Fluorescence-guided surgery for cancer patients: a proof of concept study on human xenografts in mice and spontaneous tumors in pets

Abstract

Surgery is often the first treatment option for patients with cancer. Patient survival essentially depends on the completeness of tumor resection. This is a major challenge, particularly in cases of peritoneal carcinomatosis, where tumors are widely disseminated in the large peritoneal cavity. Any development to help surgeons visualize these residual cells would improve the completeness of the surgery. For non-disseminated tumors, imaging could be used to ensure that the tumor margins and the draining lymph nodes are free of tumor deposits.Near-infrared fluorescence imaging has been shown to be one of the most convenient imaging modalities. Our aim was to evaluate the efficacy of a near-infrared fluorescent probe targeting the αvβ3 integrins (Angiostamp™) for intraoperative detection of tumors using the Fluobeam® device.We determined whether different human tumor nodules from various origins could be detected in xenograft mouse models using both cancer cell lines and patient-derived tumor cells. We found that xenografts could be imaged by fluorescent staining irrespective of their integrin expression levels. This suggests imaging of the associated angiogenesis of the tumor and a broader potential utilization of Angiostamp™. We therefore performed a veterinary clinical trial in cats and dogs with local tumors or with spontaneous disseminated peritoneal carcinomatosis. Our results demonstrate that the probe can specifically visualize both breast and ovarian nodules, and suggest that Angiostamp™ is a powerful fluorescent contrast agent that could be used in both human and veterinary clinical trials for intraoperative detection of tumors.

Preliminary safety and imaging efficacy of the near-infrared fluorescent contrast agent DA364 during fluorescence-guided surgery in dogs with spontaneous superficial tumors

“…The TBRs varied greatly between and within tumor types, as also observed in recent veterinary trials assessing another integrin-targeting probe [24,25]. Interestingly, the melanoma showed the lowest TBR, probably because the dark pigmented lesion strongly absorbed the excitation light.…”

“…The use of fixed-distance intra-operative camera systems with automatic thresholding algorithms may also help to overcome these shortcomings in future trials. Two previous veterinary clinical trials described the use of an integrin-targeting probe containing a cyclodecapeptide scaffold with 4 c (RGDfK) motifs and a fluorescent dye (Angiostamp, Fluoptics, Grenoble, France), during fluorescence-guided surgical resection of tumors in cats and/or dogs using the Fluobeam system [24,25]. In the first trial, 12 cats with fibrosarcoma underwent fluorescence-guided surgery [24], whereas in a second study only one cat with mammary gland tumors and three dogs with different tumor types (mammary gland (2) and/or ovarian (2) disseminated tumors) were enrolled [25].…”

The feasibility of folate receptor alpha- and HER2-targeted intraoperative fluorescence-guided cytoreductive surgery in women with epithelial ovarian cancer: A systematic review

“…For example, metastatic lymph nodes could be detected with fluorescence imaging in animal models of head and neck cancer using the αvβ3 integrin as a target [43]. This integrin is also overexpressed in some EOCs and shows promising results as a target in FGCS on EOC animal-models [44][45][46]. An additional reason to include multiple imaging agents, and thereby targeting different EOC markers, is [47,48].…”

Fluorescence‐guided surgery using indocyanine green in dogs with superficial solid tumours

“…The use of contrast agents engineered to recognise a specific marker of cancer (eg, antigens overexpressed by tumours) may address this shortcoming. Indeed, the use of molecularly targeted contrast agents is investigated in several human47–49 and canine17 50–53 fluorescence‐guided surgery trials. A canine trial described the intravenous administration of a fluorescent imaging agent that was activated by proteases in vivo in 19 dogs with soft tissue sarcomas or mast cell tumours.…”