Neoadjuvant triple-modality therapy with immune checkpoint blockade, anti-angiogenesis, and chemotherapy enhances pathologic response and survival in locally advanced and metastatic colorectal cancer: a multicenter cohort study.

Abstract

Objective: The current study seeks to investigate the clinical outcomes of combining immune checkpoint blockade, anti-angiogenesis, and chemotherapy in neoadjuvant treatment for individuals diagnosed with locally advanced (high-risk Stage III or initially unresectable Stage III) or resectable/unresectable Stage IV colorectal cancer, including metastatic cases.

Methods: A total of 120 individuals diagnosed with advanced colorectal cancer (stage III: n = 65; stage IV: n = 55; metastatic sites: liver n = 30, lung n = 15, peritoneal n = 10) were enrolled at three hospitals between February 2021 and December 2022. All patients underwent biopsy and pathology confirmation. Based on the treatment plan, patients were categorized into a control group (n = 60) receiving standard FOLFOX/FOLFIRI chemotherapy and an experimental group (n = 60) receiving a combination of pembrolizumab (200 mg IV q3w), bevacizumab (5 mg/kg IV q2w), and FOLFOX regimen (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-fluorouracil 400 mg/m² bolus followed by 2400 mg/m² infusion over 46 h). VEGF and bFGF levels were assessed using ELISA before and after treatment. Flow cytometry analyzed CD4 + levels and the CD4 + /CD8 + ratio, while serum tumor markers Cancer antigen 199 (CA 19-9) and Carcinoembryonic antigen (CEA) were measured by chemiluminescence immunoassay. Therapeutic outcomes, median OS, and median PFS were compared between the two groups using Kaplan-Meier analysis and log-rank tests (normality confirmed via Shapiro-Wilk test).

Results: After a 6-week treatment period, the experimental group showed a more significant reduction in VEGF (Δ = 132.0 pg/mL vs. 57.9 pg/mL) and bFGF (Δ = 51.4 pg/mL vs. 20.1 pg/mL) compared to the control group (P < 0.001). The experimental group demonstrated higher CD4 + /CD8 + ratios post-treatment (1.65 vs. 1.23, P < 0.01) and greater reductions in CA 19-9 (Δ = 42.5 U/mL vs. 23.8 U/mL) and CEA (Δ = 12.6 ng/mL vs. 6.9 ng/mL) (P < 0.01). Response rates (CR + PR: 40.0% (Experimental: 8.3% CR + 31.7% PR) vs. 18.4% (Control: 1.7% CR + 16.7% PR); DCR: 46.7% vs. 25.0%) and survival outcomes (median OS: 32.26 vs. 28.55 months; median PFS: 6.37 vs. 4.58 months) were superior in the experimental group (P < 0.05).

Conclusion: Combining neoadjuvant therapy with immune checkpoint blockade, anti-angiogenesis, and chemotherapy significantly improves tumor downstaging (as evidenced by pathologic complete response rates of 18% in the experimental group vs. 5% in the control group among resected patients) and survival outcomes, presenting a promising therapeutic approach for locally advanced and oligometastatic colorectal cancer.