FOLFIRINOX for locally advanced pancreatic cancer: Results and prognostic factors of subset analysis from a nation-wide multicenter observational study in Japan.

FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, leucovorin) treatment significantly improved overall survival in the recent phase III study and became a standard therapy for metastatic pancreatic cancer. However, treatment for locally advanced pancreatic cancer is still controversial. We conducted subset analyses from a nation-wide multicenter observational study in Japan to evaluate the tolerability and efficacy of FOLFIRINOX in patients with locally advanced pancreatic cancer and to investigate independent prognostic factors with pre-treatment variables. The study included 66 patients with unresectable locally advanced pancreatic cancer from 27 institutions in Japan who received FOLFIRINOX as first-line treatment between December 20, 2013 and December 19, 2014 and surveyed until December 2015. The median age was 63 with the Eastern Cooperative Oncology Group performance status of 0 or 1. Major Grade 3 or 4 adverse events included neutropenia (64%), leukopenia (33%), febrile neutropenia (15%), and diarrhea (15%). Severe adverse event occurred in 14 patients (11%) without fatal event. The median overall survival and progression-free survival times were 18.5 and 7.6 months, respectively. The objective response rate 15.2% and the disease control rate was 81.9%. A high modified Glasgow prognostic score (mGPS, ≥1) (95%CI 1.96-12.5) and female (95%CI 0.20-0.97) were identified as independent poor prognostic factors. First-line FOLFIRINOX treatment for locally advanced pancreatic cancer seems to be effective with acceptable toxicities. A high mGPS may be associated with poor survival in patients with locally advanced pancreatic cancer who receive FOLFIRINOX. This study was registered at the UMIN Clinical Trials Registry (UMIN000014658).

Matsumoto I ，Kamei K ，Omae K ，Suzuki S ，Matsuoka H ，Mizuno N ，Ozaka M ，Ueno H ，Kobayashi S ，Uesugi K ，Kobayashi M ，Todaka A ，Fukutomi A ... -  《-》

Chemotherapy and radiotherapy for advanced pancreatic cancer.

Pancreatic cancer (PC) is a lethal disease with few effective treatment options. Many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review synthesises all the randomised data available to help better inform patient and clinician decision-making. It updates the previous version of the review, published in 2018. To assess the effects of chemotherapy, radiotherapy, or both on overall survival, severe or life-threatening adverse events, and quality of life in people undergoing first-line treatment of advanced pancreatic cancer. We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies. The latest search dates were in March and July 2023. We included randomised controlled trials comparing chemotherapy, radiotherapy, or both with another intervention or best supportive care. Participants were required to have locally advanced, unresectable pancreatic cancer or metastatic pancreatic cancer not amenable to curative intent treatment. Histological confirmation was required. Trials were required to report overall survival. We used standard methodological procedures expected by Cochrane. We included 75 studies in the review and 51 in the meta-analysis (11,333 participants). We divided the studies into seven categories: any anti-cancer treatment versus best supportive care; various chemotherapy types versus gemcitabine; gemcitabine-based combinations versus gemcitabine alone; various chemotherapy combinations versus gemcitabine plus nab-paclitaxel; fluoropyrimidine-based studies; miscellaneous studies; and radiotherapy studies. In general, the included studies were at low risk for random sequence generation, detection bias, attrition bias, and reporting bias, at unclear risk for allocation concealment, and high risk for performance bias. Compared to best supportive care, chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.88 to 1.33; absolute risk of death at 12 months of 971 per 1000 versus 962 per 1000; 4 studies, 298 participants; moderate-certainty evidence). The adverse effects of chemotherapy and impacts on quality of life (QoL) were uncertain. Many of the chemotherapy regimens were outdated. Eight studies compared non-gemcitabine-based chemotherapy regimens to gemcitabine. These showed that 5-fluorouracil (5FU) likely reduces OS (HR 1.69, 95% CI 1.26 to 2.27; risk of death at 12 months of 914 per 1000 versus 767 per 1000; 1 study, 126 participants; moderate certainty), and grade 3/4 adverse events (QoL not reported). Fixed dose rate gemcitabine likely improves OS (HR 0.79, 95% CI 0.66 to 0.94; risk of death at 12 months of 683 per 1000 versus 767 per 1000; 2 studies, 644 participants; moderate certainty), and likely increase grade 3/4 adverse events (QoL not reported). FOLFIRINOX improves OS (HR 0.51, 95% CI 0.43 to 0.60; risk of death at 12 months of 524 per 1000 versus 767 per 1000; P < 0.001; 2 studies, 652 participants; high certainty), and delays deterioration in QoL, but increases grade 3/4 adverse events. Twenty-eight studies compared gemcitabine-based combinations to gemcitabine. Gemcitabine plus platinum may result in little to no difference in OS (HR 0.94, 95% CI 0.81 to 1.08; risk of death at 12 months of 745 per 1000 versus 767 per 1000; 6 studies, 1140 participants; low certainty), may increase grade 3/4 adverse events, and likely worsens QoL. Gemcitabine plus fluoropyrimidine improves OS (HR 0.88, 95% CI 0.81 to 0.95; risk of death at 12 months of 722 per 1000 versus 767 per 1000; 10 studies, 2718 participants; high certainty), likely increases grade 3/4 adverse events, and likely improves QoL. Gemcitabine plus topoisomerase inhibitors result in little to no difference in OS (HR 1.01, 95% CI 0.87 to 1.16; risk of death at 12 months of 770 per 1000 versus 767 per 1000; 3 studies, 839 participants; high certainty), likely increases grade 3/4 adverse events, and likely does not alter QoL. Gemcitabine plus taxane result in a large improvement in OS (HR 0.71, 95% CI 0.62 to 0.81; risk of death at 12 months of 644 per 1000 versus 767 per 1000; 2 studies, 986 participants; high certainty), and likely increases grade 3/4 adverse events and improves QoL. Nine studies compared chemotherapy combinations to gemcitabine plus nab-paclitaxel. Fluoropyrimidine-based combination regimens improve OS (HR 0.79, 95% CI 0.70 to 0.89; risk of death at 12 months of 542 per 1000 versus 628 per 1000; 6 studies, 1285 participants; high certainty). The treatment arms had distinct toxicity profiles, and there was little to no difference in QoL. Alternative schedules of gemcitabine plus nab-paclitaxel likely result in little to no difference in OS (HR 1.10, 95% CI 0.82 to 1.47; risk of death at 12 months of 663 per 1000 versus 628 per 1000; 2 studies, 367 participants; moderate certainty) or QoL, but may increase grade 3/4 adverse events. Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone, with poor quality evidence. Fluoropyrimidine-based combinations are likely to result in little to no impact on OS (HR 0.84, 95% CI 0.61 to 1.15; risk of death at 12 months of 765 per 1000 versus 704 per 1000; P = 0.27; 4 studies, 491 participants; moderate certainty) versus fluoropyrimidines alone. The evidence suggests that there was little to no difference in grade 3/4 adverse events or QoL between the two groups. We included only one radiotherapy (iodine-125 brachytherapy) study with 165 participants. The evidence is very uncertain about the effect of radiotherapy on outcomes. Combination chemotherapy remains standard of care for metastatic pancreatic cancer. Both FOLFIRINOX and gemcitabine plus a taxane improve OS compared to gemcitabine alone. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapy regimens improve OS compared to gemcitabine plus nab-paclitaxel. The effects of radiotherapy were uncertain as only one low-quality trial was included. Selection of the most appropriate chemotherapy for individuals still remains unpersonalised, with clinicopathological stratification remaining elusive. Biomarker development is essential to assist in rationalising treatment selection for patients.

Haggstrom L ，Chan WY ，Nagrial A ，Chantrill LA ，Sim HW ，Yip D ，Chin V ... -  《Cochrane Database of Systematic Reviews》

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 ... -  《-》

Carbohydrate antigen 19-9 (CA19-9) response after induction FOLFIRINOX for locally advanced pancreatic cancer identifies patients who may benefit from surgical exploration: multicentre, observational cohort study.

Which patients with locally advanced pancreatic cancer may benefit from surgical exploration after induction treatment remains debated. The aim of this retrospective cohort study was to identify independent factors for overall survival after surgical exploration for locally advanced pancreatic cancer, which are available at restaging after induction therapy. Consecutive patients with locally advanced pancreatic cancer from the Trans-Atlantic Pancreatic Surgery cohort who underwent surgical exploration after FOLFIRINOX as induction chemotherapy were included. Multivariable Cox proportional hazards analyses with contour plots were used for the predicted 3-year overall survival in patients who underwent surgical exploration. Overall, 958 patients with locally advanced pancreatic cancer were treated with FOLFIRINOX as induction therapy. At restaging, 221 patients (23.1%) had metastatic disease (M1) and 724 patients (75.6%) did not have metastatic disease (M0)-234 patients (24.4%) with M0 disease underwent surgical exploration and 490 patients (51.1%) with M0 disease did not undergo surgical exploration; restaging information was not available for 13 patients (1%). The surgical exploration cohort included 213 patients with locally advanced pancreatic cancer, after excluding 21 carbohydrate antigen 19-9 non-producers. The independent prognostic factors for overall survival after surgical exploration were post-induction carbohydrate antigen 19-9 level (HR 1.14 (95% c.i. 1.01 to 1.29)), carbohydrate antigen 19-9 decrease (HR 0.89 (95% c.i. 0.79 to 0.99)), and a WHO performance status of greater than or equal to one (HR 1.71 (95% c.i. 1.21 to 2.42)). Baseline carbohydrate antigen 19-9 was not prognostic for overall survival after surgical exploration (HR 0.98 (95% c.i. 0.90 to 1.07)). The best predicted 3-year overall survival was achieved with a greater than 80% decrease in carbohydrate antigen 19-9 and a post-induction carbohydrate antigen 19-9 less than 50 U/ml. Carbohydrate antigen 19-9 after induction therapy, carbohydrate antigen 19-9 decrease, and performance status are independent prognostic factors for overall survival after surgical exploration for locally advanced pancreatic cancer. Three-year overall survival is best in patients with a performance status of zero, a greater than 80% decrease in carbohydrate antigen 19-9, and a post-induction carbohydrate antigen 19-9 level less than 50 U/ml.

Dekker EN ，van Klaveren D ，Verkolf EMM ，de Wilde RF ，Besselink MG ，O'Reilly EM ，Paniccia A ，Katz MHG ，Tzeng CD ，Wei AC ，Zureikat AH ，Groot Koerkamp B ，Trans-Atlantic Pancreatic Surgery (TAPS) Consortium ... -  《-》

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》