinical tests. It was supposed to be used outside of the MRgFUS therapy room and without any connection to an actual ongoing intervention.