Unresectable Pancreatic Adenocarcinoma Research Articles

Gastrointestinal: A wandering pancreatic adenocarcinoma.

A 79-year-old woman was referred to our hospital complaining of upper abdominal pain. She had no history of diabetes mellitus or other malignant diseases. Blood analysis showed no atypical findings other than elevated levels of CEA and Dupan-2. Contrast-enhanced computed tomography (CT) showed a 50 × 40-mm mass with poor contrast and irregular margins in the head of the pancreas (Fig. 1). Invasion into the superior mesenteric artery and portal vein was also evident. Histopathological examination of a specimen from endoscopic ultrasound-guided fine needle aspiration revealed adenocarcinoma. We diagnosed the mass as locally advanced unresectable pancreatic adenocarcinoma, and decided to perform chemoradiotherapy in order to help control the cancer and slow down its growth. To design radiotherapy, we performed CT on inhalation and free-breathing. The pancreatic mass was on the right side of the spine on inhalation, but surprisingly appeared on the left side of the spine on free-breathing (Fig. 2). We administered radiation at 1.8 Gy/day with fixation of the mass using a body shell and also administered gemcitabine. On day 8 after therapy, the patient developed multiple cerebral infarctions associated with Trousseau syndrome. She subsequently received best supportive care. In general, pancreatic masses have been considered immovable, because the pancreas is fixed to the retroperitoneum with the duodenum. The anterior surface of the pancreas is covered by parietal peritoneum and the inferior border abuts the root of the transverse mesocolon. A loose connective tissue layer, known as the fusion fascia of Treitz in the region of the head of the pancreas and as the fusion fascia of Told in the region of the body and tail, is coherent with the posterior of the pancreas. Some reports have pointed out that the pancreas can change position in some patients, particularly women. However, few reports in the English literature have described a wandering pancreatic mass. A case of wandering neuroendocrine tumor of the head of the pancreas has been reported, involving an encapsulated mass. In that case, CT showed a shift of the large mass in the pancreas from the right to the left side of the aorta. However, wandering pancreatic adenocarcinoma has not previously been reported. Malrotated pancreas or pancreatic volvulus has been reported with wandering spleen as a very rare clinical entity, but the present case demonstrated no clinical complications, such as mobile spleen or other abdominal organs. In our case, acquired pancreatic mobilization due to tissue weakening was speculated as the cause of motility. Pancreatic carcinoma should also be considered among the differential diagnoses for mobile abdominal mass.

Prognostic value of disseminated tumor cells in unresectable pancreatic ductal adenocarcinoma: a prospective observational study

BackgroundAlthough pancreatic ductal adenocarcinoma (PDAC) rarely metastasizes to the skeleton, disseminated tumor cells have been detected in bone marrow samples from patients with this disease. The prognostic value of such findings is currently unclear. Thus, the current study aimed to clarify the prognostic information associated with disseminated tumor cell detection in samples from patients with PDAC.MethodsBone marrow aspirates were obtained from 48 patients with locally advanced (n = 11) or metastatic (n = 37) PDAC, before and after 2 months of chemotherapy. Disseminated tumor cells were detected with an mRNA panel and quantitative reverse transcription PCR. We used the highest levels measured in healthy bone marrow (n = 30) as a threshold to define the positive detection of disseminated tumor cells. Progression-free and overall survival were analyzed with Kaplan–Meier and Cox proportional hazards regression analyses.ResultsDisseminated tumor cells were detected in 15/48 (31%) bone marrow samples obtained before starting chemotherapy and in 8/25 (32%) samples obtained during chemotherapy. Patients with disseminated tumor cells detected before therapy had significantly shorter progression-free (p = 0.03; HR = 2.0) and overall survival (p = 0.03; HR = 2.0), compared to those without disseminated tumor cells in the bone marrow. When restricting disseminated tumor cell detection to keratins KRT7 and KRT8, the prognostic information was substantially stronger (p = 1 × 10–6; HR = 22, and p = 2 × 10–5; HR = 7.7, respectively). The multivariable Cox regression analysis demonstrated that disseminated tumor cell detection prior to treatment had independent prognostic value. In contrast, disseminated tumor cells detected during treatment did not have prognostic value.ConclusionsDisseminated tumor cells detected before commencing chemotherapy had prognostic value in patients with inoperable PDAC.

A clinical study following phase I/IIa trial of STNM01 to investigate the overall survival and tumor microenvironment in patients with unresectable pancreatic cancer.

4144 Background: Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. We reported last year the top-line clinical results of Phase I/IIa (PI/IIa) trial of STNM01, a synthetic RNA oligonucleotide to CHST15, as a second-line (2L) therapy in patients with progressive, unresectable pancreatic ductal adenocarcinoma (PDAC). Here we report the final PI/IIa results and follow-up clinical results investigating the changes of tumor microenvironmental parameters and the correlation with overall survival (OS). Methods: An additional clinical study was followed by PI/IIa trial (jRCT2031190055), which was a multicenter, open-label study of locoregional injections with STNM01 three times at 2 week-interval in 4 weeks as one cycle. A total of 3 cycles were repeated at maximum in combination with systemic 2L chemotherapy, oral fluoropyrimidine S-1 in the PI/IIa trial. The primary objective of this additional clinical study was OS. The secondary objectives were relations of tumor microenvironmental parameters evaluated by immunohistochemistry with OS. For comparison analyses, two-tailed unpaired t-test was performed. For correlation analyses, the Pearson coefficient analyses were performed. Results: A total of 22 patients were enrolled in the study. The average number of tumor-infiltrating CD3+ (13.8/mm2) and CD8+ T cells (8.0/mm2) at baseline in the evaluable population (n = 20) was at most one tenth or less, compared to historical data, indicating 2L population contained more T cell-immune suppressive patients. Baseline CD3+ and CD8+ T cells negatively correlated with tumoral CHST15 expression (p = 0.0051, p = 0.0478, respectively). As the final PI/IIa results, the median OS was 7.8 months with 6 and 12 months-survival rates of 68.2% and 31.8%, respectively. Disease control rate was 76.2% including 1 complete response. STNM01 led to a significant reduction in CHST15 at the end of cycle 1 compared to baseline (p = 0.0095, n = 19), and this was associated with increased CD3+ (p = 0.0331) and CD8+ T cells (p = 0.0146) and reduced CD33+ myeloid-derived suppressor cells (MDSCs) (p = 0.0281) in the tumor. Patient subpopulation who survived over 1 year (n = 5) showed a significant fold increase of CD3+ (p = 0.0033) and CD8+ T cells (p = 0.0147) and decrease of CD33+ MDSCs (p = 0.0403) at the end of cycle 1 compared to another subpopulation who survived less than 1 year (n = 13-14). Higher fold increase of CD3+ T cells (p = 0.0035, n = 19) or fold decrease of CD33+ MDSCs (p = 0.0212, n = 15) at the end of cycle 1 significantly correlated with longer OS. Conclusions: Locoregional injection of STNM01 was able to reactivate and augment tumor-infiltrating T cells while repress MDSCs. These changes in tumor immune cell profiles correlate with prolong prognosis in patients with first-line refractory, unresectable PDAC. Clinical trial information: jRCT2031190055.

High-intensity focused ultrasound (HIFU) therapy for pain palliation in advanced stage pancreatic carcinoma: A Meta-Analysis with recent studies

Background: Day by day, High-intensity focused ultrasound (HIFU) therapy is becoming more familiar in medical field because it is non-invasive technique with fewer side effects and provides promising therapeutic results. Several HIFU therapy applications have approved by many approval authorities of deferent countries since last decade. It is a novel, emerging, therapeutic modality that uses ultrasound waves, propagated through tissue media, as carriers of energy. HIFU has great potential for tumor ablation and the main mechanisms of HIFU ablation involve mechanical and thermal effects. Pancreatic adenocarcinoma is currently the fourth-leading cause of cancer-related death. Up to 60–90% of patients with advanced disease suffer cancer-related pain, severely impacting their quality of life. Current management involves primarily pharmacotherapy with opioid narcotics and celiac plexus neurolysis; unfortunately, both approaches offer transient relief and cause undesired side-effects. High intensity focused ultrasound (HIFU) is a non-invasive thermal ablation technique that has been used to treat pancreatic cancer. This meta-analysis aims to evaluate the role of HIFU in pain palliation of advanced unresectable pancreatic adenocarcinoma. Methods: Paper selection was performed electronically in PubMed up to the end of March 2021, for pain palliation treatment of advanced staged pancreatic cancer with HIFU. Relevant papers were identified through the PubMed search engine using these keywords: HIFU, pancreas, pancreatic cancer, pain and palliation. Additional studies were also done included after manual search of the selected bibliographies. Palliation results reported in studies were analyzed using a logit-transformed random-effects model using the inverse variance method, with the DerSimonian-Laird estimator for t2, and Cochran’s Q test for heterogeneity among studies. The I2 was also calculated to assess the percentage of the total variability in the different effect size estimates that can be attributed to heterogeneity among the true effects and rank correlation test of funnel plot asymmetry was done to assess possible publication bias. Results: In this meta-analysis, we includes only recent 10 year studies i.e. total number of 16 studies with 687total patients with pancreatic cancer. The total patients enrolled ranges from 7 patients in the smallest series, up to 120 in the largest study. The calculated τ2was 0.187, and I2was 41%, the Q test p-value was 0. 026, is indicating significant heterogeneity among studies. The random effects estimate of the proportion of patients with pain reduction was 0.89.08. Conclusions: We concluded that HIFU performs to be an effective tool for pain palliation in advanced staged pancreatic cancer. Prospective randomized and standardized studies are necessary to confirm the effectiveness of HIFU in relieving pain, and to evaluate for any potential impact on tumor control and patient survival.

Efficacy of primary drainage by endoscopic ultrasound-guided biliary drainage for unresectable pancreatic adenocarcinoma.

Background and AimObstructive jaundice induced by pancreatic adenocarcinoma is typically treated with biliary drainage with endoscopic retrograde cholangiopancreatography (ERCP)‐guided biliary drainage (ERCP‐BD). Recently, endoscopic ultrasonography‐guided biliary drainage (EUS‐BD) was employed as an alternative method after ERCP‐BD failed. We aimed to determine the efficacy and safety of EUS‐BD for primary biliary drainage.MethodsBetween December 2011 and February 2019, at Kawasaki General Medical Center, we retrospectively enrolled 33 patients who had undergone endoscopic biliary drainage with a metal stent, in a first attempt to relieve obstructive jaundice caused by unresectable pancreatic adenocarcinoma. We compared the technical and clinical outcomes between ERCP‐BD and EUS‐BD.ResultsTwenty‐three patients underwent ERCP‐BD and 10 underwent EUS‐BD. Both groups achieved 100% technical success. The clinical success rates were similar between the groups: 91% (21/23 patients) for ERCP‐BD and 100% (10/10 patients) for EUS‐BD (P = 0.48). Biliary obstruction recurred in 6/23 patients (26%) treated with ERCP‐BD and 1/10 patients (10%) treated with EUS‐BD (P = 0.40). Other adverse events occurred in 4/23 patients (17%) in the ERCP‐BD group and 1/10 patients (10%) in the EUS‐BD group (P = 0.99).ConclusionWe suggest that EUS‐BD could be employed for primary biliary drainage in patients with obstructive jaundice caused by unresectable pancreatic adenocarcinoma.

Class III β-Tubulin Expression Is of Value in Selecting nab -Paclitaxel and Gemcitabine as First-Line Therapy in Unresectable Pancreatic Cancer.

Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III β-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response. We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration. High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS. Class III β-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC.

High Measures of Pre-Chemoradiotherapy Platelet-to-Albumin Ratio Indicates Poor Prognosis in Locally Advanced Pancreatic Cancer Patients

PurposeIn a lack of similar research, we meant to retrospectively investigate the prognostic significance of pre-chemoradiotherapy (C-CRT) platelet-to-albumin ratio (PAR) on the survival results of locally advanced unresectable pancreatic adenocarcinoma (LAPC) patients.Patients and MethodsThe present analysis included 139 LAPC patients who received C-CRT in total. The utility of pre-C-CRT cutoff(s) reshaping survival data was explored using receiver operating characteristic (ROC) curve analysis. The primary and secondary objectives were the associations between PAR levels and overall survival (OS) and progression-free survival (PFS) outcomes.ResultsAt a median follow-up of 15.7 months (95% CI: 11.6–19.8), the overall cohort’s median and 5-year OS rates were 14.4 months (95% CI: 11.8–17) and 14.7%, respectively, while the corresponding PFS rates were 7.8 months (95% CI: 6.5–9.1) and 11.2%. Because the ROC curve analysis found 4.9 as the optimal PAR cutoff for both OS and PFS [area under the curve (AUC): 75.4%; sensitivity: 72.4%; specificity: 70.3%], we divided the patients into two PAR cohorts: PAR<4.9 (N=60) and PAR≥4.9 (N=79). Comparative analysis per PAR group exhibited significantly worse OS (11.2 vs 18.6 months, and 9.8% vs 20.9% at 5 years, P=0.003) and DFS (7 vs 14.3 months, and 7.6% vs 16.2% at 5 years, P=0.001) with PAR≥4.9 versus PAR<4.9, respectively. In multivariate analysis, the N0 nodal status, CA 19–9≤90 U/mL, and PAR<4.9 were found to be independent predictors of improved OS and PFS.ConclusionThe pre-C-CRT high PAR (≥4.9) robustly and independently prognosticated significantly worse OS and PFS results in inoperable LAPC patients who underwent definitive C-CRT.

Multiagent Chemotherapy and Stereotactic Body Radiation Therapy in Patients with Unresectable Pancreatic Adenocarcinoma: A Prospective Nonrandomized Controlled Trial

PurposeIn a prospective multicenter study, gemcitabine monotherapy followed by stereotactic body radiation therapy (SBRT) was well tolerated with outcomes comparable to chemoradiation for locally advanced pancreatic cancer (LAPC). Recent trials have reported improved survival with multiagent chemotherapy (MA-CTX) alone. This prospective trial explored whether SBRT could be safely delivered after MA-CTX. Herein, we report the long-term outcomes of adding SBRT after MA-CTX in LAPC patients and evaluate whether genetic profiles of specimens obtained before SBRT influence outcomes. Methods and MaterialsThis prospective nonrandomized controlled phase 2 trial enrolled 44 LAPC and 4 locally recurrent patients after multidisciplinary evaluation between 2012 and 2015 at a high-volume pancreatic cancer center. For induction CTX, most received modified FOLFIRINOX (mFFX), or gemcitabine and nab-paclitaxel (GnP) followed by 5-fraction SBRT for all. During fiducial placement, biopsies were obtained with DNA extracted for targeted sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform. ResultsMedian induction CTX duration was ≥4 months, and 31 patients received mFFX (65%). Among 44 LAPC patients, 17 (39%) were surgically explored, and 12 of 16 (75%) achieved a R0 resection. Median overall survival (mOS) was 20.2 and 14.6 months from diagnosis and SBRT, respectively. One- and 2-year OS from SBRT was 58% and 28%. The mOS after resection was 28.6 and 22.4 months from diagnosis and SBRT, respectively. Median local progression-free survival was 23.9 and 15.8 months from diagnosis and SBRT, respectively. The mOS for pre-SBRT CA 19-9 ≤180 U/mL versus >180 was 23.1 and 11.3 months, respectively (hazard ratio, 0.53; P = .04). Only 1 patient (2.1%) had late grade ≥2 gastrointestinal toxic effects attributable to SBRT. Despite significant pretreatment with chemotherapy, 88% of tumor specimens were effectively sequenced; survival outcomes were not significantly associated with specific mutational patterns. Quality of life was prospectively collected pre- and post-SBRT with the EORTC QLQ-C30 and PAN26 questionnaires showing no significant change. ConclusionsSBRT was safely administered with MA-CTX with minimal toxicity. A high proportion of LAPC patients underwent R0 resection with favorable survival outcomes.

Anlotinib plus nab-paclitaxel/gemcitabine as first-line treatment prolongs survival in patients with unresectable or metastatic pancreatic adenocarcinoma: a retrospective cohort.

BackgroundThe timely addition of anlotinib to the nab-paclitaxel/gemcitabine regimen may further increase the treatment efficacy for pancreatic adenocarcinoma (PDAC), which has not yet been reported. Therefore, we aimed to compare the efficacy and safety of anlotinib plus nab-paclitaxel/gemcitabine in the first-line treatment of patients with unresectable or metastatic PDAC.MethodsThis was a retrospective cohort of patients with unresectable or metastatic PDAC performed in The First Affiliated Hospital of Anhui Medical University from August 17, 2019 to April 3, 2021. Patients who received anlotinib plus nab-paclitaxel/gemcitabine treatment were defined as the anlotinib plus chemotherapy group and patients who received nab-paclitaxel/gemcitabine were defined as the chemotherapy group. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes were the objective response rate (ORR), the disease control rate (DCR), and toxic side effects. Clinical data and follow-up information were mainly obtained from hospital records or by telephone.ResultsA total of 33 patients were included in this study, with 17 cases in the anlotinib plus chemotherapy group and 16 cases in the chemotherapy group. The median PFS (mPFS) of the anlotinib plus chemotherapy group was 5 months while the mPFS of the chemotherapy group was 2.7 months (P=0.0220). The median OS (mOS) of the anlotinib plus chemotherapy group was 9 months while the mOS of the chemotherapy group was 6 months (P=0.0060). The 3-month and 6-month PFS, and the 6- and 12-month OS of the anlotinib plus chemotherapy group were significantly higher than those of the chemotherapy group (P<0.05). The proportion of patients with hematological toxicities in the anlotinib plus chemotherapy group was not significantly higher than that in the chemotherapy group.ConclusionsAnlotinib plus nab-paclitaxel/gemcitabine as a first-line treatment regimen is safe and may prolong survival compared with nab-paclitaxel/gemcitabine chemotherapy in patients with unresectable or metastatic PDAC. Randomized controlled trials with large sample sizes are warranted to further evaluate the treatment effects of anlotinib in PDAC.KeywordsPancreatic adenocarcinoma (PDAC); anlotinib; nab-paclitaxel/gemcitabine; progression-free survival (PFS); overall survival (OS)

Risk factors for interstitial lung disease induced by gemcitabine plus albumin-bound paclitaxel therapy in pancreatic ductal adenocarcinoma patients

BackgroundGemcitabine plus nab-paclitaxel (GnP) therapy is used for unresectable pancreatic ductal adenocarcinoma, but may cause interstitial lung disease (ILD) as a serious side effect. However, the risk factors for ILD in patients receiving GnP therapy are not well established. Here, we retrospectively investigated the incidence of GnP-induced ILD in pancreatic ductal adenocarcinoma patients, and the risk factors.MethodsWe investigated the patients’ background, laboratory data, previous treatment history, concomitant medications, number of doses of GnP, cumulative dosage and administration period, and occurrence of side effects.ResultsOf the 105 patients included in this study, ILD occurred in 10 (9.5%). Patients with ILD had a significantly higher frequency of concomitant treatment with Kampo medicines, especially goshajinkigan, which is considered to help prevent chemotherapy-induced peripheral neuropathy (CIPN) (odds ratio: 11.5, 95% confidence interval: 2.67–49.38). No significant differences were observed in other clinical characteristics. Notably, the severity of CIPN in patients who used goshajinkigan for prevention was not significantly different from that in patients who did not use goshajinkigan in this study.ConclusionsThese results suggest that administration of goshajinkigan to patients receiving GnP therapy for prevention of CIPN may need to be reconsidered.

Pathological outcomes of pancreatic adenocarcinoma (PA) after preoperative high biological effective dose (BED) magnetic resonance image-guided radiation therapy (MRgRT).

573 Background: Pre-operative radiotherapy (RT) for PA has the potential to reduce positive surgical margin rates and increase pathologic tumor response, which has been associated with improved survival. Increasing the BED can improve local control and overall survival for patients with unresectable PA. Use of stereotactic body radiation therapy (SBRT) to achieve a higher BED has been limited by toxicity to adjacent radiosensitive structures, but this can be mitigated by MRgRT. We describe our use of MRgRT prior to potentially curative resection of localized PA. Methods: We performed a single institution retrospective analysis of all patients with localized PA who received high BED SBRT on the MR Linac followed by surgical resection with curative intent. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events, version 5.0. Tumor response was evaluated according to the College of American Pathologists tumor regression grading criteria (CAP-TRG), ranging from CAP 0 indicating pathologic complete response to CAP grade 3 indicating no response. Ordinal logistic regression model was used to assess the association between time from RT to surgery and TRG. Follow up included MRI or CT scans at least every three months. Results: We analyzed 26 patients with borderline resectable (80.8%), locally advanced (11.5%), and resectable (7.7%) tumors who received high BED MRgRT followed by surgical resection. Median age at diagnosis was 68 years (34 - 86). Most patients received chemotherapy (80.8%) prior to RT, with 81% of these receiving FOLFINIRNOX and 19% receiving gemcitabine/nab-paclitaxel. All patients received MR-guided high BED SBRT to a median dose of 50 Gy (40 - 50) in 5 fractions. On-table adaptive replanning was performed in 88% of patients, with 74% having all 5 fractions adapted. No acute grade 2+ toxicity associated with RT was observed. The median time to resection was 50 days (37 – 115), and the procedure types included: Whipple (69%), distal (23%), or total pancreatectomy (8%). The R0 resection rate was 96% and no perioperative deaths occurred within 90 days. Complete (0) or near-complete (1) pathologic response was observed in 35% of cases and the time from RT to surgery was positively associated with TRG (R2= 0.22, p = 0.0003). The median follow-up after RT was 16.5 months (3.9- 26.2) during which 9 patients recurred, and 3 patients died of disease. The derived median progression-free survival from RT was 13.2 months. Conclusions: These initial pathology outcomes following high BED MR-guided SBRT are encouraging and suggest that the time from SBRT to surgical resection is associated with response. This finding is consistent with results from other preoperative GI tumor sites and results from prospective studies using high BED SBRT with MRI guidance in combined modality therapy against PA are eagerly awaited.

NeoOPTIMIZE: An open-label, phase II trial and biomarker discovery platform to assess the efficacy of adaptive switching of modified FOLFIRINOX (mFFX) or gemcitabine/nab-paclitaxel (GA) as a neoadjuvant strategy for patients with resectable/borderline resectable and locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).

TPS630 Background: Neoadjuvant chemotherapy (NAC) and/or chemo-RT may confer benefit to patients with localized PDAC, by better tolerability, tumor down-staging, and increased R0 resections. mFFX or GA are the current NAC backbones; however, a lack of robust predictive biomarker(s) hampers identification of patients most likely to benefit from mFFX or GA. Further, desmoplastic stroma/poor vascularity compromise NAC efficacy, but angiotensin II receptor inhibitor, losartan, might remodel vascular perfusion to enhance chemotherapy activity. We designed the NeoOPTIMIZE trial for patients with newly diagnosed localized PDAC to provide a flexible clinical platform to: 1) evaluate the feasibility and efficacy of early switching of mFFX to GA, and 2) establish a robust biomarker/imaging discovery platform to optimize the NAC backbone. Methods: NeoOPTIMIZE is an open-label, non-randomized, phase II trial to assess the efficacy of an adaptive treatment strategy that allows for early switching of NAC in patients with localized PDAC. Sixty patients (n = 40 resectable/BRCP; n = 20 locally advanced unresectable [uLAPC]) will be enrolled to receive 2 months of preoperative mFFX (oxaliplatin, 85 mg/m2; folinic acid, 400 mg/m2; irinotecan, 150 mg/m2; 5-FU, 2400 mg/m2), then restaging by a multidisciplinary tumor board (multiD-TB). Absent progression (by panc protocol CT and CA19-9 decline/increase &lt; 30% from baseline), patients continue mFFX (4 cycles). If progression (by panc protocol CT; CA19-9 increase &gt; 30%), patients switch to GA (nab-paclitaxel, 125 mg/m2; gemcitabine, 1000 mg/m2) for 2 months. After 4 months of mFFX or mFFX/GA, another restaging multiD-TB will decide to proceed with: a) RT (if vascular involvement) then resection, b) resection, or c) continued chemo (if unresectable). Losartan (50 mg PO QD) is given throughout NAC and RT regimens. The primary endpoint estimates the proportion of resectable/BRPC patients with R0 resection. Assuming that the proportion of R0 is 60%, a sample size of 32 will provide a 95% CI of 0.41 - 076. To account for a 20% dropout, 40 patients will be enrolled towards primary endpoint. A separate exploratory cohort of 20 uLAPC patients will be enrolled. Secondary endpoints include DFS, PFS, OS, and AEs. Exploratory objectives include correlating clinical outcomes data with changes in blood-based biomarkers (CA19-9, ctDNA, circulating tumor cells etc.) and research DCE-MRI. We are collecting tumors to correlate deep multi-omic analytics with clinical data. The study is open with 6 patients enrolled at time of submission. Clinical trial information: NCT04539808.

A phase 1/2 study to evaluate the safety, tolerability, and preliminary efficacy of GP-2250 in combination with gemcitabine for advanced or metastatic pancreatic adenocarcinoma.

TPS620 Background: GP-2250 is a metabolic enzyme inhibitor that selectively induces oxidative stress, mitochondrial dysfunction, and apoptosis in cancer cells by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and limiting aerobic glycolysis, an essential process for energy production in cancer cells. In vitro, increasing concentrations of GP-2250 induced proportional dose-response effects in 5 different pancreatic cancer cell lines (Buchholtz BMC Cancer 2017). Patient-derived pancreatic xenograft studies in mice demonstrated tumor growth inhibition with GP-2250 monotherapy (Braumann J Clin Oncol 2020). In combination with gemcitabine, a synergistic effect was shown with greater inhibition of pancreatic tumor growth than with either gemcitabine or GP-2250 alone. These findings support the assessment of the therapeutic potential of GP-2250 in combination with gemcitabine in patients with pancreatic cancer. Methods: This open-label phase 1/2 trial will evaluate the safety and tolerability of escalating doses of GP-2250 and the preliminary efficacy of GP-2250 in combination with gemcitabine in patients with advanced unresectable or metastatic pancreatic adenocarcinoma who have progressed on prior treatment with FOLFIRINOX chemotherapy. In phase 1, Bayesian Optimal Interval design will be used for GP-2250 dose escalation. The dose-limiting toxicity (DLT)–assessment period will be 5 weeks at each dose level (starting dose 250 mg once weekly intravenously), consisting of a 1-week run-in period with GP-2250 monotherapy, followed by a full cycle of GP-2250 plus standard dose and schedule of gemcitabine. Single patient cohorts (100% dose escalation between cohorts) will be enrolled until the occurrence of the first DLT (or cohort 4 if no DLTs occur in cohorts 1−3), after which, cohorts will be expanded to 3 patients with 35%−45% dose escalations between cohorts. Patients will receive treatment until disease progression or development of unacceptable toxicity. Primary study endpoints include safety and tolerability of GP-2250, tumor response (RECIST 1.1), disease control rate (complete response, partial response, stable disease), and duration of response. Pharmacokinetics, incidence and severity of laboratory abnormalities and treatment-emergent adverse events, progression-free survival, and overall survival will also be assessed. As of September 2021, 19 patients have been enrolled. Following completion of the phase 1/2 trial, a phase 3 first-line maintenance study will be initiated. This study is funded by Geistlich Pharma AG. Clinical trial information: NCT03854110. Clinical trial information: NCT03854110.

Sarcopenia: Prognostic Value for Unresectable Pancreatic Ductal Adenocarcinoma Patients Treated With Gemcitabine Plus Nab-Paclitaxel.

The aim of the study was to clarify the association of skeletal muscle mass and the prognosis of unresectable pancreatic ductal adenocarcinoma (PDAC) treated with gemcitabine plus nab-paclitaxel (GnP). We included 124 unresectable PDAC patients who received GnP chemotherapy. Skeletal muscle mass of the third lumbar vertebrae (L3) level was measured by computed tomography immediately before GnP initiation, and the skeletal muscle index (L3-SMI) was calculated. Sarcopenia was defined as L3-SMI less than 42 cm2/m2 in male patients and less than 38 cm2/m2 in female patients. Sarcopenia was found in 63 patients (50.8%). There was no significant difference in overall survival (OS) between sarcopenia and nonsarcopenia patients; however, in elderly patients (>70 years), the OS of sarcopenia patients was significantly poorer than that of nonsarcopenia patients (390 vs 631 days, respectively; hazard ratio, 2.64; 95% confidence interval, 1.33-5.23). Multivariate analyses in elderly patients revealed that sarcopenia and tumor stage were independent poor prognostic factors. Despite the short OS of elderly sarcopenia patients, there were no significant differences in progression-free survival or response rate. Sarcopenia diagnosed by L3-SMI is a prognostic factor in elderly patients who receive GnP for unresectable PDAC. However, GnP exhibits a certain efficacy in sarcopenia and nonsarcopenia patients.

A phase I study to evaluate the safety and tolerability of SX-682 in combination with PD-1 inhibitor as maintenance therapy for unresectable pancreatic adenocarcinoma.

TPS631 Background: Survival outcomes for advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal despite improvements in systemic therapy regimens developed over the past decade. In addition, current first-line therapies result in cumulative cytopenias and neuropathy, highlighting the need for more effective, less toxic maintenance treatment strategies. There are currently no standard approved maintenance treatments for patients with PDAC not associated with BRCA or DNA-repair mutations. Pre-clinical data suggest a potential synergistic effect of combining blockade of CXC chemokine receptors (CXCR) with immunotherapy or chemotherapy in pancreatic cancer1,2. We are currently conducting a Phase I study (NCT04477343) evaluating SX-682, an oral CXCR1/2 inhibitor, and Nivolumab as maintenance treatment for advanced PDAC. Methods: This is an open-label, dose escalation Phase I clinical trial evaluating the combination of SX-682 and Nivolumab. Patients must have histologically confirmed unresectable PDAC and have completed at least 16 weeks of first-line chemotherapy with disease stability or treatment response at time of enrollment. Radiographically measurable disease must be present per iRECIST criteria. Patients receive a 3-week run-in phase of twice-daily dosing of SX-682, followed by combination of twice-daily dosed SX-682 and every 2-week Nivolumab (240 mg IV). Dose finding of SX-682 is performed using Bayesian optimal interval (BOIN) design to determine the maximum tolerated dose (MTD) when combined with Nivolumab. Pre-treatment and one on treatment (Day 28-35) biopsies are required for enrollment to evaluate change in tumor microenvironment immune cell composition by single cell-RNA sequencing, flow cytometry, RNA RT-qPCR, and IHC. The primary endpoint is to determine MTD; the key secondary endpoint is progression-free survival (PFS), defined as the time from enrollment to progression via iRECIST criteria or death. Nine of a planned 20 patients have been enrolled. Dose-level 1 (SX-682 50 mg BID) completed enrollment without dose-limiting toxicity (DLT). Dose-level 2, which commenced in June 2021, (SX-682 100 mg BID) is without DLTs, but has not completed enrollment at time of abstract submission. Nywening TM, Belt BA, Cullinan DR, et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. 1) Gut. 2018;67(6):1112-1123. Steele CW, Karim SA, Leach JDG, et al. CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. 2) Cancer Cell. 2016;29(6):832-845. Clinical trial information: NCT04477343.

A non-surgical COMBO-therapy approach for locally advanced unresectable pancreatic adenocarcinoma: preliminary results of a prospective study.

In this short report we present a series of thirteen patients with locally advanced, unresectable, pancreatic cancer treated with a COMBO-Therapy consisting of: STEP-1: induction chemotherapy; STEP-2: concomitant chemoradiotherapy; STEP-3: stereotactic body radiotherapy boost. After four weeks from the end of each step all patients had a re-staging and a surgical re-evaluation. All patients completed STEP-1 and STEP-2. STEP-3 has been successfully delivered to 8/13 patients with a median dose of 12Gy (range 10-21Gy) in 1-3 fractions. The median LC was 20months (range 10-32) with a 2-year LC of 72.9%, and none of the patients developed G3 acute or late toxicities. The median OS was 21.5months (range 12-34), and the 2-year OS was 53.9%; the median PFS was 17.5months (range 10-27). Our non-surgical COMBO-Therapy has demonstrated a feasible profile with good tolerance. Further prospective protocols are needed to confirm our preliminary results.

Clinical significance of circulating tumor cells after chemotherapy in unresectable pancreatic ductal adenocarcinoma

Circulating tumor cells (CTCs) have emerged as liquid biopsy biomarker providing non-invasive assessment of cancer progression and biology. We investigated whether longitudinal analysis of CTCs could monitor disease progression, response to chemotherapy, and survival in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). A total of 52 patients with PDAC were prospectively enrolled in this study. Peripheral blood samples were serially collected at the time of diagnosis and after chemotherapy with clinical assessments. CTCs were isolated through a centrifugal microfluidic disc, enumerated with immunostaining against Epithelial cell adhesion molecule (EpCAM), Cytokeratin (CK), Plectin-1 and CD45, and identified by an automated imaging system. One or more CTCs were detected in 84.62% patients with unresectable PDAC at the time of diagnosis. CTC numbers were not statistically different across tumor sizes, location and metastatic sites. The absolute number of CTCs after chemotherapy was inversely related to overall survival (OS), and the decreased number of CTCs after chemotherapy was significantly associated with longer OS in patients with PDAC. Identifying CTCs and monitoring CTC changes after chemotherapy could be a useful prognostic marker for survival in patients with unresectable PDACs.

Tardive peritonitis after the endoscopic ultrasound‐guided hepaticogastorostomy: A case report

Endoscopic ultrasound‐guided biliary drainage (EUS‐BD) has become popular as a new drainage technique for malignant biliary strictures. Although EUS‐BD has been reported to show high technical and clinical success rates, the rate of adverse events is 15%. In particular, peritonitis, which is generally caused by bile leakage from the aspiration side during the procedure and occurs within a few days after EUS‐BD, needs to be considered as it can be fatal. In the present case, a jaundiced patient presented with unresectable pancreatic adenocarcinoma. Due to duodenal invasion, we performed EUS‐guided hepaticogastrostomy for biliary drainage. After the procedure, jaundice improved, and abdominal computed tomography (CT) showed only a small amount of air in the intrahepatic bile duct. However, 7 days after the procedure, the patient developed fever, and clinical findings indicated peritonitis. Abdominal CT showed food in the stomach accompanied by the appearance of perihepatic free air, with increased air in the intrahepatic bile duct. The duodenal stent insertion settled the peritonitis and improved the perihepatic free air and the air in the intrahepatic bile duct through the discharge of food from the stomach. To date, no case of tardive peritonitis associated with air leakage after EUS‐BD has been reported. We noted that even if there was no evidence of bile leakage after EUS‐BD, the possibility of tardive peritonitis due to gradual air leakage from the stent implantation side of the stomach should be considered, and careful follow‐up is needed.

Treatment and outcomes of unresectable and metastatic pancreatic cancer treated in public and private Australian hospitals.

Prior studies have reported for several cancer types that treatment in the private sector is associated with improved survival outcomes. Data for patients with locally advanced unresectable and metastatic pancreatic ductal adenocarcinoma (PDAC) have not previously been reported. Analysis of patients from January 2016 to June 2020 registered to a multicentre prospective cancer database. Baseline demographic and clinicopathologic characteristics were compared. The Kaplan-Meier method was used to compare overall survival (OS). Multivariate Cox and logistic regression analyses were used to determine predictors of mortality and first-line chemotherapy treatment, respectively. Of 822 patients, 22.5% received private care. Private patients were older (median 71.5 vs. 68.9 years, p≤.05), had better performance status (ECOG 0 to 1: 82.2vs. 73.5%, p=.05) and more likely to reside in an area with high socioeconomic advantage (67.0vs. 19.6%, p≤.01). Private patients were more likely to receive first-line chemotherapy (69.7vs. 54.2%, p≤.01) with logistic regression demonstrating private care (OR: 1.87, 95% CI: 1.20 to 2.97) as an independent predictor of receiving chemotherapy. Private patients had prolonged survival (median OS: 9.2vs. 6.9 months, HR 1.2, p=.05). Receiving first-line chemotherapy was an independent predictor of mortality, but private care was not. Care in the private system is associated with improved OS, with higher uptake of first-line chemotherapy appearing to be the main contributor. Given the discrepancy, further studies are needed to determine what factors are driving this difference.

Induction FOLFIRINOX for patients with locally unresectable pancreatic ductal adenocarcinoma.

Patients with locally advanced pancreatic adenocarcinoma (PDAC) receive induction chemotherapy with or without radiation, with the goal of R0 resection and improving survival. Herein, we evaluate the outcomes of patients who presented with Stage III PDAC and received induction FOLFIRINOX. An institutional database was queried for consecutive patients who received induction FOLFIRINOX for locally unresectable PDAC between 2010 and 2016. Clinical and radiographic parameters were assessed pre- and posttreatment, and clinical outcomes were evaluated. There were 200 patients who met the inclusion criteria. The median number of cycles of FOLFIRINOX was 8, 70% (n = 140) received radiation, and 18% (n = 36) underwent resection. Median overall survival(OS) in resected patients was 36 months (95% confidence interval [CI]: 24-56), and this group had improved OS compared to patients that did not undergo resection (hazard ratio (95% CI): 0.41 (0.26-0.64), p < 0.001). Patients (n = 112) who did not progress on induction therapy but remained unresectable had a median OS of 23.9 months (95% CI: 21.1-25.4). Nearly 20% of patients with locally advanced PDAC responded sufficiently to induction FOLFIRINOX to undergo resection, which was associated with improved OS compared to patients that did not undergo resection. Patients with stable disease who remain unresectable represent a group of patients with locally advanced PDAC who may benefit from optimization of additional nonoperative treatment.