Efficacy and tolerance of LV5FU2-carboplatin chemotherapy in patients with advanced pancreatic ductal adenocarcinoma after failure of standard regimens

{"Background": "Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence (4.8 per 100,000 worldwide in 2018) and is projected to become the second leading cause of cancer death by 2030. Five-year overall survival remains below 10%. While FOLFIRINOX and gemcitabine plus nab-paclitaxel are established first-line standards, chemotherapy options after failure of these regimens are limited. Oxaliplatin-induced cumulative peripheral neurotoxicity often necessitates dose reductions or discontinuation. Carboplatin, a platinum agent with negligible neurotoxicity and a different mechanism of action (cytotoxicity not mediated by DNA damage response but through ribosome biogenesis stress), may offer an alternative. This study aimed to report the efficacy and safety of the LV5FU2\u2013carboplatin combination in patients with advanced PDAC after failure of standard chemotherapies.", "Methods": "This retrospective study was conducted at Beaujon University Hospital (Clichy, France) and included all consecutive patients with pathologically proven, inoperable locally advanced or metastatic PDAC who received at least one cycle of LV5FU2\u2013carboplatin between July 2009 and August 2021. Patients were identified from the Chimio\u00ae software. Exclusion criteria comprised other concomitant active malignancies. The protocol consisted of carboplatin at AUC 4 mg/ml/min, folinic acid 400 mg/m\u00b2, 5-FU bolus 400 mg/m\u00b2, and 5-FU continuous infusion 2400 mg/m\u00b2 over 46 h, in a 14-day cycle. All patients received antiemetic prophylaxis. Data collected included demographics, tumor characteristics, prior treatments (including oxaliplatin details), and baseline clinical/laboratory parameters. Tumor response was assessed by RECIST v1.1. Adverse events were graded per CTCAE v4.0. PFS and OS were estimated using Kaplan\u2013Meier methods. Multivariable Cox proportional hazard models explored factors associated with survival. Variables with p < 0.25 on univariable analysis were entered into backward stepwise multivariable models.", "Key Results": "Of 111 identified patients, 91 were included (54.9% male, median age 61.6 years). LV5FU2\u2013carboplatin was introduced a median of 17.7 months (IQR: 13\u201324) after initial diagnosis, mainly as third-line (59.3%) or fourth-line (23.1%) therapy. All patients had prior oxaliplatin (median 10 cycles, IQR 6\u201313). At baseline, 90.1% had distant metastases (liver 74.7%, peritoneal 26.4%, lung 22.0%), 45.1% had extrahepatic metastases, 57.1% had opioid-requiring pain, and 13.2% had ascites. WHO performance status was 0/1 in 73.6%. Patients received a median of 3 cycles (IQR: 2.0\u20136.0) of LV5FU2\u2013carboplatin. Dose reductions occurred in 72.5% of patients. The clinical benefit rate (objective response or stabilization) was 25.2% (3.3% objective response, 22% stable disease). Median PFS was 2.7 months (95% CI: 2.4\u20133.0). On multivariable analysis, factors independently associated with shorter PFS were: ascites or opioid-requiring pain (HR 1.73; 95% CI: 1.08\u20132.78; p = 0.023), \u22652 prior treatment lines (HR 3.58; 95% CI: 1.80\u20137.13; p < 0.001), and reduced-dose carboplatin (HR 1.92; 95% CI: 1.23\u20132.98; p = 0.004). Treatment initiation >18 months after diagnosis was associated with longer PFS (HR 0.36; 95% CI: 0.22\u20130.59; p < 0.001). Median OS was 4.2 months (95% CI: 3.5\u20134.9). On multivariable analysis, opioid-requiring pain or ascites was significantly associated with shorter OS (HR 1.71; 95% CI: 1.03\u20132.86; p = 0.039). Extrahepatic metastases (HR 1.62; 95% CI: 0.98\u20132.68; p = 0.058), \u22652 prior lines (HR 1.89; 95% CI: 0.96\u20133.71; p = 0.065), and reduced-dose carboplatin (HR 1.51; 95% CI: 0.92\u20132.47; p = 0.10) showed trends toward worse OS without reaching statistical significance. Prior response or progression on oxaliplatin did not influence PFS or OS. Among 6 patients with BRCA1/2 mutations, 4 achieved tumor control (66%), with median PFS of 5.9 months and median OS of 12.1 months. Grade 3\u20134 adverse events included neutropenia (24.7%), thrombocytopenia (11.8%), anemia (7.1%), and nausea/vomiting (7.1%). Worsening of preexisting peripheral neurotoxicity occurred in 13.2% of patients. No treatment-related deaths occurred.", "Clinical Implications": "LV5FU2\u2013carboplatin demonstrates limited overall efficacy in heavily pretreated advanced PDAC, with a median OS of 4.2 months and PFS of 2.7 months. However, selected patients\u2014those without ascites or opioid-requiring pain, with longer disease evolution (>18 months from diagnosis), fewer prior treatment lines (<2), and who are fit enough to receive full-dose carboplatin\u2014may derive greater benefit. Importantly, prior efficacy or failure of oxaliplatin does not predict response to carboplatin, suggesting different mechanisms of action. The regimen has acceptable tolerability, with manageable hematologic toxicity and infrequent worsening of neurotoxicity (13.2%). The potential for enhanced efficacy in BRCA1/2-mutated patients warrants further investigation. These findings may guide clinical decision-making for patients with advanced PDAC who have exhausted standard options, though prospective studies are needed to confirm these observations."}