bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of conversion therapy for esophageal squamous cell carcinoma.
Authors: Tsuji Takayuki , Kawakubo Hirofumi , Takeuchi Masashi , Matsuda Satoru , Fukuda Kazumasa , Nakamura Rieko , Kitagawa Yuko 
Published: January 2023

362 Background: The increased efficacy of multimodality treatment allows for the consideration of conversion therapy with curative intent for initially unresectable esophageal squamous cell carcinoma (ESCC) after initial treatment. Conversion therapy has been commonly defined as treatment aiming at a curable intention after tumors initially deemed technically or oncologically unresectable or only marginally resectable respond to chemotherapy. In our institute, conversion therapy is considered for patients with para-aortic lymph node-positive advanced ESCC who have no other distant metastasis, if the para-aortic lymph node metastases have disappeared after systemic chemotherapy. Methods: There were 33 patients of unresectable esophageal cancer with positive para-aortic lymph node metastases from 2011 to 2021. Nine of these patients showed disappearance of para-aortic lymph node metastases and underwent conversion therapy, seven patients underwent esophagectomy and two patients underwent chemoradiation therapy (CRT). Characteristics, short-term and long-term results of these nine cases are studied. Results: All of the nine patients who had para-aortic lymph node metastases were treated with induction DCF (Docetaxel + Cisplatin + 5-FU) therapy as initial treatment. After disappearance of para-aortic lymph node metastasis, minimally invasive or open esophagectomy was performed in seven patients and CRT was performed in two patients. In operation group, four patients (57%) had Clavien-Dindo grade 2 or 3 complications, but no perioperative death was observed. In CRT group, there was no toxicity over CTCAE grade 3. Four of nine patients (44%) had recurrence, within mediastinum lymph node, abdominal lymph node or adrenal gland. 3-year DFS was 56% and 3-year OS was 67%. Conclusions: Conversion therapy is safe and feasible in cases that responded to systemic chemotherapy. Some cases showed good prognosis. Long-term survival is expected with conversion therapy. In our study, there was few cases that could led to conversion therapy. It is expected that more aggressive initial chemotherapy will be used in the future for patients with positive para-aortic lymph node metastases with a view to conversion therapy.
SHR-1701 plus chemotherapy as first-line treatment for unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).
Authors: wang yi , Liu Hong , Wang Qingwei , Qiao Naian , Wang Jianbo , Tan Bingxu , Cheng Bo , Chu Yunxia , Li Huajun , Cheng Yufeng 
Published: January 2023

363 Background: Platinum-based chemotherapy is the standard first-line treatment for advanced or metastatic ESCC. Recently, the combination of PD-(L)1 pathway blockade with chemotherapy has shown synergistic efficacy in a few clinical trials. SHR-1701 is a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II. The purpose of this ongoing phase II trial (ChiCTR2000039909) was to evaluate the efficacy and safety of SHR-1701 combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC in China. Methods: This trial enrolled systemic treatment-naive patients(pts) with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who had ECOG PS of 0-1. Eligible pts received SHR-1701 (30mg/kg, iv, d1, q3w) combined with up to 6 cycles of albumin-bound paclitaxel (125mg/m2, iv, d1, d8, q3w) and cisplatin (75mg/m2, iv, d1, q3w). For those without progressive disease, maintenance treatment was administrated with SHR-1701 monotherapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), safety and biomarkers. Results: As of September 21, 2022, 18 pts were enrolled. The median age was 67.5 years (range: 46–75 years) and 16 (88.9%) were male. 10 of the pts (55.6%) presented with distant metastasis. 14 pts were included in the efficacy analysis and 17 were in the safety analysis. The ORR and DCR were 85.7% and 100.0%, respectively. One patient achieved a complete response (CR) which will reach confirmation at next visit. 11 pts had partial response (PR), including 9 confirmed PR, one pending confirmation PR, and one unconfirmed PR. In addition, one PR patient got a CR target lesion. Grade 3-4 treatment-related adverse events (AEs) were observed in 23.5% of pts, including neutropenia (11.8%), leukopenia (5.9%), anemia (5.9%), emesis (5.9%) and rash (5.9%). Immune-related AEs (irAEs) were observed in 52.9%, and only one grade 3 irAE of rash occurred. Conclusions: SHR-1701 plus chemotherapy showed potential clinical benefits with acceptable toxicity as first-line treatment, and it might be a favorable option for pts with advanced ESCC. Clinical trial information: ChiCTR2000039909 .
Camrelizumab plus low-dose apatinib and SOX in the first-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: A single-arm, dose escalation and expansion study (SPACE study).
Authors: Chen Xiaofeng , Xu Hao , Wang Deqiang , Chen Xiaobing , Wang Kangxin , Jin Guangfu , Ding Yongbin , Tang Jie , Fang Yueyu , Sun Hui , Jiang Qiusheng , Pan Lanlan , Tian Yitong , Wang Rong , Xu Tongpeng , Meng Lijuan , Li Fengyuan , Shu Yongqian , Guo Fen 
Published: January 2023

365 Background: The dose escalation phase was presented early, and confirmed that the recommended phase II dose (RP2D) was camrelizumab (200 mg, d1) plus apatinib (250 mg, qd), S-1(40 mg, bid, d1-14) and oxaliplatin (130 mg/m2, d1) every 3 weeks followed by camrelizumab (200 mg, d1) plus apatinib (250 mg, qd) every 3 weeks. Methods: Patients (pts) aged 18-75 years, with unresectable or potentially resectable G/GEJ adenocarcinoma, HER2-negative or unknown HER2 status and no previous systemic therapy, were enrolled to receive combination therapy. Primary endpoint was Objective response rate (ORR) by RECIST 1.1, secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), surgical resection rate and safety. Results: From Jun, 2020 to July 2022, 35 pts were enrolled (9 pts in dose escalation phase, 26 pts in dose expansion phase), with a median follow-up of 8.0 months (95% CL, 6.7-12.2). Median age (range) was 59(19-68), 94.3% (33/35) were male, 20% (7/35) were diagnosed with GEJ adenocarcinoma, 60% (21/35) had liver metastases. At data cutoff, 33 pts were included in the efficacy analysis. The ORR was 90.9%, with 30 (90.9%) PR. SD were 1 (3.0%) with a DCR of 93.9%. In addition, 9 pts showed an unconfirmed PR with a confirmed ORR of 80.8%. Median PFS was 10.2 months (95% CI, 5.5-22.3), with the median OS not reached yet. Conversion to resectable G/GEJ adenocarcinoma was identified in 9 (25.7%) pts. Of them, 2 pts were observed complete pathology response. 94.3% pts experienced treatment related adverse event (TRAE), with 45.7% being grade ≥3. The most frequent grade ≥3 TRAE were GGT increased (31.4%, 11/35), rash (11.4%, 4/35), alkaline phosphatase increased (11.4%, 4/35)、neutrophil count decreased (8.6%, 3/35). No new safety signal was identified. Conclusions: Camrelizumab plus apatinib and SOX followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as first line therapy for patients with G/GEJ adenocarcinoma. Clinical trial information: ChiCTR2000034109 .
Preliminary results of TQB2450 (PD-L1 blockade) plus anlotinib combined with oxaliplatin and capecitabine in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: A single-arm, multicenter phase II clinical trial.
Authors: Li Ning , Deng Wen-Ying , Ma Yi-Jie , Bie Liang-Yu , Zhang Chi , Wei Chen , Luo Suxia 
Published: January 2023

367 Background: Efficacy and prognosis of chemotherapy in first-line setting for patients (pts) with advanced HER2-negative G/GEJ adenocarcinoma was dismal currently. PD-1 blockades combined with chemotherapy as first-line regimen exhibited superior efficacy for pts with G/GEJ adenocarcinoma recently, and the efficacy of tumor regression still needs to be improved. Anlotinib was a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been approved for treatment of considerable malignancies in China. We aimed to investigate the efficacy and safety of TQB2450 (PD-L1 blockade) plus anlotinib combined with CAPEOX (oxaliplatin and capecitabine) as first-line regimen for advanced G/GEJ adenocarcinoma and report the preliminary results timely. Methods: Pts with HER2-negative unresectable locally advanced or metastatic G/GEJ adenocarcinoma who did not expose to previous systemic treatment were recruited in this study. Eligible pts received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) combined with oxaliplatin (130mg/m2, d1, iv, q3w) and capecitabine (1000mg/m2, po, bid, d1~14, q3w) for 6 cycles as initial therapy. For those without disease progression (PD), maintenance therapy was adopted with TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) until PD or unacceptable toxicity. Tumor response was assessed by investigator according to RECIST version 1.1 using CT scans. The calculated sample size was 25. The primary endpoint was ORR, secondary endpoints were DoR, PFS, OS, DCR and safety. Results: From Apr 2021 to Jul 2022, a total of 20 pts were enrolled and available for efficacy evaluation. In best overall response assessment, there were 15 PR (75.0%), 4 SD (20.0%) and 1 NE (5.0%). In consequence, the preliminary ORR was 75.0% (95%CI: 50.9%~91.3%), DCR was 95.0% (95%CI: 75.1%~99.9%). Median PFS of the 20 pts was not yet reached. Furthermore, the most common treatment-emergent adverse events with the incidence >40% were thrombocytopenia (80%), anemia (75%), leukopenia (65%), decreased total protein (45%) and decreased total protein (45%). The common grade ≥3 treatment-emergent adverse events were neutropenia (15%), lymphocyte count decreased (10%), anemia (5%), leukopenia (5%), elevated aspartate aminotransferase (5%) and elevated alkaline phosphatase (5%). Conclusions: Preliminary results suggested that TQB2450 plus anlotinib combined with CAPEOX in first-line setting for advanced G/GEJ adenocarcinoma exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04891900 .
An indirect assessment of individual-level association between disease-free survival (DFS) and overall survival (OS) for resectable esophageal or gastroesophageal junction cancer (EC/GEJC): A pooled analysis of randomized controlled trials (RCTs) by an illness-death model.
Authors: Alagoz Oguzhan , Ajani Jaffer A. , Srinivasan Swetha , Kim Inkyu , Singh Prianka , Kurt Murat 
Published: January 2023

369 Background: Validation of intermediate endpoints such as DFS as surrogates for overall survival (OS) in RCTs at individual-level remains as a challenge due to difficulty of collection of individual-level patient data. This study explores the individual-level correlation between DFS and OS indirectly using reconstructed Kaplan-Meier (KM) curves from the RCTs assessing therapies for (neo)adjuvant and perioperative treatment of EC/GEJC. Methods: An illness-death model previously validated in estimating individual-level association between DFS and OS for four correlation meta-analyses, two of which were published by the GASTRIC group, in early and late stage treatment of gastric cancer was employed. Reconstructed DFS and OS data from 25 RCTs published between 1994 - 2020 was pooled separately for each arm and each endpoint. Pooled data was analyzed to estimate the correlation between DFS and OS, as measured by Pearson’s r, Spearman’s rho, and Kendall’s tau. Predictive accuracy of the approach was evaluated by comparing its OS and restricted mean survival time (RMST) predictions to their counterparts obtained from the reported OS data from the RCTs. Sensitivity of correlation measures were assessed with respect to pre-specified variations in pre-recurrence death probability, post-recurrence mortality rate, and choice of the survival model used to extrapolate reported DFS curves from the RCTs. Results: Across all RCTs, the primary cancers covered were EC (n=13), EC/GEJC(n=9), GEJC (n=2) and GEJC/gastric cancer (n=1). According to the histology, 10 RCTs studied only squamous cell carcinoma (SCC) and 9 RCTs studied only adenocarcinoma (AC) of the disease, whereas the remaining 6 RCTs included varying mixtures of SCC and AC patients. The follow-up duration ranged between 27 and 72 months across RCTs. Comparator and intervention arms of the pooled data had 2499 and 2490 patients, respectively. Predicted Pearson’s r, Spearman’s rho, Kendall’s tau were 0.67, 0.79, and 0.70, respectively with negligibly narrow 95% CIs. Across both arms of the pooled data, on average, predicted OS curves laid within the 95% CIs of the pooled OS KM-curves 92% of the time. Average deviation between the RMSTs under the model-predicted OS curves and pooled OS KM curves was 2%. In sensitivity analyses, the ranges for r, r, and t were (0.56-0.88), (0.69-0.89), and (0.61-0.80), respectively. Conclusions: Results indicate moderate-to-strong correlation between DFS and OS in early-stage treatment of EC/GEJC providing supportive evidence for the validation of DFS as a surrogate for OS. Our approach mitigates the lack of patient level data in endpoint correlation assessment but may be prone to changes in the predicted value of pre-recurrence death probability.
Trimodality therapy with carboplatin/paclitaxel (CP) or FOLFOX (FFX) for esophageal/esogastric junctional cancer (EC/EGJ): Expanded safety and efficacy data from PROTECT.
Authors: Adenis Antoine , Piessen Guillaume , Le Sourd Samuel , Bogart Emilie , Paumier Amaury , Vendrely Veronique , Glehen Olivier , Dahan Laetitia , Simmet Victor , Bergeat Damien , Samalin Emmanuelle , Chauvenet Marion , d'Journo Xavier Benoit , Hiret Sandrine , Gronnier Caroline , Baty Manon , Pannier Diane , Veziant Julie , Le Deley Marie-Cecile , Mirabel Xavier 
Published: January 2023

370 Background: When combined to preoperative radiation therapy (RT), CP and FFX regimen provide both high complete resection (R0) rate for EC/EGJ cancer (Adenis, ASCO 2022). However, it appeared that neoadjuvant chemoradiation (nCRT) with CP is associated with a severe postoperative morbidity rate higher than expected. We present here the expanded safety and efficacy analyses from the PROTECT trial. Methods: PROTECT is a randomized, phase 2 trial which included stage II/III and ECOG PS ≤2 EC or Siewert I-II EGJ cancers. Patients (pts) received FFX or CP with concurrent RT (41.4Gy, 1.8Gy, 23 fractions), followed by surgery 4-8 weeks after completion of nCRT (Messager, BMC Cancer 2016). Co-primary endpoints were proportion of R0 rate and proportion of Clavien-Dindo severe postoperative morbidity. Main secondary endpoints were nCRT and postoperative safety (NCI CTCAE v.4), DFS and OS. Results: 41/50 (82%) and 39/50 (78 %) pts received the planned chemo cycles and concurrent RT in FFX and CP arms, respectively. Grade (gr.) 3–4 AEs related to nCRT (FFX 14/50, 28%; CP 14/50, 28%) occurring in ≥5% of pts included lymphopenia (n=3, 6%; n=4, 8%), neutropenia (n=1, 2%; n=3, 6%), fatigue (n=2, 4%; n=0) and esophagitis-related to RT (n=1, 2%; n=1, 2%). No death was reported during nCRT. Surgery (FFX and CP; mini invasive: 15 and 15, hybrid: 22 and 21, open: 7 and 12) was performed in 44 and 48 pts, in FFX and CP groups, respectively. The main gr. III-V surgical complications (Clavien-Dindo scale) occurring in ≥5% of pts included esophageal fistula (n=2/43 evaluable pts, 6%; 8/48, 17%), conduit necrosis (n=2, 5%; n=1, 2%), ARDS (n=3, 7%; n=3, 6%), pleural effusion (n=3, 7%; n=4, 8%), and haemorrhage (n=0; n=3, 6%). There were no postoperative deaths. With a median follow-up of 54m, median DFS were 12.3m and 20m (HR=0.84; 95%CI: 0.52-1.35; p=0.48) and median OS were 31.7m and 45.8m (HR=0.79; 95%CI: 0.47-1.32; p=0.36) in FFX and CP arms, respectively. Prognostic factors significantly associated to DFS in univariate analysis were: R0 resection, TRG1-2 and ypT0N0 status. Conclusions: A higher than expected number of severe esophageal fistula was observed in the CP arm. We could not demonstrate a significant benefit of CP compared to FFX in terms of survival outcomes, but the study was not primarily designed to specifically address this issue. Clinical trial information: NCT02359968 .
Enhancing nanoparticle paclitaxel antitumor response through targeted inhibition of c-Met pathway by merestinib in gastric cancer models.
Authors: Kaurich Quinn , Huang Jennifer , Awasthi Niranjan 
Published: January 2023

372 Background: Gastric adenocarcinoma (GAC) is the fifth most common malignancy and the third most common cause of cancer-related deaths worldwide. Combination chemotherapy regimens are commonly used to treat GAC, but the median survival time remains less than one year. Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel, NPT), an approved treatment for breast cancer, non-small cell lung cancer and pancreatic cancer, has demonstrated high antitumor activity in previous GAC studies. Many growth factors and their receptors are overexpressed in GAC and have been implicated in its pathophysiology. Aberrant activation of the c-Met pathway has been reported in up to 50% of GAC patients. We hypothesize that merestinib, a small-molecule inhibitor of c-Met, with additional inhibition of Axl and DDR1/2 pathways, will have significant antitumor effects and will enhance nab-paclitaxel chemotherapy response in GAC preclinical models. Methods: GAC subcutaneous xenografts were established by injecting MKN-45 and SNU-1 cells in NOD/SCID mice to study treatment effects on tumor volume, tumor weight, net tumor growth, and mouse body weight. Immunohistochemistry analyses of xenograft tissues were performed using Ki67 and endomucin to examine tumor cell proliferation and microvessel density, respectively. Results: In vitro assays showed that nab-paclitaxel and merestinib decreased cell proliferation in all three GAC-associated cell lines tested, with an additive effect in combination. Reduction in cell proliferation at low doses of nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% (MKN-45, high phospho-c-Met expression), 59%, 50%, and 82% (SNU-1, low phospho-c-Met expression), and 53%, 19%, and 66% in gastric fibroblasts. Immunoblot analysis of merestinib treated MKN-45 cells revealed increased expression of pro-apoptotic proteins and decreased expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. In gastric fibroblasts, merestinib decreased phospho-ERK and increased pro-apoptotic protein expression. Phospho-c-Met and phospho-EGFR were not detected in SNU-1 immunoblots; however, phospho-ERK, phospho-VEGFR, and apoptotic protein expression increased after treatment. In MKN-45 xenografts, net tumor growth in control, nab-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3. Immunohistochemistry analysis of tumor cell proliferation and microvessel density corroborated tumor growth study results. Conclusions: These findings suggest that merestinib has strong antitumor activity in GAC and exhibits an additive effect when administered with nab-paclitaxel. These results provide compelling evidence that this therapeutic approach may lead to a clinically relevant combination to improve GAC patients’ survival.
Safety and short-term efficacy of neoadjuvant FLOT therapy in patients with resectable esophageal squamous cell carcinoma.
Authors: Yoshinami Yuri , Yamamoto Shun , Kadono Toru , Hirose Toshiharu , Ikeda Go , Ohara Akihiro , Itoyama Mai , Yokoyama Kazuki , Honma Yoshitaka , Ishiyama Koshiro , Oguma Junya , Daiko Hiroyuki , Kato Ken 
Published: January 2023

373 Background: Docetaxel and cisplatin, 5-FU (DCF) is a standard neoadjuvant treatment for resectable esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 study. However, DCF therapy showed that 18.6% of patients achieved pathological complete response but 16.3% had febrile neutropenia (FN) and needed hydration. In Western countries, 5-FU plus leucovorin, oxaliplatin, docetaxel (FLOT) is a standard perioperative treatment for resectable gastric and esophagogastric junction adenocarcinoma patients. FLOT therapy showed that 2% of patients had FN and did not need hydration. However, safety and efficacy of neoadjuvant FLOT (NeoFLOT) in locally advanced ESCC patients was unclear. Methods: The subjects for this study were patients with resectable ESCC diagnosed as cT1N1-3M0, cT2-3N0-3M0, and cT1-3N0-3M1 (UICC-TNM 8th) and received NeoFLOT therapy between Feb 2021 to July 2022 at our hospital. NeoFLOT therapy (oxaliplatin: 85 mg/m2, leucovorin: 200 mg/m2, 5-FU: 2600 mg/m2, docetaxel: 50 mg/m2, every 2 weeks) was administered for 4 courses. We evaluated adverse events (CTCAE ver. 5.0) and histopathological response. Results: We identified 16 eligible patients and 12 of all patients (75%) underwent surgery. 4 patients (25%) resulted in progressive disease (1 patient underwent chemoradiotherapy and 3 patients underwent surgery). R0 resection rate was 75% and complete pathologic response in primary tumor was seen in 2 patients (17%). The most common adverse events were hematologic toxicity, with grade 3 or 4 leukopenia in 6 patients (38%), neutropenia in 9 patients (56%). The common non-hematological toxicity, with all grades deceased appetite in 7 patients (44%) and malaise in 8 patients (50%), peripheral neuropathy in (44%). Furthermore, the incidence of FN was 6%. In patients with grade 2 or higher renal failure, no one (0%) had worsened renal function. Conclusions: NeoFLOT therapy showed well-tolerated and comparable efficacy with DCF therapy.