The efficacy and safety of Zengxiao Jiandu decoction combined with definitive concurrent chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a randomized, double-blind, placebo-controlled clinical trial

BACKGROUND: Traditional Chinese medicine (TCM) makes a synergistic and attenuative effect when combined with chemoradiotherapy. However, strong evidence-based studies are lacking. The study sought to investigate whether Zengxiao Jiandu decoction as an adjunctive therapy is superior to definitive concurrent chemoradiotherapy (DCCRT) alone in unresectable, locally advanced (LA), stage III non-small cell lung cancer (NSCLC). METHODS: Patients with unresectable LA-NSCLC were randomly assigned to receive DCCRT either combined with Zengxiao Jiandu decoction (TCM arm) or placebo therapy (Control arm), by computer-generated random assignment lists using a central randomization system. The patients were routinely followed-up every 3 months for the first 2 years after the therapy, and every 6 months for the subsequent 3 years, or earlier if clinically indicated. The primary endpoint was grade ≥3 chemoradiotherapy-related toxicities, while secondary endpoints included the completion rate of chemoradiotherapy, the clinical objective response rate (ORR), and survival. The placebo achieved full consistency in color, aroma, taste and appearance with the Zengxiao Jiandu decoction. RESULTS: From February 2019 to December 2020, 163 patients were randomly allocated to TCM arm (n=82) or Control arm (n=81). Fifty-nine (72.0%) patients in TCM arm finished chemoradiotherapy per protocol and 79 (96.3%) received protocol-specified Zengxiao Jiandu decoction. Forty-two patients in Control arm finished chemoradiotherapy per protocol. The incidence of grade ≥3 chemoradiotherapy-related toxicities was higher in Control arm than TCM arm (44.4% vs. 31.7%, P=0.094). Grade ≥3 radiation pneumonitis occurred more frequently in Control arm than TCM arm (13.6% vs. 3.7%, P=0.024). The completion rate of the protocol-specified chemotherapy was significantly higher in TCM arm than Control arm (79.3% vs. 64.2%, P=0.033), but the completion rates of the definitive-dose radiotherapy were similar. There were no significant differences in ORR between the 2 arms. The progression-free survival (PFS) of TCM arm was significantly better than Control arm (median PFS, 12.0 vs. 9.0 months, P=0.035). However, Zengxiao Jiandu decoction was not found to produce any significant benefit in overall survival. CONCLUSIONS: The Zengxiao Jiandu decoction adjunctive therapy, as compared to DCCRT alone, reduced grade ≥3 radiation pneumonitis, improved the completion rate of DCCRT, and prolonged PFS for unresectable LA-NSCLC. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000031667.