A multicenter randomized phase II trial of AHCC combined with multidisciplinary treatment for resectable/borderline resectable pancreatic ductal adenocarcinoma (jRCTs051200029).

LBA4226 Background: Malnutrition, impaired immunity, and limited tolerance to intensive chemotherapy remain major challenges in the multidisciplinary treatment of pancreatic ductal adenocarcinoma (PDAC). AHCC, a standardized extract derived from cultured Lentinula edodes mycelia, has demonstrated immunomodulatory, anti-inflammatory, and antioxidant effects and may enhance tolerance to chemotherapy. This multicenter randomized phase II trial was designed to evaluate whether long-term administration of AHCC improves clinical outcomes in patients with resectable (R) or borderline resectable (BR) PDAC undergoing multimodal treatment. Methods: This investigator-initiated, double-blind, placebo-controlled, multicenter phase II trial enrolled 230 patients with histologically confirmed resectable or borderline resectable PDAC across eight high-volume centers in Japan. Patients were randomly assigned in a 1:1 ratio to receive oral AHCC (3.0 g/day) or matched placebo, starting from the initiation of neoadjuvant therapy and continuing for up to two years postoperatively. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included 2-year overall survival (OS), treatment compliance, chemotherapy-related adverse events, and longitudinal changes in nutritional and immune parameters across treatment phases, including neoadjuvant therapy, adjuvant therapy, and post-recurrence treatment. Survival analyses will be conducted according to the intention-to-treat principle. Results: A total of 230 patients (115 per arm) were analyzed with balanced baseline characteristics. The resection rate tended to be higher in the AHCC group than in the placebo group (86.1% vs 77.4%, P=0.088). For the entire cohort, median OS was 45.1 months and median DFS 22.6 months. The primary endpoint, 2-year DFS, did not differ between groups (22.6 vs 19.2 months, P=0.809). However, median OS was significantly longer in the AHCC group (NR) than in the placebo group (38.8 months, P=0.026). Among patients with recurrence (n=135), post-recurrence survival was significantly longer in the AHCC arm (20.8 vs 10.8 months, P=0.006), whereas no difference was observed among patients without recurrence (both NR, P=0.720). Completion of neoadjuvant and adjuvant therapy rates were similar between groups. At 24 months after treatment initiation, immune-nutritional indices were significantly better preserved in the AHCC group, including NLR, PNI, CAR, and PLR (all P<0.001). Conclusions: Although AHCC did not significantly improve DFS, it was associated with significantly prolonged overall survival, particularly among patients with recurrence. Preservation of immune-nutritional status may have contributed to the observed survival benefit. Clinical trial information: jRCTs051200029.