Due to the rising interest in scientific and clinical fluorescence-guided surgery, a variety of tumor-specific fluorescent imaging agents have been developed and evaluated in Phase I and II clinical trials. These studies were mostly focused on tracer safety, dose-finding and early assessment of efficacy. In ongoing and upcoming Phase III trials, the benefit for the patient needs to be demonstrated. To conclude the actual benefit of tumor-specific imaging agents, the determination of clinical endpoints for innovative clinical trials is key. Additionally, uniformity between centers nationwide and worldwide is needed to decide whether a tracer has a positive impact on clinical decision-making.
Most Phase I and II clinical trials are performed in academic expertise centers. They are executed by trained PhD students and physician-scientists, specific fluorescent cameras and experienced personnel in the surgical theatre. Furthermore, in these exploratory studies, imaging expertise is critical to determine the actual usefulness of a novel imaging agent in the investigated disease type. Nowadays, there are a few fluorescent imaging agents that have the potential for clinical implementation.
Thus, Phase III trials are the next step in which the benefit for patients needs to be proven. To do so, the use and eventually ease of fluorescence-guided surgery should not only be demonstrated in expertise centers (mainly academic centers), but also in peripheral hospitals with clinicians that do not have highly expert fluorescence imaging experience. Therefore, selecting optimal, easy-to-implement fluorescent imaging workflows and training of non-expertise centers is a pre-requisite for providing reliable and reproducible data. Additionally, clinical endpoints for innovative clinical trials need to be established to determine the actual benefit of tumor-specific imaging agents.
Long-term clinical endpoints for fluorescence-guided surgery.
The main question prior to a Phase III trial is: what is the benefit for the patient after fluorescence-guided surgery? A common outcome parameter in Phase I and II trials is the incidence and detection of a tumor-positive resection margin. However, it is unclear whether a decline of tumor-positive surgical margins after fluorescence-guided resection is directly correlated with a better patient outcome. Therefore, ideally disease-free survival and overall survival should be used to determine the overall effect of the image-guided resection.
Nevertheless, the timeline of determining these outcome parameters is long. Namely, it takes about 5-10 years to measure the impact. Especially in patients of which the overall prognosis is relatively good. For example, breast cancer patients with an overall 10-year survival of over 80%. Moreover, as surgery is not the only treatment modality in most solid tumors, the direct effect of fluorescence-guided surgery alone in disease-free and overall survival is difficult to establish.
Short-term clinical endpoints for fluorescence-guided surgery.
Therefore, the use of margin radicality is a convenient short-term endpoint. It can be determined relatively easy based on fluorescence imaging data. We advise to evaluate this endpoint by using intraoperative pathology assisted surgery (IPAS). Namely, there is international consensus on the definition per tumor type of a free resection margin based on final histopathology. During this workflow, the resection margin of the surgical specimen can be imaged directly after surgical excision. Identifying the mean fluorescence intensity and suspected areas on the surgical margin with dedicated ex vivo imaging systems (i.e., back-table imaging) can lead to direct surgical decision making in the operating theatre. By comparing the incidence of margin radicality of patients who underwent fluorescent guided analysis of the resection margin (IPAS) to patients who underwent standard of care surgery, the imaging outcome can be correlated to the final histopathological and clinical outcome.
Moreover, we need to evaluate the need and incidence for adjuvant treatment if a tumor-positive margin is diagnosed. This is due to the fact that adjuvant treatment comes with a price for the individual patient in terms of morbidity and even sometimes mortality. Obviously, this comes paired increased health care costs. Consequently, the use of postoperative “complications” rate, such as the need for a reoperation and/or to perform adjuvant treatment, and Patient Reported Outcome Measures (so-called PROMs) can be used as clinical endpoints for clinical trials.
Clinical decision-making during fluorescence-guided surgery.
As mentioned above, besides determining feasible clinical endpoints, adequate training of participating clinicians is extremely important for fluorescence-guided surgery. In the current surgical theatre, there is a wide range of commercially available camera systems (open, laparoscopic and robotic). These imaging devices each generate different imaging outcomes with different settings and (semi-)quantitative fluorescent imaging data. When evaluating the imaging results, the variability of image output of various camera systems should be taken into account. Furthermore, it should be interpreted by experts or controlled by the use of standardized fluorescent imaging phantoms.
Therefore, in the execution of Phase III trials, the presence of an imaging expert during surgery is crucial. At the same time, intermediate inter- and intra-observer agreement evaluation combined with the use of imaging phantoms controlling for uniformity of camera settings and imaging sessions for each individual center is vital. These requirements can guide surgeons through surgery and image interpretation, and therefore, adequate and reliable clinical decision making. In turn, this serves the final market authorization of the data obtained by a pivotal phase III trial.
Task forces to determine clinical endpoints.
The translation of Phase I and II fluorescence feasibility studies towards standard clinical implementation needs adequate determination of trial endpoints. The endpoints for each disease-entity under study should be discussed, established and confirmed in (national) task forces. These task forces are led by experts on optical imaging and cooperative clinicians from all specialties. The identification of short-term postoperative results, like radicality and postoperative complications, including PROMs, are potential outcome parameters to evaluate the effect of fluorescence-guided surgery in multicenter Phase III trials. Furthermore, it is believed that a standardized back-table imaging protocol focusing on the surgical specimen, especially in tumor-specific fluorescence imaging, is a critical factor for adequate interpretation of imaging data. The mentioned task force needs to develop standardized, easy to handle imaging protocols to obtain reliable imaging results.
At TRACER, we help determine clinical endpoints, provide training platforms, standardized imaging phantoms, and cross-correlation with histopathology imaging reports. This is essential to ensure a successful translation into a manageable, reliable clinical study design assisting in future market authorization.