bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors of multidisciplinary treatment for borderline resectable and locally advanced pancreatic adenocarcinoma: Results of a dual-center study.
Authors: Kimura Nana , Igarashi Takamichi , Yamada Suguru , Murotani Kenta , Yoshioka Isaku , Takami Hideki , Shibuya Kazuto , Hayashi Masamichi , Tanaka Haruyoshi , Hirano Katsuhisa , Watanabe Toru , Tanaka Nobutake , Baba Hayato , Tohmatsu Yuuko , Sakai Ayano , Fukasawa Mina , Matsui Koshi , Okumura Tomoyuki , Kodera Yasuhiro , Fujii Tsutomu
Published: January 2023

680

Background: Multidisciplinary treatment of borderline resectable (BR)/unresectable locally advanced (UR-LA) pancreatic adenocarcinoma (PDAC) has not yet been established. The purpose of this study is to explore factors that improve prognosis in radical surgery after multidisciplinary treatment for pancreatic cancer. Methods: We evaluated the following prognostic factors in 240 PDAC patients who underwent radical resection after multidisciplinary treatment. Patients were classified into 3 groups according to NCCN guidelines (BR PDAC invading the portal vein (BR-PV), BR pancreatic cancer in contact with the major arteries such as the hepatic artery, celiac axis and superior mesenteric artery (BR-A), and UR-LA), and prognostic factors were investigated. Patients with BR PDAC were treated with chemotherapy followed by surgery, while radiation therapy was added preoperatively in most cases with arterial invasion. All patients with UR-LA underwent surgery after nab-paclitaxel plus gemcitabine (GnP) followed by chemoradiotherapy (CRT) with S-1. Results: BR-PV/BR-A/UR-LA patients were 88/111/41, respectively. Prognosis was significantly better in the NAT group than in the upfront surgery group for both BR-PV/A (P=0.004/<0.001). In univariate analysis of overall survival (OS) in 36 patients with BR-PV who underwent resection after NAT, the following factors were significantly favorable prognostic factors; tumor marker (TM) normalization (P=0.028), preoperative Glasgow prognostic score=0 (P=0.025), and preoperative prognostic nutritional index (PNI)>42.5 (P=0.022). In univariate analysis in 39 patients with BR-A, the following factors were significantly favorable prognostic factors; TM normalization (P=0.033), preoperative PNI>42.5 (P=0.013), intraoperative blood loss>830 ml (P=0.013). Multivariate analysis revealed that high preoperative PNI was an independent prognostic factor (hazard ratio 0.15 [0.02-0.85]; P=0.014) in BR-A patients. In patients with UR-LA who underwent radical resection after GnP and subsequent CRT, median duration of NAT was 8.8 months, and R0 resection was achieved in 36 patients (88%). 3-year OS was 77.4%, and 5-year OS 58.6%. Multivariate analysis revealed that CA19-9 normalization (hazard ratio 0.23 [0.02-0.88]; P=0.032) and PNI≥41.7 (HR 0.05 [0.01-0.62]; P=0.021) were independent prognostic factors. Conclusions: In both BR/UR-LA pancreatic cancer, normalization of TM and maintenance of good nutritional status during NAT until surgery may contribute to prolonged prognosis.
Perioperative or adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer: Quality of life results of the randomized phase II AIO-NEONAX trial.
Authors: Buchholz Sina , Ettrich Thomas Jens , Uhl Waldemar , Kornmann Marko , Algül Hana , Friess Helmut , Koenig Alexander , Gallmeier Eike , Lutz Manfred P. , Wille Kai , Schimanski Carl Christoph , Kunzmann Volker , Geissler Michael , Waldschmidt Dirk , Daum Severin , Perkhofer Lukas , Reinacher-Schick Anke C. , Seufferlein Thomas
Published: January 2023

694

Background: Perioperative chemotherapy (CTX) in resectable pancreatic adenocarcinoma (rPDAC) is still not considered SoC and data regarding efficacy but also quality of life (QoL) are limited. NEONAX is a prospective, randomized phase II trial in patients with rPDAC with two independent experimental arms examining perioperative (2 pre- and 4 postoperative cycles, arm A) or adjuvant (6 cycles, arm B) of Gem (1000mg/m2) and nab-P (125mg/m2) on days 1,8,15 of a 28-day cycle. The primary endpoint DFS at 18 mo. as well as DFS, OS and safety have already been reported. Here we present the QoL data of the NEONAX trial. Methods: QoL was evaluated by EORTC QLQ-C30, EORTC QLQ-PAN26 and HADS-D questionnaires at baseline, at the beginning of each CTX cycle (neoadj. and adj. in arm A, only adj. in arm B), after neoadj. treatment in arm A as well as prior and post resection and after 6 cycles of CTX. Results: Global health status score (GHS-score) (QLQ-C30) showed no difference between baseline (t1) and the timepoint after 6 cycles of CTX (t2) in the perioperative arm A (66.7/100 at both timepoints). Here patients experienced the lowest GHS-score pre- and postoperatively (50/100 in both cases). Adjuvant arm B showed a deterioration in the GHS-score of 12.5 points from timepoint 1 to 2 (62.5/100 to 50.0/100). Here the lowest GHS-score was observed within 4 weeks post-surgery (41.7/100). Physical function score (QLQ-C30) was decreased by 6.7 points (86.7/100 to 80/100) in perioperative arm A and by 26.7 points (86.7/100 to 60/100) in arm B between both timepoints. Role function (QLQ-C30) was reduced by 16.7 points (83.3/100 to 66.7/100) in arm A and by 33.3 points (83.3/100 to 50/100) in arm B between both timepoints. In the remaining subscales of the used questionnaires the two arms of the trial showed comparable median scores over the whole study period. The number of submitted questionnaires at each timepoint varied but was at large comparable in both arms. Conclusions: QoL was largely preserved in the perioperative as well as the adjuvant arm of the NEONAX trial. GHS-score was lower pre-and postoperatively in arm A. The lowest GHS-score was observed postoperatively in the adjuvant arm B. QoL was restored at the end of the treatment period in the perioperative arm A and remained slightly reduced in arm B suggesting that QoL is not substantially impaired by perioperative treatment in rPDAC. Clinical trial information: NCT02047513 . [Table: see text]
Effect of pancreatic enzyme replacement therapy (PERT) on body weight in advanced pancreatic cancer (APC).
Authors: Picozzi Vincent J. , Najjar Anas , Harb Diala E , Kort Jens J , Mandelson Meg T.
Published: January 2023

698

Background: Malnutrition/cachexia is common in PC and is associated with multiple adverse patient (pt) outcomes. Current NCCN guidelines recommend PERT in PC pts with exocrine pancreatic insufficiency (EPI). However, little evidence exists regarding the impact of PERT on clinical outcomes in PC, especially APC. Data on impact of PERT use on change in body weight is presented here. Methods: Pts in this retrospective cohort study were identified from the Virginia Mason PC database. Eligibility requirements included: 1) no upfront resection 2) no prior PC therapy 3) pancreatic stool elastase 1< 200 µg/g stool or documented clinical evidence of EPI at diagnosis 4) treatment at least to initial restaging event (8 weeks) 5) available data regarding PERT use/dosage. Weight/BMI was assessed at baseline and after 8 weeks on therapy. Two pt groups were compared; a) pts prescribed PERT for EPI at recommended package insert dose (≥ 500KU-2500/kg/meal for ≥ 3 meals/day) for ≥ 50% treatment period and b) pts who received no PERT. Pts on PERT at lower than recommended dose and /or < 50% interval between 1st treatment and reassessment were excluded from analysis. Statistical significance was determined using the T-test for continuous variables, chi-squared for categorical variables. Results: 505 total pts were study eligible; 197 (39%) pts received PERT, 308 (61%) pts did not. Pt characteristics are shown. Despite a more adverse patient population with respect to weight loss, pts receiving PERT after 8 weeks experienced less change in weight (-0.36 kg vs -1.54 kg, P = 0.025) and change in BMI ( -0.64% vs -1.96., p= 0.026). Pts with cachexia experienced a similar outcome (-0.36% vs. -2.02 %, p= 0.026). No other pt characteristics achieved statistical significance. Conclusions: Despite a more adverse population with respect to weight loss at baseline, PERT usage prescribed per package insert guidance reduced wt loss/ change in BMI loss in APC over the 1st 8 weeks of therapy. This was also true in APC pts with cachexia. Further analysis of the impact of PERT therapy in APC with respect to treatment tolerability, and toxicity, quality of life and overall survival is warranted. [Table: see text]
Long-term results from NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC).
Authors: George Thomas J. , Yothers Greg , Rahma Osama E. , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Lucas Peter C. , Colangelo Linda H. , Gollub Marc J , Hall William A. , Kachnic Lisa A. , Bajaj Madhuri , Gross Howard M. , Peterson Richard A. , Dorth Jennifer Anne , Vijayvergia Namrata , Wolmark Norman
Published: January 2023

7

Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EAs) in LARC. EAs are not intended for direct comparison, but rather to concurrently randomized control arm (CA) patients. Primary endpoint (EP) and available secondary EPs (from EA1 using veliparib [V], PARPi; and EA2 using pembrolizumab [P], anti-PD-1) have been previously reported. We present long-term outcomes of all pts enrolled (NCT02921256). Methods: Stage II/III pts with MSS LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to CA (neoadjuvant FOLFOX [x 4mo] → chemoRT [capecitabine with 50.4Gy] → surgery 8-12 wks later). EA1 added V (400mg PO BID) and EA2 added P (200mg IV Q3 wks x 6 doses) each concurrent with chemoRT. Primary EP: 4-point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α=0.10, 80% power. NAR compared by linear model controlling for clinical T4 at entry (Y/N). Secondary EPs: OS, DFS. p-values are two-sided. Results: From 10/2016-2/2018, 178 pts were randomized (88 CA, 90 EA1). From 8/2018-5/2019, 185 pts were randomized (95 CA, 90 EA2). Baseline characteristics were previously reported. Median follow-up is 3.50 yrs for the 1st comparison. Median follow-up is 3.15 yrs for the 2nd comparison. Updated primary and long-term secondary outcomes are in the table. Conclusions: With longer follow-up, addition of V to TNT provided no significant differences in the NAR score or 3yr outcomes. The addition of P to TNT was associated with a statistically significant improvement in 3yr OS, but not DFS. Correlative molecular analyses are ongoing. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie; Merck. Clinical trial information: NCT02921256 . [Table: see text]
Does neoadjuvant treatment in resectable pancreatic cancer improve disease outcomes? Systematic review and metanalysis of randomized controlled trials.
Authors: Dias e Silva Douglas , Castro Nicoly Marques , Victor Elivane da Silva , Rother Edna Terezinha , Araújo Sergio Eduardo Alonso , Moura Fernando , Uson Junior Pedro Luiz Serrano
Published: January 2023

704

Background: Neoadjuvant chemotherapy improves survival in borderline resectable pancreatic cancer (RPC). Whether these results are the same in upfront RPC is unknown. Methods: To evaluate the association of neoadjuvant treatment and outcomes in RPC a systematic review was performed including randomized trials of neoadjuvant treatment versus upfront surgery. Articles indexed in PubMed, Embase and Web of Science were evaluated. Data regarding treatment regimens, R0 rates, disease free survival (DFS) and overall survival (OS) were extracted. The outcomes were compared using a random effects model. The index I2 and the graphs of funnel plot were used for the interpretation of the data. Results: Of 3,229 abstracts, 6 randomized controlled trials were considered eligible with a combined sample size of 805 patients. Among the trials, the PACT-15, JSAP-05, and updated long-term results from PREOPANC and NEONAX trials were included. In the meta-analysis, we could see that neoadjuvant treatment in RPC does not improve DFS or OS; HR 0.72 [0.46-1.09] and HR 0.76 [0.52-1.11], respectively. Interestingly, R0 rates were improved about 20% with the neoadjuvant approach (HR 1.2 [1.04-1.37]). It is important to note that most studies evaluated gemcitabine-based regimens in the neoadjuvant setting. Conclusions: This metanalysis of six randomized controlled trials suggests that neoadjuvant chemotherapy with gemcitabine-based regimens does not improve PFS or OS in RPC compared to upfront surgery followed by adjuvant treatment. Neoadjuvant treatment improves R0 rates in about 20%. Randomized ongoing trials are eagerly waited with more active combined regimens including modified FOLFIRINOX.[Table: see text]
Exploring optimal therapeutic management of STAGE IA PDAC in the era of neoadjuvant chemotherapy.
Authors: Macchini Marina , Belfiori Giulio , Crippa Stefano , Orsi Giulia , Gasparini Giulia , Tamburrino Domenico , Schiavolena Marco , Capurso Gabriele , Falconi Massimo , Reni Michele
Published: January 2023

712

Background: Neoadjuvant chemotherapy (NAT) is currently recommended for non-metastatic pancreatic ductal adenocarcinoma (PDAC). Data on the optimal NAT duration and the proper post-surgical chemotherapy (PSC) are lacking, especially for patients (pts) who yielded a pathological stage IA. Methods: We retrospectively analyzed the outcome of PDAC pts resected between 2015 and 2020 at our institution after NAT yielding a pathologic stage of PDAC ypT1N0. Pts were analyzed basing on NAT duration (aim 1) and PSC indication (yes/no) and type (aim 2). The primary endpoint was median event-free survival (EFS) for aim 1 and median disease free-survival (DFS) for aim 2. As per secondary endpoints, overall survival (OS) and the prognostic role of clinical and pathological variables was assessed (baseline CA19.9 level; pre-operative Ca19.9 level, basal vascular involvement, grading, perineural invasion, R1 resection). Results: During the study period a total of 756 pts were resected, 363 (48%) after NAT. Of them, 72 pts (20%) achieved a pathological ypT1N0 (ypIA). Among this group 16 pts (22%) showed a T1a-T1b, 62 pts (86%) had a G1/G2 tumor, 60 pts (83%) had a R0, 36 pts (50%) had a perineural invasion and 33 (46%) had a tumor regression grade marked or completed. For aim 1 we compared 34 pts (47%) treated with NAT for not more than 4 months (Group A1) and 38 pts (53%) treated for at least 4 months (Group B1). Baseline, biochemical and radiological variables were similar between the 2 groups. No statistical difference was found in EFS (Group A1: median 46 months/ Group B1: median not reached). For aim 2 we compared 10 pts (14%) who received the same chemotherapy regimen in NAT and PSC (Group A2), 35 pts (49%) who received a different chemotherapy regimen in NAT and PSC (Group B2) and 27 (14%) pts who did not receive any PSC (Group C2). PSC were gemcitabine/nab-paclitaxel (10%) and mFOLFIRINOX (90%) in group A2, whereas gemcitabine/nab-paclitaxel (17%), mFOLFIRINOX (3%), gemcitabine (51.5%), capecitabine (17%), gemcitabine/capecitabine (8.5%), PEXG (3%) in group B2. DFS were 24 months for group B2, whereas median was not reached for group A2 e C2 (p=0.006). No statistical difference was found in OS among the groups. At multivariate analysis only grading (G3) emerged as independent factor for poor prognosis. Conclusions: In ypIA pts NAT duration and or type seem to be unrelated to the outcome. PSC performed with alternative and depotentiated chemotherapy as compared to NAT, seem to be related to a higher rate of disease recurrence. Poor differentiated/G3 tumors is confirmed as independent risk factor for poor survival in this population.
Overall survival in patients with metastatic or locally advanced pancreatic cancer following chemoradiation with novel combination of aldoxorubicin, N-803 IL-15 superagonist, and PDL1- NK cell therapy.
Authors: Seery Tara Elisabeth , Nangia Chaitali Singh , Reid Phillip D. , Fang Bruno , McKean Heidi Ann , Sender Leonard S. , Reddy Sandeep K. , Soon-Shiong Patrick
Published: January 2023

720

Background: Pancreatic cancer claimed an estimated 47,050 lives in the USA in 2020, with an expected median overall survival (OS) of 3 months in 3rd line. (Manax ASCO GI 2019), with no evidence of disease control in these late stage patients. We hypothesize that effective response against pancreatic cancer requires orchestration of both the innate and adaptive immune system to accomplish immunogenic cell death with survival benefit. Herein we report updated results of the fully enrolled cohort of a novel combination immunotherapy protocol of low-dose chemoradiation, cytokine-induced NK and T cell activation via N-803 (an IL-15 cytokine superagonist ), and allogeneic off-the-shelf PDL1-targeted high-affinity NK cell (PDL1 t-haNK) infusion. Methods: We report data from a multi-center study, on 83 3rd line or greater, subjects treated with low dose, chemo radiation Nab-paclitaxel (100 mg/ m2 IV), Gemcitabine (600 mg/m2 IV); Cyclophosphamide (50 mg PO BID) and low dose SBRT. This induction immuno-modulation therapy to induce DAMPs was followed with investigational agents activating the innate and adaptive systems: Aldoxorubicin (150 mg/m2 IV), N-803, an IL-15 superagonist (15 μg/kg SC) and PD-L1 t-haNK (~2 × 109cells/dose IV). Prophylactic G-CSF or EPO was not allowed. All treatments were administered on an outpatient basis. Results: As of submission, median follow-up is 4.9 months. Median age 62, M:F ratio 46:36. ECOG 0-1,97%. 74/83 (89%) reported at least 1 investigational product related AE (TRAE) with 63/83 (76%) reporting at least 1 TRA grade 3 or higher. The most common were anemia 41%, neutropenia 20%, thrombocytopenia 10%, all others <10%. SAEs attributed to investigational agents were reported in 8/83 (10%) patients. Treatment is ongoing for 6 subjects (7%), with 17.1 months as the longest duration on therapy to date. Median OS is 5.7 months (95% CI: 4.9, 6.4) with 26/83 alive to date. Median PFS is 2.3 months (95% CI: 2.0, 3.6) and 37% of subjects achieving stable disease >=8 weeks. Median OS in 3rd line (N=38) is 6.3 months, Median OS in 4th line or greater (N=40) is 5.0 months. Conclusions: Historical 3 month median OS in 3rd line metastatic pancreatic cancer patients has been exceeded. A doubling of survival in 3rd line is seen in QUILT 88 investigating a novel combination immunotherapy protocol of low-dose chemoradiation, N-803 and PDL1 t-haNK therapy. Updated data will be presented. Clinical trial information: NCT03563144 .
Feasibility of implantable microdosing devices to perform in vivo pharmacotyping in pancreatic cancer.
Authors: Demyan Lyudmyla , Standring Oliver , Chung Taemoon , Gazzara Emma , Lyons Scott , Weiss Matthew John , Park Youngkyu , Jonas Oliver , Tuveson David A. , King Daniel
Published: January 2023

742

Background: Current biomarkers offer modest predictive capacity for drug sensitivity testing in pancreatic cancer. Patient-specific pharmacotyping offers the potential for a more direct, personalized prediction model. Recently, an implantable microdevice was developed to facilitate in situ multi-agent pharmacotyping and has since entered clinical trials in multiple cancer types, but had not yet been tested in pancreatic cancer. Here we evaluated the use of a microdosing device (microdevice) in a mouse xenotransplant model of pancreatic cancer as proof of principle to inform future translation to the clinic. Methods: A microdevice consists of a cylindrical frame and 18 wells embedded with standard chemotherapy agents (5 FU, gemcitabine, SN 38, paclitaxel, oxaliplatin), a non-toxic polyethylene glycol (PEG) matrix as control, and doxorubicin, the auto-fluorescent properties of which allow us to determine the distance of drug diffusion for each tumor. Devices were implanted into murine xenotransplanted human organoids (hM1A and hM1E Table 1). Microdevices retrieved at 4h, 8h, and 24h post-implantation together with tumors were fixed in 10% formalin. The tissue was embedded in paraffin and sectioned parallel to the device. A distance-dependent drug diffusion rate and concentration profiles with doxorubicin were evaluated. Co-immunohistochemistry (IHC) for cleaved caspase-3 (CC3), gamma H2AX (apoptosis markers), and human mitochondria (human cancer cell marker) was performed in the area of drug diffusion to determine the cytotoxic effects of chemotherapy. Results: 15 animals were enrolled in the experiment with 100% postoperative survival. One device per animal was placed, and all devices were successfully retrieved. Microdevice insertion and exposure to PEG had no effect on tumor integrity. At 250-350µm from the well, we observed intensity from doxorubicin, suggesting drug diffusion. The signal on differential response to drugs was detected as early as 4 hours. Conclusions: Utilization of implantable microdevice to predictcancer drug sensitivity is feasible in organoid transplantation animal models of pancreatic cancer. Future work is needed to expand this model to other cancer drugs and biomarkers to evaluate the cancer drug sensitivity and to test the feasibility of this model to study the effects of chemotherapy on the tumor microenvironment. [Table: see text]
Clinical significance of CA125 in unresectable pancreatic cancer treated with first-line chemotherapy.
Authors: Motoo Iori , Ando Takayuki , Yuki Satoshi , Ito Ken , Ueda Akira , Kito Yosuke , Sakumura Miho , Kajiura Shinya , Matsuno Jun , Nakamura Yoshifumi , Inoue Yuma , Hayashi Nobuhiko , Hosokawa Ayumu , Shibuya Kazuto , Tanaka Haruyoshi , Fukasawa Mina , Fujii Tsutomu , Yasuda Ichiro
Published: January 2023

745

Background: Serum CA125 is a potential biomarker for diagnosis of peritoneal metastasis in gastric cancer. However, its significance of pancreatic cancer (PC) has not been investigated. Therefore, we aimed to clarify association between serum CA125 and ascites burden, and its kinetics during first-line chemotherapy for PC. Methods: This multicenter retrospective study comprised PC patients who received FOLFIRINOX or gemcitabine plus nab-paclitaxel in first-line setting between Jan 2014 and Dec 2021. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before chemotherapy. The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and clinical response during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 109 patients from 3 hospitals were assessable. The overall survival (OS) was significantly shorter in elevated group than that in non-elevated group (median, 10.7 vs. 21.3 months, p = 0.0002). The median value of CA125 before chemotherapy was elevated according to ascites burden (Non, 36U/ml; mild, 173U/ml; moderate/severe, 575U/ml; p < 0.0001). CA125 elevation, CA19-9 elevation, poor performance status and poor glasgow prognostic score were independent prognostic factors in multivariate analysis. After chemotherapy, the median first-time measure of CA125 was performed in day 41. Among patients with peritoneal dissemination, the median change of CA125 was correlated with clinical response (CR/PR, -0.55%/day; SD, -0.24%/day; PD, 3.35%/day, p = 0.004). After chemotherapy, first-time measure of CA125 was performed in a median of day 41. According to the ROC curve analysis, the optimal cut-off value of increase in CA125 for progressive disease was 1.56 %/day (specificity 94.1%, sensitivity 80%). The median PFS and OS were 1.4 and 6.6 months in increased group and 3.3 months and 14.0 months in non-increased group, respectively (p = 0.016 and p = 0.028). Conclusions: CA125 is considered a clinically useful marker in unresectable PC treated with first-line chemotherapy because CA125 above the ULN is a poor prognostic factor for OS and an increased CA125 can be an early predictor of progression in patients with peritoneal dissemination.
Treatment sequencing for patients with localized duodenal and ampullary adenocarcinoma.
Authors: Janardan Abhishek , George Ben , Ahmed Gulrayz , Daniel Sherin , Thapa Bicky , Mehdi Maahum , Rein Lisa , Szabo Aniko , Erickson Beth , Hall William A. , Christians Kathleen K. , Tsai Susan , Evans Douglas B. , Kamgar Mandana
Published: January 2023

783

Background: Duodenal adenocarcinomas (DA) and ampullary adenocarcinoma (AA) are rare, comprising less than 1% of all gastrointestinal cancers. Optimal treatment sequencing strategies for patients with localized DA and AA have not been prospectively validated. We analyzed the clinical outcomes of patients with localized DA and AA treated with curative intent, multimodality therapy based on treatment sequencing – upfront surgery versus neoadjuvant therapy. Methods: Our institutional database was interrogated to identify adult patients with localized DA and AA diagnosed between January 2000 to December 2019. Adjusted survival analyses were performed to compare outcomes of patients that received neoadjuvant therapy (NAT - concurrent chemo-radiation +/-induction chemotherapy) versus upfront surgery (+/- adjuvant chemotherapy). Survival time was calculated from date of diagnosis to either death (overall survival; OS) or relapse/death (relapse free survival; RFS). Log-rank test and multiple Cox proportional hazards regression were performed to compare survival between treatment groups and adjust for relevant variables. Results: We identified 79 patients – 32 (41%) with DA and 47 (59%) with AA; Median age at diagnosis was 67. Forty two patients (53%) were male. Sixty-two patients underwent surgery – 27 (43.6%) patients with DA and 35 patients (56.4%) with AA. Among patients with DA, 18 (67%) were treated with upfront surgery, while 9 (33%) were treated with NAT. Among patients with AA, 32 (91%) were treated with upfront surgery while 3 (9%) were treated with NAT. Lymph node (LN) positivity rate in DA and AA patients treated with upfront surgery was 15% and 46% respectively, compared to 50% and 0% respectively, in patients treated with NAT (p = 0.26, p > 0.99 respectively). DA patients treated with upfront surgery had a median relapse free survival (mRFS) of 3.8 years compared to 1.4 years for those treated with NAT (p = 0.370). The median overall survival m(OS) was not reached (NR) for DA patients treated with upfront surgery (4 years +) or NAT (2.6 years +) p = 0.875). AA patients treated with upfront surgery had a median RFS of 4.7 years compared to NR for patients treated with NAT (p = 0.117) while the mOS of AA patients treated with upfront surgery and NAT were 5.9 years and NR respectively (p = 0.158). Conclusions: Among DA patients, there was no difference in outcome based on sequence of treatment delivery – NAT versus upfront surgery. DA patients with more aggressive clinical phenotype were likely treated with NAT, hence similar outcomes in both groups should prompt consideration of NAT for all patients with DA. Role of NAT in AA is not clear considering the small sample size.
Risks and implications of multiple actionable pathogenic germline variants discovered by panel-based cancer predisposition testing.
Authors: Hall Michael J. , McSweeny Michelle J , Rainey Kim , Campbell Hannah , Nguyen Chau , Neumann Catherine
Published: January 2023

792

Background: Multi-gene hereditary cancer panels have revolutionized how patients with germline mutations are identified by testing multiple genes at the same time. Despite the availability of panel testing, many patients with a known familial mutation will only undergo single site genetic testing due to limitations in guideline recommendations and insurance coverage. This approach risks a failure to detect additional pathogenic variants and an inappropriate management of cancer risk. In our clinical experience, a subset of patients pursue multigene testing despite a known familial mutation. Our group has identified patients who carry more than one mutation and mutations that would have been missed if the patients had only undergone single site testing. We investigated the patients and families from our risk assessment clinic with multiple familial mutations and determined how medical management may have been changed due to the presence of multiple mutations in family. Methods: The Fox Chase Cancer Center Risk Assessment Program (RAP) Registry was queried to identify patients who carry more than one mutation. Pedigrees of patients and families identified with multiple germline mutations were reviewed. Screening management guidelines were determined from the most recent NCCN guidelines published at the time the patient tested (Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic and Genetic/Familial High-Risk Assessment: Colorectal). The RAP Registry is an IRB approved protocol (IRB 09-831). Results: 70 patients were found to carry at least 2 mutations (excluding patients with biallelic MUTYH mutations) since introducing multi-gene panel testing in 2014. The most common second mutation was the I1307K variant in the APC gene at 20% (14/70). We also identified 20 patients who would have received incomplete genetic risk assessment if they only underwent single site testing and screening management changed in 60% (12/20) of these patients. 35% (7/20) of these patients did not meet NCCN criteria for additional germline testing beyond single site testing. Conclusions: Multi-gene hereditary cancer panels identify patients and families with multiple germline mutations. Patients undergoing single site cascade testing are at risk of receiving inaccurate risk assessment based on incomplete ascertainment of germline cancer risks. Detection of additional actionable mutations will frequently lead to changes in medical management.
Use of positron emission tomography-computed tomography (PET-CT) scan in patients with gastrointestinal (GI) cancer at the University Hospital of Montreal (CHUM).
Authors: Gebai Ahmad , Melendez Pena Carlos Enrique , Aubin Francine , Ayoub Jean-Pierre M. , Charpentier Danielle , Tehfe Mustapha
Published: January 2023

793

Background: In the province of Quebec, Canada, PET-CT scan recommendations are published by the Institut national d’excellence en santé et en services sociaux (INESSS). These recommendations are based on evidence-based literature and publications from oncology societies (ASCO, NCCN...) Judicious use of PET-CT scans is particularly important in a public health system for appropriate allocation of resources. An analysis conducted by INESSS in 2017 demonstrated a remarkable use of 507 PET-CT scans per 100,000 persons in Quebec, an incidence more than twice as high as other provinces, and equivalent to that of the United States (510 per 100,000 person). Methods: We present a retrospective quality control study in which all PET-CT scans completed for oncologic purposes for patients of 18 years or older at CHUM between September 1st and November 30th, 2019, were included. Patients who had a PET-CT scan for non-oncologic purposes or weren’t followed at the CHUM were excluded. We reviewed disease characteristics of patients, and adherence to 2017 INESSS guidelines. All cancer types were analysed and classified according to imaging reason (staging, response to treatment, follow up). We herein report the use of PET-CT in GI cancers and how it compares to INESSS recommendation . Results: A total of 2331 PET-CT scans were completed in the studied period. Among them 975 PET-CT scans fit our inclusion criteria. 155 patients (16%) underwent PET-CT scans for GI cancers. Only 35% followed INESSS recommendations, 44% did not, and 21% had GI cancer types without revised clear recommendations from INESSS. Among specialists, surgeons requested most PET-CT scans (66%), but surgeons, oncologists, and gastroenterologist were equally non-adherent to guidelines (44, 45, and 43% respectively). Strikingly, 43% of PET-CT scans for GI cancers were prescribed for cancer follow up, yet 83% did not follow guidelines. Most PET-CT scans were used for colorectal (41%) or gastroesophageal cancers (28%), and only 40 and 53% followed guidelines, respectively. 49.7% of PET-CT scans did not result in treatment modification. Conclusions: In our university hospital, more than 40% of PET-CT scans prescribed don’t follow INESSS recommendations. In the interest of proper resource allocation in a public health care system, we recommend guideline adherence and discussion in multidisciplinary Tumour Boards prior to off-label use of PET-CT scans.
Is liquid biopsy useful in patients with GI malignancies and exclusive peritoneal disease?
Authors: Smolenschi Cristina , Valery Marine , Boileve Alice , Cervantes Baptiste , Tarabay Anthony , Boige Valerie , Ben-Ammar Imen , Cheaib Bianca , Gelli Maximiliano , Sourouille Isabelle , Benhaim Leonor , Fuerea Alina , Perret Audrey , Ducreux Michel , Hollebecque Antoine
Published: January 2023

809

Background: Peritoneal carcinomatosis (PC) is a common manifestation in gastro-intestinal (GI) cancers.10-20 % of patients (pts) will present isolated, unresectable peritoneal disease with poor prognosis. In the past years, circulating tumor DNA (ctDNA) has emerged as a novel and less invasive biomarker for molecular diagnosis and disease monitoring. We aimed to evaluate the ability of PC to shed ctDNA into circulation in a cohort of pts with GI cancers and isolated PC treated in our institution. Methods: We reviewed retrospectively the results of liquid biopsies obtained at progression or at diagnosis. Genomic analysis was done using Foundation One liquid CDx panel. Data on demographics, tumor type, clinical outcomes and molecular alterations (MA) have been collected. Results: Out of 400 GI pts tested, 85 with exclusively PC were included in the analysis. The main characteristics were as follows: 45(53%) female, median age of 57 years (IQR: 24-79), majority have received systemic chemotherapy (all were progressive) (n=63, 74%) with median number of previous lines 1 (range: 0-3). Most common tumor types were as follows: gastric (n=24, 28%), colorectal (n=22, 26%) and primary peritoneal (n=20, 24%) cancers. The median index of peritoneal carcinomatosis was 23(IQR: 6-39). The tumor fraction was very low or undetectable in a proportion of 81% (n=69), median Tumor Mutational Burden was 1 mutation per megabase and was not correlated to tumor volume. Gene alterations were found in a proportion of 56% of pts (n=48) but most common alteration were TP 53 (n=22 pts, 26%) and KRAS mutation (n=14 pts, 16%). Targetable MA were identified only in 11 pts (13%) as follows: ATM, ARID1A, BRAFV600E, ERBB2, krasG12C. Three of them were included in a clinical trial. Germline mutations were found in 5 pts: ATM, CDH1, BRCA2, MSH6, BAP1. For colorectal pts known KRAS and BRAF V600E mutations were confirmed in plasma in a proportion of 32% (7 pts out of 22), for pancreatic cancer the KRAS in 17% (3 out of 18) and for gastric cancer, ERBB2 amplification in 5% (1 out of 22 pts). In pts with primary peritoneal disease: pseudomyxoma and mesothelioma, one patient harbored a known germline BAP 1 and kras G12C mutation without other targetable MA. The median survival in MA group was higher compared to non-MA. Conclusions: Isolated Pc and primary peritoneal cancers have distinct clinical and biological characteristics. The clinical utility of ctDNA seems to be limited in isolated PC or primary peritoneal cancers. However, it is not very clear if this to tumor location or to the ability of peritoneum to seed ctDNA.
Perioperative changes in geriatric functions of elderly patients undergoing surgical resection for gastric cancer.
Authors: Tanaka Chie , Kanda Mitsuro , Nakanishi Koki , Umeda Shinichi , Shimizu Dai , Inokawa Yoshikuni , Takami Hideki , Hayashi Masamichi , Nakayama Goro , Fujiwara Michitaka , Kodera Yasuhiro , Hattori Norifumi
Published: January 2023

811

Background: Little knowledge is available for postsurgical changes in cognitive and physical functions that may be useful for considering indication for surgery in elderly patients with gastric cancer. We therefore conducted a prospective study aimed to determine the influence of gastrectomy on these patients. Methods: We recruited patients older than 75 years for whom gastrectomy for gastric cancer had been planned, and assessed their cognitive and physical functions, daily activities, episodes of depression, confusion, and delirium before surgery (baseline), upon discharge, and at 6 months after surgery (POM 6). Results: Among 54 elderly patients registered between February 2017 and February 2020. There were no significant decreases in MMSE scores between baseline and at POM 6, nor were there significant differences in physical function and indicators of depression and confusion between these time points. As many as 20% of patients were found to have the functional decline on the basic activities of daily living scores (BADL) after surgery compared with the baseline. The only variable significantly associated with a functional decline in BADL was postoperative complications. Conclusions: Postoperative cognitive functions did not significantly decline when compared with the baseline scores, although postoperative BADL scores of patients who experienced postoperative complications were significantly lower than those who did not.
Epidemiology and survival analysis of non-GIST GI sarcomas: A two-decade analysis of SEER database.
Authors: Nutalapati Snigdha , Patel Reema Anil , Chen Quan , Huang Bin
Published: January 2023

812

Background: Primary adult non-GIST (gastrointestinal stromal tumors) gastrointestinal sarcomas are rare, accounting for 1-2% of all GI malignancies. Given the paucity of literature, we aimed to study the epidemiology and clinical outcomes of these sarcomas. Methods: National SEER-18 registry database was analyzed from 2001 to 2019 to identify non-GIST-GI sarcomas among adults aged 20 years and older. Demographics and clinical factors, including age at diagnosis, gender, race, primary cancer site, histology group, tumor grade and treatment, were examined in descriptive analysis. Log-rank tests, KM plots and Cox regression were utilized for observed survival analysis. P-value of <0.01 was considered statistically significant. Retroperitoneal sarcomas were excluded. Results: A total of 1277 non-GIST-GI sarcomas were identified, 53.6% were male. Common primary sites include small intestine (32.4%), stomach (27.0%), colon (23.0%), esophagus (8.4%), rectum (8.3%) and anus (0.9%). Most common histological subtype was leiomyosarcoma (52.8%) followed by sarcomatoid carcinoma (10.6%), spindle cell sarcoma (6.2%), carcinosarcoma (5.9%), liposarcoma (5.2%) and angiosarcoma (4.7%). Surgery only was the most common treatment received (61.4%). Stratified by primary tumor site, five-year survival rate was highest for colon (46%; 95% CI 40-52) followed by anus (HR 44%; 95% CI 15-70), stomach (HR 42%; 95% CI 36-47), rectum (HR 36%; 95% CI 27-46), small intestine (HR 36%; 95% CI 31-41) and esophagus (HR 30%; 95% CI 21-38).Similarly, for common histological subtypes 5-year survival was highest for liposarcoma (HR 56%; 95% CI 43-68) followed by leiomyosarcoma (HR 46%; 95% CI 42-50) and spindle cell sarcoma (HR 36%; 95% CI 25-47) and lowest for carcinosarcoma (HR 15%; 95% CI 8-25) followed by sarcomatoid carcinoma (HR 17%; 95% CI 11-24), and angiosarcoma (HR 17%; 95% CI 9-28).On multivariate cox regression analysis, factors associated with unfavorable prognosis were male gender (HR 1.21; 95% CI 1.06-1.39), small intestine (HR 1.38; 95% CI 1.15-1.65) sarcomatoid sarcoma (HR 1.42; 95% CI 1.06-1.92), poorly differentiated tumors(HR 2.90; 95% CI 1.99-2.43). Esophageal primary (HR 0.66; 95% CI 0.49-0.87) and leiomyosarcoma (HR 0.81; 95% CI 0.70-0.94) had a favorable prognosis. Conclusions: Non-GIST-GI sarcomas are very rare with slight male predominance and more than three quarters of cases diagnosed among 55 years and older. Leiomyosarcoma was the most common subtype and small intestine was most common primary site. Overall liposarcoma had the highest five year survival rate and carcinosarcoma had the lowest.On multivariate analysis male gender, small intestinal primary, sarcomatoid carcinoma had unfavorable prognosis.
BAYONET trial: A multicenter phase II trial of staged combination with encorafenib + binimetinib + cetuximab following encorafenib + cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer.
Authors: Matsubara Yuki , Bando Hideaki , Kotani Daisuke , Kagawa Yoshinori , Harada Kazuaki , Osumi Hiroki , Izawa Naoki , Kawakami Takeshi , Boku Shogen , Matsumoto Toshihiko , Wakabayashi Masashi , Yoshino Takayuki
Published: January 2023

TPS271

Background: While the triplet combination of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CET) indicated higher response rate compared to the doublet combination of ENCO + CET, no significant survival benefits of the triplet combination were observed in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) according to BEACON CRC study. Although ENCO + CET is the standard 2nd-line therapy in the United States and European Union, poor prognoses are expected after disease progression. As resistant mechanisms of BRAF + EGFR blockage, several MAPK pathway alternations, including RAS and RAF mutations were reported, which suggests the additional blockade of MAPK signaling may be an effective strategy for ENCO + CET refractory mCRC. In addition, the preclinical study suggested BRAF inhibitor + anti-EGFR antibody resistant BRAF V600E-mutant colorectal cancer cell-lines were sensitive to the combination of BRAF inhibitor + MEK inhibitor + anti-EGFR antibody (Oddo D, et al. Cancer Res. 2016). Methods: BAYONET is a single-arm multicenter phase II trial to evaluate the efficacy and safety of the staged combination with ENCO + BINI + CET for patients with BRAF V600E-mutant mCRC who were refractory to ENCO + CET. The main eligibility criteria are as follows; RAS wild-type/ BRAF V600E-mutant mCRC; age ≥ 20; ECOG PS 0 or 1; within 4 weeks from the last administration of previous ENCO or CET; no administration of other systemic therapy after refractoriness to ENCO + CET; complete response, partial response, or ≥4 months of stable disease were observed in the previous ENCO + CET. Included patients receive the combination treatment of ENCO (300mg once a day) + BINI (45mg twice a day) + CET (400mg/m2 initial dose and then 250mg/m2 once a week) in a 28 day-cycle as a study treatment. The primary endpoint of this trial is 12-week progression-free survival (PFS) rate. The secondary endpoints include PFS, overall survival, objective response rate, disease control rate, time to treatment failure, and the incidence of adverse events. The targeted sample size was calculated to be 30 on the basis of a power of 80%, a significant level of 10% (one-sided), the threshold 12-week PFS rate of 20%, and the expected 12-week PFS rate of 40%. As a translational analysis, circulating tumor DNA for next-generation sequencing using Guardant360 is collected at twice time points (before and after study treatment) to investigate the resistance mechanisms. Enrollment started from Jan 2022 and is ongoing at 25 facilities in Japan. As of Sep 20, 2022, 9 patients were enrolled. Clinical trial information: jRCTs031210510 .
Trial in progress: A phase 2 study of CTX-009 in adult patients with metastatic colorectal cancer who have received two or three prior systemic chemotherapy regimens.
Authors: Fontaine Marilyn , Pilgrim Sarah , Schuetz Thomas
Published: January 2023

TPS281

Background: CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Patients with unresectable locally advanced and unresectable metastatic colorectal cancer (CRC) are sequentially treated with various combinations or single agent courses of cytotoxic chemotherapy agents including 5-fluorouracil and its orally administered family members (capecitabine, TAS-102) oxaliplatin, and irinotecan, as well with targeted therapies such as bevacizumab or aflibercept (anti-VEGF), cetuximab or panitumumab (anti-EGFR), or multitargeted tyrosine kinase inhibitors (regorafenib). In subsets of patients who have had multigene panel testing done and whose tumors have been identified as having mutations that drive their disease such as defective mismatch repair, HER-2 overexpression, or NTRK fusions specific treatments with respectively PD-1 or PD-L1 inhibitors, traztuzumab or larotrectinib or entrectinib can also be used effectively. Despite the approval of multiple new agents in the past two decades, the goals of therapy are generally palliative although some patients will have long disease-free intervals when they respond to therapy. In the cases of patients whose disease has progressed, or who have not tolerated 2 or 3 prior lines of therapy, the expectation for tumor response with the available treatments are less than 5% and the median overall survival is approximately 6 months (for 3rd line therapy) or less (for 4th line therapy). In a Phase 1 study with CTX-009, responses have been seen in patients with colorectal cancers who were treated in the 4th line setting. Since CTX-009 targets tumor induced neoangiogenesis, and monoclonal antibodies that target vascular endothelial growth factor (VEGF) has been shown to extend the lives of patients with advanced colorectal cancer, testing of CTX-009 in the setting of advanced treatment refractory colorectal cancer is justified. Methods: CTX-009 is being evaluated in an open label study in patients with previously treated metastatic CRC. This study is designed as an adaptive Simon Two Stage study, with approximately 37 patients to be enrolled into Stage 1. If criteria are met to move to Stage 2, an additional 47 patients will be enrolled, for a total of approximately 84 patients. To move to stage 2 of the study, 3 or more Complete or Partial Responses must be confirmed via RECIST 1.1. Patients will be treated in 28-day cycles, with CTX-009 administration on Day 1 and 15. The primary objective of the study is to assess the efficacy of CTX-009, as measured by Overall Response Rate (ORR). The study is currently activating sites with first patient in expected in 2022. Clinical trial information: NCT05513742 .