Recurrent Pancreatic Cancer Research Articles

Dose-escalated radiotherapy for unresectable or locally recurrent pancreatic cancer: Dose volume analysis, toxicity and outcome of 28 consecutive patients

PurposeThe role of radiotherapy for unresectable pancreatic cancer is controversial. A benefit of additional radiotherapy is supported by some observations. A dose-effect relationship was recently found by dose escalation employing image guided and intensity modulated radiotherapy.MethodsWe retrospectively evaluated 28 consecutive patients, all with history of extensive prior therapies for unresectable locally advanced/ recurrent pancreatic cancer (LAPC/LRPC). Treatment was delivered by helical tomotherapy after daily position verification with computed tomography. Dose to the planned target volume (PTV) was 51 Gy, while the dose to the macroscopic tumor was escalated by a simultaneous integrated boost to a median cumulative dose of 66 Gy (60–66 Gy). Concomitant chemotherapy consisted mainly of capecitabine (n = 23).Results10 of 28 patients presented acute toxicities > grade 2, one patient succumbed to gastrointestinal bleeding after treatment. No correlations of toxicities and dose volume histograms (DVH) of retrospectively delineated small bowel loops were observed, although average small bowel volume receiving ≥ 20 Gy was 374 ml. DVH analyses revealed a correlation of splenic parameters and acute toxicity: Vomiting, anorexia, dehydration, hematologic toxicity, fatigue, combined gastro-intestinal toxicity wit R-values between 0.392 and 0.561 (all p-values > 0.05). Only one patient developed late toxicities > grade 2. With an average follow-up time in surviving patients of 14 months median overall survival time was 19 months and median time to local recurrence 13 months. In 8 patients with available imaging of local recurrence: 5 in field recurrences, 2 marginal recurrences and one lymph node recurrence outside the high dose radiation field were observed. In univariate analysis only ΔCA-19-9 during radiotherapy was associated with local control (p = 0.029) and overall survival (p = 0.049).ConclusionDose escalated normo-fractionated radiotherapy for LAPC/LRPC seems feasible and suitable to prolong local control and in consequence long-term survival. However, in-field local progression is still frequently observed and possibilities to increase the local effectiveness should be evaluated. Exposure of the spleen was predictive for acute toxicity and should be further investigated.

Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD.

Background:Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low-dose thiopurine in IBD.Methods:Retrospective review of consecutive cases treated with allopurinol. Metabolites and their ratios (6-MMP/6-TGN) were compared pre- and post-allopurinol. Clinical and endoscopic remission were assessed.Results:Allopurinol (n = 66) reduced mean dose of AZA by 70% (p < 0.01). Baseline levels (SD) 6-TGN, 6-MMP and 6-MMP/6-TGN were 165 (64), 9388 (5234) and 59.8 (30.3), respectively. These values improved on allopurinol to 297 (102), 896 (1031) and 3.4 (4.0), respectively (p < 0.0001). Therapeutic 6-TGN level (>235) was achieved in 49/58 cases on allopurinol combination therapy, versus 9/58 monotherapy (p = 0.0001). Among the thiopurine failure group (40 patients), clinical remission or response was observed in 65% and 22% of patients, respectively. In the asymptomatic group with excessive 6-MMP, 11/14 achieved sustained remission on allopurinol. Repeat colonoscopy (n = 28) showed mostly endoscopic remission (67.9%) or improvement (17.8%). Few had unimproved lesions (14.3%). Importantly, 46% of cases had complete mucosal healing. Two patients had cancer on combination therapy (de novo pancreatic cancer and fatal recurrence of metastatic testicular cancer). Elevated transaminases were reduced on allopurinol (48.2 versus 6.9%) (p < 0.001); no change in leukopenic or infectious events occurred.Conclusion:Allopurinol in combination with low-dose thiopurine corrected excessive 6-MMP levels, resulting in clinical remission and mucosal healing in the majority of cases. The potential cancer risk of allopurinol and thiopurine combination therapy needs further research.

The TERT hypermethylated oncologic region predicts recurrence and survival in pancreatic cancer.

We explore the biomarker potential of the TERT hypermethylated oncologic region (THOR) in pancreatic cancer. We assessed the methylation status of THOR using the cancer genome atlas data on the cohort of pancreatic cancer (n=193 patients). THOR was significantly hypermethylated in pancreatic tumor tissue when compared with the normal tissue used as control (p<0.0001). Also, THOR hypermethylation could distinguish early stage I disease from normal tissue and was associated with worse prognosis. We found that THOR is hypermethylated in pancreatic tumor tissue when compared with normal tissue and that THOR methylation correlates with TERT expression in tumor samples. Our preliminary findings support the diagnostic and prognostic values of THOR in pancreatic cancer.

Pancreatic Cancer Arising From the Remnant Pancreas: Is It a Local Recurrence or New Primary Lesion?

Local recurrence of pancreatic cancer (PC) can occur in the pancreatic remnant. In addition, new primary PC can develop in the remnant. There are limited data available regarding this so-called remnant PC. The aim of this review was to describe the characteristics and therapeutic strategy regarding remnant PC. A literature search was performed using Medline published in English according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The incidence of remnant PC has been reported to be 3% to 5%. It is difficult to distinguish local recurrence from new primary PC. Genetic diagnosis such as Kirsten rat sarcoma viral oncogene homolog mutation may resolve this problem. For patients with remnant PC, repeated pancreatectomy can be performed. Residual total pancreatectomy is the most common procedure. Recent studies have described the safety of the operation because of recent surgical progress and perioperative care. The patients with remnant PC without distant metastasis have shown good long-term outcomes, especially those who underwent repeated pancreatectomy. Adjuvant chemotherapy may contribute to longer survival. In conclusion, this review found that both local recurrence and new primary PC can develop in the pancreatic remnant. Repeated pancreatectomy for the remnant PC is a feasible procedure and can prolong patient survival.

Utility of (18) F-FDG PET/CT and CECT in conjunction with serum CA 19-9 for detecting recurrent pancreatic adenocarcinoma.

The roles of different cross-sectional imaging in evaluating the recurrence of pancreatic adenocarcinoma are not well established. We evaluated the utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced computed tomography (CECT) in the diagnosis of recurrent pancreatic adenocarcinoma in conjunction with the tumor marker CA 19-9. We retrospectively reviewed the records of patients who underwent CECT and FDG PET/CT along with serum CA 19-9 measurement as a follow-up or on a clinical suspicion of recurrent disease after initial surgery for pancreatic adenocarcinoma. Two observers blinded to the other imaging modality results retrospectively reviewed and interpreted the images in consensus using a three-point scale (negative, equivocal, or positive). Pathologic analysis by biopsy or further clinical and radiologic follow-up determined the true status of the suspected recurrences. The imaging results were compared with CA 19-9 levels and true disease status. Thirty-nine patients were included in the study. Thirty-three patients (85%) had proven recurrent cancer and six patients (15%) had no evidence of disease. Twenty-four patients had elevated CA 19-9 and 15 patients had normal CA 19-9. Sensitivity, specificity, and accuracy for recurrence were 90.9%, 100.0%, and 92.3% for PET/CT and 72.2%, 66.6%, and 71.7% for CECT, respectively. Sensitivity for locoregional recurrence was 94.4% for PET/CT but only 61.1% for CECT. PET/CT detected recurrence in 12 patients who had normal levels of CA 19-9. PET/CT showed lesions not visible on CECT in five (15%) patients. Although the sensitivity and specificity of PET/CT were higher than those of CECT, they were not statistically significant (p=0.489 and p=0.1489, respectively). FDG PET/CT has a high sensitivity for pancreatic cancer recurrence. Normal CA 19-9 does not necessarily exclude these recurrences. FDG PET/CT is useful when CECT is equivocal and can detect recurrence in patients with normal CA 19-9.

740P - The impact of UGT1A1 genetic polymorphism on safety in unresectable pancreatic cancer patients receiving FOLFIRINOX therapy: A subset analysis of JASPAC 06 study

Background: UGT1A1*6 and UGT1A1*28 polymorphisms were reported to be associated with increased irinotecan-induced neutropenia. The aim of this subset analysis is to investigate the association between these polymorphisms and toxicities in patients (pts) treated with FOLFIRINOX in the JASPAC 06 study. Methods: JASPAC 06 study was a nationwide multicenter observational study of FOLFIRINOX for unresectable and recurrent pancreatic cancer. Pts who were screened for UGT1A1*6 and UGT1A1*28, and treated with either original FOLFIRINOX regimen (Oxaliplatin 85 mg/m2, Irinotecan 180 mg/m2, Levofolinate calcium [l-LV] 200 mg/m2, bolus 5-FU 400 mg/m2, and continuous 5-FU 2,400 mg/m2, every two weeks) or modified regimen (Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2, l-LV 200 mg/m2, and continuous 5-FU 2,400 mg/m2, every two weeks) as first-line chemotherapy, were analyzed in this analysis. Results: Of 399 eligible pts enrolled in JASPAC 06 study, 203 pts were eligible in this analysis. UGT1A1 was reported as wild (W) type (-/-) in 118 pts and heterozygous (H) type (-/*6, -/*28) in 81 pts. Remaining four pts with homozygote (*6/*6, *28/*28) or compound heterozygote (*6/*28) were excluded because of small population. Among 199 pts, 79 pts were treated with original regimen and 120 pts with modified regimen. In the original FOLFIRINOX group, 54/25 pts were W/H type. The median age was 60.5/60 years and PS0 was 57/52%. Incidences of grade 3/4 leukopenia, neutropenia, febrile neutropenia, diarrhea, anorexia and grade 4 neutropenia in pts with W/H type were 28/44%, 59/68%, 24/40%, 4/20%, 9/24% and 24/40%, respectively. In the modified FOLFIRINOX group, 64/56 pts were W/H type. The median age was 62.5/62 years and PS0 was 70/70%. The same toxicities as above were 22/27%, 44/50%, 5/7%, 16/7%, 14/9% and 16/20%, respectively. Conclusions: Treated with original FOLFIRINOX regimen, pts with UGT1A1 heterozygous type experienced severe toxicities more frequently than those with wild type. In such cases, careful management of not only hematologic but gastrointestinal toxicities seems to be needed. Legal entity responsible for the study: Shizuoka Industrial Foundation Pharma Valley Center Funding: Diichi Sankyo Co. Ltd Yakult Honsha Co. Ltd Disclosure: H. Fujii: Research funding: Yakult Honsha, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, Eizai, Merck, and Kyowa-Hakko Kirin, Co., Ltd. N. Mizuno: Research funding: Zeria Pharmaceutical, Taiho Pharmaceutical Co. Ltd., Merck Serono, AstraZeneca, NanoCarrier, Eisai, and MSD. Honoraria: Yakult Honsha Co., Ltd, Taiho Pharmaceutical Co. Ltd., Novartis, Pfizer, and Kyowa-Hakko Kirin. H. Ueno: Honoraria: Yakult Honsha Co., Ltd Research Funding: Yakult Honsha Co., Ltd. S. Kobayashi: Yakult Honsha (Honoraria). N. Okano: Research Funding: Yakult Honsha Co., Ltd, Daiichi Sankyo Co., Ltd. H. Takafumi: Employee of Daiichi Sankyo Co., Ltd. T. Henmi: Employee of Yakult Honsha Co.,Ltd. A. Todaka: Honoraria:Yakult Honsha Co.,Ltd, Daiichi Sankyo Co., Ltd. A. Fukutomi: Honoraria: Yakult Honsha Co.,Ltd, Daiichi Sankyo Co., Ltd. Advisory Role from Yakult Honsha Co.,Ltd. All other authors have declared no conflicts of interest.

752P - FOLFIRINOX as second-line chemotherapy for advanced pancreatic cancer: A subset analysis from the nation-wide multicenter observational study (JASPAC06)

Background: The data of FOLFIRINOX as second-line chemotherapy in advanced pancreatic cancer are very limited. The JASPAC06 study, a nation-wide multicenter observational study of FOLFIRINOX for the patients with unresectable or recurrent pancreatic cancer as any line treatment, showed the favorable efficacy and safety in Japanese clinical practice. Methods: The subjects were the patients with unresectable/recurrent pancreatic cancer who received FOLFIRINOX as second-line chemotherapy. Results: Of the 399 evaluable patients in the JASPAC06 study, 44 patients were eligible. Patients characteristics were; median age, 62 years; male, 26(59%); ECOG-PS0/1, 30(68%)/14(32%); disease status recurrent/locally/metastatic, 4(9%)/8(18%)/32(73%); biliary drainage, 11(25%); UGT1A1 status *28 and *6 wild/single heterozygous/homozygous or double heterozygous/unknown, 25(57%)/16(36%)/2(5%)/1(2%). The initial dose was reduced in 28(64%) patients. The median time to treatment failure and the number of cycles were 4.5 (range, 6-573 days) months and 6 cycles (range, 1-13 or more). The major grade 3/4 adverse events were neutropenia in 29(66%) patients, leucopenia in 17(39%), anorexia in 7(16%), febrile neutropenia in 5(11%) and anemia in 5(11%). Fatal adverse event occurred in 1 patient, which was a sudden death. The median overall survival, progression free survival and 1-year survival rate were 10.1 (95%CI, 7.1-13.1), 4.1 (95%CI, 1.5-6.8) months and 41.0%, respectively. The overall response rate and disease control rate were 28% and 65%. The reasons for discontinuation of FOLFIRINOX, excluding 2 patients ongoing treatment, were tumor progression in 38(86%) and toxicity in 4(9%). Conclusions: It was suggested that FOLFIRINOX as second-line chemotherapy in advanced pancreatic cancer was effective for the patients with good PS and toxicity was similar to that as the first-line treatment. Clinical trial identification: UMIN000014658 26 July 2014 Legal entity responsible for the study: N/A Funding: This trial was supported by Yakult Honsha Co., Ltd. and Daiichi Sankyo Co., Ltd. Disclosure: H. Ueno: Honoraria: Yakult Honsha Co., Ltd Research Funding: Yakult Honsha Co., Ltd. N. Mizuno: Yakult Honsha Co., Ltd. S. Kobayashi: Honoraria: Yakuly Honsha Co., Ltd. A. Todaka: Honoraria: Yakult Honsha Co., Ltd, Daiichi Sankyo Co., Ltd. A. Fukutomi: Honoraria: Yakult Honsha Co. Ltd, Daiichi Sankyo Co., Ltd. All other authors have declared no conflicts of interest.

Abstract 1848: Autocrine IGF1 signaling mediates the survival of pancreatic cancer cells following the ablation of oncogenes

Abstract Pancreatic cancer is an extremely lethal disease, which is mostly associated with the gain-of-function mutation in KRAS gene. Due to a very high frequency of activating mutations within the KRAS gene, mutant KRAS is considered a rational therapeutic target in pancreatic cancer. In line with the existing idea that oncogenic KRAS is required for the maintenance of pancreatic cancer, we show a complete macroscopic regression of both primary and orthotopically transplanted tumors in our ligand-regulatable (Doxycycline) mouse model of KRASG12D-driven pancreatic cancer. This finding indicate that the expression, and provides a strong rationale for the development of KRAS targeted therapy for the treatment of pancreatic cancer. However, in our current study, despite the complete macroscopic regression of PDACs upon downregulation of oncogenic KRAS, few cancer cells always survived and remained dormant for a protracted duration. These residual cancer cells were responsible for the rapid recurrence upon KRAS reactivation. Using a genome-wide gene expression (RNA-Seq) analysis of in vivo-derived bulk and residual cancer cells followed by biochemical analysis, we identified a significant increase in autocrine IGF-1/AKT signaling in residual cancer cells. We also identified IGF1 signaling as a common survival mechanism of residual cancer cells in c-MYC-driven pancreatic tumor model. Pharmacological inhibition of IGF-1R signaling significantly delayed the tumor recurrence in both the tumor models, suggesting the crucial role of IGF-1R signaling in the survival of cancer cells in the absence of oncogenic drivers. Our findings from animal models were also validated in human pancreatic cancer cell lines harboring KRAS mutations, by demonstrating a compensatory increase in IGF1 signaling in response to a conditional knockdown of KRAS in vitro and in vivo. Collectively, all our findings from mouse model and human cancer cell studies strongly indicate that residual cancer cells can survive in the absence of tumor driving oncogenes by upregulation of autocrine IGF1 signaling loop. Thus, targeting oncogenic drivers along with IGF-1R signaling might be an effective strategy for prevention of tumor recurrence in pancreatic cancer. Citation Format: Nirakar Rajbhandari. Autocrine IGF1 signaling mediates the survival of pancreatic cancer cells following the ablation of oncogenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1848. doi:10.1158/1538-7445.AM2017-1848

Abstract 2910: Inter metastatic genetic heterogeneity is a characteristic feature of recurrent pancreatic cancer

Abstract Pancreatic cancer (PDA) is a 4th leading cause of cancer death with an overall 5-year survival of 8%. Surgical resection remains the only option for cure but only 10-15% of newly diagnosed patients are eligible. While surgery clearly provides a survival benefit compared to those patients who do not undergo potentially curative resection, the vast majority of patients will recur in the pancreatic remnant, liver, lungs, and/or peritoneum. Thus, there is an unmet need to better understand the fundamental features of recurrent disease. To explore the fundamental genomic features of recurrent PDA, patients were selected from participating Gastrointestinal Cancer Rapid Medical Donation Program (GICRMDP). 10 patients who underwent surgical resection; 8 patients had a whipple procedure, 2 patients had a distal pancreatectomy and each patient received a different type of chemotherapy after surgery, was evaluated. We performed 250x whole exome sequencing (WES) of 82 unique samples from these 10 patients, using frozen samples from autopsy and FFPE tissues from matching surgical specimen. In addition to the treatment naïve primary tumor, one or more samples of the local recurrence and multiple metastases were studied. The mean depth of coverage for all samples was 317x. Copy number variations were assessed by FACETs. MSK-IMPACT was performed for orthogonal validation of a subset of variants. We found that compared to the treatment naïve resected tumor, recurrent disease contained novel mutations in genes associated with MAPK and PI3K signaling. The most common mutational signature was Signature 1 followed by Signature 3. All patients who received a platinum drug as a form of therapy had a greater proportion of Signature 3 and 9 mutations in the recurrent disease than the primary tumor. Phylogenetic studies revealed that recurrent disease is the result of three patterns: 1) dissemination of disease to distant organs before surgery was performed, 2) dissemination of disease after surgery from residual microscopic disease in the pancreatic remnant, or 3) development of a second primary tumor in the remnant pancreas. This third scenario was identified in one of six additional patients studied by IMPACT. We conclude that recurrent pancreatic cancer is multifactorial, and at least two of these scenarios could be eliminated by total pancreatectomy, thereby increasing the rate of cure by surgical resection. Our study serves as a window to an understanding of the clonal dynamics of recurrent pancreatic cancer. Citation Format: Hitomi Sakamoto, Alvin Makohon-Moore, Marc Attiyeh, Liguo Zhang, Christine A. Iacobuzio-Donahue. Inter metastatic genetic heterogeneity is a characteristic feature of recurrent pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2910. doi:10.1158/1538-7445.AM2017-2910

CHD1L Expression Increases Tumor Progression and Acts as a Predictive Biomarker for Poor Prognosis in Pancreatic Cancer.

The chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) plays a key role in controlling various cellular phenomena, including immune-mediated inflammation, transformation, apoptosis, cell cycle progression, and proliferation. This study investigated the function and clinical significance of CHD1L protein expression in pancreatic cancer (PC). We analyzed CHD1L expression in surgical specimens from 112 PC patients. The correlation between the clinical characteristics and prognosis was also determined. Futhermore, cell proliferation were measured using EDU, and a molecular mechanism of Wnt/β-catenin pathway regulation by CHD1L was explored. CHD1L protein expression was significantly higher in PC patients with regard to the tumor grade, stage, size, differentiation and lymph node status. Increased CHD1L protein expression was significantly associated with poor overall survival. Multivariate analyses revealed that high CHD1L expression was an independent predictive marker for the recurrence and poor prognosis of pancreatic cancer. Furthermore, silencing of CHD1L expression by RNAi effectively abolished the proliferative abilities of CHD1L in vivo and in vitro. We found that the Wnt/β-catenin pathway contributed to the effect of CHD1L-mediated pancreatic cancer proliferation. Taken together, our data provide a novel evidence for the biological and clinical significance of CHD1L as a potential biomarker, and we demonstrate that CHD1L-Wnt/β-catenin might be a novel pathway involved in pancreatic cancer progression.

Heterogeneity index evaluated by slope of linear regression on 18F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma.

18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of 18F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and 18F-FDG PET/CT parameters. A total of 93 pancreatic ductal adenocarcinoma patients (M:F=60:33, mean age=64.2±9.1years) who underwent preoperative 18F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each 18F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and 18F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence=9.4±8.4months). Comparing the recurrence and no recurrence patients, all of the 18F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P=0.013), TLG (P=0.007), and heterogeneity index-2 (P=0.027) were significant. Among the clinicopathologic parameters, CA19-9 (P=0.025) and venous invasion (P=0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P=0.005), TLG (P=0.004), and heterogeneity index-2 (P=0.016) with venous invasion (P<0.001, 0.001, and 0.001, respectively) demonstrated significant results. The heterogeneity index obtained using the linear regression slope, could be an effective predictor of pancreatic cancer recurrence after pancreatic cancer surgery, in addition to 18F-FDG PET/CT volumetric parameters and clinicopathologic parameters.

Primary Recurrence in the Lung is Related to Favorable Prognosis in Patients with Pancreatic Cancer and Postoperative Recurrence.

The pattern of recurrence affects the clinical outcome in tumor patients. However, the clinical significance of lung metastasis as the primary recurrence site after resection in patients with pancreatic cancer remains unclear. This study aimed to clarify the clinical significance of the primary recurrence site in patients with pancreatic cancer, in terms of prognosis and clinicopathological features. This retrospective cohort study included 220 patients with postoperative recurrence after pancreatectomy for pancreatic cancer and classified by primary site of recurrence. We focused on patients with lung metastasis as the primary recurrence and investigated its correlation with prognosis and clinicopathological factors. Twenty-four (11%) patients had lung metastasis as the primary recurrence. This recurrence pattern had the best prognosis among all recurrence patterns, including liver metastasis and local recurrence. Patients with lung metastasis as the primary recurrence had favorable overall survival and survival from the date of recurrence compared with patients with other primary recurrence sites in both univariate (P=0.0008 and P=0.0005) and multivariate analyses (P=0.0051 and P=0.0068). In terms of clinicopathological features of resected pancreatic tumors, lung metastasis as the primary recurrence was associated with lower tumor stage and histologic grade, and less vascular invasion and residual tumor volume than liver metastasis. Pancreatic cancer patients with lung metastasis as the primary recurrence after pancreatectomy have a better prognosis than those with other recurrence patterns.

Building a hepato-pancreatico-biliary program in a community hospital: a preliminary analysis

Objective: A hepatopancreaticobiliary program (HPBP) began at our academic-affiliated community teaching hospital in November 2014. Previously, most patients were referred to academic centers. This study evaluates our current progress. Methods: Elective HPB cases by two fellowship-trained surgical oncologists were prospectively tracked between 10/2012 and 8/2016. Procedure type, transfusions, length of stay (LOS), readmissions, morbidity and mortality were compared. Patients were grouped into pre-HPBP and post-HPBP. Analyses were run with SAS 9.4, with p<0.05 considered significant. Results: Operative volume increased significantly post-HPBP (22% versus 78%, p<0.0001), with 24 cases post-HPBP year 1, and 23 in the first 8 months of year 2. Pancreaticoduodenectomies (PD) (14% vs 37%) and distal pancreatectomies (DP) (14% vs 26%) increased significantly (p=0.0462). ICU admissions were similar between groups, but decreased between post-HPBP year 1 and 2 (OR 0.99, p=0.0493). Fewer pre-HPBP patients required transfusion, but transfusion volume was similar (2 vs 2.5 units, p=0.6089) between groups. Five (38%) pre-HPBP and 25 (53%) post-HPBP patients had complications (p=0.1464). Thirty-day readmissions rose from 0 to 4 (16.7%) post-HPBP (p=0.0690). Thirty-day mortality rose from 0 to 8.5% post-HPBP (p=0.5754), but all 4 died in the first 8 months (celiac artery thrombosis, CVA, hemorrhage, liver failure), 3 after PD. Post-HPBP year 2, 30-day mortality was 0, but 4.2% at 90 days (2: sepsis, recurrent anaplastic pancreatic cancer in HIV positive patient). Conclusion: The rapid growth of our HPBP revealed an unmet need for local services. The initial rise in mortality has declined, reflecting improved patient selection. Prospectively tracked data will improve outcomes and facilitate clinical pathways.

Up-regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine-resistant pancreatic cancer cells.

Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT)‐type cells are considered as underlying causes of chemoresistance, tumour recurrence and metastasis in pancreatic cancer. We aimed to describe the mechanisms – particularly glycolysis – involved in the regulation of the CSC and EMT phenotypes. We used a gemcitabine‐resistant (GR) Patu8988 cell line, which exhibited clear CSC and EMT phenotypes and showed reliance on glycolysis. Inhibition of glycolysis using 2‐deoxy‐D‐glucose (2‐DG) significantly enhanced the cytotoxicity of gemcitabine and inhibited the CSC and EMT phenotypes in GR cells both in vitro and in vivo. Intriguingly, the use of the reactive oxygen species (ROS) scavenger N‐acetylcysteine (NAC) restored the CSC and EMT phenotypes. H2O2 produced changes similar to those of 2‐DG, indicating that ROS were involved in the acquired cancer stemness and EMT phenotypes of GR cells. Moreover, doublecortin‐like kinase 1 (DCLK1), a pancreatic CSC marker, was highly expressed and regulated the stemness and EMT phenotypes in GR cell. Both 2‐DG and H2O2 treatment suppressed DCLK1 expression, which was also rescued by NAC. Together, these findings revealed that glycolysis promotes the expression of DCLK1 and maintains the CSC and EMT phenotypes via maintenance of low ROS levels in chemoresistant GR cells. The glycolysis‐ROS‐DCLK1 pathway may be potential targets for reversing the malignant behaviour of pancreatic cancer.

Efficacy of chemotherapy in patients with recurrent pancreatic cancer.

466 Background: Gemcitabine (GEM) plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) are standard first-line chemotherapy regimens for metastatic pancreatic cancer (MPC) patients. GEM and S-1 are also used for these patients in Japan. However, the phase 3 trials included a small proportion of recurrent pancreatic cancer (RPC) patients, and patients who had received adjuvant chemotherapy were excluded. In clinical practice, RPC is treated in the same way as MPC. The aim of this study is to compare the efficacy of chemotherapy between RPC and MPC. Methods: We retrospectively analyzed the patients with RPC or MPC who received GnP, FFX, GEM, or S-1 as first-line chemotherapy between January 2014 and March 2016 in our institution. RPC was defined as pancreatic cancer with recurrence after R0 or R1 resection. Overall survival (OS), progression-free survival (PFS), response rate (RR), and disease control rate (DCR) were evaluated. Multivariate analyses of OS were performed with the use of a Cox proportional-hazard model. Results: A total of 181 patients, 40 RPC and 141 MPC, were selected in this study. RPC and MPC groups were similar with respect to age, sex, and performance status (PS). However, the RPC group had lower percentage of liver metastases (P &lt; 0.001). The regimens were GnP/FFX/GEM/S-1: 10/3/20/7 in the RPC group and 37/34/67/3 in the MPC group, respectively. In the RPC group, 31 of 40 patients had received adjuvant chemotherapy; S-1/GEM: 24/7. The median OS was 16.6 months in the RPC group as compared with 9.7 months in the MPC group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.37–1.10, P = 0.11). The median PFS was 4.8 months in the RPC group and 4.4 months in the MPC group (HR 0.86, 95% CI 0.57–1.30, P = 0.47). The RR was 10% versus 14% (P = 0.79), the DCR was 50% versus 52% (P = 0.86), in the two groups, respectively. Multivariate analysis showed PS (HR 2.19, 95% CI 1.38–3.49) and liver metastases (HR 2.34, 95% CI 1.47–2.34) were independent predictors of OS. On the other hand, RPC or MPC was not found to be an independent prognostic factor (HR 1.19, 95% CI 0.67–2.13). Conclusions: It is suggested that chemotherapy in RPC may have similar efficacy compared to MPC. The relatively longer OS in the RPC group seems to associate with the lower percentage of liver metastases.

The efficacy of first-line chemotherapy in recurrent pancreatic cancer after S-1 adjuvant chemotherapy.

475 Background: In Japan, adjuvant chemotherapy with S-1 for 6 months is standard care for resected pancreatic cancer. However, the efficacy of chemotherapy for recurrent pancreatic cancer(RPC) after adjuvant S-1 chemotherapy is not well evaluated. Methods: Medical records were retrospectively reviewed for consecutive patients who had RPC after adjuvant S-1 treatment and received chemotherapy between April 2013 and July 2016. Recurrence free interval (RFI) was defined as the interval from adjuvant S-1 initiation to cancer recurrence. Overall survival (OS) and progression free survival (PFS) after 1st line chemotherapy for RPC were compared between patients with RFIs of shorter than 6 month (Group S) and longer than 6 months (Group L). Results: In the 53 patients evaluated, the median duration of adjuvant S-1 chemotherapy was 5.1 months, and the median RFI was 8.3 months. After recurrence, they received Gemcitabine alone (20 patients), Gemcitabine+nab-paclitaxel (28 patients), modified FOLFIRINOX (one patient), and other regimen (4 patients). In all patients, the median PFS was 7.3 months and the median OS was 14.8 months. When compered in two groups (group S and group L), median OS in group S and group L was 6.7 months (95% confidence interval(CI): 4.2-12.9) and NA (95% CI: 13 months-NA) , respectively (p &lt; 0.001), and median PFS was 3.8 months (95%CI: 2.5-9.1) and 7.3 months (95%CI: 3.9-15.3), respectively (p = 0.11). Multivariate Cox regression analysis revealed CEA &lt; 4.0 mg/dl before chemotherapy and an RFI of ≥ 6 months were significantly associated with longer survival. Conclusions: These data suggest that RFI &lt; 6 months is a surrogate marker for a poor prognosis in patients with RPC.

Management of recurrent pancreatic cancer after surgical resection: Systematic review, evidence mapping, and meta-analysis.

448 Background: Although almost patients with surgically resected pancreatic cancer (PC) experience recurrence, the optimal treatment option of recurrent PC is still unclear. Numerous studies have been reported about this issue, but all the scattered evidences are too small and heterogeneous to reach a conclusion. The aim of this systematic review is to perform ‘evidence mapping’ and subgroup meta-analysis. Methods: In regards to local recurrence and metastatic recurrence respectively, four treatment options including re-operation (ReOP), chemotherapy (CTx), radiotherapy (RT), best supportive care (BSC) were searched from Medline, Embase, Cochrane library, Scopus and Web of Science from 1976 to April 30, 2016. To visualize the mapping of evidence, we established a web-based mapping tool ( http://plotting-e-map.com ) and used it. In the treatment options with selected study types, subgroup meta-analyses were conducted using overall survival as a primary endpoint. Results: Among detected 12,040 studies, a total of 162 studies were included. In locally recurrent PC, overall 126 studies (39 of ReOP, 40 of CTx, 37 of RT, and 10 of BSC) were included. Median overall survival (OS) of each treatment option was 16.1 months (95% CI 4.9–22.1, I2 52%) for ReOP, 14.9 month (95% CI 7.5–18.9, I2 63%) for CTx, 13.8 months (95% CI 5.6–17.0, I2 59%) for RT. In metastatic recurred PC, overall 36 studies (10 of ReOP, 22 of CTx, no RT, 4 of BSC) were included. Median OS’s were 8.3 months (95% CI 3.6–11.2, I2 56%) for Re-OP, and 6.8 months (95% CI 4.1–9.5, I2 33%) for CTx. Conclusions: During recent 40 years, evidences showed that re-operation for highly selected patients with locally and metastatic recurrent PC could be a considerable therapeutic option. However, since the heterogeneity among the studies is relatively high, more prospective and comparative studies about re-operation with multimodality treatment are needed.

Phase 1b dose-escalation and cohort-expansion study of the safety, tolerability, and efficacy of a novel transforming growth factor-β receptor I kinase inhibitor (galunisertib [G]) administered in combination with the anti-PD-L1 antibody (durvalumab [D]) in recurrent or refractory metastatic pancreatic cancer.

TPS501 Background: Transforming growth factor-β (TGF-β) can suppress adaptive and innate anti-tumor immune responses. G (LY2157299) is an oral small molecule inhibitor of TGF-β receptor I kinase that down-regulates phosphorylation of SMAD2, abrogating activation of the canonical pathway. Programmed cell death-ligand 1 (PD-L1) is upregulated in a broad range of cancers including pancreatic; expression of PD-L1 helps tumors evade immune system detection through binding to PD-1 on cytotoxic T lymphocytes. D (MEDI4736) is an anti-PD-L1 monoclonal antibody that blocks PD-L1/PD-1 interactions. Blockade of both TGF-β and PD-L1 pathways could reverse immunosuppression associated with these molecules by activating adaptive and innate anti-tumor immune responses. Methods: This two part phase 1b open-label study will enroll patients (pts) with recurrent or refractory metastatic pancreatic cancer. Part 1 is a 3+3 dose-escalation assessment of the safety and tolerability of G (4 escalating doses) and D (constant dose). After dose-limiting toxicity evaluation, cohort expansion with approximately 25 pts at the dose determined in the dose escalation portion will occur. Eligible pts have recurrent or refractory metastatic pancreatic cancer ( ≤ 2 prior systemic regimens) regardless of PD-L1 status; ECOG PS 0-1. Pts who have received prior therapy targeting T-cell costimulation or checkpoint pathways, or have received a TGF-β R1 kinase inhibitor are not eligible. Pretreatment and on-treatment biopsies will be obtained. The primary objective is to assess safety and tolerability of G in combination with D by identifying dose-limiting toxicities and to assess safety of the combination at the dose-escalation-established dose. Secondary objectives are pharmacokinetics; immunogenicity; preliminary anti-tumor activity; overall survival. Exploratory objectives are to examine biomarkers relevant to G, D, and the disease state. Enrollment began on 15-June-2016; as of 13-Sep-2016, 1 pt entered treatment. Clinical trial information: NCT02734160.

The efficacy and safety of gemcitabine + nab-PTX for recurrence and refractory pancreatic cancer.

485 Background: Gemcitabine + nab-Paclitaxel (GnP) is considered as one of the standard first-line chemotherapy for advanced pancreatic cancer (PC), but its efficacy and safety of GnP in patients with refractory or recurrent (Ref/Rec) PC has not been fully reported. Therefore, we conducted this retrospective analysis of GnP in patients with Ref/Rec PC. Methods: Consecutive patients with PC who received GnP at the University of Tokyo Hospital were retrospectively studied. Clinical outcomes in patients with Ref/Rec PC were compared with those in patients with PC receiving GnP as 1st line therapy. Dose intensity was calculated as the total amout of drug given in eight weeks. Tumor response was evaluated using RECIST 1.1 and adverse event using CTCAE ver 4.0. Progression free survival (PFS) were evaluated using the Kaplan-Meier method and compared by long-rank test. Cox regression models were used to calculate hazard ratios (HRs) to evaluate the prognostic factors in patients with Ref/Rec PC and in patients receiving GnP as 1stline therapy. Results: A total of 80 patients (37 as 1st line, 18 refractory and 25 recurrent) received GnP between January 2015 and July 2016. There were no significant differences in patient characteristics between 1st line therapy group and Ref/Rec group other than sex (Male in 41 vs. 67%). In relative dose intensity (RDI), there were no significant difference (75 vs. 72%). AE rates, both hematologic and non-hematologic, did not differ significantly between two groups. RDI was 75 vs. 72% for gemcitabine and 80 vs. 79% for nab-Paclitaxel. Response rate and disease control rate were 23 and 93% vs. 11 and 86%. The median PFS were 9.0 (95%CI: 4.9-13.9) vs. 5.5 (95%CI: 3.5-8.0) months (p = 0.06) and 1-year survival rate were 42.9 vs. 14.3% (p = 0.16). In the multivariate analyses, HRs of RDI &lt; 70 were 2.44 (95%CI: 1.07-5.49, p = 0.04) in Ref/Rec group, while the association was not significant in the 1st line group (HR 1.70 [95%CI: 0.63-4.25], p = 0.28). Conclusions: GnP was safely administered in patients with Ref/Rec PC with DI comparable to 1st line therapy. However, PFS in refractory and recurrent group tended to be short compared to those receiving GnP as 1st line therapy. DI was associated with the prognosis only in Ref/Rec PC.

Clinical results of stereotactic body radiotherapy (SBRT) in the treatment of isolated local recurrence of pancreatic cancer after R0 surgery: A retrospective study

ObjectiveTo evaluate the efficacy and the feasibility of SBRT for selected patients with isolated local recurrence of pancreatic cancer after radical surgery. MethodsA retrospective analysis was performed on patients treated with SBRT for isolated local recurrence from resected pancreatic adenocarcinoma, after multidisciplinary board evaluation. Prescription dose was 45 Gy in 6 fractions for all patients. Primary end-point was freedom from local progression (FFLP). Secondary end-points were overall survival (OS), progression free survival (PFS) and toxicity. Local control was defined according to RECIST criteria. Acute and late toxicity was scored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. ResultsBetween January 2011 and February 2015, 31 patients with isolated local recurrence of resected pancreatic cancer were treated with SBRT. Pancreato-duodenectomy (PD) was performed on 24 patients and distal pancreatectomy (DP) in 7 cases, all with radical resection (R0). Median local recurrence disease free interval (DFI) was 14 months. Median follow-up was 12 months. FFLP was 91% and 82% at 1 and 2-years, respectively. Median PFS was 9 months. Median OS was 18 months. At univariate analysis, OS was correlated with a DFI>18 months. No cases of acute G3 toxicity or greater occurred. ConclusionsSBRT seems to be an effective and safe therapeutic option for isolated local recurrence of pancreatic cancer after surgery. Encouraging local control rate, very low toxicity profile and effective pain control suggest the crucial role of SBRT in the treatment of these long-survivors selected patients.