A Novel Multi-Mode Thermal Therapy for Colorectal Cancer Liver Metastasis: A Pilot Study

Abstract

A novel multi-mode thermal therapy was developed for local tumor ablation and the systemic stimulation of anti-tumor immunity, consisting of a rapid liquid nitrogen freezing, and followed by the radiofrequency heating of target tumor tissue. This pilot study aimed to compare the therapeutic effects of the new therapy with conventional radiofrequency ablation (RFA) on patients with colorectal cancer liver metastasis (CRCLM). From August 2016 to September 2019, thirty-one patients with CRCLM received either multi-mode thermal therapy (n = 17) or RFA (n = 14). Triphasic contrast-enhanced magnetic resonance imaging (MRI), routine blood tests, and peripheral blood immune responses were evaluated before the treatment and in 1, 3, 6, and 12 months after. Local tumor response and progression-free survival (PFS) were assessed using the Kaplan-Meier method, and pre- and post-treatment immune cell counts were analyzed using Mann-Whitney U and Wilcoxon tests. A significantly longer PFS was observed in the multi-mode thermal therapy group in comparison to that of the conventional RFA group (median, 11.4 versus 3.4 months, p = 0.022). It was found that multi-mode therapy induced the functional maturation of dendritic cells, promoted CD4⁺ T cell-mediated antitumor responses, and decreased regulatory T cells, contributing to better therapeutic efficacy in CRCLM patients.

Keywords: colorectal cancer liver metastasis; multi-mode thermal therapy; thermal immune response.

Figure 1

Operational procedure of the multi-mode thermal therapy: a representative case. (A) The axial CT imaging showing a 40 mm liver tumor in the patient; (B) the plan for freezing; (C) the plan for heating; (D) freezing process using seven cryo-probes (CryoHitTM, GALIL Medical, Israel). The low signal area near the cryo-probes indicating the formation of ice ball; (E) the first step of radiofrequency ablation (RFA), the probe with 4.0 cm active tip (MedSphere, Shanghai, China) inserted to the bottom of the tumor; (F) the staged retreat heating process to make the heating range cover the entire tumor.

Figure 2

Multi-mode thermal therapy prolongs the progression-free survival (PFS) in patients with malignant hepatic tumors. (A) Imaging assessment of a patient treated with multi-mode thermal therapy; (B) summary of the long-term and short-term PFS patients in the multi-mode and radiofrequency ablation (RFA) groups; (C) summary of the follow-up status and the results of follow-up termination of all patients; (D) Kaplan-Meier curves for PFS. The p-value indicating the between-group differences.

Figure 3

Multi-mode therapy reversed the patients’ preoperative status with improved prognosis. The basic levels and the prognostic significance of the neutrophil-lymphocyte ratio (NLR) (A), lymphocytes (B), neutrophils (C), monocyte-lymphocyte ratio (MLR) (D), and monocytes (E) in the multi-mode therapy and conventional radiofrequency ablation (RFA) groups. * p < 0.05, the p-value indicating the between-group differences.

Figure 4

Changes in interleukin (IL)-12 and IL-10 expressions by the CD11c⁺CD86⁺ DCs in patients treated with the multi-mode thermal therapy or conventional radiofrequency ablation (RFA). (A–D) The proportion of CD11c⁺CD86⁺ DCs (A), the expressions of IL-12 (B) and IL-10 (C) in the CD11c⁺CD86⁺ DCs, and the IL-12/IL-10 ratio (D) at each time point were analyzed by flow cytometry. All data are shown as the means ± standard deviations (SDs). * p < 0.05, the p-value indicating the between-group differences.

Figure 5

Changes in CD4⁺ T cell subsets in patients treated with multi-mode and radiofrequency ablation (RFA) therapy. (A–F) The proportion of CD4⁺ T cells (A), the ratio of Th1/Th2 subsets (CD3⁺CD4⁺IFN-γ⁺/CD3⁺CD4⁺IL-4⁺) (B), the proportion of Tregs (CD3⁺CD4⁺CD25⁺Foxp3⁺) (C), the proportion of Th2 subsets (CD3⁺CD4⁺IL-4⁺) (D), the proportion of Th17 subsets (CD3⁺CD4⁺IL-17⁺) (E), and the expression of PD-1 on CD4⁺ T cells (CD3⁺CD4⁺PD-1⁺) (F) were analyzed by flow cytometry. All data are shown as the means ± standard deviations (SDs). * p < 0.05, ** p < 0.01, the p-value indicating the between-group differences.

Figure 6

Changes in CD8⁺ T cell subsets in patients treated with multi-mode and radiofrequency ablation (RFA) therapy. (A–D) The proportion of CD8⁺ T cells (A), the expression level of interferon (IFN)-γ (B), Granzyme-B (C), and Perforin (D) were analyzed by flow cytometry. All data are shown as the means ± standard deviations (SDs). * p < 0.05, ** p < 0.01, the p-value indicating the between-group differences.