bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of fecal microbiota transplantation in patients with anti-PD-1–resistant/refractory gastrointestinal cancers.
Authors: Peng Zhi , Zhang Xiaotian , Xie Tong , Cheng Siyuan , Han Zihan , Wang Shulin , Ban Zongwen , Xu Xiaomin , Zhu Zhengnong , Zhu Jing , Yin Xiaochen , Li Sumin , Shen Lin
Published: January 2023

389

Background: Gut microbiome that changed the response to anti-PD-1 therapy (aPD-1) against melanoma by fecal microbiota transplantation (FMT) has been reported. To investigate whether resistance to aPD-1 against gastrointestinal (GI) cancers can be overcome by FMT, this single arm, open label, investigator-initiated trial explored the efficacy of combination of FMT + nivolumab in patients with aPD-1 resistant/refractory (aPD-1r)-GI cancers. Methods: Ten patients were planned to be enrolled. Interim analysis was planned when at least one patient demonstrated effective outcome. FMT capsules were from healthy donors. FMT capsules (CFU≥1×1012) were administered in the first week. Nivolumab (3mg/kg, q2w) combined with a maintenance dose of FMT capsules (CFU≥1.5×1011) were started at Week 2 and continued for 6 cycles or until progress of disease (PD) after 3 cycles of treatment. If patient responded to the treatment and would be benefit from the treatment beyond 6 cycles, patients would enter the Expended Excess Program to continue the therapy. RECIST v1.1 evaluation was performed every 3 cycles. Stool samples were collected every 2 weeks for metagenomic analysis of gut microbiota. Results: 8 aPD-1r patients were enrolled and finished the study by the time of this analysis. Nivolumab + FMT therapy was well tolerated. No serious adverse reaction was observed. 8 patients completed 3 cycles of treatment. Metagenomic analysis of gut microbiota from Responders (R) and Non-Responders (NR) groups revealed the gut microbial composition of R group is significantly closer to that of the donor than NR group, which indicated much better colonization of donor microbiota in R. Alpha diversity was significantly higher in R than that in NR, along with a set of differential bacterial species and biological process functions including dTMP biosynthetic process enriched, suggesting gut microbiome’s potential role in the treatment. The flow cytometry analysis indicated a significant increase of IFN-ϒ+ cells in PBMCs in R at Day 8 after FMT (the highest increase during the study), before combination therapy had started. A significant increase in Ki-67+ cells in PBMCs was also observed in the R group. Relative abundance of differential bacterial species enriched in R were found to be significantly negative correlated with tumor markers like CA199 and tumor volume, and some were positively correlated with expression of CD3+CD4+ cells and CD3+CD8+ cells. Conclusions: FMT+aPD-1 may overcome the resistance to aPD-1 against GI cancer via changing gut microbiota structure. Trial registration number: NCT04130763. Keywords: gastrointestinal cancers; fecal microbiota transplantation; anti-PD-1 therapy. Clinical trial information: NCT04130763 .
Long-term outcomes from adding durvalumab to neoadjuvant treatment of operable gastroesophageal cancers: Results from a multicenter study LUD2015-005.
Authors: Middleton Mark R. , Karydis Ioannis , Lu Xin , Ryan Aileen , Venhaus Ralph Rudolph , Ramirez Kristen Auferio , Macri Mary , Ricciardi Toni , Lawrence Megan , Scott-Brown Martin , Griffiths Gareth Owen , Collins Linda , Griffiths Lucinda , Wilding Sam , Lord Simon , Owen Richard , Petty Russell D.
Published: January 2023

398

Background: Phase III studies have shown a survival benefit for the addition of immune checkpoint inhibitors to conventional chemotherapy for patients with gastroesophageal cancer (GEC). Large scale studies of chemoimmunotherapy prior to and after surgery are under way. We sought to characterise the effects of the PDL1 inhibitor durvalumab (D) with standard neo-adjuvant chemo(radio)therapy regimens in an open label phase I/II study in patients (pts) with operable GEC (LUD2015-005, NCT02735239, EudraCT 2015-005298-19). Methods: In pts identified as suitable for potentially curative surgery we gave D (750mg q2w) alongside their standard treatment. Pts had D only at first then Oxaliplatin and Capecitabine (CapOx) q3w or fluorouracil, leucovorin, oxaliplatin and taxotere (FLOT) starting with the third cycle of D. Chemotherapy and further D were given for 6 (CapOx) or 8 (FLOT) weeks before pts had surgery and for up to 12 further infusions of D after operation. Patients on FLOT could also have more chemotherapy. Pts suitable for chemoradiotherapy (CXRT, CROSS regimen) were offered two cycles of D before starting their treatment, and were able to have up to 12 further cycles after recovering from surgery. Participants were followed for toxicity, response and survival from the time of study enrolment until death, for 3 years or until June 2022 when the study ended. Results: 11 pts received D-CapOx, 9 D-FLOT and 15 D-CXRT. All were evaluable for safety and efficacy. Treatment side effects were as expected for the agents used with diarrhoea, nausea and fatigue the most commonly reported and no new safety signals. 156 of 160 planned pre-op D doses were given. Only 2 out of 35 patients did not have surgery, both due to progressive disease on D-CXRT. 23 of the 33 patients having surgery had post-operative treatment. Amongst 33 evaluable pts 2 (5.7%) and 6 (17.1%) had complete or partial pre-op responses (RECIST) and 3 (8.6%) progression prior to surgery. Tumor regression at surgery (Mandard 1-3) occurred in 24/33 pts. Median recurrence free survival was 25.4 months (mo) (D-CapOx), 32.0 mo (D-FLOT) and not reached (D-CXRT). 2 year survival was 81.8%, 77.8% and 77.8% respectively in the 3 arms. Conclusions: Adding D to standard neo-adjuvant regimens for GEC is well tolerated. Survival times and response rates exceeded those expected for the regimens used (2 year survivals with FLOT 68% and CROSS 67%) in this non-randomised multi-centre trial. Clinical trial information: NCT02735239 .
Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study.
Authors: Tabernero Josep , Prager Gerald W. , Fakih Marwan , Ciardiello Fortunato , Van Cutsem Eric , Elez Elena , Cruz Felipe Melo , Wyrwicz Lucjan , Stroyakovskiy Daniil , Papai Zsuzsanna , Poureau Pierre-guillaume , Liposits Gabor , Cremolini Chiara , Bondarenko Igor , Modest Dominik Paul , Benhadji Karim A. , Fougeray Ronan , Leger Catherine , Amellal Nadia , Taieb Julien
Published: January 2023

4

Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bev) demonstrated promising efficacy in a randomized phase 2 trial of heavily pretreated patients (pts) with metastatic colorectal cancer (mCRC). SUNLIGHT was conducted to confirm these findings. Methods: The global phase 3 SUNLIGHT study enrolled pts aged ≥18 years with histologically confirmed mCRC, ECOG PS 0/1, and treated with 1-2 prior chemotherapy regimens in an advanced setting, including fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (if medically considered) and/or anti-EGFR monoclonal antibody for RAS wild-type tumors. Pts were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) alone or combined with Bev (5 mg/kg on days 1 and 15). Primary endpoint was overall survival (OS). Results: Between Nov 2020 and Feb 2022, 492 pts were randomised to receive FTD/TPI + Bev (n = 246) or FTD/TPI (n = 246). Baseline characteristics were balanced between arms. FTD/TPI + Bev significantly extended OS over FTD/TPI, median OS was 10.8 months vs 7.5 months, respectively (HR, 0.61; 95% CI, 0.49, 0.77; P< 0.001). OS rates at 12 months were 43% in the FTD/TPI + Bev arm and 30% in the FTD/TPI arm. Median progression-free survival was 5.6 months in the FTD/TPI + Bev arm and 2.4 months in the FTD/TPI arm (HR, 0.44; 95% CI, 0.36,0.54; P< 0.001). Grade ≥3 adverse events (AEs) were not significantly increased in the FTD/TPI + Bev arm vs the FDT/TPI arm (72.4% vs 69.5%). No new safety signals were noted. Conclusions: FTD/TPI + Bev provided a statistically significant and a clinically meaningful 3.3-month improvement in OS, extending mOS up to 10.8 months, with a 39% reduction in the HR of death in pts with refractory mCRC and with a predictable and acceptable safety profile. Clinical trial information: NCT04737187 .
Endoscopic submucosal dissection in early gastric cancer with papillary histological type.
Authors: Lee Jung Hwan
Published: January 2023

412

Background: Gastric papillary adenocarcinoma has been regarded as differentiated-type adenocarcinomas along with well- or moderately-differentiated tubular adenocarcinomas in current endoscopic submucosal dissection (ESD) indication. We aimed to investigate lymph node metastasis (LNM) and to verify the safety of ESD in patients with papillary early gastric carcinoma (P-EGC). Methods: 4,264 patients with early gastric cancer (EGC) underwent curative gastrectomy between October 2000 and December 2017 at National Cancer Center, Korea. Among them, 45 patients were pathologically confirmed with P-EGC. We compared clinicopathological factors among differentiated-type EGC except P-EGC (n=2,106), undifferentiated-type EGC (n=2,113), and P-EGC. Logistic regression model was used to investigate risk factors of LNM. Results: P-EGCs were frequently located in lower third of the stomach (71.1%, P < 0.001), and about half of them (46.7%, P < 0.001) had elevated morphology. Mucosal cancer of P-EGC (37.9%) was significantly lower than differentiated-type (48.8%) and undifferentiated-type EGC (22.2%, P < 0.001). Angiolymphatic invasion and LNM occurred most frequently in P-EGC (46.9% and 20.0%, respectively) compared to differentiated-type (18.9% and 9.2%, respectively) and undifferentiated-type EGCs (10.9% and 11.7%, respectively; P < 0.001 and P = 0.004, respectively). P-EGC that was not mixed with other pathological type tended to have increased risk of LNM referent to differentiated EGC. (Odd ratio [OR] 2.53, 95% confidence interval [CI], 0.99-6.50). Among 45 patients with P-EGC, 13 patients met the current ESD indication; 3 patients corresponded to absolute indication and 10 patients did expanded indication. One patient had LNM and met expanded criteria with submucosal invasion less than 500 μm. In multivariate analysis, OR for LNM meeting expanded indication of P-EGC was 40.67 (95% CI, 2.54-702.76) referent to that of absolute indication compared to LNM meeting expanded indication of non-papillary EGC (10.28, 95% CI, 1.37-77.04). Conclusions: When ESD was applied to P-EGC, it should be carefully performed because of high rate of submucosal invasion and high risk of LNM even in with submucosal invasion less than 500 μm.
LAG3-related factors to predict response to nivolumab monotherapy in advanced gastric cancer (WJOG10417GTR study).
Authors: Tsugaru Kai , Boku Narikazu , Kudo-Saito Chie , Shoji Hirokazu , Imazeki Hiroshi , Takahashi Naoki , Kawakami Takeshi , Amanuma Yusuke , Wakatsuki Takeru , Okano Naohiro , Narita Yukiya , Yamamoto Yoshiyuki , Kizawa Rika , Nagashima Kengo , Aoki Kazunori , Muro Kei
Published: January 2023

425

Background: Blocking immune checkpoint (IC) pathways, particularly mediated by PD1 and PDL1, has attracted great attention as a promising strategy for treating gastrointestinal cancer. However, the clinical responses are low in many cases, and thus a new treatment strategy and its biomarker are urgently needed for improving the clinical outcome. Blocking other IC molecules, including LAG3, has been evaluated in many clinical trials, while the therapeutic efficacy and the predictive biomarkers remains to be determined due to the same issues as anti-PD1/PDL1 therapy. Methods: We analyzed soluble LAG3 (sLAG3) in sera by ELISA, and LAG3+ cells by flow cytometry, using fresh peripheral blood (PB) obtained from 91 patients with advanced gastric cancer (AGC) before and about one month after nivolumab monotherapy (2 courses) in the WJOG10417GTR study, according to the protocol approved by the IRB (August 2018 - November 2020). Progression-free survival (PFS) and overall survival (OS) were compared between high/low groups divided by the cutoff value determined by visually assessing the continuous trend and change point of log hazard ratios obtained by applying penalized splines to each molecular marker. This study was supported by ONO PHARMACEUTICAL CO., LTD. and Bristol Myers Squibb. Results: Posttreatment values were significantly more associated with patients’ prognosis rather than baseline values, and the sLAG3-high group showed significantly shorter PFS/OS as compared to the low group divided by the median: median PFS (mPFS) 51.5 vs 95.5 days (HR = 2.04, P = 0.002), and median OS (mOS) 188 vs 393 days (HR = 1.81, P = 0.032). Patients with high levels of LAG3+ PBCs after treatment showed worse prognosis as compared to those with low levels divided by the cutoff values: a CD3+CD4+LAG3+ T-cell subset, mPFS 43 vs 72 days (HR = 2.23, P = 0.015) and mOS 178 vs 282 days (HR = 1.56, P = 0.249); a CD3+CD8+LAG3+ T-cell subset, mPFS 57 vs 69 days (HR = 1.89, P = 0.012) and mOS 228 vs 303 days (HR = 1.40, P = 0.233); and a CD56+LAG3+ NK subset, mPFS 57 vs 88 days (HR = 2.15, P = 0.003) and mOS 217 vs 409 days (HR = 1.88, P = 0.031). Patients with sLAG3-high/CD56+LAG3+ NK-high levels showed markedly worse prognosis than those with low/low levels (mPFS-HR = 10.55, P < 0.001; and mOS-HR = 4.59, P < 0.001). Conclusions: Patients with posttreatment high levels of sLAG3 and LAG3+ cells in PB showed poor prognosis of AGC patients after the nivolumab therapy, suggesting that these are useful predictive biomarkers. LAG3 may be a promising target in immunotherapy for AGC. Clinical trial information: UMIN000032686 .
The role of serial circulating tumor DNA for predicting clinical outcomes of chemotherapy in patients with advanced gastric cancer.
Authors: Kim Sheehyun , Lim Yoojoo , Kang Jun-Kyu , Kim Hwang-Phill , Kim Tae-You , Kim Tae-Yong
Published: January 2023

433

Background: Serial circulating tumor DNA (ctDNA) analysis enables us to detect minimal residual disease, to estimate recurrence and to trace evolution of cancer. However, the role of ctDNA in patients with advanced gastric cancer (AGC) who received palliative chemotherapy is still unclear. We performed this study to evaluate if serial ctDNA can predict clinical outcomes of chemotherapy and propose evolutionary findings during chemotherapy. Methods: The patients with histopathologically confirmed AGC and who received palliative chemotherapy were enrolled. Serial blood sample for ctDNA sequencing were obtained at baseline (BL) (before first-line chemotherapy), after first cycle and every 2-3 months until disease progression. ctDNA sequencing was performed for all samples using the next-generation sequencing (NGS) platform with a targeted gene panel including 106 genes. Single nucleotide variants (SNVs), insertions and deletions (Indels), and copy number variants (CNVs) were identified by ctDNA sequencing while serial ctDNA were monitored by tracing changes in the variants. ctDNA clearance was defined as no detection of any kind of variants or variant allele frequency (VAF) less than 0.1%. Results: A total of 50 patients were registered and 248 samples were collected. Median age was 62. HER2-positive GC were 5 (10.0%) and 49 received fluoropyrimidine plus platinum (1 did not receive chemotherapy). Response rate and median progression-free survival (PFS) were 42.9% and 10.7 months (95% CI, 7.9-13.6). Among 40 who were available for BL ctDNA, patients who were detected with ctDNA variant (D group) were 21 (52.5%). TP53 mutation was the most frequently observed genetic alteration in BL ctDNA (76.2%) and median copy numbers of ERBB2 in HER2-positive GC were 28 (range 2-42). D group were more frequently observed in tubular or papillary adenocarcinoma than in poorly cohesive carcinoma (69.0% vs. 9.1%, p = 0.001). Patients who were not detected with any kind of ctDNA variant (ND group) showed a trend in longer PFS, compared to D group, however it was not significant (10.5 vs 7.9 months, p = 0.29). In serial analysis during first-line chemotherapy, ctDNA clearance was observed in 14 (70.0%) out of 20 in D group. Patients with ctDNA clearance showed significantly longer PFS, compared with patients without ctDNA clearance (9.8 vs. 3.6 months, p < 0.001). Among 32 patients who had disease progression, increased VAF or re-development of previous BL ctDNA variants were observed in 16 (50.0%). Increased VAF or re-development of BL ctDNA were detected in 2.1 months earlier than clinical or radiologic deterioration. Conclusions: Serial ctDNA could predict clinical outcomes of chemotherapy and detect disease progression earlier than clinical or radiological findings in AGC. Further study for serial ctDNA is needed to find out the resistant mechanism and evolutionary process in cancer.
CA125 kinetics as a potential biomarker of prognosis in nivolumab monotherapy for patients with advanced gastric cancer and peritoneal metastasis.
Authors: Ando Takayuki , Yuki Satoshi , Kito Yosuke , Ueda Akira , Motoo Iori , Ito Ken , Sakumura Miho , Ueda Yuko , Kajiura Shinya , Nakada Naokatsu , Nakajima Koji , Hosokawa Ayumu , Harada Kazuaki , Kawamoto Yasuyuki , Komatsu Yoshito , Yasuda Ichiro
Published: January 2023

445

Background: The ascites develop in large proportion of patients during salvage-line chemotherapy for advanced gastric cancer (AGC). Serum CA125 is reported to be potential biomarker in peritoneal metastasis and associate with prognosis in first-line treatment for AGC. Therefore we aimed to clarify the association between serum CA125 and therapeutic efficacy for AGC treated with third of later-line nivolumab monotherapy (Nivo). Methods: This multicenter retrospective study comprised AGC patients who received Nivo in third line or later setting between Jun. 2015 to May 2019. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before Nivo (cut-off, 37 U/ml). The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between CA125 kinetics and ascites burden during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 50 patients from 5 hospitals were assessable. The proportion of poor PS, moderate/severe peritoneal effusion, low albumin was significantly larger in CA125 elevated group (n=29) than those in non-elevated group. The median value of CA125 before Nivo was elevated according to ascites burden (none, 31.0 U/ml; mild, 49.4 U/ml; moderate/severe, 187.0 U/ml; p<0.001). The overall survival was significantly shorter in elevated group than that in non-elevated group (median, 3.2 vs. 9.4 months, p=0.035). After Nivo, first-time measure of CA125 was performed in a median of day 27. The median change of CA125 was correlated with ascites response (CR/PR, 0.04%/day; SD, 2.06%/day; PD, 4.17 %/day, p=0.013). ROC curve analysis showed that the optimal cut-off value of CA125 kinetics for ascites progression was 2.4%/day (specificity 75%, sensitivity 70%). The progression free survival in increased group was significantly shorter than that of non-increased group in patients with peritoneal dissemination (median, 1.4 vs 3.3 months, p=0.016). Conclusions: The serum CA125 before Nivo was associated with ascites burden. Further, CA125 kinetics after Nivo was associated with prognosis in AGC patients with peritoneal dissemination.
Analysis of the role of tumor microenvironment on clinical outcomes of chemotherapy in patients with advanced gastric cancer using high plex digital spatial profiling.
Authors: Kim Tae-Yong , Lee Hye Seung , Bae Jihong , Park Yujun , Oh Do-Youn , Yoon Jeesun , Nam Soo Kyung , Kwak Yoonjin
Published: January 2023

456

Background: Tumor consists of not only cancer cells but also various immune cells or stromal cells. And tumor microenvironment (TME) is known to be associated with response and resistance to treatment. However, the role of TME in the response to chemotherapy in advanced gastric cancer (AGC) remains unclear. We evaluated whether TME can affect the survival in patients with AGC who received first-line chemotherapy using high plex digital spatial profiling (DSP). Methods: Patients with AGC who received first-line chemotherapy were registered. Archival tumor tissue before first-line chemotherapy were obtained and tissue microarrays (TMAs) were made. Regions of interest (ROIs) were selected on each TMA and high plex DSP including RNA transcript was performed in all ROIs using GeoMx DSP (Whole Transcriptome Atlas) after masking by cytokeratin (CK) immunofluorescence. Differentially expressed gene (DEG), geneset enrichment analysis (GSEA), gene ontology (GO) and cell subsets were analyzed separately in CK-positive and CK-negative areas, using EdgeR, mSigDb, DAVID and CIBERSORT. Results: Thirty-three tumor tissues from 33 patients and 5 normal tissues were analyzed. All patients received fluoropyrimidine and platinum doublet chemotherapy. HER2+ was 15.2% and all with HER2+ AGC received trastuzumab plus chemotherapy. Five received nivolumab plus chemotherapy. Response rate was 48.5% and progression-free survival (PFS) was 9.8 months (95% CI, 6.85-NA). In CK-positive area, high expression of PIGR (polymeric Immunoglobulin receptor gene) (FDR q=0.013) and low expression of IFNE (FDR q=0.027) were associated with long PFS. Response to interferon beta (FDR q=0.044), cytokine-cytokine receptor interaction (FDR q=0.014) and antigen processing and presentation pathway (FDR q=0.015) were less activated in patients with long PFS in GO and GSEA. Although the density of CD8+ T cell did not affect PFS (6.9 vs. 10.8, p=0.25), high density of CX3CR1+memory CD8+T cells (Tmem) showed longer PFS (18.3 vs. 6.6 months, p=0.01), compared with low density of CX3CR1+CD8+Tmem. In CK-negative area, low density of CD8+ T cells were associated with longer PFS (6.3 vs. 18.3 months, p= 0.008). Conclusions: TME particularly in CK-positive area might affect survival for chemotherapy in AGC. PIGR and CX3CR1+CD8+Tmem were suggested as good candidate markers for predicting clinical outcomes of chemotherapy, indicating further analysis of TME will be needed especially in patients with AGC who received immune checkpoint inhibitors.
Development of a postoperative nomogram to predict overall survival in gastric cancer using variables the AJCC recommends for collection and registration.
Authors: Bando Etsuro , Ji Xinge , Kattan Michael W. , Koseki Yusuke , Furukawa Kenichiro , Fujiya Keiichi , Tanizawa Yutaka , Terashima Masanori
Published: January 2023

468

Background: The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for individual risk prediction model for the era of tailored therapy. This study aimed to develop a postoperative gastric cancer nomogram for prediction of overall survival (OS). Methods: The nomogram was developed using data of 4,990 patients with primary gastric cancer who underwent macroscopically complete resection (residual tumor: R0 or R1) at Shizuoka Cancer Center (Shizuoka, Japan), and it was created with a multivariable Cox proportional hazard regression model. Fifteen pathological or host-related variables (age, sex tumor location, tumor size, macroscopic type, histology, depth (pT), number of positive nodes (pN), number of negative nodes, location of positive nodes, lymphovascular invasion, lavage cytology (CY), tumor margin, serum CEA and serum CA19-9) were collected. They are recommended to collect and register by the AJCC. The model was validated internally using measures of discrimination (Harrell’s C-index), calibration and decision curve analysis. A stage-specific subset survival analysis of the three risk groups (low, intermediate, high) calculated using the nomogram was performed. Results: In the development procedure, multivariable analysis for OS selected 11 variables for constructing the nomogram. The developed nomogram showed good discrimination, with a C-index of 0.812; that of the American Joint Committee on Cancer (AJCC) pathological stage was 0.756. The nomogram performed well in the calibration and decision curve analyses. A stage-specific subset survival analysis of the three risk groups calculated using the nomogram also showed the superiority of nomogram-prediction when compared to AJCC ordinal staging. Conclusions: This new postoperative risk model accurately predicts OS in gastric cancer and can be used for patient counseling in clinical practice and clinical trial eligibility determination.
Tislelizumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: Impact on health-related quality of life in RATIONALE-301 population.
Authors: Finn Richard S. , Qin Shukui , Kudo Masatoshi , Meyer Tim , Boisserie Frederic , Li Songzi , Chen Yaxi , Barnes Gisoo , Abdrashitov Ramil , Zhu Andrew X. , Vogel Arndt
Published: January 2023

495

Background: RATIONALE-301 (NCT03412773), a global Phase 3 study, comparing tislelizumab (TIS) to sorafenib (SOR) as 1L treatment in adult patients (pts) with unresectable HCC (uHCC), met its primary endpoint of OS non-inferiority. This analysis examined the HRQoL outcomes in pts in both arms. Methods: Systemic therapy-naïve adults with histologically confirmed uHCC were randomized 1:1 to receive TIS (200 mg IV Q3W, n=342) or SOR (400 mg PO BID, n=332). HRQoL was assessed using EORTC QLQ-C30, QLQ-HCC18 and EQ5D-5L. A mixed model for repeated measures using key pre-specified PRO endpoints of global health status/quality of life (GHS/QoL), physical functioning and fatigue scales of the QLQ-C30, and HCC18 index score, fatigue and pain scores at the key pre-specified clinical cycles 4 and 6 were performed. Time to deterioration was examined with the Kaplan-Meier method using the PRO endpoints. Results: At both cycles, TIS had better HRQoL outcomes than SOR, as indicated by LS mean differences in GHS/QoL, physical functioning, fatigue and HCC symptom index, but not for pain. TIS had a lower risk for deterioration of QLQ-C30 GHS/QoL (hazard ratio [HR] 0.68 [95% CI, 0.49-0.94]), physical functioning (0.53 [0.39-0.73]) and fatigue (0.48 [0.37, 0.63]) as well as for deterioration in the HCC18 index (0.53 [0.34-0.81]) and fatigue (0.60 [0.46-0.80]). Both arms had a similar risk for deterioration in pain (HR 0.78 [0.56-1.09]). TIS maintained while SOR declined EQ-5D-5L VAS (general health status) scores at cycle 4 (mean change from baseline =-0.4 [SD = 14.52] vs -4.3 [12.92]) and cycle 6 (-0.2 [17.03] vs -5.4 [13.09]). Conclusions: Pts with HCC treated with 1L TIS had better HRQoL outcomes compared with pts treated with SOR, particularly in terms of fatigue and physical functioning. These results, along with effects an overall survival, response rate, and a favorable safety profile, support the benefit of TIS as a potential 1L treatment option for uHCC. Clinical trial information: NCT03412773 .[Table: see text]
Utility of AST to platelet ratio index (APRI) score in predicting post-surgical outcomes in patients with cholangiocarcinoma.
Authors: Aslam Faaiq , Loveday Tristan , Uson Junior Pedro Luiz Serrano , Borad Mitesh J.
Published: January 2023

502

Background: Cholangiocarcinoma (CCA) is an epithelial malignancy of the intrahepatic or extrahepatic biliary tree, primarily driven by chronic inflammation and fibrosis. Given fibrosis has shown to correlate with malignancy and the aminotransferase-platelet ratio index (APRI) score, a marker for hepatic fibrosis, has shown to be useful in prognosticating hepatocellular carcinoma, this study aimed to assess the utility of APRI score in prognosticating post-surgical outcomes in CCA patients. Methods: 152 CCA patients at the Mayo Clinic that underwent surgical resection were retrospectively analyzed. Statistical analyses were then conducted to determine the relationship between APRI score and demographic factors, laboratory values (CA19-9, albumin, bilirubin, INR, alkaline Phosphatase, ALT, AST, and platelet count), pathology features, and outcome data. Results: When looking at demographic factors, no relationship between APRI score and age (r = -0.19, p = 0.02), sex (2-sample t-test p = 0.16) and race (ANOVA p = 0.81) were identified. There was a negative correlation between APRI score and albumin (m = -0.35, r = -0.35, p < 0.01) and a positive correlation with bilirubin (m = 0.13, r = 0.23, p = 0.01) and ALT (m = 0.01, r = 0.47, p < 0.01). No correlation between the other laboratory values analyzed was identified. Similarly, there was no relationship between APRI score and pathology features (tumor grade t-test p = 0.41, N Stage ANOVA p = 0.94, Vascular Invasion t-test p = 0.59, and Perineural invasion t-test p = 0.14), except for T3 stage which had a higher APRI score compared to T1, T2, and T4 (ANOVA p = 0.01). Likewise, APRI also did not correlate with post-surgical outcomes like recurrence (t-test p = 0.22) and mortality (t-test p = 0.39). Conclusions: In summary, despite being driven by chronic inflammation, APRI score, a marker for hepatic inflammation and a surrogate for liver fibrosis, did not serve as a reliable prognostication tool of post-surgical outcomes in CCA patients. These data suggest that although chronic inflammation is thought to be one of the primary drivers of disease, the role of other factors such as genetic and cellular signaling abnormalities may play a more prominent role in patients with CCA. In conclusion, APRI score did not serve as a useful prognostication tool in surgically resected CCA patients. Future studies should focus on other prognostic factors such as genomic and transcriptomic biomarkers in CCA.
Extending surgical resection for hepatocellular carcinoma beyond Barcelona Clinic for Liver Cancer (BCLC) stage A: A novel application of the modified BCLC staging system.
Authors: Wee Ian , Moe Fiona , Sultana Rehena , Ang Reiko , Quek Pearly , Goh Brian , Chan Chung Yip , Cheow Peng Chung , Chung Alexander , Raj Prema , Koh Ye Xin , Mack Peter , Ooi London Lucien , Tan Ek Khoon , Teo Jin Yao , Kam Juinn Huar , Chua Jacelyn , Ng Ashley , Goh Jade , Chow Pierce K. H.
Published: January 2023

503

Background: Intermediate hepatocellular carcinoma is a heterogenous group of disease. We aimed to prognosticate survival after surgical resection of HCC stratified by stage with amalgamation of the modified Barcelona Clinic Liver Cancer (BCLC) staging system and location of tumour. Methods: This single-institutional retrospective cohort study included patients with HCC who underwent surgical resection between 1st January 2000 to 30th June 2016. Participants were divided into 6 different subgroups based on the Milan Criteria (MC), the “Up-to-7” criteria, and location of lesions: A-u) Within MC with Unilobar lesions; A-b) Within MC + Bilobar lesions; B1-u) Out of MC + within Up-To-7 + Unilobar lesions; B1-b) Out of MC + within Up-to-7 + Bilobar lesions; B2-u) Out of MC + Out of Up-To-7 + Unilobar lesions; B2-b) Out of MC + Out of Up-To-7 + Bilobar lesions. A separate survival analysis was conducted for solitary HCC lesions according to three subgroups: A-S (Within MC); B1-S (Out of MC + within Up-To-7); B2-S (Out of MC + out of Up-To-7). The respective primary and secondary time-to-event outcomes were overall survival (OS) and recurrence-free survival (RFS). Results: 794 of 1043 patients with surgical resection for HCC were analysed. Groups A-u (64.6 %), A-b (58.4 %) and B1-u (56.2 %) had 5-year cumulative overall survival (OS) rates above 50% after surgical resection and median OS exceeding 60 months (P=0.0001). The 5-year cumulative recurrence-free survival rates (RFS) were 40.4% (group A-u), 38.2% (group A-b), 36.3% (group B1-u), 24.6% (group B2-u), and 7.3% (group B2-b)(P=0.0001). For solitary lesions, the 5-year OS for the subgroups were A-S (65.1%), B1-S (56.0%) and B2-S (47.1%) (P=0.0003). Compared to A-S, there was also a significant trend towards relatively poorer OS as the lesion sizes increased in B1-S (HR 1.46, 95%CI 1.03 – 2.08) and B2-S (HR 1.65, 95%CI 1.25 – 2.18). Conclusions: We adopted a novel approach combining the modified BCLC B sub-classification and dispersion of tumour to show that surgical resection may be curative in a select subgroup of patients with intermediate HCC that fall outside BCLC Stage A, specifically those with unilobar lesions and are within the “up-to-7” criteria. Furthermore, We found that size prognosticates resection outcomes in solitary tumours.
Real-world treatments and outcomes of resected biliary tract cancers in British Columbia, Canada.
Authors: Boutin Mélina , Safro Maria , Yang Jenny , Jafari Helia , Davies Janine Marie , Gill Sharlene
Published: January 2023

505

Background: Complete resection followed by adjuvant chemotherapy is standard of care for patients with localized cholangiocarcinoma (CC) or gallbladder cancer (GBC) but is not always feasible and recurrence rates remain high. Understanding the exact proportions and reasons for treatment failure is important to design new approaches, data regarding this information remain scarce. Methods: We performed a retrospective population-based review of patients with GBC or CC (intrahepatic (ICC) or extrahepatic (ECC)) resected between 2005-2019 using the BC Cancer provincial database. Chart review was conducted to characterize demographics, treatments and outcomes. Results: 594 patients were identified of whom 416 (70%) had disease recurrence. Baseline characteristics and treatments received are shown in the table. Most GBCs (96%) were diagnosed incidentally. Repeat oncologic resection was performed for 55% of these, the most common reason for not proceeding was interval disease progression between initial cholecystectomy and planned re-resection (24%). Adjuvant chemotherapy was received by 51% of 163 patients after 2017 and consisted of capecitabine (86%), gemcitabine (4%), cisplatin and gemcitabine (5%) or chemoradiation (4%). Common reasons for not receiving adjuvant therapy were post op complications or comorbidities (18 and 24%), progression (17%) and patient’s preference (17%). Of those receiving adjuvant therapy, 31% did not complete all planned cycles due to progression (45%) or intolerance (55%). Median overall survival (OS) after resection was 31.6 and 18.0 months respectively for R0 and R1 resection (HR 0.43, 95% CI 0.35-0.53), 29.4 and 19.0 months with and without reresection for GBC (HR 0.55, 95% CI 0.41-0.73), and 29.4 and 25.9 months with and without adjuvant therapy (HR 0.79, 95% CI 0.61-1.02). Stage, R0 resection, re-resection for GBC and adjuvant chemotherapy remained associated with improved OS in multivariate analysis. Taken together, only 25% of patients in the more contemporary cohort of 2017-2019 had complete (R0) resection and completed adjuvant chemotherapy. Conclusions: Complete resection, including reresection for incidentally diagnosed GBCs, and adjuvant chemotherapy were associated with improved outcomes in this retrospective cohort, yet many patients were not able to complete these treatments. Neoadjuvant strategies may improve treatment delivery and ultimately, outcomes. [Table: see text]
Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with fluorouracil and folinic acid with or without panitumumab as maintenance therapy: An analysis of the Panama trial (AIO KRK0212).
Authors: Ballhausen Alexej , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Mueller Lothar , Koenig Alexander , Fischer von Weikersthal Ludwig , Sommerhäuser Greta , Alig Annabel Helga Sophie , Goekkurt Eray , Haas Siegfried , Kurreck Annika , Stahler Arndt , Held Swantje , Reinacher-Schick Anke C. , Kasper Stefan , Heinemann Volker , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul
Published: January 2023

51

Background: The PANAMA study demonstrated superior progression-free survival (PFS) with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. We report health-related quality of life (HRQOL) analyses of the PANAMA study. Methods: HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression. All patients who received at least one dose of induction therapy and completed at least one HRQOL assessment were included into the analysis. HRQOL outcomes were mean changes in EORTC QLQ-C30 from baseline (prior to cycle 1 of induction therapy) to each cycle of treatment (both induction and maintenance therapy). The trial is registered with ClinicalTrials.gov (NCT01991873). Results: In total, 349/377 (93%) of the induction and 237/248 pts (96%) of the maintenance group completed at least one HRQOL assessment and were included in the HRQOL analysis population. There were no significant differences in any of the EORTC QLQ-C30 items between both treatment arms before induction therapy and at randomization. From baseline to cycle 6 of induction therapy there was significant improvement in mean EORTC QLQ-C30 global health status (GHS)/QOL, functioning (except for cognitive functioning) and symptom (except for nausea and vomiting, dyspnea, appetite loss, constipation, and financial difficulties) scores in the randomized population. During maintenance therapy, no significant differences between FU/FA plus Pmab and FU/FA alone were observed. In both arms of the trial, GHS/QOL scores were maintained or trended to improve from baseline (start of induction therapy) to cycle 10 of maintenance therapy (FU/FA plus Pmab: mean difference 9.48 [95% CI 1.96-17.00]; p=0.014); FU/FA arm (mean difference 6.52 [95% CI –1.9-14.95]; p=0.128). Conclusions: Using the established EORTC QLQ-C30 assessment, the addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer did not impair the HRQOL endpoints analyzed compared to FU/FA alone. These results, along with previously reported improvement in PFS, may support clinical decision-making concerning maintenance treatments. Clinical trial information: NCT01991873 .
Etiologies of cirrhosis by ethnicities of patients with hepatocellular carcinoma.
Authors: Chang Jeremy , Ajmera Veeral , Fowler Kathryn J , Burgoyne Adam
Published: January 2023

515

Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. While there are several factors that can impact patient outcomes, ethnicity remains a major contributor towards disease incidence and the expected clinical course. There are various etiologies that can lead to the development of HCC among different ethnic groups, though further studies are required to identify the most pertinent risk factors in recent years. Methods: This was a single center, retrospective study in HCC patients to identify differences in cirrhosis etiologies based on ethnicity. All patients were diagnosed with HCC between March 2014 and April 2022. Possible causes of cirrhosis included alcohol, hepatitis B virus (HBV), hepatitis C virus (HCV), nonalcoholic fatty liver disease (NAFLD), and other chronic liver disease. Results: A total of 276 patients were included in this study. For ethnic background, there were 97 Latino, 97 White, 50 Asian, 16 Black, and 16 patients of other ethnicities. With regards to significant differences in the etiologies of cirrhosis, 58 patients (59.8%) of White ethnicity were found to have cirrhosis related to HCV compared to 71 patients (39.7%) of all other ethnic groups (p = 0.002). In addition, when comparing Latino to non-Latino patients, there was a greater proportion of patients with cirrhosis due to NAFLD (24.7% vs 10.1%, p = 0.002) and cirrhosis from alcohol consumption (24.7% vs 10.1%, p = 0.002). HBV also varied significantly by ethnicity with 16 Asian patients (32%) found to have HBV cirrhosis compared to 5 patients (2.2%) of other ethnic groups (p <0.001). See table for additional details. Conclusions: Our study demonstrates significant differences in the cirrhosis etiologies of HCC patients depending on ethnicity. With the incidence and mortality rates of HCC continuing to rise worldwide, it is important for clinicians to be aware of these differences so that the appropriate preventative measures can be pursued.[Table: see text]
An observational study of best supportive care with or without oral capecitabine in patients with metastatic gallbladder cancer.
Authors: Kumar Shaleen , Srivastava Abhinav , Kapoor Vishwas , Misra Shagun , Rastogi Neeraj
Published: January 2023

521

Background: Patients with metastatic (M+) gallbladder cancer (GBC) have a median survival between 3 - 6 months and therefore palliation of symptoms without compromising quality of life (QoL) is the principal goal of treatment. This study aimed to compare overall survival (OS), toxicity and QoL in patients receiving best supportive care (BSC) with or without oral capecitabine (X). Methods: Patients with M+ GBC and a KPS of ≥70 were prospectively assigned to BSC + X - arm A or BSC alone - arm B, based on physician discretion. Arm A received BSC + X @1650 mg/m2 d1-14, repeated every 21 days for a maximum of 6 cycles. BSC measures included pain palliation; ascitic fluid drainage; jaundice mitigation and other palliative measures. Overall survival (OS) was computed by the Kaplan-Meier method from the date of histologic confirmation and compared using log-rank test. Qol was measured using FACT-Hep v4 administered at baseline, 3 and 6 months. Mean differences in scores were compared using Mann Whitney / Independent t-test and the linear mixed effects model was used for longitudinal analysis to determine the impact of treatment and time on QoL. Results: Between December 2020 to April 2022, 64 patients were assigned, 32 to each arm; data analysed August 2022. For the arms A vs B, the mean age (years) ± SD was 53.3±10.3 vs 54.5±10.3, p=0.21; females, 72% vs 73%, p=0.21; KPS 70, 9% vs 44%, p=0.008; pre-treatment biliary drainage, 9% vs 31%, p=0.06. In arm A, 78% and 21% completed 3 and 6 cycles of X. Median survival was 3.6 vs 2.0 mo, p=0.001; 26 and 27 patients succumbed (~83%), and at 6 months the survival probability was 28% vs 0% respectively; vomiting grade 1-2, 50% vs 78%, p=0.02; diarrhoea grade 1-2, 59% vs 9%, p=0.00; hand-foot syndrome – only arm A, grade 1, 2 & 3 were 32%, 6.5% & 3.2% p=0.001. Baseline QoL mean scores (Table) were significantly worse for most domains in arm B. However, there was no difference in the longitudinal QoL scores between the two treatment arms – FACTG total score (arm*time p=0.759). Conclusions: Not withstanding better prognosis patients of M+ GBC receiving X with BSC compared to BSC alone, a 2 month difference in median survival in favour of arm A was associated with worse diarrhoea and hand-foot syndrome and no discernable impact on longitudinal QoL scores between the two treatment arms.[Table: see text]
Benefits of measuring urinary protein/creatinine ratio in lenvatinib treatment for unresectable hepatocellular carcinoma.
Authors: Morishita Koki , Suzuki Hidetaka , Tauchi Junko , Takeno Misaki K , Yamaguchi Shota , Inoue Kanae , Taira Tomonao , Eguchi Hiroki , Okumura Kei , Shibuki Taro , Satake Tomoyuki , Watanabe Kazuo , Imaoka Hiroshi , Sasaki Mitsuhito , Mitsunaga Shuichi , Kawasaki Toshikatsu , Ikeda Masafumi
Published: January 2023

529

Background: Proteinuria is a well-known lenvatinib (LEN)-associated adverse event. The standard management of proteinuria includes measurement of the urinary protein/creatinine ratio (UPCR) in patients with a qualitative result for proteinuria of ≥1+. Although several studies have shown a good correlation of the UPCR with the qualitative result, it remains unclear how the management of proteinuria by measuring the UPCR might affect the clinical outcomes. This study was aimed at revealing the effect of measuring UPCR on the treatment efficacy and safety in unresectable hepatocellular carcinoma (uHCC) patients receiving LEN. Methods: We retrospectively analyzed the data of uHCC patients who received LEN between March 2018 and February 2022 at National Cancer Center Hospital East. Patients in the UPCR group were monitored by measurement of the UPCR when the qualitative result was ≥2+, while those in the non-UPCR group were not. LEN was withdrawn when the UPCR was ≥3.5 in the UPCR group, and the qualitative result for proteinuria was ≥3+ in the non-UPCR group. Results: A total of 89 patients were included in this study, of which 39 had a qualitative result for proteinuria of ≥2+. Of these 39 patients with proteinuria, 22 were classified into the UPCR group and the remaining into the non-UPCR group. Of the 209 qualitative results of ≥2+ in the UPCR group, 10 (4.8%) corresponded to a UPCR of ≥3.5. The relative dose intensity of LEN during the first 8 weeks was significantly higher in the UPCR group (64.4%) than in the non-UPCR group (52.8 %, p = 0.047). The time to treatment failure was 12.6 months (95% CI, 6.3-16.9) in the UPCR group and 5.5 months (95% CI, 2.1-11.0) in the non-UPCR group (p = 0.125). The rate of change in eGFR from the baseline to the end of treatment was not significantly different between two groups. Conclusions: Measurement of UPCR might contribute to avoiding unnecessary interruption of LEN, because the UPCR values in most patients were below 3.5.
Early tumor shrinkage as a predictor of survival in patients with locally advanced pancreatic cancer treated with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel combination therapy: An exploratory analysis of JCOG1407.
Authors: Tezuka Shun , Ozaka Masato , Furuse Junji , Uemura Kohei , Sano Yusuke , Nakachi Kohei , Imaoka Hiroshi , Unno Michiaki , Shirakawa Hirofumi , Shimizu Satoshi , Kato Naoya , Kojima Yasushi , Sano Keiji , Ueno Makoto
Published: January 2023

547

Background: Early tumor shrinkage (ETS) has been reported as a prognostic predictor of chemotherapy for colorectal cancer. However, few studies have examined the potential of ETS in chemotherapy for pancreatic cancer. Herein, we evaluated whether ETS could be a prognostic predictor in patients treated with modified FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) or GnP (gemcitabine plus nab-paclitaxel) for locally advanced pancreatic cancer (LAPC), as an exploratory analysis of JCOG1407, a randomized phase II selection design trial comparing modified FOLFIRINOX and GnP for LAPC. Methods: Of 126 patients enrolled in JCOG1407, 112 with measurable lesions were included in this exploratory analysis. ETS was defined as a ≥ 20% reduction in tumor diameter compared with baseline at the initial imaging assessment 6–10 weeks after initiating chemotherapy. Patients were divided into two cohorts based on their ETS status as described above: the ETS cohort that achieved ETS and the non-ETS cohort that failed to achieve ETS. The impact of ETS on overall survival (OS) was compared using multivariable Cox regression analysis in (ⅰ) the modified FOLFIRINOX group, (ⅱ) the GnP group, and (ⅲ) the overall population. Results: Herein, we included 55 patients in the modified FOLFIRINOX group and 57 in the GnP group. Notably, 14 (25.5%) and 24 (42.1%) patients achieved ETS in the modified FOLFIRINOX and GnP groups, respectively. In the modified FOLFIRINOX group, the median OS in the ETS and non-ETS cohorts was 2.5 and 1.7 years, respectively; the adjusted hazard ratio (HR) of the ETS to the non-ETS cohort for OS was 0.37 (95% confidence interval [CI], 0.15-0.93). In the GnP group, the median OS in the ETS and non-ETS cohorts was 2.0 and 1.7 years, respectively; the adjusted HR of the ETS to the non-ETS cohort for OS was 0.51 (95% CI, 0.26-1.01). In the overall population, the median OS in the ETS and non-ETS cohorts was 2.3 and 1.7 years, respectively; the adjusted HR of the ETS to the non-ETS cohort for OS was 0.45 (95% CI, 0.27-0.75). Conclusions: We noted a trend toward increased survival in patients who achieved ETS, suggesting that ETS may be a prognostic predictor in patients with LAPC treated with modified FOLFIRINOX or GnP.