A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis

Abstract

Background: Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) study.

Methods: The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor.

Results: In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%–10.9%] vs 45.6% [28.9%–72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit.

Conclusions: Bicarbonate markedly enhances the anticancer activity of TACE.

Funding: Funded by National Natural Science Foundation of China.

Clinical trial number: ChiCTR-IOR-14005319.

Keywords: bicarbonate; cancer biology; hepatocellular carcinoma; human; lactic acidosis; transarterial chemoembolization.

Conflict of interest statement

No competing interests declared.

Figures

Figure 1.. Viable tumor residues (VTR) after treatment of cTACE verus TILA-TACE.

Patients’ demographic parameters were described in Table 1. The relative therapeutic improvement by TILA-TACE was 81.1%. Relative therapeutic improvement by bicarbonate is defined as [(μ1-μ2)/μ1] × (100%), where μ1 is the mean of viable tumor residues after treatment (cTACE) and μ2 the mean residual after treatment (TILA-TACE), and the maximal therapeutic improvement is 100%. Differences in VTR between two groups were statistically significant (p<0.0001), as assessed using the general linear model after adjustment for viable tumor volume before treatment

Figure 2.. Tumor objective response to cTACE or TILA-TACE categorized according to EASL criteria.

Rate of tumor response to treatment and representative MRI images of tumor before and after treatment (A) in the cTACE group (n=27) and (B) in the TILA-TACE group (n=30). (C) The difference in tumor responses between two groups was statistically significant (p<0.0001), as assessed by the proportional odds model after adjustment for viable tumor volume before treatment. CR, complete necrosis; PR, viable tumor volume less than 50% of the viable tumor volume before treatment; SD, viable tumor volume larger than 50% of the viable tumor volume before treatment; PD, viable tumor volume larger than 100% after treatment.

Figure 3.. Viable tumor residues after treatment with cTACE or TILA-TACE in the randomized controlled study.

The relative therapeutic improvement by TILA-TACE was 80.1%. Differences in VTR between two arms were statistically significant (p=0.0009), as assessed using the general linear model after adjustment for viable tumor volume before treatment.

Figure 4.. Tumor objective response to cTACE or TILA-TACE according to EASL criteria.

Twenty patients were randomly assigned to treatment of cTACE or TILA-TACE. (A) Tumor response rate to cTACE and representative MRI images of tumor before and after treatment. 10 patients were treated with cTACE. (B) Tumor response rate to TILA-TACE and representative MRI image of tumor before and after treatment. 10 patients were treated with TILA-TACE. (C) The pattern of tumor response to TILA-TACE and cTACE. The difference between 2 groups was statistically significant (p=0.003), as assessed using proportional odds model. CR, complete necrosis; PR, viable tumor volume less than 50% of the viable tumor volume before treatment; SD, viable tumor volume larger than 50% of the viable tumor volume before treatment; PD, viable tumor volume larger than 100% after treatment.

Figure 5.. Kaplan-meier analysis of cumulative survival of patients receiving TILA-TACE or cTACE treatment.

(A) Cumulative survival of patients described in Table 1. p=0.0052. (B) Survival of patients described in Table 2. Left panel, all patients; right panel, patients who initially assigned to cTACE but subsequently crossed over to TILA-TACE treatment were excluded. p>0.05. (C) Cumulative Survival of patients pooled from Table 1 and 2. p=0.0133.