Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.
Ontology highlight
ABSTRACT: Background
Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial.Methods
Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers.Results
In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47-0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65-1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13-0.70).Conclusions
SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS.Clinical trial registration
ISRCTN71070888; ClinialTrials.gov (NCT03529175).
SUBMITTER: Corrie PG
PROVIDER: S-EPMC7283477 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ImportanceFOLFIRINOX (leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) and gemcitabine plus nab-paclitaxel are the 2 common first-line therapies for metastatic adenocarcinoma of the pancreas (mPC), but they have not been directly compared in a clinical trial, and comparative clinical data analyses on their effectiveness are limited.ObjectiveTo compare the FOLFIRINOX and gemcitabine plus nab-paclitaxel treatments of mPC in clinical data and evaluate whether there are differences in overall survival and posttreatment complications between them.Design, setting, and participantsThis retrospective, nonrandomized comparative effectiveness study used data from the AIM Specialty Health-Anthem Cancer Care Quality Program and from administrative claims of commercially insured patients, spanning 388 outpatient centers and clinics for medical oncology located in 44 states across the US. Effectiveness and safety of the treatments were analyzed by matching or adjusting for age, Charlson Comorbidity Index, ECOG performance status (PS) score, Social Deprivation Index (SDI), liver and lymph node metastasis, prior radiotherapy or surgical procedures, and year of treatment. Patients with mPC treated between January 1, 2016, and December 31, 2019, and followed up until June 30, 2020, were included in the analysis.InterventionsInitiation of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel.Main outcomes and measuresOutcomes were overall survival and posttreatment costs and hospitalization. Median survival time was calculated using Kaplan-Meier estimates adjusted with inverse probability of treatment weighting and 1:1 matching.ResultsAmong the 1102 patients included in the analysis (618 men [56.1%]; median age, 60.0 [IQR, 55.5-63.7] years), those treated with FOLFIRINOX were younger (median age, 59.1 [IQR, 53.9-63.3] vs 61.2 [IQR, 57.2-64.3] years; P < .001), with better PS scores (226 [39.9%] with PS of 0 in the FOLFIRINOX group vs 176 [32.8%] in the gemcitabine plus nab-paclitaxel group; P = .02), fewer comorbidities (median Charlson Comorbidity Index, 0.0 [IQR, 0.0-1.0] vs 1.0 [IQR, 0.0-1.0]), and lower SDI (median, 36.0 [IQR, 16.2-61.0] vs 42.0 [IQR, 23.8-66.2]). After adjustments, the median overall survival was 9.27 (IQR, 8.74-9.76) and 6.87 (IQR, 6.41-7.66) months for patients treated with FOLFIRINOX and gemcitabine plus nab-paclitaxel, respectively (P < .001). This survival benefit was observed among all subgroups, including different ECOG PS scores, ages, SDIs, and metastatic sites. FOLFIRINOX-treated patients also had 17.3% fewer posttreatment hospitalizations (P = .03) and 20% lower posttreatment costs (P < .001).Conclusions and relevanceIn this comparative effectiveness cohort study, FOLFIRINOX was associated with improved survival of approximately 2 months compared with gemcitabine plus nab-paclitaxel and was also associated with fewer posttreatment complications. A randomized clinical trial comparing these first-line treatments is warranted to test the survival and posttreatment hospitalization (or complications) benefit of FOLFIRINOX compared with gemcitabine plus nab-paclitaxel.
| S-EPMC9178436 | biostudies-literature
Project description:BackgroundNab-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 methodsPatients 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).ResultsIn 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).ConclusionSequential AG and FFX showed acceptable toxicity as first-line treatment with no limiting neurotoxicity, while high response rate and survival justify randomized trials.
| S-EPMC8637474 | biostudies-literature
Project description:BackgroundThe clinical consequences of pancreatic exocrine insufficiency and its treatment in advanced pancreatic ductal adenocarcinoma (PDAC) are poorly investigated. This retrospective study aims at investigating the pancreatic enzyme replacement therapy (PERT) use and its impact on survival and maldigestion-related symptoms in advanced PDAC patients undergoing chemotherapy.MethodsA retrospective analysis was conducted on advanced PDAC patients, treated with first-line gemcitabine plus nab-paclitaxel at two academic institutions (March 2015-October 2018). Data were correlated with overall survival (OS) using Cox regression model. Kaplan-Meier curves were compared using Log-Rank test.ResultsData from 110 patients were gathered. PERT was administered in 55 patients (50%). No significant differences in baseline characteristics with those who did not receive PERT were found. Median OS for the entire group was 12 months (95% CI 9-15). At multivariate analysis, previous surgical resection of the primary tumor, (HR 2.67, p=0.11), weight gain after 3 months (HR 1.68, p=0.07) and PERT (HR 2.85, p ≤ 0.001) were independent predictors of OS. Patients who received PERT reported an improvement of maldigestion-related symptoms at 3 months more frequently than patients who did not (85.2% vs 14.8%, p ≤ 0.0001).ConclusionPERT is associated with significantly prolonged survival and maldigestion-related symptoms alleviation in advanced PDAC patients.
| S-EPMC8458827 | biostudies-literature
Project description:Aim: To compare the overall survival (OS) among patients who received first-line modified gemcitabine plus nab-paclitaxel (G/nab-P) or 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (mFOLFIRINOX) for metastatic pancreatic cancer. Methods: A single-center, retrospective, real-world study was conducted. Results: The median OS was 9.4 months versus 7.5 months in the mFOLFIRINOX and modified G/Nab-P groups, respectively (p = 0.16). An exploratory subgroup analysis excluding patients who received one infusion and had an Eastern Cooperative Oncology Group performance score of 2 demonstrated similar OS of 11.3 months and 8.9 months, respectively. Median progression-free survival and time-to-treatment failure were not significantly different. Higher rates of adverse events were noted with mFOLFIRINOX. Conclusion: mFOLFIRINOX did not significantly prolong OS compared with modified G/nab-P and was associated with increased toxicities.
| S-EPMC9724069 | biostudies-literature
Project description:PurposeSince the introduction of nab-paclitaxel plus gemcitabine (nab-P+GEM) as first-line (1L) treatment for metastatic pancreatic adenocarcinoma (mPDAC), optimal second-line (2L) chemotherapy after progression is unclear. We assessed clinical outcomes of 2L chemotherapy for disease that progressed on 1L nab-P+GEM.Materials and methodsAmong the 203 patients previously treated with 1L nab-P+GEM for mPDAC at Asan Medical Center, between February and December 2016, records of 120 patients receiving 2L chemotherapy after progression on nab-P+GEM were retrospectively reviewed. The response rate and survival were evaluated along with analysis of prognostic factors.ResultsFluoropyrimidine-oxaliplatin doublets (FOLFOX or XELOX) were used in 78 patients (65.0%), fluoropyrimidine monotherapy in 37 (30.8%), and liposomal irinotecan plus fluorouracil in two (1.7%). The median progression-free survival (PFS) and overall survival (OS) were 3.29 months and 7.33 months from the start of 2L therapy. Fluoropyrimidine-oxaliplatin regimens and fluoropyrimidine monotherapy did not yield significantly different median PFS (2.89 months vs. 3.81 months, p=0.40) or OS (7.04 months vs. 7.43 months, p=0.86). A high neutrophil-lymphocyte ratio (> 2.2) and a short time to progression with 1L nab-P+GEM (< 6.4 months) were independent prognostic factors of poor OS with 2L therapy.Conclusion2L fluoropyrimidine-oxaliplatin doublets and fluoropyrimidine monotherapy after failure of 1L nab-P+GEM had modest efficacy, with no differences in treatment outcomes between them. Further investigation is warranted for the optimal 2L chemo-regimens and sequencing of systemic chemotherapy for patients with mPDAC.
| S-EPMC6962478 | biostudies-literature
Project description:BackgroundThis exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT).MethodsPatients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival.ResultsThe majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment.ConclusionsThese findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.
| S-EPMC4947701 | biostudies-literature
Project description:ImportanceFluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (GA) are first-line chemotherapy regimens for pancreatic cancer. Their relative efficacy in the setting of localized disease is unknown.ObjectiveTo evaluate radiographic and serologic measures of responses associated with first-line chemotherapy with FOLFIRINOX or GA, and to determine the association between these drug regimens, putative measures of response, and survival.Design, setting, and participantsThis case series assessed 485 consecutive patients who were diagnosed as having previously untreated localized pancreatic ductal adenocarcinoma at The University of Texas MD Anderson Cancer Center between January 1, 2010, and December 31, 2017, and who received at least 3 cycles of first-line chemotherapy with FOLFIRINOX or GA. The median (range) follow-up duration was 33 (2-28) months.ExposuresAdministration of FOLFIRINOX (285 patients [59%]) or GA (200 patients [41%]) as first-line chemotherapy.Main outcomes and measuresResection rate, radiographic metrics (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and change in tumor volume or anatomic staging), a serologic metric (serum cancer antigen 19-9 level), and overall survival after administration of first-line chemotherapy.ResultsIn total, 485 patients (266 [55%] male) were included in the analysis. Patients treated with FOLFIRINOX were generally younger (median [range] age at diagnosis: 61 [30-81] vs 71 [36-89] years; P = .001) and had better performance status as indicated by the Eastern Cooperative Oncology Group scale (range 0-4, with lower numbers representing better performance) score of 2 or lower (274 patients [96%] vs 165 patients [82%] P = .001) but more invasive tumors than patients who received GA (91 [32%] vs 90 [45%] resectable tumors; P = .01). After propensity score matching to control for these biases, many objective serologic and radiographic metrics of response associated with administration of FOLFIRINOX or GA-including low rates of local tumor downstaging-did not differ. However, RECIST partial response was more common among patients treated with FOLFIRINOX (27 of 140 patients [19%]) than with GA (8 of 140 patients [6%]; P = .001). Moreover, (chemo)radiation (50% vs 34%; P = .001) was more commonly administered to and pancreatectomy (27% vs 16%; P = .01) was subsequently performed more frequently for patients initially treated with FOLFIRINOX. The overall survival duration of patients treated with either regimen was similar (hazard ratio, 1.48; 95% CI, 0.97-2.26; P = .07).Conclusions and relevanceIn this cohort of patients with localized pancreatic adenocarcinoma who received FOLFIRINOX or GA as their first line of therapy, FOLFIRINOX was associated with higher rates of RECIST partial response and subsequent pancreatectomy than GA, but the overall survival associated with these regimens was similar.
| S-EPMC7364337 | biostudies-literature
Project description:BackgroundPancreatic cancer is mostly diagnosed in an advanced stage and treated with systemic therapy with palliative intent. Nowadays, the doublet chemotherapy of Gemcitabine and nab-paclitaxel (Gem-Nab) is one of the most frequently used regimens worldwide, but is not ubiquitarily available or reimbursed. Therefore, we compared the clinical efficacy of Gem-Nab to a historical control of patients treated with gemcitabine and oxaliplatin (Gem-Ox) at our tertiary cancer center, which was the standard treatment prior to the introduction of FOLFIRINOX.MethodsThis single-center retrospective real world study includes 121 patients diagnosed with locally advanced or primary metastatic pancreatic adenocarcinoma who were treated with chemotherapy doublet, with either Gem-Nab or Gem-Ox in palliative first-line. Survival rates were analyzed using the Kaplan-Meier method, and comparisons were made with log-rank tests. Gem-Ox was considered as standard first line therapy at our institution for patients who were deemed fit for doublet chemotherapy between the years 2006 to 2012. These patients were compared to a cohort of patients treated with the new standard first-line therapy of Gem-Nab between 2013 and 2020.ResultsA total of 554 patients with pancreatic cancer of all stages were screened, and 73 patients treated with Gem-Nab and 48 patients treated with Gem-Ox in the palliative first-line setting were identified and included in this analysis. Patients receiving Gem-Ox had a statistically significantly better performance score (ECOG PS) when compared to the Gem-Nab group (Odds ratio (OR) 0.28, 95% CI 0.12-0.65, p = 0.005), more often suffered from locally advanced than metastatic disease (OR 3.10, 95% CI 1.27-7.91, p = 0.019) and were younger in age (OR 0.95, 95% CI 0.91-0.99, p = 0.013). Median overall survival (OS) of the whole study cohort was 10.3 months (95% CI 8.5-11.6). No statistically significant difference in OS could be observed between the Gem-Nab and the Gem-Ox cohort (median OS: 8.9 months (95% CI 6.4-13.5) versus 10.9 months (95% CI 9.5-13.87, p = 0.794, HR 1.27, 95% CI 0.85-1.91)). Median progression-free survival (PFS) was 6.8 months in the entire cohort (95% CI 4.9-8.4). No statistically significant difference in PFS could be observed between the Gem-Nab and the Gem-Ox cohort (median PFS: 5.8 months (95% CI 4.3-8.2) versus 7.9 months (95% CI 5.4-9.5) p = 0.536, HR 1.11, 95% CI 0.74-1.67). Zero-truncated negative binomial regressions on OS and PFS adjusting for gender, age, performance status (ECOG PS), and CA19-9 levels yielded no significant difference between Gem-Nab or Gem-Ox.ConclusionFrom our analysis, we could evidence no difference in outcome parameters in this retrospective analysis despite the worse prognostic pattern for GemOX. Therefore, we suggest Gem-Ox as potential first line treatment option for inoperable locally advanced or metastatic pancreatic cancer, especially if Gem-Nab is not available.
| S-EPMC10501299 | biostudies-literature
Project description:BackgroundThe Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling.MethodsPatients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib).ResultsSeventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment.ConclusionsAdding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population.Trial registrationClinicalTrials.gov Identifier: NCT01088815.
| S-EPMC7029016 | biostudies-literature
Project description:There is currently no standard second-line treatment for metastatic pancreatic adenocarcinoma (MPA), and progression-free survival is consistently <4 months in this setting. The aim of this study was to evaluate the efficacy and tolerability of Nab-paclitaxel plus gemcitabine (A+G) after Folfirinox failure in MPA.From February 2013 to July 2014, all consecutive patients treated with A+G for histologically proven MPA after Folfirinox failure were prospectively enrolled in 12 French centres. A+G was delivered as described in the MPACT trial, until disease progression, patient refusal or unacceptable toxicity.Fifty-seven patients were treated with Nab-paclitaxel plus gemcitabine, for a median of 4 cycles (range 1-12). The disease control rate was 58%, with a 17.5% objective response rate. Median overall survival (OS) was 8.8 months (95% CI: 6.2-9.7) and median progression-free survival was 5.1 months (95% CI: 3.2-6.2). Since the start of first-line chemotherapy, median OS was 18 months (95% CI: 16-21). No toxic deaths occurred. Grade 3-4 toxicities were reported in 40% of patients, consisting of neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%) and thrombocytopenia (6.5%).A+G seems to be effective, with a manageable toxicity profile, after Folfirinox failure in patients with MPA.
| S-EPMC4651133 | biostudies-literature