Image-Guided Intervention and Therapy: The First Time Right

B. H. W. Hendriks, D. Mioni, W. Crooijmans and H. van Houten

Philips Research, High Tech Campus 34, Eindhoven, The Netherlands

1 Introduction

In 2006, Dr Elias Zerhouni, director of the U.S. National Institutes of Health, outlined the vision that “medicine in the future has to be predictive, personalized, and very precise to the individual, and it has to be pre-emptive.”¹ He stressed the importance of imaging in understanding complex biological systems, a topic we reviewed in FTM-2006.² He also articulated a second and perhaps even bolder vision: “Twenty-five years from now, I hope that we won't perform any more open surgery. There would be no need to essentially take the risk of full exposure of the human body to go to a targeted region that needs to be affected.”¹ How this might be achieved is the topic we address in this chapter.

In cardiology, one of the main causes of mortality today, major progress has already been made through minimally invasive interventions, such as placing a stent. Heart rhythm disorders can also be treated using catheters, by first mapping the disturbed pattern of electrical activity around the heart chambers, followed by selectively altering the current paths through local tissue ablation. Valve replacement is also rapidly gaining ground. These procedures require careful navigation and steering of the various catheters, which can be optimized using 3D X-ray and ultrasound imaging methods, combined in real time with physiological models and image processing – thereby enabling proper eye–hand coordination.

However, a catheter today is a purely mechanical device, controlled via external imaging and manual steering. Our vision for the future is that the efficiency and positive outcome of catheter-based cardiovascular procedures can be drastically improved by adding in-body sensing and imaging to catheters. Advances in miniaturization technology allow us to build intelligence into the catheter, to provide local imaging, localization, and control capabilities. Examples are MEMS-based ultrasound transducers³ that can be mounted onto the tip of a catheter, and real-time 3D optical shape sensing along its length. We expect that such smart catheter devices will disrupt the field of minimally invasive procedures. The ultimate solution will have a control loop between in-body sensing information and external imaging and therapy planning and delivery – enabled by adaptive therapy planning software.

In the field of cancer, the other major cause of death, we believe that a lot can be gained, thanks to advances in imaging and genomics that are enabling precision diagnostics. Precision diagnostics can be realized through image-guided focal biopsies, followed by molecular pathology. Image-guided targeted therapy delivery is possible through local administration of drugs, or by precise local delivery of energy to the tumor. These procedures require again smaller and smarter interventional instruments that can be controlled with a high level of precision, such as a photonically enhanced biopsy needles that can discriminate between tissue types.

Apart from the advances in disease management, the current healthcare system is also rapidly changing due to various economic realities the world is facing. These realities require a more integrated approach along the care continuum. Informatics solutions and healthcare transformation services play an important role in enabling this evolution.

It is our firm belief that the predictive, personalized, precise, and preemptive medicine of the future requires a care continuum approach, where image-guided therapy will play an important role.

2 Societal challenge: Rapid rise of cardiovascular diseases

Today, almost 30% of all global deaths are caused by cardiovascular disease (CVD) and by 2030 about 24 million people will die every year from it. This creates a burden on the healthcare system with costs up to 500 billion euros.⁴ Major contributors to heart disease include (i) electrical signal disorders (atrial fibrillation, sudden cardiac arrest); (ii) blockage of coronaries (insufficient power for contraction); (iii) valve problems (inefficient blood circulation); and (iv) damaged myocardial tissue (insufficient contraction, insufficient output).

In the recent past, treating heart disease meant open-heart surgery, where the patient's chest was exposed for direct access to the heart. This kind of procedure was expensive, due to long recovery stays in the hospital and a high risk of complications. Furthermore, the patient had to be in a reasonable health to be eligible for this kind of procedure.

The introduction of minimally invasive image-guided procedures based on X-ray guidance in combination with catheters that can be inserted into the body via a small incision has completely revolutionized this treatment. This represents a significant improvement for the patients, due to fewer restrictions on patient eligibility and lower risks. Furthermore, the faster recovery and shorter hospital stays has helped to reduce the burden of CVD on the healthcare system.

• Innovative products using X-rays

X-rays, discovered by the German physicist Wilhelm Conrad Röntgen, led to the development of X-ray systems for diagnostic and interventional procedures. One of the first diagnostic X-ray system was the Metallix machine, introduced in 1928 (see Fig. 1).⁵ Subsequent versions played an important role in tuberculosis testing in the 1950s and later for cardiovascular procedures (see Fig. 1). Over the years, advances in X-ray tubes, imaging intensifiers, and source-detector geometries have improved the imaging capabilities tremendously. Furthermore, the introduction of a source-detector geometry (C-arm geometry, angiography system) that could be rotated around the patient became the standard geometry for cardiovascular applications. Rotational cone beam computed tomography (CT), in which a complete series of projections is acquired on a conventional angiography system while the C-arm made a continuous rotation over an angle greater than 180° around the patient made it possible to make three-dimensional data sets, as illustrated in Fig. 2. To overcome the limited soft tissue visibility, which is easily seen in computed tomography (CT)⁶ and magnetic resonance imaging (MRI),⁷ the rotational angiography system was further improved to make CT-like imaging possible on these systems. A further development worth mentioning is the introduction of a more intuitive working environment and data management across the entire procedure, first introduced for electrophysiology procedures (EP).⁵ Due to the increasing number of older people, the prevalence of heart attacks resulting from irregular rhythms in the heart's EP system has been increasing. To treat these disorders, an electrophysiologist uses X-ray imaging and many other medical devices, such as electrophysiology recorders, ultrasound scanners, and ablation and navigation equipment. To deal with this complexity, an EP-cockpit was developed that provides an integrated package of equipment that could be controlled from one console. This allows performing the diagnostics, planning the procedure, and executing the treatment with real-time feedback to the physiologist.

Apart from the hardware developments, improvements have been made in image processing due to the increasing computing power and advances in X-ray detectors such as the one shown in Fig. 1(d). The rotational cone beam CT acquisition of Fig. 2 enables three-dimensional (3D) visualization of structures such as the vessel tree, shown in Fig. 3(a). Such data are essential for assessment of brain aneurysms and to perform precise measurements important for therapy planning. By using contrast injections, blood flow can be assessed (see Fig. 3(b)), which is important for determining occlusions in the blood vessels. Combining images from different imaging modalities enhances the visualization of tissue structures by combining the best of different worlds – see Fig. 3(c). When one of the imaging modalities is performed in real time, for instance real-time low-dose two-dimensional X-ray fluoroscopy combined with the preoperatively acquired 3D cone beam CT image, applications such as real-time 3D catheter navigation for therapy delivery become possible. Further improvement has been achieved by adding anatomical intelligence through physiological modeling, as shown in Fig. 3(d). Using patient-specific electronic organ models allows for efficient and quantitative inspection of the data, as well as automated anatomical structure recognition. This is key for more precise therapy planning, such as aortic valve annulus diameter measurement, important for selection of the right transcatheter aortic valve implant.

Due to these innovative X-ray products, treating heart disease has become a simpler procedure with a highly positive impact on the patient's quality of life. Image guidance has opened the way for using minimally invasive techniques, where patients are quickly treated and are often discharged from the hospital the same day rather than having to stay for week-long hospital recoveries.

• Innovative products using ultrasound

Similar to X-rays, ultrasound has a long history and is widely used in a range of clinical applications. It dates back to 1942, when ultrasound was first used as a diagnostic tool to locate brain tumors and the cerebral ventricles,⁸ followed by the diagnosis of gallstones and foreign bodies in 1948. In the field of obstetrics and gynecology, ultrasound was first employed in 1958. Ultrasound advances are strongly linked to the development of piezoelectric materials for transducers, as well as the manufacturing of microbeam-forming arrays that form the heart of the handheld ultrasound transducers for 3D ultrasound imaging. Advances in electronics and computing power have resulted in high-performance ultrasound imaging systems (see Fig. 4(a)) and ultramobile tablet-based ultrasound systems, illustrated in Fig. 4(a) and (b), respectively. The miniaturization of the transducer array and driving electronics made it possible to integrate ultrasound transducers into catheters, enabling ultrasound imaging in cardiovascular and endoscopic procedures (see Fig. 4(c)).

A new technology that has the potential to further advance ultrasound imaging is based on capacitive micromachined ultrasonic transducer (cMUT) technology.³ This technology, based on silicon IC processing, allows the ultrasound interconnect and the transducer to be made in one process (i.e., both flexible and rigid components made in one step). An arbitrary shape with a highly flexible interconnect can be made, as illustrated in Fig. 5.

The current state of the art is 3D real-time ultrasound. In obstetric gynecology, this allows almost realistic imaging of the fetus (see Fig. 6(a) and (b)). In cardiology, the transesophageal echocardiogram (TEE) probe enables 3D visualization of heart structures such as the mitral valve that are important for structural heart disease treatments (see Fig. 6(c) and (d)).⁹

Both external as well as in-body imaging has played an important role in driving cardiovascular procedures to the current state of the art. Today, these cardiovascular procedures are performed in hybrid rooms, shown in Fig. 6(e), where combined X-ray and ultrasound enables soft tissue anatomical imaging, including functional and blood flow measurements with real-time 3D insight, as shown in Fig. 6(f).

3 Societal challenge: Rapid rise of cancer

According to the World Health Organization,¹⁰ cancer is one of the leading causes of morbidity and mortality, with approximately 14 million new cases and 8.2 million deaths in 2012. The number of new cancer cases is expected to grow to 24 million in 2030. The most common cancers are lung, breast, prostate, liver, and colorectal. Lung cancer is the most common cancer, with 1.8 million new cases and 1.59 million deaths in 2012. Breast cancer is the most frequent cancer in women, while prostate cancer is the second most common cancer in men. Liver cancer is largely a problem in less developed regions, where it accounts for 83% of the cancer cases reported.

• Innovative products precise diagnostics

Various imaging modalities are used in oncology. Apart from the X-ray and ultrasound imaging that we discussed earlier for cardiovascular applications, there are three other commonly used imaging modalities: computer tomography (CT) imaging,⁶ MRI,⁷ and positron emission tomography (PET).¹¹ In CT imaging, an X-ray source and detector rotate while the patient is advanced through the bore of the system. This way of imaging provides cross-sectional and tomographic images of the patient with good tissue contrast at the expense of exposure to a fairly large dose of X-ray radiation. MRI uses magnetic fields and radio waves to investigate the anatomy and physiology of the patient's tissue. A strong magnetic field (several Tesla) is used to align the magnetic moments of protons. When a radiofrequency pulse is applied, the magnetization alignment is altered, which in turn causes a change in the magnetic flux that can be detected by the receiver coils of the system. Since this change depends on the local magnetic field near the proton, by applying additional magnetic fields (gradient fields) the distribution of the protons can be determined. MRI provides superb soft tissue contrast at the expense of longer acquisition times. It is also more costly than CT imaging. Finally, PET is a nuclear imaging technique that detects pairs of gamma rays that are emitted by a positron-emitting radionuclide (tracer). Functional processes in the body can then be imaged by administering a tracer conjugated to a biologically active molecule (such as fluorodeoxyglucose) to the patient. The metabolic activity related to the uptake of the tracer is used to investigate the presence of cancer metastasis.

Spectral CT is one of the recent technology advances that have become available in the clinic (see Fig. 7(a)).¹² In addition to the intensity-based contrast typically used in CT, this imaging technique provides the energy levels of the detected X-ray photons. In oncology, it is expected that spectral CT will improve lesion characterization and quantification in the diagnostic stage, and also provide a better understanding of the efficacy of cancer treatments applied.

Another new development is digital MRI, shown in Fig. 7(b), in which digital broadband architectures, available on modern MRI systems, lead to enhanced image acquisition speed, signal-to-noise ratio (SNR), and volumetric imaging. In oncology it results in finer visualization of soft tissue organs, such as the breast, prostate, or liver.

Furthermore, the combination of digital PET and CT, shown in Fig. 7(c), results in the enhancement of resolution, sensitivity, and quantitative accuracy compared to analog PET systems, making cancerous lesions easier to detect and their metabolic activity easier to measure. Once radiologists using imaging have found a suspicious lesion, the next step is to harvest a tissue sample for further analysis. To obtain these tissue samples, biopsy needles are inserted into the lesion using image guidance. To further enhance the biopsy yield of cancerous tissue, more accurate biopsy taking methods have been developed. For example, in prostate biopsies, preoperative MRI images that show a lesion in the prostate are combined with real-time transrectal ultrasound images. Combining the imaging with electromagnetic sensing, the tip of the needle can be guided to the lesion, as illustrated in Fig. 8(a).¹³ Another way to improve the biopsy yield is by equipping the biopsy needle with optical fibers enabling tissue discrimination at the tip of the needle via optical spectroscopy, as shown in Fig. 8(b). In this way, the needle can confirm whether the lesion has been reached before the actual biopsy is taken.¹⁴

Treatment selection is determined after histopathology and increasingly after additional molecular diagnostics. Oncology dashboards are under development to support treatment selection. For instance in a prostate dashboard, the information from different disciplines dealing with prostate cancer patients (urology, radiology, pathology, and genetics) comes together in an integrated manner to show 36 anatomical zones of the prostate, where the pathological findings are annotated by the respective specialists, allowing for a more personalized treatment including active surveillance, surgery, radiotherapy, brachytherapy,¹⁵ or focal therapy.

Apart from surgery and chemotherapy, radiotherapy is an important option in cancer treatment.¹⁶ Nowadays, over 50% of patients are treated with radiation therapy. In this treatment, high-energy beams are directed toward the cancerous cells to destroy them. Since the radiation also destroys normal cells, careful planning and delivery are important to minimize the comorbidity. Today's treatment delivery with radiotherapy starts by making a simulation scan for every treatment plan. By applying tumor characterization and organ risk knowledge, the final treatment plan is made. This planning phase can take several days, delaying treatment delivery. Typically, radiotherapy is delivered in 30 sessions over the course of 6 weeks. Since no real-time image guidance or replanning is used, changes due to setup uncertainty, weight loss, tumor response, and anatomy changes impact the radiotherapy delivery and result in suboptimal treatment. To overcome these drawbacks, current advances are aiming toward real-time adaptive planning and personalized treatment delivery. For this, radiotherapy systems are combined with imaging systems, allowing real-time imaging of the anatomy and tumor characteristics. The therapy delivery plan can then be adapted during the treatment.

Another cancer treatment where imaging plays an important role is in embolization therapy.¹⁷ In this procedure, various substances (such as coils, ethanol, polyvinyl alcohol, and microspheres) are injected in the blood vessel feeding the tumor to block or reduce the blood flow. First, an image of the vascular tree is made to determine the main vessel feeding the tumor. A catheter is advanced under image guidance toward this vessel and small particles are injected into the blood vessel to plug it up, a procedure called transarterial embolization (TAE). The procedure can be enhanced by loading the particles with chemotherapy or with radioactive particles.

Local treatment of the tumors can be performed percutaneously by placing a needle tip inside the tumor under ultrasound or CT image guidance and ablating the tissue.¹⁸ Different types of ablation are used. In radiofrequency ablation, high-energy radio waves are applied at the tip of the needle, heating the tumor and destroying cancer cells. A similar technique is to apply microwaves to heat the tissue. Another local therapy technique is freezing with very cold gases that are passed through the needle, a technique known as cryotherapy. A final method used is the injection of concentrated alcohol directly into the tumor to destroy the cancer cells. For all these techniques, imaging plays an essential role for planning and accurate needle placement to make sure that all tumor cells are treated while normal tissue and critical structures are spared as much as possible.

These examples in oncology show that imaging and image guidance play an important role to realize Zerhouni's vision to make the future of medicine predictive, personalized, precise to the individual, and preemptive.

4 Drivers of change in healthcare

Today, changes in healthcare are driven by three main economic realities. Clinical and economic outcomes are driving provider reimbursement, where compliance with the standard of care results in the “consumerization” of healthcare. Then, there is a move from treating illness to maintaining population wellness, shifting the emphasis to avoidance of injuries, complications, and readmissions. Finally, connecting everyone through common health information will unlock the power in the rich but highly disconnected islands of information in currently existing systems.

Healthcare needs to be seen along the “health continuum.” We see professional healthcare and consumer markets converging into a single health continuum, enabled by connected health technology. This continuum starts with a focus on healthy living and prevention, which empowers consumers to take control over their own health and enables countries to increase the health of the overall population. Next, the continuum includes definitive diagnostics and minimally invasive treatments, optimized with respect to both quality and cost. And finally, the continuum encompasses recovery and home care, which means care shifts as soon as possible to settings outside the hospital that are more comfortable and cost-effective. Telecare will enable patients to recapture a healthy life again, and avoid relapsing. Governments, insurers, medical professionals, patients, and caregivers all need to work together to realize the health continuum.

5 Conclusion

In conclusion, medical imaging has dramatically changed medical practice over the last century, enabling specialists to see inside the human body without incision and perform intricate therapeutic procedures without open surgery.

Nowadays, the challenges have increased substantially with today's healthcare industry drivers, but at the same time medical imaging provides new avenues for technology innovation that will play a central role in realizing Zerhouni's vision that “medicine in the future has to be predictive, personalized, and very precise to the individual, and it has to be pre-emptive.”

We have discussed the impact of imaging on the diagnostic and therapeutic stages of the world's most common diseases that have an unprecedented impact on our modern societies. In line with the WHO Global Noncommunicable Disease Action Plan, individuals taking ownership of their health and acting on modifiable risk behaviors (physical activity, healthy diet, and nonuse of tobacco) will open up completely new spaces for innovation. The overarching goal is the prevention of a significant amount of premature deaths. This is a topic for a future chapter in trends in microelectronics.

Acknowledgments

The authors thank T. M. Bydlon for attentive reading of the manuscript.

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