FOLFOX-Based Transarterial Infusion Chemotherapy for Unresectable Colorectal Cancer: Protocol of an Open-Label, Multicentre, Randomised, Controlled, Phase Ⅱ Trial

CRC is the third leading cause of new cancer cases and the second leading cause of cancer-related deaths worldwide. Current therapeutic modalities for CRC include surgical resection, IVC, radiotherapy, immunotherapy, targeted therapy, and their combinations. As a mainstream systemic treatment for CRC, IVC leads to widespread drug distribution but relatively low intratumoral drug accumulation. Compared with IVC, TAIC involves selective arterial catheterization to deliver chemotherapeutic agents directly to the tumor feeding vessels. Hepatic tumors receive their blood supply predominantly through branches of the hepatic artery. Hepatic artery infusion chemotherapy (HAIC) yields significantly superior outcomes compared to IVC and is currently widely employed for the treatment of primary and secondary hepatic malignancies. HAIC in combination with IVC can offer long-term durable disease control in the clinical treatment of liver cancer compared with IVC. CRC is also predominantly grown through angiogenesis. Therefore, we raise the question whether sequential IVC administered after intensive TAIC achieves better clinical efficacy than IVC alone for the treatment of uCRC. However, no prospective clinical trials have been conducted to compare the efficacy of these two strategies. This prospective study was therefore designed to fill this clinical knowledge gap. We hypothesize that intensive TAIC followed by sequential IVC yields superior clinical efficacy compared with IVC alone for the treatment of uCRC. This is a prospective, multicenter, randomized, open-label clinical trial. It aims to investigate whether intensive TAIC followed by sequential IVC is clinically more effective than IVC alone in the treatment of uCRC. Eligible patients will be randomly allocated into two groups upon enrolment: the intervention group (TAIC group) and the control group (IVC group). Patients will be randomly assigned at a 1:1 ratio with no blinding implemented. Randomization will be conducted by an independent trial statistician via a secure system with complete allocation concealment using the permuted block randomization method. Stratification factors consist of primary tumor location, presence of liver metastases, RAS/BRAF mutational status, and participating study center. Patients in the control group will receive FOLFOX-based IVC every 2 weeks for a total duration of 8 weeks. Patients in the TAIC group will receive FOLFOX-based TAIC at Week 0 and Week 4 and receive FOLFOX-based IVC at Week 2 and Week 6. For patients with CRLM, targeted agent selection is determined based on the RAS and BRAF mutational status and the primary tumor location. The primary endpoint is ORR. The secondary endpoints include Quality-of-life (QoL), clinical complete response (cCR) rate, pathological complete response (pCR) rate, the rate of conversion to resection (CTR), overall survival (OS), progression-free survival (PFS), and AEs. Primary and secondary efficacy analyses will be conducted for both the intention-to-treat (ITT) population and the per-protocol (PP) population. Safety analyses will be based on patients who received at least one dose of the assigned study treatment. Categorical variables will be presented as counts and percentages, while continuous variables will be presented as means with standard deviations or medians with interquartile ranges, as appropriate. Pearson's chi-square test or Fisher's exact test will be used for between-group comparisons of categorical variables. Continuous variables will be compared using Student's t-test or the Mann-Whitney U test as appropriate. Longitudinal QoL scores will be analyzed using linear mixed-effects models for repeated measurements, which naturally accommodate missing data under the missing at random assumption. For time-to-event endpoints of OS and PFS, the Kaplan-Meier method and Cox proportional hazards regression analysis will be applied. Between-group survival differences will be assessed using the log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) will be estimated from Cox regression models. All statistical tests will be two-sided, and a P value < 0.05 will be considered statistically significant. All statistical analyses will be performed using the current version of R software. Patients in the IVC group will receive FOLFOX-based IVC every 2 weeks for a total duration of 8 weeks. The FOLFOX regimen consists of oxaliplatin (85 mg/m²) and leucovorin (400 mg/m²), each administered as a 2-hour intravenous infusion, and fluorouracil (2400 mg/m²) administered as a 44-hour continuous intravenous infusion.

For patients with CRLM, targeted therapy will be selected according to RAS/BRAF status and primary tumor side. Cetuximab will be administered by intravenous injection for the treatment of RAS/BRAF wild-type left-sided CRLM. Bevacizumab will be administered by intravenous injection for the treatment of RAS/BRAF wild-type right-sided CRLM and RAS/BRAF mutant CRLM irrespective of primary tumor location. Patients in the TAIC group will receive FOLFOX-based TAIC at Week 0 and Week 4 and receive FOLFOX-based IVC at Week 2 and Week 6. The FOLFOX-based TAIC consists of oxaliplatin (85 mg/m²) and leucovorin (400 mg/m²), each administered as a 2-hour transarterial infusion, and fluorouracil (2400 mg/m²) administered as a 44-hour continuous transarterial infusion. The IVC and targeted therapy regimens are the same as those in the IVC group. The dosage-calculation strategies of anticancer drugs, drug exposure and infusion durations, and supportive care, including symptom management and prevention of complications, do not differ significantly between TAIC and IVC groups. Treatment will be continued until disease progression (PD), unacceptable toxicity, or surgical resection. Prior to each TAIC procedure, the right femoral artery will be punctured using the Seldinger technique according to tumour vascular supply. A microcatheter will be advanced into the tumour-feeding branch of the superior mesenteric artery, inferior mesenteric artery or internal iliac artery. Chemotherapeutic agents will be administered through the microcatheter.