Advanced Unresectable Pancreatic Ductal Adenocarcinoma Research Articles

Stereotactic radiotherapy plus anti PD-1 therapy in patients with locally advanced unresectable pancreatic cancer: Results from a phase 1/2 clinical trial (CA209-9KH).

649 Background: The outcomes after the treatment for pancreatic ductal adenocarcinoma (PDAC) are generally disappointing. Except for MSI high tumors, PDAC is considered to be resistant to immune checkpoint inhibitors (ICI). Radiotherapy is thought to be a potential option to foster the effect of ICI. This investigator-initiated trial evaluated safety and efficacy of combining stereotactic radiotherapy (SRT) and ICI. Methods: In this open-label, multicenter phase 1/2 study, patients (pts) aged ≥ 18 years with histologically confirmed locally advanced unresectable PDAC with no distant metastases were enrolled after initial four cycles of induction chemotherapy with FOLFIRINOX. The experimental treatment consisted of SRT (32 Gy in 4 fractions/4 weeks) and sequential nivolumab (N) therapy (3mg/kg every two weeks) administered until disease progression or unacceptable toxicity. After N discontinuation pts could continue treatment with standard chemotherapy regimens. The primary end point was safety (events graded according to NCI CTCAE 4.03 criteria). The secondary objectives were progression free survival (PFS), overall survival (OS), evaluation of selected biomarkers, and quality of life (QoL; EORTC QLQ-C30 questionnaire). The PFS and OS were defined as the time from enrollment to event (i.e., did not include 3-month of ICT and screening). Results: A total of 22 pts. were screened, and 15 pts. were enrolled. Median age was 58 (range 38-74) years, and 53 % were males. All tumors were microsatellite (MS) stable or had unknown MS status. All patients underwent SRT according to the study protocol and all started N. The median number of N cycles was 11 (range 2-17). The toxicity of SRT was low and non-significant. The toxicity of N therapy was expectable. No Grade 4-5 toxicity was observed. Three pts. discontinued therapy because of toxicity (liver test elevation in two cases and unmanageable arthralgia). Median PFS and OS were 8.1 and 13.0 months, resp.; 12-month PFS and OS were 0 % and 66.7%, resp.; and 24-month OS was 8.9 %. The level of selected biomarkers correlated with clinical or radiological disease control. The QoL assessed by pts during the therapy was acceptable, deterioration of QoL in most cases occurred with tumor progression. Conclusions: The toxicity of SRT and N therapy was low and acceptable. There was no unexpected toxicity of combination of SRT of PDAC primary tumor and N, but this regimen did not lead to any long-term treatment responses. Trial registration: EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432. The study was financially supported by Bristol-Meyer-Squibb. Clinical trial information: NCT04098432 .

Updates to NeoOPTIMIZE: An open-label, phase II trial and biomarker discovery platform to assess the efficacy of adaptive switching of modified FOLFIRINOX (mFFX) or gemcitabine/nab-paclitaxel (GA) as a neoadjuvant strategy for patients with resectable/borderline resectable and locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).

TPS776 Background: Neoadjuvant chemotherapy (NAC) and/or chemo-RT may confer benefit to patients with localized PDAC, by better tolerability, tumor down-staging, and increased R0 resections. mFFX or GA are the current NAC backbones; however, a lack of robust predictive biomarker(s) hampers identification of patients most likely to benefit from mFFX or GA. Further, desmoplastic stroma/poor vascularity compromise NAC efficacy, but angiotensin II receptor inhibitor, losartan, might remodel vascular perfusion to enhance chemotherapy activity. We designed the NeoOPTIMIZE trial for patients with newly diagnosed localized PDAC to provide a flexible clinical platform to: 1) evaluate the feasibility and efficacy of early switching of mFFX to GA, and 2) establish a robust biomarker/imaging discovery platform to optimize the NAC backbone. Methods: NeoOPTIMIZE (NCT04539808) is an open-label, non-randomized, phase II trial assessing the preliminary efficacy of an adaptive treatment strategy that allows for early switching of NAC in patients with localized PDAC. Sixty patients (n = 40 resectable/BRCP; n = 20 locally advanced unresectable [uLAPC]) will be enrolled to receive 2 months of preoperative mFFX (oxaliplatin, 85 mg/m2; folinic acid, 400 mg/m2; irinotecan, 150 mg/m2; 5-FU, 2400 mg/m2), then restaging by a multidisciplinary tumor board (multiD-TB). Absent progression (by panc protocol CT and CA19-9 decline/increase < 30% from baseline), patients continue mFFX (4 cycles). If progression (by panc protocol CT; CA19-9 increase > 30%), patients switch to GA (nab-paclitaxel, 125 mg/m2; gemcitabine, 1000 mg/m2) for 2 months. After 4 months of mFFX or mFFX/GA, another restaging multiD-TB will decide to proceed with: a) RT (if vascular involvement) then resection, b) resection, or c) continued chemo (if unresectable). Losartan (50 mg PO QD) is given throughout NAC and RT regimens. The primary endpoint estimates the proportion of resectable/BRPC patients with R0 resection. Assuming that the proportion of R0 is 60%, a sample size of 32 will provide a 95% CI (0.41, 076). To account for a 20% dropout, 40 patients will be enrolled towards primary endpoint. A separate exploratory cohort of 20 uLAPC patients will be enrolled. Secondary endpoints include DFS, PFS, OS, and AEs. Exploratory objectives include correlating clinical outcomes data with changes in blood-based biomarkers (CA19-9, ctDNA, circulating tumor cells etc.) and research DCE-MRI. To date, the trial has enrolled 19 patients: 8 resectable, 7 BRCP, and 4 uLAPC. Clinical trial information: NCT04539808 .

NeoOPTIMIZE: An open-label, phase II trial and biomarker discovery platform to assess the efficacy of adaptive switching of modified FOLFIRINOX (mFFX) or gemcitabine/nab-paclitaxel (GA) as a neoadjuvant strategy for patients with resectable/borderline resectable and locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).

TPS630 Background: Neoadjuvant chemotherapy (NAC) and/or chemo-RT may confer benefit to patients with localized PDAC, by better tolerability, tumor down-staging, and increased R0 resections. mFFX or GA are the current NAC backbones; however, a lack of robust predictive biomarker(s) hampers identification of patients most likely to benefit from mFFX or GA. Further, desmoplastic stroma/poor vascularity compromise NAC efficacy, but angiotensin II receptor inhibitor, losartan, might remodel vascular perfusion to enhance chemotherapy activity. We designed the NeoOPTIMIZE trial for patients with newly diagnosed localized PDAC to provide a flexible clinical platform to: 1) evaluate the feasibility and efficacy of early switching of mFFX to GA, and 2) establish a robust biomarker/imaging discovery platform to optimize the NAC backbone. Methods: NeoOPTIMIZE is an open-label, non-randomized, phase II trial to assess the efficacy of an adaptive treatment strategy that allows for early switching of NAC in patients with localized PDAC. Sixty patients (n = 40 resectable/BRCP; n = 20 locally advanced unresectable [uLAPC]) will be enrolled to receive 2 months of preoperative mFFX (oxaliplatin, 85 mg/m2; folinic acid, 400 mg/m2; irinotecan, 150 mg/m2; 5-FU, 2400 mg/m2), then restaging by a multidisciplinary tumor board (multiD-TB). Absent progression (by panc protocol CT and CA19-9 decline/increase < 30% from baseline), patients continue mFFX (4 cycles). If progression (by panc protocol CT; CA19-9 increase > 30%), patients switch to GA (nab-paclitaxel, 125 mg/m2; gemcitabine, 1000 mg/m2) for 2 months. After 4 months of mFFX or mFFX/GA, another restaging multiD-TB will decide to proceed with: a) RT (if vascular involvement) then resection, b) resection, or c) continued chemo (if unresectable). Losartan (50 mg PO QD) is given throughout NAC and RT regimens. The primary endpoint estimates the proportion of resectable/BRPC patients with R0 resection. Assuming that the proportion of R0 is 60%, a sample size of 32 will provide a 95% CI of 0.41 - 076. To account for a 20% dropout, 40 patients will be enrolled towards primary endpoint. A separate exploratory cohort of 20 uLAPC patients will be enrolled. Secondary endpoints include DFS, PFS, OS, and AEs. Exploratory objectives include correlating clinical outcomes data with changes in blood-based biomarkers (CA19-9, ctDNA, circulating tumor cells etc.) and research DCE-MRI. We are collecting tumors to correlate deep multi-omic analytics with clinical data. The study is open with 6 patients enrolled at time of submission. Clinical trial information: NCT04539808.

Retrospective Cohort Study of Caveolin-1 Expression as Prognostic Factor in Unresectable Locally Advanced or Metastatic Pancreatic Cancer Patients.

Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients.

Efficacy of EUS-RFA in pancreatic tumors: Is it ready for prime time? A systematic review and meta-analysis.

Background and study aims Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) can be used in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). We performed a systematic review and meta-analysis to evaluate the efficacy of EUS-RFA in treatment of locally advanced unresectable PDAC and other pancreatic tumors. Patients and methods A comprehensive search was done of multiple electronic databases and conference proceedings including PubMed, EMBASE, Web of Science databases, Google Scholar and manual search of references (from inception through May 2019) to identify the studies reporting use of EUS-RFA for pancreatic lesions. The primary outcome was to evaluate technical and clinical success of the procedure. The secondary outcome was to study overall adverse events (AEs). Results Thirteen studies reporting 165 EUS-RFA procedures on 134 patients were included. Of 134 patients, 27.94 % (38) had unresectable locally advanced PDAC, 40 % (53) had PNETs, 3 % (4) had metastasis to the pancreas and 30 % (41) had other lesions. The pooled technical success rate calculated out of the total number of procedures was 100 % (95 % CI [99.18 – 100], I2 = 0 %). The pooled clinical success rate calculated out of the total number of patients was 91.58 % (95 % CI [82.5 – 98.08], I2 = 21.5 %). The pooled overall AE rates were 14.67 % (95 % CI [4.77 – 27.46], I2 = 56.19 %) out of which abdominal pain was the most common with 9.82 % (95 % CI [3.34 – 18.24], I2 = 23.76 %). Low to moderate heterogeneity was noted. Conclusion EUS-RFA has high technical (100 %) and clinical success (91.5 %) rates. Further multicenter trials are needed to further validate our findings.

Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer

BackgroundThe immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine...

The Sustained Induction of c-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a. IMPLICATIONS: The strategies we have devised, including the patient-derived primary cells and the unique, drug-resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis.

Prognostic significance of nutritional and inflammatory markers in patients with locally advanced unresectable (UR-LA) pancreatic ductal adenocarcinoma treated with chemotherapy

Introduction: Several nutritional and inflammatory markers have been reported to be involved in cancer progression. The aim of this study is to evaluate whether nutritional and inflammatory biomarkers such as the Glasgow prognostic score (GPS), the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the systemic-immune-inflammation index (SIII), controlling nutritional status (CONUT) score, prognostic nutritional index (PNI), and the lymphocyte-to-monocyte ratio (LMR) could predict the prognosis in patients with locally advanced unresectable pancreatic ductal adenocarcinoma (UR-LA PDAC) who underwent chemotherapy as first-line therapy, using disease-specific survival as the primary outcome. Method: All UR-PDAC patients were retrospectively evaluated between January 2011 and May 2017 at Toyama University Hospital. Baseline clinicopathological characteristics and pre-treatment laboratory values such as absolute neutrophil, lymphocyte and platelet counts, C-reactive protein, albumin and CA19-9 levels, were collected. Result: A total of 175 patients were diagnosed as UR-PDAC, and 36 patients were diagnosed as UR-LA PDAC. Among them, 34 patients who underwent chemotherapy were enrolled in this study. There were significant relationships between poor survival and elevated GPS, elevated PLR, decreased PNI, elevated SIII, decreased LMR, and low CONUT score (p=0.008, p=0.002, p=0.019, p=0.001, p=0.039, and p=0.038, respectively, by log-rank test). The median survival time of patients with GPS score of 0-1 was significantly longer than that of patients with GPS score of 2 (23.7 vs 13.4 months, respectively). There was no significant difference in survival in pre-treatment CA19-9 level, tumor location, maximum tumor diameter, and additional radiotherapy. Multivariate analysis using Cox regression model revealed that GPS was an independent prognostic factor. Conversion surgery was performed after successful downstaging in 4 patients (12%). Conclusion: Pre-treatment GPS may predict clinical outcome in patients with UR-LA PDAC undergoing chemotherapy as first-line therapy.

Unexpected pharmacokinetics of evofosfamide observed in phase III MAESTRO study.

2568Background: Evofosfamide (Evo) is a prodrug of Br-IPM that is preferentially activated under hypoxic conditions. Hypoxia in locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC)...

Clinical Significance of Histological Effect and Intratumor Stromal Expression of Tenascin-C in Resected Specimens After Chemoradiotherapy for Initially Locally Advanced Unresectable Pancreatic Ductal Adenocarcinoma.

Tenascin-C (TN-C) is an extracellular matrix protein that is up-regulated in pancreatic ductal adenocarcinoma (PDAC) stroma and associated with tumor invasion. We examined intratumor stromal expression of TN-C in resected specimens and the histologic effect of chemoradiotherapy (CRT) as prognostic indicators in initially locally advanced unresectable (UR-LA) PDAC. Among 110 UR-LA PDAC patients enrolled in the CRT protocol from February 2005 to December 2015, 46 who underwent curative-intent resection were classified as high (tumor destruction >50%) and low (≤50%) responders according to the Evans grading system. Tenascin-C expression was immunohistologically evaluated in all patients except one with complete response. The 12 high responders achieved a significantly higher R0 rate than did the 34 low responders (83.3 vs 47.1%), but disease-specific survival (DSS) time was not significantly different (median survival time, 29.8 vs 21.0 months). Tenascin-C expression was inversely correlated with histologic effect of CRT. The 22 patients with negative TN-C had significantly longer DSS time than did the 23 with positive TN-C (29.3 vs 17.1 months). In multivariate analysis, only TN-C expression was a significant prognostic factor for DSS. Intratumor stromal expression of TN-C is a strong prognostic indicator in UR-LA PDAC patients with resection after CRT.

Correlation Between the Acquisition of Resistance to Gemcitabine Therapy and the Expression of HuR in Pancreatic Ductal Adenocarcinoma: A Case Report

Recently, several studies have revealed the usefulness of biomarkers to predict the response to chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Among them, human antigen R (HuR) is reported as a powerful marker for response to gemcitabine chemotherapy for PDAC. The present report describes a patient with PDAC who underwent gemcitabine therapy before resection and after recurrence, and HuR expression was examined at multiple stages. A 72-year-old man was diagnosed with locally advanced unresectable PDAC invading the common hepatic artery. After 9 cycles of gemcitabine treatment, a computed tomography (CT) scan demonstrated a partial response. He underwent distal pancreatectomy with portal vein resection. The pathologic assessment for response to the chemotherapy was grade Ib by Evans's criteria, and HuR expression was high. Serum carbohydrate antigen 19-9 (CA19-9) level rose rapidly at 4 months after the first resection. A CT scan and needle biopsy revealed a solitary recurrence in the abdominal wall, and HuR expression remained high. After 4 cycles of gemcitabine and S-1 combination therapy, a CT scan demonstrated a partial response, and serum CA19-9 decreased. However, after 2 additional cycles of the therapy, a CT scan demonstrated progressive disease, and serum CA19-9 increased slightly. By laparotomy, an abdominal wall recurrence and multiple peritoneal dissemination were found. HuR expression in the biopsy specimen obtained during the laparotomy was decreased. Although gemcitabine therapy was reinitiated, the disease progressed rapidly so the treatment was stopped. In this case, a correlation between the acquisition of resistance to gemcitabine therapy and change in HuR expression was demonstrated.

MAESTRO: A randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).

4007Background: Hypoxia in PDAC is associated with disease progression and poor prognosis. Evo is a hypoxia-activated prodrug of Br-IPM that is preferentially activated under hypoxic conditions. Th...

Evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma: Primary analysis of the randomized, double-blind phase III MAESTRO study.

193 Background: Pancreatic ductal adenocarcinoma (PDAC) is invariably diagnosed at an advanced stage and has poor clinical outcome. Hypoxia is a significant prognostic factor in PDAC progression and is associated with poor prognosis. Evofosfamide (Evo, previously known as TH-302) is a hypoxia-activated prodrug of bromo-isophosphoramide mustard (Br-IPM) that is preferentially activated under hypoxic conditions. The addition of Evo to gemcitabine (Gem) significantly improved progression-free survival (PFS) in a randomized phase II trial in advanced PDAC (NCT01144455). Methods: MAESTRO is an international, randomized, double-blind, placebo-controlled phase III trial of Evo/Gem vs Placebo/Gem in patients (pts) with measurable, locally advanced unresectable or metastatic PDAC (NCT01746979). Evo and Gem were administered intravenously at a dose of 340 mg/m2 and 1,000 mg/m2, respectively, on days 1, 8, and 15 of a 28-day cycle. Treatment continued until disease progression. Key eligibility criteria included ECOG PS 0/1 and no neoadjuvant or adjuvant chemotherapy <6 months prior to entry. The primary endpoint was overall survival (OS) with the study designed to detect a HR of 0.75 with 90% power. Secondary endpoints included PFS and objective response rate (ORR), employing a hierarchical testing procedure with a 2-sided α=0.05 at each level. Results: A total of 693 pts were randomized to treatment with Evo/Gem (n=xxx) or Placebo/Gem (n=yyy). Baseline pt characteristics were similar between treatment arms. The OS HR was X.XX (95% CI: Y.YY, Z.ZZ; p=A.AAA). Median OS was AA.A months (m) for Evo/Gem vs BB.B m for Placebo/Gem. Median PFS was C.C m and D.D m, respectively (HR E.EE [95% CI: F.FF, G.GG; p = H.HHH). ORR was JJ.J% with Evo/Gem vs KK.K% with Placebo/Gem (p = L.LLL). Grade ≥3 adverse events (AEs) occurring in >5% of pts in treated with Evo/Gem were: TBC. Conclusions: The data from the MAESTRO trial will make an important contribution to our understanding of PDAC treatment. Clinical trial information: NCT01746979.

Human Equilibrative Nucleoside Transporter 1 Expression in Endoscopic Ultrasonography-Guided Fine-Needle Aspiration Biopsy Samples Is a Strong Predictor of Clinical Response and Survival in the Patients With Pancreatic Ductal Adenocarcinoma Undergoing Gemcitabine-Based Chemoradiotherapy.

ObjectivesThis study aimed to clarify whether pretreatment human equilibrative nucleoside transporter (hENT1) expressions in endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS-FNAB) specimens obtained from resectable, borderline resectable, and locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC) are concordant with those in the resected specimen after gemcitabine-based chemoradiotherapy (Gem-CRT) and to validate the utility of hENT1 expression using EUS-FNAB samples as a prognostic marker.MethodsWe evaluated the relationship between hENT1 expressions assessed by immunohistochemical staining and clinical outcomes in 51 of 76 patients with PDAC who were diagnosed by EUS-FNAB and received preoperative Gem-CRT.ResultsThe concordance rate of hENT1 expressions was 89.2% (K = 0.681). Median survival time (month) in the 51 whole patients and 37 patients with resection was significantly longer in hENT1 positive than in hENT1 negative: 25.0 and 30.0 versus 9.0 and 9.0, respectively. A multivariate analysis confirmed that hENT1 expression was an independent prognostic factor in both whole patients and those with resection. Regardless of T3 and T4, hENT1-positive patients with resection had significantly better prognosis than hENT1-negative patients, whose prognosis was similar to those without resection.ConclusionsThe assessment of hENT1 expression using EUS-FNAB samples before Gem-CRT provides important information on patients with PDAC who can benefit from curative-intent resection.

Radiofrequency Ablation of Pancreatic Ductal Adenocarcinoma: An Evolving Comrade?

Background: Pancreatic ductal adenocarcinoma (PDAC) presents a challenge for the surgeon due to its aggressiveness and to the stagnation of the management options in cases where complete resection is not feasible. Radiofrequency ablation (RFA) in PDAC is described by a few studies as a promising technique. Methods: We present our 12 years’ experience in locally advanced unresectable PDAC with a series of 19 patients. The mean age was 66.8 years. The mean tumour diameter was 8.1 cm. In all patients, RFA was performed during laparotomy using Cooltip&copy, in some with IOUS monitoring, followed by palliative bypass procedures. Results: The postoperative period was relatively uneventful. A repeat CT showed remarkable changes in the size and morphology of the tumour. We observed significant improvement in pain relief. The mean survival with the RFA was 19.3 months (6 - 30 months). Conclusions: Our series suggest that RFA for locally advanced and unresectable PDAC in carefully selected patients (excluding multifocal disease) presents a promising, effective and safe associate for the surgeon. RFA plays a complimentary role to current standard palliative therapy, which may prolong survival and improve quality of life. Whether the laparoscopic approach or other non-invasive methods are feasible, will be a challenge for the following years.

Abstract A145: Radiation therapy induces tumor-promoting immune suppression in the microenvironment of pancreatic carcinoma

Abstract Radiation therapy (RT) has shown marginal efficacy in patients with pancreatic ductal adenocarcinoma (PDA). Two of the past three randomized controlled trials investigating the efficacy of RT for patients with locally advanced unresectable PDA have shown a statistically significant worse survival by 40% or more for patients receiving RT. We postulated that RT reprograms inflammatory cells within the tumor microenvironment to an immune suppressive phenotype limiting the efficacy of RT in invasive PDA and accelerating disease progression in surrounding pre-invasive foci. We found that RT markedly accelerates the progression of pre-invasive PDA in a dose-dependent manner and reduces animal survival by more than 6 months. In both invasive and pre-invasive PDA, RT reprograms immunogenic macrophages towards an immune-suppressive M2 phenotype resulting in CD8 T cell scarcity and Th2 and Treg differentiation of CD4 T cells. Moreover, adoptive transfer of T cells harvested from RT-treated tumors accelerates tumor growth in recipient hosts. We show that M-CSF blockade concurrent with RT prevents immune-suppressive macrophage and T cell reprogramming and markedly enhances the efficacy of RT in PDA. These data suggest that targeting macrophage reprogramming can unleash the utility of RT for PDA. Citation Format: Lena Tomkötter, Gregor Werba, Susanna Nguy, Sara Alothman, Dalia Alqunaibit, Shaun Tiwari, Nancy Ngoc Giao Ly, Donnele Daley, Atsuo Ochi, Rocky Barilla, Alejandro Torres-Hernandez, Ilenia Pellicciotta, Kevin Du, George Miller. Radiation therapy induces tumor-promoting immune suppression in the microenvironment of pancreatic carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A145.

Evolving Treatment Options for Locally Advanced Unresectable Pancreatic Ductal Adenocarcinoma

The best treatment strategy for patients with locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC) remains the subject of considerable debate. This report presents a case of a 58-year-old woman with locally advanced unresectable PDAC who was treated with sequential FOLFIRINOX for 8 cycles followed by chemoradiation, and continues to show durable disease control 18 months later. The respective roles of systemic therapy and chemoradiation for locally advanced PDAC are discussed, including optimal sequencing of these modalities, recent improvements in chemotherapy, and the question of whether radiotherapy improves survival outcomes in this disease context.

Pancreatic Ductal Adenocarcinoma

Patients who undergo an R0 resection of their pancreatic ductal adenocarcinoma (PDAC) have an improved survival compared with patients who undergo an R1 resection. It is unclear whether an R1 resection confers a survival benefit over locally advanced (LA) unresectable tumors. Our aim was to compare the survival of patients undergoing an R1 resection with those having LA tumors and to explore the prognostic significance of a 1-mm surgical margin. Clinicopathologic data from a pancreatic cancer database between January 1993 and July 2008 were reviewed. Locally advanced tumors had no evidence of metastatic disease at exploration. A total of 1705 patients were evaluated for PDAC in the Department of Surgery. Of the 1084 (64%) patients who were surgically explored, 530 (49%) were considered unresectable (286 locally unresectable, 244 with distant metastasis). One hundred fifty-seven (28%) of the resected PDACs had an R1 resection. Patients undergoing an R1 resection had a slightly longer survival compared with those who had locally advanced unresectable cancers (14 vs 11 months; P < 0.001). Patients with R0 resections had a favorable survival compared with those with R1 resections (23 vs 14 months; P < 0.001), but survival after resections with 1-mm margin or less (R0-close) were similar to R1 resections: both groups had a significantly shorter median survival than patients with a margin of greater than 1 mm (R0-wide) (16 vs 14 vs 35 months, respectively; P < 0.001). Patients undergoing an R1 resection still have an improved survival compared with patients with locally advanced unresectable pancreatic adenocarcinoma. R0 resections have an improved survival compared with R1 resections, but this survival benefit is lost when the tumor is within 1 mm of the resection margin.