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PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Background: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. Methods: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. Results: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. Conclusions: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit.

This randomized, open-label trial compared the efficacy and safety of adjuvantWe assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma toTwo hundred eighty-seven of 432 patients and 310 of 434 patients completedThe primary end point (independently assessed DFS) was not met despite favorable OS seen with

Background: Recently, anti-PD-L1 in combination with cytotoxic chemotherapy has shown significant survival benefit in a randomized phase 3 trial for unresectable or metastatic biliary tract cancer (BTC). However, no biomarker including PD-L1 expression has been established to predict clinical outcomes, and there is an unmet need for a novel predictive biomarker for anti-PD-1 or PD-L1 therapy. Here, we assessed TILs using artificial intelligence (AI)-powered spatial analysis in advanced BTC treated with anti-PD-1 beyond 1st line treatment. Methods: An AI-powered whole-slide image (WSI) analyzer (Lunit SCOPE IO, Lunit, Seoul, Korea) was used to segment tumor epithelium and stroma, and identification of intratumor TIL (iTIL) and stromal TIL (sTIL). H&E stained WSI from pre-treatment samples was acquired from Asan Medical Center (n =166), and a total of 154 samples (92.8%) after quality control were used for the final analysis. Immune phenotypes (IP) were defined as follow: inflamed as high iTIL and sTIL; immune-excluded as low iTIL and high sTIL; immune-desert as low TIL overall. Among them, 20 patients were available for multi-color flow cytometry analysis (FACS) using peripheral blood mononuclear cells, collected at baseline, C1D8, and C2D1. Results: All patients (n=154) were treated with anti-PD-1 (pembrolizumab or nivolumab) monotherapy, and 72 of 154 patients (46.8%) were treated as 2nd line. Gemcitabine plus cisplatin (GemCis) was used prior to anti-PD-1 as first-line therapy in all patients. Overall, 15 (9.7%) patients showed inflamed IP. With median follow-up duration of 15.4 months, the inflamed IP group showed better overall survival (17.2 vs. 6.6 months, P=0.03), and progression-free survival (PFS; 4.5 vs. 2.6 months, P=0.09) along with higher PFS rate at 12 months (33.3% vs. 11.5%, P=0.035), and overall response rate (26. 7% vs. 8.6%, P=0.053) than other phenotype groups. There was no significant difference in median PFS with GemCis among IP groups (P=0.74). In the FACS available subgroup, inflamed IP showed higher baseline central memory T (Tcm)+effector memory T (Tem)/Tnaive ratio than other IPs. With the administration of anti-PD-1, Tcm+Tem/Tnaive ratio was increased, while the proportion of PD1+CD8+T, CD39+CD8+T, CD103+CD8+T and Treg were decreased in the inflamed IP group than other phenotype groups. Conclusions: Immune phenotypes classified by AI-powered spatial TIL analysis was effective to predict the clinical outcomes of patients with advanced BTC treated with anti-PD-1 therapy. Citation Format: Yeong Hak Bang, Kyunghye Bang, Jin Ho Shin, Hyunseok Yoon, Kyu-Pyo Kim, Inkeun Park, Jae Ho Jeong, Heung-Moon Chang, Baek-Yeol Ryoo, Chiyoon Oum, Seulki Kim, Yoojoo Lim, Gahee Park, Chan-Young Ock, Changhoon Yoo. Spatial analysis of tumor-infiltrating lymphocytes in tumor microenvironment as biomarker for immune checkpoint inhibition in biliary tract cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4333.

Purpose This study evaluated the efficacy of adjuvant chemotherapy (AC) in patients with resected ampulla of Vater (AoV) carcinoma.Materials and Methods Data from 646 patients who underwent surgical resection at Asan Medical Center between 2000 and 2017 were retrospectively reviewed.Results The median age of the patients was 62 years, and 54.2% were male. Patients were classified into AC group (n=165, 25.5%) and no AC group (n=481, 74.5%). With a median follow-up duration of 88 months, in patients with stage I, II, III, median recurrence-free survival (RFS) was not reached, 44 months, and 15 months, respectively, and the median overall survival (OS) were not reached, 88 months and 35 months, respectively. Despite no statistical significance, RFS and OS were better in stage II patients with AC than in those without AC (median RFS, 151 months vs. 38 months; p=0.156 and median OS, 153 months vs. 74 months; p=0.299). In multivariate analysis for RFS and OS, TNM stage, R1 resection status, presence of lymphovascular invasion, and perineural invasion remained significant factors, whereas AC (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.54 to 1.00; p=0.052) was marginally related with RFS. After propensity score matching in only stage II/III patients, RFS and OS with AC were numerically longer than those without AC (HR, 0.80; 95% CI, 0.60 to 1.06; p=0.116 and HR, 0.77; 95% CI, 0.56 to 1.06; p=0.111).Conclusion AC with fluoropyrimidine did not improve survival of patients with resected AoV carcinoma. However, multivariate analysis with prognostic factors showed a marginally significant survival benefit with AC.

Purpose In biliary tract cancer (BTC), standard chemotherapy has limited benefit and no molecular targeted agents have been approved. This study investigated the genetic profile of BTC to identify potential new therapeutic targets and predictive biomarkers. Methods Targeted exome sequencing was performed for 124 patients with BTC [gallbladder cancer (GBC), 25; intrahepatic cholangiocarcinoma (ICC), 55; extrahepatic cholangiocarcinoma (ECC), 44]. Survival analysis was performed in 112 patients who received palliative chemotherapy for locally unresectable or metastatic disease. Results Genetic alterations were observed in 104 patients (83.8%); the most commonly mutated genes were TP53 (44.4%), KRAS (29.0%), ARID1A (12.1%) and IDH1 (9.7%). IDH1/2 mutations appeared more frequently in ICC (23.6%, P = 0.0002) than in GBC (4.0%) or ECC (2.3%), while ERBB2/3 mutations were found only in GBC (20.0%) and ECC (11.4%). Patients harbouring TP53 mutations had shorter overall survival (OS; median 15.2 vs. 37.8 months, P = 0.018), while IDH1 mutations showed a tendency for longer progression-free survival (PFS; 10.6 vs. 6.1 months, P = 0.124). Potentially actionable genetic alterations were found in 54.8%, and 7.1% received appropriate molecular targeted therapy in the clinical trial setting. Germline or somatic mutations in DNA damage repair (DDR) genes were found in 63.5% of patients and were significantly associated with longer PFS (6.9 vs. 5.7 months, P = 0.013) and OS (21.0 vs. 13.3 months, P = 0.009) in patients who received first-line platinum-containing chemotherapies (n = 88). Conclusions A subgroup of patients with BTC may benefit from targeted therapy by the aid of genetic information. In particular, DDR alterations may be a predictive biomarker for response to platinum-containing chemotherapy in patients with BTC.

BackgroundWe evaluated the clinical implications of epithelial–mesenchymal transition (EMT) markers and peritumoral immune cell infiltration in patients with biliary tract cancer (BTC) treated with gemcitabine plus cisplatin (GemCis).MethodsForty-five patients with advanced BTC who received GemCis were included as the study population. We conducted multiplex immunohistochemistry and examined EMT markers and their correlations with immune cell infiltrate at the invasive tumor margin. Study population was subdivided into two groups: twenty-four patients with overall survival (OS) less than 10 months (short-term survivor group, SS) and 21 with OS of 20 months or longer (long-term survivor group, LS).ResultsThe density of tumor cells expressing epithelial marker E-cadherin (E-cadherin+ CK+) at the invasive tumor margin tended to be higher in the LS group than in the SS group (p = 0.065). The density of tumor cells expressing mesenchymal marker vimentin (vimentin+ CK+) was significantly higher in the SS group than in the LS group (p = 0.021). Accordingly, the density of E-cadherin- vimentin+ CK+ cells was also significantly higher in the SS group (p = 0.020). The density of OX40 expressing cells (OX40+) was significantly higher in the SS group than in the LS group (p = 0.006). The density of vimentin+ CK+ cells was positively correlated with FoxP3+ CD4+ regulatory T-cells (r = 0.29, p = 0.047) and OX40+ cells (r = 0.48, p < 0.001).ConclusionsEMT-related features were enriched in BTC patients with poor survival outcomes and were associated with the immunosuppressive tumor microenvironment.

Adjuvant chemotherapy is the standard treatment after curative-intent surgery for pancreatic ductal adenocarcinoma (PDAC). The phase-3 ESPAC-4 trial demonstrated significantly improved overall survival (OS) with Gemcitabine plus capecitabine (GemCap) over Gemcitabine (Gem) in Europe. We conducted a retrospective efficacy and safety evaluation of GemCapThis retrospective analysis included 292 patients with PDAC who received adjuvant Gem or GemCap after curative resection between January 2017 and December 2020 at Asan Medical Center, Seoul, Korea.Adjuvant Gem and GemCap were administered to 161 (55.1%) and 131 (44.8%) patients, respectively. The Gem group had significantly older patients (median 66Adjuvant GemCap showed the consistent clinical outcomes with the ESPAC-4 trial. As mFOLFIRINOX is the new standard treatment for medically fit patients with resected PDAC, further evaluation of optimal adjuvant chemotherapy in daily practice is warranted.

Purpose Gemcitabine plus cisplatin (GemCis) is the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). In ABC-02 study, the BTC patients received up to 6-8 cycles of 3-weekly GemCis; however, those without progression often receive more than 6-8 cycles. The clinical benefit of maintenance treatment in patients without progression is uncertain. Materials and methods Advanced BTC patients treated with GemCis between April 2010 and February 2015 at Asan Medical Center, Seoul, Korea, were retrospectively analysed. The patients without progression after 6-8 cycles were stratified according to further treatment i.e., with or without further cycles of GemCis (maintenance vs. observation groups). The primary endpoint was overall survival (OS) and progression-free survival (PFS). Results Among the 740 BTC patients in the initial screen, 231 cases (31.2%) were eligible for analysis (111 in the observation group, 120 in the maintenance group). The median OS from the GemCis initiation was 20.5 months (95% confidence interval [CI], 15.4 to 25.6) and 22.4 months (95% CI, 17.0 to 27.8) in the observation and maintenance groups, respectively (p=0.162). The median PFS was 10.4 months (95% CI, 7.0 to 13.8) and 13.2 months (95% CI, 11.3 to 15.2), respectively (p=0.320). Conclusions GemCis maintenance is not associated with an improved survival outcome.

4009 Background: Survival outcomes are historically poor in patients (pts) with advanced/metastatic iCCA, with median overall survival (mOS) times of approximately 1 year with first-line gemcitabine plus cisplatin and approximately 6 months with second-line chemotherapy. Futibatinib, a highly selective, irreversible FGFR1–4 inhibitor, demonstrated efficacy with durable responses in pts with iCCA harboring FGFR2 fusion/rearrangements in the pivotal FOENIX-CCA2 phase 2 study (NCT02052778). At the primary analysis of this trial (data cutoff: October 1, 2020), an objective response rate (ORR) of 41.7% was observed, with a median duration of response (mDOR) of 9.7 mo. Here, we report updated efficacy (including mature OS data) and safety data from the final analysis with an additional 8 mo of follow-up. Methods: FOENIX-CCA2 was a single-arm phase 2 study that enrolled pts with advanced/metastatic iCCA with FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; including gemcitabine plus platinum-based chemotherapy). Pts received futibatinib 20 mg once daily until PD/intolerability. The primary endpoint was ORR per RECIST v1.1 by independent central review. Secondary endpoints were DOR, disease control rate (DCR), progression-free survival (PFS), OS, safety, and patient-reported outcomes. Results: At the time of the final data cutoff (May 29, 2021), median follow-up was 25.0 mo, and 96/103 pts (93%) had discontinued tx. The median number of tx cycles was 13.0 for a median tx duration of 9.1 mo. The confirmed ORR was 41.7% (43/103) and thereby the same as of the primary analysis, as was the DCR (at 82.5%). The ORR was consistent across pt subgroups. The mDOR was 9.5 mo, and 74% of responses lasted ≥6 mo. mPFS was 8.9 mo, with a 12-mo PFS rate of 35.4%. Mature mOS was 20.0 mo, with a 12-mo OS rate of 73.1% . No new safety signals were identified. Common tx-related adverse events (TRAEs) included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). TRAEs resulted in tx discontinuation in 4 pts (4%). No tx-related deaths occurred. Quality of life was maintained from baseline to tx cycle 13. Conclusions: Findings from the final analysis of FOENIX-CCA2 confirm the results of the primary analysis and reinforce the durable efficacy and continued tolerability of futibatinib in previously treated pts with advanced/metastatic iCCA harboring FGFR2 fusion/rearrangements. Mature OS data were consistent with data from the primary analysis and far exceed historical data in this patient population. Clinical trial information: NCT02052778.

546 Background: The benefit of adjuvant chemotherapy (ACT) following curative-intent surgery in pancreatic ductal adenocarcinoma (PDAC) patients who had received neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) remains unidentified. This retrospective analysis aimed to assess the clinical relevance of ACT in patients who underwent surgery following neoadjuvant mFOLFIRINOX. Methods: Between January 2017 and December 2020, 220 patients received neoadjuvant mFOLFIRINOX and underwent pancreatectomy for localized PDAC at the Asan Medical Center, Seoul, Korea. Patients unable to undergo curative-intent surgical resection (R0 or R1) and those with histological types other than ductal adenocarcinoma were excluded. Survival outcomes were compared according to ACT administration. Disease-free survival (DFS) was defined as the duration between surgery and recurrence or death of any etiology, whichever occurred first; and overall survival (OS) was that between surgery and death from any etiology. Results: ACT was administered to 150 (68.2%) patients. ACT recipients were significantly younger (median age, 61 vs. 64, p = 0.035) and they received significantly fewer cycles of neoadjuvant chemotherapy (median, 7 vs. 9, p = 0.0001) compared to non-recipients. As ACT, mFOLFIRINOX (n = 98, 65.3%), gemcitabine monotherapy (n = 39, 26.0%), and gemcitabine-capecitabine (n = 4, 2.7%) were administered. ACT recipients showed significantly better survival outcomes compared to non-recipients; median DFS 13.4 months (95% CI, 10.7–18.8) vs. 8.3 months (95% CI, 4.9–16.0), respectively (p = 0.0042); and median OS 33.4 months (95% CI, 29.9–NA) vs. 23.8 months (95% CI, 17.9–NA), respectively (p = 0.0021). DFS and OS were significantly better in ACT recipients regardless of the lymph node (LN) status during surgery (p = 0.033 for DFS and p = 0.027 for OS in negative LN; and p = 0.032 for DFS and p = 0.012 for OS in positive LN). There was no significant difference in DFS (p = 0.79) and OS (p = 0.49) between mFOLFIRINOX and gemcitabine-based regimens. In multivariate analysis, ACT remained significant as a favorable prognostic factor (DFS, hazard ratio [HR] 0.43 (95%CI, 0.26–0.71, p = 0.001); OS, HR 0.33 (95%CI, 0.17–0.64, p = 0.001). Conclusions: In PDAC patients who underwent surgery following neoadjuvant mFOLFIRINOX, ACT may be associated with improved survival outcomes. Its benefit was not affected by the LN status and ACT regimens.

Background Nab-paclitaxel plus gemcitabine (AG) is standard first-line chemotherapy for patients with metastatic pancreatic cancer (mPC). However, prognostic factors for patients with mPC treated with AG, are largely unknown. We retrospectively identified prognostic factors, including inflammation-based prognostic scores, in patients with mPC, and recurrent pancreatic cancer treated with AG as first-line treatment. Method A total of 203 patients with histologically-confirmed recurrent or metastatic pancreatic cancer who were treated with first-line AG in Asan Medical Center, Seoul, Korea, between February 2016 and December 2016 were included in this analysis. As inflammation-based scores, baseline neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and modified Glasgow prognostic scores (mGPS) were tested. Result Median age was 62 years and 116 patients (57%) were male. With median follow-up duration of 21.5 months, median progression-free survival (PFS) was 7.1 (95% CI 6.2-7.9) months, and overall survival (OS) was 15.1 (95% CI 12.6-17.6) months. In the multivariate analysis, PFS was significantly associated with liver metastasis (HR 1.43), distant lymph node metastasis (HR 1.48), and elevated CA19-9 (HR 1.56). In multivariate analysis for OS, elevated CA19-9 (HR 1.75), liver metastasis (HR 1.76), distant lymph node metastasis (HR 1.41), and high mGPS (mGPS ≥1 vs.0: HR 1.64) were independent prognostic factors. NLR and PLR were not significantly associated with PFS and OS. Conclusion Among the inflammation based prognostic scores, mGPS was a reliable prognostic indicator that could stratify survival outcomes in patients with recurrent or mPC who received AG as first-line chemotherapy.

Purpose More than half of patients with bile duct cancer (BDC) develop recurrence even after curative resection. Recurrent BDC has a poor prognosis, and no optimal treatment modality has been established. We therefore analyzed our experience on the survival outcomes of radiation therapy (RT) for recurrent extrahepatic bile duct cancer (EHBDC). Patients and methods We retrospectively analyzed the records of patients with recurrent EHBDC who underwent concurrent chemoradiation therapy (CCRT) or RT alone at our institution between January 2001 and June 2015. Freedom from locoregional progression (FFLP), progression-free survival (PFS), and overall survival (OS) were assessed, and univariate and multivariate analyses were performed to identify the prognostic factors. Results A total of 76 patients were included in the analysis. The median OS was 16 months and the rates of 2-year FFLP, PFS, and OS were 61%, 25%, and 33%, respectively. Among the evaluable patients, the first site of failure was the locoregional area in 16 patients, distant metastasis in 27, and both sites in 8. On univariate analysis, disease-free interval (p = 0.012) and concurrent chemotherapy (p = 0.040) were found as significant prognostic factors for OS. One patient with CCRT developed a grade 3 hematologic toxicity, and two patients experienced late grade 3 toxicities including duodenal ulcer bleeding and obstruction. Conclusions RT for recurrent EHBDC showed favorable survival and local control with limited treatment-related toxicities. Considering that the most common pattern of failure was distant metastasis, further studies on the optimal scheme of chemotherapy and RT are warranted.

547 Background: For patients who underwent curative-intent upfront surgery, adjuvant chemotherapy is the current standard of care. The previous, randomized phase 3 ESPAC-4 study showed significantly improved overall survival (OS) with GEMCAP compared to GEM. However, this study was conducted in European countries and its implication in Asian patients has not been explored yet. We conducted a retrospective analysis to evaluate the efficacy and safety of GEMCAP compared to GEM regimen. Methods: Between January 2017 and December 2020, a total of 292 patients who received adjuvant GEM or GEMCAP after curative-intent surgery in Asan Medical Center, Seoul, Korea, were included in this retrospective analysis. Results: Adjuvant GEM and GEMCAP were administered in 161 patients (55.1%) and 131 patients (44.8 %), respectively. Compared the GEMCAP group, age of patients were significantly older in the GEM group (median 66 vs 63 yo, p = 0.025); otherwise, there was no significant difference in baseline characteristics between two groups. With the median follow-up duration of 39.4 months (95% CI 36.9 - 45.0 months) in GEM group and 39.4 months (95% CI 34.7-41.6 months) in GEMCAP group, the median OS was 36.8 months (95% CI 29.7-43.5 months) and 46.1 months (95% CI 31.5 months – not reached) in the GEM group and GEMCAP group, respectively (unadjusted HR 0.72, 95% CI 0.51-1.02, p = 0.065). The median recurrence-free survival was 14.3 months (95% CI, 12.9-17.7 months) and 17.0 months (95% CI, 13.3-28.8 months) in the GEM group and GEMCAP group, respectively (p = 0.52). In the GEMCAP group, hand-foot skin reaction (any grade, 15.27 % vs 0.62 %, p < 0.001), neutropenia (78.6% vs 67.7%, p=0.037) and thrombocytopenia (30.53% vs 20.5%, p=0.035) were more common in the GEMCAP group compared to the GEM group. In multivariate analysis, adjuvant GEMCAP was significantly associated with better OS compared to adjuvant GEM (adjusted HR 0.64, 95% CI, 0.44-0.91, p = 0.014). Otherwise, moderate or poor histologic grade, lymph node positive, positive resection margin, and elevated CA 19-9 levels (> median) were significantly associated with poorer OS. Conclusions: In this retrospective analysis for Korean patients, adjuvant GEMCAP showed consistent clinical outcomes shown in the ESPAC-4 trial. As mFOLFIRINOX is the new standard of care for medically fit patients with resected pancreatic adenocarcinoma, further evaluation of optimal adjuvant chemotherapy in daily practice is warranted.

Background: Adjuvant chemotherapy is the standard treatment after curative-intent surgery for pancreatic ductal adenocarcinoma (PDAC). The phase-3 ESPAC-4 trial demonstrated significantly improved overall survival (OS) with Gemcitabine plus capecitabine (GemCap) over Gemcitabine (Gem) in Europe. We conducted a retrospective efficacy and safety evaluation of GemCap versus Gem in an Asian population. Methods: This retrospective analysis included 292 patients with PDAC who received adjuvant Gem or GemCap after curative resection between January 2017 and December 2020 at Asan Medical Center, Seoul, Korea. Results: Adjuvant Gem and GemCap were administered to 161 (55.1%) and 131 (44.8%) patients, respectively. The Gem group had significantly older patients (median 66 versus 63 years, p = 0.001); otherwise, the groups had similar baseline characteristics. With median follow-up durations of 39.4 [95% confidence interval (CI), 36.9–45.0] and 39.4 (95% CI, 34.7–41.6) months in the Gem and GemCap groups, the median OS was 36.8 (95% CI, 29.7–43.5) and 46.1 (95% CI, 31.5–not reached) months in the Gem and GemCap groups, respectively [unadjusted hazard ratio (HR) = 0.7; 95% CI, 0.5–1.0; p = 0.07). The median recurrence-free survival was 14.3 (95% CI, 12.9–17.7) and 17.0 (95% CI, 13.3–28.2) months, respectively ( p = 0.5). Hand-foot skin reactions (any grade, 15.3% versus 0.6%; p median) were significantly associated with worse OS. Conclusions: Adjuvant GemCap showed the consistent clinical outcomes with the ESPAC-4 trial. As mFOLFIRINOX is the new standard treatment for medically fit patients with resected PDAC, further evaluation of optimal adjuvant chemotherapy in daily practice is warranted.

Background: Despite the scarcity of data based on randomized trials, FOLFIRINOX is widely used in the management of borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). We investigated the clinical outcomes of neoadjuvant FOLFIRINOX in patients with BRPC and LAPC. Methods: This single-center retrospective analysis included a total of 199 consecutive patients with BRPC or LAPC who received conventional or modified FOLFIRINOX between February 2013 and January 2017. An independent radiologist reviewed all baseline computed tomography or magnetic resonance imaging scans were reviewed for vascular invasion status. Results: With median follow-up duration of 40.3 months [95% confidence interval (CI), 36.7–43.8] in surviving patients, median progression-free survival (PFS) and overall survival (OS) were 10.6 (95% CI, 9.5–11.7) and 18.1 (95% CI, 16.0–20.3) months, respectively. The 1-year PFS rate was 66.0% (95% CI, 65.3–66.7%), and the 2-year OS rate was 37.2% (95% CI, 36.5–37.9%). PFS and OS did not differ between BRPC and LAPC groups [median PFS, 11.1 months (95% CI, 8.8–13.5) versus 10.1 months (95% CI, 8.4–11.8), p = 0.47; median OS, 18.4 months (95% CI, 16.1–20.8) versus 17.1 months (95% CI, 13.2–20.9), p = 0.50]. Curative-intent conversion surgery (R0/R1) was performed in 63 patients (31.7%). C•A 19-9 response, objective tumor response to FOLFIRINOX, and conversion surgery were independent prognostic factors for OS. Conclusion: FOLFIRINOX was effective for management of BRPC and LAPC. Given the potential for cure, a significant proportion of patients can undergo conversion curative-intent surgery following FOLFIRINOX.

Background: The association between optimal carbohydrate antigen (CA) 19-9 concentration after neoadjuvant chemotherapy (NACT) and prognosis has not been confirmed in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). Methods: This retrospective study included 122 patients with BRPC and 103 with LAPC who underwent surgery after NACT between 2012 and 2019 in a tertiary referral center. Prognostic models were established based on relative difference of the CA 19-9 (RDC), with their prognostic performance compared using C-index and Akaike information criterion (AIC). Results: CA 19-9 concentrations of 37&ndash, 1000 U/mL before NACT showed prognostic significance in patients with BRPC and LAPC (hazard ratio [HR]: 0.262, 95% confidence interval [CI]: 0.092&ndash, 0.748, p = 0.012). Prognostic models in this subgroup showed that RDC was independently prognostic of better overall survival (HR: 0.262, 95% CI: 0.093&ndash, 0.739, p = 0.011) and recurrence free survival (HR: 0.299, 95% CI: 0.140&ndash, 0.642, p = 0.002). The prognostic performances of RDC (C-index: 0.653, AIC: 227.243), normalization of CA 19-9 after NACT (C-index: 0.625, AIC: 230.897) and surgery (C-index: 0.613, AIC: 233.114) showed no significant differences. Conclusion: RDC was independently associated with better prognosis after NACT in patients with BRPC or LAPC. Decreased CA19-9 after NACT was a prognostic indicator of better survival and recurrence, as was normalization of CA 19-9 after both NACT and surgery.

Supplemental material, Supplementary_Table for FOLFIRINOX in borderline resectable and locally advanced unresectable pancreatic adenocarcinoma by Changhoon Yoo, Inhwan Hwang, Tae Jun Song, Sang Soo Lee, Jae Ho Jeong, Do Hyun Park, Dong Wan Seo, Sung Koo Lee, Myung-Hwan Kim, Jae Ho Byun, Jin-hong Park, Dae Wook Hwang, Ki Byung Song, Jae Hoon Lee, Woohyung Lee, Heung-Moon Chang, Kyu-pyo Kim, Song Cheol Kim and Baek-Yeol Ryoo in Therapeutic Advances in Medical Oncology

Background/Aim: The aim of this study was to examine the efficacy and safety of direct oral anticoagulants for cancer-associated venous thromboembolism (VTE) in patients with active cancer. Patients and Methods: This study included patients with advanced unresectable/metastatic upper gastrointestinal (GI) or hepatopancreatobiliary (HPB) cancers with high risks of VTE and bleeding. Results: No significant differences were noted in potential bleeding factors between the rivaroxaban (n=105) and low-molecular-weight heparin (LMWH) (n=69) groups. Rivaroxaban exhibited similar risk of recurrent/aggravated VTE compared with LMWH (p=0.625) but increased risk of major bleeding (17.4% vs. 7.6%; p=0.072), clinically relevant bleeding (31.9% vs. 14.3%; p=0.019), and total bleeding (40.6% vs. 19%; p=0.010). The multivariate analysis regarded rivaroxaban as a significant factor for major bleeding (p=0.043) and clinically relevant bleeding (p=0.043). Conclusion: Rivaroxaban exhibits comparable efficacy but increases bleeding risks compared with LMWH in patients with active unresectable/metastatic upper GI tract or HPB cancers, requiring extra caution of higher major bleeding risks.

Background We aimed to comprehensively evaluate the prognostic value of inflammation-based prognostic scores, including the modified Glasgow Prognostic Score (mGPS), neutrophil–lymphocyte ratio (NLR), and platelet–lymphocyte ratio (PLR), exclusively in patients with advanced intrahepatic cholangiocarcinoma (iCCA). Methods Between May 2010 and April 2015, 305 patients with histologically documented unresectable or metastatic iCCA were treated with first-line gemcitabine plus cisplatin (GemCis). Among these, 257 patients had complete data for inflammation-based prognostic scores and were included. Results Median age was 59 (range: 27–78) years, and 158 patients (61.5%) were males. High mGPS was independently associated with poor progression-free survival (PFS; mGPS ≥1 vs. 0: median, 3.9 vs. 5.5 months; P = 0.001) and overall survival (OS; mGPS ≥1 vs. 0; median, 6.9 vs. 14.1 months; P = 0.002) in the multivariate analysis. Regarding high NLR (> median) and PLR (> median), although a potential association existed with poor PFS or OS in the univariate analysis, these did not remain as significant in the multivariate analyses. Conclusion The current study suggests that mGPS might be the relevant prognostic index that could stratify the survival outcomes of patients with unresectable or metastatic iCCA who received first-line GemCis.

Background FGFR2 fusions occur in ~15% of patients (pts) with iCCA, a rare cancer with a poor prognosis. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown activity across tumor types, including iCCA, in a phase 1 study. The pivotal phase 2 FOENIX-CCA2 trial (NCT02052778) is evaluating futibatinib in iCCA harboring FGFR2 fusions/rearrangements. Here, we report the first efficacy, safety, and quality of life (QoL) data for the complete FOENIX-CCA2 population. Methods Eligible pts had unresectable/metastatic iCCA with an FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; excluding FGFR inhibitors). Pts received futibatinib 20 mg QD until PD/intolerability. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review (target ORR: 20%). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and patient-reported outcomes (PROs). Subgroup analyses were performed by pt characteristic and molecular alteration. Results Among 103 pts (56% female), 53% had received ≥2 prior tx. FGFR2 fusions were present in 78% (23% had FGFR2-BICC1 fusions) and FGFR2 rearrangements in 22%. At data cutoff (Oct 1, 2020), 72 pts (70%) had discontinued tx. The study met its primary objective with a confirmed ORR of 41.7% (43/103). Responses were durable, with a median (m) DOR of 9.7 mo and 72% of responses ≥6 mo. DCR was 82.5%. mPFS was 9.0 mo; mOS was 21.7 mo, with a 12-mo OS rate of 72%. ORR was consistent across pt demographic subgroups (≥65 y: 65.2%; 2 prior tx: 38.7%). Common tx-related AEs (TRAEs) were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%). The most frequent grade 3 TRAE, hyperphosphatemia (30%), resolved with adequate management (median 7 d). Retinal disorders (all grade 1-2) were reported in 8% of pts. TRAEs were managed with dosing interruptions (50%)/reductions (54%); 2 pts discontinued tx due to TRAEs. No tx-related deaths occurred. ORRs were consistent in pts with dosing interruptions (40.2%) or reductions (46.8%). PROs were stable through 11.0 mo of tx. In exploratory biomarker analyses, ORR was consistent in pts with FGFR2 fusions (43.8%) and other FGFR2 rearrangements (34.8%) and in pts with BICC1 (41.7%) and non-BICC1 (44.6%) fusion partners. Notably, no obvious differences in ORR were observed in pts with co-occurring genetic alterations, including TP53 comutations (ORR, 38.5% [5/13]). Additional biomarker data will be presented. Conclusions Futibatinib resulted in frequent, durable objective responses in pts with iCCA harboring FGFR2 fusion/rearrangements, regardless of pt baseline characteristic, molecular alteration, or comutation. AEs were manageable with dosing modifications that did not impact response. QoL was maintained. Citation Format: Lipika Goyal, Funda Meric-Bernstam, Antoine Hollebecque, Chigusa Morizane, Juan W. Valle, Thomas B. Karasic, Thomas A. Abrams, Robin Kate Kelley, Philippe Cassier, Junji Furuse, Heinz-Josef Klümpen, Heung-Moon Chang, Li-Tzong Chen, Yoshito Komatsu, Kunihiro Masuda, Daniel Ahn, Yaohua He, Nital Soni, Karim A. Benhadji, John A. Bridgewater. Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT010.

Introduction Germline BRCA mutations may have therapeutic implications as surrogate markers of DNA-damage repair status in pancreatic ductal adenocarcinoma (PDAC). We performed a prospective study to evaluate the efficiency of risk criteria based on personal or family history of breast and ovarian cancer for determining germline BRCA mutations in PDAC patients with Asian ethnicity. Methods Between November 2015 and May 2016, we screened consecutive PDAC patients with locally advanced unresectable or metastatic disease who were referred for systemic chemotherapy. Analyses for germline BRCA mutations were performed if patients had one or more first-degree or second-degree relatives with breast or ovarian cancers or had a personal medical history of these diseases. DNA was extracted from whole blood, and all coding exons and their flanking intron regions of BRCA1 and BRCA2 were sequenced. Results A total of 175 patients were screened for personal and family history and 10 (5.7%) met the inclusion criteria for genetic sequencing. Pathogenic germline BRCA2 mutation [c.7480C>T (p.Arg2494*)] was identified in one male patient, resulting in a frequency of 10% for the risk-stratified patients and 0.6% for the unselected PDAC population. Two patients had germline BRCA2 variants of uncertain significance [c.1744A>C (p.Thr582Pro) and c.68-7T>A]. Conclusion Personal or family history of breast or ovarian cancers is a feasible, cost-effective risk categorization for screening germline BRCA mutations in Asian PDAC patients as 10% of this population had the pathogenic mutation herein. Future validation from a large, prospective cohort is needed.

OBJECTIVE Given the rarity of the disease, the post-resection clinical course of localized pancreatic acinar cell carcinoma (ACC) is largely unknown. Therefore, we aimed to analyze the outcomes of patients with localized pancreatic ACC who underwent curative surgical resection. METHODS We retrospectively analyzed the outcomes of 20 patients with resectable pancreatic ACC who underwent surgery. RESULTS Altogether 20 patients were included in the study, with a median age of 57 years and a male predominance. There were eight pure ACC, 10 mixed acinar–neuroendocrine carcinomas and two mixed acinar–ductal adenocarcinomas. Among the 15 patients who were staged histologically, 3, 8 and 4 were at stages IB, IIA and IIB, respectively. Eleven patients received adjuvant chemotherapy (5-fluorouracil-based [n = 9]; gemcitabine [n = 1]; etoposide plus cisplatin [n = 1]). In a median follow-up period of 27.1 months, disease recurred in 10 patients, most commonly in the liver (90%). Median recurrence-free survival and overall survival were 16.9 months and 75.0 months, respectively. Elevation of cancer antigen 19-9 (CA19-9), lymph node metastasis and neural invasion were significantly associated with poor overall survival (P = 0.007, P = 0.027 and P = 0.016, respectively). CONCLUSIONS Compared with ductal adenocarcinoma, resectable pancreatic ACC has a favorable prognosis after surgery. Considering that distant metastasis is the most common pattern of recurrence, further studies are necessary to define the role of adjuvant chemotherapy for improving survival outcomes.

Purpose Pancreatic acinar cell carcinoma (ACC) is a rare cancer of the exocrine pancreas. Because of its rare incidence, the efficacy of chemotherapy in this patient population has been largely unknown. Therefore, we retrospectively analyzed the outcomes of patients with advanced pancreatic ACC who received chemotherapy. Materials and methods Between January 1997 and March 2015, 15 patients with unresectable or metastatic pancreatic ACC who received systemic chemotherapy were identified in Asan Medical Center, Korea. Results The median age was 58 years. Eleven and four patients had recurrent/metastatic and locally advanced unresectable disease. The median overall survival in all patients was 20.9 months (95% confidence interval [CI], 15.7 to 26.1). As first-line therapy, intravenous 5-fluorouracil were administered in four patients (27%), gemcitabine in five (33%), gemcitabine plus capecitabine in two (13%), oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) in two (13%), and concurrent chemoradiotherapy followed by capecitabine maintenance therapy in two (13%). The objective response rate (ORR) to chemotherapy alone was 23% and the median progression-free survival (PFS) was 5.6 months (95% CI, 2.8 to 8.4). After progression, second-line chemotherapy was administered in eight patients, while four patients received FOLFOX and the other four patients received gemcitabine. The ORR was 38%, and patients administered FOLFOX had significantly better PFS than those administered gemcitabine (median, 6.5 months vs. 1.4 months; p=0.007). The ratio of time to tumor progression (TTP) during first-line chemotherapy to TTP at second-line chemotherapy was significantly higher in patients administered FOLFOX (4.07; range, 0.87 to 8.30) than in those administered gemcitabine (0.12; range, 0.08 to 0.25; p=0.029). Conclusion Our results suggest that oxaliplatin-containing regimens may have improved activity against pancreatic ACC.

Borderline resectable pancreatic cancer (BRPC) is a potentially resectable disease but is associated with poorer survival compared to primary resectable disease. There has been no prospective trial that compare the efficacy of FOLFIRNOX and gemcitabine-based regimen for BRPC. Between February 2013 and December 2014, 18 patients with BRPC receiving FOLFIRINOX were reviewed retrospectively. For comparative analysis, data for all BRPC patients (n=18) in our previous phase 2 study of neoadjuvant fixed-dose rate-gemcitabine plus capecitabine were pooled. Patients received a median 6 cycles (range, 3-13) of FOLFIRINOX. Surgical resection was performed in 12 patients (67%) and R0 resection in 9 patients. Median progression-free survival (PFS) and overall survival (OS) were 16.8 (95% confidence interval [CI], 9.4-24.2) and 21.2 (95% CI, 14.2-28.2) months, respectively. Patients who underwent surgical resection showed significantly better PFS (p=0.01) and OS (p=0.003) than those unresected. In the exploratory analysis, patients receiving FOLFIRINOX showed significantly longer PFS compared to those receiving fixed-dose rate-gemcitabine plus capecitabine (median 16.8 months [95% CI, 9.4-24.2] vs. 6.5 months [1.6-11.3]; p = 0.04). There was a trend toward improved OS in patients who received FOLFIRINOX (median 21.2 months [95% CI, 14.2-28.2]) compared to those who received fixed-dose rate-gemcitabine plus capecitabine (13.6 months [11.8-15.4]; p=0.12). FOLFIRINOX was feasible and effective as neoadjuvant chemotherapy for patients with BRPC and may have improved efficacy compared to a gemcitabine-based regimen.

The efficacy of lung metastasectomy is well established in several cancers, including colorectal cancer. However, little is known about the result of lung metastasectomy in carcinoma of the ampulla of Vater. Only two case reports have reported the efficacy of metastasectomy in ampullary cancer patients with pulmonary metastasis. We report the result of bilateral lung metastasectomy in a patient with ampullary cancer. A 63-year-old woman underwent pylorus-preserving pancreaticoduodenectomy for carcinoma of the ampulla of Vater. About three years after the surgery, two non-calcified lung nodules in the right lower and left upper lobes had developed. Wedge resections of both lung nodules were performed and the pathological examination showed that the lung nodules were pulmonary metastases from the ampullary cancer. Ten years after the lung surgery, the patient is well and there is no evidence of recurrence. Surgical resection could be considered in patients with pulmonary metastasis from ampulla of Vater cancer, even when the metastases are bilateral.

Aim: It remains unclear whether capecitabine combined with cisplatin would show similar effects compared with standard therapy using gemcitabine and cisplatin in advanced biliary tract cancer (BTC). Methods: Patients with advanced BTC who were treated with first-line chemotherapy at Asan Medical Center were retrospectively analyzed. All patients received either cisplatin followed by gemcitabine on days 1 and 8 every 3 weeks (GP group), or capecitabine on days 1–14 with cisplatin on day 1 every 3 weeks (XP group). Results: Of the 134 patients who met the inclusion criteria, 78 received XP and 56 were treated with GP. After a median follow-up of 26.2 months, the progression-free survival was 5.7 months for XP versus 4.1 months for GP (hazard ratio [HR] = 0.81, P = 0.31). The overall survival (OS) was 11.0 months for XP versus 9.8 months for GP (HR = 0.84, P = 0.36). In the multivariate analysis, there were no significant differences in PFS and OS between the two groups. Conclusion: XP seems to be as effective as GP in patients with advanced BTC. The XP regimen is feasible and might offer increased convenience regarding the schedule of drug administration.

PURPOSE Since the introduction of nab-paclitaxel plus gemcitabine (nab-P+GEM) as first-line (1L) treatment for metastatic pancreatic adenocarcinoma (mPDAC), optimal second-line (2L) chemotherapy after progression is unclear. We assessed clinical outcomes of 2L chemotherapy for disease that progressed on 1L nab-P+GEM. Materials and Methods Among the 203 patients previously treated with 1L nab-P+GEM for mPDAC at Asan Medical Center, between February and December 2016, records of 120 patients receiving 2L chemotherapy after progression on nab-P+GEM were retrospectively reviewed. The response rate and survival were evaluated along with analysis of prognostic factors. RESULTS Fluoropyrimidine-oxaliplatin doublets (FOLFOX or XELOX) were used in 78 patients (65.0%), fluoropyrimidine monotherapy in 37 (30.8%), and liposomal irinotecan plus fluorouracil in two (1.7%). The median progression-free survival (PFS) and overall survival (OS) were 3.29 months and 7.33 months from the start of 2L therapy. Fluoropyrimidine-oxaliplatin regimens and fluoropyrimidine monotherapy did not yield significantly different median PFS (2.89 months vs. 3.81 months, p=0.40) or OS (7.04 months vs. 7.43 months, p=0.86). A high neutrophil-lymphocyte ratio (> 2.2) and a short time to progression with 1L nab-P+GEM (< 6.4 months) were independent prognostic factors of poor OS with 2L therapy. CONCLUSION 2L fluoropyrimidine-oxaliplatin doublets and fluoropyrimidine monotherapy after failure of 1L nab-P+GEM had modest efficacy, with no differences in treatment outcomes between them. Further investigation is warranted for the optimal 2L chemo-regimens and sequencing of systemic chemotherapy for patients with mPDAC.

TAS-120 is a highly selective, irreversible fibroblast growth factor receptor (FGFR) 1–4 inhibitor in development as a once-daily oral treatment for intrahepatic cholangiocarcinoma (iCCA). An ongoing phase 1/2 study of TAS-120 in CCA showed tolerability and preliminary efficacy, particularly in patients with FGFR2 rearrangements. The purpose of FOENIX-CCA2 (NCT02052778) is to evaluate the efficacy and safety of TAS-120 in patients with iCCA with FGFR2 rearrangements. FOENIX-CCA2 is a global, single-arm study of TAS-120 in patients with iCCA bearing FGFR2 gene fusions and other rearrangements including deletion, duplication, truncation, or rearrangement of unknown significance. The study will enroll approximately 100 patients with locally advanced or metastatic iCCA that progressed after ≥1 systemic therapies and with an ECOG PS of 0 or 1. Prior systemic therapy must include gemcitabine plus platinum-based chemotherapy and no prior FGFR inhibitor. Screening for FGFR2 gene rearrangements will be performed at a central laboratory or locally and confirmed by a central laboratory. The primary endpoint is objective response rate based on RECIST v1.1. Secondary endpoints include duration of response, disease control rate, overall survival, progression-free survival, safety, and health-related quality of life.

PurposeStereotactic body radiation therapy (SBRT) is a promising treatment modality for locally advanced pancreatic cancer (LAPC). We evaluated the clinical outcomes of SBRT in patients with LAPC.Patients and methodsWe retrospectively analyzed the medical records of patients with LAPC who underwent SBRT at our institution between April 2011 and July 2016. Fiducial markers were implanted using endoscopic ultrasound guidance one week prior to 4-dimensional computed tomography (CT) simulation and daily cone beam CT was used for image guidance. Patients received volumetric modulated arc therapy or intensity modulated radiotherapy using respiratory gating technique. A median dose of 28 Gy (range, 24-36 Gy) was given over four consecutive fractions delivered within one week. Survival outcomes including freedom from local disease progression (FFLP), progression-free survival (PFS), and overall survival (OS) were analyzed. Acute and late toxicities related to SBRT were assessed.ResultsA total of 95 patients with LAPC were analyzed, 52 of which (54.7%) had pancreatic head cancers. Most (94.7%) had received gemcitabine-based chemotherapy. The 1-year FFLP rate was 80.1%. Median OS and PFS were 16.7 months and 10.2 months, respectively; the 1-year OS and PFS rates were 67.4% and 42.9%, respectively. Among 79 patients who experienced failure, the sites of first failures were isolated local progressions in 12 patients (15.2%), distant metastasis in 55 patients (69.6%), and both in 12 patients (15.2%). Seven patients (7.4%) were able to undergo surgical resection after SBRT and four had margin-negative resections. Three patients (3.2%) had grade 3 nausea/vomiting during SBRT, and late grade 3 toxicity was observed in another three patients.ConclusionsLAPC patients who received chemotherapy and SBRT had favorable FFLP and OS with minimal treatment-related toxicity. The most common pattern of failure was distant metastasis, which warrants further studies on the optimal scheme of chemotherapy and SBRT.

720 Background: Borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAUPC) are heterogeneous disease entity with various prognosis. Based on the phase III PRODIGE trial, (m)FOLFIRINOX has been widely used for the management of patients with BRPC and LAUPC. Considering the lack of large phase 3 trial of (m)FOLFIRINOX for BRPC and LAUPC, real-life evidences of (m)FOLFIRINOX are needed. Methods: In this retrospective analysis, 199 patients who received at least one dose of (m)FOLFIRINOX between February 2013 and January 2017 were included. Endpoints of this study were objective response rates (ORR), surgical resection rate, progression-free survival (PFS) and overall survival (OS). Results: Median age was 60 years (range, 33-79) and 62.3% of patients were male. Pancreas head (n=112, 56.3%) was the most common primary tumor site, followed by body (n=42, 21.1%) and multifocal (n=34, 17.1%). By an independent radiology review, patients were classified to BRPC (n=75, 37.7%) and LAUPC (n=124, 62.3%). With median 40.3 months (95% CI, 36.7-43.8) of follow-up duration in surviving patients, ORR was 26.6% (n=53), median PFS and OS were 10.6 months (95% CI, 9.5-11.7) and 17.1 months (95% CI, 13.2-20.9), respectively. There was no difference in PFS and OS between BRPC and LAUPC (median PFS, 11.1 months [95% CI, 8.8-13.5] vs. 10.1 months [95% CI, 8.4-11.8], p=0.47); (median OS, 18.4 months [95% CI, 16.1-20.8] vs. 17.1 months [95% CI, 13.2-20.9], p=0.50). Curative-intent surgery (R0 and R1) was done in 63 patients (33.2%, 49 for R0 and 14 for R1) after treatment with (m)FOLFIRINOX. Resection rates were 58.2% in BRPC patients and 19.4% in LAUPC patients (p

Background In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). Patients and methods This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40–60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40–60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS. Results A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82–1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67–0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. Conclusion TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.

Purpose: Hepatitis B virus infection is a well-known risk factor for intrahepatic cholangiocarcinoma. However, its prognostic impact has rarely been investigated in advanced intrahepatic cholangiocarcinoma. Methods: Between April 2010 and May 2015, 296 patients with unresectable or metastatic intrahepatic cholangiocarcinoma who received gemcitabine plus cisplatin (GemCis) were categorized into a hepatitis B virus group (n=62; 21%) and a non-hepatitis B virus group (n=234; 79%). Clinicopathological features and survival outcomes were retrospectively reviewed and analyzed. Results: The median age of patients was 59 years (range, 27–78). The median overall survival with first-line GemCis was 9.4 months (95% CI 8.4, 10.4). Compared to the non-hepatitis B virus group, the hepatitis B virus group was younger (median age, 57 vs. 61 years, P = 0.001), mainly male (74% vs. 57%, P = 0.02), and had lower frequency of elevated cancer antigen (CA) 19-9 (34% vs. 59%, P = 0.001) and alkaline phosphatase (43% vs. 61%, P = 0.01). In a univariate analysis, the hepatitis B virus infection showed a marginal relationship with poor overall survival compared to the non-hepatitis B virus infection (median, 8.3 vs. 10.0 months; P=0.13). A multivariate analysis of potential prognostic factors revealed a significant association with poor overall survival in the hepatitis B virus group (hazard ratio (HR) =1.50, P = 0.02). Initial metastatic disease (vs. recurrent/unresectable disease; HR=1.50), metastatic sites ⩾ 2 (vs. 0–1; HR=1.51), Eastern Cooperative Oncology Group performance status ⩾ 2 (vs. 0–1; HR=1.93), elevated total bilirubin (vs. normal; HR=1.83), and low albumin (vs. normal; HR=1.52) were significantly related to an unfavorable overall survival. Conclusions: This study suggests that the hepatitis B virus infection may be associated with distinctive clinicopathological characteristics and poor outcome in advanced intrahepatic cholangiocarcinoma treated with GemCis.

Purpose nab-paclitaxel plus gemcitabine (AG) and FOLFIRINOX have been established as standard first-line treatment in metastatic pancreatic cancer (mPC). We performed retrospective analysis comparing the efficacies of AG and FOLFIRINOX in daily practice setting. Materials and Methods We analyzed 308 patients who presented initially as mPC and received AG (n = 149) or FOLFIRINOX (n = 159) as first-line treatment between 2013 and 2016. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Result There were no significant differences between the two groups in terms of baseline characteristics, except older age and higher Charlson Comorbidity Index (CCI) score in AG group. The response rates (34% vs 34%) and median PFS (6.8 vs 5.1 months) were comparable between two groups (p = 0.88 and p = 0.19, respectively), while median OS was significantly better with AG than FOLFIRINOX (11.4 vs 9.6 months; p = 0.002). Elevated baseline CA19–9 level and liver metastasis were independent adverse prognostic factors for PFS and OS. In subgroup analyses, PFS with AG was better in patients with age ≥ 65 years, peritoneal metastasis, and higher CCI than that with FOLFIRINOX. Conclusion Both AG and FOLFIRINOX showed comparable efficacy outcomes in daily practice setting. AG might be preferentially considered in patients with peritoneal metastasis, comorbid medical conditions or old age.

Given the rarity of the disease, the post-resection clinical course of localized pancreatic acinar cell carcinoma (ACC) is largely unknown. Therefore, we aimed to analyze the outcomes of patients with localized pancreatic ACC who underwent curative surgical resection.We retrospectively analyzed the outcomes of 20 patients with resectable pancreatic ACC who underwent surgery.Altogether 20 patients were included in the study, with a median age of 57 years and a male predominance. There were eight pure ACC, 10 mixed acinar-neuroendocrine carcinomas and two mixed acinar-ductal adenocarcinomas. Among the 15 patients who were staged histologically, 3, 8 and 4 were at stages IB, IIA and IIB, respectively. Eleven patients received adjuvant chemotherapy (5-fluorouracil-based [n = 9]; gemcitabine [n = 1]; etoposide plus cisplatin [n = 1]). In a median follow-up period of 27.1 months, disease recurred in 10 patients, most commonly in the liver (90%). Median recurrence-free survival and overall survival were 16.9 months and 75.0 months, respectively. Elevation of cancer antigen 19-9 (CA19-9), lymph node metastasis and neural invasion were significantly associated with poor overall survival (P = 0.007, P = 0.027 and P = 0.016, respectively).Compared with ductal adenocarcinoma, resectable pancreatic ACC has a favorable prognosis after surgery. Considering that distant metastasis is the most common pattern of recurrence, further studies are necessary to define the role of adjuvant chemotherapy for improving survival outcomes.

Biliary tract cancer (BTC) is a heterogeneous group of diseases comprising intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer. Although gemcitabine plus cisplatin (GEMCIS) was established as the standard first-line chemotherapy based on the ABC-02 trial, more data are needed to define the clinical course of BTC and its prognostic factors with the standard GEMCIS treatment. Between April 2010 and June 2016, 740 patients with histologically documented cholangiocarcinoma and gallbladder cancer were treated with first-line GEMCIS in Asan Medical Center, Seoul, Korea. In 389 patients with measurable disease (53%), the objective response rate was 13% (n = 50) and there was no significant difference between primary tumor sites (p = 0.45). With a median follow-up duration of 27.3 months (95% CI 24.2–30.5), the median PFS and OS were 5.2 months (95% CI 4.7–5.6) and 10.4 months (95% CI 9.6–11.2), respectively. In multivariate analysis, male gender (female versus male, hazard ratio [HR] 0.83), baseline CA 19-9 level (elevated versus normal, HR 1.31), initially metastatic disease (versus locally advanced disease, HR 1.92), poor performance status (2 versus 0–1, HR 1.45), and measurable disease by RECIST criteria (versus non-measurable, HR 1.40) were significantly associated with a poorer OS (all p

Efficacy of targeted agents, such as everolimus and sunitinib, has been demonstrated in prospective trials on patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Considering the heterogeneous clinicopathological characteristics of neuroendocrine tumors (NETs), evaluation of treatment outcomes in a real-world setting is necessary. Clinical records of 44 patients with GEP-NET who were treated with everolimus or sunitinib between March 2007 and October 2014 were retrospectively reviewed. Considering the distinct characteristics of pancreatic NETs (pNETs) and non-pancreatic gastrointestinal NETs (GI-NETs), efficacy analysis was performed separately. Pancreas was the most common primary site (n = 28, 64%), followed by rectum (n = 10, 23%) and stomach (n = 3, 7%). Sunitinib and everolimus were administered in 27 (61%) and 17 (39%) patients, respectively. In patients with pNET, median progression-free survival (PFS) with everolimus and sunitinib was 16.6 months (95% CI 8.0–25.1) and 8.0 months (95% CI 0.0–17.4), respectively (p = 0.51). Among non-pancreatic GI-NET patients, median PFS with everolimus and sunitinib was 14.7 months (95% CI 2.4–27.0) and 1.7 months (95% CI 0.5–3.0), respectively (p = 0.001). Compared to patients treated with everolimus, tumor grade 3 (30 vs. 0%) and history of prior cytotoxic chemotherapy (70 vs. 50%) were more common in patients treated with sunitinib. Both everolimus and sunitinib were effective in GEP-NET patients. Outcomes of everolimus therapy in GEP-NETs were consistent with those reported elsewhere. Poor efficacy of sunitinib in non-pancreatic GI-NETs may be attributable to the baseline characteristics associated with poor clinical outcomes.

Background: We aimed to assess the efficacy of second-line fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer (BTC) after failure of gemcitabine plus cisplatin (GEMCIS). Methods: We retrospectively examined patients with histologically documented advanced BTC who received first-line GEMCIS between December 2010 and June 2015. Among 748 patients treated with first-line GEMCIS, 321 (43%) subsequently received fluoropyrimidine-based second-line systemic chemotherapy. Results: Fluoropyrimidine monotherapy and fluoropyrimidine–platinum combination were used in 255 and 66 patients, respectively. In patients with measurable disease, the overall response rate (ORR) was 3% and disease control rate was 47%. After a median follow-up of 27.6 months (range, 0.9–70.4 months), the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval (CI), 1.6–2.2) and 6.5 months (95% CI, 5.9–7.0), respectively. The ORR was significantly higher in patients who received fluoropyrimidine–platinum combination compared with those who received fluoropyrimidine alone (8 vs 1%, P=0.009), although the PFS (P=0.43) and OS (P=0.88) did not significantly differ between these groups. Conclusions: Fluoropyrimidine-based chemotherapy was modestly effective as a second-line chemotherapy for advanced BTC patients after failure of GEMCIS. Fluoropyrimidine–platinum combination therapy was not associated with improved survival outcomes, as compared with fluoropyrimidine monotherapy.

4000 Background: In metastatic pancreatic cancer (PC), nab-P/G demonstrated significantly longer overall survival (OS) vs G. APACT assessed efficacy & safety of nab-P/G vs G in surgically resected PC. Methods: Treatment (tx)-naive patients (pts) with histologically confirmed PC, macroscopic complete resection, ECOG PS 0/1, & CA19-9 < 100 U/mL were eligible. Stratification factors: resection status (R0/R1), lymph node status (LN+/−), & geographic region. Tx was initiated ≤ 12 wks postsurgery. Pts received nab-P 125 mg/m2 + G 1000 mg/m2 or G 1000 mg/m2 on days 1, 8, 15 of six 28-day cycles. Primary endpoint was disease-free survival (DFS) by independent reviewer (IR); IRs received baseline clinical data & scans. Secondary endpoints were OS & safety. ≈438 DFS events were needed for 90% power to detect an HR for disease recurrence or death of 0.73 with nab-P/G vs G at a 2-sided significance level of 0.05. Results: 866 pts were randomized. Median age was 64 y (range, 34 - 86); most pts had ECOG PS 0 (60%), LN+ (72%), & R0 (76%). 69% of pts completed 6 tx cycles ( nab-P/G, 66%; G, 71%). Median follow up for OS was 38.5 mo. Median IR-assessed DFS (439 events) was 19.4 mo ( nab-P/G) vs 18.8 mo (G) (HR, 0.88; 95% CI, 0.729 - 1.063; stratified log-rank P = 0.1824). Investigator-assessed DFS (571 events) was 16.6 mo ( nab-P/G) vs 13.7 mo (G) (HR, 0.82; 95% CI, 0.694 - 0.965; nominal P = 0.0168). Interim OS (427 events) was 40.5 mo ( nab-P/G) vs 36.2 mo (G) (HR, 0.82; 95% CI, 0.680 - 0.996; nominal P = 0.045). Grade ≥ 3 TEAEs were reported in 86% vs 68% of pts with nab-P/G vs G. The most common grade ≥ 3 hematologic & nonhematologic TEAEs with nab-P/G vs G were neutropenia (49% vs 43%) & fatigue (10% vs 3%). TEAEs led to death in 2 pts in each arm. Conclusions: IR DFS with nab-P/G was not significantly longer vs G; median DFS with G was longer than historical data. DFS by investigator (sensitivity analysis) and interim OS were improved with nab-P/G vs G (HR 0.82 for both). Adjuvant nab-P/G may be an option for pts who are ineligible for FOLFIRINOX. Additional OS follow-up may better support nab-P/G as an option in the adjuvant setting. Clinical trial information: NCT01964430.