bluuebunny/crossref_metadata_2025 huggingface dataset:
Early-onset colorectal cancer: Real-world genomic data from the community-based Sarah Cannon Cancer Centers Network.
Authors: Fontana Elisa , Jones Carissa , Misch Amanda , Schlauch Daniel , Spigel David R. , Arkenau Hendrik-Tobias , McKenzie Andrew Jacob
Published: January 2022

198

Background: Rising incidence in early-onset colorectal cancer (EO-CRC) is a recent phenomenon observed especially in the US. We exploited Sarah Cannon’s web-based analytics platform, to compare the genomic profiles of EO-CRC to late-onset colorectal cancer (LO-CRC). Methods: Commercial NGS testing performed in oncology practices are routinely extracted and harmonized into the Genospace database. Data from CRC adenocarcinomas were selected; patients (pts) with unknown microsatellite instability (MSI) status were excluded. To reduce the confounding effect of MSI-high hypermutated tumors, only MSI-stable (MSS) tumors were analyzed. Reports generated from archival tissue samples were analyzed separately from those generated from plasma, since liquid biopsies were more likely to be post-treatment. Results: NGS reports from 1,477 MSS CRC pts were analysed. Compared to LO, EO pts had same sex distribution and significantly lower prevalence of Caucasian ethnicity (53% LO vs. 43% EO, p < 0.01). 1029 were tissue (18.7% EO) and 448 plasma (17.8% EO) tests. Of 68 CRC-related genes assessed in tissue, 2 were significantly enriched in EO: BRCA1 mutation (3% LO vs. 7.3% EO p 0.01); PTEN mutation (3% LO vs. 6.2% EO p 0.05). Looking at panel-wide gene association, 19 genes (tissue) were enriched in EO, though none were significant after multiple testing correction. In plasma, ATM alterations were significantly higher in LO (17.3% LO vs. 3.8% EO p <0.001, FDR 0.16), (likely clonal haematopoiesis). No difference in tissue nor plasma TMB were observed [tissue: median (IQ): LO 5.04 (3.5 - 7); EO 4.39 (2.5 – 6.1); TMB >10: 7% LO vs. 6% EO; plasma: median (IQ): LO 8.73 (5.7 – 13.4); EO 7.19 (2.9 – 12.6); TMB >10: 12% LO vs. 14% EO]. Overall, tissue and plasma genomic profiles were concordant, except for EGFR alterations (4.5% tissue, 21.6% plasma, possibly acquired amplification post-EGFR therapy). Conclusions: Here we provide real-world insight from pts across the US. In MSS CRC, tissue and plasma genomic profiles of EO pts do not significantly differ from LO pts. Epigenetic and transcriptional events should be investigated. Enrichment for BRCA1 and PTEN mutations in EO pts may have important screening and therapeutic implications; germline status will be further investigated.
Colontown University: Patient-created disease education.
Authors: Seybold Nancy , George Manju
Published: January 2022

205

Background: PALTOWN’s Facebook community, COLONTOWN, serves over 6,000 colorectal cancer (CRC) patients and caregivers. 81% of members are late stage patients (or late stage caregivers), and 85% are under the age of 60. They are highly motivated to find reliable information about treatment options as quickly as possible. Many arrive with little prior CRC education. Here we illustrate the creation of a patient-centric disease education program, COLONTOWN University (CTU), developed from the conversations and information journeys in COLONTOWN. Methods: CTU is a unique model for disseminating patient-facing disease education. CTU’s patient and caregiver staff develop original resources from a patient perspective, and work with principal investigators, testing companies, and other partners to create content specifically designed for the Learning Centers. Each Center provides resources to address the information needs of patients across both the spectrum of disease education and of CRC disease experience. Within the University’s online platform, self-contained Learning Centers offer structured resource libraries on topics of high interest to patients. Results: CTU creates patient-centric disease education that is accessible and more sophisticated than typical patient education materials. The discussions in COLONTOWN, in groups focused on specific biomarkers, metastases locations, and treatment modalities, provide members with the framework for understanding their disease. CTU gives them the resources they need to have informed discussions with their care teams. The CTU platform provides insight into what resources are most utilized. Survey tools facilitate an understanding of whether patients feel they have access to more treatment options, and have more productive interactions with their care teams, as a result of the education provided by CTU and the conversations with their peers in COLONTOWN. Conclusions: In its first year, CTU has become the education resource of choice for the thousands of members of COLONTOWN. Clinicians, principal investigators, and industry have all been enthusiastic partners in the development of resources. The positive response to CTU demonstrates the value of this model of patient-driven disease education.[Table: see text]
Deviation from the precisely timed age-associated patterns revealed by blood metabolomics to find CRC patients at risk of relapse at the CRC diagnosis.
Authors: Thyparambil Sheeno P. , Zhu Xiurui , Zhang Yani , Sun Hui , Peng Junjie , Cai Sanjun , Li Yaqi , Fu Chen , Bao Pingping , Hao Shiying , Li Zhen , Ding Yun , Yao Xiaoming , Liao Wei-Li , Heaton Robert , Han Zhi , Tian Lu , Schilling James , Sylvester Karl G. , Ling Xuefeng
Published: January 2022

206

Background: Human serum metabolome profiles have been analyzed to explore the molecular changes that occur with aging. We hypothesized that deep metabolic profiling of sera with different ages would allow the identification of distinct metabolic chronologic patterns as a normal biological baseline to study personal aging. We further hypothesized that metabolic assessment of this chronologic deviation, resulting from advanced precancerous lesion (APL) and stage I/II/III CRC, from the normal reference baseline, would be instrumental for prognosis of relapse revealing underlying pathophysiology. Methods: A cohort of normal (n=3,616, training; n=1,170, testing), 631 advanced adenoma, 1,019 stage I, 404 stage II and 417 stage III serum samples were assembled. Innovative global LCMS metabolomic production were applied to deep profile these subjects. Identification of the age-associated molecular patterns in normal subjects, modeled with an elastic net algorithm, established the reference baseline to mirror a metabolic clock. CRC associated deviation from the precise chronologically paced metabolic patterns was quantified to associate the clinical endpoints of relapse, OSF and PFS, and to identify the tightly associated metabolic pathways. Results: We observed that for those CRCs, the predicted metabolic age can differ from the chronological age with consistent variations, resulting “older” or “younger” metabolic age subgroup in reference to the chronological age. Significant disruptions from the normal baseline were observed in CRCs patients, and consistent stage specific patterns were observed. Outlier, “Older” or “younger” metabolic age subgroup, CRC patients were found with significant future relapse enrichment. Predictive models were derived to case find the patients at risk of future relapse at the CRC diagnosis timepoint. Conclusions: Deviations from the meticulously timed metabolic aging patterns may provide utility to allow prognosis of future clinical endpoints of relapse and overall survival. Close examination of the underlying metabolic pathways, associated with CRC stage specific metabolic patterns, disrupting the baseline ageotypes, not only may improve the sensitivity and specificity of prognostic tests of CRC relapse, but also shed new insights into CRC therapeutics.
Real-world effectiveness and safety of camrelizumab-based neoadjuvant therapy in resectable esophageal cancer: Initial results of a prospective multicenter observational study.
Authors: Zhang Yi , Shen Guoyi , Xu Rongyu , Huang Guozhong , Yang Shengsheng , Zheng Qingfeng , Huang Zhijun , Duan Hongbing , Ma Liangyun , Yang Libao , Yi Yunfeng , Liu Rongxing , Li Kezhi , Chen Shaogeng
Published: January 2022

250

Background: Camrelizumab, a fully humanized monoclonal anti-PD-1 antibody, has shown promising efficacy with good tolerance in neoadjuvant therapy of resectable locally advanced esophageal cancer (EC). The present study aimed to investigate the effectiveness and safety of camrelizumab-based neoadjuvant therapy in a comparatively larger number of resectable EC patients in a real-world setting and initial results were reported here. Methods: In this prospective multicenter observational study (ChiCTR2000039170), patients with histologically confirmed resectable EC who were scheduled for camrelizumab-based neoadjuvant therapy at the discretion of treating physicians/ oncologists were included. Eligible patients were aged ≥ 18 years, had ECOG PS of 0-1, measurable disease per RECIST v1.1, adequate organ function, and expected survival time of ≥ 3 months, as well as provided written informed consent. The primary endpoint was safety. The secondary endpoints were major pathologic response (MPR), pathologic complete response (pCR), R0 resection rate, overall response rate (ORR), one-year overall survival (OS) rate, and disease-free survival (DFS). Results: At total of 166 patients (62.9 ± 9.2 years, and 84.2% male) were enrolled between October 20 2020 and August 26 2021. All patients received neoadjuvant camrelizumab plus chemotherapies (primarily nab-paclitaxel and nedaplatin) except one receiving camrelizumab alone. Overall, 109 patients (65.7%) experienced treatment-related adverse events (TRAEs), most commonly reactive cutaneous capillary endothelial proliferation (RCCEP, 45.3%), cough (10.4%), and pneumonia (8.5%). Thirteen (7.8%) patients experienced grade 3-4 TRAEs. There was no grade 5 toxicity. At the data cutoff, 141 (84.9%) patients were evaluable for radiological response, 82 (69.5%) patients underwent surgical resection. The ORR was 70.9% (100/141) and the R0 resection rate was 97.5% (79/82). Among the 81 patients available for pathologic assessment, 51 (63.0%) patients achieved MPR and of which, 15 (18.5%) had pCR. The median survival times have not been reached at the time of data analysis. Conclusions: The real-world data of our resectable EC patients showed effectiveness and safety profiles of camrelizumab-based neoadjuvant therapy consistent with those observed in previous trials.
Prognostic value of patient reported outcomes (PROs) in advanced gastroesophageal cancer (GO): A systematic review.
Authors: Naher Sayeda Kamrun , Grimison Peter S. , Siu Ho Wai Derrick , Mercieca-Bebber Rebecca , Stockler Martin R.
Published: January 2022

251

Background: To summarise the prognostic value of PROs in advanced GO cancer. Methods: We searched multiple databases using search terms developed with medical librarians. Studies examining the relationship between baseline PROs and prognosis were included. Two reviewers screened articles and extracted data on study design, survival, univariable and multivariable relationships between PROs and prognosis. QUAL-SYST was used for quality assessment. Discrepancies were resolved by a third reviewer. Results: Of 3002 abstracts, seven studies were included: four pooled analyses of randomised controlled trials (RCTs), two RCTs and one cohort study. Five received QUAL-SYST scores >65%. Total 3,408 patients and 2,761(81%) with PRO data. Median survival ranged from 4.5 to 9.5 months. In one univariable analysis for oesophageal squamous cell cancer (SCC), physical functioning and fatigue measured by QLQ-C30 had prognostic significance. For adenocarcinoma, physical functioning, global QOL, role functioning, emotional functioning (QLQ-C30) were significant in three studies. Pain was significant in three studies (QLQ-C30 n=2, EQ-5D-3L n=1). Fatigue (QLQ-C30) was significant in two studies. Appetite loss (QLQ-C30) was significant in two studies. In multivariable analyses for oesophageal SCC (QLQ-C30) physical and social functioning had prognostic significance. In adenocarcinoma, physical functioning, role functioning, appetite loss, global QOL, social functioning and pain showed prognostic significance (Table). One study showed adenocarcinoma patients with lower anorexia (FAACT-A/CS scores of >37) lived longer (19.3 months) than patients with low scores ≤37 (6.7 months). Conclusions: Baseline PROs for multiple functional domains, symptoms (pain, appetite loss) and overall QOL have prognostic significance in advanced GO cancer. Further research is needed to establish clear levels of the relationship which could assist in communication with patients about prognosis, and stratification for clinical trials.[Table: see text]
REVIVE study: A prospective observational study in chemotherapy (CTx) after nivolumab (NIVO) therapy for advanced gastric cancer (AGC).
Authors: Matsushima Tomohiro , Narita Yukiya , Misumi Toshihiro , Sakamoto Yasuhiro , Matsuoka Hiroshi , Tanioka Hiroaki , Kawakami Takeshi , Miwa Hiroto , Shoji Hirokazu , Ishiguro Atsushi , Yamada Takanobu , Fushida Sachio , Miura Kou , Shinozaki Katsunori , Mizukami Takuro , Nishina Tomohiro , Moriwaki Toshikazu , Mitani Seiichiro , Nakamura Michio , Muro Kei
Published: January 2022

257

Background: NIVO therapy is a standard care treatment for heavily pretreated patients with AGC. Improvement in objective response rate (ORR) to CTx after NIVO therapy for various cancer types has been reported. However, the efficacy and safety of CTx for AGC after progression on NIVO remains unclear. Methods: The REVIVE trial was a prospective, multicenter, observational study that evaluated the efficacy and safety of CTx in NIVO-refractory or NIVO-intolerant patients (pts) with AGC (UMIN000032182). The primary endpoint was overall survival (OS) of CTx following NIVO therapy. The median threshold and expected survival times were set as 4.0 and 7.0 months (M). The secondary endpoints are ORR, disease control rate (DCR), progression-free survival (PFS), and incidence of adverse events (AEs), including immune-related adverse events (irAEs). CTx consisted of irinotecan alone (IRI), trifluridine/tipiracil alone (FT), and oxaliplatin-containing regimens (OX). Results: Of 395 pts treated with NIVO who met the eligibility at formal registration from Jun 2018 to Sep 2020, 199 pts who received CTx after NIVO were evaluated. Pt characteristics were as follows: median age, 69 years; male, 70%; ECOG PS 0/1/2, 38/51/12%; histology (diffuse/intestinal), 39/59%; metastatic lesions (peritoneum/liver/lung), 38/34/15%; number of metastatic organ sites (0–1/≥2), 40/60%; measurable lesions, 83%; and CTx regimens (IRI/FT/OX), 64/31/5%. Median OS and PFS were 7.5 M (95%CI, 6.7–9.7) at 145 events for OS and 2.9 M (95%CI, 2.2–3.5) at 184 events for PFS. The ORR and DCR were 17.0% (95%CI, 11.6–23.6) and 46.7% (95%CI, 38.9–54.6). Median OS, median PFS, ORR, and DCR according to CTx regimens (IRI/FT/OX) were 8.1/7.1/6.2 M, 3.3/2.8/2.4 M, 18.9/10.9/25.0%, and 47.8/43.5/50.0%, respectively. At the start of CTx, 42 pts had irAEs due to prior NIVO therapy. The most common any-grade and grade ≥3 AEs during CTx included decreased appetite (46% and 7.5%), fatigue (26% and 2.5%), nausea (24% and 1.5%), constipation (16% and 0%), and diarrhea (28% and 4.0%). No treatment-related deaths were observed. Conclusions: Prior NIVO therapy may lead to improved prognosis after CTx without unexpected AEs in pts with AGC, warranting further investigations after NIVO is approved as first-line treatment.[Table: see text]
Examining value-based care outcomes in gastric and esophageal patients with and without access to registered dietitians: A retrospective cohort study of patients enrolled in the oncology care model.
Authors: Smith Karen , Torres Vanessa , Jensen Terry Lynn , Ortega Lance , Hudson Kathryn Elizabeth , Hoverman John Russell , Wilfong Lalan S.
Published: January 2022

264

Background: Patients with gastric and esophageal cancers are at high risk for malnutrition. Appropriate nutrition care provided by a registered dietitian (RD) as part of a multidisciplinary care team is supported by evidenced-based guidelines and clinical studies focused on surgical outcomes. However, Medicare does not routinely cover outpatient RD services for oncology patients which limits access to this care. Examining quality outcomes for patients in clinics with and without access to a RD can help define the value of this service. Methods: We used a retrospective cohort design to analyze Total Cost of Care (TCOC), hospital admissions and Length of Stay (LOS), and Emergency Department (ED) and Observation visits for patients with gastric and esophageal cancer who were enrolled in the Oncology Care Model (OCM) during Performance Periods (PP) 1-6 (July 1, 2016 – June 30, 2019). We divided patients from a geographically concentrated metropolitan hub into cohorts based on clinic access to a RD. Each patient’s initial OCM episode of care was used for analysis. Results: We identified 253 OCM patients with gastric or esophageal cancer from PP1-6. Of these, 109 were treated at 9 clinics with an RD and 144 in 16 clinics without a RD. In the RD cohort 42.2% of patients were admitted to the hospital with a LOS of 6.8 days. In the non-RD cohort 45.8% of patients were admitted to the hospital with a LOS of 9.4 days. TCOC for the 6-month episode was lower in the RD cohort at $ 39,033 vs the non-RD cohort at $49,359. There were 0.56 ED and observation visits per patient in the RD cohort and 0.8 ED and observation visits per patient in the cohort without a RD. Conclusions: Amongst OCM patients with gastric and esophageal cancers, treatment at a clinic with a RD was associated with lower TCOC, reduced LOS for patients that were admitted to the hospital and fewer ED and observational visits. This analysis shows the potential benefit of RD services in an outpatient setting and justifies further study. Future prospective studies will need to evaluate which interventions are most impactful.[Table: see text]
Proposal of modified textbook outcome for improving the quality of gastric cancer surgery: A single-center study.
Authors: Kim Sara , Kim Sa-Hong , Choi Jong-Ho , Choe Hwi Nyeong , Park Ji-Hyeon , Kong Seong-Ho , Kwak Yoonjin , Park Do Joong , Lee Hye Seung , Lee Hyuk-Joon , Kim Woo Ho , Yang Han-Kwang
Published: January 2022

270

Background: Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Since 2014, the national healthcare quality assessment has been implemented for gastric cancer in Korea, which has the highest incidence. The proportion of early gastric cancer through early detection is high in Korea, and gastric cancer surgery has a great influence on outcome index. The aim of this study is to find indicators that can improve Textbook outcome (TO) in patients undergoing gastric cancer surgery. Comparing with Western data, we intended to propose a modified TO (mTO). Methods: Using a prospective clinical database, we included consecutive cases of gastrectomy for primary gastric cancer between 2014 and 2016. TO was achieved when 10 original indicators proposed by the DUCA group were satisfied. We propose to adjust the index of the number of retrieved lymph nodes from 15 to 30 as the modified TO(mTO) indicator for improving the quality of gastrectomy. For comparison with Western data, we calculated TO, mTO and survival in stage I versus Stage II and III. Results: A total of 2,153 patients were included. TO was achieved in 80.1 percents by 10 original indicators. Most of the indicators showed more than 90 percents of TO satisfaction. Five-year survival was significantly different between the TO (90.0%) and non-TO (76.1%) groups ( P < 0.001). For 608 patients in stage II and III, TO was 72.9 percents, which was much higher than the Western publications. Five-year survival were 74.8 percents for the TO group and 56.8 percents for the non-TO group in stage II and III patients. We found that the number of metastatic lymph nodes increases as the stage increases and even the number of metastatic lymph nodes in stage IIIC exceeded 19. The modified textbook outcome (mTO) for stage II and III was 65.3 percents, and five–year survival was significantly different between mTO (74.0%) and mnon-TO (62.1%) groups ( P < 0.001). To prevent R1 resection and minimize the proportion of remnant total gastrectomy, we performed frozen study examinations of the proximal and distal margins as to ensure high oncological safety. Conclusions: Data from a high volume gastric cancer center showed the high textbook outcome rates. It suggests that the minimum number of lymph node retrievals should be at least 30, even in advanced gastric cancer, and routine intraoperative frozen study examination are necessary to increase R0 resection.
X versus XELOX versus PF in definitive concurrent chemoradiotherapy (DCRT) for local-advanced squamous esophageal cancer (ESCC): 2021 update from a multicenter, open-label, randomized III trial, CRTCOESC trial.
Authors: Jia Ruinuo , Shan Tanyou , Wan Lixin , Zheng Anping , Hui Shuang , Xu Zhiqiao , Wang Feng , Zheng Guobao , Lu Ping , Zhang Guifang , Zheng Yingjuan , Cui Yanhui , Luo Xiaoyong , Zhang Weiguo , Li Wanying , Li Ruonan , Zhou Fuyou , Gao Shegan
Published: January 2022

274

Background: PF (5-fluorouracil plus cisplatin) is the standard regimen for local advanced ESCC with DCRT. CRTCOESC aims to evaluate the effect and safety of X (capecitabine) regimen versus XELOX (capecitabine plus oxaliplatin) and PF in Chinese local advanced ESCC with DCRT by randomized, open-label, multicenter designed. Methods: Patients with ESCC (T2-4N0-2M0) were randomized to 3 groups as X (capecitabine 625mg/m2, bid d1-5, 6 weeks), XELOX (oxaliplatin: 65mg/m2, d1, 8, 22, 29; capecitabine: 625mg/m2, bid d1-5; 6 weeks), or PF (cisplatin: 75mg/m2 d1, 29, 5-Fu: 750mg/m2 CIV24h d1-4, d29-32), Intensity Modulated Radiation Therapy (IMRT) was delivered by 50Gy/2Gy currently. In addition, quadratic randomize were done within all groups to decide whether 2 cycles chemotherapy adding or not after DCRT. 2-year OS and Grade 3-5 AEs were the primary endpoints, 2-year PFS and short-term efficacy (STE) as rates of CR and ORR (CR+PR) (confirmed by gastroscopy biopsy at 16 weeks) were the secondary endpoints. Results: 249 pts successfully were accrued from 13 centers during 2014.10-2020.04. All pts were finished DCRT and evaluated STE at 16 weeks. 229 pts were followed up for 2- years. There were no differences between 3 groups on patients’ baseline characters including age, gender, ECGO score, clinical stage, pathology grade and smoking. In X, XELOX and PF groups, the 2-year OS were 73.8% (59/80), 74.3% (55/47) and 73.3% (55/75) ( P = 0.991), the median OS were 41.43 (3.29), 53.3 (7.686) and 44.6 (4.946) (months, P = 0.896); the incidences of AEs (grade 3-5) were 24.1% (20/83), 31.8% (28/88) and 43.6% (34/78) ( P = 0.03); the 2-year PFS were 63.7% (51/80), 60.8% (45/74) and 61.3% (46/75) ( P = 0.922), the median PFS were 38.467 (2.965), 39.5 (7.619) and 35.8 (4.435) (months, P = 0.87); the CR rate were 36.1% (30/83), 36.4% (32/88), and 35.9% (28/78) ( P = 0.998), and the ORR were 73.5%, 79.5%, and 75.6% ( P = 0.64), respectively. There were no differences on OS, PFS and rates of CR and ORR between 3 groups but the incidence of AEs in X group was the lowest significantly. Subgroup analysis results shown adding 2 cycles chemotherapy after CRT had both OS and PFS advantages but lacked statistically significance. Conclusions: Compared with PF, DCRT with X or XELOX shown lower incidence of AEs and similar OS, PFS and STE. X regimen carried out the lowest AEs incidence. Adding 2 cycles chemotherapy after DCRT seemly had advantages on OS and PFS. Clinical trial information: NCT02025036.
The efficacy and safety of neoadjuvant camrelizumab and chemotherapy for locally advanced thoracic esophageal squamous cell carcinoma.
Authors: Xu Weili , Jiang Youhua , Wang Changchun , Wu Jie , Li Jianqiang , Hu Yuqian , Lu Weishan , Shen Dijian , Wang Yinjie , Chen Qixun
Published: January 2022

278

Background: To explore the efficacy and safety of neoadjuvant camrelizumab and chemotherapy for locally advanced thoracic esophageal squamous cell carcinoma (ESCC) by an open label, single-arm, phase 2 clinical trial (ClinicalTrials.gov, Identifier number: NCT04506138). Methods: The eligible patients were arranged to receive 2 cycles of camrelizumab (200mg, day 1) combined with carboplatin (AUC = 5, day 1) and albumin paclitaxel (100 mg/m2, day 1, 8). All treatments were given intravenously in 3-week cycle. Patients underwent surgery within 4-6 weeks after the completion of neoadjuvant treatment. The primary endpoint was pathologic complete response (pCR), and secondary endpoints were major pathological response (MPR), safety and feasibility. The quality of life (QoL) was assessed by the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scale and EQ-5D-3L scale. Results: A total of 46 patients were recruited, among whom the clinical stage II, III, and IVa at baseline were 11 (23.9%), 33 (71.7%), and 2 (4.3%), respectively. Forty-five patients completed 2 cycles of neoadjuvant treatment. One patient received 1 cycle of neoadjuvant treatment and then lost to be followed up. Eight patients did not receive surgery. Except 1 patient accept exploratory surgery, 37 patients (37/46, 80.4%) achieved R0 resection. Eight patients (8/37, 21.6%) had pCR in both primary tumors and lymph nodes. MPR of primary tumors and lymph nodes was observed in 18 patients (18/37, 48.6%). During neoadjuvant treatment period, all 46 patients presented with treatment-related AEs (TRAEs) of any grade. Seven patients (7/46,15.2%) experienced grade ≥ 3 TRAEs. One patient suffered grade 5 immune-associated pneumonia. The most common TRAEs were anemia (32/46, 70.0%), followed by thrombocytopenia (15, 32.6%), leukopenia (14, 30.4%), neutropenia (13, 28.3%), rash (12, 26.1%), reactive cutaneous capillary endothelial proliferation (RCCEP) (7, 15.2%). The median interval between the first cycle of neoadjuvant treatment and surgery was 64 days (range, 56-77 days). Symptom scores in FACT-E scale were improved by neoadjuvant treatment (t = -2.60, P = 0.01). PD-L1 CPS (< 10 vs ≥ 10), PD-L1 TPS (< 1% vs ≥ 1%) and TMB (split according to top 20% of TMB value) had no effect on the pCR rate and MPR rate. Conclusions: Neoadjuvant camrelizumab combined with chemotherapy achieved a promising pathologic response, which was effective and safe. Meanwhile, neoadjuvant treatment improved QoL of patients. Some larger multi-center trials are undergoing for further confirmation of efficacy and safety. Clinical trial information: NCT04506138.
A multicenter randomized phase III study of albumin-bound paclitaxel combined with S-1 (AS) versus oxaliplatin combined with S-1 (SOX) for first-line treatment of advanced gastric cancer (GAPSO study).
Authors: Dai Yuhong , Yu Xiongjie , Xu Huiting , Zhuang Liang , Zhang Mingsheng , Zou Yanmei , Fu Qiang , Qiu Hong , Yuan Xianglin
Published: January 2022

282

Background: Albumin-bound paclitaxel has been proven to be an active agent in advanced gastric cancer, and was approved by PMDA Japan for use as a second-line treatment of advanced gastric cancer. The aim of this study was to evaluated the efficacy and safety of AS and SOX in the first-line treatment of advanced gastric cancer. Methods: Patients diagnosed with unresectable locally advanced, recurrent or metastatic human epidermal growth factor receptor type 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma were randomized (1:1) to either AS group (albumin-bound paclitaxel 260mg/m2 d1 or 130mg/m2 d1, 8; S-1 40 mg [BSA < 1.25 m2], 50 mg [1.25 ≤ BSA < 1.50 m2] and 60 mg [BSA ≥1.50 m2] b.i.d. d1-14, every 3wks) or SOX group (oxaliplatin 130mg/m2 d1; S-1 40 mg [BSA < 1.25 m2], 50 mg [1.25 ≤ BSA < 1.50 m2] and 60 mg [BSA ≥1.50 m2] b.i.d. d1-14, every 3wks). Primary endpoint was progression-free survival (PFS), secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. Results: Between March 2019 and March 2021, 96 patients were enrolled and 85 patients (AS group, n = 43; SOX group, n = 42) who received at least one dose of study drug and had at least one postbaseline efficacy evaluation were included in the final analysis. 34 (79.0%) patients in the AS group and 35 (83.3%) in the SOX group had discontinued treatment. Of these 85 patients, 78.8% had two or more organs involved, 61.2% had peritoneal dissemination, and more than 1/4 had massive ascites. Patient demographics and disease characteristics were generally balanced between arms. With median follow-up 15.4 months (95% CI, 8.8-21.9), the median PFS of AS group vs. SOX group was 9.2 vs.5.1 months (HR = 0.58 [95% CI 0.36-0.96], p = 0.034); and the median OS was 14.4 vs. 15.4 months (HR = 0.73 [95%CI 0.40-1.34], p = 0.375). Tumor response was assessable in 33 patients according to RECIST V1.1 in both cohorts, the ORR and DCR were similar in AS vs. SOX arm (ORR: 54.5% vs. 51.5%, P = 0.805; DCR: 78.8% vs. 78.8%, P = 1.000). The main grade 3 or worse treatment-related adverse events were neutropenia (30.2% vs 23.8%), Leucopenia (11.6% vs 11.9%) and peripheral sensory neuropathy (4.7% vs 7.1%) in AS and SOX group. The study was planned to be adjusted, due to the widespread use of immunotherapy in first-line treatment of gastric cancer. Conclusions: The results of this study indicated that in previously untreated patients with unresectable locally advanced, recurrent or metastatic HER2-negative gastric or GEJ adenocarcinoma, AS achieved better PFS than SOX, with an inadequate power. The toxicities were controllable and consistent with previously reported. Clinical trial information: NCT03801668.
A phase II study of FOLFOX combined with nab-paclitaxel (FOLFOX-A) in the treatment of metastatic or advanced unresectable gastric, gastroesophageal junction adenocarcinoma: Big Ten Cancer Research Consortium—BTCRC-GI15-015.
Authors: Benson Al Bowen , Kocherginsky Masha , Kasi Pashtoon Murtaza , Uboha Nataliya Volodymyrivna , Lou Emil , Chen Yolande , Hochster Howard S. , Kircher Sheetal Mehta , Mulcahy Mary Frances
Published: January 2022

283

Background: Doublet platinum or taxane-based therapies are the current standard backbone of treatment for advanced gastric/GEJ adenocarcinoma. Previously, anthracycline based triplets have been aborted due to lack of efficacy and toxicity. We hypothesize that the combination of FOLFOX and nab-paclitaxel (FOLFOX-A) will have a higher efficacy, a better tolerability, and enhanced patient reported outcomes. Methods: Phase II single arm trial of FOLFOX + nab-paclitaxel in chemotherapy–naïve unresectable, advanced gastric/GEJ adenocarcinoma. Nab-paclitaxel 150 mg/m2 · Oxaliplatin 85 mg/m2 · Leucovorin 400 mg/m2 · 5-FU 2400 mg/m2 over 46-48 hrs every 14 days. Primary objective was response rate.Evaluable disease according to RECIST v1.1 for solid tumors was required. Her-2 positive gastric tumor patients and those with clinically significant peripheral neuropathy were excluded. A Simon (1989), optimal two-stage design was employed. Response rates and Clopper-Pearson confidence intervals are reported. Progression free (PFS) and overall (OS) survival were estimated using the method of Kaplan-Meier. Results: A 29% response rate was observed in Stage 1 and therefore the study continued enrolling all planned 39 patients. Median age was 63 (range 20-80) years, 29 (74%) were male, 30 patients now are off treatment due to progression (17), initiation of alternative therapy (5) and side effects (3). 38 patients started treatment. Of the 35 patients evaluable for response, 14 (40.0%; 95%CI: 23.9% - 57.9%) had CR/PR as best response, with disease control rate of 80.0%. Progression-free (PFS) and overall survival (OS) were available for 36 patients, with median follow-up duration of 20 months (range: 1.9 - 34.45 months). Median PFS was 6.6 months (95%CI: 5.7 – 13.0), with 28.6% (95%CI: 15.2% - 53.9%) 12-month PFS rate. There were 21 deaths, median OS was 11.0 months (95%CI: 9.6 – 21.7), 12-month OS rate was 46.6% (95%CI: 30.9% - 70.3%). Treatment-related grade 3–4 toxicities included peripheral sensory neuropathy, anemia (18.4% each), decreased neutrophil count (15.8%), and diarrhea (7.9%). One patient died due to multi-organ failure, not treatment-related. 23 patients required dose reductions or discontinuation of at least 1 component of the 3-drug regimen due to toxicity. Median number of cycles completed was 4 (range: 0-30). Conclusions: FOLFOX-A has a significant response rate, expected toxicities, and should be considered for future investigation in combination with immunotherapy given the recent approvals.
Usefulness of an S-1 dosage formula: An exploratory analysis of randomized clinical trial (JCOG1001).
Authors: Kawakami Takeshi , Yasui Hirofumi , Mizusawa Junki , Hasegawa Hiroko , Imazeki Hiroshi , Kano Kazuki , Sato Yuya , Iwasa Satoru , Takiguchi Shuji , Kurokawa Yukinori , Doki Yuichiro , Boku Narikazu , Yoshikawa Takaki , Terashima Masanori
Published: January 2022

288

Background: Although the S-1 dose is determined by body surface area (BSA), its blood concentration and adverse events are affected by renal function. One study had reported the clinical utility of an S-1 dosage formula for calculating the dose for target blood concentration based on renal function (Booka E. Gastric Cancer 2016;19:876-86.). The present study aimed to explore the usefulness of this formula in adjuvant chemotherapy for gastric cancer. Methods: Ad hoc analyses was performed using data from patients enrolled in a phase III trial, JCOG1001, to evaluate the role of bursectomy for resectable advanced gastric cancer. In the abovementioned trial, patients with stage II/III received adjuvant S-1 chemotherapy based on BSA. The present study calculated the S-1 dose using the following formula: 1447.8 * (14.5+0.301*CLcr+8.23*SEX [male=1, female=0])*BSA (mg/day). Patients were divided into three groups, overdosed (OD), equal dosed (ED), and underdosed (UD), by comparing the initial dosage administered with that recommended by the formula. Results: Among the 686 eligible pts, 324, 304, and 58 were respectively classified as OD/ED/UD, with the following characteristics: median age, 67.5/64/53.5 years; men 188/229/57 (58%/75%/98%); undifferentiated type, 168/172/38 (52%/57%/66%); and pStage III, 212/200/41 (65%/66%/71%). Median relative dose intensity in OD/ED/UD pts was 93.8%/108.8%/75.0% based on the formula-recommended dose. The planned adjuvant S-1 therapy was completed in 69%/74%/74%, dose reduction and treatment schedule alteration were required in 31%/21%/9% and 20%/17%/9%, and treatment was terminated due to adverse events in 25%/18%/12%. The 5-year relapse-free (RFS) and overall survival (OS) OD/ED/UD patients were 66.6%/69.2%/74.0% and 77.0%/74.3%/77.3%, in pStage II 80.2%/85.6%/93.8% and 88.3%/90.1%/100%, and pStage III 59.6%/60.4%/65.8% and 67.0%/70.0%/67.7%, respectively. OD pts had significantly higher incidences of grade 3 or higher anemia, thrombocytopenia, diarrhea, stomatitis than ED and UD pts. Conclusions: Despite no difference in survival, this formula improved treatment compliance in OD patients receiving adjuvant S-1 chemotherapy for gastric cancer.[Table: see text]
Phase II study of SHR1210 and trastuzumab in combination with CAPOX for neoadjuvant treatment of HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Li Ning , Li Zhi , Fu Qiang , Zhang Bin , Zhang Jian , Wan XiangBin , Lu Chaomin , Wang Jinbang , Deng Wenying , Wei Chen , Ma Yijie , Bie Liangyu , Wang Mengyu , Luo Suxia
Published: January 2022

296

Background: Perioperative treatments have significantly improved survival in patients with resectable gastric cancer. PANTHERA study had showed a significant tumor shrinkage for HER2 positive advanced gastric cancer treated with anti-PD-1 agent, transtuzumab and chemotherapy. SHR1210, a human IgG4 monoclonal antibody that binds to PD-1, has shown remarkable clinical efficacy in various cancers. We aimed to assess the activity and safety profile of the addition of SHR1210 and trastuzumab to CAPOX for neoadjuvant treatment of HER2-positive gastric or GEJ adenocarcinoma. Methods: In this ongoing, single-arm, phase II study, we recruited patients from Henan Cancer Hospital in China with histopathologically diagnosed resectable HER2-positive gastric or GEJ adenocarcinoma who had clinical T3/N+ or higher stage. Patients were given 4 cycles of transtuzumab (loading dose of 8mg/kg, with subsequent doses of 6 mg/kg, q3w) and CAPOX (oxaliplatin 130 mg/m2 day 1, capecitabine 1000 mg/ m2 bid po day 1-14, q3w) in combination with 3 cycles of SHR1210 (200mg, iv, d1, q3w), followed by surgery and 4 postoperative cycles of CAPOX. The primary endpoint was pathological complete response (pCR). The secondary endpoints included major pathological remission (MPR) and objective response rate (ORR). This trial is registered with ClinicalTrials.gov, number NCT03950271. Results: Between Jan 20, 2020, and Sept 15, 2021, 22 patients were enrolled and commenced treatment. Four patients had not completed neoadjuvant treatment. Twopatitents refused surgery. Sixteen patients who experienced D2 resection, 9 (56.3%) achieved MPR, including 5 (31.3%) with pCR (ypT0N0M0). The R0 rese-ction rate was 100%. The ORR was 77.3%. The main grade 3 or 4 treatment-related adverse events (TRAEs) included lymphocytopenia (22.7%), neutropenia(13.6%), thrombocytopenia (13.6%) and anaemia (5%). Most frequent grade 1 or 2 TRAEs were Nausea (68.2%), lymphocytopenia (63.6%), leukopenia (59.1%), Anaemia (59.1%), Thrombocytopenia (50%), Serum aspartate aminotransfe-rase increased (45.5%) and hypothyroidism (31.8%). There was no surgical del-ays or unexpected surgical complications related to drug toxicity. Conclusions: Neoadjuvant combination of SHR1210, transtuzumab and CAPOX is a safe and efficacious treatment option for patients with HER2-positive gastric or GEJ adenocarcinoma. More importantly, 31.3% pCR rate is encouraging. Our clinical study is still enrolling, and the survival effects are under follow up. Clinical trial information: NCT03950271.
Neoadjuvant PD-1 inhibitor tislelizumab combined with s-1 plus oxaliplatin in patients with local advanced gastric cancer or gastroesophageal junction adenocarcinoma: Interim results of a single-arm, phase II trial.
Authors: Tao Kaixiong , Yin Yuping , Lin Yao , Li Wei , Li Ruidong , Liu Weizhen , Xiong Zhen , Zeng Xiangyu , Cai Ming , Wu Cuanqing , Zhang Peng
Published: January 2022

300

Background: D2 radical surgery and adjuvant chemotherapy is mainly treatment scheme of Gastric/gastroesophageal junction (G/GEJ) cancer. Nevertheless, the prognosis of patients with G/GEJ cancer still remain variation after normative therapy. Further, neoadjuvant therapy showed highlighted application value and Immuno-oncology therapy is newly prominent in improving prognosis of patients with G/GEJ cancer recently. Methods: We conduct a prospective, single-arm, open-label, non-randomized phase II trials of PD-1 inhibitor Tislelizumab combined with S-1 plus Oxaliplatin (SOX) in Patients with Local Advanced G/GEJ cancer (NCT04890392). Treatment is performed for 3 cycles (21 days/1 cycle) and all patients are evaluated tumor pathology regression after D2 radical surgery performed, and are followed up. The primary endpoints were tumor major pathology response (MPR) and other events of tumor response assessed by tumor regression grade (TRG). We also recode the variation of immunological indicators during treatment and develop a predictive nomogram to predict the probability of patients reached MPR. Results: 13 of 21 patients (61.9%) reached MPR after treatment and 5 of 21 patients had a complete tumor response (23.8%). While 2 of 21 patients were assessed as disease progression (9.5%). there was no significant difference in MPR (TRG = 0&1) between gastric cancer and gastroesophageal junction cancer (6/11 vs. 7/10. P = 0.525). Adverse events occurred in 11 of 21 patients (52.4%) in the cohort. Grade III-IV adverse event occurred in only 1 of 21 patients (4.8%). the variation of CD3+ and CD4+ immune cell counts and TNFα of patients reached MPR was significantly higher than patients not reached MPR during treatment (CD3+, P = 0.044; CD4+, P = 0.042; TNFα, P = 0.048). Further, we developed the predictive nomogram of MPR consisted of age, Hb and TNFα and the AUC of nomogram was 0.890; the C-index was 0.885. Conclusions: Neoadjuvant PD-1 Inhibitor Tislelizumab combined with SOX shows greatly potential of therapeutic application in patients with G/GEJ cancer with no-increasing treatment-related adverse events. While this predictive nomogram may help therapists more accurately apply this scheme and explore improvement. Clinical trial information: NCT04890392.
A randomized, controlled, multicenter study of nab-paclitaxel plus cisplatin followed by surgery versus surgery alone for locally advanced esophageal squamous cell carcinoma (ESCC).
Authors: Liu Junfeng , Wang Yan , Cao Bingji , Zhang Shaowei , Cao Fumin , Gao Liping , Sun Nan , Ma Yuquan
Published: January 2022

310

Background: Taxane is one of the commonly used chemotherapy drugs for ESCC. Nab-paclitaxel, a small particle albumin-bound form of paclitaxel, showed potentially efficacy in metastatic ESCC. This randomized, controlled, multi-center study is conducted to evaluate the efficacy and safety of nab-paclitaxel plus cisplatin in neoadjuvant treatment of ESCC. Methods: Two hundred and two patients with resectable locally advanced ESCC which was located in the middle or lower third of the esophagus were enrolled and randomly assigned in a 1:1 ratio to receive neo-adjuvant chemotherapy or surgery alone. Patients were treated with either two 3-week cycles of nab-paclitaxel (125mg/m2, iv, d1, 8) and cisplatin (75mg/m2, iv, d1), followed by esophagectomy 4-6 weeks after neoadjuvant (the treatment arm) or directly underwent esophagectomy (the control arm). The primary endpoint was overall survival (OS), the secondary endpoints included 1-, 2-, and 3-year OS rate, 1-, 2-, and 3-year disease-free survival (DFS) rate, R0 resection rate, reduction stage rate, chemotherapy-related adverse events. Results: Between April 2019 and June 2021, we randomly assigned 67 patients, of whom 31 in the treatment arm and 33 in the control arm were analyzed. There was no difference in baseline characteristics between the two arms. In the treatment arm, 24 patients underwent R0 resection, and 2 did not undergo surgery although chemotherapy was completed. All patients in control arm underwent R0 resection. In the treatment arm, the pathological complete response (pCR) rate was 20.83%, the major pathological response (mPR) rate was 33.33%, and the down-staging rate was 58.33%. No difference in survival benefit was observed between the two arms. The 1- and 2-year DFS rates of the treatment arm and the control arm were 88.99% vs 75.58% (HR = 0.421, 95%CI: 0.087̃2.032, P = 0.281) and 88.99% vs 66.13% (HR = 0.387, 95%CI: 0.082̃1.833, P = 0.231), respectively. The 1-year and 2-year OS rates of the treatment arm and control arm were 93.21% vs 75.32% (HR = 0.293, 95%CI: 0.061̃1.409, P = 0.125) and 86.56% vs 75.32% (HR = 0.444, 95%CI: 0.115̃1.716, P = 0.239). The neoadjuvant chemotherapy was well tolerated. According to NCI-CTC AE V.5.0, the most common adverse events were hematological toxicity, including neutropenia (16.13%), anemia (3.23%) and hypoproteinemia (3.23%), no grade IV adverse events occurred. Conclusions: Nab-paclitaxel plus cisplatin for ESCC reveals a promising efficacy and safety, and has a tendency to prolong DFS and OS compared with surgery alone. The long-term results are worthy of further exploration. Clinical trial information: NCT03964753.
Gastric endoscopic submucosal dissection using a detachable assistant robot.
Authors: Kim Sang Hyun , Choi Hyuk Soon , Lee Jae Min , Keum Bora , Kim Byung Gon , Hong Daehie , Jeen Yoon Tae , Chun Hoon Jai ,   Korea University College of Medicine
Published: January 2022

318

Background: Effective traction and counter-traction for visualizing the dissection plane in endoscopic submucosal dissection (ESD) is difficult to be achieved with a conventional endoscope. We developed a robotic assistive traction device for flexible endoscopy that provides multi-directional traction during ESD. We compared its safety and efficiency in ESD between experienced and novice endoscopists. Methods: Robotic ESD was performed by experienced and novice endoscopist groups (n = 2, each). The outcomes included time to complete each ESD step, total procedure time, size of the dissected mucosa, rate of en bloc resection, and major adverse events. Furthermore, incision and dissection speeds were compared between groups. Results: Twenty gastric lesions were resected from nine live pigs. The submucosal incision speed was significantly faster in the expert group than in the novice group (P = 0.002). There was no significant difference in the submucosal dissection speed between the groups (P = 0.365). No complications were reported in either group. Conclusions: When the robot was assisting in the ESD procedure, the dissection speed improved significantly, especially in the novice surgeons. Our robotic device can provide simple, effective, and safe multidirectional traction during ESD.
Real-world effectiveness of anlotinib in combination with PD-1 inhibitors as second-line or later therapy for advanced or metastatic esophageal squamous cell carcinoma.
Authors: Hong Yonggui , Wu Tao , Lu Ping , Chang Zhiwei , Liang Wei , Zhang Guifang , Wang Junsheng
Published: January 2022

320

Background: Anti-PD-1 mAb treatment has been shown to be effective in the treatment of esophageal cancer. Anlotinib has been approved in China as a second-line treatment for advanced esophageal cancer because of its good tolerance and efficacy. In the treatment of esophageal cancer, antiangiogenic target therapy combined with immunotherapy has been preliminarily recognized internationally. The purpose of this study is to investigate the efficacy and safety of anlotinib in combination with PD-1 inhibitors in second-line or later therapy during the treatment of esophageal cancer in the real world setting.(A LOT-EC3, NCT04966611). Methods: This is a prospective, multicenter real-world study. The esophageal cancer patients who received anlotinib in combination with PD-1 inhibitors in second-line or later therapy were enrolled. The primary endpoint was PFS (progression-free survival), and secondary endpoints were ORR (objective response rate), DCR (disease control rate) and OS (overall survival). The response to treatment was evaluated according to RECIST version 1.1. In addition, adverse events were evaluated by CTCAE v5.0. Results: From Jul 2020 to Sep 2021, 40 patients with a median age of 65.5 (range: 48̃81) were enrolled, in which the metastasis of more than 1 organ occurred in 62.5% of the 40 patients; the metastasis of more than 2 organs occurred in 37.5% (15 patients). 26 (65.0%) and 14 (35.0%) patients received anlotinib combined with PD-1 inhibitors as second line and third & above line therapy, respectively. Among all patients, 1 patient achieved complete response (CR), 11 patients partial response (PR), 23 patients stable disease (SD), illustrating an ORR of 30.0% and a DCR of 87.5%. In the second line therapy, ORR was 30.8 %, DCR was 92.3%. In the third & above line, ORR with 28.6%, DCR with 78.6% was observed. Median PFS was not reached. For all the 40 patients, 27 of which were treated with Camrelizumab, 10 were treated with Sintilimab, other 3 patients were treated with other kinds of PD-1 inhibitors. There was no significant difference in DCR between different PD-1 inhibitors. Treatment related adverse events (trAEs) occurred in 22 (55%) patients. 4 patients had grade 3 or more trAEs. No patient died due to trAE. Conclusions: Anlotinib combined with PD-1 inhibitors is found to be a reasonable option in second-line or later therapy for the treatment of advanced esophageal cancer. To our best knowledge, this is the first summarized real-world study on anlotinib combined with PD-1 inhibitors in advanced esophageal cancer. The treatment effects are similar to the outcomes in comparable clinical trials, which support the further recommendation of anlotinib combined with PD-1 inhibitors in the treatment of esophageal cancer. Clinical trial information: NCT04966611.