Unresectable Pancreatic Adenocarcinoma Research Articles

LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001): results from arm 1 of a non-randomised, single-centre, phase 1/2 study

Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma. LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 μL of LOAd703 at 5 × 1010 (dose 1), 1 × 1011 (dose 2), or 5 × 1011 (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants. Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8+ effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response. Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing. Lokon Pharma, the Swedish Cancer Society, and the Swedish Research Council.

Assessing Endoscopic Ultrasound-Guided Radiofrequency Ablation in Unresectable Pancreatic Ductal Adenocarcinoma: A Single-Center Historic Cohort Study.

/aims: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has emerged as an alternative for the local treatment of unresectable pancreatic ductal adenocarcinoma (PDAC). We aim to assess the feasibility and safety of EUS-RFA in patients with unresectable PDAC. The following was a historic cohort compounded by locally advanced (LA) and metastatic (m) PDAC naïve patients, who underwent EUS-RFA between October 2019 to March 2022. EUS-RFA was performed with a 19-g needle electrode with a 10 mm active tip for energy delivery. Study primary endpoints were feasibility, safety, and clinical follow-up; secondary endpoints were performance status (PS), local control (LC) and overall survival (OS). Twenty-six patients were selected: 15/26 LA-PDAC and 11/26 mPDAC. Technical success was achieved in all patients with no major adverse events. Six months after EUS-RFA, OS was 11/26 (42.3%), with significant PS improvement (P=.03). LC was achieved, with tumor reduction from 39.5 to 26 mm (P=.04). Post-treatment hypodense necrotic area was observed at six-month follow-up in 11/11 alive cases. Metastatic disease was a significant factor for OS worsening (HR 5.021; IC 95% 1.589 - 15.87; P=.004) CONCLUSIONS: EUS-RFA of pancreatic adenocarcinoma is a minimally invasive and safe technique that may have an important role as targeted therapy for local treatment of unresectable cases, as well as an alternative for poor surgical candidates. Also, RFA may play a role in downstaging cancer with potential OS increase in non-metastatic cases. Large prospective cohorts are required to evaluate this technique in clinical practice.

Pretherapeutic factors predicting conversion surgery in unresectable pancreatic ductal adenocarcinoma: A retrospective study.

Recently, conversion surgery (CS) has been reported to improve the prognosis in patients with unresectable pancreatic ductal adenocarcinoma (UR-PDAC) with a favorable response to intense chemotherapy or chemoradiotherapy. However, few pretherapeutic parameters predict the attainability of CS in patients with UR-PDAC. The present study aimed to explore the pretherapeutic predictors for the attainability of CS in patients with UR-PDAC. The present study retrospectively evaluated 130 patients with UR-PDAC treated at Gifu University Hospital (Gifu, Japan) from January 2015 to December 2021. Survival analysis was performed using the Simon and Makuch-modified Kaplan-Meier method. The hazard ratio (HR) was estimated using a time-varying Cox regression model. The association between each predictor and CS was evaluated using the univariate analysis and age-adjusted Fine-Gray sub-distribution hazard model. The bootstrap bias-corrected area under the receiver operating characteristic curve analysis for predicting CS was used to assess the cut-off values for each predictor. The cumulative incidence rate was calculated with CS as the outcome when divided into two groups based on the cut-off value of each pretherapeutic predictor. Among the 130 patients included in the analysis, only 14 (11%) underwent CS. The median survival time was significantly longer in patients who underwent CS compared with patients without CS (56.3 vs. 14.1 months; P<0.001). The age-adjusted Fine-Gray sub-distribution hazard regression showed that the total protein (TP) [HR 2.81, 95% confidence interval (CI) 1.19-6.65; P=0.018], neutrophil-to-lymphocyte ratio (NLR) (HR 0.53, 95% CI 0.31-0.90; P=0.020), and lymphocyte-to-monocyte ratio (LMR) (HR 1.28, 95% CI 1.07-1.53; P=0.006) were significantly associated with CS. Moreover, TP ≥6.8, NLR <2.84 and LMR ≥3.87 were associated with a higher cumulative incidence of CS. In conclusion, pretherapeutic TP, NLR and LMR are clinically feasible biomarkers for predicting the attainability of CS in patients with UR-PDAC.

Biweekly gemcitabine plus nab-paclitaxel as first-line therapy for older adult patients with unresectable pancreatic cancer: A prospective study.

672 Background: Although the number of older adult patients (aged ≥ 75 years) with pancreatic cancer (PC) is increasing, there are still limited data regarding chemotherapy for these patients, who experience adverse events more frequently than younger patients with PC. In this study, we evaluated the efficacy and safety of biweekly gemcitabine plus nab-paclitaxel (GnP) as first-line therapy for older adult patients with unresectable PC. Methods: We conducted a single-center prospective study. Patients aged ≥ 75 years with pathologically proven unresectable pancreatic adenocarcinoma were enrolled after obtaining written informed consent. Patients were treated with a modified regimen of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 15 of every 28-day cycle. The primary endpoint was the overall response rate. Secondary endpoints included disease control rate, overall survival, progression-free survival, 1-year survival rate, 2-year survival rate, and adverse events. Results: From August 2018 to March 2021, 17 patients were enrolled (locally advanced 4; metastatic 13). Five patients (29.4%) were men, and the median age was 77 years (range: 75-81). The median Geriatric 8 score was 13 points (range 6-17). Biliary drainage was performed in three patients. The overall response rate was 47.1% (8/17). Disease control rate was 82.4% (14/17). Median overall survival was 16.8 months (95% confidence interval (CI) 5.9-24.6) and median progression-free survival was 8.3 months (95% CI: 4.9-10.1), respectively. The 1-year survival rate and 2-year survival rates were 58.8% and 29.4%, respectively. Grade 3 or 4 hematologic adverse events and non-hematologic adverse events were observed in 17.6% (3/17) and 29.4% (5/17), respectively. No deaths was observed in association with biweekly GnP regimen. Conclusions: Biweekly GnP as first-line therapy can provide favorable treatment outcomes with tolerable toxicity in older adult patients with unresectable PC. Clinical trial information: jRCTs051190038 .

Survival outcome of different treatment sequences in patients with locally advanced and metastatic pancreatic cancer

BackgroundDespite some therapeutic advances, improvement in survival rates of unresectable and/or metastatic pancreatic ductal adenocarcinoma (PDAC) has been minimal over recent decade. We aimed to evaluate the impact of different treatment sequences on clinical outcomes of advanced PDAC at our academic institution.MethodsIn this single institution retrospective analysis, we assessed characteristics and survival rates of unresectable and/or metastatic pancreatic PDAC patients who started a systemic treatment between 01/2015 and 12/2021. Survival analyses were performed by Kaplan-Meier and Cox proportional hazards model.ResultsThe number of 285 patients received at least two lines of treatment, but only 137 patients were suitable for third-line treatment. Subgroup analysis showed that thirty-seven patients received A line (gemcitabine/nab-paclitaxel or nab-paclitaxel combined therapy to FOLFIRINOX) therapy, 37 patients received B line (nab-paclitaxel combined therapy to gemcitabine combined therapy to FOLFIRINOX) therapy, 21 patients received C line (nab-paclitaxel combined therapy to gemcitabine combined therapy to oxaliplatin or irinotecan combined therapy) therapy. Survival rates for different treatment lines were significantly different and median overall survival (OS) was 14.00, 18.00, and 14.00 months, respectively (p<0.05).ConclusionOur study provides real-world evidence for the effectiveness of different treatment sequences and underscores the treatment sequences on survival outcome when considering the entire management in advanced PDAC.

Correlation of maintenance chemotherapy and improved survival in patients with locally advanced unresectable pancreatic head adenocarcinoma receiving neoadjuvant chemotherapy and concurrent chemoradiotherapy

Correlation of maintenance chemotherapy and improved survival in patients with locally advanced unresectable pancreatic head adenocarcinoma receiving neoadjuvant chemotherapy and concurrent chemoradiotherapy

Phase II study of SOXIRI (S-1/oxaliplatin/irinotecan) chemotherapy in patients with unresectable pancreatic ductal adenocarcinoma

BackgroundTo provide data on the safety and efficacy of a combination chemotherapy regimen consisting of S-1, oxaliplatin, and irinotecan (SOXIRI) as a first-line therapy in unresectable pancreatic ductal adenocarcinoma (UPDA) patients. MethodsPatients with UPDA and no prior treatment chemotherapy in the UPDA setting were enrolled. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS) and adverse events. Patients received 80 mg/m2 S-1 twice a day for 2 weeks in an alternate-day administration cycle, 85 mg/m2 oxaliplatin on Day 1, and 150 mg/m2 irinotecan on Day 1 of a 2-week cycle. ResultsIn these 62 enrolled patients, the ORR was 27.4 %, median OS was 12.1 months, and median PFS was 6.5 months. Major grade 3 or 4 toxicity included neutropenia (22.3 %), leucopenia (16.1 %), nausea (9.7 %), vomiting (9.7 %), thrombocytopenia (6.5 %), anorexia (8.5 %), anemia (4.8 %), and diarrhea (1.6 %). No treatment-related deaths occurred. In addition, the analysis of 32 patients suffering pain revealed that the rate of pain relief was 34.4 %. ConclusionSOXIRI might be a standard regimen with an acceptable toxicity profile and favorable efficacy for use as chemotherapy in patients with UPDA.

Liquid Biopsy: A Highly Useful Tool to Decide Personalized Therapy in Veteran Patients with Metastatic Pancreaticobiliary Cancer

Abstract Introduction/Objective Pancreatic cancer is one of the leading causes of death in Veteran patients. Early detection and treatment of the pancreatic cancers are key to the successful management of pancreatic cancer with good patient outcome. The National Comprehensive Cancer Network (NCCN) recommends tumor molecular profiling in all patient cases of unresectable or metastatic pancreatic adenocarcinomas and biliary tract cancers who are candidates for chemotherapy. This testing can be performed using liquid biopsy to obtain this molecular profiling from circulating tumor cells (CTC) to obtain information that may impact treatment. However, the literature of metastatic pancreaticobiliary cancers targeted by liquid biopsies and the mutations found is sparse, particularly for the veteran population. Methods/Case Report A retrospective review was performed of all patients with a submitted liquid biopsy specimen at a Veteran Affairs Medical Center (VAMC) from April 2020 to March 3rd, 2023, to examine those patients with metastatic pancreaticobiliary cancers, specifically pancreatic adenocarcinoma, and cholangiocarcinoma. Information on mutations detected was collected. Results (if a Case Study enter NA) There were a total of 5 patient specimens with a history of metastatic pancreatic adenocarcinoma (4 cases/5) and cholangiocarcinoma (1 case/5). The first liquid biopsy from a patient with a history of metastatic pancreaticobiliary cancer was sent on April 14th, 2020, and the last was sent on November 12th, 2021. TP53 was detected on all the successfully tested pancreatic adenocarcinoma cases. Other mutations detected in the individual pancreatic adenocarcinoma cases were KRAS, TET2 BCOR, DNMT3A, FUBP1, RAD21, and STAG2. The mutations found on the single cholangiocarcinoma case included DNMT3A and TP53. 1 of the 4 cases sent on a patient with pancreatic adenocarcinoma resulted in a sample failure. Conclusion Liquid biopsies provided comprehensive molecular profiling in cases of metastatic pancreatic adenocarcinoma and biliary tract cancer in the veteran population treated at a local VAMC to help decide on personalized therapy, in compliance with the recommendations of the NCCN. The results of this pilot quality assurance study help highlight the potential of liquid biopsies to detect most commonly mutated genes such as KRAS and T53 in pancreatic cancer.

Genomic profile and clinical features of MSI-H and TMB-high pancreatic cancers: real-world data from C-CAT database.

Microsatellite instability high (MSI-H) and tumor mutational burden high (TMB-high) pancreatic cancer are rare, and information is lacking. Based on the C-CAT database, we analyzed the clinical and genomic characteristics of patients with these subtypes. We retrospectively reviewed data on 2206 patients with unresectable pancreatic adenocarcinoma enrolled in C-CAT between July 2019 and January 2022. The clinical features, proportion of genomic variants classified as oncogenic/pathogenic in C-CAT, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) of chemotherapy as first-line treatment were evaluated. Numbers of patients with MSI-H and TMB-high were 7 (0.3%) and 39 (1.8%), respectively. All MSI-H patients were TMB-high. MSI-H and TMB-high patients harbored more mismatch repair genes, such as MSH2, homologous recombination-related genes, such as ATR and BRCA2, and other genes including BRAF, KMT2D, and SMARCA4. None of the 6 MSI-H patients who received chemotherapy achieved a clinical response, including 4 patients treated with gemcitabine plus nab-paclitaxel (GnP) therapy, whose DCR was significantly lower than that of microsatellite stable (MSS) patients (0 vs. 67.0%, respectively, p = 0.01). Among the TMB-high and TMB-low groups, no significant differences were shown in ORR, DCR (17.1 vs. 23.1% and 57.1 vs. 63.1%, respectively), or median TTF (25.9 vs. 28.0weeks, respectively) of overall first-line chemotherapy. MSI-H and TMB-high pancreatic cancers showed some distinct genomic and clinical features from our real-world data. These results suggest the importance of adapting optimal treatment strategies according to the genomic alterations.

Modified FOLFIRINOX as the first-line chemotherapy in unresectable and metastatic pancreatic adenocarcinoma—a single-center experience in India

Modified FOLFIRINOX as the first-line chemotherapy in unresectable and metastatic pancreatic adenocarcinoma—a single-center experience in India

Implication of Skeletal Muscle Loss in the Prognosis of Patients with Pancreatic Ductal Adenocarcinoma Receiving Chemotherapy.

Objective The effect of sarcopenia on the prognosis of patients undergoing chemotherapy for unresectable pancreatic ductal adenocarcinoma remains largely unexplored. In this retrospective study, we investigated the relationship between sarcopenia and the prognosis of patients receiving first-line nanoparticle albumin-bound paclitaxel plus gemcitabine for unresectable pancreatic ductal adenocarcinoma. Patients and Methods We enrolled 251 patients with unresectable metastatic or locally advanced pancreatic ductal adenocarcinoma who had received chemotherapy between January 2015 and December 2020 at Kitasato University Hospital. Univariate and multivariate analyses were performed using the stratified Cox proportional hazards model to determine variables significantly associated with the progression-free and overall survival. Propensity score matching was performed to mitigate selection bias effects. Results In the propensity score-matched cohort, the progression-free and overall survival were not significantly different between the sarcopenia and non-sarcopenia groups (p=0.335, and 0.679 respectively). The skeletal muscle index decreased by 4.4% and 6.5% in the sarcopenia and non-sarcopenia groups, respectively, during the early treatment phase (p=0.084). There were no significant differences between groups with regard to major adverse events or drug toxicity occurrences. Both the progression-free and overall survival were significantly shorter in the skeletal muscle index loss group than in the non-skeletal muscle index loss group (p=0.026 and 0.045, respectively). Conclusions Skeletal muscle index loss during the initial treatment phase may be an early marker for the long-term prognosis of patients receiving nanoparticle albumin-bound paclitaxel plus gemcitabine as first-line treatment for unresectable pancreatic ductal adenocarcinoma.

Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.

EUS-guided radiofrequency ablation plus chemotherapy versus chemotherapy alone for pancreatic cancer (ERAP): An observational open-label pilot study.

No study has compared EUS-guided radiofrequency ablation (EUS-RFA) plus systemic chemotherapy (CMT) with CMT alone for unresectable pancreatic ductal adenocarcinoma. This study compared the results of treatment in patients receiving EUS-RFA plus concomitant CMT (group A; n = 14) with those receiving CMT (group B; n = 14) as a pilot study. From July 2017 to August 2018, 4 and 2 patients from groups A and B, respectively, withdrew from the study because of progression of the disease. In total, 10 and 12 patients from groups A and B, respectively, completed the study. All 30 EUS-RFA procedures were successful. Mean maximal tumor diameter before treatment of group A (n = 10) versus B (n = 12) was 62.2 ± 21.0 versus 50.5 ± 22.0 mm, respectively (P = not significant). After treatment, no statistically significant difference in mean maximal tumor diameter was found between both groups. However, in group B, mean maximal tumor diameter was significantly increased from 50.5 ± 22.0 to 56.3 ± 18.7 mm, respectively (P = 0.017). Tumor necrosis occurred in group A versus B at 10 of 10 (100%) versus 6 of 12 (50%) patients, respectively (P = 0.014). After treatment, group A patients could reduce the mean narcotic pain drug dosage at 26.5 mg of morphine equivalent per day (from 63.6 to 37.1 mg, P = 0.022), whereas group B patients could not reduce the dosage of pain-controlled medication. No statistically significant difference in 6-month mortality rate was found. In group A, 1 procedure-related nonsevere adverse event (n = 1 of 30 [3.3%]) occurred in 1 patient (n = 1 of 14 [7.1%]). In this study, the mean tumor diameter of group B was significantly increased after the treatment. Group A had a significantly higher rate of necrosis of tumor and required less narcotic.

Optimization of laser dosimetry based on patient-specific anatomical models for the ablation of pancreatic ductal adenocarcinoma tumor

Laser-induced thermotherapy has shown promising potential for the treatment of unresectable primary pancreatic ductal adenocarcinoma tumors. Nevertheless, heterogeneous tumor environment and complex thermal interaction phenomena that are established under hyperthermic conditions can lead to under/over estimation of laser thermotherapy efficacy. Using numerical modeling, this paper presents an optimized laser setting for Nd:YAG laser delivered by a bare optical fiber (300 µm in diameter) at 1064 nm working in continuous mode within a power range of 2–10 W. For the thermal analysis, patient-specific 3D models were used, consisting of tumors in different portions of the pancreas. The optimized laser power and time for ablating the tumor completely and producing thermal toxic effects on the possible residual tumor cells beyond the tumor margins were found to be 5 W for 550 s, 7 W for 550 s, and 8 W for 550 s for the pancreatic tail, body, and head tumors, respectively. Based on the results, during the laser irradiation at the optimized doses, thermal injury was not evident either in the 15 mm lateral distances from the optical fiber or in the nearby healthy organs. The present computational-based predictions are also in line with the previous ex vivo and in vivo studies, hence, they can assist in the estimation of the therapeutic outcome of laser ablation for pancreatic neoplasms prior to clinical trials.

Circulating tumor DNA in unresectable pancreatic cancer is a strong predictor of first-line treatment efficacy: The KRASCIPANC prospective study

BackgroundThere is no robust predictor of response to chemotherapy (CT) in unresectable pancreatic adenocarcinomas (UPA). The objective of the KRASCIPANC study was to analyze the kinetics of cell-free DNA (cfDNA)/circulating tumor DNA (ctDNA) as a predictor of response to CT in UPA. MethodsBlood samples were collected just before first CT and at day 28. The primary endpoint was the kinetics of KRAS-mutated ctDNA by digital droplet PCR between D0 and D28 as a predictor of progression-free survival (PFS). ResultsWe analyzed 65 patients with a KRAS-mutated tumor. A high level of cfDNA and KRAS-mutated ctDNA at D0, as well as the presence of KRAS-mutated ctDNA at D28, were strongly associated with lower centralized disease control rate (cDCR), shorter cPFS and OS in multivariate analysis. A score combining cfDNA level at diagnosis ≥ or <30 ng/mL and presence or not of KRAS-mutated ctDNA at D28 was an optimal predictor of cDCR (OR=30.7, IC95% 4.31–218 P=.001), PFS (HR=6.79, IC95% 2.76–16.7, P<.001) and OS (HR=9.98, IC95% 4.14–24.1, P<.001). ConclusionA combined score using cfDNA level at diagnosis and KRAS-mutated ctDNA at D28 is strongly associated with patient survival/response to chemotherapy in UPA. Trial RegistrationClinicalTrials.gov Identifier: NCT04560270

Prognostic impact and risk factors of early recurrence after conversion surgery following neoadjuvant therapy in patients with initially unresectable pancreatic ductal adenocarcinoma

Prognostic impact and risk factors of early recurrence after conversion surgery following neoadjuvant therapy in patients with initially unresectable pancreatic ductal adenocarcinoma

Clinical outcomes of patients who are frail and elderly with unresectable pancreatic ductal adenocarcinoma (PDAC) treated with chemotherapy.

e16281 Background: Gemcitabine plus nab-paclitaxel and fluorouracil (5-FU)-based chemotherapy, such as FOLFIRINOX and FOLFOX, are standard treatment for unresectable PDAC. While older age and poor performance status (PS) are established negative prognostic factors, most clinical trials exclude these vulnerable populations. We aimed to assess the impact of older age and reduced PS in a real-world cohort of patients with PDAC who received chemotherapy. Methods: We retrospectively reviewed patients with unresectable or metastatic PDAC treated with first line (1L) therapy at Mount Sinai Health System from 1/2012 to 12/2021. We evaluated the association between age (≥ 75 vs. &lt; 75) and PS (ECOG PS ≥ 2 vs. &lt; 2) on overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Chemotherapy tolerability was compared between these vulnerable and non-vulnerable populations using Chi-squared and Mann-Whitney tests. Results: 254 patients were evaluable. The median age of the full cohort was 66 years, and 130 (51.2%) patients were male. All patients had locally advanced (29.8%) or metastatic disease (70.2%). 47.6% of patients received gemcitabine-based and 49.6% received 5-FU-based 1L therapy. 41 patients (16.1%) had ECOG PS ≥ 2, and 60 (23.6%) were 75 or older. The type of 1L chemotherapy and rate of adverse events (AEs) requiring dose change or discontinuation did not differ significantly between patients with ECOG PS ≥ 2 and PS &lt; 2. However, patients with ECOG PS ≥ 2 received a shorter duration of therapy (median 2.6 vs. 3.4 months, P = 0.018), and the reason for discontinuation was more often due to clinical deterioration (56.1% vs. 29.6%, P = 0.004). As a result, fewer continued on to second-line (2L) therapy (29.3% vs. 51.2%, P = 0.016). ECOG PS ≥ 2 was associated with worse OS (HR 1.6, 95% CI 1.1-2.4, P = 0.016) in univariate analysis but not in multivariate analysis. ECOG PS ≥ 2 correlated with worse PFS in both univariate and multivariate analyses (HR 1.6, 95% CI 1.1-2.3, P = 0.009; HR 1.5, 95% CI 1.1-2.2, P = 0.023). Patients older than 75 were more likely to receive gemcitabine-based therapy (83.3% vs. 40.2%, P &lt; 0.001). While no significant differences in duration of therapy, rate of AEs, or reasons for discontinuation were observed based on age, older patients were less likely to receive 2L therapy (28.3% vs. 53.6%, P = 0.001). Age ≥ 75 was associated with worse OS (HR 1.6, 95% CI 1.19-2.25, P = 0.003) and worse PFS (HR 1.4, 95% CI 1.05-1.89, P = 0.024) in univariate but not multivariate analyses. Objective response rates did not differ based on PS or age. Conclusions: Reduced PS was associated with worse clinical outcomes and poor chemotherapy tolerance, but older patients appeared to tolerate gemcitabine-based regimens. Future studies should more specifically address the treatment needs of frail and elderly patients.

The Prognostic Utility of a Geriatric Assessment for Patients with Pancreatic Cancer Receiving Gemcitabine-based Chemotherapy: A Prospective Observational Study.

Objective To evaluate the effect of a pretreatment geriatric assessment on the clinical outcomes in older patients with unresectable or recurrent pancreatic ductal adenocarcinoma (PDAC) scheduled to receive gemcitabine (GEM)/GEM+nab-paclitaxel (GnP). Patients Older patients with unresectable PDAC scheduled to receive GEM/GnP who visited Kyorin University Hospital and cooperating institutions were enrolled and followed from April 2015 to March 2020. The maximum observation period was two years. All patients underwent a cancer-specific geriatric assessment (CSGA) and optional geriatric assessment (GA) before treatment initiation and two months after the start of treatment. The patients' background characteristics, tumor progression, tumor site, and regimen (GEM/GnP) were examined in a Cox proportional hazards model. The relationship between the overall survival (OS) and GA score was also determined. Eligible patients (age ≥70 years old with histopathologically confirmed unresectable or recurrent PDAC) were scheduled to receive first-line chemotherapy. Results The performance status (PS) and activities of daily living (ADL)/instrumental ADL (IADL) scores at baseline correlated with the OS. Furthermore, even in cases with normal baseline values, lower Frontal Assessment Battery scores and higher Geriatric Depression Scale-Short Form scores after treatment initiation were significantly correlated with OS. Conclusion The baseline PS, ADL, and IADL may be prognostic factors in older PDAC patients. In addition, a normal frontal lobe function and depression scores prior to treatment initiation that rapidly worsened during treatment were independently associated with a reduced OS. Selecting appropriate interventions and improving the therapeutic environment may prolong the OS in such patients.

Molecular profiling as a predictor of treatment response and survival in unresectable pancreatic ductal adenocarcinoma.

e16279 Background: To date, few targetable mutations have been found to enhance PDAC treatment. Next-generation sequencing (NGS) of somatic mutation profiles may help tailor cytotoxic chemotherapy selection and guide translational research. Methods: We analyzed NGS data from a retrospective cohort of 142 patients with unresectable biopsy-proven PDAC from August 2009 to December 2022. Individual mutations were grouped into 14 distinct signaling pathways: cell cycle, DNA damage repair, KIT, ErbB2, TP53, MAPK-RAS, PIK3, TGF-beta, NOTCH, ALK, FLT3, FGFR, and WNT. Treatment selection, duration of response, and survival were recorded. We stratified patients based on their first-line therapy, either FOLFIRINOX (FFX) or gemcitabine/nab-paclitaxel (GA). We present median time-to-first progression (PFS1) and overall survival (OS) based on the presence or absence of mutations in these pathways. The time-to-event endpoint was estimated by the Kaplan-Meier method. Results: Of 142 samples, 131 were analyzed for PFS1; 57 received FFX, and 60 received GA. In the FFX group, no pathway predicted PFS1 with statistical significance. In the GA group, KIT pathway mutations (n = 10) showed improved PFS1 vs. non-KIT mutated tumors (10.3 mos vs. 6.2 mos, p = 0.02). Similar improvement in PFS1 was seen for mutations in the PIK3 pathway (n = 25, 6.6 vs. 5.7, p = 0.02) and FLT3 pathway (n = 4, 13.1 vs. 6.2, p = 0.02). 125 samples were analyzed for OS. KIT pathway mutations (n = 21) showed a better OS vs. non-KIT mutated samples (21.3 mos vs. 12.2 mos, p = 0.04), as did NOTCH mutated samples (n = 44, 15 vs. 12.3, p &lt; 0.01). FLT3 pathway mutations showed a trend toward improved OS (23.6 vs. 13, p = 0.3). PIK3 mutated tumors had no difference in OS. 8 samples were KRAS WT; removing these from the analysis did not change the results. Conclusions: In this sample, KIT, FLT3, and PIK3 pathway mutated tumors had improved PFS1 with GA (but not FFX) treatment. Tumors with KIT and NOTCH pathway mutations had an improved OS. This and similar analyses could help identify potential drivers of treatment response for unresectable pancreatic tumors. [Table: see text]

Efficacy of Fully Covered Self-Expandable Metal Stents for Distal Biliary Obstruction Caused by Pancreatic Ductal Adenocarcinoma: Primary Metal Stent vs. Metal Stent following Plastic Stent.

Fully covered self-expandable metallic stents (FCSEMSs) are inserted in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) to resolve malignant distal bile duct obstructions. Some patients receive FCSEMSs during primary endoscopic retrograde cholangiopancreatography (ERCP), and others receive FCSEMSs during a later session, after the placement of a plastic stent. We aimed to evaluate the efficacy of FCSEMSs for primary use or following plastic stent placement. A total of 159 patients with pancreatic adenocarcinoma (m:f, 102:57) who had achieved clinical success underwent ERCP with the placement of FCSEMSs for palliation of obstructive jaundice. One-hundred and three patients had received FCSEMSs in a first ERCP, and 56 had received FCSEMSs after prior plastic stenting. Twenty-two patients in the primary metal stent group and 18 in the prior plastic stent group had recurrent biliary obstruction (RBO). The RBO rates and self-expandable metal stent patency duration did not differ between the two groups. An FCSEMS longer than 6 cm was identified as a risk factor for RBO in patients with PDAC. Thus, choosing an appropriate FCSEMS length is an important factor in preventing FCSEMS dysfunction in patients with PDAC with malignant distal bile-duct obstruction.