Sequential first-line treatment with nab-paclitaxel/gemcitabine and FOLFIRINOX in metastatic pancreatic adenocarcinoma: GABRINOX phase Ib-II controlled clinical trial

Abstract

Background: Nab-paclitaxel/gemcitabine (AG) and FOLFIRINOX (FFX) are promising drugs in metastatic pancreatic cancer (MPC). This study evaluated a new first-line sequential treatment (AG followed by FFX) in MPC that might overcome resistance to primary therapy and delay tumor progression. Patients and methods: Patients with histologically/cytologically confirmed MPC were included in a multicentric trial receiving AG (day 1, 8 and 15) followed by FFX (day 29 and 43). In phase Ib, three dose-levels were tested for maximum tolerated dose (MTD) and recommended phase II dose. In phase II, the main outcome was the objective response rate (ORR) and secondarily safety, progression-free survival (PFS) and overall survival (OS). Results: In phase Ib, we included 33 patients (31 assessable) of median age 61.0 years (range 42-75 years) and represented by 54.8% males. Five dose-limiting toxicities were reported without any death. The main grade 3/4 toxicities were neutropenia with spontaneous resolution (35.5%/32.3%), venous thromboembolism (grade 3: 22.6%) and thrombopenia (grade 3: 29.0%), while the MTD was not reached. In phase II, we included 58 patients of median age 60 years (range 34-72 years), 50% males and with Eastern Cooperative Oncology Group stage score 0 and 1 of 37.9% and 62.1%, respectively. They received a median of 4 (1-9) cycles in 8.5 months (0.5-19.8 months). The ORR was 64.9% [95% confidence interval (CI) 51.1% to 77.1%], and neurotoxicity was remarkably low. The main grade 3-4 toxicities were venous thromboembolism, thrombopenia, neutropenia/febrile neutropenia, nausea, diarrhea, weight loss and asthenia without any death. Tumor response was complete in 3.5% and partial in 61.4%, while disease was stable in 19.3% and progressive in 15.8% of patients. The median PFS was 10.5 months (95% CI 6.0-12.5 months) and median OS was 15.1 months (95% CI 10.6-20.1 months). Conclusion: Sequential AG and FFX showed acceptable toxicity as first-line treatment with no limiting neurotoxicity, while high response rate and survival justify randomized trials.

Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: A Systematic Review and Meta-Analysis

“…Three included studies, encompassing 144 patients, reported on the prevalence of VTE in pancreatic cancer patients [ 32 , 33 , 81 ]. However, a meta-analysis could not be performed due to insufficient number of studies.…”

“… Forest plot showing the estimated overall pooled prevalence of VTE in cancer patients undergoing chemotherapy [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , …”

Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells

“…Therefore, 5-FU and PTX, which are critical in the clinic in the present study, were selected. The 5-FU inhibits the DNA synthesis by reducing thymidylate synthase activity, while PTX inhibits depolymerization of tubulin and subsequent cell division ( 21 , 22 ). Dysregulation of various components in distinct pathways is the major common cause for drug resistance, including alterations in drug transport, EMT transition, miRNA dysregulations, cell cycle changes, autophagy regulation, DNA damage repair machinery, tumor microenvironment interactions, and stemness enhancement ( 23 ).…”

Efficacy and safety of FOLFIRINOX as second-line chemotherapy for advanced pancreatic cancer after gemcitabine-based therapy: A systematic review and meta-analysis

“… 22 New regimens such as FOLFIRINOX and AG have shown stronger effects in pancreatic cancer patients. 23 Yet the single use of gemcitabine and combined regimens containing gemcitabine are still applied in quite a high proportion of advanced pancreatic cancer patients. 24 , 25 Patients that accept gemcitabine-based chemotherapy as first-line therapy usually receive single drug or combined regimens containing 5-FU, capecitabine or S-1 after disease progression.…”