We previously revealed that intratumoral lactic acidosis was a key factor to protect cancer cells against glucose deprivation-induced death and unraveled the underlying mechanisms. When lactic acidosis was converted to lactosis by a base, its protective role was abolished. Transarterial chemoembolization (TACE), a major modality for unresectable hepatocellular carcinoma (HCC), kills cancer cells through occluding tumor afferent arteries and delivering concentrated anticancer drugs locally into tumors. Meanwhile, TACE also enhances and traps intratumoral lactic acidosis, which may permit cancer cell surviving under stresses, antagonizing anticancer activity of TACE. According to our hypothesis, converting intratumoral lactic acidosis to lactosis by a base in combination with TACE, may deliver far more robust anticancer effects than TACE alone. Here we attempt to test this hypothesis.
Methods:This is a single-armed study. 59 patients (38 BCLC B stage and 21 BCLC C stage) bearing large HCC (5-17 cm) received a modified TACE (TILA-TACE, targeting-intratumoral-lactic-acidosis TACE) treatment. In TILA-TACE, 5% sodium bicarbonate, which was to convert intratumoral lactic acidosis to lactosis, was infused through tumor feeding arteries alternatively with doxorubicin-lipiodol emulsion with the dose adjusted to tumor size, followed by permanent embolization. Retreatment was based on the evidence of viable tumor residuals. The portal vein tumor thrombosis and hepatic vein tumor thrombosis of patients of BCLC C category were treated with conformal radiotherapy. The primary endpoints were objective response rate (ORR) to treatment and overall survival (OS).
Results and clinical implications:
1. One course of TILA-TACE treatment achieved 100%. The average ORR responding to cTACE reported globally was 35%.
2. The 1-, 2-, and 3-year survivals of the 59 patients (38 BCLC B stage and 21 BCLC C stage) receiving TILA-TACE treatment were 78.2%, 61.8%, and 56.1%, respectively, with a median survival beyond 41 months.
3. The study highlighted a beyond 3-year median survival of advanced HCC patients. The 1-, 2-, and 3-year OS of HCC patients of BCLC stage C category were 78.4%, 56.0%, and 56.0%, respectively, but the median survival of these patients was not reached. It is well known that even treated with sorafenib, the recommended therapy for advanced HCC, the median survival of patients of this category was less than 1 year.
4. Also notably, 27 patients with HCC > 10 cm were 100% responded to TILA-TACE treatment with 44.4% CR. The 1-, 2-, and 3-year survivals were 79.2%, 67.9%, and 67.9%, respectively, with a median survival beyond 3 years. It has been well recognized that tumor > 10 cm is a relative contraindication for cTACE treatment. It was reported that CR rate was 0% in tumor >10 cm and the median survival for patients with HCC > 10 cm treated with cTACE was around 10 months.
This pilot study supports our hypothesis that neutralizing intratumoral lactic acidosis may deliver a novel approach to control tumors whose glucose supply could be blocked through occluding tumor feeding vessels. The next step is to design a prospective randomized controlled study.
Citation Format: Ming Chao, Hao Wu, Kai Jin, Bin Li, Jianjun Wu, Guangqiang Zhang, Xun Hu. Neutralizing intratumoral lactic acidosis markedly enhances the efficacy of TACE for intermediate and advanced hepatoceullar carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-247.