Adjuvant Gemcitabine-based Chemotherapy Research Articles

HPB O01 - Colonization of bile with gammaproteobacteria reduces survival after surgery for pancreatic cancer in patients receiving gemcitabine-based adjuvant chemotherapy

Abstract Background Evidence suggests that the biliary microbiome influences the progression of pancreatic ductal adenocarcinoma (PDAC) in patients undergoing adjuvant chemotherapy. Specifically, Gammaproteobacteria (GPB) has been shown to have the potential to develop mutations which can metabolise gemcitabine into an inactive form. This study hypothesised that GPB influences survival in patients with PDAC undergoing adjuvant gemcitabine-based chemotherapy following surgery. Method This was a retrospective study of patients undergoing pancreatoduodenectomy from 2010 to 2020. Associations between patient and tumour characteristics, survival data, and results of intraoperative bile cultures (GPB+ or GPB-) were investigated. Analysis of patients matched by chemotherapy regimen and numbers of cycles of adjuvant therapy was also performed. Survival was analysed using Kaplan–Meier curves and Cox regression analysis. Results Analysis of 359 patients revealed that adjuvant gemcitabine-based therapy improved overall survival (OS). Patients who receive gemcitabine-based chemotherapy with a GPB+ biliary culture had a shorter OS compared to those who were GPB-, and a median survival of 17.9 vs 26.1 months, P=0.006. After matching for key chemotherapy variables, survival was greater in the GPB- group 26.8 vs 19.8, P=0.016. This association was not seen among patients who received no adjuvant therapy or non-gemcitabine based therapy. Conclusion Patients receiving gemcitabine-based chemotherapy after surgery are likely to have reduction in OS if they have a biliary culture positive for GPB.

1511P The influence of intratumoral bacteria and peri-operative antibiotic treatment on the outcome of resected pancreatic cancer patients treated with adjuvant gemcitabine-based chemotherapy

1511P The influence of intratumoral bacteria and peri-operative antibiotic treatment on the outcome of resected pancreatic cancer patients treated with adjuvant gemcitabine-based chemotherapy

Predicting post-recurrence survival for patients with pancreatic cancer recurrence after primary resection: A Bi-institutional validated risk classification

BackgroundOver 80% of patients will develop disease recurrence after radical resection of pancreatic ductal adenocarcinoma (PDAC). This study aims to develop and validate a clinical risk score predicting post-recurrence survival (PRS) at time of recurrence. MethodsAll patients who had recurrence after undergoing pancreatectomy for PDAC at the Johns Hopkins Hospital or at the Regional Academic Cancer Center Utrecht during the study period were included. Cox proportional hazard model was used to develop the risk model. Performance of the final model was assessed in a test set after internal validation. ResultsOf 718 resected PDAC patients, 72% had recurrence after a median follow-up of 32 months. The median overall survival was 21 months and the median PRS was 9 months. Prognostic factors associated with shorter PRS were age (hazard ratio [HR] 1.02; 95% confidence interval [95%CI] 1.00–1.04), multiple-site recurrence (HR 1.57; 95%CI 1.08–2.28), and symptoms at time of recurrence (HR 2.33; 95%CI 1.59–3.41). Recurrence-free survival longer than 12 months (HR 0.55; 95%CI 0.36–0.83), FOLFIRINOX and gemcitabine-based adjuvant chemotherapy (HR 0.45; 95%CI 0.25–0.81; HR 0.58; 95%CI 0.26–0.93, respectively) were associated with a longer PRS. The resulting risk score had a good predictive accuracy (C-index: 0.73). ConclusionThis study developed a clinical risk score based on an international cohort that predicts PRS in patients who underwent surgical resection for PDAC. This risk score will become available on www.evidencio.com and can help clinicians with patient counseling on prognosis.

Adjuvant therapy in biliary tract cancers: oral fluoropyrimidine as a beginning

Biliary tract cancer is a group of malignant tumours, mostly adenocarcinoma, arising from different sites of the biliary tract with diverse aetiology, molecular profiling, TNM classification, and surgical procedures and outcomes of resectable diseases. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar Radical surgical resection remains the only curative treatment, but postoperative relapse is common. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar Developing effective adjuvant therapy is mandatory. However, two modern observation-controlled phase 3 trials, the BCAT trial 2 Ebata T Hirano S Konishi M et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018; 105: 192-202 Crossref PubMed Scopus (192) Google Scholar and the PRODIGE 12-ACCORD 18 trial, 3 Edeline J Benabdelghani M Bertaut A et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019; 37: 658-667 Crossref PubMed Scopus (230) Google Scholar did not show the benefit of adjuvant gemcitabine-based chemotherapy in resected biliary tract cancers. BILCAP 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Google Scholar was the first phase 3 study to support the role of adjuvant chemotherapy, with oral capecitabine, for resected biliary tract cancers. 5 Shroff RT Kennedy EB Bachini M et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019; 37: 1015-1027 Crossref PubMed Scopus (198) Google Scholar , 6 Yoo C Jeong H Kim KP et al. Adjuvant gemcitabine plus cisplatin (GemCis) versus capecitabine (CAP) in patients (pts) with resected lymph node (LN)-positive extrahepatic cholangiocarcinoma (CCA): a multicenter, open-label, randomized, phase 2 study (STAMP). Proc Am Soc Clin Oncol. 2022; 404019 Google Scholar , 7 Stein A Arnold D Bridgewater J et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015; 15: 564 Crossref PubMed Google Scholar The recommendation mainly relied on a significant improvement in overall survival by the prespecified sensitivity analysis (hazard ratio [HR]=0·71, 95% CI 0·55–0·92) but not on overall survival (ie, the primary endpoint; HR=0·81, 95% CI 0·63–1·04) in the primary, intention-to-treat analysis, 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Google Scholar and is thus debatable. The adjusted HR for overall survival increased to 0·84 (95% Cl 0·67–1·06) and the HR for recurrence-free survival was 0·81 (95% Cl 0·65–1·01) in the extension report, 8 Bridgewater J Fletcher P Palmer DH et al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. J Clin Oncol. 2022; 40: 2048-2057 Crossref PubMed Scopus (11) Google Scholar which further weakened the recommendation. 9 Edeline J Malka D Capecitabine: still a standard option in the adjuvant setting of biliary tract cancer?. J Clin Oncol. 2022; 40: 3667-3668 Crossref PubMed Scopus (1) Google Scholar Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trialAlthough long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. Full-Text PDF

Individual patient data meta-analysis of adjuvant gemcitabine-based chemotherapy for biliary tract cancer: combined analysis of the BCAT and PRODIGE-12 studies

BackgroundAlthough gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies. MethodsWe performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan–Meier curves and a Cox regression model stratified on the trial. ResultsTwo hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio [HR] = 0.91 [95% confidence interval [CI] 0.71–1.16]; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%–47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%–43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 [95%CI: 0.78–1.35]; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%–57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%–56.5%) for observation. ConclusionWith 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.

Analysis of Radiation Therapy Quality Assurance in NRG Oncology RTOG 0848

<h3>Purpose/Objective(s)</h3> NRG/RTOG 0848 is a two-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiotherapy (RT) following adjuvant gemcitabine-based chemotherapy (2^nd step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed for each patient who underwent RT. QA findings were reviewed, frequencies & reasons for resubmissions are reported. <h3>Materials/Methods</h3> Patients were treated using either a 3D-conformal RT (3DCRT) or intensity-modulated RT (IMRT) technique. In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume (CTV) through the creation of specific regions of interest. The planning target volume (PTV) was established by expanding the CTV by 0.5 cm in all directions. Treatment planning data, including pre-operative imaging, surgical and pathology reports, simulation images with isodose lines, structure set, and dose volume histograms were submitted for review. One of two radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and then resubmitted for review until approved. Treatment started after final approval of the RT plan. <h3>Results</h3> Of the 354 patients who underwent second randomization, 180 were randomized to the RT arm. Of these, 160 received RT and were included in the QA analysis. Most patients (86%) were treated using IMRT. Resubmissions were more common for patients planned with 3D-CRT (43%) than with IMRT (31%). In total, at least one resubmission of the treatment plan was required for 33% of patients (see Table 1). Among patients requiring resubmission, the majority only needed to be resubmitted once (87%). The most common reasons for resubmission were unacceptable deviations with respect to the pre-operative gross target volume (GTV, 61%) and the pancreatojejunostomy (48%), leading to unacceptable deviations of the contours of the CTV and PTV (70% for each). Most patients requiring a resubmission had 5-9 unacceptable deviations (46%). Unacceptable deviations were similar for the few treatment plans that needed to be resubmitted more than once. <h3>Conclusion</h3> One third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on pretreatment QA for adjuvant pancreas cancer trials. Rigorous QA is of critical importance for clinical trials involving RT to ensure that the true impact of RT can be assessed. Moreover, RT QA serves as an educational process by training radiation oncologists on best practices.

Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma.

Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma.

Immunity-Related Gene Signature Identifies Subtypes Benefitting From Adjuvant Chemotherapy or Potentially Responding to PD1/PD-L1 Blockage in Pancreatic Cancer.

Tumor microenvironment comprises of a variety of cell types, which is quite complex and involved in chemotherapy and immune checkpoint blockage resistance. In order to explore the mechanisms involved in tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC), we first constructed an immunity-related 18-gene signature using The Cancer Genome Atlas (TCGA) PDAC project data. Then we applied the 18-gene signature to divide PDAC patients into low score and high score groups. Patients in high score group showed inferior prognosis, which was validated in another four independent cohorts, including Ruijin cohort. High score group showed significant enrichment of pathways involved in cell division and cell cycle especially in G1/S phase transition. In high score group, IHC analysis revealed higher levels of the proliferative indexes of Ki67 and PCNA than that in low score group. Prognostic analysis confirmed that patients in high score group could benefit from the gemcitabine-based adjuvant chemotherapy. In low score group, the programmed cell death 1 ligand 1(PD-L1) (+) cases showed worse prognosis but higher T cell infiltration than PD-L1(−) cases. Our immunity-related 18-gene signature could effectively predict PDAC prognosis, and it might be a practical predictive tool to identify PDAC subtype benefitting from gemcitabine-based adjuvant chemotherapy or potentially responding to PD1/PD-L1 blockade therapy.

Long Term Follow-up of a Phase II Study of Autophagy Inhibition with Hydroxychloroquine (HCQ) and Preoperative (Preop) Short Course Chemoradiation (SCRT) Followed by Early Surgery for Resectable Ductal Adenocarcinoma of the Head of Pancreas (PDAC)

PDAC is highly dependent on autophagy, a metabolic process that renders cancer cells resistant to cytotoxic therapies. HCQ has been shown to be a potent inhibitor of autophagy, has preclinical activity, and clinical evidence of increased response rates. We evaluate the efficacy of concurrent and adjuvant HCQ with preop SCRT and adjuvant chemotherapy. Patients with radiographically resectable, biopsy-proven PDAC of the head were enrolled from 12/2011-09/2016 on this IRB-approved, NCI-sponsored clinical trial (NCT01494155). Eligibility included no CT involvement of SMA or celiac artery; adequate renal, hepatic and hematopoietic functions; and ECOG PS 0/1. Pts received either 5 Gy x 5 with protons or 3 Gy x 10 with photons concurrent with Cape 825 mg/m2 BID wk 1 and 2 M-F. HCQ was started at 400 mg po BID 1 wk prior to radiation through SCRT until the day before surgery. Surgery was performed 1-3 wks after completion of SCRT. Patients were recommended to receive 6 mo of gemcitabine-based chemotherapy after surgery. Pts resumed HCQ after discharge from surgery and continued until progression. Follow-up was performed every 3 months with CT scanning every 6 mo. 50 pts were enrolled on study and all are evaluable for this analysis. Median age- 69 (range 54-85), female- 24 pts (48%), pre-treatment CA19-9 median 69.5 U/mL (range <1-10235) Gr 3 toxicity was noted in 3 (6%) pts (vomiting-1, nausea-1, hyperglycemia-2). 50 pts completed SCRT. 47 pts underwent resection. Reasons for no resections were: metastatic disease-2, intercurrent illness- 1. 38 pts had R0 resection, 9 had R1 resection. 31/47 had positive nodes. 1 pt had no viable tumor at resection. Of the 47 resected pts, 10 pts remain on HCQ. Median follow up in 13 surviving pts is 51.6 months. mPFS is 13.0 mo, mOS 18.7 mo. OS-2 yr- 42,0% OS-4yr- 24.2%, PFS-2-yr 32.0%, PFS-4-yr- 19.8%. Most common sites of recurrence were liver (24%), lung (12%) and peritoneum (10%). HCQ with preop SCRT and adjuvant gemcitabine-based chemotherapy is well tolerated but did not meaningfully impact median OS. Further pathologic/correlative studies to identify long-term survivors and extreme responders are ongoing.

55P Adjuvant gemcitabine-based chemotherapy for biliary tract cancer: Pooled analysis of the BCAT and PRODIGE-12 studies

55P Adjuvant gemcitabine-based chemotherapy for biliary tract cancer: Pooled analysis of the BCAT and PRODIGE-12 studies

Anthracycline-based and gemcitabine-based chemotherapy in the adjuvant setting for stage I uterine leiomyosarcoma: a retrospective analysis at two reference centers

BackgroundRadically resected early uterine leiomyosarcoma (eULMS) is still marked by a poor prognosis. Adjuvant strategies investigated up to now have not been corroborated by controlled studies. We retrospectively reviewed the clinical outcome of eULMS patients treated with adjuvant anthracycline-based or gemcitabine-based chemotherapy at two Italian reference centers.MethodsIn this explorative, retrospective, cohort analysis, we included all the consecutive patients with radically resected eULMS treated at two centers between 1997 and 2017.ResultsA total of 109 consecutive patients were included. Sixty-six (60%) received an anthracycline-based regimen, whereas 43 (40%) received a gemcitabine-based regimen. Median disease-free survival (DFS) was 41.3 months with anthracycline-based regimens compared to 20.9 months with gemcitabine-based regimens (HR: 0.49; 95% CI: 0.30–0.80; P = 0.004). In the multivariable model, anthracycline-based regimens were independently associated with a better DFS. No difference in terms of overall survival was observed.ConclusionsDFS was not the same by using an anthracycline-based or a gemcitabine-based adjuvant chemotherapy for patients with radically resected eULMS. The results of our study are in line with recent prospective controlled evidence in limb and superficial trunk soft tissue sarcomas. The role of anthracycline-based adjuvant chemotherapy should still be viewed as a research issue in eULMS.

FOLFIRINOX versus sequential 5-FU, oxaliplatin, and irinotecan-based regimens in patients with recurrent pancreatic cancer (rPDAC).

e16791 Background: There is a paucity of data to guide treatment for rPDAC after curative resection and gemcitabine-based adjuvant chemotherapy. Our aim was to investigate whether combination treatment upfront with all active agents is better than sequential administration of these drugs in patients with rPDAC following curative therapy. Methods: We retrospectively analyzed overall survival (OS), progression-free survival (PFS), response rate (RR), and adverse events (AEs) in patients treated for rPDAC. Patients received FOLFIRNOX upfront versus sequential therapy in the following order based on patient’s presence of toxicities (FOLFOX —&gt; FOLFIRI, FOLFOX—&gt; liposomal irinotecan/5FU, liposomal irinotecan/5FU —&gt; FOLFOX). Each treatment was administered per NCCN guidelines with regulated staging scans, blood work, and office visits. Data was collected about chemotherapy dose, ECOG performance status (PS), RR, PFS, OS, and AEs. Results: 55 patients were identified with ECOG PS ≤ 2 and male:female ratio 35:20. Results for FOLFIRINOX, FOLFOX followed by FOLFIRI, FOLFOX followed by liposomal irinotecan/5FU, and vice versa are as follows respectively: PFS 4.0, 3.5, 3.5, and 3.0 months; OS 8.0, 7.5, 7.0, and 8.3 months; RR 10%, (8%, 3%), (9%, 4%), and (3%, 5%). One of the patients in the mFOLFIRINOX was able to undergo metastasectomy. The table summarizes the toxicities and dose modifications seen. Conclusions: Upfront FOLFIRINOX versus sequential regimens of oxaliplatin and irinotecan-containing regimens resulted in similar PFS and OS but higher AEs as expected. However, surgery was only possible in patients receiving FOLFIRINOX. Our findings support the use of sequential treatment in rPDAC who are not potential surgical candidates. Further investigative work is warranted to optimize sequencing of active agents in this setting where prognosis has historically been poor. [Table: see text]

Resected Pancreatic Cancer With N2 Node Involvement Is Refractory to Gemcitabine-Based Adjuvant Chemotherapy.

Lymphatic metastasis is a major determinant of the outcome of resected pancreatic cancer. Gemcitabine-based adjuvant chemotherapy can improve the outcome of resected pancreatic cancer. However, the efficacy of gemcitabine against pancreatic cancer stratified by nodal involvement is unclear. In this study, patients who had undergone curative resection of pancreatic adenocarcinoma (612 cases) were included. The efficacy of adjuvant gemcitabine-based regimen, stratified by nodal status (negative, positive) or N substage (N0, no nodal involvement; N1, 1-3-node involvement; N2, ≥4-node involvement), was examined. Both the node-negative (hazard ratio [HR] = 0.62, 95% confidence interval [CI], 0.44-0.87, P = .006) and node-positive subgroups (HR = 0.45, 95% CI, 0.33-0.62, P < .001) benefited from gemcitabine-based adjuvant chemotherapy. Patients with N0 (ie, the node-negative subgroup) or N1 (HR = 0.36, 95% CI, 0.25-0.52, P < .001) disease benefited from gemcitabine-based chemotherapy. However, patients with N2 tumors (HR = 0.95, 95% CI, 0.50-1.78, P = .867) had poor response to gemcitabine-based treatment. Therefore, we postulate that resected pancreatic cancer with N2 node involvement is refractory to gemcitabine-based adjuvant chemotherapy. A more intensive adjuvant regimen may be required for N2 subgroup patients.

Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P=0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P =0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

IL17RB expression might predict prognosis and benefit from gemcitabine in patients with resectable pancreatic cancer

Background(Interleukin 17 Receptor Beta) IL17RB has been implicated in several malignancies. However, its role in the progression of and chemosensitivity in pancreatic cancer remains unknown. We aimed to determine the clinical significance of IL17RB expression in the prognosis of resectable pancreatic cancer and in the benefits from gemcitabine treatment. Materials and methodsWe used microarray and immunohistochemical staining techniques to evaluate IL17RB expression in 91 resectable pancreatic cancer tissues and their respective matched adjacent non-cancerous tissues. Quantitative real-time PCR and Western blotting were used to evaluate IL17RB in human pancreatic cancer cell lines after gemcitabine treatment. The correlation between IL17RB expression and overall survival and disease-free survival times were analyzed. ResultsIL17RB expression correlated with lymph node metastasis and (Vascular endothelial growth factor) VEGF expression. Cox proportional model showed that high IL17RB expression is a significant negative prognostic factor for both (overall survival) OS and (disease-free survival) DFS. Kaplan–Meier survival curves confirmed significantly reduced median overall and DFS time in high IL17RB patients as compared with low IL17RB patients. Furthermore, Cox proportional model confirmed a correlation between adjuvant treatment with gemcitabine-based chemotherapy and IL17RB expression. Kaplan–Meier survival curves showed that low IL17RB expression was associated with longer OS and DFS in patients than high IL17RB expression and gemcitabine-based adjuvant chemotherapy. In human pancreatic cancer cell lines, the messenger RNA and protein levels of IL17RB were significantly enhanced after gemcitabine treatment. ConclusionsIL17RB predicts the prognosis and benefit from gemcitabine in patients with resectable pancreatic cancer.

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer

BackgroundIn early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. Materials and methodsPatients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. ResultsOf 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. ConclusionctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Postoperative nonalcoholic fatty liver disease is correlated with malnutrition leading to an unpreferable clinical course for pancreatic cancer patients undergoing pancreaticoduodenectomy.

This study aimed to clarify the impact of postoperative nonalcoholic fatty liver disease (NAFLD) on the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC). One hundred and eight patients with pancreatic cancer undergoing pancreaticoduodenectomy (PD) with curative intent in between 2005 and 2016 were enrolled in this study. Post-PD NAFLD was assessed by computed tomography (CT), which was routinely performed at 3months, 6months, and 1year after surgery. The clinical impact of post-PD NAFLD was examined from an oncological perspective. There were 50 (46.2%) post-PD NAFLD patients. The NAFLD group showed significantly lower CT values at 3months, 6months, and 1year after surgery than those without NAFLD. Patients with NAFLD showed significant body weight loss and a decrease in serum albumin level after surgery compared with those without NAFLD. Consequently, the 70% completion rate of adjuvant chemotherapy with gemcitabine, but not S1, was significantly lower in the NAFLD group than in the non-NAFLD group. The 5-year overall survival and disease-free survival rates were comparable between the two groups. Post-PD NAFLD was associated with malnutrition in patients with PDAC, reducing their tolerance to gemcitabine-based adjuvant chemotherapy. Post-PD NAFLD needs to be emphasized and requires special nutritional intervention in patients with PDAC.

Membrane human equilibrative nucleoside transporter 1 is associated with a high proliferation rate and worse survival in resected intrahepatic cholangiocarcinoma patients not receiving adjuvant treatments

Human equilibrative nucleoside transporter 1 (hENT-1) is a membrane nucleoside transporter mediating the intracellular uptake of nucleosides and their analogues. hENT-1 was recently reported to have a predictive role in intrahepatic cholangiocarcinoma (iCC) patients receiving adjuvant gemcitabine-based chemotherapy, but its biological and clinical significance in iCC remains unsettled. This study investigated the role of hENT-1 in regulating tumour growth and predicting the survival of 40 resected iCC patients not receiving adjuvant treatments. hENT-1 expression was found to be significantly higher in iCC than in the matched non-tumoural liver. Patients harbouring hENT-1 localised on the tumour cell membrane had a worse overall survival than membrane hENT-1–negative patients (median 21.2 months vs 30.3 months, p = 0.031), with an adjusted hazard ratio of 2.8 (95% confidence interval 1.01–7.76). Moreover, membrane hENT-1–positive patients had a higher percentage of Ki67-positive cells in tumour tissue than membrane hENT-1-negative patients (median 23% vs 5%, p < 0.0001). Functional analyses in iCC cell lines revealed that hENT-1 silencing inhibited cell proliferation and induced apoptosis in HUH-28 cells expressing hENT-1 on the cell membrane, but not in SNU-1079 cells expressing the transporter only in the cytoplasm. Overall, these findings suggest that membrane hENT-1 is involved in iCC proliferation and associated with worse survival in resected iCC patients. Further prospective studies on larger cohorts are required to confirm these results and better define the potential prognostic role of membrane hENT-1 in this setting of patients.

Identifying Clinical Factors Which Predict for Early Failure Patterns Following Resection for Pancreatic Adenocarcinoma in Patients Who Received Adjuvant Chemotherapy Without Chemoradiation.

The role of radiation therapy (RT) in resected pancreatic cancer (PC) remains incompletely defined. We sought to determine clinical variables which predict for local-regional recurrence (LRR) to help select patients for adjuvant RT. We identified 73 patients with PC who underwent resection and adjuvant gemcitabine-based chemotherapy alone. We performed detailed radiologic analysis of first patterns of failure. LRR was defined as recurrence of PC within standard postoperative radiation volumes. Univariate analyses (UVA) were conducted using the Kaplan-Meier method and multivariate analyses (MVA) utilized the Cox proportional hazard ratio model. Factors significant on UVA were used for MVA. At median follow-up of 20 months, rates of local-regional recurrence only (LRRO) were 24.7%, LRR as a component of any failure 68.5%, metastatic recurrence (MR) as a component of any failure 65.8%, and overall disease recurrence (OR) 90.5%. On UVA, elevated postoperative CA 19-9 (>90 U/mL), pathologic lymph node positive (pLN+) disease, and higher tumor grade were associated with increased LRR, MR, and OR. On MVA, elevated postoperative CA 19-9 and pLN+ were associated with increased MR and OR. In addition, positive resection margin was associated with increased LRRO on both UVA and MVA. About 25% of patients with PC treated without adjuvant RT develop LRRO as initial failure. The only independent predictor of LRRO was positive margin, while elevated postoperative CA 19-9 and pLN+ were associated with predicting MR and overall survival. These data may help determine which patients benefit from intensification of local therapy with radiation.

Role of adjuvant therapy in resected stage IA subcentimeter (T1a/T1b) pancreatic cancer.

The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB). A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment. A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring <1 cm (T1a/T1b). Approximately 94.2% of patients had negative surgical margins (815 patients) and 46.9% (410 patients) received adjuvant therapy. The median OS was significantly different for patients who received adjuvant therapy compared with patients who did not (70.7 months vs 46.9 months; P = .0001). For patients with tumors measuring <1 cm, survival was not found to be significantly different between patients who received adjuvant treatment compared with those who did not (not reached vs 85.3 months; P = .54). In the multivariable analysis, none of the covariates (treatment group, Charlson-Deyo Score, age, insurance, and facility status) demonstrated significant differences for patients with tumors measuring <1 cm. The current study is the first to demonstrate no survival benefit for adjuvant therapy in patients with resected subcentimeter PDAC.