The current status and future prospects for molecular imaging-guided precision surgery

Molecular imaging is increasingly being used to diagnose a range of diseases and to monitor and guide therapy, particularly in cancer. In this setting, molecular imaging often aids in the selection of systemic versus locoregional therapies [1]. The combination of diagnostics and therapy is commonly referred to as theranostics. In the nuclear medicine imaging literature, this approach typically refers to the application of radionuclide therapy based on demonstration of high expression of a therapeutic target presented on a diagnostic scan using PET or SPECT. However, a less-well recognized aspect of theranostics is the use of imaging to guide device-based interventions. Prime examples include percutaneous needle placement [2] and liver embolization [3]. These approaches are generally guided by imaging techniques such as ultrasound, or CT and SPECT ‘scout’ scans. Image -guided therapy equally applies to surgery, a field where precision planning can directly impact patient care. Image guidance can in particular be used to illuminate surgical targets (diseased tissue) or non-targets (healthy tissue that needs to be spared).

In surgery, favorable outcomes are achieved by excising all diseased tissue. At the same time the severity of complications is related to the invasiveness of an intervention. Hence, a balance needs to be created between the need for radical removal of disease and minimizing the scope of surgery. Accordingly, there is a drive towards minimal-invasive and more personalized interventions, while providing patients and healthcare professionals more confidence in the efficacy of radical resection, as well as uncomplicated postoperative recovery. From the very beginning of surgical practice decision-making has been guided by the tactile and visual senses of the operating surgeon. The technological advances made in the last century now allow these senses to be complemented via the use of preoperative imaging roadmaps (e.g., CT, MRI, SPECT and PET) and intraoperative target visualization in the form of white-light endoscopic video-image guidance. This evolution is helping minimally invasive ‘key-hole’ approaches to gradually replace open surgery. A clear example is the rise of robot-assisted laparoscopic surgery [4], which some now consider the standard-of-care in the resection of prostate cancer [5, 6]. The flip side of this minimally invasive trend is the loss of “touch” and thus a growing reliance on image guidance. An obvious next step in advancing image guidance in minimally invasive surgery is the inclusion of intraoperative molecular imaging strategies. Such strategies can help assist in target identification to guide resection of disease sites more accurately, while preserving delicate healthy anatomy and have led to the development of the concept of image-guided surgery [7, 8].

Historically, image-guided surgery has been pursued using different modalities. Since the late 1950s fluorescence imaging has been implemented during angiography ([9‐11]; Fig. 1). In the 1960s, intraoperative X-ray devices started to be used to provide imaging as guidance for orthopedic surgical interventions [12] and intraoperative ultrasound (US) was introduced to guide surgeons during neurological and cardiac surgery. The latter became more widely accepted in the late 1970s, mainly for application in general surgery [13]. Since the 1980s, radioactive tracers (radiotracers) have been implemented to highlight lymph nodes [14, 15], and later tumors [16]. Although scarce, there have even been reports describing the use of intraoperative magnetic resonance imaging during neurosurgery (first report in 1994, [17]). More exotic modalities are the use of magnetic particles [18, 19], optoacoustics [20], and Raman spectroscopy [21]. Digital navigation based on preoperative computed tomography (CT) or magnetic resonance imaging (MRI) roadmaps has been seen since the 1990’s with examples in head-and-neck, neuro- and orthopedic surgery [22]. Combined these approaches provide the foundations for evolving image-guided surgery.

The success of image-guided surgery is driven by the synergy between four main generic components: 1) relevance and accessibility of the target (medicine), 2) imaging agents (chemistry/pharmacology/pharmaceutics), 3) modalities used to detect or navigate towards the target defined in via imaging (engineering/imaging physics), and 4) interpretation of the imaging data (computer visualization). In this review, the status and future prospects of these four aspects of image-guided surgery is addressed. In addition, we indicate how each of the components can contribute to transition of new concepts from a laboratory setting into standard clinical care pathways (translational medicine).

Clinical translation of novel image-guided surgery technologies beyond research and development requires establishment of an evidence-base that demonstrates the safety and effectiveness of these procedures, while reimbursement requires evaluation of cost-effectiveness. Strictly speaking, image-guided surgery technologies need to provide either better outcome for the patient or improve the workflow for medical professionals, if not both, and at a reasonable cost. In this regard, patient benefit can be scored by looking at short-term complication rates and long-term outcomes across cohorts with and without use of image guidance. Unfortunately, availability of such data is limited as most studies seem to focus on proof-of-principle studies. Exceptions to the rule are represented by reports for 5-ALA [185], sentinel node procedures in melanoma patients [186], ICG-^99mTc-nanocolloid [48, 187, 188], and ^99mTc-PSMA-I&S [189, 190]. Assessment of the impact of implementing image-guidance on surgical procedural performance, is traditionally performed via use of qualitative questionnaires and the recording of surgical time [191]. Conceptually, it is challenging to make objective and quantitative assessments regarding the adequacy of surgery or a surgeon’s performance, since many individual factors may impact outcomes. Recently, as result of the performance-guided surgery paradigm, kinematic assessments have been put forward as a means to score the proficiency of a surgeon [192]. This approach has the potential to provide short term means to define the added value of an image-guidance technology [183]. Uniquely, assessment of the surgeon’s performance based on kinematics will not only allow study of how chemical and engineering efforts enhance the surgical experience but will also allow assessment of how these approaches complement each other. Ultimately such assessments can be related to outcome data.

As image-guided surgery solutions are quite often technically challenging. In essence, ethics and regulations provide a healthy translational hurdle to protect patients, while financial aspects may also constrain development. from a practical perspective, lead compounds and detection device prototypes must be developed and refined in research setting and often not within the domain of patient care. While this helps preventing the patient exposure to potentially harmful technologies, it also means that some approaches can become more ‘technology-driven’ than ‘clinical-need-driven’. Ideally all developments should be done with clinical translation in mind and based on real-life unmet surgical needs. But even with these prerequisites, it is extremely challenging to translate laboratory findings to the clinic. An example of the challenges faced is the extrapolation of findings in small animal disease-models to patients. Besides the obvious anatomical differences, which will reflect on tracer pharmacokinetics, the performance characteristics of modalities employed in small animals are not necessarily recapitulated in human instrumentation [50]. Regularly, images depicting surgery in mice that claim translational potential are published, but one should perhaps approach such claims with healthy skepticism. Phantoms can provide a size matched intermediate to test modalities on, but at the same time these settings are even more artificial than small animal disease models. This leaves large animal models like those used for surgical training purposes [180] as prime candidates for assessment of clinical potential of novel intraoperative imaging approaches. In large animals, the same type of tracers, modalities or software solutions can be used as are used in patients (note: devices used on animals can no longer be used for clinical purposes). These can then also be validated in a surgical environment that is close to the intended use. A limitation is that large animal surgical-training-models are less suited as disease models as creation of such models is a costly and time-consuming ordeal that raises several ethical issues. An approach that can provide a solution from a technical perspective but at the same time demands ethical considerations is the emerging possibility wherein companion animals with cancer become potential subjects for new technology assessments [193]. An example can be found in in dogs with naturally acquired tumors [194]. Together, it seems likely that both small- and large-animal evaluations are needed to best prepare an image guidance technology for clinical evaluation. Such evaluations, combined with toxicity testing, will gather the evidence needed to apply for ethical approval for first-in-human evaluations.

Clinically surgical tasks are divided according to anatomy, disease indication and even the type of surgical intervention. This helps ensure expertise for surgeons and helps create some form of quality assurance from a healthcare perspective. From a technological perspective, however, most of these boundaries seem irrelevant. Physical and technical factors (e.g., open vs laparoscopic, soft tissue vs rigid anatomies) drives the design of new technologies. That said, most chemical and engineering efforts mentioned above still find applications in multiple settings. The success stories in the field of image-guided surgery are based on technologies that maximally align with innovations made in other fields. For example, initial work on fluorescence laparoscopy presented in prostate cancer surgery [195] was later transferred to breast surgery [196] and the technique is now also implemented during i.e., laparoscopic colorectal surgery [94, 197]. Such knowledge sharing can be considered highly valuable as it helps boost innovation across disciplines.

With all the promising technologies being developed under the umbrella of image-guided surgery, it remains essential to maintain a helicopter view of this highly multidisciplinary and rapidly expanding field. Hereby, we need to make sure that the clinical needs remain aligned with tracer chemistry, device physics and the increasing digitization of the operating room.