Periodic Reporting for period 1 - TAcTIC (TArgeTed molecular Imaging and surgery for gastro-intestinal Cancer)
Période du rapport: 2019-08-01 au 2021-01-31
Incomplete tumor removal during oncologic gastrointestinal (GI) resections is associated with higher recurrence and mortality rates. Because neoadjuvant chemo-radiotherapy has become a standard treatment modality for GI cancers, subsequent downstaging makes identification of the primary tumor vs. healthy or scar tissue during surgery even more challenging. Near infrared (NIR) fluorescence imaging can aid surgeons in delineating tumors by selectively enhancing malignant tissue in real-time. The Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in epithelial cancers, making it a promising target for GI cancer imaging. We have developed an EpCAM-specific fluorescent agent and performed a study for the clinical translation, that commenced with a phase I first-in-human study in healthy volunteers to evaluate the safety, tolerability and pharmacokinetics (PK). Subsequently, a pilot study was performed in oncologic patients to assess its feasibility for the fluorescence imaging and detection of lower GI (i.e. colorectal) and upper GI (i.e. gastric and oesophageal) cancers.
The studies demonstrated a successful clinical translation, where the EpCAM-specific fluorescent agent was demonstrated to be safe and well tolerated in healthy volunteers patients without signs of toxicity or hypersensitivity reactions. Further development of the EpCAM-specific fluorescent agent for widespread use in oncologic surgery may be warranted given the ubiquitous overexpression of EpCAM on different types of epithelial tumors.
The study empowered tumor fluorescence during open surgery of colorectal, gastric and oesophageal cancer with clear tumor demarcation ex vivo. Remarkably, it also disclosed no fluorescence in patients with a complete response of tumor and locoregional lymph nodes, plausibly signifying that the EpCAM-specific fluorescent agent is tumor-specific, as it did not bind to chemoradiotherapy-induced fibrosis. This stipulates that the EpCAM-specific fluorescent agent may be a promising tool for the management of cancer patients as it can play a role in the endoscopic surveillance of rectal and oesophageal cancer patients eligible for the Watch-and-Wait (W&W) strategy after neoadjuvant therapy. The W&W strategy was implemented as an organ-preserving approach to decrease morbidity and improve long-term quality of life by preventing unnecessary surgery in patients with a clinical complete response after neoadjuvant therapy. In rectal cancer, local tumor regrowth rates occur in up to 25% of patients, where it is almost exclusively situated within the bowel wall. In oesophageal cancer, chemoradiotherapy with and without surgery are both widely accepted therapeutic approaches for the curative treatment of locally advanced oesophageal cancer. A prospective randomized controlled trial showed that the addition of surgery after chemoradiotherapy, improves local tumor control but doesn’t increase the survival rate as this is similar between patients receiving chemoradiotherapy and surgery or chemoradiotherapy alone. These findings make it sensible that NIR endoscopy with the EpCAM-specific fluorescent agent could be a safe and beneficial value in monitoring tumor regrowths in rectal and oesophageal cancer patients. In addition, EpCAM could be useful in the endoscopic screening methods for gastric and oesophageal cancers to help diagnose these tumors in an earlier stage. More than 70% of the gastric cancers are diagnosed in an advanced-stage due to a lack of specific clinical signs of early gastric cancer, also clarifying the dull prognosis of this cancer type. Hence, screening techniques play an important role in earlier detection for improved outcomes and mortality rates. Alternative techniques have previously been suggested to improve the performance of endoscopy for better detection of pre-cancerous gastric or oesophageal lesions, such as chromoendoscopy or the use of an antiperistaltic agent. NIR endoscopy with the EpCAM-specific fluorescent agent could also aid in this respect to accentuate (pre)cancerous lesions that are difficult to identify with conventional endoscopy.
The studies demonstrated a successful clinical translation, where the EpCAM-specific fluorescent agent was demonstrated to be safe and well tolerated in healthy volunteers patients without signs of toxicity or hypersensitivity reactions. Further development of the EpCAM-specific fluorescent agent for widespread use in oncologic surgery may be warranted given the ubiquitous overexpression of EpCAM on different types of epithelial tumors.
The study empowered tumor fluorescence during open surgery of colorectal, gastric and oesophageal cancer with clear tumor demarcation ex vivo. Remarkably, it also disclosed no fluorescence in patients with a complete response of tumor and locoregional lymph nodes, plausibly signifying that the EpCAM-specific fluorescent agent is tumor-specific, as it did not bind to chemoradiotherapy-induced fibrosis. This stipulates that the EpCAM-specific fluorescent agent may be a promising tool for the management of cancer patients as it can play a role in the endoscopic surveillance of rectal and oesophageal cancer patients eligible for the Watch-and-Wait (W&W) strategy after neoadjuvant therapy. The W&W strategy was implemented as an organ-preserving approach to decrease morbidity and improve long-term quality of life by preventing unnecessary surgery in patients with a clinical complete response after neoadjuvant therapy. In rectal cancer, local tumor regrowth rates occur in up to 25% of patients, where it is almost exclusively situated within the bowel wall. In oesophageal cancer, chemoradiotherapy with and without surgery are both widely accepted therapeutic approaches for the curative treatment of locally advanced oesophageal cancer. A prospective randomized controlled trial showed that the addition of surgery after chemoradiotherapy, improves local tumor control but doesn’t increase the survival rate as this is similar between patients receiving chemoradiotherapy and surgery or chemoradiotherapy alone. These findings make it sensible that NIR endoscopy with the EpCAM-specific fluorescent agent could be a safe and beneficial value in monitoring tumor regrowths in rectal and oesophageal cancer patients. In addition, EpCAM could be useful in the endoscopic screening methods for gastric and oesophageal cancers to help diagnose these tumors in an earlier stage. More than 70% of the gastric cancers are diagnosed in an advanced-stage due to a lack of specific clinical signs of early gastric cancer, also clarifying the dull prognosis of this cancer type. Hence, screening techniques play an important role in earlier detection for improved outcomes and mortality rates. Alternative techniques have previously been suggested to improve the performance of endoscopy for better detection of pre-cancerous gastric or oesophageal lesions, such as chromoendoscopy or the use of an antiperistaltic agent. NIR endoscopy with the EpCAM-specific fluorescent agent could also aid in this respect to accentuate (pre)cancerous lesions that are difficult to identify with conventional endoscopy.