bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4 year (yr) follow-up of CheckMate 649.
Authors: Shitara Kohei , Moehler Markus H. , Ajani Jaffer A. , Shen Lin , Garrido Marcelo , Gallardo Carlos , Wyrwicz Lucjan S. , Yamaguchi Kensei , Cleary James M. , Elimova Elena , Bruges Maya Ricardo Elias , Karamouzis Michalis , Skoczylas Tomasz , Bragagnoli Arinilda , Liu Tianshu , Tehfe Mustapha , Feeney Kynan , Wang Rui , Nathani Raheel , Janjigian Yelena Y. 
Published: January 2024

306 Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and an acceptable safety profile in previously untreated, advanced non-HER2+ GC/GEJC/EAC, leading to approvals in many countries. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy at 2 and 3-yr follow-ups. We present 4-yr follow-up results for NIVO + chemo vs chemo from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. HER2+ patients (pts) were excluded. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 1581 pts were randomized to NIVO + chemo or chemo. At the 48-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table) OS benefit with NIVO + chemo was observed in most prespecified subgroups. Objective response rates (ORR) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). In the exploratory analysis of OS by response at the 18-week landmark timepoint, there were numerically more pts achieving response with NIVO + chemo vs chemo, and median OS (95% CI) with NIVO + chemo was numerically longer in responders vs non-responders both in pts with PD-L1 CPS ≥ 5 (20.5 [17.5–25.0] vs 14.0 [11.6–15.7]) and all randomized pts (19.4 [17.5–21.7] vs 13.1 [11.6–14.4]). No new safety signals were identified, consistent with the 3-yr follow-up. Conclusions: NIVO + chemo is the first PD-1 inhibitor/chemo combination to demonstrate long-term efficacy and acceptable safety after 4 yrs of follow up in previously untreated advanced GC/GEJC/EAC. These results are consistent with earlier follow-ups, further supporting NIVO + chemo as a standard 1L treatment in these pts. Clinical trial information: NCT02872116 .[Table: see text]
Abemaciclib in patients (pts) with esophageal cancer (EC) with CDKN2A loss or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Al Baghdadi Tareq , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Yost Kathleen J , Chiu Vi Kien , Duvivier Herbert Leon , McKean Meredith , Rueter Jens , Taylor Mark A. , Grantham Gina N. , Gregory Abby , Hinshaw Dominique C. , Halabi Susan , Schilsky Richard L. 
Published: January 2024

308 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with EC with CDKN2A loss or mut treated with abemaciclib are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 200 mg (four 50 mg tablets) of abemaciclib twice daily for a total daily dose of 400 mg until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete or partial (PR) response per RECIST v. 1.1, or stable disease of at least 16 weeks (wks) duration (SD16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled; otherwise, the cohort is closed. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. DOR is defined as time from pt’s first documented OR to progressive disease. Results: 10 pts with EC (8 adenocarcinoma, 2 squamous) and CDKN2A loss (n=5) or CDKN2A mut (n=5) were enrolled from Dec 2019 to June 2022. 6 pts had HER2 negative EC, 1 pt had HER2 low EC, 1 pt had HER2 positive EC, and 2 pts were not tested for HER2. All pts were evaluable for efficacy and toxicity. Table summarizes pt demographics and outcomes. 1 pt with CDKN2A loss had a 27-wk PR for a DC rate of 10% (1-sided 90% CI, 1% to 100%) and OR rate of 10% (95% CI, <1% to 45%). The null DC rate was not rejected (p=0.80). Median PFS was 8 wks (95% CI, 2 to 13) and median OS was 17 wks (95% CI, 9 to 35). The pt with PR had HER2 negative adenocarcinoma, ECOG PS of 1 and 2 prior lines of therapy. 4 pts had 12 serious adverse events at least possibly related to tx, including anemia, atrial fibrillation, increased creatinine, dehydration, dyspnea, generalized muscle weakness, heart failure, lung infection, pericardial effusion and thrombocytopenia. 4 pts had a drug-related grade 3 AEs including anemia, increased bilirubin and thrombocytopenia. Conclusions: Abemaciclib monotherapy did not demonstrate sufficient clinical activity in pts with advanced EC with CDKN2A loss or mut for continued evaluation in this pt population. Other tx should be considered for these pts, including tx offered in clinical trials. Clinical trial information: NCT02693535 . [Table: see text]
Phase 2 study of trastuzumab deruxtecan as neoadjuvant treatment for HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003).
Authors: Takahari Daisuke , Kawazoe Akihito , Machida Nozomu , Minashi Keiko , Yamagata Yukinori , Hara Hiroki , Omori Takeshi , Yamamoto Manabu , Yasui Hisateru , Nakayama Izuma , Yamada Takanobu , Kano Masayuki , Yoshikawa Takaki , Wakabayashi Masashi , Komura Yu , Sato Akihiro , Kuwata Takeshi , Kojima Motohiro , Kinoshita Takahiro , Shitara Kohei 
Published: January 2024

309 Background: Currently no HER2 directed therapy is available in the perioperative setting for gastric and gastroesophageal junction (GEJ) cancer. Trastuzumab deruxtecan (T-DXd) received regulatory approval based on the encouraging efficacy demonstrated in the DESTINY-Gastric01 and DESTINY-Gastric02 studies in pretreated patients (pts) with metastatic gastric and GEJ cancer. This multicenter phase 2 study aimed to evaluate the clinical activity and safety of neoadjuvant T-DXd for locally advanced gastric and GEJ cancer. Methods: Eligible pts possessed previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort enrolled pts exhibiting HER2-positivity, defined as IHC 3+ or IHC 2+ with ISH+ by local assessment. An exploratory cohort included patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with serum HER2-ECD exceeded 11.6 ng/ml. Treatment included three cycles of T-DXd administered every 3 weeks, followed by surgery. The primary endpoint was the major pathological response (MPR) rate by central assessment, with an expected rate of 45% and a futility threshold of 20%. The planned sample size in the main cohort was 27 pts with one-sided alpha of 10% and power of 90%, while an additional 10 pts would be enrolled into the exploratory cohort. Pre- and post-treatment samples were subjected to biomarker analyses. Clinical trial identification: NCT05034887. Results: Between November 2021 and November 2022, 27 pts were enrolled into the main cohort from seven Japanese sites. The majority of the pts had IHC3+ (24pts). The primary sites were gastric (16 pts) and GEJ (11 pts). Clinical stages ranged from II/III/IVa: 2/21/4 pts. Of the cohort, 26 pts completed planned 3 courses of T-DXd and one pt discontinued because of toxicity. R0 resection was achieved in 25 pts, with one undergoing R1 resection. The MPR rate as the primary endpoint was 14.8% (80% CI 6.6 % - 27.5 %) which did not surpass the predefined 20%. The pCR rate was 3.7% (95% CI 0.1 % - 19.0 %). There were no new safety signals during T-DXd treatment and during the post-surgery phase. Biomarker analyses remain ongoing. Conclusions: T-DXd monotherapy showed modest single agent activity for locally advanced HER2-positive gastric or GEJ adenocarcinoma in this phase 2 study. An additional cohort combining perioperative T-DXd with capecitabine and durvalumab is planned, to assess whether treatment efficacy and outcomes can be enhanced. Clinical trial information: NCT05034887 .
Larynx-preserving treatment strategy for patients with resectable cervical esophageal squamous cell carcinoma.
Authors: Tsubosa Yasuhiro , Inoue Masazumi , Tokizawa Kazunori , Mayanagi Shuhei 
Published: January 2024

311 Background: Preservation of the larynx is an important treatment strategy for cervical esophageal squamous cell carcinoma (CESCC), because surgery for CESCC often involves laryngectomy. At our hospital, we actively perform dCRT (cisplatin + 5-fluorouarcil + radiation 60Gy) to preserve laryngeal function. In this study, we compared the treatment results of esophagectomy and definitive chemoradiation (dCRT) for resectable CESCC and examined larynx-preserving treatment strategies. Methods: Patients who were treated for resectable CESCC at our hospital from January 2003 to March 2019 were divided into surgery group and dCRT group for the initial treatment. All patients were eligible for both treatments. The treatment results were compared retrospectively. Results: Of all 61 patients, 23 patients received surgery and 38 received dCRT. There was no significant difference in patients’ characteristics between 2 groups. In surgery group, 19 cases lost their laryngeal function by surgery (82.6%). Recurrence was observed in 7 cases, of which only 3 case was local. In CRT group, 33 cases (86.8%) achieved complete response, of which 16 cases relapsed. 8 cases (21.1%) lost their laryngeal function by additional surgery after dCRT. There was no significant difference in 5-year survival rate between two groups (surgery, 60.8%; dCRT, 70.1%; p = 0.750). In dCRT group, 5-year laryngeal-preserving survival rate was 64.8%, and esophageal stenosis before treatment was the independent risk factor for non-larynx preservation. 5-year laryngeal-preserving survival rate was 78.5%, and 5-year survival rate was 85.4% for non-stenotic cases in dCRT group, which were significantly higher than those for stenotic cases. 5-year laryngeal-preserving survival rate was also high in the patients with Ce localized tumor (72.6%). In those patients, non-stenotic patients and cT1-T3 patients had significantly high 5-year laryngeal-preserving survival rate (87.5% and 92.3%). Conclusions: dCRT for CESCC was comparable to surgery in terms of long-term prognosis, and the rate of larynx preservation was high. Among the cases where the tumor was localized to Ce, the laryngeal preservation rate was particularly high in non-stenotic cases and cases with cT1-T3, and dCRT should be actively indicated for these cases.
Role of immunotherapy in gastroesophageal cancer with liver metastasis: A meta-analysis of phase III randomized clinical trials.
Authors: Bawek Sawyer , Gurusinghe Sayuri , Aijaz Ali , Attwood Kristopher , Mukherjee Sarbajit 
Published: January 2024

319 Background: Recent studies have demonstrated a poor response to immunotherapy in patients with colorectal cancer with liver metastasis. The role of immune checkpoint inhibitors (ICIs) for patients with gastroesophageal (GE) cancer with liver metastasis remains unclear. Our objective was to investigate if ICIs are beneficial in patients with GE cancer with liver metastasis. Methods: We searched PubMed, Embase, ESMO, and ASCO Meeting Abstracts for phase III randomized clinical trials (RCTs) testing ICIs in metastatic/advanced GE cancer from 2017 to 2023. All phase III RCTs of metastatic GE cancer treated with ICIs that had available data on liver metastasis were analyzed. A meta-analysis was conducted on the survival outcomes (overall and progression-free survival), where hazard ratios were obtained, with 95% confidence intervals, using the standard random effects model. To assess the heterogeneity of the study outcomes, the I2 statistic was obtained. The I2 statistic represented the variability in the meta-analysis attributed to study heterogeneity. These analyses were applied to the overall cohort of studies, as well as within the liver metastasis (yes or no) sub-cohorts. All analyses were conducted in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: Seven Phase III RCTs were includedthat had available data on overall survival and/or progressive free survival in patients with liver metastasis. Of these, six were in the frontline setting and one in the later line. Overall, 6,109 patients were included. Overall survival was similar among all patients (HR 0.72 [0.67,0.77], p<0.001, I2=0.0%), patients with no liver metastasis (HR 0.73 [0.67,0.81], p<0.001, I2=0.0%), and patients with liver metastasis (HR 0.74 [0.67,0.81], p<0.001, I2=0.0%), indicating that ICIs’ benefit on OS is consistent. Progression-free survival (PFS) was also similar among all patients (HR 0.63 [0.57,0.70], p<0.001, I2=54.7%); those with no liver metastasis (HR 0.62 [0.51,0.76], p<0.001, I2=62.3%), and with liver metastasis (HR 0.66 [0.57,0.76], p<0.001, I2-0.0%). Funnel plots were used to identify a potential bias for studies included in the analysis and showed no significant sources of bias for OS and PFS. Conclusions: In this meta-analysis, ICIs were beneficial in patients with GE cancer with and without liver metastasis. However, the majority of the trials were in the frontline setting where ICIs were combined with chemotherapy. Further subgroup analyses should be performed with individual patient-level data to identify patients who respond best to ICIs.
Applying the fragility index to randomized controlled trials evaluating total neoadjuvant therapy for rectal cancer.
Authors: McKechnie Tyler , Brennan Kelly , Eskicioglu Cagla , Farooq Ameer , Patel Sunil 
Published: January 2024

32 Background: A relatively novel summary measure that is not commonly reported in randomized controlled trials (RCTs) is the fragility index (FI). FI describes the number of additional events required for an outcome to lose statistical significance. It has been applied to a number of medical subspecialities such as critical care, orthopedic surgery and colorectal surgery. Recently, there has been significant interest in, and adoption of, total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC). A number of RCTs have assessed TNT, but the robustness of these practice changing RCTs has never been evaluated. As such, we designed the present study to assess the robustness of the RCTs evaluating TNT for LARC using the FI. Methods: Relevant articles were identified through a recently published review article by Johnson et al. in the Canadian Journal of Surgery, that narratively reviewed all of the previously published RCTs evaluating TNT for LARC. We manually searched Google Scholar and PubMed to identify any other relevant RCTs. Outcomes within these RCTs that were either dichotomous outcomes or time to event outcomes were eligible for inclusion if the reported effect size had an associated p-value of less than 0.05. The main outcome was the FI for each statistically significant outcome. Walsh et al.’s method of calculating FI was utilized. A RCTs results were considered fragile if the FI was less than the loss to follow up for a given outcome. Correlations between FI and research characteristics were assessed using the Spearman’s rank correlation coefficients. Results: Ten RCTs were identified with 25 outcomes having statistically significant differences between groups (p-values < 0.05). Eleven outcomes were time-to-event outcomes, while the remainder were dichotomous outcomes. About half (n=13) were oncologic outcomes (i.e., survival, recurrence), while the rest (n=12) were short- and long-term complications. The median FI was 2 (interquartile range [IQR] 1-16). The number of patients lost to follow-up exceeded the FI in 17 outcomes (68.0%) and thus these results were considered “fragile”. Lower FI was associated with high risk of bias (rho=-0.5594) and higher loss to follow-up (i.e., greater than 5% vs. less than 5%) (rho=-0.4394), while higher FI was associated with large sample size (i.e., greater than 500 patients vs. less than 500 patients) (rho=0.5120). Conclusions: The robustness of outcomes from trials assessing TNT for LARC was found to be questionable. Most of these outcomes were fragile, as determined by the FI. In most cases, two or less additional events would have resulted in a loss of statistical significance of the reported results. Those using the results of these studies, including clinicians and health policy experts, should apply caution when interpreting these types of trials.
Clinicopathological characteristics and lymph node metastasis rates in early gastric lymphoepithelioma-like carcinoma: Implications for endoscopic resection.
Authors: Kim Tae-Se , Min Byung-Hoon , Min Yang Won , Lee Hyuk , Lee Jun Haeng , Rhee Poong-Lyul , An Ji Yeong , Kim Jae J. 
Published: January 2024

321 Background: We aimed to clarify the clinicopathological features and the rate of lymph node metastases (LNM) of early gastric lymphoepithelioma-like carcinoma (LELC). Methods: We compared the clinicopathological characteristics of 82 LELC and 5758 well- or moderately differentiated (WD or MD) tubular adenocarcinoma patients who received gastrectomy for single early gastric cancer (EGC). Results: Compared to the control group, early LELC patients were younger, had a higher prevalence of proximally located tumors, more frequent Epstein-Barr virus (EBV) infection, more frequent deep submucosal invasion (SM2 or SM3, 85.4% versus 29.9%, P < 0.001) but less frequent lymphatic invasion (4.9% versus 16.2%, P = 0.009). Among tumors with deep submucosal invasion, early LELC patients had smaller tumor sizes, less frequent lymphatic invasion (5.7% versus 40.1%, P < 0.001) and a lower rate of LNM (7.1% versus 19.4%, P = 0.016) than the control group. LNM rates of LELC patients with mucosal, shallow submucosal invasion (SM1) and deep submucosal invasion were 0%, 0%, and 7.1%, respectively. Lymphatic invasion was the only significant risk factor in the regression analysis for LNM in LELC patients. Among 12 patients with mucosal or shallow submucosal invasion and 27 patients with deep submucosal invasion having small tumor sizes (less than 2 cm) and no lymphatic invasion, there was no LNM. Conclusions: Given the low rate of LNM, the same curability criteria of ESD for WD or MD EGC may be applied to early LELC and even more flexibly for those considered non-curative ESD only because of deep submucosal invasion.
A randomized phase III study comparing 2-weekly docetaxel, cisplatin and 5-FU (bDCF) with cisplatin and 5-FU (CF) in patients with metastatic or recurrent esophageal cancer: JCOG1314 (MIRACLE).
Authors: Tsushima Takahiro , Hironaka Shuichi , Tsubosa Yasuhiro , Kato Ken , Nomura Motoo , Hara Hiroki , Kitagawa Yuko , Koyanagi Kazuo , Kajiwara Takeshi , Takegawa Naoki , Matsubara Hisahiro , Baba Hideo , Morita Masaru , Masuzawa Toru , Hasegawa Hiroko , Kojima Takashi , Machida Ryunosuke , Sasaki Keita , TAKEUCHI HIROYA , Kadowaki Shigenori 
Published: January 2024

322 Background: For metastatic or recurrent esophageal cancer, 2-drug combination of cisplatin and 5-FU (CF) has long been a standard of care before the emergence of immune checkpoint inhibitors (ICIs). Previous phase I/II study of 3-drug combination, 2-weekly docetaxel plus CF (bDCF) showed promising antitumor activity (JCOG0807). We conducted JCOG1314, a randomized phase III study to confirm the survival superiority of bDCF over CF. Methods: Main eligibility criteria were metastatic or recurrent esophageal cancer; histologically proven squamous cell carcinoma or adenocarcinoma; age 20 to 75; no previous systemic therapy for metastatic disease. Patients were randomly assigned to CF arm (cisplatin 80 mg/m2 on day 1, and 5-FU 800 mg/m2 on days 1-5, every 28 days), or bDCF arm (docetaxel 30 mg/m2 on day 1 and day 15 in addition to CF, every 28 days). The primary endpoint was overall survival (OS). To detect a 3-month difference in median OS [hazard ratio (HR) = 0.73] with study-wise, one-sided alpha level of 5% and power of 75%, 240 patients were required. Results: A total of 240 patients were randomly assigned to bDCF (n = 121) and CF (n = 119) between September 2014 to April 2021. Patient background in bDCF/CF arm was median age, 65/64 years; ECOG performance status 0, 69%/75%; metastatic disease, 63%/67%, ≥2 metastatic organs, 59%/56%; squamous cell carcinoma, 94%/97%. As a data cut-off of April 2023, all 240 patients discontinued protocol treatment. The reasons for treatment discontinuation in bDCF/CF arm were disease progression, 58%/71%; adverse events (AEs), 35%/27%; refusal, 1%/1%; others, 7%/5%, respectively. With a median follow-up of 15.3 months (m), bDCF arm was not superior to CF arm in terms of OS with a median of 16.2 m versus 14.8 m [HR, 0.90; 95% confidence interval (CI), 0.68–1.19; p = 0.23], however, progression-free survival (PFS) in bDCF arm was favorable compared to CF arm with a median of 6.0 m versus 5.2 m (HR, 0.68; 95% CI, 0.52–0.88). Response rate in bDCF/CF arm was 52.8%/45.6%. Major grade 3 or 4 AEs observed in bDCF/CF arm were neutropenia (37.8%/27.1%); anorexia (25.2%/16.1%); fatigue (10.1%/15.3%); hyponatremia (13.4%/13.6%). No treatment related death was observed. Subsequent therapy in bDCF/CF arm was provided for 87%/89% of patients. Conclusions: JCOG1314 did not reach its primary objective, although bDCF was associated with significant increases in PFS. CF is still the standard therapy in patients with metastatic or recurrent esophageal cancer if ICIs are not applicable. Clinical trial information: jRCTs031180143 .