bluuebunny/crossref_metadata_2025 huggingface dataset:
Intra-operative radiation for pancreatic cancer: Initial experience at the Hadassah Medical Center.
Authors: Cornejo Gianella , Blumenfeld Philip , Hubert Ayala
Published: January 2024

634

Background: Prognosis following surgery for pancreatic cancer (PC) remains poor. Local recurrence is common and negatively impacts survival rate. In an effort to improve local control and potentially improve survival, we have adopted a strategy of adding intra-operative electron radiation therapy (IOeRT) to selected patients undergoing pancreatic resection (PR) for PC. Here we report our initial experience with this treatment modality. Methods: 14 patients (10 male, 4 female), age between 44 - 81 years (mean 66.17), who underwent PR (Head 7, Body7) between 1/2021-1/2023 were included in this analysis. Patients selected for IOeRT included patients that according to surgeon assessment were at risk not to achieve satisfactory resection margins by surgery alone. All had resectable or borderline resectable disease according to standard criteria. 8 patients underwent pre-op chemotherapy followed by stereotactic body radiotherapy (SBRT) to a dose of 25-40 Gy in 5 fractions to the tumor and regional lymphatics followed by PR (5 Whipple, 3 distal pancreatectomy) and IOeRT, 3 patients received preop SBRT followed by PR (3 distal pancreatectomy) + IOeRT, 2 patients underwent PR (whipple 1, distal pancreatectomy 1) + IoeRT, and 1 received neoadjuvant chemotherapy followed by SBRT only and did not undergo surgery due to tumor progression. Immediately following resection, mobile IOeRT accelerator using a 40-80mm applicator with a level of 0-15 degrees was directed at the tumor bed deemed at high risk for recurrence. 10-20 Gy was delivered using 6-8 MeV electrons to the 90% isodose line at the discretion of the treating radiation oncologist. Data including serial imaging, genomic analysis, radiation protocol, complications, pathological results and outcome was collected for analysis. Results: Mean follow up was 9.7 months (2-21). 8 patients are alive: 7 pts with no evidence of disease and 1 pt with liver metastases. 6 patients died: 4 with distant metastatic disease, 1 from disease progression prior to surgery and 1 from early post-op sepsis. Negative surgical margins were achieved in 10 patients of which 2 mutated BRCA gene carriers showed complete pathological response (both who received combined neoadjuvant chemotherapy followed by SBRT). Post-operative complications possibly attributed to RT included hepatic artery occlusion (1 pt), portal vein stenosis (1 pt) and prolonged GI tract dysfunction (1pt). Conclusions: Combining RT with resection appears feasible and safe. Our data possibly show a reduction in local recurrence following resection of PC, however, longer follow up is necessary. Refinements in patient selection and treatment protocol may further improve outcomes. Larger scale studies are required to determine the benefit of this modality.
The impact of a pancreatic cancer multi-disciplinary clinic on patient-centric outcomes.
Authors: Hannon Connor , Quinn Patrick L. , Iacono Stephanie , Konik Rachel , Sarna Angela , Di Tosto Gennaro , Maxey-Kohn Krista , Cloyd Jordan M. , Pawlik Timothy M. , Manilchuck Adrei , Noonan Anne M. , Mittra Arjun , Rahman Shafia , Malalur Pannaga G. , Dillhoff Mary , Manne Ashish , Ejaz Aslam
Published: January 2024

641

Background: A one-day multi-disciplinary clinic allows for a comprehensive evaluation of patients in a single-visit format. This study aims to evaluate the impact of a one-day pancreatic cancer multi-disciplinary clinic (PMDC) on patient-centric outcomes. Methods: Patients with pancreatic cancer who were seen at The Ohio State University PMDC from January 2021 to March 2023 were identified. Patient-centric outcomes were evaluated including time from diagnosis to first evaluation and treatment, number of supportive care referrals completed, and number of physical trips to the medical center leading up to the first treatment. Outcomes were compared to pancreatic cancer patients seen in the year prior to the opening of the PMDC (non-PMDC). Results: Among the 139 PMDC and 141 non-PMDC patients, the median number of days between referral and treatment initiation was similar (PMDC: 33 days (IQR: 22, 44) vs. non-PMDC: 32 days (IQR: 23, 42); p >0.9). The median time between diagnosis and treatment initiation was also similar (PMDC: 28 days (IQR: 19, 37) vs. non-PMDC: 30 days (IQR: 21, 37); p=0.4). Of note, PMDC patients received more supportive care visits within 30 days of diagnosis (PMDC: 2 (IQR: 1, 2) vs. non-PMDC: 0 (IQR: 0, 1) ; p <0.001) and completed more visits with cancer providers (PMDC: 7 (IQR: 6, 8) vs. non-PMDC: 5 (IQR: 4, 7); p <0.001) compared with non-PMDC patients. In addition, PMDC patients also required fewer physical trips to the medical center (PMDC: 4 (IQR: 3, 5) vs. non-PMDC: 4 (IQR: 3, 6); p <0.001). Conclusions: Pancreatic cancer patients seen in a one-day multi-disciplinary clinic attend a greater number of coordinated appointments and receive more supportive care services with fewer physical trips to the medical center compared with patients not seen in a PMDC clinic. Future studies should focus on the long-term patient-centric benefits of a multi-disciplinary approach for cancer patients.
The economic impact of short-term imaging with metastatic pancreatic ductal adenocarcinoma.
Authors: Bayless Abbey , Regan Christina , Hahn Andrew , Travis Bethany , Hunter David , Irwin Chase , Koo Phillip , Dragovich Tomislav , Choti Michael A. , Kundranda Madappa N. , Chang John
Published: January 2024

643

Background: Although modern cancer treatment has significantly improved overall survival, this comes with a high financial cost. Based on an NIH report on Financial Burden of Cancer Care, treating pancreatic adenocarcinoma (PDAC) costs $108K, $18K, and $125K for initial treatment, during follow-up, and in last year of life, respectively. During the course of treatment, patients will visit the hospital for acute symptoms for which cross-sectional imaging is obtained within 45 days of subsequent scheduled follow-up imaging. This presents an opportunity for cost saving if data could be collected to identify an algorithm to avoid unnecessary duplication of imaging in a short interval. The purpose of this pilot study is to evaluate tumor growth trajectory within this short time span of 45 days to guide future trials to clarify the circumstances for which a subsequent follow up study is necessary. Methods: We retrospectively identified patients from our tumor registry from 2016 to 2019 who were diagnosed with metastatic PDAC (mPDAC). Subjects were included for analysis if they met the following criteria: 1) diagnosed with mPDAC; 2) had at least 2 CT abdomen/pelvis (CTAP) within 45 days of each other with one of the studies being obtained in the emergency department; and 3) had at least 1-3 measurable lesions as defined by RECIST 1.1 criteria. Tumor dimension was measured on axial images with the largest cross-section. For our primary outcome we used paired t-tests to evaluate the difference in mean size of all lesions (primary and metastatic). We also performed sub-group analyses comparing mean size of primary and metastatic lesions separately. An alpha level of 0.05 was used to determine statistical significance. Results: We screened 383 subjects from the tumor registry and identified 28 subjects suitable for our study. 18 subjects were female and 10 were male. We identified 69 target lesions, 23 of which were primary and 46 were metastatic. The mean sum of the largest dimension of target lesions was 2.82 cm on the initial study and 3.23 on the latter study (p<0.001). The mean sum of the largest dimension of the primary lesion was 3.62 cm on the initial study and 3.89 on the latter study (p=0.01). For metastatic lesions, the initial sum was 2.38 cm while the latter was 2.85 (p<0.001). Conclusions: Our finding of increase in tumor size in 45 days for mPDAC suggests that mPDAC is aggressive and can grow even in short time span. This suggests that if progression is identified on a study obtained within 45 days of scheduled follow-up, the follow-up study could be cancelled to avoid added cost to the patient. However, if the earlier study is stable or shows response, the scheduled follow-up may still be necessary to demonstrate continued stability/response.
A phase I/II study of antroquinonol in combination with nab-paclitaxel and gemcitabine for patients with metastatic pancreatic cancer.
Authors: Shan Yan-Shen , Li Chung-Pin , Khan Gazala , Lee Woo Jin , Choi Hye Jin , Chang Heung-Moon , Lee Moon Hee , Wallmark John M. , Chen Pei-Ni
Published: January 2024

648

Background: The survival of metastatic pancreatic cancer (mPC) is still disappointing though advancement in recent regimens. Antroquinonol, a new chemical entity, has been proposed for the treatment of neoplasms. In this phase I/II trial, we investigated the dose and efficacy of antroquinonol combined with gemcitabine and nab-paclitaxel (Gem/Nab-P) on mPC patients. Methods: Patients with chemo-naive, metastatic PDAC were enrolled. In the phase I, run-in drug-drug interaction (DDI) and dose escalation in a 3 + 3 designed to determine the maximal tolerated dose (MTD) of antroquinonol for phase II study. Gem/Nab-P (gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8, and 15 every 4 weeks) was given from cycle 0 in phase I. The dose of antroquinonol was escalated from 200mg orally three times a day since the first cycle of Gem/Nab-P. The primary end points were median PFS and 6-month PFS rate. This trial is registered at ClinicalTrials.gov: NCT03310632. Results: In the phase I study of 15 patients, the MTD of antroquinonol was 300mg tid. In the phase II study of 40 patients, the median PFS was 5.3 (95% CI: 3.7–7.5) months and 6-month PFS rate was 40% (95% CI: 21%–57%), whereas median OS was 12.6 (95% CI: 8.8–15.8) months and12-month OS rate was 59.9% (95% CI: 37.8%–76.4%), respectively. The adverse events including hematological and non-hematological classes were decreased in the antroquinonol plus Gem/Nab-P, the GI discomforts were increased but manageable. Conclusions: In this phase I/II trial, antroquinonol plus Gem/Nab-P showed good efficacy in survival and less adverse events than a first-line strategy of Gem/Nab-P for mPC patients. Clinical trial information: NCT03310632 . [Table: see text]
Safety and efficacy of chemotherapy for patients with unresectable pancreatic cancer concomitant with collagen disease: A multicenter retrospective observational study.
Authors: Asama Hiroyuki , Okuyama Hiroyuki , Kawamoto Yasuyuki , Umemoto Kumiko , Yamai Takuo , Kobayashi Satoshi , Watanabe Masafumi , Hamamoto Yasuo , Furukawa Takaaki , Kitano Yohei , Motoya Masayo , Suzuki Yuko , Ohba Akihiro , Watanabe Kazuo , Okano Naohiro , Shioji Kazuhiko , Kobayashi Noritoshi , Imaoka Hiroshi , Terashima Takeshi , Ueno Makoto
Published: January 2024

650

Background: In patients with collagen disease, such as rheumatoid arthritis, steroids and immunomodulators are often used for treatment. These treatments increase the risk of adverse events, including infections; thus, cancer patients with collagen disease are often excluded from clinical trials of chemotherapy for cancer. Therefore, evidence is lacking regarding the safety and efficacy of chemotherapy for pancreatic cancer concomitant with collagen diseases. Methods: This was a multicenter, retrospective study in Japan. Patients who started first-line chemotherapy or chemoradiotherapy for unresectable pancreatic cancer between January 2015 and December 2019 and had concurrent collagen diseases were included. We evaluated adverse events (AEs), discontinuation of anticancer treatment due to AEs, progression-free survival (PFS) and overall survival (OS). Results: A total of 52 patients were enrolled from 20 institutions in Japan, and a total of 101 regimens were administered. Concomitant collagen diseases included rheumatoid arthritis (n=35), systemic lupus erythematosus (n=5), Sjögren's syndrome (n=4), vasculitis syndrome (n=3), dermatomyositis/polymyositis (n=2), polymyalgia rheumatica (n=1), systemic sclerosis (n=1), and Behçet’s disease (n=1). The most common regimens for pancreatic cancer were gemcitabine/nab-paclitaxel (GnP, n=40), S-1 monotherapy (n=18), gemcitabine monotherapy (n=15), modified FOLFIRINOX (n=10), S-1 concurrent radiotherapy (n=5), and FOLFOX (n=4). Treatment discontinuation due to AEs occurred in 21 regimens (20.8%). The most common causes of discontinuation were thrombosis in 4 regimens, interstitial lung disease (ILD) in 3 regimens, and fatigue in 3 regimens. Infection as an adverse event was observed in 7 regimens (6.9%). By regimen, GnP had the highest discontinuation rate for adverse events of 37.5% and an incidence of ILD of 15.0%. The median PFS was 5.6 months in first-line therapy, and the median OS was 11.1 months. By regimen, the median PFS (5.8 months) and median OS (13.3 months) for metastatic patients receiving first-line GnP were comparable to those in previous reports on GnP for patients without collagen disease. Conclusions: Patients with pancreatic cancer concomitant with collagen disease have a high discontinuation rate due to AEs, and attention should be given to the occurrence of thrombosis and ILD.
Neoadjuvant SBRT plus regional nodal irradiation with concurrent capecitabine for patients with resectable pancreatic cancer: Survival analysis of prospective phase 1 trial.
Authors: Basree Mustafa , Witt Jacob , Weber Sharon M. , Uboha Nataliya Volodymyrivna , Minter Rebecca , Lubner Meghan G. , Abbott Daniel Erik , Deming Dustin A. , LoConte Noelle K. , Zafar Syed Nabeel , Patel Monica Arun , Lubner Sam Joseph , Kratz Jeremy D. , Ritter Mark A. , Mohindra Pranshu , Bassetti Michael F.
Published: January 2024

652

Background: Radiation may have a role in management of patients with early-stage pancreatic cancer. However, the role of regional nodal irradiation (RNI) is not well defined despite the high frequency of occult nodal disease. The goal of this trial was to evaluate the safety and feasibility of stereotactic body radiation therapy (SBRT) to primary disease with RNI, combined with capecitabine as a neoadjuvant approach for patients with resectable pancreatic cancer. Updated survival analysis will be presented here. Methods: This is a prospective, single institution, phase IA/B dose-escalation trial that enrolled patients with biopsy-proven, resectable, pancreatic adenocarcinoma between 2014 – 2019 (NCT1918644). Patients were enrolled into one of the 3 cohorts with escalating dose levels. Neoadjuvant SBRT to the primary tumor was delivered in 5 fractions of 5, 6, or 7 Gy with concomitant capecitabine. All patients received RNI 5 Gy x 5 fractions. Our initial report found no dose-limiting toxicities (Witt et al IJROBP 2020). Clinicopathologic features were summarized using descriptive statistics. Kaplan-Meier curves were employed for survival analysis. Results: Seventeen patients were enrolled on the protocol with sixteen evaluable (94.1%). Thirteen (76.5%) patients proceeded to surgery. Median follow up was 31.1 months (2.0 – 73.2). Among the evaluable patients, 63% were male, median age at diagnosis was 73 years (63 – 84), pre-treatment CA 19-9 149.5 U/mL (2.0 – 19358.0). The majority of patients had cT2-3 (94%) and cN0 (87.5%) disease. In patients who underwent resection, median time from radiation to surgery was 19.7 days (14.8 – 42.4), with median of 18 lymph nodes removed (11 – 27). Pathologically involved nodes were present in 69.2% of patients with a median of 2 nodes (1 – 10). Five patients (31.3%) received neoadjuvant chemotherapy, and ten (62.5%) received adjuvant chemotherapy. At the time of data cutoff, median overall survival was 31.1 months (2.3 – 73.6), and median locoregional control and distant metastasis free survivals were 32.8 months (4.0 – 59.5) and 15.3 months (0.4 – 73.6), respectively. No further radiation related toxicities were noted since the prior report. Conclusions: Neoadjuvant chemoradiation with SBRT and capecitabine to primary disease with RNI is feasible and provided a promising signal of durable local control in our study, despite high rates of pathological nodal involvement. Further investigation of this strategy is warranted in a larger cohort of patients. Clinical trial information: NCT1918644 .
Anlotinib plus chemotherapy as first-line therapy for patients with gastrointestinal tumor with unresectable liver metastasis: Updated results from a multi-cohort, multi-center phase II trial ALTER-G-001-cohort C.
Authors: Wu Junwei , Zhou Chenfei , Yan Jun , Han Zhengxiang , Wang Chun , Qin Zhiquan , Jiang Jinling , Wang Chunbing , Tang Xinyu , Zhu Lingjun , Chen Jun , Mao Yong , Wei Xiaowei , Shangguan Chengfang , Zhang Jun
Published: January 2024

653

Background: Advanced gastrointestinal (GI) tumors, such as colorectal, gastric and pancreatic cancers (CRC, GC, and PC), and esophageal squamous cell carcinoma (ESCC), 20%-50% with liver metastases (LMs) have a poor prognosis. Previous trials showed that anlotinib plus chemotherapy has promising clinical activity and a tolerable safety profile for advanced CRC and ESCC, especially with LMs. In this phase II trial, we assessed the efficacy and safety of anlotinib plus chemotherapy as first-line treatment for LMs GI tumors. Methods: Patients with unresectable LMs GI tumors and without previous systemic treatment would be divided into cohort A (CRC), cohort B (ESCC), and cohort C (other GI tumors, such as PC, GC, biliary tract cancer (BTC), etc.). In cohort C, patients received induction therapy: anlotinib plus standard chemotherapy. Patients without PD and radical resection received anlotinib and metronomic capecitabine (500 mg, PO, BID, days 1-21, q3w) maintenance until PD or unacceptable toxicity. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints were DoR, PFS, OS, DCR, radical resection rate for LMs, and safety. Results: As of September 14, 2023, 41 patients were enrolled in cohort C (29 PC, 6 GC, 5 BTC, and others), the median age was 64 years (34-74), 63.4% male, 92.7% ECOG-PS 1 and 56.1% had LMs only. The majority of the pancreatic cancer patients (26/29) received gemcitabine plus nab-paclitaxel chemotherapy combination with anlotinib as induction therapy. After induction therapy, 4 patients (1 PC, 2 GC, 1 BTC) received surgical resection. Of 37 evaluable patients in cohort C, ORR and DCR were 45.9% and 86.5% (PR, n=17; SD, n=15, 12 SD had reduced tumor size). Of 25 evaluable pancreatic cancer patients, 12 had PR, 10 had SD, ORR and DCR were 48% and 88%. According to the Kaplan-Meier method, the median DoR was 4.2 months (95%CI, 1.7-6.6) and the median PFS was 5.5 months (95%CI, 4.7-6.3). 37 patients in cohort C had TEAEs and ≥ grade 3 TEAEs (51.2%) mainly included neutropenia (19.5%), white blood cell decreased (12.2%), and blood platelet decreased (9.8%). Conclusions: Anlotinib plus chemotherapy as first-line treatment has shown promising efficacy and acceptable safety and maybe a favorable option for advanced LMs GI tumors, especially for pancreatic cancer. Clinical trial information: NCT05262335 .
Multisite external validation of blood test for colorectal neoplasia screening in a majority average-risk screening cohort of 449 subjects.
Authors: Friedland Shai , Watson Drew , Rex Douglas K. , Nimgaonkar Ashish , Zhang Zhen , Atkins Alex , Hsieh Ben , Lai Jr-Ming , Su Stephen , Wu Jen-chia , Shao Hung-Jen , Tesoriero Jessica , Hannah Lindsey , McGowan John , Mishkin Daniel S , Gupta Ekta , Gupta Samir , Sninsky John J. , Mei Rui
Published: January 2024

66

Background: The FirstSight CRC screening blood test was previously shown to have sensitivities of 92.1% and 54.5% for CRC and AA at a specificity of 90.6% for 1,038 subjects from 18 clinical sites. In this report, we describe the independent external validation of the predefined FirstSight CRC screening blood test with new subjects from 16 sites dispersed across the US, 4 of which are new and did not participate in the previous study. Methods: The validation study included subjects from two sources: Average-risk, asymptomatic screening subjects from screening clinics supplemented with diseased-only subjects from surgical oncology centers. Blood was drawn before bowel prep for colonoscopy or treatment. External validation as well as Monte Carlo cross-validation (MCCV) methods were used to evaluate the performance of the pre-defined FirstSight assay, algorithm, and clinical thresholds in this independent external validation set. Results include sensitivity and specificity to detect CRC and AA and 95% confidence intervals. Results: The study cohort (55.2% female; mean age 56.9 yrs.) consisted of 449 subjects (White 61.7%; Black 14.5%; Hispanic 18%; AAPI and Middle Easterners 5.8%). The majority of them, 376 (84%), were asymptomatic, average-risk screening subjects (including 1 CRC, 53 AA, and all 322 negative subjects). An additional 73 (16%) diseased subjects (39 CRC and 34 AA) were enriched due to low disease prevalence. The FirstSight algorithm derives a test score from 0 to 100 as a quantitative measure of AA and CRC risk with a cutpoint to assign a binary low- or high-risk designation. The previously described cutpoint of 47.2 yielded a test specificity of 90.0%, and 90.0% and 52.9% sensitivity for the detection of CRC and AA, respectively. Here we report a higher cutpoint 50 with identical sensitivities but improved specificity to 90.7%. Point estimates of sensitivity and specificity, including CRC staging, and Clopper-Pearson exact 95% confidence intervals based on the external validation results are presented below. Conclusions: An external validation included 449 subjects from a multi-site, majority average-risk CRC screening study successfully validated the FirstSight Blood Test’s high performance as previously established with 1,038 subjects. The results bring forth confidence in the Test’s reproducibility in a large-scale clinical trial. Clinical trial information: NCT05127096 . [Table: see text]
Postoperative complications following neoadjuvant therapy and surgery in a phase 2 borderline resectable pancreatic cancer clinical trial (Alliance A021501).
Authors: Snyder Rebecca A , Zemla Tyler J. , Shi Qian , Segovia Diana I. , Ahmad Syed , O'Reilly Eileen Mary , Herman Joseph M. , Katz Matthew H. G.
Published: January 2024

664

Background: Postoperative complications in patients with borderline resectable pancreatic cancer treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. Further, the impact of preoperative hypofractionated radiotherapy on postoperative outcomes is largely unknown. We sought to quantify perioperative morbidity among patients with pancreatic cancer who received neoadjuvant modified FOLFIRINOX chemotherapy with or without hypofractionated radiotherapy on a multicenter clinical trial. Methods: The A021501 phase 2 trial randomized patients with borderline resectable pancreatic ductal adenocarcinoma to 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX then hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (Dec 31, 2016-Jan 1, 2019). Patients underwent resection according to defined operative standards at enrolling centers without specific requirements for either surgeon or hospital volume. Surgical complications and adverse events were assessed and captured at a single time point of 90 days after surgery and compared between treatment arms. Results: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n=32, Arm 1; n=19, Arm 2) at 28 institutions. Vascular resection was performed in 19 patients (37%). One patient in Arm 2 died within 90 days after surgery. Rates of any surgical complication were 19% (n=6) in Arm 1 and 42% (n=8) in Arm 2 (p=0.07). Median length of stay was 7 days (range 5-38 days). Five (10%) patients required reoperation within 90 days. Readmission rates were higher in Arm 2 than Arm 1 (16% vs. 42%, p=0.04) but there were no differences in rates of reoperation, pancreatic fistula or abscess requiring drainage, or wound infection between study arms. 54% of patients (n=26/48) experienced a grade 3 or higher adverse event, with no difference between treatment arms (47% versus 67%, p=0.7). Rates of initiation of adjuvant therapy did not differ between treatment arms (66% vs. 68%, p=0.4). Pancreatic fistula and abscess were associated with adjuvant therapy (p<0.01). No difference in overall survival was observed based on occurrence of surgical complications (HR 1.1; 95% CI 0.5-2.6). Conclusions: In this national cooperative group study of patients with borderline resectable pancreatic cancer,postoperative complications following neoadjuvant chemotherapy, radiation, and surgical resection were consistent with rates previously reported by high-volume institutions and using large datasets. Multimodality trials of preoperative therapy for locoregionally advanced pancreatic cancer may be safely performed in the cooperative group setting. Clinical trial information: NCT02839343 .
ARC-8: Phase 1/1b randomized study of quemliclustat + gemcitabine/nab-paclitaxel ± zimberelimab in patients with treatment-naive metastatic pancreatic adenocarcinoma.
Authors: Wainberg Zev A. , Manji Gulam Abbas , Bahary Nathan , Ulahannan Susanna Varkey , Pant Shubham , Uboha Nataliya Volodymyrivna , Oberstein Paul Eliezer , Lu Lawrence H , Scott Jennifer R. , Wu Wilson , Rhee Joon , Nuyten Dimitry S. A. , O'Reilly Eileen Mary
Published: January 2024

665

Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) remains a challenging cancer to treat, with median survival of <1 year. In PDAC, extracellular adenosine (eADO) produced from ATP is released from tumor cells and suppresses antitumor immune responses. Quemliclustat (Q) is a potent and selective small-molecule inhibitor of soluble and cell-bound CD73, a key enzyme involved in the production of eADO within the tumor microenvironment. Elevated CD73 expression is found in 40-60% of PDAC and correlates with poor clinical outcome. ARC-8 evaluated Q ± anti-PD-1 antibody zimberelimab (Z) in combination with gemcitabine/nab-paclitaxel (G/nP). Methods: ARC-8 (NCT04104672) is a phase 1b dose escalation and expansion study in patients (pts) with treatment-naive mPDAC. Q 100mg was previously determined as the recommended dose for expansion (Manji et al., 2021). Q 100 mg is administered with standard doses of G/nP with Z (240 mg IV Q2W) in the dose expansion (Cohort A; QZ+G/nP) and in randomized (2:1) cohorts either with Z (Cohort A1; QZ+G/nP) or without Z (Cohort A2; Q+G/nP). Adverse events (AEs) are recorded and graded per NCI CTCAE 5.0. Clinical activity is assessed every 8 weeks per RECIST v1.1. Endpoints include measures of safety and median overall survival (OS). Results: As of June 19, 2023, 122 patients with untreated mPDAC were treated with Q 100mg, including 93 pts treated with QZ+G/nP (dose escalation, n=6; cohort A, n=26; and randomized cohort A1, n=61) and 29 pts treated with Q+G/nP (Cohort A2). Median age was 66 years, 66% ECOG of 1, and 65% had liver metastasis at baseline. Median survival follow-up was 21 months (mos). Efficacy is summarized in Table 1. All patients reported AE, 85% Grade 3+ AE, and 23% discontinued study treatment due to AE. Most common Grade 3+ AE was neutrophil count decreased (31%) and anemia (25%). Conclusions: Results from ARC-8 demonstrate the addition of Q 100 mg ± Z to G/nP was safe and tolerable, with no significant added toxicity to GnP. Modulation of eADO with Q may confer benefit beyond radiographic measures of disease. The OS is promising and supports further development of Q in mPDAC. Clinical trial information: NCT04104672 . [Table: see text]
Biweekly gemcitabine plus nab-paclitaxel as first-line therapy for older adult patients with unresectable pancreatic cancer: A prospective study.
Authors: Ikezawa Kenji , Imai Toshihiro , Takada Ryoji , Yamai Takuo , Fukutake Nobuyasu , Ohkawa Kazuyoshi
Published: January 2024

672

Background: Although the number of older adult patients (aged ≥ 75 years) with pancreatic cancer (PC) is increasing, there are still limited data regarding chemotherapy for these patients, who experience adverse events more frequently than younger patients with PC. In this study, we evaluated the efficacy and safety of biweekly gemcitabine plus nab-paclitaxel (GnP) as first-line therapy for older adult patients with unresectable PC. Methods: We conducted a single-center prospective study. Patients aged ≥ 75 years with pathologically proven unresectable pancreatic adenocarcinoma were enrolled after obtaining written informed consent. Patients were treated with a modified regimen of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 15 of every 28-day cycle. The primary endpoint was the overall response rate. Secondary endpoints included disease control rate, overall survival, progression-free survival, 1-year survival rate, 2-year survival rate, and adverse events. Results: From August 2018 to March 2021, 17 patients were enrolled (locally advanced 4; metastatic 13). Five patients (29.4%) were men, and the median age was 77 years (range: 75-81). The median Geriatric 8 score was 13 points (range 6-17). Biliary drainage was performed in three patients. The overall response rate was 47.1% (8/17). Disease control rate was 82.4% (14/17). Median overall survival was 16.8 months (95% confidence interval (CI) 5.9-24.6) and median progression-free survival was 8.3 months (95% CI: 4.9-10.1), respectively. The 1-year survival rate and 2-year survival rates were 58.8% and 29.4%, respectively. Grade 3 or 4 hematologic adverse events and non-hematologic adverse events were observed in 17.6% (3/17) and 29.4% (5/17), respectively. No deaths was observed in association with biweekly GnP regimen. Conclusions: Biweekly GnP as first-line therapy can provide favorable treatment outcomes with tolerable toxicity in older adult patients with unresectable PC. Clinical trial information: jRCTs051190038 .
Maintenance therapy with olaparib or selumetinib plus durvalumab (S+D) according to genetic profile of metastatic pancreatic adenocarcinoma (m-PDAC) controlled with modified FOLFIRINOX (mFFX): A phase II randomized MAZEPPA GERCOR D19-02 PRODIGE-72 study.
Authors: Hammel Pascal , Ben Abdelghani Meher , Roth Gael , Ulusakarya Ayhan , Ghiringhelli François , Toullec Clemence , Borg Christophe , Hentic Dhome Olivia , Trouilloud Isabelle , Dahan Laetitia , Hiret Sandrine , Bouche Olivier , Rinaldi Yves , Blanc Jean-Frédéric , De La Fouchardiere Christelle , Neuzillet Cindy , Kamal Maud , Falcoz Antoine , Turpin Anthony , Guimbaud Rosine
Published: January 2024

673

Background: Maintenance treatments in m-PDAC patients (pts) after FFX induction is discussed. We assessed the efficacy of genetic-driven maintenance in pts with controlled disease. Methods: In this multicenter, open-label, phase II study, PS 0-1 pts with histologically confirmed m-PDAC controlled after 4 months (mo) of mFFX received a genetically-driven maintenance therapy (centralized analysis): BRCAness - olaparib 300 mgx2/d (Arm A); no BRCAness, but KRAS mutation - randomization (2:1) to S+D (1500 mg IV q4w + 75 mg PO BID; Arm B) or FOLFIRI q2w (Arm C), until confirmed progression or toxicity. Statistical hypotheses: Arm A, PFS4mo rate after inclusion - H0: PFS4mo ≤40%, H1: PFS4mo ≥70%; Arm B and C, H0: PFSc=PFSb, H1: PFSc<PFSb (one-sided 2.5% α-type I-error and 10% β-type 2). A prespecified single interim analysis for futility using a-spending function with O’Brien-Fleming boundaries was planned after 33.1% of events (~93 pts). The Kaplan-Meier method and a swimmer plot were applied. Results: 124 pts were included in the study; Arm A: 16 pts (male: 9, median age: 67 years, PS 0: 9 pts) received olaparib; PFS 4mo: 50%; median PFS: 3.7 mo (1.7-9.4), ORR: 13%, median OS: 18 mo (5.5-21.5). Arm B/Arm C: at interim analysis (12/5/2022): 104 pts were randomized (Arm B/Arm C: 70/34); median PFS in Arms B and C: 3.5 mo (95% CI 2.1-3.9) vs 5.7 mo (95% CI 2.2-10.7), respectively. Due to futility, inclusions were stopped. At final analysis (data cutoff: 06/15/2023) with median follow up of 11.2 mo (95% Cl 9.4-13.1): 108 pts (male: 53%, age: 63.5 years, PS 0: 44%) were treated (Arm B/Arm C: 72/36). 123/124 pts (ITT population) had ≥1 cycle treatment (median: 4.0 [IQR, 2.0-6.0]). Primary endpoint was not met: median PFS 3.7 mo (95% Cl 2.1-5.0) in Arm B vs 6.6 mo in Arm C (95% Cl 2.6-8.7); HR=1.6 (0.99-2.58), P=0.0523. Median OS (entire population): 12.7 mo (95% CI 8.7-18.2); 10.1 mo (95% CI 8.3-20.6) in Arm B and 17.3 mo (95% CI 8.4-20.9) in Arm C. The toxicity profile: ≥1 grade 3-4 treatment-related arms (A/B/C) was as expected: 18.8%, 23.6%, 28.6% of pts. Conclusions: MAZEPPA study did not meet its primary endpoint of improving PFS4mo in m-PDAC pts treated with S+D maintenance vs those receiving FOLFIRI. Data on genomic alterations analyses will be presented at the congress. Clinical trial information: NCT04348045 .
Stereotactic body radiotherapy compared to conventionally fractionated radiotherapy for locally advanced or oligometastatic pancreatic cancer.
Authors: Mizrahi Ofri , Falick Michaeli Tal , Hubert Ayala , Wygoda Marc R. , Blumenfeld Philip
Published: January 2024

677

Background: Pancreatic cancer, particularly in its locally advanced and oligometastatic forms, poses a formidable therapeutic challenge. Radiotherapy remains an important treatment in an attempt to gain local control, however there is no consensus on whether stereotactic body radiotherapy (SBRT) is appropriate as compared to conventionally fractionated radiotherapy (CFRT). Herein, we report our experience. Methods: We conducted a retrospective analysis of patients with locally advanced and oligometastatic pancreatic cancer who received definitive radiotherapy at our institution between January 2010 and March 2023 with SBRT 30-50 Gy in 3-5 fractions or CFRT 50-60 Gy in 25-30 fractions. We excluded all patients with resectable disease who underwent surgery. Clinicopathological data, treatment regimens, and radiation parameters were collected and analyzed. Results: A total of 51 patients (17 females, 34 males; median age: 67.9 years). 24 patients (47.1%) were treated with CFRT, and 27 patients (52.9%) were treated with SBRT. Median time of follow-up for the entire cohort was 14.4 months. A total of 13 patients (25%) experienced a Local failure (LF) at a median time of 18.5 months, with no difference observed between CFRT and SBRT groups. Cancer-specific mortality (CSM) was statistically significant with a lower mortality rate in SBRT (37%) vs CFRT group (63%) (p<0.004). Several treatment characteristics and dosimetric factors such as sex, age, receipt of chemotherapy, type of chemotherapy, use of elective nodal irradiation, GTV size, biologically equivalent dose (BED) corrected prescribed dose, minimum dose to GTV, or max dose to GTV did not predict local failure. There was no difference in QOL and toxicity between the two groups. Conclusions: In our cohort, local failure rates remain high and were similar between patients treated with SBRT compared to those treated with conventionally fractionated radiotherapy. We were unable to identify any specific predictors for local recurrence in this patient population. Our observation of a lower CSM rate among patients who received SBRT needs further study. The findings underscore the need to further improve radiotherapeutic approaches in an attempt to improve local control in locally advanced disease.
Exocrine pancreatic insufficiency as a possible predictor of pancreatic cancer development.
Authors: Gore James , Romo Karina G. , Peeples James , Noor Abdullah A. , Uwaifo Gabriel I.
Published: January 2024

679

Background: Chronic and acute pancreatitis are established risk factors for pancreatic cancer. Chronic pancreatitis and pancreatic cancer are also common causes of exocrine pancreatic insufficiency (EPI), which is characterized by inadequate pancreatic secretion of exocrine digestive enzymes. Although the association between EPI and pancreatic cancer has been thought to be linked by preceding chronic pancreatitis, it is unclear if EPI, regardless of etiology, is a risk factor or early marker for pancreatic cancer or cancer in general. Methods: This is a retrospective observational study utilizing the electronic health records of Ochsner Health System, Louisiana, over a 3-year period from January 2017 to January 2020 to identify patients with a diagnosis of EPI by ICD-10 codes. Two cohorts were reviewed: patients with EPI (n=677) and patients with pancreatitis (n=1852). Both history of acute and/or chronic pancreatitis were included in the pancreatitis cohort. The cohorts were compared based on cancer prevalence at the start and end of the 3 year observation period. Results: In the EPI cohort, the cancer prevalence was 15.95% (108) at start, and 43.9% (297) at end, (p<0.05); and pancreatic cancer prevalence at start was 6.65% (123) and 29.8% (552) at end (p<0.05). In the pancreatitis cohort, the cancer prevalence was 5.4% (100) at start and 15.9% (294) at end (p<0.05); and pancreatic cancer 0.8% at start and 5% at end (p<0.05). Conclusions: Over a 3 year period, the rise in prevalence of general cancer and pancreatic cancer was higher in the EPI cohort compared to the pancreatitis cohort. Additionally, there was a statistically significant 2.8-fold increase in prevalence of cancer diagnosis and 4.5-fold increase in prevalence of pancreatic cancer diagnosis in the EPI cohort over the 3 year observation period. Though this is an observational study, it suggests the possibility that EPI, regardless of etiology, may be an independent predictor/risk factor for the development of future cancer in general and pancreatic cancer in particular. In addition it appears that this risk potential is substantively greater than that from a history of pancreatitis alone.
Enhanced blood-based colorectal cancer screening with improved performance in detection of early stage disease.
Authors: Duenwald Sven , Young Greenwald William , He Yupeng , Xiong Liyang , Forouzmand Elmira , Gaile Daniel , Valouev Anton , Raymond Victoria M. , Talasaz AmirAli , Chudova Darya
Published: January 2024

68

Background: Blood based colorectal cancer (CRC) screening has been validated for use in average risk populations (ECLIPSE NCT#04136002; Guardant Health, USA). Here we present the performance of an enhanced version of a blood-based screening test developed to optimize detection of low shedding tumors by leveraging epigenomic features of cell-free DNA (cfDNA). Test performance was assessed across screen-relevant individuals from the intended use population, including a collection of screen-detected CRC and enriched cohort of individuals with endoscopy finding of CRC. Methods: We trained a regression model to classify whether aberrant cfDNA originated from individuals with CRC or non-ACN individuals and compared performance to an original model in a fixed set of screen-relevant samples sequenced to a median of 11M reads per sample across a panel approximately 1Mb in size. Model optimization focused on identifying training settings and samples to maximize detection of low shedding screen-relevant tumors and introduced noise reduction techniques to minimize technical variation. The final enhanced model was trained in over 4500 samples; the calling cut-off was set targeting 90% specificity in the average-risk population following US-Census age distribution. Analytical Limit of Detection (LoD) was estimated using ~5,000 in silico dilution samples generated from blood samples from 25 CRCs and ~1,650 non-ACNs. Results: This training approach yielded a 2X improvement in the analytical LoD95 (0.004% vs 0.008%) compared to the original model validated in the ECLIPSE trial. The model also yielded an increase in overall CRC clinical sensitivity from 84% to 91%, N=45, with notable sensitivity improvement from 76% to 88% in detecting early localized stage I/II CRC, N = 25, while maintaining specificity at 91%. Conclusions: This enhanced cfDNA-based CRC screening blood test shows improved performance in early stage CRC detection demonstrating the potential of continuous improvement in the performance of cfDNA-based screening tests powered by data and clinical insights.
Kinetics of CA19-9 decline in a randomized phase III study of irinotecan liposome injection, oxaliplatin, 5-fluorouracial/leucovorin (NALIRIFOX) or nab-paclitaxel plus gemcitabine (GEM+NABP) in patients who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas (NAPOLI 3).
Authors: Chandana Sreenivasa R , Wainberg Zev A. , Melisi Davide , Macarulla Teresa , Pazo Cid Roberto A. , De La Fouchardiere Christelle , Dean Andrew Peter , Kiss Igor , Lee Woo Jin , Goetze Thorsten , Van Cutsem Eric , Paulson Andrew Scott , Bekaii-Saab Tanios S. , Pant Shubham , Hubner Richard , Xiao Zhimin , Li Jia , Benzaghou Fawzi , O'Reilly Eileen Mary
Published: January 2024

687

Background: The NAPOLI 3 study (NCT04083235, N = 770) reported that NALIRIFOX improved overall survival (OS) vs Gem+NabP with manageable toxicity in 1L treatment of metastatic pancreatic adenocarcinoma. We explored changes in CA19-9 levels and their potential associations with efficacy as an important tumor marker in pancreatic adenocarcinoma. Methods: In NAPOLI 3, CA19-9 was evaluated at baseline and every 8 weeks until patients discontinued study treatment. The detection limit of CA19-9 was 8000 kU/L in this study. The Cox proportional hazards regression and logistic regression were employed to investigate the relationship between CA19-9 decrease and OS, progression-free survival (PFS), and overall response rate (ORR). Results: Patients with evaluable CA19-9 (levels =< 8000) at baseline and additional measurements at weeks 8 and 16 were included in the analysis (NALIRIFOX, n = 179; Gem+NabP, n = 194). The median baseline CA19-9 level was 378.0 and 409.7 kU/L for the NALIRIFOX and Gem+NabP arms, respectively. Overall, patients with (vs without) any CA 19-9 decrease by week 16 had a higher ORR (59.9% vs 35.2%; p = 0.002), a longer median PFS (9.2 vs 6.2 months; p < 0.001) and a longer median OS (14.2 vs 8.7 months; p = 0.005), respectively in a pooled analysis of the treatments. In the NALIRIFOX arm, patients with any CA19-9 decrease by week 16 had a higher confirmed ORR of 65.1% compared with those without at 42.4% ( p < 0.001), a median PFS of 9.5 vs 7.1 months ( p < 0.001) and a median OS of 15.4 versus 8.4 months ( p = 0.004), respectively. In the Gem+NabP arm, patients with CA19-9 decrease by week 16 had a higher ORR of 55.5% compared with those without at 23.8% ( p = 0.012), a median PFS of 7.6 versus 5.8 months ( p < 0.001) and a median OS of 13.7 versus 11.9 months ( p = 0.235), respectively. Conclusions: CA19-9 decrease by week 16 has the potential to be an early prognostic factor for OS, PFS and ORR. The results should be interpreted with caution as a considerable percentage of patients were excluded due to non-evaluable CA19-9 that exceeded the lab detection limit of 8000 kU/L. Clinical trial information: NCT04083235 .
Clinical outcomes and molecular characteristics of patients with pancreatic acinar cell carcinoma.
Authors: Eslinger Cody , Yee Claire , Seddighzadeh Bobak , Elsabbagh Zaid , Pai Rish , Hartley Christopher P. , Bekaii-Saab Tanios S. , Starr Jason S. , Halfdanarson Thorvardur Ragnar , Sonbol Bassam Bassam
Published: January 2024

688

Background: PACC is a rare malignancy originating from the exocrine pancreas, accounting for less than 1% of all pancreatic cancers. Due to the rarity of the disease entity, there is a paucity of data to guide treatment decisions. This retrospective study aims to provide additional clinical characteristics and outcomes to aid in future treatment decisions. Methods: Pathology records from Mayo Clinic (AZ, FL, MN) patients (pts) denoting acinar or mixed-acinar cell carcinoma were searched between 2002 to 2023 and selected for retrospective review. Pt demographics, treatment courses, and next generation sequencing (NGS) were collected. Results: A total of 62 pts (74% male, n = 46) were identified with median age 64 years old. Histologic subtypes were 67% pure acinar cell carcinoma (42/62), 24% mixed acinar-neuroendocrine (15/62), and 8% mixed acinar-adenocarcinoma (5/62). AJCC stages at diagnosis were 34% stage I/II (21/62), 16% stage III (10/62), and 50% stage IV (31/62). Early-stage disease was treated with upfront surgical resection (81%, 17/21). Locally advanced disease received neoadjuvant therapy (NAT) followed by surgical resection (80%, 8/10). FOLFIRINOX was most often chosen as NAT (65%, 11/17), while others received gemcitabine-based NAT. The R0 resection rate was 86%. The 3 and 5-year survival estimates for stage III were 90.9% (95% CI: 75.4 – 100%) and 67.3% (95% CI: 42.3 – 100%), respectively. The 3 and 5-year survival estimates for stage IV were 36.6% (95% CI: 18.6 – 71.9%) and 29.3% (95% CI: 13.1 – 65.5%), respectively. Median survival time for stage IV was 3 years. Somatic NGS testing was done in 24 pts with alterations found in: homologous recombination (HR) in 42% (10/24); RAF alterations in 25% (6/24); mismatch repair (MMR) in 13% (3/24; none of them with MMR germline mutations), 1 ETV6-NTRK3 fusion, and 1 FGFR mutation. Germline NGS testing was done in 21 pts and alterations in HR were seen in 33% (7/21) of pts. This led to additional therapeutic options in 46% (11/24) of pts. Conclusions: Unlike PDAC, PACC is a genomically diverse disease, with potentially targetable alterations in RAF, HRD, and MMR genes, offering additional therapeutic options for significant number of pts. In addition, more than one-third of the pts harbored germline mutations in HR genes. Therefore, somatic and germline testing should be considered for any pt diagnosed with PACC.
The prognostic value of mutational signatures in pancreatic cancer.
Authors: Light Nicholas , Zhang Amy , Hamza Oumaima , Jang Gun Ho , Dodd Anna , Wilson Julie , O'Kane Grainne M. , Tsang Erica S , Notta Faiyaz , Knox Jennifer J. , Gallinger Steven , Grant Robert C
Published: January 2024

689

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor overall survival (OS), however there are significant outliers. Understanding the biological factors driving PDAC cancer may reveal new biomarkers and treatment strategies. Mutational signatures, imprinted in the cancer genome, encode the life history of the cancer and may be used to stratify tumors into clinically-relevant subgroups. Methods: In this study we performed mutational signature analysis (MutationalPatterns, COSMIC v3.3) on whole genomes from 434 PDAC patients, comprising 167 patients with resected primary tumors, and 267 advanced PDACs from patients enrolled in the COMPASS trial. We evaluated whether the mutational signatures detected associate with OS using the log-rank test in the overall cohort and stratified by disease stage, adjusting for multiple hypotheses with 5% false discovery rate (FDR). We further characterized these associations in exploratory analyses. Results: Among the 55 COSMIC signatures detected in the overall cohort, the presence of three signatures significantly associated with OS after FDR correction. SBS85, a signature associated with indirect effects of activation-induced cytidine deaminase, was present in 18/434 (4.1%) samples, and was significantly associated with improved OS in the overall study population (log-rank p=6.5e-4, FDR-adjusted-p=0.026). SBS93, a signature of unknown etiology previously seen in other gastrointestinal cancers, was present in 4/434 (0.9%) samples, and was significantly associated with worse OS in the overall study population (log-rank, p=7e-6; FDR-adjusted-p=1.1e-3). SBS33, also of unknown etiology and previously seen in other gastrointestinal cancers, was present in 73/434 (16.8%) samples. It was seen more frequently in advanced disease (Fisher’s-exact p=1.9e-4), but was significantly associated with worse OS only in the resected cohort (log-rank, p=2.3e-4, FDR-adjusted-p=0.012). Conclusions: We identified three mutational signatures—SBS85, SBS93, and SBS33—that have not previously been described in PDAC and associate with OS. Further characterization of these novel signatures in PDAC and their underlying biology may uncover new treatment avenues.