Protocol for Evaluation of Oncological Treatment in Patients With CRLM Using Zebra Fish Avatars-may This Model Improve Resection Rates and Survival in Patients With Upfront Non-resectable Metastatic Disease?

The possibilities to predict oncological tumor response for individual patients with GI malignancies in order to tailor a personalized oncological treatment, are currently limited. This means that most of the information used to decide upon oncological treatment pertains to a group of patients rather than individuals. Similarly, most of the chemotherapy regimens used is not individually tailored although it has been shown to be beneficial for certain cohorts of patients. In colorectal cancer, KRAS (Kirsten rat sarcoma) and BRAF mutation status predict the response to drugs targeting various steps in the EGFR/KRAS/BRAF signaling pathway, whereas MSI/MMR status may predict the outcome of immune checkpoint inhibitors [1]. As chemotherapy, as well as other cancer treatments, may have severe side effects the treatment may not only be ineffective but may also cause severe adverse events even shortening the patient's life and inhibit the chance of curative tumor resection. For this reason, pre-treatment response evaluation in an avatar model of zebrafish, would be most valuable.

From a clinical point of view the easiest situation is in the adjuvant setting. At this point the whole tumor is available for analysis and larger pieces of tissues may be used in the avatar model. 5-fluorouracil or capecitabine (a 5-FU prodrug) either alone or in combination with oxaliplatin is the current standard adjuvant treatment in stage III colon cancer and stage II colon cancers with 2+ risk factors. Other types of combination regimens including e.g. irinotecan have so far failed to show benefit in the adjuvant situation.

In the neoadjuvant setting, i.e. preoperative treatment to patients with resectable CRLM, combinations of 5-FU (or capecitabine) and either oxaliplatin or irinotecan may improve the outcome of surgery and long term prognosis. It is currently not known which regimen is most efficient for the individual patient.

In the most severe scenario, where the patient presents with unresectable CRLM, either palliative chemotherapy or downsizing/conversion chemotherapy is indicated. For the latter group of patients, it is of uttermost importance to provide as potent treatment as possible in the first line, as the 10

The therapeutic window is narrow and further clinical and/or radiological progression on the first line therapy may preclude further oncological and surgical interventions. Fit patients may benefit from a triplet of 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI). However, this is a toxic regimen, and older or less fit patients are more commonly offered a doublet of 5-FU and either oxaliplatin or irinotecan. There may be an additional value when the chemotherapy is combined with antibodies targeting VEGF or, for those tumors expressing wild type KRAS, the EGF receptor.