Nai-Jung Chiang

Background: Upfront resection (UR) followed by adjuvant chemotherapy remains the standard treatment for resectable pancreatic cancer. There is increasing evidence suggesting favourable outcomes toward neoadjuvant chemotherapy (NAC) followed by surgery. Methods: All clinical staging with resectable pancreatic cancer patients treated at a tertiary medical centre from 2013 to 2020 were identified. The baseline characteristics, treatment course, surgery outcome and survival results of UR or NAC were compared. Results: Finally, in 159 resectable patients, 46 patients (29%) underwent NAC and 113 patients (71%) received UR. In NAC, 11 patients (24%) did not receive resection, 4 (36.4%) for comorbidity, 2 (18.2%) for patient refusal and 2 (18.2%) for disease progression. In UR, 13 patients (12%) were unresectable intraoperatively; 6 (46.2%) for locally advanced and 5 (38.5%) for distant metastasis. Overall, 97% of patients in NAC and 58% of patients in UR completed adjuvant chemotherapy. As of data cut-off, 24 patients (69%) in NAC and 42 patients (29%) in UR were still tumour free. The median recurrence-free survival in NAC, UR with adjuvant chemotherapy and without adjuvant chemotherapy were 31.3 months (95% CI, 14.4–not estimable), 10.6 months (95% CI, 9.0–14.3) and 8.5 months (95% CI, 5.8–11.8), P=0.036; and the median overall survival in each group were not reached (95% CI, 29.7–not estimable), 25.9 months (95% CI, 21.1–40.5) and 21.7 months (12.0–32.8), P=0.0053. Based on initial clinical staging, the median overall survival of NAC was not significantly different from UR with a tumour less than or equal to 2 cm, P=0.29. NAC patients had a higher R0 resection rate (83% versus 53%), lower recurrence rate (31% versus 71%) and harvested median number lymph node (23 versus 15). Conclusion: This study demonstrates that NAC is superior to UR in resectable pancreatic cancer with better survival.

Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 (FGFR2) fusion and isocitrate dehydrogenase (IDH)- and BRAF mutation-enriched populations have survival benefits from the corresponding inhibitors. Several interesting targeted agents for monotherapies or combination therapies with other compounds are currently ongoing or recruiting. Here, we review the published data from clinical trials of second-line therapies after the failure of gemcitabine-based chemotherapy in ABTC. The results were stratified by different genetic alternations, as well as by chemotherapy, targeted therapy and immunotherapy.

Background: The prognostic significance of cardiac radiation dose in esophageal cancer after definitive concurrent chemoradiotherapy (CCRT) remains largely unknown. We aimed to investigate the association between cardiac dose-volume parameters and overall survival (OS) in esophageal squamous cell carcinoma (ESCC) after definitive CCRT. Methods: One hundred and twenty-one ESCC patients undergoing definitive CCRT with intensity modulated radiotherapy technique between 2008 and 2018 were reviewed. Cardiac dose-volume parameters were calculated. Survival of patients and cumulative incidence of adverse events were estimated by the Kaplan–Meier method and compared between groups by the log-rank test. The prognostic significance of cardiac dose-volume parameters was determined with multivariate Cox proportional hazards regression analysis. Results: Median follow-up was 16.2 months (range, 4.3–109.3). Median OS was 18.4 months. Heart V5, V10, and V20 were independent prognostic factors of OS. Median OS was longer for patients with heart V5 ≤ 94.3% (24.7 vs. 16.3 months, p = 0.0025), heart V10 ≤ 86.4% (24.8 vs. 16.9 months, p = 0.0041), and heart V20 ≤ 76.9% (20.0 vs. 17.2 months, p = 0.047). Lower cumulative incidence of symptomatic cardiac adverse events was observed among patients with heart V5 ≤ 94.3% (p = 0.017), heart V10 ≤ 86.4% (p = 0.02), and heart V20 ≤ 76.9% (p = 0.0057). Patients without symptomatic cardiac adverse events had a higher 3-year OS rate (33.8% vs. 0%, p = 0.03). Conclusions: Cardiac radiation dose inversely correlated with survival in ESCC after definitive CCRT. Radiation dose to the heart should be minimized.

Background: The literature regarding pericardial effusion after definitive concurrent chemotherapy and intensity modulated radiotherapy (IMRT) for esophageal cancer was lacking. This study aimed to investigate the risk factors of pericardial effusion in esophageal cancer patients undergoing definitive concurrent chemotherapy and IMRT. Methods: A total of 126 consecutive esophageal cancer patients treated with definitive concurrent chemotherapy and IMRT between 2008 and 2018 were reviewed. The pericardial effusion was determined on computed tomography scan of the chest and graded by the Common Terminology Criteria for Adverse Events, version 4.0. The cumulative incidence of pericardial effusion was estimated by the Kaplan–Meier method and compared between groups by the log-rank test. The risk factors of pericardial effusion were determined with multivariate Cox proportional hazards regression analysis. Results: The median follow-up time was 14.0 months. Thirty-seven (29.4%) patients had pericardial effusion after a median interval of 6.6 months since the end of IMRT. The cumulative incidence of pericardial effusion of any grade was higher in patients with mean heart dose > 23.45 Gy (p = 0.00018), heart V30 > 33.55% (p = 0.00015), mean pericardium dose > 20.33 Gy (p = 0.00027), and pericardium V20 > 42.55% (p = 0.00018). Furthermore, eight (6.3%) patients had symptoms related to pericardial effusion and were considered as cases with pericardial effusion ≥ grade 3. The cumulative incidence of pericardial effusion ≥ grade 3 was higher in patients with pericardium V30 > 65.80% (p = 0.00028), V40 > 55.35% (p < 0.0001), and V60 > 24.70% (p = 0.0021). Multivariate analyses showed the above dose-volume parameters predicted the risk of pericardial effusion in esophageal cancer. Conclusions: Dose-volume parameters predicting the risk of pericardial effusion were identified in esophageal cancer treated with definitive concurrent chemotherapy and IMRT. They could be applied as constraints of IMRT for esophageal cancer.

Endoscopic, ultrasound-guided tissue acquisition (EUS-TA) with rapid on-site evaluation is recommended as a first choice in the diagnosis of pancreatic lesions. Since EUS facilities and rapid on-site evaluation are not widely available, even in medical centers, an alternative for precise diagnoses of pancreatic tumor is warranted. The percutaneous computed tomography-guided, core needle biopsy (CT-CNB) is a commonly applicable method for biopsies. Our institute has developed a fat-transversing approach for pancreatic biopsies which is able to approach most tumors in the pancreas without penetrating organs or vessels. Herein, we report a 15-year experiment of pancreatic tumor coaxial CT-CNB in 420 patients. The success rate of tissue yielding by the technique was 99.3%. The overall sensitivity, specificity, and accuracy were 93.2%, 100%, and 93.4%, respectively. The diagnostic accuracy could be increased to 96.4% in 2016–2018 (after the learning curve period). The overall complication rate was 8.6%. Neither life-threatening major complications, nor seeding through the biopsy tract, were observed. Our study supported the hypothesis that CT-CNB could be a complementary option for diagnostic tissue acquisition in patients with unresectable or metastatic pancreatic tumors when EUS-TA is either unsuitable or unavailable.

Background: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma, which is highly associated with Epstein-Barr virus (EBV) infection and abundant lymphoplasmacytic cells infiltration. However, the genetic background of LELCC and the immune profiling of their microenvironment remain largely un-elucidated. Methods: Retrospectively collected formalin-fixed, paraffin-embedded (FFPE) tissue of 5 EBER-positive LELCCs and 7 non-LELCCs were included. PDL1 expression was examined by anti-PD-L1 immunohistochemical (IHC) 22C3 PharmDx (Agilent Technologies, Santa Clara, CA, USA). Peripheral blood mononuclear cells (PBMCs) from two LELCC patients were served as background of germline mutations. Gene expression profiling was determined by next generation sequencing (ACTOnco^®+ Comprehensive Cancer Panel, ACT Genomics Co., LTD) on DNA samples. The nCounter^® PanCancer Immune Profiling Panel (NanoString Technologies, Inc., Seattle, WA, USA) was used for Immune profiling on RNA samples. Results: All EBV-related LELCCs were positive for PD-L1 staining, with combined positive score of 25 to 80, mainly in peritumoral immune cells. After adjusting for frequency of germline mutation from PBMC, only mutations with allele frequency less than or around 10% were considered as somatic mutations. Overall, LELCCs with 10 nonsynonymous somatic mutations were detected in 4 LELCCs with 0 to 5 mutations per sample. Identified mutations included BARD1 (allele frequency: 8.1%), EPHA5 (5.8%), MUC16 (7.6%), TNFAIP3 (5.8%), CD19 (5.6%), PTEN (8.8%), TET1 (7.2%), RECQL4 (6.4%), CD79B (10.1%), and KDM5A (10.2%), with all 20% of incidence. Each mutation is independent between four cases. Of the immune profiling, EBV-related LELCCs display significantly higher signature of cytotoxic cells, CD45 cells, T cells, Th1 cells, CD8 T cells, NK cells, and B cells than those of non-LELCC. Of the one LELCC patient who had anti-PD-1 treatment after gemcitabine/cisplatin therapy failure got a durable partial response to the anti-PD-1 immunotherapy. Conclusions: LELCC is highly correlated with PDL1 expression in tumor and immune cells. Based on results of NanoString immune panel, EBV-related LELCC is characterized by a T cell-inflamed tumor microenvironment.

Gemcitabine plus platinum, notably cisplatin, is conceived as the standard regimen for advanced biliary tract cancer (ABTC). S-1 consists of tegafur and two biomodulators that maintain high serum 5-flurouracil concentrations while reducing gastrointestinal toxicity. A phase II study, JCOG0805 showed that gemcitabine plus S-1 was more promising than S-1 alone in ABTC, and a recently phase III JCOG1113 (FUGA-BT) showed gemcitabine plus S-1 (GS) is non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) benefit. Our TCOG T1308 trial also demonstrated that modified GS is an active regimen with excellent safety profiles as the first-line treatment in patients with ABTCs. For the triplet regimen, KHBO1002 trial, a single-arm phase II study of GC plus S-1 combination therapy (GCS), demonstrated a favorable survival benefit in ABTC patients. Recently, KHBO1401 trial was aimed to confirm the superiority of GCS to GC in terms of survival in patients with ABTC. This phase III study demonstrated the significant survival benefits of GCS treatment over GC treatment (13.5 versus 12.6 months, P=0.046), indicating that GCS could be a new standard treatment for patients with advanced BTC in Japan. In this talk, I will briefly introduce above clinical trials and share our experience of S-1 application in the treatment of ABTCs.

Background: Cholangiocarcinoma (CCA) is the second most common primary hepatobiliary malignancy, with significantly increasing incidence in last two decades. Most patients are diagnosed late. Surgery still served as the mainstay treatment but early relapse. Circulating tumor cells (CTCs) have been detected by EpCAM-based capture method which has emerged as a promising biomarker in oncology. However, data regarding the application of the above in the detection of CTCs in CCA is scarce. Furthermore, there is an urgent need to develop a new capture probe for CCA. Methods: An integrated microfluidic platform with the automatic functions of red blood cells (RBCs) lysis, isolation of pellets and depletion of white blood cells (WBCs) was applied. The CTCs were enriched with magnetic beads (MB) surface functionalized with anti-EpCAM and a novel glycosaminoglycan (SCH-45), followed by immunostaining with DAPI, CK17, and CD45 to distinguish CTCs from WBCs, in spiked blood samples and clinical blood samples from CCA patients. Results: Using this integrated microfluidic platform, a CCA cell line, Huh28, was clearly bound onto both MB-SCH45 and MB-anti-EpCAM, with immunostaining of DAPI(+), CK17(+), and CD45(−). The average recoveries of the spiked cancer cells using MB-SCH45 and MB-anti-EpCAM, were experimentally found to be 77.8%±10.2% and 85.6%±14.4%, respectively. For thirty blood samples from patients with stages III–IV CCA, the new capture probe, SCH45, was capable of isolating CTCs in all samples, which seemed to be more specific when compared to the traditional EpCAM probe. The dynamic change of CTCs number was highly correlated with the response to chemotherapy prospectively in 5 patients with intrahepatic CCA. Conclusions: This microfluidic system could detect CTCs in only 1 mL of blood, which only took 2.5 h. The new probe, SCH45, may serve as a potential biomarker for CTC isolation.

PEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV, in patients with advanced refractory solid tumors. Patients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m2 (dose expressed as the irinotecan hydrochloride trihydrate salt) as a 90-min intravenous infusion on day 1, followed by 24 h infusion of 5-FU 2,000 mg/m2 and LV 200 mg/m2 on days 1 and 8, every 3 weeks. A total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m2 (two patients). DLT was observed in four patients, two at the 100 mg/m2 dose level (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), and two at the 120 mg/m2 dose level (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea). The MTD of PEP02 was determined as 80 mg/m2. The most common treatment-related adverse events were nausea (81%), diarrhea (75%) and vomiting (69%). Among the six patients who received the MTD, one patient exhibited partial response, four patients had stable disease and one showed progressive disease. Pharmacokinetic data showed that PEP02 had a lower peak plasma concentration, longer half-life, and increased area under the plasma concentration-time curve from zero to time t of SN-38 than irinotecan at similar dose level. The MTD of PEP02 on day 1 in combination with 24-h infusion of 5-FU and LV on days 1 and 8, every 3 weeks was 80 mg/m2, which will be the recommended dose for future studies. The trial was retrospectively registered ( NCT02884128 ) with date of registration: August 12, 2016.

745 Background: S-1 is a new oral fluoropyrimidine-derived combo and has been shown activity in patients with various cancers in phase II/III studies. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenesis activities and has been approved for the first-line treatment of advanced HCC, RCC and radioactive iodine-resistant thyroid cancer. In xenograft mouse models, sorafenib showed its activity to enhance the cytotoxicity of chemotherapeutic agents. Therefore, a phase I dose-escalation study to determine the dose-limiting toxicity and maximum dose of S-1 in combination with standard dosing of sorafenib in patients with refractory solid tumors was conducted. Methods: Eligible patients would receive escalating dose (30, 35 and 40 mg/m2, twice daily) of S-1 in a standard 3+3 phase I study design. Treatment was consisted of continuous sorafenib 400 mg bid plus S-1 30-40mg/m2 bid, D1-14, every 21 days per cycle. DLTs were assessed during the first two cycles of treatment, and treatment would be continued until disease progression, the occurrence of unacceptable toxicity or consent withdrawal. Results: A total of 13 patients were included, 7 in 30 mg/m2 dose level and 6 in 35 mg/m2 dose level. DLT occurred in 2 of 6 patients with 35 mg/m2 twice daily, manifested as grade 3 skin rash and prolonged grade 2 hand-foot-skin reaction in one each; while there was no DLT observed in 30 mg/m2 cohort. Seven patients achieved durable tumor control, included one pancreatic neuroendocrine tumor patient who had a sustained PR for 27.9 months, and durable stable diseases (>6 months of progression-free survival) in 3 out of 4 colorectal cancer patients, 2 of 2 biliary tract cancer patients and 1 of 2 pancreatic cancer patients. Conclusions: The recommended dose of S-1 in this combination was 30mg/m2 bid. Preliminary results suggested sorafenib/S-1 combination is feasible and deserves for further exploration in refractory advanced gastrointestinal tract cancers. Clinical trial information: NCT01128998.