Pancreatic adenocarcinoma: Beyond first line, where are we?
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ABSTRACT:
SUBMITTER: Cherri S
PROVIDER: S-EPMC8108033 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:While an increasing number of therapeutic options are now available for the first-line treatment of locally advanced or metastatic pancreatic cancer, the optimal choice for treatment in the second-line setting and beyond is less well defined. A variety of cytotoxic agents, either alone or in combination, have been evaluated, although primarily in the context of small single-arm or retrospective studies. Most regimens have been associated with median progression-free survival rates in the range of 2-4 mo and overall survival rates between 4-8 mo, highlighting the very poor prognosis of patients who are candidates for such treatment. Targeted therapies studied in this chemotherapy-refractory setting, meanwhile, have produced even worse efficacy results. In the current article, we review the clinical evidence for treatment of refractory disease, primarily in patients who have progressed on front-line gemcitabine-based chemotherapy. In the process, we highlight the limitations of the available data to date as well as some of the challenges in designing appropriate clinical trials in this salvage setting, including how to select an appropriate control arm given the absence of a well-established reference standard, and the importance of incorporating predictive biomarkers and quality of life measures whenever possible into study design.
| S-EPMC3942828 | biostudies-literature
Project description:Immunotherapy has dramatically changed the cancer treatment landscape during the past decade, but very limited efficacy has been reported against pancreatic cancer. Several factors unique to pancreatic cancer may explain the resistance: the well-recognized suppressive elements in the tumor microenvironment, the functional and structural barrier imposed by the stroma components, T-cell exhaustion, the choice of perhaps the wrong immune targets, and microbial factors including gut dysbiosis and the unexpected presence of tumor microbes. Furthermore, we discuss various strategies to overcome these barriers.
| S-EPMC8639640 | biostudies-literature
Project description:BackgroundNab-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.MethodsPatients 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.ResultsIn 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).ConclusionsSEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS.Clinical trial registrationISRCTN71070888; ClinialTrials.gov (NCT03529175).
| S-EPMC7283477 | biostudies-literature
Project description:Background:Systemic chemotherapy is the standard treatment for locally advanced and metastatic pancreatic cancer, but there is no consensus on the optimum regimen. We aimed to compare and rank the locally advanced and metastatic pancreatic adenocarcinoma chemotherapy regimens evaluated in randomized controlled trials (RCTs) in the past 15 years. Materials and methods:PubMed, Embase, Cochrane Collaboration database, and ClinicalTrials.gov were searched for RCTs comparing chemotherapy regimens as first-line treatment for locally advanced and metastatic pancreatic adenocarcinomas. By using Bayesian network meta-analysis, we compared and ranked all included chemotherapy regimens in terms of overall survival, progression-free survival, response rate, and hematological toxicity. Results:The analysis included 68 RCTs, with 14,908 patients and 63 treatment strategies. For overall survival, NSC-631570 (hazard ratio [HR] vs gemcitabine monotherapy 0.44, 95% credible interval: 0.24-0.76) and gemcitabine+NSC-631570 (HR 0.45, 0.24-0.86) were the two top-ranked chemotherapy regimens. For progression-free survival, PEFG (cisplatin + epirubicin + fluorouracil + gemcitabine) ranked first (HR 0.51, 0.34-0.77). PG (gemcitabine + pemetrexed) (odds ratio [OR] 4.68, 2.24-9.64) and FLEC (fluorouracil + leucovorin + epirubicin + carboplatin) (OR 4.52, 1.14-24.00) were ranked the most hematologically toxic, with gastrazole having the least toxicity (OR 0.03, 0.00-0.46). Conclusion:The chemotherapy regimens NSC-631570 and gemcitabine+NSC-631570 were ranked the most efficacious for locally advanced and metastatic pancreatic adenocarcinomas in terms of overall survival, which warrants further confirmation in large-scale RCTs.
| S-EPMC6254987 | biostudies-other
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:IntroductionMetastatic pancreatic ductal adenocarcinoma (mPDAC) is a common cancer with poor survival outcomes. Although treatment options are limited, real-world treatment patterns and outcomes are not well understood, particularly beyond first-line treatment. This study described real-world treatment patterns and outcomes for mPDAC in the USA.MethodsThis retrospective analysis used electronic health record-derived de-identified data of patients with mPDAC diagnosed between January 1, 2014 and June 30, 2021. Treatments were classified into six groups: (1) standard combination chemotherapy; (2) nonstandard combination chemotherapy; (3) single-agent chemotherapy; (4) targeted therapy; (5) clinical study drugs; and (6) off-label therapies. Analyses were descriptive in nature. Treatment utilization and switching, and time on treatment and time to discontinuation, were described by first-line (1LOT) and second-line (2LOT) treatment groups. Median overall survival (mOS) from 1LOT and 2LOT was stratified by treatment group, and for 1LOT on the basis of whether patients received further treatment.Results1LOT included 6979 patients, 3241 (46%) of whom received further 2LOT. Standard combination chemotherapy was the most common 1LOT (70%) and 2LOT (46%). Nonstandard combination chemotherapy was used more as 2LOT (35%) than 1LOT (11%). First-line time on treatment was generally higher than second-line time on treatment, and time to discontinuation was lower than time on treatment. mOS in days (months) from 1LOT was 271 (8.9), 252 (8.3), 219 (7.2), 170 (5.6), 280 (9.2), and 182 (6.0), and mOS from 2LOT was 202 (6.6), 193 (6.3), 186 (6.1), 193 (6.3), 179 (5.9), and 97 (3.2), for groups 1-6, respectively. Within group 1, mOS from 1LOT was 318 days (10.4 months) for FOLFIRINOX and 241 days (7.9 months) for gemcitabine and nab-paclitaxel.ConclusionMost patients with mPDAC received 1LOT in line with clinical practice guidelines, yet mOS remains poor. This study highlights the need for novel therapies to demonstrate improved patient survival compared with therapies in current clinical practice guidelines.
| S-EPMC9618512 | biostudies-literature
Project description:Lessons learnedPreclinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the antitumor effects of oxaliplatin. In this phase II, single-arm study, FOLFOX with dasatinib in previously untreated patients with mPC only showed only modest clinical activity, with a progressive-free survival of 4 months and overall survival of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-fluorouracil and oxaliplatin in a subset of exceptional responders.BackgroundSrc tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance antitumor effects of FOLFOX regimen (FOLFOX-D).MethodsIn this single-arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1-14, oxaliplatin 85 mg/m2 intravenous (IV) on day 1 every 14 days, leucovorin (LV) 400 mg/m2 IV on day 1 every 14 days, 5-fluorouracil (5-FU) bolus 400 mg/m2 on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m2 on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with preplanned comparison to historical controls.ResultsForty-four patients enrolled with an estimated median PFS of 4.0 (95% confidence interval [CI], 2.3-8.5) months and overall survival (OS) of 10.6 (95% CI, 6.9-12.7) months. Overall response rate (ORR) was 22.7% (n = 10): one patient (2.3%) with complete response (CR) and nine patients (20.5%) with partial response (PR). Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%).ConclusionThe addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated patients with mPC.
| S-EPMC8488773 | biostudies-literature
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:Hepatocellular carcinoma (HCC) has high mortality. The option of systemic therapy has increased significantly over the past five years. Sorafenib was the first multikinase inhibitor, introduced in 2007, as a treatment option for HCC, and it was the only effective systemic treatment for more than ten years. It was not until 2017 that several breakthroughs were made in the development of systemic strategies. Lenvatinib, another multikinase inhibitor, stood out successfully after sorafenib, and has been applied to clinical use in the first-line setting. Other multikinase inhibitors such as regorafenib, ramucirumab and cabozantinib, were approved in quick succession as second-line therapies. Concurrently, immune checkpoint inhibitors (ICIs) have readily become established treatments for many solid tumors, including HCC. The most studied ICIs to date, target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These ICIs have demonstrated efficacy in treating advanced HCC. More recently, combination of bevacizumab and atezolizumab (ICI targeting PD-L1) was approved as the gold-standard first-line therapy. Combination of ICIs with nivolumab and ipilimumab was also approved in the second-line setting for those who failed sorafenib. At the moment, numerous clinical trials in advanced HCC are underway, which will bring continuous change to the management, and increase the survival, for patients with advanced HCC. Our review article: (1) summarizes United States Food and Drug Administration (US FDA) approved systemic therapies in advanced HCC, (2) reports the evidence of currently approved treatments, (3) discusses potential drugs/drug combinations being currently tested in phase III clinical trials, and (4) proposes possible future directions in drug development for advanced HCC.
| S-EPMC9406660 | 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