bluuebunny/crossref_metadata_2025 huggingface dataset:
Pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC): Final outcomes of a phase 2 trial.
Authors: Kelley Robin Kate , Bracci Paige M. , Keenan Bridget , Behr Spencer , Ibrahim Faaiz , Pollak Marin , Gordan John , Ko Andrew H. , Van Loon Katherine , Atreya Chloe Evelyn , Cinar Pelin , Venook Alan P. , Fong Lawrence
Published: January 2022

444

Background: Immune checkpoint inhibitors (ICI) have limited activity as monotherapy in unselected patients with ABC; the objective response rate (ORR) of PEM was 5.8% in the multicenter phase 2 KEYNOTE-158 trial. GM-CSF modulates immune cells including monocytes and the innate immune response and has demonstrated safety and prolonged survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial was designed to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Single-center, phase 2 trial with Simon’s 2-stage design and expansion cohort (EC) (NCT02703714). Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior ICI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 and EC) or in cycles 1 and 2 (Stage 2). Primary endpoint was objective response rate (ORR) by RECIST 1.1, H0 5% vs. H1 20%. Key secondary endpoints were safety, progression-free survival (PFS), OS, PD-L1 expression. Exploratory endpoints included relationship between efficacy outcomes and anatomic subsite, risk factors, and tumor genotype. Results: Overall, 42 patients enrolled between 5/2016-12/2019: n = 9 in Stage 1, n = 18 in Stage 2, and n = 15 in EC. Overall: median age 61; female 67%; intrahepatic (ICC) 67%, extrahepatic (ECC) 26%, gallbladder (GBC) 7%; stage IV 90%; hepatitis B/C virus positive (HBV/HCV+) 24%; microsatellite instability (MSI-H)/stable (MSS)/unknown n = 1/35/6. Immune-related (ir)AE occurred in 69%, grade 3/4 treatment-related (tr)AE in 10%, all-cause serious (S)AE in 36%, and trSAE in 7%. ORR was 12% (95% CI: 4, 26), with median PFS of 63 days (95% CI: 55, 125), PFS at 6 months in 27% (95% CI: 14, 43), and median OS 3of 93 days (95% CI: 243, 573). There was no significant difference in ORR, PFS, or OS by anatomic subsite or tumor PD-L1 expression; HBV/HCV+ showed trends toward higher ORR (30% vs 6%, p = 0.08) and longer median PFS (276 vs 63 days, p = 0.06) and OS (1033 vs 323 days, p = 0.052). Conclusions: The combination of PEM plus GM-CSF was safe and well-tolerated with higher ORR than expected for PEM monotherapy in a predominantly MSS ABC population but did not meet target ORR threshold for efficacy. ORR and median PFS and OS were highest in patients with underlying HBV or HCV infection. Immune profiling of on-treatment biopsies and peripheral blood are ongoing to ascertain influence of both PEM and GM-CSF on circulating and tumor immune microenvironment. Clinical trial information: NCT02703714.
Updated results of the phase II ALTER-H003 trial: Anlotinib plus toripalimab as a first-line treatment for patients with unresectable hepatocellular carcinoma.
Authors: Lin Haifeng , Ma Jie , Zhuo Manyun , Zhang Chengsheng , Luo Jingru , Zhuang Xiaohong , Zeng Zhiming , Yang Lihua
Published: January 2022

446

Background: The combination therapies of anti-angiogenic with anti-PD-1/L1 agents have shown superior efficacy over sorafenib in the first-line treatment for uHCC. Anlotinib, a multi-targeted tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit, is approved for treatment of several malignancies in China. Toripalimab is a humanized lgG4 mAb against PD-1. Preliminary results demonstrated good efficacy and tolerable safety of the combined regimen. Here we updated the results with more enrolled patients and longer follow-up duration. Methods: This single arm, multicenter, phase II trial of ALTER-H003 was planned to enroll 30 pts without prior systemic treatment to receive anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. Primary endpoint was ORR according to mRECIST and irRECIST. Secondary endpoints included PFS, OS, DCR, DoR and safety. Results: By the cutoff date of September 18, 2021, 31 pts were enrolled and treatment duration ranged from 0.23+ to 14.65+ months. Among 26 evaluable pts, the confirmed ORR and DCR according to mRECIST was 34.6% (95% Cl 17.2%-55.7%) and 92.3% (95% Cl 17.2%-55.7%), respectively. The DoRs ranged from 1.38 month to 9.69 month. The preliminary median PFS was 10.2m (95% Cl 6.1-14.3) and the median OS have not reached yet. 28 of 31 pts (90.3%) occurred treatment-related adverse events (TRAEs). Grade 3-5 TRAEs were recorded in 14 pts (45.2%). Immune-Related TRAEs (irTRAEs) occurred in 21 pts (67.7%), while 5 patients (16.1%) had grade 3-5 irTRAEs. The most common grade 3 TRAEs included hypertension (n = 3, 9.7%), hand-foot skin reaction (n = 2, 6.5%), arthralgia (n = 2, 6.5%), total bilirubin increased(n = 2, 6.5%) and fatigue (n = 2, 6.5%). The grade 3 irTRAEs were total bilirubin increased (n = 2, 6.5%), AST increased (n = 1, 3.2%), fever (n = 1, 3.2%), arthralgia (n = 1, 3.2%) and fatigue (n = 1, 3.2%). No grade 4 TRAEs occurred.1 patient had an irTRAE that led to death (immune-related pneumonitis). Conclusions: This combination therapy of anlotinib plus toripalimab in the first-line treatment for uHCC yielded satisfactory anti-tumor efficacy and manageable toxicity. The study is still ongoing and detailed data will be presented. Clinical trial information: ChiCTR1900028295.
The therapeutic strategy for choosing lenvatinib in systemic therapy for unresectable hepatocellular carcinoma.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Yasui Yutaka , Kaneko Shun , Kirino Sakura , Inada Kento , Tanaka Yuki , Ishido Shun , Yamashita Koji , Nobusawa Tsubasa , Hayakawa Yuka , Matsumoto Hiroaki , Kakegawa Tatsuya , Higuchi Mayu , Takaura Kenta , Tanaka Shohei , Maeyashiki Chiaki , Tamaki Nobuharu , Nakanishi Hiroyuki , Izumi Namiki
Published: January 2022

447

Background: In systemic therapy for unresectable HCC, atezolizumab plus bevacizumab is recommended as first-line, and there are no established strategies after the immunotherapy. Lenvatinib (LEN) showed a high radiological response rate both in clinical trials and real-world practice, while it was reported that age and ALBI grade 2 were associated with the discontinuation of LEN. The aim of this study is to investigate the best candidates for LEN therapy by using clinical variables. Methods: A total of 104 patients who received LEN at our institution between Apr 2018 and Feb 2021 was enrolled. The risk factors associated with overall survival (OS) and progression-free survival (PFS) were analyzed by a Cox proportional hazard model. Results: The median observation period was 12.8 months, and the median duration of LEN was 4.5 months. The median age was 74 years, and 90 patients were Child-Pugh A. BCLC stage B patients were 43%, and median AFP was 172 ng/mL. The median OS and PFS were 17.9 and 6.2 months. In this study, 72 patients received LEN as the first line. In a multivariate analysis of first-line patients, ECOG PS≥1, modified ALBI 2b or 3, AFP≥400 ng/mL, the existence of major vascular invasion (MVI), and neutrophil to lymphocyte ratio (NLR)≥2.8 were significant risk factors associated with OS and PFS. The median OS in patients with 0-1 risk factor (n = 33) was significantly longer than the patients with 2-5 risk factors (n = 39) (22.3 vs. 16.7 months, p <.0001). The median PFS in patients with no risk factor (n = 10) was 13.8 months, while the median PFS was 4.8 months in the patients with ≥2 risk factors. Among 28 patients without MVI and treated with LEN as second or later line, the median OS of the patients with 0-2 risk factors was significantly longer than those with 3-4 risk factors (21.7 vs. 7.7 months p = 0.0008). The median PFS in patients with 0-1 risk factor was 14.7 months, even though they had an experience of systemic therapy. Conclusions: LEN is strongly recommended to the patients with ECOG PS0, modified ALBI 1 or 2a, AFP < 400ng/mL, no MVI, and low NLR (< 2.8). When the patients would fulfill all these conditions, the median OS and PFS is over 20 and 12 months, both in patients with and without experience of systemic therapy.
A multicenter phase II trial to assess the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy toward R0 surgical resection in advanced colorectal liver metastases with mutant-type KRAS: NEXTO-mt trial.
Authors: Watanabe Genki , Mise Yoshihiro , Oba Masaru , Saiura Akio , Inoue Yosuke , Takahashi Yu , Kishi Yoji , Suyama Koichi , Takayama Tadatoshi , Noie Tamaki , Nishioka Yujiro , Akamatsu Nobuhisa , Arita Junichi , Kokudo Norihiro , Hasegawa Kiyoshi
Published: January 2022

450

Background: The oncological benefit of bevacizumab plus mFOLFOX6 in advanced colorectal liver metastases (CRLMs) in terms of conversion to curative resection remains unknown. This multicenter phase II trial aimed to evaluate the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy for advanced CRLMs harboring mutant-type KRAS. Methods: Patients who had advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included in this study. The induction chemotherapy of bevacizumab plus mFOLFOX6 was administered and assessed for resectability every 4 cycles. If the unresectable CRLMs were converted to be resectable, liver resection was planned after a waiting period of 4–6 weeks and followed by postoperative chemotherapy up to 12 cycles. The primary endpoint was R0 resection rate. The secondary endpoints were safety, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). The trial was conducted following approval from the Institutional Ethics Review Board of all institutions and registered in the University Hospital Medical Information Network Clinical Trials Registry (registration number: UMIN000009530). Results: Between February 2013 and December 2017, 29 patients from six centers were enrolled in this trial. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality after liver resection occurred. During the median follow-up of 30.7 months (range, 7.2–82.6 months), the median OS for the 29 patients was 49.1 months. The 3-year PFS and OS rates were 7.4%, and 64.4%, respectively. The 3-year RFS rate was 10.0% in 20 patients who achieved R0 or R1 resections. Conclusions: Bevacizumab plus mFOLFOX6 achieved a high R0 resection rate with a favorable survival for patients with advanced CRLMs harboring mutant-type KRAS. Clinical trial information: UMIN000009530.
Stereotactic body radiotherapy (SBRT) with functional treatment planning in patients with hepatocellular carcinoma (HCC) and advanced hepatic cirrhosis: Survival outcomes and toxicity.
Authors: Kirichenko Alexander V. , Hasan Shaakir , Liang Yun , Lee Danny , Godla Aishvarya , Renz Paul , Abel Stephen , Uemura Tadahiro , Machado Lorenzo , Thai Ngoc
Published: January 2022

460

Background: To evaluate outcomes and dosimetric parameters of ablative stereotactic body radiotherapy (SBRT) with functional treatment planning for localized hepatocellular carcinoma (HCC) in patients with Child-Pugh B (CP-B) hepatic cirrhosis. Methods: Liver SPECT with 99mTc-sulfur colloid was co-registered to 3D-CT for identification and avoidance of functional hepatic parenchyma during SBRT in patients with advanced cirrhosis. Functional liver volumes (FLV-SPECT) were compared to anatomical liver volumes, as were dosimetric parameters when radiation dose constraints were adapted exclusively to FLV-SPECT. Hepatic function, toxicity, and radiographic response were documented every 4–6 months following SBRT. Results: With a median follow-up of 25 months 37 patients (48 lesions treated) with CP-B cirrhosis received SBRT to a median dose 48 Gy (4–5 fractions). FLV-SPECT volume loss (509 cc or 41.3%, p < 0.001) was observed in all patients, while the functional and anatomical liver volumes matched well in a control group of non-cirrhotic/non-HCC patients. While tumors received ablative irradiation, mean dose to FLV-SPECT was maintained at 1.3 – 16 Gy (median 9.17 Gy), well below the liver threshold tolerance to radiation. Seventeen patients successfully completed liver transplant at a median time to transplant of 6.5 months. The dropout rate from the transplant list was 9 % with intrahepatic progression outside treated tumors. Eight of 10 patients with intrahepatic progression received additional SBRT during follow-up. Overall 2-year survival rate was 65% with no incidence of RILD or CP class migration from B to C was observed at 6+ months post SBRT. Two patients completed liver SBRT on a hybrid linear accelerator combined with MRI scanner (Unity MR-Linac, Elekta) utilizing Super-Paramagnetic Iron Oxide (SPIO) nanoparticle agent as an alternative contrast media for functionally active liver parenchyma. Prolonged SPIO-contrast retention also allowed per fraction treatment plan adaptation and enhanced tumor imaging. Conclusions: SBRT planning with 99mTc sulfur colloid SPECT allows identification and conformal avoidance of residual functionally active hepatic parenchyma in patients with CP-B cirrhosis. We report high local control and low toxicity leading to satisfactory pre- and post-liver transplant outcomes. Prospective clinical trial investigating MRI-SPIO functional treatment planning for liver SBRT is ongoing at our institution.
Prognostic significance of serum CA 19-9 response and dynamics in patients with intrahepatic cholangiocarcinoma undergoing surgical resection.
Authors: DiPeri Timothy P. , Newhook Timothy E. , Tzeng Ching-Wei D. , Chun Yun Shin , Lee Sunyoung S. , Javle Milind M. , Vauthey Jean-Nicolas , Tran Cao Hop Sanderson
Published: January 2022

479

Background: Pre and post-operative elevation of serum CA 19-9 have been associated with poor outcomes and increased risk of recurrence in patients with resected intrahepatic cholangiocarcinoma (ICC). We sought to investigate the impact of CA 19-9 response and dynamics on survival for patients with ICC undergoing surgical resection. Methods: Clinicopathologic characteristics were abstracted from a prospectively maintained database at a tertiary cancer care center for patients with ICC undergoing surgical resection from 2003 to 2020. Exclusion criteria included CA 19-9 non-producers (≤ 1 U/mL at baseline), missing baseline/pre-operative or postoperative CA 19-9 value, or total bilirubin > 2 mg/dL. Overall (OS) and recurrence-free survival (RFS) was compared among patients when categorized by baseline (neoadjuvant)/pre-operative (upfront surgery) and post-operative CA 19-9 values: normal (> 1 to 37 U/mL), intermediate (> 37 to 200 U/mL), and elevated (> 200 U/mL). Patients were then stratified by perioperative CA 19-9 response (responder [non-normal to normal CA 19-9 OR 50% reduction in CA 19-9; normal to normal CA 19-9], non-responder [non-normal to non-normal CA 19-9 OR < 50% reduction in CA 19-9; normal to non-normal CA 19-9]) and CA 19-9 dynamics (normal to normal, non-normal to normal, non-normal to non-normal, normal to non-normal CA 19-9 values). Results: A total of 112 patients were identified including 67 (59.8%) who underwent upfront surgery and 45 (40.2%) who received neoadjuvant therapy. Patients with a normal CA 19-9 at diagnosis had median RFS and OS durations of 61 and 163 months, followed by intermediate CA 19-9 (20 and 98 months) and elevated CA 19-9 (18 and 46 months, p = 0.308 RFS; p = 0.295 OS). Those who had a normal CA 19-9 post-operatively had the best median RFS and OS (46 and 163 months), followed by intermediate CA 19-9 (13 and 58 months) and elevated CA 19-9 (5 and 8 months, p = 0.059 RFS; p = 0.005 OS). When stratified by perioperative CA 19-9 response, responders had a median RFS of 36 vs. 13 months in non-responders (p = 0.143), and a median OS of 98 months vs. 88 months in non-responders (p = 0.077). Patients with normal CA 19-9 post-operatively had longer RFS/OS (normal to normal, 48/98 months; non-normal to normal, 30/not estimable months) than those who had non-normal CA 19-9 both pre- and post-operatively (non-normal to non-normal, 7/34 months, p = 0.018 RFS; p = 0.007 OS). Conclusions: Patients with normal CA 19-9 levels post-operatively, who had either normal or elevated CA 19-9 pre-operatively, had the greatest RFS and OS durations. A normal (or normalized) post-operative CA 19-9 may inform patient-centered decisions on adjuvant therapy and/or surveillance intensity.
Meta-analysis of surrogate endpoints for survival in patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitor-based regimens.
Authors: Zhu Andrew X. , Lin Yong , Ferry David Raymond , Widau Ryan C , Saha Abhijoy
Published: January 2022

483

Background: Overall survival (OS) remains the gold standard for demonstrating clinical benefit in advanced hepatocellular carcinoma (HCC). While surrogate radiology-based endpoints for OS, such as progression-free survival (PFS) and objective response rate (ORR) are commonly used in the field of oncology, they remain controversial in the setting of HCC where antiangiogenic agents were the mainstay of treatment until recently. Immune checkpoint inhibitors (CPIs) as monotherapy or in combination have shifted the treatment paradigm in HCC. We investigated the surrogacy of radiology-based endpoints from CPI clinical trials in advanced HCC. Methods: Study level data were collected for disclosures published in EMBASE, PubMed, Clinicaltrials.gov and conference abstracts. Keywords used included (abbreviated here): immune CPIs, advanced or metastatic HCC and ORR, PFS and OS. Key inclusion criteria included: Phase I, II and III trial data, and patients with advanced or metastatic HCC who received CPI monotherapy or in a combination regimen. The endpoints investigated were median OS (mOS), median PFS (mPFS) and ORR (RECIST v1.1). A weighted Pearson correlation coefficient, with weights corresponding to the number of patients in the different treatment arms of the trials, was calculated between ORR/mOS, ORR/mPFS and mPFS/mOS in all arms, arms that included only patients with Child-Pugh A liver function, and arms in the first-line therapy setting. 95% confidence intervals (CIs) based on the empirical bootstrap re-sampling method are also reported. Results: Eighteen clinical trials (8 randomized trials and 10 multi-cohort trials) published between 2017 and 2021, including 3,246 patients across 32 treatment arms, were selected for inclusion in this meta-analysis. Ten trials included CPI monotherapy arms, 5 trials included CPI + TKI arms, 4 trials included CPI + anti-angiogenic monoclonal antibody arms, and 2 trials included CPI + CPI arms. There was 1 CPI + chemotherapy arm and 1 CPI + CPI + TKI arm in separate trials. Weighted Pearson correlation coefficients and corresponding 95% CIs are presented in the table. Conclusions: Our analysis suggests ORR/mOS, ORR/mPFS, and mPFS/mOS are positively correlated, with ORR/mPFS more strongly correlated compared to the other pairs, in patients with advanced HCC who were treated with CPI-based regimens. [Table: see text]
Neuroendocrine tumors: Ten years of experience in a Mexican oncology reference center.
Authors: Torres-Cisneros Eduardo Rey , Burguete-Torres Alan , Buenaventura Cisneros Sergio , Bruni-Guerrero Carla Renata , Wimer-Castillo Blanca Otilia , Hernández-Barajas David , Vidal-Gutiérrez Oscar , Salazar-Mejía Carlos Eduardo
Published: January 2022

503

Background: Neuroendocrine tumors (NETs) are infrequent neoplasms that originate in the neuroendocrine cells of the embryological endoderm. Few data exist about the epidemiology and clinical characteristics of these tumors in the Mexican population. Methods: We performed a retrospective analysis of patients with pathology-confirmed NET treated at an Oncology Reference Center in North-East Mexico from 2010 to 2019. Clinical characteristics were recorded and an evaluation of overall survival (OS) using the Kaplan-Meier method was performed. Results: Fifty-three patients were included in the final analysis. The mean age at diagnosis was 54 +/- 16.36 years and 53% were men. Primarily affected sites were the gastroenteropancreatic tract [GEP] (47%), lung and mediastinum (21%), unknown primary (21%), and others (11%). Regarding the clinical stage at presentation, 22.6% of patients with NETs had localized disease, while 22.6% had regional spread and 54.7% were considered to have metastatic disease at diagnosis. Median OS was 42 months for all patients with NETs. In the GEP group, the median OS was 64 months, whereas for the lung/ mediastinum group was 8 months and for the unknown primary group was 5 months. Median OS stratified by stage was as follows: Localized disease: Not reached (NR), locoregional (20 months), and metastatic disease (8 months). Conclusions: To our knowledge, this is the first study published in English literature reporting the clinical characteristics and survival of Mexican patients with NETs. It is necessary to expand the information regarding these neoplasms to improve access of these patients to standard treatments and therefore improve their outcomes.
Treatment response and clinical outcomes of neuroendocrine neoplasms treated with immune checkpoint inhibitors: A single-institution experience.
Authors: Hauser Haley , Le Tiffany , Chou Joanne F. , Heffernan Olivia , DeMore April , Gonen Selin , Capanu Marinela , Reidy Diane Lauren , Raj Nitya Prabhakar
Published: January 2022

506

Background: Immune checkpoint inhibitors (ICIs) have antitumor activity in some solid tumors, however a role for ICI’s in the treatment of neuroendocrine neoplasms (NENs) is uncertain. We analyzed response and outcomes of NENs, both well differentiated neuroendocrine tumors (WDNET) and poorly differentiated neuroendocrine carcinomas (PDNEC), treated with ICIs at Memorial Sloan Kettering Cancer Center during the past decade. Methods: Patients with NENs who received ICIs between 2010-2021 were identified. Demographics, pathology characteristics, treatment response and outcomes were recorded. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. Analysis of next-generation sequencing (NGS) results from archival tumor tissue was performed. Results: 57 patients with NENs treated with ICIs were identified (WDNET-16; PDNEC-41). All patients had heavily-treated metastatic disease (median number of prior systemic treatments, WDNET-4, PDNEC-2). Median time from diagnosis to ICI treatment was 41.5 months in WDNET, 8 months in PDNEC. WDNET response: 1 (6%) partial response (PR), 4 (25%) stable disease (SD), 10 (63%) progressive disease (PD). PDNEC response: 6 (15%) PR (5 microsatellite stable, 1 unknown), 3 (7%) SD, 32 (78%) PD. Median duration of ICI treatment: 2 months (range 0-27) in WDNET, 1 month (range 0-16) in PDNEC; median duration of treatment for the 7 responders was 11 months (range 2-27). While receiving ICIs, 3 PDNEC responders developed PD in an escape lesion (2 brain, 1 nodal) after response in all other disease sites and successfully continued ICI treatment post-RT of escape lesion. Six-month PFS was 20% [95%CI: 7%-55%] and 9.8% [95%CI: 4%-25%], OS 60% [95%CI: 40%-91%] and 37% [95%CI: 25%-56%], respectively in WDNET and PDNEC. NGS results were available in archival tumor tissue of 35 patients (61%); most common alterations were TP53 (20/26, 77%) and RB1 (14/26, 54%) in PDNEC versus ATM, SMAD4, CREBBP, and IRS2 (all 1/9, 11%) in WDNET. Conclusions: We observed limited activity for ICI’s in NEN treatment, primarily restricted to a subset of PDNEC. PFS/OS findings were consistent with historical data, reflecting the pathogenesis of distinct NEN subtypes.
A natural history of gastroenteropancreatic neuroendocrine tumors evaluated at a tertiary cancer center: An observational study of 2,067 cases.
Authors: Powers Benjamin Daniel , Ahmad Yaser , Diaz Gabriel , Tarhan Ozlem , Al-Toubah Taymeyah E. , Haider Mintallah , Fleming Jason B. , Strosberg Jonathan R. , Anaya Daniel A.
Published: January 2022

508

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the second most prevalent digestive cancer and are increasing in incidence. With relatively indolent tumor growth, survival is often long, even for patients with metastatic disease. However, few studies have assessed long-term survival. Therefore, we analyzed the overall survival (OS) of a cohort of GEP-NET patients at a tertiary cancer center from 2000-2015. Methods: 2,707 patients with a pathologic diagnosis of GEP-NET were identified. 640 patients presented for second-opinion visits and were excluded, leaving 2,067 patients, of whom, 2,053 had vital status data for analysis. Primary sites included jejunum/ileum (small bowel), pancreas, gastric, colorectum, appendix, duodenum, and unknown. OS time was calculated from the date of pathologic diagnosis to the date of last follow-up or death. The reverse Kaplan-Meier method was used to calculate follow-up time. Vital status was identified through linkage to the Florida Cancer Registry. Kaplan-Meier (KM) curves and log-rank test were used for OS analyses. Results: The median age of the cohort was 60.7 years. The median follow-up time was 148.9 months (12.4 years). 1,431 (69.2%) patients presented with distant metastatic disease. Most patients, 1,351 (65.5%), underwent treatment at another facility before presentation. The median OS was 132.2 months (11.0 years) for the cohort and was 108.0 and 245.5 months for patients presenting with and without metastasis, respectively (p < 0.001). For metastatic patients, unknown primary tumor site was associated with the worst median OS (55 months), followed by rectal (77 months), gastric (84 months) and pancreatic (85 months; p < 0.001). Duodenal and small bowel had the longest median OS at 147 and 143 months, respectively. Surgery for metastatic disease had an OS benefit (155.7 months) compared to no surgery (98.3 months). Conclusions: In a large cohort of predominantly metastatic GEP-NET patients with extended follow-up time, median OS was over 11 years and 9 years for patients with metastatic disease. These results suggest that OS at a tertiary cancer center may be greater than historical national administrative analyses when given adequate follow-up time, which is important to avoid bias in survival estimates.[Table: see text]
Risk of myelodysplastic syndrome/acute leukemia with sequential capecitabine/temozolomide and 177Lu-dotatate.
Authors: Al-Toubah Taymeyah E. , Pelle Eleonora , Strosberg Jonathan R.
Published: January 2022

513

Background: The treatment landscape for neuroendocrine tumors includes alkylating-agent chemotherapy and peptide receptor radiotherapy (PRRT) with 177Lu-Dotatate. The risk of MDS/AML associated with 177Lu-Dotatate is approximately 2-3%. Several small prior studies have suggested substantially higher rates of MDS/AML (approximately 10%) in patients who have also received alkylating agent chemotherapy with streptozocin or temozolomide, either combined with PRRT or sequentially. Methods: Retrospective study of all patients with advanced NENs treated at the Moffitt Cancer Center between 1/2008 and 9/2019 who received treatment with CAPTEM. Results: 462 patients received treatment with CAPTEM, among whom 49 received also received PRRT. Median follow-up was x months. 4 patients developed MDS/AML, all of whom had also received both CAPTEM and PRRT. None of the patients who received CAPTEM chemotherapy without PRRT developed a long-term hematological malignancy. Conclusions: 8% of patients who received both CAPTEM and PRRT developed MDS or AML, a risk that is higher than that associated with PRRT alone. This cumulative risk needs to be considered when sequencing treatments in NETs.
Association of personalized and tumor-informed ctDNA with patient survival outcomes in pancreatic adenocarcinoma.
Authors: Botta Gregory P. , Abdelrahim Maen , Aushev Vasily N. , Esmail Abdullah , Drummond Bridgette , Sharma Shruti , Kalashnikova Ekaterina , Hook Nicole , Chandana Sreenivasa R , Tejani Mohamedtaki Abdulaziz , Malla Midhun , Schafer Liudmila N. , Kasi Pashtoon Murtaza , George Giby V. , Aleshin Alexey , Dayyani Farshid , Hanna Diana L.
Published: January 2022

517

Background: Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death, with a recurrence rate of 85% after curative surgery and a 5-year survival rate of 10%. Serum biomarkers like CA 19-9 lack sensitivity and specificity (10% of patients fail to produce CA 19-9), and are poor indicators of molecular residual disease (MRD). Circulating tumor DNA (ctDNA) detection allows for MRD identification months ahead of radiological findings, and may assess molecular response and patient outcomes. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA in a prospective clinical cohort of patients. Serial time points were collected for unresectable, borderline resectable, and resectable subsets of patients to monitor ctDNA levels in response to treatment (see Table). Results: 93 patients were included, with a median age of 67.3 yrs and 45% female. 285 timepoints were analyzed for ctDNA presence, with each patient having between 1 and 7 timepoints (median 3 timepoints per patient). 46 patients had one or more samples positive for ctDNA, resulting in an anytime ctDNA positivity rate of 49.5%. Anytime positivity correlated with the stage of disease (p<0.001). Within ctDNA-positive samples, observed levels were 0.04-1227 mean tumor molecules per mL of plasma (mean 35.1, median 1.02 MTM/mL). During the follow-up period (median 13.5 months, range 1-80 months), 36 patients had recurrence or disease progression events. Recurrence-free survival (RFS) strongly correlated with post-operative anytime ctDNA positivity: Hazards Ratio 8.0 (95% CI 3.4-18.7), p =1.6e-6. For 49 patients, CA 19-9 measurements were available. Elevated CA 19-9 was not correlated with RFS (p=0.35). Conclusions: Our study demonstrates the feasibility of tumor-informed ctDNA-based MRD testing in PDAC, in 93 patients of all stages. ctDNA positivity correlated with patient survival outcomes more strongly than CA19-9. Our data suggests patients can benefit from personalized and tumor-informed MRD testing.[Table: see text]
Liquid biopsy for diagnosis in patients with suspected pancreatic and biliary tract cancers: PREVAIL ctDNA pilot trial.
Authors: Mencel Justin , Feber Andrew , Begum Ruwaida , Carter Paul , Smalley Michaela , Bourmpaki Elli , Shur Josh , Zar Sameer , Kohoutova Darina , Popat Sanjay , George Angela , McVeigh Terri Patricia , Hubank Michael , Peckitt Clare , Fribbens Charlotte Victoria , Watkins David J. , Rao Sheela , Chau Ian , Cunningham David , Starling Naureen
Published: January 2022

522

Background: Most patients with pancreatic cancer (PC) and biliary tract cancer (BTC) present with advanced disease. In confirmed cases, circulating tumour DNA (ctDNA) may be detected through liquid biopsy in 80-90%. Obtaining a diagnostic biopsy can be technically challenging, require complex invasive procedures and may not be feasible due to comorbidity. Reduction in capacity of aerosol generating diagnostic procedures in many healthcare systems due to COVID19 has highlighted the unmet need for simple, non-invasive diagnostic tools. We piloted the use of ctDNA to support the diagnostic pathway in patients with suspected cancer across 6 tumour types, here we present its use in PC/BTC. Methods: This single centre prospective cohort pilot trial was conducted at the Royal Marsden from June 2020 to August 2021. 16 patients were planned each in the PC and BTC cohorts. Eligibility included radiologically suspicious PC/BTC without histological diagnosis, patients with prior non-diagnostic biopsy and inaccessible tumours. Liquid biopsy for ctDNA was collected for plasma based next generation sequencing, using a custom 59 gene panel of common variants in PC/BTC tumours, including analysis for somatic, copy number and structural variants. Clonal haematopoiesis of indeterminate potential (CHIP) and germline variants were identified and subtracted. A molecular tumour board (MTB) reviewed results for interpretation and clinical context. Primary outcome was the proportion of patients with a ctDNA result consistent with a diagnosis of malignancy following MTB discussion. Results: 32 patients with suspected PC (n= 16) and BTC (n=16) were recruited. Baseline characteristics are shown in table. ctDNA was detected in 69% and 56% of patients with suspected PC and BTC respectively. MTB discussion confirmed all variants detected were consistent with a diagnosis of malignancy. At the time of data cut off, 23 patients had a subsequent biopsy. The sensitivity and specificity of ctDNA as a diagnostic tool was 80% (90% CI 49.3-96.3) and 100% (90% CI 36.8-100) for PC respectively, and 100% (90% CI 60.7-100) and 75% (90% CI 24.9-98.7) for BTC respectively. There were 2 false negatives in the PC cohort subsequently diagnosed with PC, and 1 false positive in the BTC cohort subsequently diagnosed with oesophageal cancer. Conclusions: ctDNA can be used to support a diagnosis of cancer in patients with radiologically suspected PC/BTC. A blood first, tissue second strategy in the diagnosis of PC/BTC could improve diagnostic efficiency, speed, and add resilience to the current diagnostic pathway. Clinical trial information: NCT04566614. [Table: see text]
Hypofractionated radiotherapy to the pancreas: U.K. experience.
Authors: Teoh Suliana , Sabbagh Ahmad , Wadsley Jonathan , Low Lori , Harrison Claire , O'Hare Jolyne , Goody Rebecca , Summers Kitty , Wilson David , Walther Julie , Wilson Fiona , Radhakrishna Ganesh , Aitken Katharine , Owens Rob , Mukherjee Somnath
Published: January 2022

525

Background: During the COVID19 pandemic, many centres in the UK, shifted towards utilising hypofractionated radiotherapy (RT) to pancreas. We aim to report the UK experience in hypofractionated radiotherapy to the pancreas in 2020. Methods: We retrospectively identified patients receiving either moderate hypofractionated (15 fractions) or ultra-hypofractionated (3-5 fractions) RT to the pancreas from 7 centres in the UK. Rates of toxicity, progression, death and potential prognostic factors were assessed. Univariate and multivariate Cox proportional hazards analyses were performed. Results: 92 patients from 7 centres were included in the analysis (median age 71 (range 49-88). 90% had performance status of 0-1. 66% had locally advanced disease. 53% had RT delivered over 3-5 fractions (n = 49, median: 30Gy/5f, range:30-40Gy in 3-5f). The rest had 15-fraction RT with or without concurrent chemotherapy (n = 43, median: 45Gy/15f, range: 36-45Gy/15f). Induction chemotherapy (CT) was used in 64% (FOLFIRINIOX –42/59). Median follow-up was 13 months from first treatment (induction CT or RT). Median overall survival (OS) among all patient was 17 months, (95% CI-14.5-19.5 months). On multivariable analysis, induction CT was the only predictor of improved PFS (median survival (MS) 12 vs 5 months; hazard ratio [HR] 0.23; 95% confidence interval [CI]: 0.12-0.44, p < 0.001) and OS (MS 24 vs 11 months; HR 0.15; 95% CI: 0.07 – 0.34, p < 0.001). There were no deaths. 4 patients had grade 3+ toxicities (transaminitis, cholecystitis and gall bladder perforation, small bowel obstruction and diarrhoea) –all had concurrent CT. Conclusions: Our survival outcome appears to be comparable with published data from CT + concurrent chemoradiotherapy. Induction CT appears to improve outcome. Careful selection of patients can help maximise advantage in this patient population.
Early-onset pancreatic cancer: Defining contemporary presentation, treatment, and outcomes in the under 50 age group using real-world data.
Authors: Mendis Shehara Ramyalini , Lipton Lara Rachel , Ananda Sumitra , Michael Michael , McLachlan Sue-Anne , Thomson Benjamin N. , Knowles Brett , Fox Adrian , Nikfarjam Mehrdad , Usatoff Val , Shapiro Julia , Clarke Kate , Pattison Sharon Tracy , Chee Cheng Ean , Zielinski Rob , Wong Rachel , Gibbs Peter , Lee Belinda
Published: January 2022

533

Background: The incidence of pancreatic cancer is increasing in younger patients (pts). Early onset pancreatic cancer (EOPC) is reportedly diagnosed at a later stage, potentially compromising outcomes compared to later onset pts (LOPC). With recent gains in staging and neo/adjuvant regimens, we sought to elaborate on the characteristics of EOPC and LOPC in a contemporary real-world cohort. Methods: The PURPLE registry, a prospectively collected multi-site data set on consecutive pancreatic cancer pts was interrogated. Patient, tumor, treatment and outcome data were extracted for EOPC vs LOPC. EOPC were those diagnosed prior to age 50 and LOPC after age 50. Resectability status was per MDT consensus. Results: Of 1534 pts, 93 (6%) were EOPC (51% male) and 1442 (94%) LOPC (51% male). EOPC had better ECOG performance status (0-1: 95% vs 81%, Relative Risk [RR] 1.2, p < 0.001) and Charlson Comorbidity Index Score (0-2: 98% vs 28%, RR 3.5, p < 0.001). Primary tumor site (head/body/tail: 66%/11%/20% for EOPC and 68%/17%/14% for LOPC), and staging (resectable/borderline resectable/locally advanced/metastatic: 29%/16%/14%/41% for EOPC vs 28%/9%/21%/41% for LOPC) did not differ. 25 (93%) of EOPC and 320 (79%) LOPC resectable pts underwent resection (p = 0.13). 12 (80%) EOPC and 36 (26%) LOPC borderline resectable pts underwent resection (RR 3.0, p < 0.001). Resection margin status (R0 vs R1 vs R2) did not differ. Resected EOPC more frequently received neoadjuvant therapy (30% vs 9%, RR 3.2, p = 0.001). EOPC were more likely to receive palliative chemotherapy in the advanced/metastatic setting (77% vs 49%, RR 1.6, p < 0.001), and were more likely to receive first line (1L) FOLFIRINOX than gemcitabine-nab-paclitaxel (36% vs 18%, RR 2, p = 0.019). Median overall survival (OS) was superior for EOPC (24 vs 12 months, Hazard Ratio [HR] 0.55, p < 0.001). For resectable pts, relapse free survival (RFS) did not differ but OS was superior for EOPC (undefined vs 27.7 months, HR 0.26, p = 0.004). In borderline resectable pts, RFS was similar and OS only numerically superior for EOPC (31.2 vs 17.7 months, p = 0.20). For locally advanced disease, 1L progression free survival (PFS1) was similar and OS was superior for EOPC (27.8 vs 11 months, HR 0.40, p = 0.008). There was no difference in PFS1/OS for metastatic pts. Conclusions: EOPC are fitter, with similar stage at diagnosis as LOPC. EOPC are more likely to receive neoadjuvant chemotherapy and undergo resection when presenting with borderline resectable disease. EOPC receive more treatment and have superior OS, with RFS/PFS1 not statistically different to LOPC.
Impact of venous thromboembolism in hospitalized patients with pancreatic cancer: A nationwide inpatient sample (NIS) study.
Authors: Thalambedu Nishanth , Ullah Waqas , Gundarlapalli Sravani
Published: January 2022

535

Background: Pancreatic cancer (PC) has a strong association with venous thromboembolism (VTE) but the impact of it on mortality and morbidity is unknown. Inpatient costs contribute significantly to the overall cancer care costs even though there is a modest improvement in survival of pancreatic cancer patients. This study aims to determine the mortality trends and associated health care utilization in PC patients with and without VTE and to analyze its impact on hospitalized patients. Methods: We used National Inpatient Sample (NIS) to extract data for all patients above 18years of age hospitalized with a primary diagnosis of Pancreatic cancer from 2002-2018 using ICD-9 and ICD-10 codes. Unadjusted odds ratio for dichotomous outcomes were calculated, and independent t test analysis was done for continuous outcomes. Results: The odds of all-cause mortality (OR 1.35, 95% CI 1.33-1.37, p<0.001) and stroke (OR 1.82, 95% CI, 1.76-1.87, p<0.001) were significantly higher in pancreatic cancer patients with VTE compared to without VTE. PC patients with VTE were found to have significantly higher average cost of hospitalization (US $56101 vs US $46325, p<0.001) and longer length of stay(LOS) (8.20 vs 6.83, p<0.001) when compared to patients without VTE. Conclusions: Hospitalized PC patients with VTE have higher odds of mortality and stroke when compared to PC patients without VTE. Similarly, VTE in PC patients is shown to increase the hospitalization costs and overall length of stay.[Table: see text]
Predictors of early mortality in early and late onset pancreatic cancer (PC).
Authors: Kadakia Kunal C. , Trufan Sally J. , Musselwhite Laura W. , Wesson Zachary J. , Hwang Jimmy J. , Salem Mohamed E.
Published: January 2022

543

Background: The incidence of early-onset PC (EOPC) is rising and is associated with substantial mortality. We sought to identify independent predictors of early mortality in a cohort of EOPC and matched older patients (pts). Methods: Pts with EOPC (≤50 years) and matched cohorts of average (51-69, AOPC) and late (≥70, LOPC) onset PC by sex, race, year of diagnosis, and presence of metastatic disease were identified using the institutional tumor registry for years 2011-2018. Demographic and clinicopathologic characteristics were retrieved. Overall time of survival was assessed using Kaplan-Meier curves and the Cox Proportional Hazards modeling. Multivariable regression was conducted to evaluate for predictors of early mortality in non-metastatic and metastatic pts, defined as either death within six months of diagnosis compared to those surviving at least 12 months. Results: In total, 100 pts with EOPC (median age 47, range 29-50), 100 pts with AOPC (median age 60, range 51-69), and 100 pts with LOPC (median age 78, range 70-93) were analyzed. Of these, 46% were female, 28% were black, and 43% had metastatic disease at presentation. In non-metastatic pts, the 12-mo. survival rate by age group was: EOPC 74.4% (95% CI 59-85), AOPC 60% (95% CI 43-73), and LOPC 32.4% (95% CI 18-47). Variables associated with mortality within 6 months of diagnosis in non-metastatic pts on univariable analysis included age group, BMI ≤25, ECOG performance status (PS), neutrophil-to-lymphocyte ratio ≥5 (NLR5), CA 19-9 ≥130, no surgical resection, and no adjuvant chemotherapy. Multivariable regression confirmed no surgical resection (Odds Ratio [OR] 9.6, 95% CI 3-29), no receipt of chemotherapy (OR 6.9, 95% CI 2-21), and NLR5 (OR 5.4, 95% CI 1-22) as independent predictors for early mortality in non-metastatic pts. In metastatic pts, the 12-mo. survival rate by age group was: EOPC 32.6% (95% CI 19-47), AOPC 27% (95% CI 15-41), and LOPC 5.8% (95% CI 1-16). On univariable analysis, variables associated with mortality within 6 months of diagnosis included age group, ECOG PS, and NLR5. Multivariable regression confirmed LOPC (OR 11.6, 95% CI 2-61) and NLR5 (OR 11, 95% CI 2-54) as independent variables for early mortality. Race, sex, BMI, CA 19-9, smoking, alcohol use, primary tumor location, and site of metastases were not associated with early mortality in metastatic pts. No difference in independent predictors of early mortality between EOPC and older pts were identified. Conclusions: In this cohort of EOPC and matched older pts, LOPC (age ≥70) and NLR5 were independently associated with early mortality by 6 months in metastatic pts. In non-metastatic pts, lack of curative intent surgery, no receipt of chemotherapy, and NLR5 were independently associated with early mortality. There were no independent predictors for early mortality that distinguished EOPC and older pts. Further work is needed to identify prognostic factors unique to EOPC.
Palliative care and end-of-life care in metastatic pancreatic cancer.
Authors: O'Brien Jenny , Halsey Brenton S. , Connors Meghan , Berardi Giuliana , Upadhyay Vruksha , Bauman Jessica R , Dotan Efrat
Published: January 2022

544

Background: Patients with metastatic pancreatic cancer (mPC) have a 5-year survival of 2.7%. Studies have shown that patients with mPC receive aggressive end of life (EOL) care which has been associated with worse quality of life for patients and high use of resources when they are least likely to benefit patients. Methods: A retrospective database of patients with mPC treated at Fox Chase Cancer Center between 2010 and 2019 was analyzed for utilization of palliative care and EOL care. Statistical analysis was performed using one-sample Z tests calculated in Excel. Results: We identified 610 patients with mPC, of whom 39% received palliative care, 56% were referred to hospice, and 91.8% are deceased. The average time from mPC diagnosis to palliative care consult was 232 days, the average time from palliative care consult to death was 121 days. Patients who received palliative care were less likely to receive chemotherapy within 14 days of death (7.7% vs 13.3%, p =0.05), more likely to have a DNR code status (83.3% vs 44.5%, p < 0.0001), and more likely to be referred to hospice (83.9% vs 35.9%, p < 0.0001). The average length of time on hospice was 24 days with no difference between those who received palliative care and those who did not. Patients who were referred to hospice were also less likely to receive chemotherapy within 14 days of death (6.7% vs 19.8%, p < 0.0001). Conclusions: Patients with mPC who had a palliative care team involved in their care were significantly less likely to receive aggressive EOL care.
Clinical relevance of adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma who underwent surgery following neoadjuvant modified FOLFIRINOX.
Authors: Lee So Heun , Yoo Changhoon , Kang Sora , Chang Heung-Moon , Jeong Jae Ho , Kim Kyu-Pyo , Ryoo Baek-Yeol
Published: January 2022

546

Background: The benefit of adjuvant chemotherapy (ACT) following curative-intent surgery in pancreatic ductal adenocarcinoma (PDAC) patients who had received neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) remains unidentified. This retrospective analysis aimed to assess the clinical relevance of ACT in patients who underwent surgery following neoadjuvant mFOLFIRINOX. Methods: Between January 2017 and December 2020, 220 patients received neoadjuvant mFOLFIRINOX and underwent pancreatectomy for localized PDAC at the Asan Medical Center, Seoul, Korea. Patients unable to undergo curative-intent surgical resection (R0 or R1) and those with histological types other than ductal adenocarcinoma were excluded. Survival outcomes were compared according to ACT administration. Disease-free survival (DFS) was defined as the duration between surgery and recurrence or death of any etiology, whichever occurred first; and overall survival (OS) was that between surgery and death from any etiology. Results: ACT was administered to 150 (68.2%) patients. ACT recipients were significantly younger (median age, 61 vs. 64, p = 0.035) and they received significantly fewer cycles of neoadjuvant chemotherapy (median, 7 vs. 9, p = 0.0001) compared to non-recipients. As ACT, mFOLFIRINOX (n = 98, 65.3%), gemcitabine monotherapy (n = 39, 26.0%), and gemcitabine-capecitabine (n = 4, 2.7%) were administered. ACT recipients showed significantly better survival outcomes compared to non-recipients; median DFS 13.4 months (95% CI, 10.7–18.8) vs. 8.3 months (95% CI, 4.9–16.0), respectively (p = 0.0042); and median OS 33.4 months (95% CI, 29.9–NA) vs. 23.8 months (95% CI, 17.9–NA), respectively (p = 0.0021). DFS and OS were significantly better in ACT recipients regardless of the lymph node (LN) status during surgery (p = 0.033 for DFS and p = 0.027 for OS in negative LN; and p = 0.032 for DFS and p = 0.012 for OS in positive LN). There was no significant difference in DFS (p = 0.79) and OS (p = 0.49) between mFOLFIRINOX and gemcitabine-based regimens. In multivariate analysis, ACT remained significant as a favorable prognostic factor (DFS, hazard ratio [HR] 0.43 (95%CI, 0.26–0.71, p = 0.001); OS, HR 0.33 (95%CI, 0.17–0.64, p = 0.001). Conclusions: In PDAC patients who underwent surgery following neoadjuvant mFOLFIRINOX, ACT may be associated with improved survival outcomes. Its benefit was not affected by the LN status and ACT regimens.