FOLFIRINOX Chemotherapy Research Articles

FOLFIRINOX regulated tumor immune microenvironment to extend the survival of patients with resectable pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly malignant tumors worldwide due to its ineffective diagnosis and poor prognosis. The longest median overall survival (OS) to PDAC patients has been provided by FOLFIRINOX. It is essential to identify the mechanisms of FOLFIRINOX to gain new insights for the treatment of PDAC. We compared gene expression levels of PDAC patients who received neoadjuvant FOLFIRINOX prior to surgery with those of patients who received no neoadjuvant chemotherapy. Bioinformatics analysis was applied to screen differentially expressed genes (DEGs). Three microarray data sets were downloaded to analyze gene expression data between PDAC and adjacent non-tumor tissues. Overlapping DEGs were subjected to Kaplan-Meier survival analysis. The genes relating to poor outcomes and would be decreased after FOLFIRINOX were input into the Oncomine, University of Alabama Cancer (UALCAN), and LinkedOmics databases to analyze the gene expression and regulation networks. A total of 83 differentially expressed genes (DEGs) were screened and subjected to bioinformatics analysis, which indicated FOLFIRINOX influenced the immune microenvironment of PDAC. Seventy-three genes significantly associated with the OS of PDAC patients. A Venn diagram revealed CXCL5 and PLAU were related to poor outcomes and would decrease after FOLFIRINOX chemotherapy of PDAC patients. It turned out that CXCL5 participated in the immune response-regulating signaling pathway in PDAC patients. FOLFIRINOX regulated tumor immunity by reducing expression of the immunosuppressive gene CXCL5, laying a foundation for further study of combination therapy of FOLFIRINOX and immunotherapy.

Adjuvant chemotherapy in patients with resected pancreatic cancer following neoadjuvant FOLFIRINOX chemotherapy: an international multicenter study

Adjuvant chemotherapy in patients with resected pancreatic cancer following neoadjuvant FOLFIRINOX chemotherapy: an international multicenter study

An ultrasound responsive microbubble-liposome conjugate for targeted irinotecan-oxaliplatin treatment of pancreatic cancer

Survival rates in pancreatic cancer have remained largely unchanged over the past four decades with less than 5% of patients surviving five years following initial diagnosis. FOLFIRINOX chemotherapy, a combination of folinic acid, 5-fluoruracil, irinotecan and oxaliplatin, has shown the greatest survival benefit for patients with advanced disease but is only indicated for those with good physical performance status due to its extreme off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the targeted delivery of drug payloads to solid tumours and involves using low intensity ultrasound to disrupt (burst) MBs in the tumour vasculature, releasing encapsulated or attached drugs in a targeted manner. In this manuscript, we describe the preparation of a microbubble-liposome complex (IRMB-OxLipo) carrying two of the three cytotoxic drugs present in the FOLFIRINOX combination, namely irinotecan and oxaliplatin. Efficacy of the IRMB-OxLipo complex following UTMD was determined in Panc-01 3D spheroid and BxPC-3 human xenograft murine models of pancreatic cancer. The results revealed that tumours treated with the IRMB-OxLipo complex and ultrasound were 136% smaller than tumours treated with the same concentration of irinotecan/oxaliplatin but delivered in a conventional manner, i.e. as a non-complexed mixture. This suggests that UTMD facilitates a more effective delivery of irinotecan/oxaliplatin improving the overall effectiveness of this drug combination and to the best of our knowledge, is the first reported example of a microbubble-liposome complex used to deliver these two chemotherapies.

An Australian Three-Centre Feasibility Study of Neoadjuvant Modified FOLFIRINOX and Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer with Collection of Baseline Circulating Tumor Cells

Stereotactic body radiotherapy (SBRT) has an increasing role for treatment of locally advanced pancreatic adenocarcinoma (LAPC). Selection of appropriate cases may be improved with identification of useful prognostic and predictive clinical biomarkers. This study aimed to establish the feasibility and safety of neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) chemotherapy followed by SBRT for patients with LAPC (including borderline resectable), and to identify a role for circulating tumor cells (CTCs) in prognostication. Eligible patients were enrolled to a three-center prospective pilot study (MASTERPLAN Pilot ACTRN12617001642370). Eligibility criteria included age > 18 years, histological confirmation of PA, ECOG 0-1, with confirmation of borderline resectable (BRPC) or unresectable LAPC according to NCCN guidelines. The initial patient cohort was enrolled in a sub-study, to collect peripheral blood CTCs at baseline (bCTCs) which was correlated with overall survival (OS), progression free survival (PFS) and locoregional relapse free survival (LRFS). Patients received 4 cycles of mFOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil), followed by insertion of pancreatic fiducials and 5 fractions of SBRT to a dose of 30Gy with a simultaneous integrated boost to 45Gy, determined by proximity to organs at risk. Acute toxicity was collected to 3 months post-SBRT. Between April 2018 and October 2019, 12 patients were enrolled (initial 10 to the bCTC sub-study). The median follow-up from diagnosis was 10 months (range 4-18). Three patients did not commence treatment after enrollment, and 2 patients did not proceed to SBRT after mFOLFIRINOX. Seven patients with a median age of 62 years completed trial therapy. The median CA19.9 at baseline was 225kU/L (range 1-2558), 72% had BRPC and 57% were lymph node positive. One patient with BRPC proceeded to resection with positive surgical margins. At the time of evaluation, two further patients with BRPC were awaiting re-evaluation prior to surgery. Of those alive at 6 and 12 months follow up, local control was achieved in 83.3% and 66.7% of patients respectively. The first patient experienced acute Grade 3 neutropenia. Thereafter, G-CSF was administered with mFOLFIRINOX and no further Grade 3 toxicities were seen. Six patients experienced Grade 2 acute toxicity, and no patients developed Grade 4 toxicity. Nine patients had bCTCs collected, and of these, 6 completed trial therapy. The median number of CTCs was 11 per 8mls blood (range 1-12), and in this study bCTCs did not significantly correlate with OS, PFS or LRFS, however due to small numbers interpretation of this data is limited. Neoadjuvant mFOLFIRINOX with G-CSF and SBRT to 30-45Gy is feasible and safe. A role of bCTCs in prognostication was not identified in this small study.

S1497 Hepatoid What/Where?

INTRODUCTION: Hepatoid carcinoma (HC) of the pancreas is a rare malignancy with only 34 cases reported in the literature. HC displays morphological and serological features similar to hepatocellular carcinoma and may arise in organs derived from the foregut endoderm, such as the pancreas. We present a case of a gentleman with unresectable HC of the pancreatic head who presented with painless jaundice and weight loss. CASE DESCRIPTION/METHODS: A 58-year-old Caucasian male presented acutely to our facility with a history of painless jaundice, scleral icterus, and 20 pound unintentional weight loss. Laboratory tests revealed a total bilirubin of 31.6 mg/dL and an alkaline phosphatase of 424 mg/dL. A 6 cm mass in the pancreatic head was seen on computed tomography. The patient underwent endoscopic ultrasound with fine needle aspiration of the mass and endoscopic retrograde cholangiography with biliary stenting to relieve the obstruction. Immunohistochemical studies revealed the mass to be CK7, PASD, CEA, and HepPar-1 positive, consistent with HC of the pancreas. Imaging studies demonstrated involvement of the portal vein with mediastinal lymphadenopathy and staged his tumor as T3N2M0. He therefore was not a candidate for surgical resection. FOLFIRINOX chemotherapy was started, however follow-up imaging displayed progression of disease, including metastatic disease to the left lung and the surrounding lymph nodes. He subsequently developed recurrent biliary obstruction and gastric outlet obstruction due to tumor growth. This was treated with repeat biliary stenting and placement of a duodenal stent. Unfortunately, he had continued disease progression and died 10 months after his initial presentation. DISCUSSION: Hepatoid carcinoma of the pancreas is a rare and aggressive cancer with no known etiology or standardized treatment regimen. Explanations in the literature include origin from ectopic liver tissue or transdifferentiation. Patient prognosis depends on the stage at diagnosis. To date, all documented cases of unresectable HC led to patient death within one year of diagnosis. Diagnosis is made with a combination of clinical, laboratory, imaging, and immunochemical features. Further study is required to more fully understand the etiology of hepatoid carcinoma to help develop guidelines for adjuvant therapy options if the cancer is unresectable. DISCLAIMER: The views expressed are the authors and do not reflect the official policy of the Department of the Army, the Department of Defense or the U.S. Government.Figure 1.: Fluoroscopic image of esophagogastroduodenoscopy post biliary stent placement.Figure 2.: Endoscopic ultrasound image of pancreatic head mass.Figure 3.: Computed tomographic image with IV contrast at the time of initial presentation showing the 4.6 × 5.3 × 6 cm mass in the pancreatic head abutting the portal vein.

S1547 When and Where to Look? Hepato-Biliary Malignancy in Lynch Syndrome

INTRODUCTION: Patients with Lynch Synrome have well established germline mutations in DNA mismatch repair genes that put them at higher risk for the development of multiple different types of malignancy. Risk of development of colorectal cancer is probably the most well described followed by associations with endometrial, stomach, renal pelvis, brain, skin, amongst others. Current guidelines recommend screening based on probability of these malignancies. CASE DESCRIPTION/METHODS: A 34 year old male known to carry the mutation for Lynch Syndrome was admitted with generalized fatigue. The patient reported feeling progressively worse and described associated symptoms of pruritus, dark urine and light colored stools. As part of his surveillance for Lynch Syndrome, he undergoes a colonoscopy every 2 years and an EGD every 4 years; both of which were recently normal. He otherwise has no other past medical history and takes no medications. Exam notable for normal vital signs, scleral icterus and jaundice. Labs significant for AST 112 IU/L, ALT 299 IU/L, ALP 137 IU/L, total bilirubin 8.3 mg/dL, direct bilirubin 5.4 mg/dL. A CT scan showed moderate intra and extra hepatic biliary ductal dilatation, pancreatic ductal dilatation, and an ampullary lesion. Ampullary mass seen and biopsied via ERCP, pathology showing moderately differentiated adenocarcinoma of pacnreatobiliary type. He was treated with Whipple surgery and FOLFIRINOX chemotherapy regimen. DISCUSSION: Lynch Syndrome is diagnosed in patients and families with germline mutations in DNA mismatch repair genes. This mutation puts patients at much higher risk of developing multiple types of cancer. Our case describes a patient with pancreatobiliary type adenocarcinoma of the ampulla. Small intestinal cancer is thought to affect a small population of patients with Lynch syndrome (anywhere from 0.4-12%) and society guidelines differ on appropriate screening with some recommending periodic capsule endoscopy. Routine screening for pancreatic cancer is only recommended in patients and families with Lynch syndrome who have a family member or members diagnosed with pancreatic disease. As patients with Lynch Syndrome are at risk for malignancy in virtually any location, data on less common presentations and development of noninvasive testing will be more and more valuable.

CT-determined resectability of borderline resectable and unresectable pancreatic adenocarcinoma following FOLFIRINOX therapy.

We aimed to assess the ability of CT-determined resectability, as defined by a recent version of NCCN criteria, and associated CT findings to predict margin-negative (R0) resection in patients with PDAC after neoadjuvant FOLFIRINOX chemotherapy. Sixty-four patients (36 men and 28 women; mean age, 58.8years) with borderline resectable or unresectable PDAC who received neoadjuvant FOLFIRINOX were evaluated retrospectively. CT findings were independently assessed by two abdominal radiologists according to NCCN criteria (version 3. 2019). Tumor resectability was classified as resectable, borderline resectable, or unresectable, and change in resectability was classified as regression, stability, or progression. The associations of R0 resection rate with CT-determined resectability and change in resectability categories were evaluated, as were the sensitivity and specificity of NCCN criteria for R0 resection. Factors associated with R0 resection were identified by logistic regression analysis. R0 resection rate did not differ significantly among the resectable, borderline resectable, or unresectable PDAC (67-73%, p = 0.95) or among PDAC with regression, stability, or progression (56-77%, p = 0.39). The sensitivity and specificity for R0 resection were 67% and 37%, respectively, for resectability (resectable/borderline vs. unresectable) and 80% and 21%, respectively, for changes in resectability (regression/stable vs. progression). Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with R0 resection (p = 0.01). CT-determined resectability after neoadjuvant FOLFIRINOX chemotherapy was relatively insensitive and non-specific for predicting R0 resection. Low-contrast enhancement of soft tissue contacting artery may increase the ability of CT to predict R0 resection. • Margin-negative resection rate of pancreatic cancer following FOLFIRINOX therapy did not differ among each resectability (67-73%, p = 0.95) based on NCCN criteria or changes in resectability categories (56-77%, p = 0.39). • The sensitivity and specificity for margin-negative resection were 67% and 37% for resectability (resectable/borderline vs. unresectable) and 80% and 21% for changes in resectability (regression/stable vs. progression). • Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with margin-negative resection (p = 0.01).

P-260 Naïve indirect treatment comparison of PanCO, a pilot study of OncoSil P-32 microparticles combined with gemcitabine + nab-paclitaxel or FOLFIRINOX chemotherapy versus standard-of-care treatment in unresectable locally advanced pancreatic cancer

Pancreatic cancer is a malignancy with a very poor prognosis and remains an area of high unmet medical need. Current standard treatment for patients with unresectable locally advanced pancreatic cancer (LAPC) is limited to chemotherapy (CT-only) or chemoradiotherapy following induction CT (ICT+CCRT). International guidelines (e.g. ESMO, ASCO and NCCN) recommend gemcitabine monotherapy as well as other regimens containing gemcitabine or fluoropyrimidines (capecitabine, 5FU) plus other agents, or ICT+CCRT, for the treatment of LAPC. Brachytherapy using beta-emitting phosphorus-32 (P-32) microparticles enables a predetermined radiation dose to be implanted into pancreatic tumours via endoscopic ultrasound (EUS) guidance. The results of a prospective, interventional, open-label, single-arm pilot study of P-32 microparticles (OncoSil TM ; OncoSil Medical) combined with gemcitabine + nab-paclitaxel or FOLFIRINOX chemotherapy demonstrated encouraging safety and efficacy in patients with unresectable LAPC (the PanCO study: NCT03003078). In the absence of a head-to-head randomised controlled trial, a naïve indirect treatment comparison was used to assess the results of the PanCO study against state-of-the-art (SOTA) therapy obtained from a systematic literature review (SLR) of published scientific literature from prospective clinical studies. A SLR was conducted to identify published clinical data on SOTA/‘standard-of-care’ treatments from prospective phase II and III clinical studies in patients with unresectable LAPC treated with CT-only or ICT+CCRT. The SLR outcomes were then compared with the results of the PanCO study in a naïve indirect treatment comparison and analysed using a binomial test. The SLR identified clinical outcomes including overall survival (OS), progression-free survival (PFS), one-year survival, resection rate, disease control rate (DCR) and overall response rate (ORR). In total, there were 46 included studies, comprising 57 arms and 4,327 patients, 2,350 of whom had LAPC. The PanCO study enrolled 50 patients (Intention-to-Treat [ITT] population) of which 42 were implanted with P-32 microparticles (Per Protocol [PP] population), with a median follow-up of 16.1 months. Median OS was significantly longer (p<0.001) in the PanCO study than CT-only and/or ICT+CRT regimens (PanCO PP: 16.0 months; ITT: 15.5 months; vs. SLR combined: 12.7 months; CT-only: 12.7 months; ICT+CCRT: 12.6 months), representing a ∼20% reduction in the risk of death compared to CT-only and ICT+CCRT studies (Hazard Ratio PP: 0.79; ITT: 0.82). One-year survival rates in PanCO were significantly higher than SOTA (p<0.001; PanCO PP: 64.0%; ITT: 63.4%; vs. SLR combined: 52.5%; CT-only: 50.4%; ICT+CCRT: 55.2%). The rate of surgical resection in PanCO was significantly greater than SOTA (p<0.001; PanCO PP: 23.8%; ITT: 20.0%; vs. SLR combined: 9.9%; CT-only: 7.7%; ICT+CCRT: 11.5%). Median PFS was significantly longer (p<0.001) than the SLR combined or CT-only regimens (PanCO PP and ITT: 9.3 months; vs. SLR combined: 7.6 months; CT-only: 6.6 months; ICT+CCRT: 9.1 months). DCR and ORR were also significantly higher than the combined SLR or CT-only regimens (ORR/DCR: PanCO PP 31.0%/100%; ITT: 29.8%/95.7%; vs. SLR combined: 18.2%/80.1%; CT-only: 14.7%/71.3%; ICT+CCRT: 24.2%/88.5%, respectively). The naïve indirect treatment comparison to state-of-the-art therapy indicated that P-32 microparticles combined with standard-of-care chemotherapy may provide significant and clinically relevant benefits for patients with unresectable LAPC and a valuable treatment option in an area of high unmet medical need.

O-1 PanCO: Updated results of an open-label, single-arm pilot study of OncoSil P-32 microparticles in unresectable locally advanced pancreatic adenocarcinoma (LAPC) with gemcitabine + nab-paclitaxel or FOLFIRINOX chemotherapy

Unresectable LAPC has a poor prognosis. Current standard-of-care (SoC) is limited to chemotherapy or chemo-radiotherapy. Phosphorus-32 (P-32) microparticles comprise a brachytherapy device that implants a predetermined dose of beta radiation-emitting P-32 into pancreatic tumors via endoscopic ultrasound (EUS) guidance. Here, we report updated results of the pilot PanCO study of P-32 microparticles combined with SoC chemotherapy in patients with unresectable LAPC.

P-126 Markers of tumour inflammation are prognostic for overall survival in patients with advanced pancreatic ductal adenocarcinoma receiving FOLFIRINOX chemotherapy

Pancreatic duct adenocarcinoma (PDAC) remains a devastating disease with little improvement in survival figures over the last decades. Better characterization and identification of high risk groups are needed to tailor their management. Herein we explore the prognostic role of different clinical biomarkers in patients with PDAC treated with FOLFIRINOX.

Folfirinox chemotherapy prolongs stent patency in patients with malignant biliary obstruction due to unresectable pancreatic cancer

Background: Stent insertion for biliary decompression to relieve jaundice and subsequent biliary infection is necessary for patients with biliary obstruction caused by pancreatic cancer, and it is important to keep the stent patent as long as possible. However, few studies have compared stent patency in terms of chemotherapy in patients with pancreatic cancer. This study aimed to evaluate the differences in stent patency in terms of recently evolving chemotherapy.Methods: Between January 2015 and May 2017, 161 patients with pancreatic cancer who had undergone biliary stent insertion with a metal stent were retrospectively analyzed. The relationship between chemotherapy and stent patency was assessed. Additionally, overall survival according to the treatment, risk factors for stent patency, and long-term adverse events were evaluated.Results: Median stent patency was 42 days for patients with the best supportive care and 217 days for patients with chemotherapy (conventional gemcitabine-based chemotherapy and folfirinox) (P < 0.001). Furthermore, the folfirinox group showed the longest median stent patency and overall survival, with 283 days and 466 days, respectively (P < 0.001) despite higher adverse events rate. Patients who underwent folfirinox chemotherapy after stent insertion had better stent patency in multivariate analysis (HR = 0.26; 95% CI: 0.12–0.60; P = 0.001).Conclusions: Compared with patients who received best supportive care only, patients who underwent chemotherapy after stent insertion had better stent patency. More prolonged stent patency can be expected for patients with folfirinox than conventional gemcitabine-based chemotherapy.

A phase II trial of preoperative FOLFIRINOX followed by gemcitabine-based chemoradiotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma (BR PDAC).

4638 Background: Preoperative (preop) therapy is widely accepted as the standard of care for patients (pt) with BR PDAC with limited evidence for a specific regimen. This study aimed to assess the efficacy of FOLFIRINOX (FOL) chemotherapy followed by gemcitabine-based chemo-radiotherapy (RT) as preop therapy in pt with BR-PDAC. Methods: This single arm Simon two stage phase II trial in pt with BR PDAC was conducted in two phases. The first phase included 4 cycles of FOL, and the second included weekly gemcitabine (1000 mg/m2) for 6 cycles with concomitant intensity-modulated RT (50.4 Gy in 28 fractions)(Gem/RT).The primary aim was to compare R0 resection rate (H0: ≤40% vs Ha≥60%) using one-sample one-sided Z test. Secondary outcomes, including overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier method. Results: Of 22 enrolled pt, 18 (81.8%) completed preoperative treatment. Median age at diagnosis was 63.4 years and 12 (54.5%) were female. There were 10 (45.5%) Hispanics, 4 (18.2%) non-Hispanic black, and 8 (36.4%) non-Hispanic white. Tumor location was predominantly head/neck (21, 95.5%), 15 (68.1%) had T2/3, and 9 (40.9%) had N2 (clinical) disease. Fourteen (64.6%) pt, had venous involvement, 5 (22.7%) had arterial, and 3 (13.6%), both. In the first phase, 20 (90.9%) completed 4 cycles of FOL, 6 (27.3%) required dose-reduction and dose was delayed in 12 (54.5%). Stable disease (SD) was achieved in 10 (52.6%), partial response (PR) in 8 (42.1%) and disease progression (PD) in 1 (5.3%) pt. Of 21 pt that entered the second phase, 18 (85.7%) completed 6 cycles of Gem/RT, 5 (26.3%) required dose-reduction and dose was delayed in 6 (31.6%). SD was achieved in 10 (55.6%), PR in 3 (16.7%) and PD in 5 (27.8%). All pt experienced at least one grade 1 adverse event (AE) and 12 (54.5%) at least one grade 3/4 AE, of which neutropenia was the most common-11 (50%). Of the 15 (68.1%) pt who underwent surgical resection, 12 (80%) achieved R0 margins and 5 (33.3%) required vascular reconstruction. The R0 rate among pt that received &gt;1 cycle of FOLFIRINOX was 54.5%. Adjuvant chemotherapy was offered to 6/15 pt (40%). The PFS and OS will be reported. Conclusions: An R0 resection rate of 54.5% with this limited sample size is significant at the 10% level. Neoadjuvant FOLFIRINOX followed by concomitant Gem/RT was well-tolerated. The study will be amended to include adjuvant FOL in line with the PRODIGE intergroup adjuvant study results. Clinical trial information: NCT01897454 .

Response to FOLFIRINOX neoadjuvant chemotherapy is associated with a high prevalence of Tbet expressing T cells in pancreatic cancer patients

Abstract FOLFIRINOX is the first line treatment option for patients with pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant chemotherapy has a beneficial effect on overall survival in PDAC in comparison with upfront surgery and adjuvant therapy. However, chemotherapy has not yet been successfully combined with immune therapy in PDAC. Herein, we characterize the immunologic effect of FOLFIRINOX and thus provide a rationale for future combination with immune therapy in PDAC. Peripheral Blood Mononuclear Cells were obtained from treatment-naïve (n=20) and FOLFIRINOX-treated patients (n=15) with primary PDAC tumors. Immune cell subset composition was assessed by using mass cytometry (CyTOF). Response to FOLFIRINOX was defined as a reduction in tumor size by more than 30%. 8 of 15 patients were considered responders with a range from 32 to 60% reduction in tumor volume. Responders to FOLFIRINOX showed a significantly higher proportion of CD8+ T cells and lower proportion of monocytes in their peripheral blood compared to treatment naïve patients (both p&amp;lt;0.05). Responders to FOLFIRINOX treatment also showed a significantly lower percentage of CD39+ Treg cells and a significantly higher percentage of CXCR3+CCR6+ Th1/Th17 cells compared to treatment naïve patients (both p&amp;lt;0.05). Lastly, FOLFIRINOX responders showed significantly higher proportions of Tbet expressing CD4+ and CD8+ T cells compared to non-responder patients (both p&amp;lt;0.05). Taken together, our study reveals that neoadjuvant chemotherapy with FOLFIRINOX could enhance functional T cells and down-regulate suppressor cells in circulation. Thus, combination neoadjuvant FOLFIRINOX chemotherapy with immunotherapy may improve clinical outcome.

Time intervals to diagnosis and chemotherapy do not influence survival outcome in patients with advanced pancreatic adenocarcinoma.

BackgroundThe effect of treatment delay on survival in pancreatic ductal adenocarcinoma (PDAC) remains unclear. AimsThis study aimed to assess the prognostic impact of time to diagnosis and chemotherapy in advanced PDAC and factors influencing the time intervals. Methodsadvanced PDAC patients receiving chemotherapy in five centers in the decade 2007–2016 were included. Key time points during care pathway from clinical presentation to beginning of chemotherapy were retrospectively collected. Multivariate Cox proportional hazard model was performed. ResultsA total of 409 patients were included (mean age 66.1 ± 10.3 years; 250 metastatic (61%); 139 received FOLFIRINOX chemotherapy (34%). The median overall survival (OS) was 7.2 months. The median times from first symptoms and from first specialist visit to the beginning of chemotherapy were respectively 100 days and 47 days. None of time intervals was significantly associated with OS. Significant prognostic factors were FOLFIRINOX chemotherapy (HR 0.6 [0.5–0.8]; P < 0.001), metastasis (HR 1.6 [1.3–2.0]; P = 0.001), WHO PS ≥ 2 (HR 1.6 [1.2–2.1]; P < 0.001) and acute pancreatitis as first symptom (HR 2.9 [1.7–4.9]; P < 0.001). Jaundice shortened time to diagnosis (P < 0.001). Acute pancreatitis (P < 0.001) and diabetes (P = 0.01) increased time to treatment. ConclusionWait times from clinical presentation to beginning of chemotherapy do not influence survival in advanced PDAC.

Modified FOLFIRINOX versus sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced pancreatic adenocarcinoma: A real-world analysis.

711 Background: Therapy options for second-line treatment of advanced pancreatic adenocarcinoma (PDAC) are limited and preferred regimens have not been established. This study compared the efficacy and safety of modified FOLFIRINOX (mFFX) and sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced PDAC. Methods: This was a retrospective single-center analysis of all patients who received mFFX or sequential chemotherapy between December 2014 and May 2019 as second-line treatment for advanced PDAC. The sequential arm included all patients intended to be treated with sequential chemotherapy even if finished with either FOLFIRI or FOLFOX. For efficacy analysis, progression-free survival (PFS), overall survival (OS), and response rate (RR)of all the patients, excluding those with locally advanced pancreatic cancer (LAPC), were evaluated. For safety analysis, we evaluated the incidence of grade ≥3 adverse events in all the patients. Results: Seventy-four patients (mFFX 44; sequential 30) were included.The patients characteristics (mFFX/sequential) are as follows:median age 64/67 years, performance status (ECOG) 0 50%/53%, and LAPC 16%/13%. In contrast to sequential therapy, the mFFX group showed better OS and RR. However, there was no significant difference between mFFX and sequential therapy in PFS (median 4.4 [95% confidence interval (CI) 1.8-7.9] vs. 4.6 [95% CI 2.0-6.2] months; hazard ratio [HR] 0.88 [95% CI 0.51-1.56]; p = 0.657), OS (median 10.6 [95% CI 5.9-13.8] vs. 8.5 [95% CI 5.0-12.2] months; HR 0.71 [95% CI 0.37-1.41]; p = 0.318), and RR (8.1% vs. 3.8%; odds ratio 1.94 [95% CI 0.19-19.87]; p = 1.000). In the safety analysis, grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 36.4%, 6.8%, and 16.0%, respectively, with mFFX and 0%, 0% and 3.3%, respectively, with sequential chemotherapy. Conclusions: Whereas certain trends were observed, there were no significant differences in efficacy between mFFX and sequential chemotherapy. Considering the incidence of grade ≥3 adverse events with mFFX, sequential chemotherapy could be considered as one of the second-line treatment options for advanced PDAC.

Better disease control rate and survival after FOLFIRINOX chemotherapy in patients with locally advanced pancreatic cancer compared to patients with metastatic disease

Background: Outcomes of FOLFIRINOX chemotherapy in patients with locally advanced pancreatic cancer (LAPC) are scarce. Most literature is based on FOLFIRINOX response in metastatic patients only. This study aims to investigate if LAPC patients show better response and survival compared to patients with metastatic disease. Material & Methods: Patients who received FOLFIRINOX for pancreatic cancer (PDAC) within the Erasmus Medical Center until May 2018 were retrospectively identified. Objective response was evaluated with CT scans, using the RECIST criteria. The objective response rate (ORR) is calculated as the proportion of patients with complete (CR) or partial response (PR). The disease control rate (DCR) is calculated as the proportion of patients with CR, PR or stable disease. Results: From January 2012 to May 2018, 119 patients received FOLFIRINOX; 70 patients with LAPC and 49 with metastatic disease. 64/70 LAPC patients underwent diagnostic laparoscopy prior to chemotherapy to confirm the absence of metastases. The ORR was 25.8% in the LAPC group, 20.9% in the metastatic group (P=0.563). The DCR was 86.4% in the LAPC group, 65.1% in the metastatic group (P=0.009). The median progression free survival (PFS) was 10.7 months [95% CI 8.2-13.1] in the LAPC group and 7.0 months [95% CI 6.3-7.7] in the metastatic group (P=0.005). The median overall survival (OS) was 15.2 months [95% CI 11.5-18.9] in the LAPC group and 7.9 months [95% CI 5.2-10.5] in the metastatic group (P<0.001). LAPC responders showed a median OS of 22.2 months [95% CI 17.3-27.1], responders in the metastatic group 13.5 months [95% CI 9.6-17.4] (P=0.001). LAPC patients with progression under chemotherapy showed a median OS of 6.7 months [95% CI 3.1-10.4], metastatic patients with progression 4.9 months [95% CI 4.2-5.6] (P=0.041). Conclusion: LAPC patients treated with FOLFIRINOX show a higher DCR, PFS and OS compared to patients with metastatic disease.

Survival and complications of pancreatectomy following FOLFIRINOX chemotherapy in borderline resectable and locally advanced pancreatic cancer: A pan-European cohort

Survival and complications of pancreatectomy following FOLFIRINOX chemotherapy in borderline resectable and locally advanced pancreatic cancer: A pan-European cohort

Neoadjuvant FOLFIRINOX versus neoadjuvant chemoradiotherapy and adjuvant chemotherapy for (borderline) resectable pancreatic cancer: Update on the PREOPANC-2 study

Background: The recent Dutch PREOPANC-1 study demonstrated that neoadjuvant gemcitabine based chemoradiotherapy (CRT) followed by adjuvant gemcitabine has a superior radical resection rate and survival outcomes compared to upfront resection in patients with (borderline) resectable pancreatic cancer ((B)RPC). Potentially, neoadjuvant FOLFIRINOX could further improve these Results. The PREOPANC-2 study aims to investigate whether neoadjuvant chemotherapy with FOLFIRINOX improves overall survival compared to neoadjuvant gemcitabine based chemoradiotherapy and adjuvant chemotherapy in (B)RPC patients. Material & Methods: This multicenter randomized controlled trial (RCT) includes patients with pathologically proven (B)RPC and a WHO performance score 0 or 1. Resectability is defined as ≤90 degrees arterial and ≤270 degrees venous and involvement. Patients are randomized to receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) added during the second cycle, followed by surgery and adjuvant 4 cycles of gemcitabine (arm B). The primary endpoint is overall survival by intention-to-treat. Secondary endpoints include progression- and disease-free survival, quality of life, and (R0) resection rate. Furthermore, a variety of circulating biomarkers including ctDNA, miRNA, tumor-educated platelets, immune profiling and proteomics will be collected at five sampling moments during neoadjuvant and perioperative treatment. 252 events are needed for a power of 80% to find 7 months difference in overall survival. Total sample size is 368 patients, with an accrual period of 3 years and 1.5 year of follow-up after last inclusion. Results: Ten out of 18 DPCG centers have started accruing patients, and 33 (9%) patients have been randomized. Most high-volume centers have started, with a current accrual rate of 5 - 10 patients per month. Biomarkers have been collected from >90% of sampling moments. Conclusion: Neoadjuvant FOLFIRINOX is a promising treatment for (B)RPC patients. The PREOPANC-2 evaluates its effectiveness in an RCT.

Effects of neoadjuvant FOLFIRINOX and gemcitabine-based chemotherapy on cancer cell survival and death in patients with pancreatic ductal adenocarcinoma.

Background: The progression and response to systemic treatment of cancer is substantially dependent on the balance between cancer cell death (apoptosis and necroptosis) and cancer cell survival (autophagy). Although well characterized in experimental systems, the status of cancer cell survival and cell death in human pancreatic ductal adenocarcinoma (PDAC), especially in response to chemotherapy and different types of chemotherapy is poorly described. Results: The median (95% confidence interval) survival was 31.6 (24.5–44.5) months after FOLFIRINOX versus 15.8 (2.0–20.5) months after gemcitabine-based therapy (p = 0.039). PDAC tissue autophagy was reduced compared to normal pancreata based on reduced BECLIN-1 expression and LC3-Lamp-2 colocalization, whilst necroptosis (RIP-1) was increased. Neoadjuvant therapy was associated with further reduced autophagy based on p62/SQSTM-1 accumulation, and increased necroptosis (RIP3 and pMLKL) and apoptosis (BAX, cleaved CASPASE-9 and CASPASE-3) markers, increased nuclear p65 (NF-κB) and extracellular HMGB1 expression, with greater CD8+ lymphocyte infiltration. Survival was associated with reduced autophagy and increased apoptosis. Necroptosis (RIP-3, pMLKL) and apoptosis (BAX and cleaved CASPASE-9) markers were higher after FOLFIRINOX than gemcitabine-based treatment. Patients and methods: Cancer cell autophagy, apoptosis, and necroptosis marker expression was compared in pancreatic tissue samples from 51 subjects, comprising four groups: (1) surgical resection for PDAC after FOLFIRINOX (n = 11), or (2) after gemcitabine-based (n = 14) neoadjuvant therapy, (3) patients undergoing PDAC resection without prior chemotherapy (n = 13), and (4) normal pancreata from 13 organ donors. Marker expression was undertaken using semi-automated immunofluorescence-FACS-like analysis, defining PDAC cells by CK-7+ expression.

Abstract C45: NT219, a novel bispecific inhibitor of STAT3 and IRS1/2, combined with chemotherapy or MEK inhibitor in gemcitabine-resistant pancreatic tumors, induced tumor regression

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, with poor outcome of current treatments. Major contributors to therapeutic resistance in PDAC include Kras mutations, a dense desmoplastic stroma, and activation of feedback signaling pathways. STAT3 and Insulin Receptor Substrate 1/2 (IRS1/2) regulate tumor survival and metastasis, the crosstalk of the tumor and its microenvironment, and play major role in drug resistance. NT219 is a novel bispecific inhibitor of IRS1/2 and STAT3, leading to IRS1/2 elimination and STAT3 dephosphorylation. The purpose of this study was to assess NT219 activity in PDAC PDX models and define schedule and regimens and combinations to overcome resistance to optimize future clinical protocols. Methods: Patient-derived tumor xenograft (PDX) models of mutated KRAS pancreatic cancer were used to test the efficacy of NT219 in combination with gemcitabine, trametinib, and folfirinox. RNAseq was used to analyze the pharmacodynamic effect of NT219. Pharmacokinetic profile of NT219 was tested. Results: Chemoresistent tumors of 4 PDAC PDX models were exposed to NT219 with gemcitabine demonstrated reversal of pre-existing resistance. One of these models demonstrated complete response in 5 out of 10 mice upon addition of NT219 to gemcitabine. Similar results were observed when NT219 was combined with trametinib (a MEK inhibitor) and with folfirinox (chemotherapy). There was a correlative dose-escalation response of both plasma and tumor levels and the therapeutic effect. NT219 delivered prior to gemcitabine showed a much better response than the inverse schedule/drug administration. RNAseq analysis of the tumors revealed that the combined treatment with NT219 and gemcitabine lowered the levels of IRS1 to 20% of the control group. Similar reductions were observed for STAT3-regulated genes, as well as for Ki67 (a proliferation marker), cyclin D (prognostic marker), and TGFβ (driver of epithelial to mesenchymal transition). Conclusion: NT219 overcomes gemcitabine acquired resistance in PDAC. The combination of NT219 with modern chemotherapy in pancreatic cancer may enhance efficacy and delay acquired resistance in this fatal disease. Citation Format: Hadas Reuveni, Lana Kupershmidt, Neta Moskovits, Evgeny Solomonov, Salomon M Stemmer, Izhak Haviv. NT219, a novel bispecific inhibitor of STAT3 and IRS1/2, combined with chemotherapy or MEK inhibitor in gemcitabine-resistant pancreatic tumors, induced tumor regression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C45.