A phase III randomized clinical trial evaluating perioperative therapy (neoadjuvant chemotherapy versus chemoradiotherapy) in locally advanced gallbladder cancers (POLCAGB).

Abstract

4007 Background: Locally advanced Gallbladder cancers (LAGBC)initially deemed not suitable for R0 resection receive either neoadjuvant chemotherapy (NACT)or neoadjuvant chemoradiation (NACRT)downstaging for resection and to improve outcomes. Methods: This is a randomized phase 3 trial (NCT02867865) that included fit patients with LAGBC adenocarcinoma,. T3/T4 with liver infiltration ( > 2cm, < 5cm); N1 nodal status; obstructive jaundice (type I/II biliary obstruction) ;duodenal or colonic abutment with no mucosal infiltration , < 180°vascular involvement. The patients were randomized (1:1) to NACT arm (Gemcitabine + platinum for four cycles) versus NACRT arm (55 -57Gy with concurrent gemcitabine followed by two cycles of chemotherapy) and were then evaluated for surgery. A sample size of 314 patients was required to detect a 5.5 months difference (11 mo.to 16.5 mo in the test arm) with median overall survival (OS) as the primary endpoint (hazard ratio, 0.7; 2-sided α = 0.05; β = 0.2). Secondary endpoints were event free survival (EFS),R0 resection rates and post-operative complication rates. Due to slow accrual Institutional Ethics committee requested the investigators for interim analysis and approval was obtained for the same. Results: From Oct 2016 to Sept 2024 , 124 patients (64 NACT, 60 NACTRT)were enrolled at 2 centers. At the time of analysis 93 OS events were observed in 124 patients. Median follow-up was 62 (range 6.9-94) months. More number of patients underwent R0 resection in NACRT than NACT arm 51.6 vs 29.7% (p = 0.01) In the intention to treat analysis, the NACTRT arm showed improved OS compared to the NACT arm [21.8 mo.vs.10.1 mo. p = 0.006]. EFS was 10.6 mo. vs 4.9 months, p = 0.006]. Similar results were noted in the per protocol analysis(n = 110). Clavien Dindo postoperative morbidity of grade 3 and above was 4/22 (18.18%) in NACT arm vs 9/32(28.12%) in NACRT arm (p = 0.30). The interim analysis demonstrated a significant improvement in efficacy in the NACRT arm. Based on the current data, the conditional power was calculated to be 99.96%. Conclusions: This trial demonstrates that the addition of concurrent chemoradiation to chemotherapy improves overall survival and resection rates in patients with locally advanced gallbladder cancers. These results provide important evidence to guide treatment decisions in this traditionally difficult to treat set of gallbladder cancers. Clinical trial information: NCT02867865 . Treatment outcomes. Outcome measures NACTRTN=60 NACTN=64 HR p Patients surgically explored 39(65%) 29(45.3%) 0.03 Patients undergoing R0 resection 31 (51.6%) 19 (29.7%) 0.01 Median OS (months) (95% CI) 21.8 (14.6-29.14) 10.1 (8.5-11.7) HR- 0.5695%CI- 0.37-0.84 0.006 5 Year survival (95% CI) 27 (17.7-43)% 18 (10-31) % EFS (months) (95% CI) 10.6 (6.07-15.5-15) 4.89 (3.06-6.73) HR-0.5895%CI- 0.39-0.85 0.006 5 Yr EFS (%) 21 (12-35.7)% 12.7 (6-24.6)%