Real-world clinical outcome of unresectable locally advanced & de-novo metastatic pancreatic ductal adenocarcinoma: a multicentre retrospective study.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited treatment options yielding poor outcomes. This study aimed to evaluate the real-world clinical characteristics, treatment patterns, and outcomes of patients with locally advanced unresectable and de-novo metastatic PDAC in Saudi Arabia, providing regional data to compare with international benchmarks. This is a retrospective, multicentre study involving 350 patients diagnosed with unresectable locally advanced or de-novo metastatic PDAC between January 2015 and November 2023. Data were collected from 10 oncology centers across Saudi Arabia. The median age at diagnosis was 60 years, with 63% of patients presenting with multiple metastatic sites, primarily in the liver (66.3%). FOLFIRINOX was the most common first-line treatment (55.1%), followed by gemcitabine plus nab-paclitaxel (15.1%). The median PFS for first-line treatment was 5.3 months, with FOLFIRINOX achieving the longest PFS (6.5 months). The median OS was 10.34 months for the entire cohort, with better survival outcomes observed in patients receiving FOLFIRINOX (12.3 months). Independent prognostic factors for PFS and OS included performance status, first-line regimen, and neutrophil-lymphocyte ratio (NLR). Among patients tested, 7.1% had deficient mismatch repair (d-MMR), and 5.8% harbored BRCA mutations. This real-world study confirms that clinical outcomes for locally advanced unresectable and metastatic PDAC in Saudi Arabia are consistent with international data, with FOLFIRINOX showing superior outcomes over gemcitabine-based regimens. However, both treatments reflect the persistent poor prognosis of PDAC, underscoring the need for novel therapeutic strategies. Further research is warranted to optimize treatment selection and improve survival outcomes in this population.

Aseafan M ，Alfakeeh AH ，Tashkandi E ，Mahrous M ，Alghamdi M ，Alshamsan B ，Al-Hajeili M ，Bakhsh S ，Alshammari K ，Almugbel FA ，Alfagih AH ，Allehebi A ，Montaser M ，Elsafty MH ，Elnaghi KAE ，Issa I ，Bakshi E ，AlSubaie S ，AlMutairi B ，Mokhtar H ，Aboelatta M ，Bukhari N ，Alzahrani AM ，Elhassan T ，Alqahtani A ，Bazarbashi S ... -  《BMC CANCER》

Prognostic and predictive significance of inflammatory markers in patients with locally advanced unresectable and metastatic pancreatic cancer treated with first-line chemotherapy FOLFIRINOX or Gemcitabine/Nabpaclitaxel.

Novisedlakova M ，Chovanec M ，Ciernikova S ，Danihel L Jr ... -  《-》

Comparison of first-line chemotherapy regimens in unresectable locally advanced or metastatic pancreatic cancer: a systematic review and Bayesian network meta-analysis.

In advanced pancreatic ductal adenocarcinoma (PDAC), first-line chemotherapy is the standard of care. Due to the absence of head-to-head comparisons in clinical trials, we performed this systematic review and network meta-analysis to compare treatment options for PDAC in terms of their efficacy and toxicity. PubMed, the Cochrane Central Register of Controlled Trials, Embase, and oncological meetings websites were searched until Nov 15, 2023. We included phase 2-3 randomised controlled trials published after Jan 1, 2000, evaluating first-line treatments in patients with previously untreated, unresectable, locally advanced or metastatic PDAC. Primary endpoints assessed were progression-free survival and overall survival. Summary data were extracted from published reports. The deviance information criterion was used to choose between a random-effects or fixed-effects model. Hazard ratios (HRs) with 95% credible intervals were estimated using a Bayesian approach. The risk of bias was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool and studies were graded as low, some concerns, or high risk of bias. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. This systematic review and network meta-analysis is registered with PROSPERO, CRD42023450330. 6050 records were screened and 79 randomised controlled trials (22 168 patients) were included in the analysis. Gemcitabine was the most frequent comparator (in 50 [63%] of 79 trials) and was considered as the reference treatment. A fixed-effect model was used to analyse the primary outcomes. Regarding progression-free survival (71 trials, 19 479 patients), the most effective treatments were gemcitabine plus nab-paclitaxel alternating folinic acid, fluorouracil, and oxaliplatin ([FOLFOX] HR 0·32, 95% credible interval 0·22-0·47), cisplatin, nab-paclitaxel, capecitabine, and gemcitabine ([PAXG] 0·35, 0·22-0·55), and liposomal irinotecan in combination with fluorouracil, leucovorin, and oxaliplatin ([NALIRIFOX] 0·43, 0·34-0·54), followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin ([FOLFIRINOX] 0·55, 0·47-0·65) and gemcitabine plus nab-paclitaxel (0·62, 0·54-0·72). Similar results were observed for overall survival (79 trials, 22 104 patients): PAXG (HR 0·40, 95% credible interval 0·25-0·65), gemcitabine plus nab-paclitaxel alternating FOLFOX (0·46, 0·32-0·66), and NALIRIFOX (0·56, 0·45-0·70) had the highest benefit, followed by FOLFIRINOX (0·66, 0·56-0·78) and gemcitabine plus nab-paclitaxel (0·67, 0·59-0·77). The overall risk of bias was low to some concerns. Certainty of evidence was low. Our findings suggest that NALIRIFOX and FOLFIRINOX should be the preferred options for patients who can tolerate these regimens, with gemcitabine plus nab-paclitaxel remaining a viable alternative, particularly in patients unfit for triplet therapy. Phase 3 randomised controlled trials investigating concomitant or sequential quadruplets are warranted. None.

Mastrantoni L ，Chiaravalli M ，Spring A ，Beccia V ，Di Bello A ，Bagalà C ，Bensi M ，Barone D ，Trovato G ，Caira G ，Giordano G ，Bria E ，Tortora G ，Salvatore L ... -  《-》

Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial.

The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer. In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, fluorouracil 400 mg/m2 by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m2 for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136. Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3-48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7-56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35-1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8-27·6), median overall survival was 18·5 months (95% CI 14·4-21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9-28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55-1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase. Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival. Celgene.

Kunzmann V ，Siveke JT ，Algül H ，Goekkurt E ，Siegler G ，Martens U ，Waldschmidt D ，Pelzer U ，Fuchs M ，Kullmann F ，Boeck S ，Ettrich TJ ，Held S ，Keller R ，Klein I ，Germer CT ，Stein H ，Friess H ，Bahra M ，Jakobs R ，Hartlapp I ，Heinemann V ，German Pancreatic Cancer Working Group (AIO-PAK) and NEOLAP investigators ... -  《The Lancet Gastroenterology & Hepatology》

Gemcitabine/nab-Paclitaxel versus FOLFIRINOX for palliative first-line treatment of advanced pancreatic cancer: A propensity score analysis.

Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head comparison between these treatments has yet been performed. We conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX. In unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329). This real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.

Riedl JM ，Posch F ，Horvath L ，Gantschnigg A ，Renneberg F ，Schwarzenbacher E ，Moik F ，Barth DA ，Rossmann CH ，Stotz M ，Schaberl-Moser R ，Pichler M ，Stöger H ，Greil R ，Djanani A ，Schlick K ，Gerger A ... -  《-》