Recurrent Pancreatic Cancer Research Articles

Treatment and survival of pancreatic cancer recurrence in the Netherlands - preliminary results of a nationwide analysis

Background: Despite the high rate of recurrence after resection of pancreatic ductal adenocarcinoma (PDAC), Dutch and European guidelines for standardized follow-up are lacking. This has led to different surveillance strategies in daily clinical practice. In this context, data on the exact incidence, symptomatology, treatment and survival following PDAC recurrence in the Netherlands are lacking. Methods: A multicenter retrospective observational cohort study was performed in 17 Dutch pancreatic cancer centers. Data from the first 10 centers were used for preliminary analyses. All patients registered in the prospective Dutch Pancreatic Clinical Audit who underwent PDAC resection (2014-2016) were included. Additional data on follow-up and treatment of PDAC recurrence were collected. Mean survival was evaluated using Kaplan-Meier curves. Multivariable linear regression was performed to compare survival rates between patients who underwent treatment for recurrence and patients who received best supportive care. Survival analyses were stratified for symptomatic and asymptomatic patients. Results: 401 resected patients with a median follow-up of 15 months (IQR 9-25 months) were analyzed. A total of 305 patients (76%) developed PDAC recurrence at a median follow-up of 9 months (IQR 6-15 months). Median overall survival in these patients was 13 months (IQR 9-21 months). In total, 91 patients (30%) underwent treatment for PDAC recurrence. Treatment was independently associated with longer survival, in both symptomatic patients (HR0.16 (95%CI 0.09-0.30); P<0.001) and asymptomatic patients (HR0.16 (95%CI 0.04-0.63); P=0.01). Of 57 patients with asymptomatic recurrence, 25 patients (44%) received palliative treatment, as compared with 63 (29%) of 214 symptomatic patients (P=0.04). Conclusion: Treatment of both asymptomatic and symptomatic PDAC recurrence seems independently associated with improved survival. As these Results are subjected to confounding by indication, lead-time bias and guarantee-time bias, prospective studies are needed to determine the true value of standardized follow-up and treatment of PDAC recurrence, accounting for psychosocial and economic aspects.

Prognostic Factors in Patients With Recurrent Pancreatic Cancer: A Multicenter Database Analysis.

The prognosis of pancreatic cancer remains poor with a high incidence of recurrence even after curative resection. The aim of this study was to investigate prognostic factors in patients with recurrent pancreatic cancer using the multicenter database. The subjects were 196 patients with recurrent pancreatic cancer who underwent resection between 2008 and 2015. We retrospectively investigated the relation between clinicopathological characteristics of the patients and overall survival from recurrence using univariate and multivariate analyses. In univariate analysis, the positive lymphatic invasion (p=0.0240), time to recurrence from resection <1 year (p<0.0001), sites of recurrence except for local or lymph node (p=0.0273), liver recurrence (p=0.0389) and peritoneal recurrence (p<0.0001) were significantly associated with poor overall survival from recurrence. In multivariate analysis, time to recurrence from resection <1 year (p<0.0001) and peritoneal recurrence (p<0.0001) were independently associated with poor overall survival from recurrence. Time to recurrence from resection <1 year and peritoneal recurrence were significant independent predictors of poor overall survival from recurrence in patients with recurrent pancreatic cancer.

Alpha DaRT: Revolutionary Alpha-Emitters Brachytherapy

Diffusing Alpha-emitters Radiation Therapy (‘Alpha DaRT’) is a revolutionary new cancer treatment modality, which enables – for the first time - the treatment of solid tumors by alpha particles. The basic idea is to insert into the tumor an array of implantable seeds, whose surface is embedded with a low activity of radium 224. Each seed continuously emits into the tumor, by recoil, a chain of short-lived alpha emitting atoms (progeny of radium) which spread by diffusion and convection over several mm around it, creating a continuous “kill region” of high alpha-particle dose. After many years of basic work on the technology and associated physics, as well as an extensive campaign of preclinical studies in mice, Alpha DaRT has recently entered clinical trials, in the framework of a new company, Alpha TAU Medical Ltd. The first trial, in Rabin Medical Center (Israel), focuses on recurrent skin and oral cavity squamous cell carcinoma, and tumor size < 5 centimeters in the longest diameter. So far, 15 of the enrolled patients have completed follow-up. Tumor locations included the chin, ear, tongue, lip, nose, forehead, scalp and parotid skin areas. Treatment was delivered based on a CT-simulation pre-treatment plan. DaRT seeds were inserted under local anesthesia using a specially designed applicator. The seeds (1 cm long and 0.7 mm in diameter) each carrying an activity of 2 μCi 224Ra were placed 5-6 millimeters from each other, based on a DaRT-specific dosimetry model. The total 224Ra activity administered was ∼5 μCi per gram of tumor. Two to four weeks after implantation the seeds were removed, and six weeks after treatment CT was performed to assess the effect of treatment. Blood tests and urinalysis were performed during the treatment. The number of DaRT seeds inserted into the tumor was in the range of 7-169 seeds, and treatment duration was 14 to 26 days. Initial efficacy results for a single application of DaRT seeds, for 15 subjects who have reached the study endpoint, are highly promising: eleven subjects (11/15, 73%) had a Complete Response to the treatment and four (4/15, 27%) had Partial Response (substantial reduction in tumor volume). The treatment was shown to be safe for both the patient and medical staff. Local side effects of the treatment were minimal, amounting to erythema, swelling and mild to moderate pain in the insertion area, which resolved either by the time the seeds were removed or shortly after. Radioactivity measurements of 212Pb in the blood were consistent with a biokinetic model of DaRT, which predicts negligible dose levels to distant organs. No clinically significant abnormal blood or urine lab results, or clinically significant changes in vital signs were observed. Based on the successful outcomes of the first clinical trial, clinical protocols are in preparation for various indications with leading research centers worldwide, including cutaneous and mucosal neoplasia, neoadjuvant and recurrent rectal cancer, recurrent prostate cancer, inoperable breast cancer, recurrent gynecological cancer, sarcoma and pancreatic cancer.

Developing a preoperative serum metabolome-based recurrence-predicting nomogram for patients with resected pancreatic ductal adenocarcinoma

We investigated the potential application of preoperative serum metabolomes in predicting recurrence in patients with resected pancreatic cancer. From November 2012 to June 2014, patients who underwent potentially curative pancreatectomy for pancreatic ductal adenocarcinoma were examined. Among 57 patients, 32 were men; 42 had pancreatic head cancers. The 57 patients could be clearly categorized into two main clusters using 178 preoperative serum metabolomes. Patients within cluster 2 showed earlier tumor recurrence, compared with those within cluster 1 (p = 0.034). A nomogram was developed for predicting the probability of early disease-free survival in patients with resected pancreatic cancer. Preoperative cancer antigen (CA) 19–9 levels and serum metabolomes PC.aa.C38_4, PC.ae.C42_5, and PC.ae.C38_6 were the most powerful preoperative clinical variables with which to predict 6-month and 1-year cancer recurrence-free survival after radical pancreatectomy, with a Harrell’s concordance index of 0.823 (95% CI: 0.750–0.891) and integrated area under the curve of 0.816 (95% CI: 0.736–0.893). Patients with resected pancreatic cancer could be categorized according to their different metabolomes to predict early cancer recurrence. Preoperative detectable parameters, serum CA 19–9, PC.aa.C38_4, PC.ae.C42_5, and PC.ae.C38_6 were the most powerful predictors of early recurrence of pancreatic cancer.

Unique circulating immune signatures for recurrent acute pancreatitis, chronic pancreatitis and pancreatic cancer: A pilot study of these conditions with and without diabetes

ObjectiveThis exploratory study seeks to identify distinct circulating immune signatures among patients having recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic adenocarcinoma (PDAC). MethodsA retrospective analysis of human serum samples from collaborating institutions of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) was performed. Samples came from the North American Pancreatitis Studies 2 (NAPS2) cohort and the Pancreatic Adenocarcinoma Gene Environment Risk Study (PAGER) and were analyzed using a 62-plex Luminex assay in a blinded fashion. Group and pairwise comparisons were performed to identify unique immune signature panels and to calculate diagnostic utility using area under the curve analysis. ResultsA total of 179 patients’ samples were included: 41 controls, 40 CP, 78 PDAC and 20 RAP patients, of which 20 controls, 20 CP, and 58 PDAC patients had diabetes mellitus (DM). A unique immune signature panel could discriminate RAP, CP, and PDAC from controls with an AUC range from 0.77 to 0.86 (95% CI range: 0.64–0.94), RAP from CP, and CP from PDAC with an AUC of 0.77 (95% CI 0.64–0.90) and 0.76 (95% CI 0.67–0.86), respectively. Furthermore, an immune signature panel could also discriminate PDAC-DM from DM controls with an AUC of 0.96 (95% CI: 0.93–1.00) ConclusionThis study identifies unique immune analytes that may serve as novel diagnostic and predictive non-invasive biomarkers of RAP, CP, and PDAC. Further validation is warranted in prospective cohorts as developed by the CPDPC.

Pancreatic resection for cancer-the Heidelberg technique.

Pancreatic cancer is associated with high recurrence rates, and any surgery should aim to prevent local recurrence. However, systematic resection of putatively tumor-infiltrated soft tissue adjacent to the celiac branches and superior mesenteric artery has not regularly been applied in pancreatic head resection. We describe a technique of vessel-oriented pancreatic head resection, allowing for extended removal of lymphatic and neural tissue that is situated in the TRIANGLE in between the celiac trunk, the superior mesenteric artery, and the portal vein. Vessel-oriented dissection or vascular resection facilitates complete removal of putatively tumor-infiltrated soft tissue, thus potentially reducing the risk of isolated local recurrence in pancreatic cancer.

167P - Prognostic impact of the C-reactive protein/albumin ratio in advanced pancreatic cancer treated with GEM plus nab-PTX or FOLFIRINOX: Based on the results of a multicenter retrospective study (the NAPOLEON study)

BackgroundGEM plus nab-PTX (GnP) and FOLFIRINOX (FFX) have been shown to improve overall survival for advanced pancreatic cancer patients. However, clinical utility of C-reactive protein/albumin ratio (CAR) as prognostic factor for the patients treated with GnP or FFX remains unclear. We conducted the exploratory analysis to elucidate prognostic impact of CAR using a multicenter retrospective study (the NAPOLEON study) cohort which examined the efficacy and safety of GnP and FFX in clinical practice. MethodsBetween December 2013 to March 2017, 255 patients with unresectable advanced or recurrent pancreatic cancer who received GnP or FFX as 1st-line chemotherapy at 14 centers participating in the NAPOLEON study were examined. Patient characteristics at the start of 1st and 2nd line chemotherapy including age, gender, ECOG performance status, primary tumor site, disease status, metastatic site, underwent biliary drainage or not, treatment regimen at 1st line chemotherapy, LDH and CAR were analyzed to investigate correlation with prognosis by Cox regression model. The cut-off value of CAR adopted 0.54 based on a previous study. Patients were divided into groups according to CAR level less than 0.54 (CAR-low) and 0.54 or greater (CAR-high). ResultsCox regression analysis of OS identified underwent biliary drainage (HR: 1.76, 95%CI: 1.19–2.61), CAR-high (HR: 1.52, 95%CI: 1.05–2.21), and higher LDH level (HR: 2.10, 95%CI: 1.36–3.22) as significant factors at the start of 1st-line chemotherapy. Similarly, Cox regression analysis of OS identified a poor PS (HR: 1.62, 95%CI: 1.07–2.47), a high level of CA19-9 (HR: 2.14, 95%CI: 1.07–4.29) and CAR-high (HR: 2.15, 95%CI: 1.32–3.49) as significant factors at the start of 2nd-line chemotherapy. Eighty-six of 140 patients (82.7%) with CAR-high at the start of 1st-line chemotherapy still remained CAR-high at the start of 2nd-line chemotherapy. ConclusionsCAR may be useful prognostic factor at the start of both 1st and 2nd-line treatment. Almost all the patients with CAR-high before 1st line treatment still remained CAR-high after 1st line treatment. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

The Value of CA19-9 After Irreversible Electroporation for Pancreatic Cancer.

Carbohydrate antigen 19-9 (CA19-9) is a tumor marker for pancreatic cancer. Irreversible electroporation (IRE) is an experimental treatment modality for pancreatic cancer. The aim of this study was to evaluate whether percutaneous IRE lowers the CA19-9 level in pancreatic cancer and whether this correlates with improved overall survival. Seventy-one patients with locally advanced pancreatic cancer or local recurrence after resection were treated. Patients with missing data, metastatic disease and normal serum CA19-9 before IRE were excluded. This left 35 cases for analysis. The median CA19-9 did not decrease in the cohort after IRE treatment (282 U/ml before versus 315 U/ml after; p=0.80). The 25th percentile of patients with the best CA19-9 response had improved overall survival compared to the 25th percentile with the worst response (mean 13.1 versus 8.1 months, respectively; p=0.01). IRE did not lower the level of CA19-9 in pancreatic cancer cases. However, a response in CA19-9 was correlated with improved survival.

Gemcitabine and Z650 in Treating Patients With Metastatic or Recurrent Pancreatic Cancer

Gemcitabine and Z650 in Treating Patients With Metastatic or Recurrent Pancreatic Cancer

Selection of chemotherapy based on geriatric assessment for elderly patients with pancreatic cancer

Abstract Background There is no established Method to select chemotherapy regimens for elderly patients with unresectable or recurrent pancreatic cancer. Geriatric assessment (GA) potentially enables the optimization of treatment choice for this group of elderly patients. To validate treatment allocation based on GA, we performed a prospective interventional study of elderly patients with pancreatic cancer. Methods Eligibility criteria included age ≥ 75, potential indication for chemotherapy, history of no prior chemotherapy except for postoperative adjuvant chemotherapy, and the ability to answer a questionnaire. Based on GA, patients were classified into fit, vulnerable or frail groups. Combination with gemcitabine and nanoparticle albumin-bound paclitaxel (GnP), which is the standard treatment for nonelderly patients, was administered to fit patients, gemcitabine alone (Gem) to vulnerable patients, and best supportive care to frail patients. GA was performed before treatment group allocation and at three and six months later. The primary endpoint was the time to treatment failure (TTF). Results Out of eight patients, five were classified as fit, and three were classified as vulnerable. Three out of the five fit patients received GnP, the other two received Gem, and the three vulnerable patients also received Gem. The median TTF was 20.0 weeks (95% confidence interval; 0-55.7), and the median overall survival was not reached at this time. Three patients who received GnP discontinued the treatment due to adverse events: interstitial lung disease in one patient and drug eruption in two patients. One fit patient who ceased GnP treatment due to drug eruption received FOLFIRINOX and achieved stable disease for over ten months. A vulnerable patient who received Gem was alive for over nine months. Conclusion GA is a promising procedure for optimizing treatment selection for elderly patients with pancreatic cancer.

Surgery for Recurrent Pancreatic Cancer: Is It Effective?

Despite improvements to surgical procedures and novel combinations of drugs for adjuvant and neoadjuvant therapies for pancreatic adenocarcinoma, the recurrence rate after radical surgery is still high. Little is known about the role of surgery in the treatment of isolated recurrences of pancreatic cancer. The aim of this study was to review the current literature dealing with surgery for recurrent pancreatic cancer in order to examine its feasibility and effectiveness. An extensive literature review was conducted according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and 14 articles dealing with re-resections for recurrent pancreatic adenocarcinoma were analyzed, focusing on the characteristics of the primary neoplasm and its recurrence, the surgical procedures used, and patient outcomes. Data were retrieved on a total of 301 patients. The interval between surgery for primary pancreatic cancer and the detection of a recurrence ranged from 2 to 120 months. The recurrence was local or regional in 230 patients, and distant in 71. The median overall survival was 68.9 months (range 3–152) after resection of the primary tumor, and 26.0 months (range 0–112) after surgery for recurrent disease. The disease-free interval after the resection of recurrences was 14.2 months (range 4–29). Although data analysis was performed on a heterogeneous and limited number of patients, some of these may benefit from surgery for isolated recurrence of pancreatic adenocarcinoma. Further studies are needed to identify these cases.

Collagen gel droplet-embedded culture drug sensitivity test (CD-DST) predicts the effect of adjuvant chemotherapy on pancreatic cancer.

We evaluated the clinical effectiveness of collagen gel droplet-embedded culture drug sensitivity tests (CD-DSTs) in predicting the efficacy of adjuvant chemo-therapeutic treatments for pancreatic cancer (PC). The clinicopathological characteristics and prognoses of 22 PC patients who underwent CD-DST after pancreatectomy at Tohoku University between 2012 and 2016 were analyzed retrospectively. Eligibility criteria were resectable or borderline resectable PC, successful evaluation for 5-fluorouracil sensitivity by CD-DST, treatment with S-1 adjuvant chemotherapy, and no preoperative chemotherapy. The rate of successful evaluation by CD-DST was 52.3% in PC. The optimal T/C ratio, defined as the ratio of the number of cancer cells in the treatment group (T) to that in the control group (C), for 5-fluorouracil was 85% using receiver operating characteristic curve analysis. The sensitive group (T/C ratio < 85%; n = 11) had a better recurrence-free survival rate than the resistant group (T/C ratio ≥ 85%; n = 11; P = 0.029). A Cox proportional hazards regression model demonstrated that sensitivity to 5-fluorouracil was an independent predictor of recurrence on multivariate analysis (hazard ratio 3.28; 95.0% CI 1.20-9.84; P = 0.020). CD-DSTs helped to predict PC recurrence after S-1 adjuvant chemotherapy.

Abstract 2854: Clinical significance of Cofilin-1 expression in pancreatic cancer

Abstract Background: Pancreatic cancer is one of the most malignant tumors. The prognosis of patients with pancreatic cancer remains poor, with a 5-year survival rate of less than 10%. Therefore, identification of new biomarkers and development of therapeutic drugs are urgent issues. As a result of genetic research using public database, we focused on Cofilin-1. In recent years, it has been revealed that cancer cells form invadopodia to destroy extracellular matrix and cause hematogenous metastasis, and it is suggested that Cofilin-1 has a key role in stabilizing the structure of the invadopodia. However the significance of Cofilin-1 expression in cancer invasion is not clear. The purpose of this study is to verify the relationship between the expression of Cofilin-1 and patient’s prognosis in pancreatic cancer. Methods: At first, we examined the relationship between Cofilin-1 expression level and clinicopathological factors or prognosis using GSE21501 and TCGA, which are public databases of patients with pancreatic cancer. We set the cut-off value, and divided into the two groups, the high Cofilin-1 and low groups. Then, we evaluated expression of Cofilin-1 with immunohistochemical (IHC) staining in 200 pancreatic cancer patients who underwent curative surgery during April 2004 to March 2018 at the department of gastroenterological surgery, Kumamoto University. After that, we examined the relationship between Cofilin-1 expression and prognosis. Results: In silico analyses using GSE21501 and TCGA dataset, high expression of Cofilin-1 is associated with early recurrence and poor prognosis. Then, we evaluated expression of Cofilin-1 with IHC staining using original scoring. The score is calculated by multiplying each scores classified into 4 stages from 0 to 3 in intensity of Cofilin-1 expression and area of that. 0 to 3 of the score was the low expression group (n=93), 4 to 9 is the high expression group (n=107). The result showed that high Cofilin-1 expression is associated with high occurrence of lymph node metastasis. In addition, both the relapse free and overall survivals were significantly worse in the high Cofilin-1 group. Cox proportional hazard analysis revealed that the high Cofilin-1 expression was an independent poor prognostic predictor. Conclusion: In both silico analysis and IHC staining, high Cofilin-1 expression is associated with poor prognosis, especially high recurrence rate in patients with pancreatic cancer. Cofilin-1 may be useful as a biomarker for early recurrence in pancreatic cancer. Citation Format: Rumi Itoyama, Shigeki Nakagawa, Toshihiko Yusa, Yosuke Nakao, Takanobu Yamao, Naoki Umezaki, Tatsunori Miyata, Hirohisa Okabe, Hiromitsu Hayashi, Katsunori Imai, Yo-ichi Yamashita, Akira Chikamoto, Hideo Baba. Clinical significance of Cofilin-1 expression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2854.

Abstract 1160: Endoplasmic reticulum stress disrupts stemness-related transcriptional regulatory network: Implication for therapy response in cancer

Abstract Pancreatic cancer is the third leading cause of cancer-associated deaths in the United States. We have recently demonstrated that endoplasmic reticulum (ER) stress correlates with improved survival in human pancreatic cancer patients on gemcitabine therapy. Cancer cell stemness is a significant contributor of poor response to therapy and disease recurrence. We also observed that inducing ER stress can diminish stemness in cancer cells. Hence, to investigate the mechanism of ER stress-mediated alterations in diminishing cancer stemness, we investigated the impact of ER stress on transcriptomic alterations by performing RNAseq studies. We subjected cancer cells to treatment with thapsigargin and the harvested mRNA was utilized for RNAseq analysis. We observed significant alterations in mRNA expression levels of the stemness-associated gene set, which also showed significant enrichment in Ingenuity pathway analysis. Hence, our studies demonstrate that ER stress regulates stemness at the transcriptional level. Our ongoing and future studies will target individual genes/pathways to identify their relative contributions to ER stress-mediated regulation of stemness. Considering the role of stemness in disease recurrence, our studies will provide novel mechanistic insights that may lead to novel therapies for targeting disease recurrence in pancreatic cancer. Citation Format: Appolinaire Olou, Kamiya Mehla, Pankaj Singh. Endoplasmic reticulum stress disrupts stemness-related transcriptional regulatory network: Implication for therapy response in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1160.

Risk Factors for Recurrence of Pancreatic Cancer After Surgery

Despite advances in imaging, chemotherapy, and surgery, pancreatic ductal adenocarcinoma (PDAC) still conveys a poor prognosis in most cases, with true

Management of isolated recurrence after surgery for pancreatic adenocarcinoma.

Recurrence of pancreatic cancer after primary pancreatectomy occurs in the vast majority of patients. The role of surgical treatment for recurrent pancreatic cancer is not well established. Patients who underwent primary pancreatectomy with curative intent from 2000 to 2014 at a single large-volume centre were evaluated retrospectively. CT or PET was used to select patients with an isolated recurrence. The clinicopathological features and survival outcomes were compared according to treatment modalities. Of the 1610 patients with pancreatic cancer who underwent resection, 1346 (83·6 per cent) were diagnosed with recurrent pancreatic cancer. Recurrence was locoregional in 366 patients (27·2 per cent), distant multifocal in 251 (18·6 per cent), distant isolated in 188 (14·0 per cent), locoregional plus distant in 153 (11·4 per cent) and peritoneal seeding in 388 (28·8 per cent). Of the 1346 patients with recurrence, 197 (14·6 per cent) had isolated recurrence; of these, 48 (24·4 per cent of all isolated recurrences; 3·6 per cent of all recurrences) underwent resection. Median survival of the 197 patients after diagnosis of isolated recurrence was 14·7 months; it was longer in patients who underwent surgical resection than among those treated non-surgically (23·5 versus 12·0 months; P= 0·014). Multivariable analysis showed that chemotherapy and resection for recurrence were associated with better prognosis. Median survival after recurrence was longest in the 23 patients with isolated pulmonary recurrence (33·3 months). Survival after recurrence was better in patients who underwent resection of isolated recurrence in the remnant pancreas (median 28·0 versus 12·0 months, P= 0·010) and lung (median 36·5 versus 9·5 months; P= 0·010) than in those who did not undergo resection. Surgical resection may be considered an option for treatment of patients with isolated recurrent pancreatic cancer.

Systemic treatment could predict satisfactory long-term results after surgical resections in recurrent and metastatic pancreatic cancer

The possible benefit of frozen section (FS) analysis during (PD) for pancreatic ductal adenocarcinoma (PDAC) and of additional resection up to total pancreatectomy (TP) is debated. Aim of this work is to evaluate the prognostic role of positive FS analysis after PD for PDAC.Multicentric retrospective analysis on prospective databases of three institutions. Based on FS analysis patients were classified as FS negative/FS positive. All positive FS patients underwent extended PD (EPD) or TP. Postoperative outcomes, disease-free (DFS) and disease-specific survival (DSS) were evaluated.Of 371 patients, 58 (16%) had positive FS. This resulted in 313 (84%) SPD (standard pancreatoduodenectomy), 22 (6%) EPD and 36 (10%) TP. Postoperative mortality was higher in patients undergoing TP (11% compared to 4.5% in EPD and 1% in SPD; p = 0.01). 26% of patients underwent neoadjuvant therapy, and it did not decrease the rate of positive FS. Systemic/local relapse rates were 59% and 41% in negative FS group, and 78% and 22% in positive FS group (p = 0.031). Median DFS and DSS were 20 and 37 months in negative FS group, and 12 and 23 months in positive FS patients (p = 0.001). Independent predictors of recurrence were G3, N1/N2 status and positive FS. R1 resection, G3, N1/N2 status, perineural invasion and positive FS were independent predictors of DSS.Positive FS analysis is a poor prognostic factor after PD for PDAC. It is significantly associated with a high rate of R1 resection at final histology, PDAC recurrence and poor survival.

Significance of the inflammation-based prognostic score in recurrent pancreatic cancer

BackgroundAlthough the prognosis of recurrent pancreatic cancer (RPC) is improving with the appearance of new anticancer drugs, prognostic indicators for RPC are still poorly understood. The aim of this study was to evaluate significance of the inflammation-based prognostic score, including modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and Prognostic Nutritional Index (PNI), in patients with RPC. MethodsThis study reviewed 263 patients of pancreatic ductal adenocarcinoma at our institution between 2006 and 2015. A receiver operating characteristics curve analysis was performed to determine the cut-off values. The prognostic significance of the inflammation-based prognostic scores were evaluated by a multivariate analysis. Results172 patients (65.4%) who had recurrence was included in this study. The optimal PNI for predicting 1-year survival after recurrence was 40 with higher area under receiver operating characteristics curve value (0.704) in comparison with other inflammation-based prognostic scores. A univariate and multivariate analysis revealed that liver metastasis (P < 0.001) and PNI < 40 (P < 0.001) were independently associated with the survival time after recurrence. When each of the two predictors was counted as one point and the points were calculated for all cases, a good stratified survival curve was obtained, showing the shorter survival in the higher points: median survival times of 2, 1, and 0 points were 4.3, 11.1, and 21.2 months, respectively (P < 0.001). ConclusionsInflammation-based prognostic scores, especially PNI is useful clinical biomarker for predicting the survival time after recurrence in patients with pancreatic adenocarcinoma.

Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.

e15787 Background: Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. We hypothesize that sustained response against pancreatic cancer requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low-dose chemotherapy, SBRT, cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with recurrent metastatic pancreatic cancer was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral CEA vaccine, yeast Ras vaccine, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 12 subjects with 3rd-line or greater metastatic pancreatic cancer were treated. All treatment was administered in an outpatient setting. AEs were primarily hematologic and managed by planned chemo dose reduction. Grade ≥3 TRAEs were observed in 9 out of 12 subjects, predominately chemotherapy-related neutropenia. 9 out of 12 subjects (75%) had a best response of stable disease (≥ 8 weeks). Median PFS is 7.1 months (4.4 – 8.8) and median OS is 8.2 months (5.7 – 9.7) with 1 subject continuing treatment. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting. Preliminary OS of 8.2 months is encouraging for this heavily-pretreated population. Clinical trial information: NCT03586869.

A phase Ib dose-escalation and cohort-expansion study of safety and activity of the transforming growth factor (TGF) β receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer.

4124 Background: Pancreatic cancer (PC) is characterized by a highly immunosuppressive microenvironment, and immune checkpoint inhibitors as monotherapy have been ineffective to date. TGFβ is commonly viewed as a powerful immunosuppressive cytokine, and inhibition of its signaling reverses this suppression and activates adaptive immune responses. A combination of TGFβ and PD-L1 inhibition may act synergistically to induce immune restoration and to improve antitumor responses. This Phase 1b study (NCT02734160) evaluated the combination of galunisertib plus durvalumab in recurrent or refractory metastatic PC. Methods: Eligible patients (pts) were ≥18 years old, had ECOG status ≤1, and had not received treatment with anti-PD-1, anti-PD-L1, or TGFβ R1 kinase inhibitors. The primary objective was to assess the safety and the recommended dose of galunisertib given 14 days on/14 days off in combination with durvalumab 1500 mg every 4 weeks. Four dose levels of galunisertib were tested in the dose escalation portion of the study: 50 mg QD, 50 mg BID, 80 mg BID and 150 mg BID, followed by the cohort expansion portion of the study at the recommended Phase 2 dose (RP2D). Secondary objectives included preliminary assessment of activity by response rate, (RECIST v1.1), median PFS (mPFS), and OS (mOS). Results: 42 pts (25F/17M) were treated in the study (median age 56.5 y; 71.4% had received ≥2 prior systemic regimens). There was no dose limiting toxicity and galunisertib 150 mg BID was chosen as the RP2D. In the 32 pts treated at this dose, Grade ≥3 related AEs included AST and GGT elevations (2 pts each), and ALT and alkaline phosphatase elevations, and neutropenia (1 pt each). One partial response and 7/32 stable diseases were observed (disease control rate 25%); mPFS was 1.9 months (95% CI: 1.5, 2.2) and mOS was NR (95% CI: 3.6, NR). Biomarker data will be presented at the meeting. Conclusions: The combination of galunisertib plus durvalumab had an acceptable tolerability and safety profile. The activity of this combination in second and third line PC patients warrants further consideration. Clinical trial information: NCT02734160.