BACKGROUND: Survival rates of patients with advanced pancreatic cancer (APC) have been improved with palliative chemotherapy series. The current preferred first-line regimen consists of combination therapy of 5-fluorouracil (5-FU)/leucovorin (LV), irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus albumin-bound paclitaxel (GNP). After failure of first-line chemotherapy, there are a few options for subsequent therapy including switch to the unused first-line regimen or nano-liposomal irinotecan and 5-FU/LV. However, there are limited studies on the efficacy of third-line chemotherapy after failure of second-line chemotherapy. AIM: To identify patients with APC who might benefit from third-line chemotherapy. METHODS: Medical records from a single tertiary hospital were retrospectively reviewed between 2012 and 2021. The study included patients with histologically or cytologically confirmed metastatic or locally APC who underwent first-line FOLFIRINOX or GNP and subsequently received third-line chemotherapy. Overall survival (OS) after diagnosis and OS after third-line chemotherapy (OS3) were defined as the interval from the diagnosis to all-cause death and the time between the initiation of the third-line chemotherapy to all-cause death, respectively. RESULTS: A total of 141 patients were enrolled. The median patient age at diagnosis was 61.8 years (36.0-86.0), and 54.9% were male. The first-line regimen was FOLFIRINOX (67.4%) or GNP (32.6%). The second-line regimen was FOLFIRINOX (27.0%), GNP (52.5%), or other (20.6%). The median OS was 19.0 months, and the median OS3 and progression-free survival after third-line treatment were 15.3 and 7.3 weeks, respectively. With regard to the best tumor response during third-line chemotherapy, 1.4% had partial response, 24.8% had stable disease, and 59.6% had progressive disease. The following clinical factors before third-line chemotherapy affected OS3: Good performance status (PS), serum carbohydrate antigen 19-9 (CA19-9) level <
1000 U/mL, duration of second-line chemotherapy ≥ 19 weeks, and no peritoneal seeding. CONCLUSION: This study identified that patients with good PS, CA19-9 <
1000 U/mL, second-line chemotherapy ≥ 19 weeks, and no peritoneal seeding before starting third-line treatment may benefit more from third-line chemotherapy.