bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of the timing of immune checkpoint inhibitors infusion in patients with advanced hepatocellular carcinoma.
Authors: Pascale Alina , Allard Marc Antoine , Benamar Amal , Levi Francis , Adam Rene , Rosmorduc Olivier
Published: January 2024

457

Background: Experimental and clinical data in melanoma and lung cancer suggest that the response to immune checkpoint inhibitors (ICI) may be influenced by circadian rhythms. However, similar findings are lacking in hepatocellular carcinoma (HCC). The aim of this study was to assess the impact of infusion timing of atezolizumab, an ICI, associated or not with bevacizumab, as first line systemic treatment in advanced HCC. Methods: We retrospectively analyzed all consecutive patients, who received, as first line systemic treatment, at least two cycles of atezolizumab +/- bevacizumab for advanced HCC in Paul Brousse Hospital, Villejuif, France, between January 2020 and October 2022. We split them in two groups: 1) patients receiving the first two cycles after 1 pm (afternoon group); 2) patients receiving at least one of the two first cycles before 1 pm (morning or mixed group). Cox regression models were used to assess the prognostic value of ICI infusion timing for the overall survival (OS). Results: A total of 131 patients were analyzed. 119 patients (90.8%) were male, with a median age of 70 years [35; 88]; 40 patients (31%) had performance status (PS) ≥ 1. 103 patients (79%) had cirrhosis; 61 patients (46.6%) had portal hypertension. 49 patients (37.4%) had metastatic HCC and 52 patients (40.6%) had portal vein thrombosis at diagnosis. The mean initial level of alpha-fetoprotein was 5,212.8 ng/mL (SD: 18,681.8). 36 patients (27.5%) received only atezolizumab. 41 patients were included in the first group and were compared to 90 patients included in the second group. There were no significant clinical differences between the two groups. The median OS was significantly lower in the afternoon group compared to the morning or mixed group (11.5 months vs 18.7 months, p = 0.015). In univariate analysis, PS ≥ 1 (p = 0.025), initial level of alpha-fetoprotein (p = 0.030), monotherapy by atezolizumab (p = 0.004) and the first two cycles of ICI infusion after 1 pm (p = 0.018) were significantly correlated with OS. The first two cycles of ICI infusion after 1 pm remains an independent factor significantly associated with OS in the multivariate Cox model, with HR 2.29, 95% CI: 1.27-4.14, p = 0.005 (Table). Conclusions: Our results suggest that the afternoon infusion of the first two cycles of ICI is associated with lower outcomes in patients with advanced HCC, independently of other prognostic factors. There may be confounding factors due to the variability of administration of further perfusions. Larger data are needed to confirm such findings. [Table: see text]
Efficacy and safety of a combination of sintilimab, bevacizumab plus gemcitabine, and albumin-bound paclitaxel for initially unresectable gallbladder carcinoma: A prospective, single-arm phase II study.
Authors: Wang Miao , Zhou Jiamin , Xu Weiqi , Pan Qi , Mao Anrong , Zhang Ning , Feng Yun , He Xigan , Lin Zhenhai , Wang Longrong , Zhang Yongfa , Zhu Hongxu , Ding Zhiwe , Wang Yixiu , Yu Bingran , Zhang Ti , Wang Lu
Published: January 2024

489

Background: Immune checkpoint inhibitors plus chemotherapy had demonstrated important therapeutic advantages in biliary tract cancers (TOP-AZ and Keynote-966). At present the data of gallbladder carcinoma (GBC) is in blank condition almost, and the effectiveness remains to be improved. Further, the addition of bevacizumab to PD-1 inhibitors has improved the clinical results in carcinomas, such as hepatocellular carcinoma, for which therapeutic options have been limited. This study intended to explore the safety and efficacy of sintilimab combined bevacizumab with chemotherapy in the first-line treatment of initially unresectable GBC. Methods: The study was an ongoing open-label, single-arm, phase II trial (Clinical Trial ID: NCT05757336), which consisted of 2 parts: safety-run-in part, where pts received sintilimab (200mg/kg, iv, d1, Q3W) + bevacizumab (7.5mg/kg, iv, d1, Q3W) + gemcitabine (1000mg/m2, iv, d1, Q3W) and albumin-bound paclitaxel (125mg/m2, iv, d1, Q3W), followed by experimental part to evaluate the efficacy and safety of this strategy. The primary endpoint was safety and objective response rate (ORR) assessed by RECIST v1.1. Secondary objectives included disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: No DLT was reported at safety-run-in part. Up to the end of Sept 2023, 15 patients were enrolled with a median age of 60.4 years (range 46-75), 26.7% were male. Median follow-up time was 3.68 months. All patients completed at least one tumor response evaluation, confirmed ORR was 60.0% and DCR was 93.3%. Median PFS and OS was not reached yet. Grade 3 TRAEs occurred in 40.0% of patients (n=6), and the most common TRAEs (incidence≥5%) among them were rash (20.0%), AST elevation (6.7%), fever (6.7%), platelet count decreased (6.7%), fatigue (6.7%), pneumonitis (6.7%). Conclusions: The combination of sintilimab, bevacizumab and AG chemotherapy was tolerable and showed a promising ORR in initially unresectable GBC patients. This regimen could be a feasible and safe option for initially unresectable GBC, but this needs further validation. Clinical trial information: NCT05757336 .
Preliminary results of ALTER-H006: A phase II study of TQB2450 plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after radical resection.
Authors: Mao Xianhai , Duan Xiaohui , Wu Dongde , Zhou Cuncai , Tian Yifeng , Shen Jian , Xu Guohui , Lai Jianlin
Published: January 2024

494

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Surgical resection remains as the mainstay of curative treatment option, However, the recurrence rate after surgical resection could be high especially in patients with CNLC stage IIb (tumor number ≥ 4) and IIIa (vascular invasion). Herein we evaluated the efficacy and safety of the anti-angiogenic tyrosine kinase inhibitor, anlotinib, plus TQB2450, a novel programmed death-ligand 1 (PD-L1) inhibitor as an adjuvant treatment for HCC with high risk of recurrence after radical resection. Methods: This prospective, multiple-center, single-arm phase II study (NCT05111366) enrolled histologically confirmed resectable HCC pts for CNLC Stage IIb/IIIa with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b) portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. At 4-8 weeks after R0 resection, adjuvant therapy was started with anlotinib (12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year). Primary endpoint was 1-year recurrence-free survival (RFS) rate; secondary endpoints were RFS, 1-year overall survival (OS) rate, and safety. Results: Between January 2022 and August 2023, a total of 22 pts from 4 centers were enrolled, 21 pts included in per-protocol set analysis. The 21 pts were predominantly male (95 %, n = 20), and the median age was 50 years (range: 33–75). Eight pts (38%) had CNLC Stage IIb and 13(62%) had CNLC Stage IIIa HCC. Among them, 19 pts received at least once tumor assessment. According to RECIST 1.1, out of 21 pts, 16 showed no recurrence, 3 relapsed, 1 dropped out and 1 discontinued due to serious adverse events. The 1-year RFS rate was 62.31%（95%CI: 17.15-88.08）, while the median RFS was not mature. Additionally, safety profile exhibited that the regimen was tolerable. 16 of 22 pts (73%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 6 pts (27 %) including hypertension (13.5 %), neutropenia (9 %), and bleeding (4.5 %). Conclusions: The present study indicated that anlotinib plus TQB2450 as adjuvant treatment for HCC with high risk of recurrence after radical resection exhibited potential efficacy and tolerable safety profile. The conclusion should be validated in more participants included subsequently. Clinical trial information: NCT05111366 .
Comparison of neoadjuvant treatment modalities for locally advanced intrahepatic cholangiocarcinoma.
Authors: Garita Esteban , Tahir Muhammad Mohid , Sucre Santiago , Juarez Juan Jose , Peters Mary Linton Bounetheau , Sarwar Ammar , Bullock Andrea J.
Published: January 2024

510

Background: The only curative therapy available for intrahepatic cholangiocarcinoma (IHCC) is resection. Nonetheless, most patients (pts) are diagnosed at a more advanced stage. In this population, using neoadjuvant treatment—locoregional therapies, systemic chemotherapy, or a combination—may improve survival outcomes and downstage them to resectable. We present data comparing survival outcomes (median overall survival [mOS], median progression-free survival [mPFS]) and resection rate (RR) among pts with locally advanced IHCC who received chemotherapy (CT-only), Y90-TARE with chemotherapy (Y90+CT) or Y90-TARE alone (Y90-only) as neoadjuvant treatment. Methods: A retrospective chart review of all pts from October 2015 to December 2022 with biopsy-proven IHCC was completed. Exclusion criteria included ECOG ≥ 2, stage IV extrahepatic disease, and having received previous treatment for IHCC. We defined the Y90+CT arm as pts who received ≤ 4 cycles before Y90 or chemotherapy < 8 weeks after Y90. Statistical analysis was performed with Chi-square, Fisher’s Exact, and Kruskal-Wallis tests. Kaplan-Meier analysis was used for survival calculations and a Log-rank test to compare the arms. Survival is reported as median and 95% confidence interval [CI]. Results: A total of 56 pts were included: 23 pts in the CT-only arm, 15 in the Y90+CT arm, and 18 in the Y90-only arm. The median age at diagnosis was 69 years (IQR 59-74), and 54% were male. There was no statistically significant difference in age at diagnosis or sex between the three arms. RR was 1/23 (4%), 5/10 (50%), and 7/11 (64%) in the CT-only, Y90+CT, and Y90-only arms, respectively (CT-only vs. Y90+CT, p<0.03; CT-only vs. Y90-only, p=0.01). mOS and mPFS for the cohort were 16.3 months [15.3–17.3] and 7.4 months [5.1–9.6]. Per arm, the mOS were 12.4 months [10.1—14.6], 24.3 months [23.3—25.3], and 24.3 months [23.0—25.6] for CT-only, Y90+CT, and Y90-only arms, respectively (CT-only vs. Y90+CT, p<0.03; CT-only vs. Y90-only, p<0.01). The mPFS were 3.5 months [1.1—5.9], 6.2 months [3.8—8.6], and 10.5 months [8.3—12.6], respectively (CT-only vs. Y90-only, p<0.01; Y90+CT vs. Y90-only, p<0.02). Conclusions: In the neoadjuvant setting, including Y90 as a treatment modality may improve survival outcomes and resection rates compared to using chemotherapy alone. Further analysis will include running the Cox multivariate regression model to control for factors that may affect treatment selection in this population.
PROOF 301: Results of an early discontinued randomized phase 3 trial of the oral FGFR inhibitor infigratinib vs. gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma (CCA) with an FGFR2 gene fusion/rearrangement.
Authors: Abou-Alfa Ghassan K. , Borbath Ivan , Roychowdhury Sameek , Goyal Lipika , Lamarca Angela , Macarulla Teresa , Shroff Rachna T. , Oh Do-Youn , Javle Milind M. , Tamas Catalin , Savastano David M , Van Veenhuyzen David Friedrich , Xu Cindy , Solanas Jacki , Freas Elizabeth
Published: January 2024

516

Background: Infigratinib (BGJ398), an oral inhibitor of fibroblast growth factor receptor (FGFR)1-3 with demonstrated clinical activity and a manageable adverse event profile in a phase 2 study in patients with previously treated, unresectable or metastatic CCA with an FGFR2 fusion or other rearrangement, represented one of the few targeted treatment options after progression on first-line therapy, as per FDA conditional approval. The confirmatory phase III trial PROOF 301 of infigratinib versus gem/cis as frontline treatment of FGFR2 Gene Fusions/Translocations CCA was early discontinued. Here we report the efficacy and safety in the patients accrued prior to termination. Methods: Eligible patients were randomized 2:1 to infigratinib 125 mg on days 1-21 of a 28-day cycle vs intravenous gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. The primary endpoint was progression-free survival (PFS), confirmed by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), investigator determined PFS, overall response rate (ORR), best overall response (BOR), disease control rate (DCR), duration of response (DOR), and safety and tolerability. Crossover to the investigational arm was permitted at progression. Results: Over 40 months, a total of 1127 patients were pre-screened at 120 sites and 48 enrolled. In a 2:1 randomization, 29 patients received infigratinib and 19 received gem/cis. Upon progression, 2 patients crossed over from gem/cis to infigratinib. Median PFS (95% CI) by BICR was 7.4 (5.4, not evaluable [NE]) and 8.0 (3.4, NE) months with infigratinib and chemotherapy, respectively. The ORRs by BICR were 37.9 % with infigratinib and 15.8 % with gem/cis. Grade 3–4 adverse events occurred in 79.3% and 58.8% patients treated with infigratinib and chemotherapy. Conclusions: Infigratinib showed a preliminary signal of efficacy in the first-line treatment of FGFR2-rearranged CCA, but due to early termination of the study, the power is insufficient to draw conclusions regarding its efficacy in comparison to gem/cis. This study highlights the challenge of performing confirmatory studies in biomarker-selected subpopulations of rare tumors and the importance of exploring alternative approaches to delivering confirmatory data for regulatory purposes. Clinical trial information: NCT03773302 .
Number of subsequent treatments and time to recurrence in hepatocellular carcinoma.
Authors: Juarez Juan Jose , Birda Vaibhav , Sucre Santiago , Garita Esteban , Pacheco-Barrios Kevin , Paredes Rodrigo , Bullock Andrea J. , Sarwar Ammar , Peters Mary Linton Bounetheau
Published: January 2024

526

Background: Hepatocellular carcinoma (HCC) is often managed with locoregional therapies including surgical resection, ablation, transcatheter arterial chemoembolization (TACE), and selective internal radiation therapy (Y90). Most patients require multiple treatments over several years due to ongoing development of new lesions, distinct from other cancer types. Our project aims to analyze this treatment trajectory and the impact of treatment selection. Here we present an interim analysis focusing on the number of subsequent therapies and time to first recurrence (TTR). Methods: We identified 202 patients newly diagnosed with HCC between 2019-2021 who were seen in the BIDMC Liver Tumor Multidisciplinary Clinic. Complete abstraction of medical records was performed in 51 patients to date. Our primary outcome was of the number of subsequent therapies depending on the selected first-line locoregional therapy. Incidence risk ratios (IRR) were obtained via a crude and adjusted (age, gender, race, Child Pugh) linear regression model. Ablation was used as the reference treatment. Secondary outcomes included survival analysis of TTR, overall survival (OS) and time to initiation of systemic therapy. TTR was defined as the appearance of new lesions, excluding residual disease. Results: Mean age at diagnosis was 65 years old, 73% were male, and 92% ECOG 0. 37 patients out of 50 had recurrence, almost all local (97%). The total number of subsequent therapies received was 110; the most common treatment received on first recurrence was ablation (59%) followed by Y90 (24%). Patients who received TACE were more likely to undergo a higher number of subsequent therapies in both the unadjusted (IRR 2.51, p<0.001, 95%CI 1.6-3.9) and adjusted analysis (IRR 4.43 p<0.001, 95%CI 2.5-8.1) with 4.4 (2-9) mean subsequent treatments when compared to ablation with a mean number of subsequent treatments of 1.47 (0-7). Y90 had 1.85 (0-7) mean subsequent treatments and surgery 1.87 (0-7), with inconclusive results regarding IRR when compared to ablation. Median TTR was 19.1 months (10.2-29.3) with ablation having the longest time with 22.2 months (13.2-31.1), followed by surgery with 20.3 months (13.3-29.3), Y90 with 19.1 months (6-NR) and TACE with 12.1 (6.1-21.2). Median OS was not reached, and only 5 patients started systemic therapy. Conclusions: This interim analysis shows that patients treated with TACE as the first locoregional therapy are likely to undergo a higher number of subsequent treatments when compared to ablation.
Molecular predictors of response to first-line systemic therapies in advanced hepatocellular carcinoma.
Authors: Chang Jeremy , Conner Elizabeth , Fowler Kathryn J , Tamayo Pablo , Burgoyne Adam
Published: January 2024

534

Background: With numerous advances in systemic therapy for advanced hepatocellular carcinoma (HCC) over the past several years, there are now multiple first-line treatment options which can be considered. These options include combination atezolizumab with bevacizumab (atezo/bev), programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) targeted agents, and oral multikinase inhibitor monotherapy. However, further guidance is needed to predict which patients will respond to best to each regimen. Methods: We performed a single center, retrospective study to determine the association between responses to first-line therapies in advanced HCC and various molecular alterations. Patients received first-line therapy with either atezo/bev, PD-1/PD-L1 monotherapy, or oral multikinase inhibitor monotherapy with treatment responses determined by imaging. All patients underwent next-generation sequencing (NGS) with testing performed on peripheral blood or tumor tissue. Results: A total of 116 patients with advanced HCC were included in this study. For first-line therapies, 45 (38.8%) patients received atezo/bev, 41 (35.3%) received oral multikinase inhibitor monotherapy, and 30 (25.9%) received PD-1/PD-L1 monotherapy. There was no association between treatment responses and patient ethnicity, age, or underlying cirrhosis etiology for any regimen. However, when analyzing NGS results, atezo/bev recipients with telomerase reverse transcriptase (TERT) promoter alterations had significantly higher rates of disease progression (PD) compared those without TERT promoter alterations (91.7% vs 54.6%, p = 0.03). In addition, in the oral multikinase inhibitor monotherapy group, those with CTNNB1 alterations had significantly greater PD rates compared to patients without these alterations (66.7% vs 31%, p = 0.04). There were no significant correlations between molecular alterations and responses in the PD-1/PD-L1 monotherapy group (Table). Conclusions: In our study, advanced HCC patients who received first-line systemic therapies were found to have significant correlations between TERT promoter and CTNNB1 alterations and responses to atezo/bev and oral multikinase inhibitor monotherapy, respectively. Given the widespread use of these regimens in the HCC treatment paradigm, additional studies are needed to confirm these findings and determine their impact on survival outcomes.[Table: see text]
Genomic and immune landscape of biliary tract cancers with ARID1A, PBRM1, and BAP1 alterations.
Authors: King Gentry Teng , Berg Rachel , Yilma Binyam , Stoppler Melissa Conrad , Hsieh Ronan Wenhan , Safyan Rachael A , Zhen David Bing , Coveler Andrew L. , Cohen Stacey A. , Shankaran Veena , Chiorean E. Gabriela , Harris William Proctor
Published: January 2024

557

Background: Alterations in ARID1A, PBRM1 and BAP1 subunits of the SWI/SNF complex are common in biliary tract cancers (BTCs) and have been implicated in tumor microenvironment (TME) immunomodulation. However, there is heterogeneity in outcomes, with PBRM1 and BAP1 conferring improved survival vs worse survival with ARID1A. We explored relationships between ARID1A, PBRM1 and BAP1 alterations with putative immunotherapy biomarkers and genomic co-alterations. Methods: We examined BTC patients in the Tempus database with ARID1A, PBRM1 and BAP1 alterations. Co-alterations were identified through next-generation sequencing (NGS) using the Tempus xT assay, a targeted, tumor-normal-matched DNA panel that detects SNVs, indels, and CNVs in 648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Samples additionally underwent whole transcriptome RNA-seq via the Tempus xR assay (Tempus Labs, Chicago, IL). Immune biomarkers explored include MSI-H, PD-L1, Tumor Mutation Burden (TMB), and immune cell infiltration by RNA sequencing. Parameters were analyzed between two groups: BTC with ARID1A, vs BTC with PBRM1 and/or BAP1 alterations. Results: 696 BTC patients with ARID1A, PBRM1 and BAP1 alterations were included. Overall, there was low frequency of MSI-H (3.2%), PD-L1-positivity (5.7%) and TMB >10 mt/Mb (4.7%). Among the two groups, there was a higher proportion of MSI-H patients in ARID1A BTC vs PBRM1 and/or BAP1 BTC (4.9% vs 1.4%, p=0.01). Macrophages were the predominant immune cell (46%), followed by CD4+ T-cells (23%) and NK cells (12%). CD8+ T cells were the least encountered (5%). B-Cells were seen more in ARID1A vs PBRM1 and/or BAP1 (9% vs 6%, p <0.001) while macrophages were more frequent in PBRM1 and/or BAP1 vs ARID1A (49% vs 44%, P <0.001). Co-alterations in SMAD4, TP53, ARID2 and KRAS were more frequent in ARID1A BTC while IDH2 and NRAS were more common in PBRM1 and/or BAP1. Within the PBRM1 subgroup, TP53 was most frequently encountered (33%), while CDKN2A alterations were most frequently encountered in BAP1 BTC (35%) (Table 1). Conclusions: This is the largest known data set exploring the genomic and immune landscape of BTC with ARID1A, PBRM1 and BAP1 alterations. Macrophages were the dominant immune cell TME and may be a target of interest. Co-alteration profile is distinct between ARID1A- vs PBRM1- and/or BAP1-altered BTC.[Table: see text]
Survival and progression-free survival in patients undergoing curative resection for intrahepatic cholangiocarcinoma.
Authors: Ozturk Nazli Begum , Jamil Laith H.
Published: January 2024

562

Background: Intrahepatic cholangiocarcinoma (iCCA) is a relatively rare but increasingly prevalent form of primary liver cancer. Surgical resection with negative margins is the mainstay of the treatment for patients with resectable-iCCA. However, given the rarity of iCCA and its low resectability rate, well-defined prognostic markers and outcomes for patients undergoing curative hepatectomy are lacking. We aimed to analyze the characteristics and outcomes of patients undergoing liver resection for iCCA. Methods: All consecutive patients with confirmed iCCA who underwent hepatectomy between 7/2006-3/2023 at our institution were included. Patients who received neoadjuvant therapy were excluded. Demographic, clinical, radiological, histopathological, recurrence, and survival data were collected. Overall survival was calculated from the date of liver resection to the date of death or last clinical encounter. Continuous variables are reported as median and interquartile range (IQR) 1 and IQR3, and categorical variables as counts and percentages. Results: A total of 83 patients (43 male, 40 female) were included in the final analysis. The median age at resection was 67 years (58.0-74.0). Histologically proven liver disease was present in 30.12% and liver cirrhosis was present in 9.63% of patients. Among all patients, hypertension was present in 61.44%, diabetes mellitus in 25.30%, inflammatory bowel disease in 7.22%. The median tumor size was 4.4 cm (3.0-6.2). Tumor histologic grade was 55.42% moderately differentiated tumor, 37.3% poorly differentiated tumor, and 7.22% well differentiated tumor. Of all patients, 37.66% had lymph node invasion, 35.61% had perineural invasion, and 30.76% had vascular invasion on liver histology. Positive surgical margins were present in 20.73% of patients. The duration from liver resection to the last follow-up or death was 1.6 years (0.80-3.20). The 1-, 3-, and 5-year recurrence-free survival rates were 72.78, 34.95, and 15.88% respectively. The 1-, 3-, and 5-year overall survival rates were 90.9%, 65.9, 44.2%, respectively. Advanced iCCA stage at diagnosis ( p<0.001), presence of lymph node metastasis ( p=0.03), vascular invasion ( p=0.02), and age<50 ( p=0.01) were associated with significantly worse overall survival. There was no statistically significant survival difference between patients with concurrent liver disease and those without (6.88 vs 4.35 years, p=0.46.). Conclusions: Our results demonstrate that iCCA carries a substantial risk of recurrence despite curative resection. The presence of advanced stage at diagnosis, lymph node involvement, vascular invasion, and age<50 were associated with significantly worse overall survival. Liver disease had no significant effect on the survival outcomes. Predictive markers of recurrence and survival in patients vary in the literature and remain to be validated.
Real-world 177Lu-DOTATATE peptide receptor radionuclide therapy: Treatment outcomes with dosing variations and in non-midgut neuroendocrine tumors.
Authors: Lee Hwan , Kipnis Sarit , O'Brien Sophia , Eads Jennifer Rachel , Katona Bryson W. , Pryma Daniel A.
Published: January 2024

593

Background: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE has been used for neuroendocrine tumors (NETs) since its approval in the United States based on demonstrated progression-free survival benefit in grade 1-2 midgut NETs. The recommended dosing is 7.4 GBq (200 mCi) every 8 weeks for 4 doses in total. We examined the post-PRRT outcomes with dosing variations and in patients with non-midgut NETs. Methods: The medical records of 108 PRRT-naïve NET patients who received at least one cycle of PRRT at a single academic institution were reviewed. Among the patients with Ki-67 index ≤ 20%, progression-free survival (PFS) and overall survival (OS) were compared between midgut and non-midgut NETs. Among the patients who did not develop disease progression or mortality during the treatment course, PFS and OS were compared based on dosing variations. Dosing variations were defined as "reduced” (50% of 7.4 GBq/cycle), “delayed” (>12 weeks between cycles), or “fewer” (<4 cycles) doses. Kaplan-Meier survival analysis with log-rank test was used for statistical analysis. Results: Median clinical follow-up was 18.7 months, during which disease progression and death occurred in 54 (50%) and 20 (18%) patients, respectively. Among the 98 patients with Ki-67 index ≤ 20%, those with non-midgut tumors (n=55) showed significantly shorter PFS compared to those with midgut tumors (n=43) with the hazard ratio of 2.0 ( P=0.014, median of 15.6 vs. 26.9 mo.). No difference in OS was found between the two groups ( P=0.83). Among the 93 patients who did not develop disease progression or mortality during the course of PRRT, dosing variations were used in 23 patients. The types of dosing variations were “reduced” in 4 (17%) patients, “delayed” in 16 (70%) patients, and “fewer” in 7 (30%) patients. The reasons for dosing variations were hematologic in 9 (39%) patients, hepatic in 2 (9%) patients, renal in 1 (4%) patient, other medical in 3 (13%) patients, functional in 3 (13%) patients, and logistical in 6 (26%) patients. No difference in PFS ( P=0.20) or OS ( P=0.24) was found based on the presence or absence of dosing variations. Conclusions: Patients with non-midgut NETs show approximately twice the rate of disease progression over time following PRRT than those with midgut NETs. Administering reduced, delayed, or fewer doses of PRRT may still offer comparable benefit compared to the recommended dosing.
Liquid biopsies for faster diagnosis of suspected advanced pancreatic and biliary tract cancers: ACCESS, a UK innovation programme.
Authors: Jones Lauren , Mencel Justin , Mullen Reed , Sardo Infirri Sofia , MacDonald Alan , Fribbens Charlotte Victoria , Rao Sheela , Mahmood Asif , Galloway Daniel , Gupta Sanjay , Chadwick Georgina , Chau Ian , Ni Melody , McVeigh Terri Patricia , Popat Sanjay , Hubank Michael , Cunningham David , George Angela Joy , Starling Naureen
Published: January 2024

614

Background: Tissue diagnosis in biliary tract (BTC) and pancreatic (PC) cancer is challenging due to anatomical location and patient (pt) factors (frailty, sepsis); approximately 25% of invasive biopsies are nondiagnostic, requiring repeat procedure. Most BTC and PC pts present with advanced disease. In stage III and IV solid tumours, Guardant 360 (G360) 74 gene panel liquid biopsy (LB) detects ctDNA in 80%/85% of BTC/PC. ACCESS is a real-world innovation programme evaluating the impact of adding G360 to the current invasive diagnostic pathway for suspected BTC/PC in 6 hospitals in West London; (n=240). Methods: This is a pre-planned interim analysis of the first sequential 65 pts with G360 in ACCESS. Patients were age>18 years, ECOG ≤ 2 with high radiographic suspicion of stage III/IV BTC or PC without histological diagnosis at registration or other malignancies within 3 years. Positive LBs were reviewed at molecular tumour board with 4 pre-specified levels of diagnostic certainty: diagnostic/consistent/possibly/not consistent. Tumour board review followed. Endpoints include repeat biopsy rate, change in time to diagnosis, quality of life, health economic assessment and patient satisfaction. Results: 64 patients were analysed (1 excluded). 50% female, median age 73 years (43-94), suspected cancer sites 14%/77%/9% BTC/PC/either BTC or PC. Suspected stage III/IV disease 38%/62%. ctDNA detection rate was 80%/100%/82% in overall cohort/BTC/PC. Most commonly detected LB alterations in suspected BTC/PC were TP53, APC, ATM, CDK/TP53, KRAS, CDKN2A, ARID1A. In BTC and PC, diagnostic method was liquid biopsy alone/liquid and tissue biopsy/tissue alone in 16%/49%/33%. 17% had repeat biopsy. Sensitivity/specificity of cancer diagnosis (all-comers) using liquid biopsy was 86% (95% CI 73.3-94.2)/38.5% (95% CI 13.9-68.4). Conclusions: There is a high ctDNA detection rate with high level diagnostic certainty, promising for future genomic transformation of BTC/PC diagnostic pathways, potentially reducing repeat invasive biopsies, speeding up diagnosis, facilitating precision therapy, with ACCESS defining a blueprint for molecular integration of liquid biopsies. Full recruitment is planned to complete in March 2024.
Amplified Sciences PanCyst Pro Panel to accurately identify non-mucinous pancreatic cyst fluid.
Authors: Thomas Mini , Sheik Daniel , Byers Kaleb , Rajesh U. Chinna , Ramsey Curtis , Davisson V. Jo
Published: January 2024

617

Background: Pancreatic cysts are rarely symptomatic, and, consequently, are detected incidentally during routine imaging analyses for unrelated disorders. Guidelines for diagnosis of pancreatic cysts rely on imaging and supportive analyses of fluid extracted during endoscopic ultrasound with fine-needle aspiration (EUS-FNA). Unfortunately, currently available protein markers and assays are not sufficiently accurate to rule-out patients in whom a non-mucinous pancreatic cyst has formed. Since non-mucinous pancreatic cysts seldom progress to cancer, this patient population is at risk of being subjected to the severe physical, emotional, and financial burdens associated with unwarranted surveillance, testing, and possible surgical intervention. Furthermore, identification of mucinous pancreatic cysts does not establish the risk of progression to cancer (rule-in) or the need for surgical intervention. Methods: To address the unmet needs in pancreatic cyst diagnosis, Amplified Sciences has combined a panel of markers with a clinically translated surface enhanced Raman spectroscopy (SERS)-based protease activity assay as a rule-out diagnostic tool. The tri-analyte panel was tested on a cohort of 185 retrospective samples gathered from three separate institutions (UPMC, IU Health, and UCSF) and consumed only 12 µL of cyst fluid per sample. The goals of this study were to establish the negative predictive value (NPV) of this panel prior to translation to a CLIA-regulated laboratory and create a preliminary algorithm for analysis. Results: The results of this statistically powered study show that protease activity outperforms carcinoembryonic antigen (CEA), a current standard diagnostic marker for pancreatic cyst fluid, in sensitivity, specificity, and NPV. Furthermore, in combination, the tri-analyte panel identifies non-mucinous pancreatic cysts with 99% sensitivity and a negative predictive value >95%. Conclusions: These results support the use of this panel in clinical settings as a diagnostic tool to rule-out patients from surgical intervention, as well as the use of SERS as an optical detection mode for clinical diagnostics. Future work will continue to address the unmet need for improved diagnostic information through multiplexed analyses of markers that consume comparatively minimal volume of pancreatic cyst fluid samples. Studies will also seek to build on the SERS platform by introducing more dyes, substrates, assays, and analytical methods. Amplified Sciences would like to acknowledge significant efforts to build the clinical samples cohort from Gina Zhu, Kelli Ifuku, and Dr. Kimberly Kirkwood from USCF, Christine Decapite and Dr. Randall Brand from UPMC, and Michele Yip-Schneider and Dr. C. Max Schmidt from IU Health.
Neoadjuvant chemotherapy vs upfront resection: A challenging choice in resectable pancreatic ductal adenocarcinoma.
Authors: Fekrmandi Fatemeh , Hagerty Brendan , Liu Qian , Schneider Tyce , Malik Nadia , Fountzilas Christos , Kukar Moshim , Cherkassky Leonid , Calvo Benjamin
Published: January 2024

620

Background: Pancreatic ductal adenocarcinoma (PDAC) remains an immense challenge within oncology, with only 15-20% of cases initially qualifying as resectable. Based on National Cancer Database analyses there is an increase in neoadjuvant chemotherapy (NACT) use, with potential downstaging effects. Yet, a subset of neoadjuvant-treated patients fail to proceed with curative-intent surgery, leading to worse outcomes. This retrospective analysis aims to uncover factors that predict NACT use and the impact on survival outcomes. Methods: A cohort of 543 consecutive non-metastatic PDAC patients treated at an NCCN-designated comprehensive cancer center between 2015 and 2022 were prospectively enrolled into a REDCap database. Based on NCCN resectability criteria, initial CT staging placed 96 patients as upfront resectable. Survival outcomes were compared using univariate and multivariate cox regression analyses. Results: Within 96 resectable patients, 45 (47%) underwent upfront surgery, 36 (37%) received NACT followed by surgery and 15 (16%) only received chemotherapy. The majority were CA19-9 secretors (94%) with 54% lower values during chemotherapy. While 60% of patients experienced up to 35% tumor size reductions on NACT, 20% had stable disease, and 20% showed progressive disease. The patients who received NACT were significantly younger (p = 0.01), with higher baseline CA19-9 (p < 0.01) and more frequently underwent stent placement (p = 0.01), table 1. Median overall survival for the upfront surgery, NACT+surgery and chemotherapy groups were 32.8, 23.7 and 20.2 months (log-rank test p<0.01) subsequently. On univariate analysis initial presentation with weight loss (p = 0.02, HR = 2.08) and high baseline CA19-9 (log2-scaled, p = 0.01, HR = 1.13) were predictive of worse overall survival. After adjusting for potential confounding variables, patients in chemotherapy group had significantly worse survival compared to the upfront surgery group (P < 0.01, HR = 3.14). These 15 patients failed to undergo surgery due to diverse reasons, including distant progression (7), local progression (3), performance status decline or death during chemotherapy (2), refusal due to chemotherapy side effects (2), and indecision and loss to follow-up (1). Conclusions: These findings underscore the need for more robust selection criteria in resectable PDAC patients to undergo NACT. Leveraging real-world data helps identify predictive factors of treatment decision making and their impact on patient survival outcomes. [Table: see text]
De-escalation and dose density in real-world patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.
Authors: Dennen Syvart , Shao Anran , Dennen Syvart , Cockrum Paul , Paluri Ravi Kumar
Published: January 2024

628

Background: FOLFIRINOX (FFX) is a recommended first-line (1L) treatment for patients (pts) with mPDAC and good performance status but is known for high toxicity. To make the regimen more tolerable for pts, clinicians may omit components and/or reduce doses (referred to as “de-escalation”). To better understand the frequency and degree of de-escalation in outpatient clinical practice, we examined real-world (RW) treatment patterns among mPDAC pts receiving FFX in 1L. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2022 who initiated treatment with FFX in 1L within 90 days of their diagnosis for metastatic disease were included in the study. Receipt of FFX was defined as receiving all four regimen components within 28 days of 1L initiation. Modified FFX (mFFX) was defined as administration of <150mg/m2 of irinotecan or <2,720mg/m2 5-FU total (bolus + infusion) during cycle 1. 6-week dose density was defined as the actual dose received of each component in the 6 weeks following treatment initiation as a percent of the expected dose over 3 two-week cycles [expected FFX dose defined as 2800 mg/m2 of 5-FU (bolus + infusion), 400 mg/m2 of leucovorin, 180 mg/m2 of irinotecan, and 85 mg/m2 of oxaliplatin per cycle]. Results: 1,215 mPDAC pts met the study inclusion criteria, with >99% receiving mFFX. The median age at 1L initiation was 65yr (IQR: 58–71), 57% were male, 68% were white, 15% had an ECOG score of 0, 39% had an ECOG score of 1, and 6% had an ECOG of 2. The median number of FFX cycles was 5 (IQR: 2–9). In the first administration, 97% of pts received FFX/mFFX, 2% received FOLFIRI (omitting oxaliplatin), and 1% received other combinations. The number of pts in treatment declined over subsequent administrations, as did the number receiving FFX: by the 10th administration, 390 pts were treated, with 74% receiving mFFX, 13% FOLFIRI, 5% FOLFOX (omitting irinotecan), and 7% other combinations. At the 15th administration, 149 pts continued treatment, with 36% receiving mFFX, 44% FOLFIRI, 5% FOLFOX, 8% 5FU + leucovorin, and 7% other (either 5FU alone or with oxaliplatin and/or irinotecan). Median 6-week dose density was 69% for 5FU (IQR: 40–93%), 100% for leucovorin (IQR: 66–133%), 83% for irinotecan (IQR: 56–130%), and 99% for oxaliplatin (IQR: 68–127%). Conclusions: De-escalation was common among pts continuing FFX/mFFX treatment, with oxaliplatin the most frequently omitted component in later administrations. Over the 6 weeks following FFX treatment initiation, the actual vs. standard dose was lowest for 5FU, followed by irinotecan, while median leucovorin and oxaliplatin doses were close to standard dose over 3 two-week cycles. The omission of components of the regimen may indicate that mFFX lacks tolerability for many pts.
Non-responders to neoadjuvant chemotherapy in pancreatic adenocarcinoma: Characteristics and outcomes.
Authors: Hagerty Brendan , Fekrmandi Fatemeh , Kukar Moshim , Cherkassky Leonid , Calvo Benjamin
Published: January 2024

662

Background: For patients with localized pancreatic adenocarcinoma, resection and systemic therapy remain the mainstays of curative-intent treatment. Neoadjuvant chemotherapy has been frequently employed with the goals of addressing systemic disease early and improving patient selection for surgery. Those who do not respond to neoadjuvant therapy present a challenge with a lack of randomized data to aid in decision making. Here we sought to define the characteristics and outcomes of those patients to guide clinical practice. Methods: This was a single-institution retrospective cohort study using a prospectively maintained database of those diagnosed with pancreatic adenocarcinoma. Patients included in the study were those who received neoadjuvant chemotherapy. Non-responders were defined as those with both no radiographic and no biochemical response at the first re-assessment after initiation of therapy. Results: A total of 176 patients were identified who were treated with neoadjuvant chemotherapy with curative intent. Of those, 42 (23.8%) patients had no evidence of either radiographic or biochemical response. Of those patients, 14 were upfront resectable (33.3%) and 20 were borderline resectable (47.6%). An additional 8 (19%) were locally advanced. Most patients received FOLFIRINOX as a first line chemotherapy agent (n = 25, 59.5%). A total of 12 (28.6%) patients underwent neoadjuvant radiation therapy. A total of 19 (45.2%) proceeded to surgery and two of those were found to be unresectable at exploration, resulting in 17 (40.5%) who ultimately received curative-intent resection. Exactly half (n = 21) of the patients had their chemotherapy switched (CS). Of those who had CS, 11 (52.4%) had evidence of local tumor progression on their initial restaging scan compared to just 3 (14.3%) of those who did not (p = 0.02). Additionally, patients who had CS had higher incidence of vascular involvement on their initial scan (90.5% vs 52.3%, p = 0.051). A total of 6 (28.6%) who underwent CS had subsequent biochemical response compared 4 (19.0%) of those who did not. Ultimately, 6 (28.6%) of those who had CS ultimately proceeded to surgery compared to 13 (61.9%) of those who did not (p = 0.062). Interestingly, there was no significant difference in median overall survival between those who had CS (18.6 months) and those who did not (19.9 months, p = 0.525). Conclusions: Non-responders to frontline neoadjuvant systemic therapy present a clinical challenge and have poor rates of curative-intent resection. Chemotherapy switch was employed mostly in cases with worse prognostic factors and thus infrequently lead to resection. Despite this, patients who underwent CS had similar overall survival to those who did not. These data suggest there may be a role for chemotherapy switch in those who do not respond to front line chemotherapy.
Paclitaxel protein bound (A) plus gemcitabine (G) plus cisplatin (C) and hydroxychloroquine (HCQ) neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC).
Authors: Borazanci Erkut Hasan , Jameson Gayle S. , Snyder Courtney Edwards , Thosani Amar , Sckolnik Steven , Korn Ronald Lee , Rahmanuddin Syed , Mocan Dan , Pearse Shelby , Gordon Michael S. , Von Hoff Daniel D. , Modasi Aryan , Amini Albert
Published: January 2024

667

Background: Neoadjuvant therapy has become the consensus treatment for individuals with locally advanced (LA) and borderline resectable (BR) PDAC. Neoadjuvant therapy for resectable (R) PDAC has been in greater use due to concerns over micro metastases at diagnosis. Typical therapies involve the use of multiagent systemic chemotherapy with or without radiation therapy. In retrospective studies, Cancer Antigen 19-9 (CA 19-9) normalization in borderline resectable (BR) and locally advanced (LA) PDAC has been associated with greater OS. The addition of cisplatin (C) to gemcitabine (G) and paclitaxel protein bound (A), has shown promising clinical data in a previously reported study in advanced PDAC [JAMA Oncol. 2020;6(1):125-132]. HCQ has been shown to target autophagy in PDAC and has demonstrated higher response in combination with GA. We conducted a prospective, phase 2 clinical trial of patients with R, BR, and LA PDAC utilizing a regimen combining A + G + C + HCQ with the primary endpoint of CA 19-9 normalization (NCT04669197). Methods: Eligibility criteria include patients with histologically confirmed R, BR, or LA PDAC, elevated CA 19-9, and a KPS ≥ 70% with normal end organ function. Doses are A 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2 on days 1, 8 of a 21-day cycle (IV) along with HCQ 600 mg po bid. Primary objective is to evaluate CA 19-9 normalization with the neoadjuvant chemotherapy. Secondary objectives are to assess R0 rate, pathologic complete response (pCR), safety and tolerability, radiologic response rate (by RECIST 1.1), and 2 year overall survival (OS) from date of study entry. Exploratory objectives include evaluating imaging biomarkers and vascular involvement by tumor in relation to therapy. Results: To date all planned 12 patients have been enrolled, 11 evaluable. 8 male, 4 female; age range 50 to 76 yo. Patient classifications is 3 R; 4 BR; 5 LAPC. Most common drug related grade (gr) 3-4 adverse events (AEs) are: thrombocytopenia gr 3 27%, gr 4 27%, anemia gr 3 36%, and neuropath gr 3 36%. CA 19-9 normalization occurred in 36% (4/11) who have completed at least 1 cycle of treatment. To date, 3 individuals went to surgery, with 3 achieving R0. Overall response rate in measurable patients is 45% (1CR, 4 PR). Median OS and 2-year survival data are not yet matured. Conclusions: In patients with non-metastatic PDAC, the use of A+G+C+HCQ resulted in a CA 19-9 normalization rate in 36% of individuals. Most patients did not go to surgery. The OS data is maturing. Supported by grants from the HonorHealth Foundation and Marley Foundation. Clinical trial information: NCT04669197 .
Trends in colorectal cancer screening from NHIS survey: Analysis of modalities impact on overall screening.
Authors: Ebner Derek W. , Finney Rutten Lila J , Miller-Wilson Lesley-Ann , Markwat Niels , Vahdat Vahab , Ozbay A. Burak , Limburg Paul J.
Published: January 2024

67

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality among men and women combined in the United States (US). Although the national screening rate has increased over the years, it remains below the target of 80% recommended by the National Colorectal Cancer Roundtable for improved CRC outcomes. In most recent years, and particularly during COVID-19, screening-eligible individuals preferred at-home, non-invasive screening options over invasive tests such as colonoscopy due to convenience and accessibility. The objective of this study was to understand the CRC screening trends over the last two decades, and the impact of various screening modalities on the overall CRC screening rate. Methods: Using National Health Interview Survey (NHIS) data from 2005 onwards, we examined CRC screening (colonoscopy, mt-sDNA, FIT/FOBT, and sigmoidoscopy) rates among adults aged 50-75 years. A pseudo-time-series cross-sectional (pseudo TSCS) analysis was conducted including random effects Generalized Least Square (GLS) regression model to estimate the relative impact of each modality on the overall increase in CRC rates from 2018 to 2021. Results: Among 50-75 years old individuals, the estimated CRC screening use increased by 32% from 2005 to 2021 (47.7% to 69.9%). Between 2018 to 2021, the rates increased from 64% to 70%, driven largely by increased use of mt-sDNA, a 62.1% increase from 2018 to 2021 (2.5% to 6.6%). During this time period, colonoscopy utilization increased by 4.4% (61.2% to 64.0%), while FOBT/FIT utilization increased by 3.6% (5.3% to 5.5%). A pseudo-TSCS analysis showed that mt-sDNA contributed substantially to the overall CRC screening rate increase during years 2018-2021 (77.3%; p < 0.0001). Conclusions: While CRC screening rates are increasing, they remain below the national goal of 80%. Mt-sDNA as a home-based, non-invasive screening, recommended at a 3-year interval, has been leveraged to improve overall CRC screening rates, particularly to address the screening backlog created during the COVID-19 pandemic. A collaborative approach between healthcare providers and screening-eligible individuals is needed to empower patients with choice for their CRC screening modality to achieve the national goal.