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Reducing nihilism in metastatic pancreatic ductal adenocarcinoma: Treatment, sequencing, and effects on survival outcomes.

ABSTRACT: BACKGROUND:Real-world practice patterns, treatment sequencing, and outcomes in patients with metastatic pancreatic cancer remain unclear. Previous research indicates that the likelihood of patients with metastatic pancreatic cancer receiving or continuing cancer-directed therapy is low-a phenomenon called nihilism. This retrospective, descriptive analysis examined clinical characteristics, treatment patterns, and outcomes for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). METHODS:Treatment patterns were examined using electronic health records from the Flatiron Health database covering the period from January 1, 2014, to June 30, 2019. Real-world overall survival [rwOS]) was compared for a subgroup of patients receiving treatment and a matched subgroup not receiving treatment. RESULTS:Of 7666 patients, 5687 (74.2%) received at least one line of systemic therapy. A greater proportion of patients receiving treatment than not receiving treatment had an initial diagnosis of stage IV disease (68.8% vs 61.2%, respectively). Among patients receiving an initial therapy, fewer than half (38.2%; 2174/5687) received second-line treatment, mostly because they died, and only 34.3% (745/2174) of those receiving second-line treatment advanced to third-line treatment. The rwOS for patients receiving at least one line of systemic therapy was 8.1 months versus 2.6 months for matched patients not receiving treatment (hazard ratio, 0.41; 95% confidence interval, 0.38-0.45; 1470 patients per group). CONCLUSIONS:Systemic therapy provided significant clinical benefit for patients who were eligible and chose to receive it, particularly when treatment was consistent with guideline recommendations. The large proportion of patients initiating treatment suggests that nihilism with mPDAC is diminishing.

SUBMITTER: O'Reilly EM

PROVIDER: S-EPMC7666752 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Reducing nihilism in metastatic pancreatic ductal adenocarcinoma: Treatment, sequencing, and effects on survival outcomes.

O'Reilly Eileen M EM Cockrum Paul P Surinach Andy A Wu Zheng Z Dillon Allison A Yu Kenneth H KH

Cancer medicine 20200930 22

<h4>Background</h4>Real-world practice patterns, treatment sequencing, and outcomes in patients with metastatic pancreatic cancer remain unclear. Previous research indicates that the likelihood of patients with metastatic pancreatic cancer receiving or continuing cancer-directed therapy is low-a phenomenon called nihilism. This retrospective, descriptive analysis examined clinical characteristics, treatment patterns, and outcomes for patients with metastatic pancreatic ductal adenocarcinoma (mPD ...[more]

PMID: 32997898

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, with systemic therapy being the mainstay of treatment. Survival continues to be limited, typically less than 1 year. The PDAC microenvironment is characterized by a paucity of malignant epithelial cells, abundant stroma with predominantly immunosuppressive T cells and myelosuppressive-type macrophages (M2), and hypovascularity. The current treatment options for metastatic PDAC are modified (m)FOLFIRINOX /FOLFIRINOX or nab-paclitaxel and gemcitabine in patients with good performance status (PS) (ECOG 0-1/KPS 70-100%) and gemcitabine with or without a second agent for those with ECOG PS 2-3. New therapies are emerging, and the current guidelines endorse both germline and somatic testing in PDAC to evaluate actionable findings. Important themes related to new therapeutic approaches include DNA damage repair strategies, immunotherapy, targeting the stroma, and cancer-cell metabolism. Targeted therapy alone (outside small genomically defined subsets) or in combination with standard cytotoxic therapy, thus far, has proven disappointing in PDAC; however, novel therapies are evolving with increased integration of genomic profiling along with a better understanding of the tumor microenvironment and immunology. A small but important sub-group of patients have some of these agents available in the clinics for use. Olaparib was recently approved by the US Food and Drug Administration for maintenance therapy in germline BRCA1/2 mutated PDAC following demonstration of survival benefit in a phase 3 trial. Pembrolizumab is approved for patients with defects in mismatch repair/microsatellite instability. PDAC with wild-type KRAS represents a unique subgroup who have enrichment of potentially targetable oncogenic drivers. Small-molecule inhibitors including ERBB inhibitors (e.g., afatinib, MCLA-128), TRK inhibitors (e.g., larotrectinib, entrectinib), ALK/ROS inhibitor (e.g., crizotinib), and BRAF/MEK inhibitors are in development. In a small subset of patients with the KRASG12C mutation, a KRASG12C inhibitor, AMG510, and other agents are being investigated. Major efforts are underway to effectively target the tumor microenvironment and to integrate immunotherapy into the treatment of PDAC, and although thus far the impact has been modest to ineffective, nonetheless, there is optimism that some of the challenges will be overcome.

Project description:Importance:Pancreatic ductal adenocarcinoma (PDAC) has a higher incidence and worse outcomes among black patients than white patients, potentially owing to a combination of socioeconomic, biological, and treatment differences. The role that these differences play remains unknown. Objectives:To determine the level of survival disparity between black and white patients in a modern PDAC cohort and whether treatment inequity is associated with such a disparity. Design, Setting, and Participants:This cohort study used data on 278?936 patients with PDAC with database-defined race from the National Cancer Database from January 1, 2004, to December 31, 2015. The median follow-up for censored patients was 24 months. The National Cancer Database, comprising academic and community facilities, includes about 70% of new cancer diagnoses in the United States. Race-stratified receipt of therapy was the primary variable of interest. Multivariable analyses included additional demographic and clinical parameters. Data analysis was initially completed on November 30, 2018, and revised data analysis was completed on June 27, 2019. Main Outcomes and Measures:Overall survival was the primary outcome, analyzed with Kaplan-Meier and multivariable Cox proportional hazards regression modeling. Results:The cohort included 278?936 patients (137?121 women and 141?815 men; mean [SD] age, 68.72 [11.57] years); after excluding patients from other racial categories, 243?820 of the 278?936 patients (87.4%) were white and 35?116 of the 278?936 patients (12.6%) were black. Unadjusted median overall survival was longer for white patients than for black patients (6.6 vs 6.0 months; P?<?.001). Black patients presented at younger ages than white patients (15?819 of 35?116 [45.0%] vs 83?846 of 243?820 [34.4%] younger than 65 years; P?<?.001) and with more advanced disease (20?853 of 31?600 [66.0%] vs 135?317 of 220?224 [61.4%] with stage III or IV disease; P?<?.001). Black patients received fewer surgical procedures than white patients for potentially resectable stage II disease (4226 of 8097 [52.2%] vs 39?214 of 65?124 [60.2%]; P?<?.001) and slightly less chemotherapy for advanced disease (2756 of 4067 [67.8%] vs 17?296 of 25?227 [68.6%] for stage III disease [P?=?.001]; 8208 of 16?104 [51.0%] vs 58?603 of 105?616 [55.5%] for stage IV disease [P?<?.001]). Decreased survival for black patients persisted in multivariable modeling controlled for sociodemographic parameters (hazard ratio, 1.04 [95% CI, 1.02-1.05]). Conversely, modeling that controlled specifically for clinical parameters such as disease stage and treatment revealed a modest survival advantage (hazard ratio, 0.94 [95% CI, 0.93-0.96]) among black patients. Resection was the factor most strongly associated with overall survival (hazard ratio, 0.39 [95% CI, 0.38-0.39]). Conclusions and Relevance:Black patients with PDAC present at younger ages and with more advanced disease than white patients, suggesting that differences in tumor biology may exist. Black patients receive less treatment stage for stage and fewer surgical procedures for resectable cancers than white patients; these findings may be only partly associated with socioeconomic differences. When disease stage and treatment were controlled for, black patients had no decrease in survival.

Project description:BACKGROUND:Neoadjuvant radiotherapy has been shown to improve marginal negative resection and local control of Pancreatic Ductal Adenocarcinoma (PDAC). However, whether it improves overall survival (OS) in patients with non-metastatic PDAC remains controversial. Therefore, the purpose of this study was to analyze the benefits of only surgery, neoadjuvant radiotherapy, adjuvant radiotherapy, and surgery plus chemotherapy for OS in patients with non-metastatic PDAC. METHODS:PDAC diagnosed by surgical histopathology in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016 was selected. Kaplan-Meier analysis was used to compare the prognosis of patients with different treatments. Cox proportional risk model was used to analyze independent predictors of OS. Propensity score matching (PSM) was used to analyze the tumor prognosis of different treatment methods. RESULTS:Before PSM analysis, the OS of surgery plus chemotherapy (HRs?=?0.896, 95%CIs, 0.827-0.970; P?=?0.007) were significantly better than the other three treatments for stage T1-3N0M0 PDAC patients. For stage T1-3N?+?M0 patients, adjuvant radiotherapy (HRs?=?0.613, 95% CIs, 0.579-0.649; P?<?0.001) had significantly better OS than surgery plus chemotherapy and neoadjuvant radiotherapy. For stage T4N0M0 patients, neoadjuvant radiotherapy (HRs?=?0.482, 95% CIs, 0.347-0.670; P?<?0.001) had significantly better OS than surgery plus chemotherapy and adjuvant radiotherapy. For stage T4N?+?M0 patients, neoadjuvant radiotherapy (HRs?=?0.338, 95% CIs, 0.215-0.532; P?<?0.001) had significantly longer OS than adjuvant radiotherapy and surgery plus chemotherapy. Even after PSM, Chemotherapy plus surgery was still the best treatment for T1-3N0M0 patients. Postoperative adjuvant radiotherapy had the best prognosis among T1-3N?+?M0 patients, and neoadjuvant radiotherapy was the best treatment for T4 patients. CONCLUSIONS:For patients with non-metastatic PDAC, neoadjuvant radiotherapy, adjuvant radiotherapy and surgery plus chemotherapy were superior to only surgery in OS. For patients with stage T4 non-metastatic PDAC, neoadjuvant radiotherapy had the potential to be strongly recommended over adjuvant radiotherapy and surgery plus chemotherapy. However, neoadjuvant radiotherapy failed to benefit the survival of T1-3N0M0 stage patients, and surgery plus chemotherapy was preferred. For T1-3N?+?M0, neoadjuvant radiotherapy had no obvious advantage over adjuvant radiotherapy or surgery plus chemotherapy in OS, and adjuvant radiotherapy was more recommended.

Dataset Information

Reducing nihilism in metastatic pancreatic ductal adenocarcinoma: Treatment, sequencing, and effects on survival outcomes.

Publications

Reducing nihilism in metastatic pancreatic ductal adenocarcinoma: Treatment, sequencing, and effects on survival outcomes.

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