bluuebunny/crossref_metadata_2025 huggingface dataset:
Rationale for the utilization of biological targeted agents (bTAs) in the treatment of metastatic colorectal cancer (mCRC), single tertiary cancer center experience.
Authors: Barrera Ivan , Lakehal Yahia A. , Kavan Tomas , Kavan Petr
Published: June 2021

e15589

Background: Worldwide treatment for 1st line (1LTx) mCRC included doublet or triple chemotherapy with or without bTAs. In Quebec, the anti-EGFR therapy (panitumumab or cetuximab) was only recently approved in this setting for patients RAS WT, Bevacizumab (B) not eligible. In this study we evaluated the rational and outcomes using bTAs. Methods: Retrospective study assessing mCRC pts treated with or without bTAs at any time throughout the course of therapy at the Jewish General Hospital between 2010-2018. Pts were divided in 3 groups according to their 1LTx for analysis: Chemotherapy alone (1LChA), Chemotherapy plus B (1LChB), and anti-EGFR with or without chemotherapy (1LaEGFR). The primary objective was to assess the rational of bTAs prescription based in 1LTx selection. Secondary objectives included safety, PFS and OS. Results: Among a total of 463 pts with mCRC; 196 pts (42.3%) received 1LChA, 246 pts (53.2%) 1LChB, and 21 pts (4.5%) 1LaEGFR respectively. 1LChA group, 51% omitted bTAs for physician-patient preferences, 96 pts (49%) had contraindications for B, and 79 pts (40.3%) were potentially candidates for aEGFR, but did not receive it. 152/196 (77.5%) pts continued to 2LTx and 34.8% received bTAs. As for the 3LTx, 78/196 (40%) received a treatment, 48.7% received bTAs. The most common grade 3-4 adverse events (AEs) were hypertension and bowel perforation in B, gastrointestinal (GI) symptoms and skin reaction (SR) in aEGFR. 1LChB group, 31 pts (12.6%) presented AEs related to B. 191/246 pts (77.6%) continued to 2LTx with 48 pts (25%) receiving ChB despite progression in 1LTx on this bTA and 19 pts (10%) receiving aEGFR. The most common AEs reported in 2LTx were GI symptoms and neuropathy. In 3LTx, 54/91pts (59.3%) received aEGFR therapy and 8 pts (14.8%) had SR AEs. 46 pts (18.6%) continued to 4LTx, 13/46 pts (28.2%) received aEGFR. 1LaEGFR group, the most common AEs were SR and GI symptoms. 11/21 pts (52.3%) continued to 2LTx; 5 pts (45.4%) switching bTA class and receiving ChB. 81% pts started treatment between 2017-2018 and had at least two contraindication criteria for. The median PFS for the 1LChA and 1LChB groups were 10 and 11.5 months, respectively, and were not statistically significant (p=0.22). The OS with 1LChA and 1LChB was 33.26 vs. 27.80 months (p=0.27). The PFS and OS between 1LChA and 1LaEGFR were 10 vs 11 months (p= 0.27) and 33.26 vs. 35.07 months (p=0.13). Conclusions: The outcome and tolerability of bTAs in mCRC appear similar in our institution and randomised trials. We were not able to detect any significant difference among the three groups of comparison. The 1LaEGFR available data in this subset of patients are limited. Our data highlights the importance of optimal therapeutic sequencing to prolong OS. Dedicated studies are needed in order to determine the best bTAs therapeutic strategy in mCRC.
Clinical, pathologic, and demographic characteristics of colorectal cancer in patients under age 50 in a third level Mexican cancer center.
Authors: Serrano Villamayor Omar , Rodriguez Benigno , Villegas Osorno Diana Alejandra , Amador Geovani , Andrade Moreno Raul Alejandro , López Zepeda Lorena , Enciso López Ervin Saúl , Shveid Gerson Daniela , Camarin Sanchez Efrain Isaias , Martínez-Herrera José Fabián , Villalobos Alberto , Regalado Porras Gabriela Olivia , Olivares Guillermo , Gerson Cwilich Raquel
Published: June 2021

e15592

Background: Colorectal cancer (CRC) is the most common gastrointestinal neoplasia, with 1.36 million cases worldwide, representing the third cause of death due to cancer. Commonly affects people after the 6th decade of life, but recently the diagnosis in patients below 50 years is increasing. Methods: We conducted an observational, retrospective, longitudinal analysis based on medical records of patients diagnosed with colorectal cancer treated in the ABC Medical Center. Information was collected between January 2016 and January 2021. Descriptive statistics were utilized regarding data analysis. Results: We identified 289 patients with CRC, of which 23 (8.2%) patients were less than 50 years of age at diagnosis. Gender distribution reflected slightly more feminine patients (56%). The median age at diagnosis was 43 years, oncologic family history in first- or second-degree family members was documented in 31.4% of patients. At diagnosis, 22% of patients presented with an early-stage neoplasm, 31% had locoregional disease and 50% had advanced disease. Left sided disease was present in 78% of patients, 8% on the right colon and 13% were in rectum. Adenocarcinoma was found in 95% of patients. Mucinous pattern was present in 39% of patients studied, intestinal tumors in 21%, singlet ring cells in 4.3%. Histologic grade was G2: 69%. Molecular analysis was conducted in 86% of tissue biopsies. Regarding RAS mutations, 15% were positive (Gly12asp, K117N and Gly13Asp), but none in NRAS. BRAF mutation was studied in 43% of patients, no mutations were found. The search for microsatellite instability was conducted in all tumors, finding it present in only one patient (5%). At median follow up of 31.8 months, 91.4% remainded alive. Patients with early stage cancer were given adjuvant therapy in 69%. mean RFS was 40 months. All patients diagnosed in stage IV disease received systemic therapy, with a medium PFS of 10 months. First line treatment was FOLFOX in 58% of patients. Target therapy with anti-EGFR and anti-VEGF was prescribed in 83.3% and 8.3% of patients in the first line respectively. Conclusions: We found that patients under 50 years with dignosis of colorectal cancer, have a family history of cancer in up to a third of patients, the most frecuent histology reported was adenocarcinoma with mucinous pattern. We observed a low frecuency of KRAS mutations compared with literature reports. A longer follow-up is requiered to asses overall survival.
Chemotherapy completion rate for locally advanced rectal cancer at a safety-net hospital.
Authors: Wlodarczyk Jordan , Dewberry Sean , Roy Varun , Ault Glenn , Cologne Kyle , Lee Sang Won , Koller Sarah
Published: June 2021

e15597

Background: Patients with locally advanced rectal cancer (LARC) typically receive chemoradiation prior to surgery, followed by adjuvant chemotherapy (standard). Recently there has been a growing trend toward total neoadjuvant therapy (TNT), in which all chemotherapy is given in the neoadjuvant setting, having the advantage of higher chemotherapy completion rates. Data exploring adherence to both standard therapy and TNT within a vulnerable, underserved population is lacking. Within our safety-net hospital, we determined the chemotherapy completion rates for LARC patients who received TNT vs standard treatment. We also compared two populations within the standard treatment group- those who received all doses of prescribed adjuvant chemotherapy (AC) and those who did not. Methods: A retrospective chart review was performed for all patients with LARC (stage II or III) presenting to Los Angeles County + USC Medical Center from 2015 to 2020. Patients who progressed prior to receiving their first dose of chemotherapy and patients lost to follow-up were excluded. Patient demographics, stage, neoadjuvant/adjuvant treatment, operative characteristics, and postoperative course were abstracted. T-tests and Wilcoxon rank-sum tests were used to compare means and medians, respectively; chi-squared tests were used to compare categorical variables. Results: 67 patients were included- 59 in the standard group and 8 in the TNT group. Mean follow-up was 30 months. All patients in the TNT group completed neoadjuvant chemotherapy. In the standard treatment group, the overall AC completion rate was 81% (n = 48) (Complete Group). 19% (n = 11) did not receive all prescribed doses of AC (Incomplete Group). Compared to patients in the Incomplete Group, patients in the Complete Group were significantly older (mean age 55 vs 48, p = 0.017), had a shorter mean time interval from surgery to initiation of AC (9 weeks vs 13 weeks, p = 0.016), and were less likely to experience a delay in receiving AC > 90 days (15% vs 46%, p = 0.022). In total, 12 patients (20%) in the standard group experienced a delay in AC, of which six (50%) were due to anastomotic leak and/or pelvic abscess. Three of those patients who experienced a delay (25%) required either drain placement or re-operation to address their complication. More patients in the Complete Group went on to have their temporary stomas reversed compared to those in the Incomplete Group (94% vs 70%, p = 0.031). Conclusions: While this population had a high AC completion rate, a meaningful proportion of all patients (though more in the Incomplete Group) experienced a delay in AC > 90 days, with surgical complications responsible for the delay in half of these patients. In contrast, all patients who received TNT completed neoadjuvant chemotherapy. TNT may be a reasonable alternative to reduce therapy delays and further improve chemotherapy completion rates in an underserved population.
Is shift-work associated with increased risk of rectal cancer? A meta-analysis.
Authors: Sun Chenyu , Cheng Ce , Kozma Kelly , Chandra Gopika , Kim Na Hyun , Bhan Chandur
Published: June 2021

e15600

Background: Globally, more than 1.8 million people were diagnosed of colorectal cancer (CRC) in 2018, with over 30% of CRC in the rectum. Shift-work, involving circadian disruption, sleep deprivation and lifestyle changes, was designated as a probable cause of cancer by The International Agency for Research on Cancer. Previous studies investigating the impact of permanent night-shift work and rotating shift-work on rectal cancer risk showed controversial results. Thus, this meta-analysis was conducted. Methods: A comprehensive literature search on PubMed was conducted to identify all relevant studies published prior to January 2021 according to the established inclusion criteria. The quality assessment was performed by the Newcastle-Ottawa Scale (NOS). The pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated to estimate the association between the shift-work and rectal cancer risk. Based on heterogeneity significance, random-effect or fixed-effect model was used. Subgroup analyses were conducted to explore the night-shift and rotating-shift, respectively. Sensitivity analysis and publication bias detection were performed, and trim and fill analysis was also conducted. All statistical analyses were performed using RevMan software (version 5.3; Cochrane library) and STATA 15.0 statistical software (Stata Corp., College Station, TX), and all P values were two-tailed, the test level was 0.05. Results: Thirty-seven articles were obtained from database searching. Three articles involving 1,063 rectal cancer cases were included. All studies were considered moderate to high quality. All included studies investigated on the association between shift-work and rectal cancer risk. A statistically significant association between shift-work and increased rectal cancer risk was found (OR 1.53, 95%CI: 1.31, 1.79, P< 0.00001, I 2 = 35%). In subgroup analyses, night-shift work was associated with a non-statistically significant increased risk of rectal cancer (OR 1.25, 95%CI: 0.47, 3.32, P = 0.66, I 2 = 93%). In contrast, Rotating-shift was associated with a statistically significant increased rectal cancer risk (OR 1.35, 95%CI: 1.10, 1.65, P = 0.004, I 2 = 6%). Sensitivity analysis confirmed the stability of the result. Funnel plot, Egger's test (t = 1.69, P = 0.341), and Begg's test (z = 1.04, P = 0.296) found no publication bias of analysis. Trim and fill analysis on fixed-effect model showed the pooled OR kept stable after adding two “missing” studies (OR 1.403, 95%CI: 1.224, 1.609, P <0.05). Conclusions: The current meta-analysis demonstrates that shift-work is associated with increased rectal cancer risk. However, no association between night-shift work and rectal cancer risk was found. In contrast, association between rotating-shift work and increased rectal cancer risk was found. More original studies on this topic are needed to further explore shift-work impacts on rectal cancer risk.
Retrospective cohort of total neoadjuvant therapy (TNT) in high-risk locally advanced rectal cancer (HR-LARC): Additional sintilimab (PD-1) in tri-modality approach.
Authors: Li Yingjie , Wang Lin , Zhang Xiaoyan , Yao Yunfeng , Liu Xinzhi , Dong Qiushi , Wu Aiwen
Published: June 2021

e15604

Background: TNT is an emerging practice adapted to ensure all patients (pts) receive of systemic therapy, particularly for pts with high risk recurrence. Our previous phase II trial of TNT in MRI stratified HR-LARC demonstrated high down-staging rate and improved complete response with acceptable toxicity (manuscript under review). The aim of this retrospective cohort study was to evaluate the feasibility of sintilimab in combination with chemotherapy in TNT tri-modality treatment of pts with HR-LARC. Methods: HR-LARC pts who were given 3 cycles of sintilimab (200mg, iv, q3w) in combination with CapeOx followed by sequential long-course radiotherapy (IMRT GTV50.6 Gy/CTV 41.8 Gy/22f), 2 cycles CapeOx and surgery were enrolled from Beijing Cancer Hospital, CHN. The high risk was defined as middle to low RC (≤8cm to ARJ or 12 cm per sigmoidoscopy) with ≥1 factor from MRI features: clinical stage T3c/d-T4a/b, or N2 or MRF (+) or EMVI (+). The clinical outcomes included pathological response, major response rate (cCR+MPR), R0 resection rate, and toxicity. Results: From Feb 2019 to Oct 2020, 19 cases were identified with median distal location 4 cm (3-7), T2/T3/T4 1/15/3, N1/N2a/N2b 7/4/8, MRF+ 8/11, EMVI+ 8/11. Other characteristics were pMMR/MSS 100%, age 67y (47-78), male 57.9%, PS 1 100%, c-stage III 100% (18), median diameter of primary lesion 5.1 cm (2.1-7.5). As of 30th Dec 2020, 84.2% (16/19) received neoadjuvant therapy and completed surgical resection, with R0 resection rate 100%. One pts denied surgery and two chose watch & wait since achieving cCR 10.5% (2/19). Of 16 resection pts, 13 had sphincter-sparing surgery (LAR or TaTME). One had Hartmann procedure, and two had abdominal perineal resection. The sphincter preservation rate was 84.2% (16/19). The pCR was 26.3% (5/19), and MPR was 47.3% (9/13). The major response rate was 57.9% (11/19), 4/2/13 of which completed intact TNT schema, induction and RT, and induction phase only, respectively. Treatment related adverse events (TRAE) occurred in 6 pts (31.6%) in grade (gr) 1-2 (CTCAE 5.0) without any gr 3-5 events occurred. Immune-related AEs were found in 2 pts with hypothyroidism (gr 1,2). Postoperative complications included two gr2 (Clavien-Dindo) events of anastomtic bleeding and infection. Of note, 3 pts with anastomotic stenosis got stoma reversion after dilation. Conclusions: Given the impressive response rate (57.9%), this retrospective analysis suggested a potential enhanced anti-cancer activity and good tolerability in pMMR/MSS HR-LARC from sintilimab in combination with TNT. The encouraging results warrant further evaluation of this approach in prospective trial.
PD-1 antibody (Camrelizumab) for metastatic EBV positive gastric cancer: A prospective single-arm, open-label, phase 2 trial.
Authors: Qiu Miaozhen , Wang De-Shen , Sun Yu-Ting , Zhao Qi , Guan Wen-Long , Xu Rui-hua
Published: June 2021

e16014

Background: Programmed cell death 1 (PD-1) inhibitors have been approved as third line therapy for patients with metastatic gastric cancer (mGC). Epstein–Barr virus (EBV)-positive is a potential predictor to response of PD-1 inhibitors. The aim of this study was to assess the efficacy and safety of camrelizumab as salvage treatment in metastatic EBV positive GC patients and explored the potential biomarkers associated with response (NCT03755440). Methods: In this prospective single-arm, phase II study, stage IV EBV positive GC patients received 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), which were based on RECIST V.1.1. Secondary endpoints were progression free survival (PFS), overall survival (OS), disease control rate (DCR), durationn of response (DoR), and toxicity. Exploratory analysis included association between response and tumor mutational burden (TMB) and cell death ligand-1 (PD-L1) expression. Results: According to Simon’s optimum two-stage design with α = 0.05 and β = 0.20. P0 = 15% (null hypothesis), the presence of at least 1 success in the 6 patients enrolled in the first stage allowed the trial to proceed to the second stage in which 13 more patients were needed to be enrolled for the minimum total of 20 patients (5% lost to follow-up calculated). Six eligible patients were enrolled at the first stage. All the patients were HER2 negative and pMMR. None of the patients had an objective response. The DCR was 66.7%. The median PFS was 2.2 months (95% CI: 1.5 months-not reached (NR)) and median OS was 6.8 months (95% CI: 1.7 months-NR). The most common treatment-related adverse event (TRAE) was reactive cutaneous capillary endothelial proliferation. No grade 3 or worse TRAEs were found. Only one patient had PD-L1 combined positive score (CPS) ≥1 but got disease progression. Three patients were TMB > 10Mb and two of them got stable disease while one got disease progression. Conclusions: EBV positive is not a good predictor for response to PD-1 inhibitors. Potential biomarkers are needed to identify EBVaGC patients who might respond to PD-1 inhibitors. Clinical trial information: NCT03755440.
A prospective, randomized, controlled, multicenter study of apatinib combined with S-1 plus docetaxel as adjuvant therapy for locally advanced gastric cancer.
Authors: Shan Zhili , Guo Feng , Chen Hong , Li Dapeng , Mao Zhongqi , Zhou Jun , Wu Yongyou , Sheng Xudong , Hu Lijun , Su Jiang , Cheng Xu , Kong Zhiyuan , Qiu Huizhu , Shan Li , Wu Jianzhong , Qiang Zhenghai , GU Yulan , Zhou Xiaojun
Published: June 2021

e16019

Background: Postoperative adjuvant chemotherapy is commonly given after the curative resection of gastric cancer (GC) in both Eastern and Western countries. Several studies have investigated the feasibility and safety of S-1 plus docetaxel or S-1 plus cisplatin. However, the best choice of adjuvant treatment for patients with gastric cancer is still debated. Apatinib, an oral small molecular of VEGFR-2 TKI, has been confirmed to improve OS and PFS with acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy. In this study, we aimed to evaluate the efficacy and safety of apatinib combined with S-1/docetaxel for locally advanced gastric cancer (T3-4aN+M0). Methods: This is a prospective, randomized, controlled, multicenter clinical study. Patients with locally advanced gastric cancer, pathological stage T3-4aN+M0 who underwent D2 lymphadenectomy without prior anti-cancer therapy were included. All these patients were assigned to group A or B. Patients in group A received 6 cycles (21 days a cycle) of adjuvant therapy using S-1 (80-120mg/d, d1-14), and docetaxel (40mg/m2, d1). Group B received the same regimen with the addition of apatinib (250mg, qd.). The primary endpoint was disease-free survival (DFS). The final analysis cutoff date was 30 November, 2020. Results: A total of 45 patients were enrolled from January 2019 to November, 2010 and assigned to group A (21) or group B (24). The DFS was not reached in both of the groups. The 1-year disease-free survival rate was 60% in group A and 90% in the group B, while the difference was not significant. The main AEs in group A were anemia (55%), nausea (50%) and neutropenia (40%); The most common AEs in group B were anemia (45%) neutropenia (40%) and diarrhea (25%). There were no treatment-related deaths. The longest administered time of apatinib with no progression was 457 days. And the median time to receive apatinib was 329 days. Conclusions: Combination of apatinib with S-1/docexal chemotherapy shows clinical benefits in locally advanced gastric cancer (T3-4aN+M0), with tolerable toxicity. The study is still ongoing to reach our final endpoint, DFS. Clinical trial information: ChiCTR2000038900.
Camrelizumab combined with albumin paclitaxel and cisplatin as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESCC).
Authors: Lv Huilai , Tian Yang , Huang Chao , Li Zhenhua , Tian Ziqiang
Published: June 2021

e16021

Background: The pathologic complete response (pCR) rate is improved by neoadjuvant therapy in locally advanced ESCC, but occurs less than 10% of patients(pts) with neoadjuvant chemotherapy agents. Immunotherapy has become a new promising treatment. Camrelizumab (anti-PD-1) is standard of care as second-line therapy for advanced ESCC in China. Therefore, we intended to evaluate the efficacy and safety of Camrelizumab combined with albumin paclitaxel and cisplatin as neoadjuvant therapy for pts with locally advanced ESCC. Methods: We retrospectively analysed locally advanced ESCC pts with clinical stage Ⅱ-ⅣA. Eligible pts were aged 18–75 years with no prior any therapy. Pts received 2-4 cycles neoadjuvant therapy which including Camrelizumab (200mg IV q3w), albumin paclitaxel (260 mg/m2 IV q3w) and cisplatin (75 mg/m2 IV q3w). Surgery was performed 4-6 weeks after neoadjuvant therapy. The primary endpoint was pCR, the secondary endpoints were major pathologic response (MPR), R0 resection rate, objective response rate (ORR), disease-free survival (DFS) and safety. Results: From Jul 27 2019 to Sep 26 2020,16 pts were enrolled and available evaluated. 8 pts (50%) had clinical complete response (cCR), and the ORR was 87.5% (14/16). All pts underwent surgery and surgical treatment was not delayed. The pCR was 43.8% (7/16), MPR was 75% (12/16). Notably, R0 resection rate was 100% (16/16). None of 16 pts progressed, the DFS was not yet achieved. The average intraoperative blood loss was 131ml (100-200ml) and the average hospitalization time after operation was 14 days (11-21 days). No patient developed anastomotic leak and other surgical treatment-related toxicity. The grade 1-2 treatment-related AEs were reactive cutaneous capillary endothelial proliferation (RCCEP) (n = 3,18.8%), weakness (n = 2, 12.5%), Myelosuppression (n = 1, 6.2%) and hypothyroidism (n = 1, 6.2%). No serious AEs resulted in termination of treatment, and treatment-related death was not observed. Conclusions: The addition of camrelizumab to albumin paclitaxel and carboplatin was demonstrated encouraging clinical efficacy and acceptable safety as neoadjuvant therapy, and might be a favorable option for pts with locally advanced ESCC. Further registered clinical trials are expected.
Impact of low skeletal muscle mass and density on outcomes of locally advanced esophageal cancer patients treated with radical radiotherapy.
Authors: Lv Jiahua , Yang Ningjing , Jia Hongyuan , Liang Long , Wu Lei , Wang Yi , Wan Gang , Wang Qifeng , Li Tao
Published: June 2021

e16047

Background: Low skeletal muscle mass and density are independent predictors of clinical outcomes in multiple gastrointestinal cancers. However, its effect on the long-term survival of locally advanced esophageal cancer patients undergoing radical radiotherapy is still unclear. Methods: Patients with stage II-III esophageal cancer undergoing radical radiotherapy, enrolled in a observational cohort study, were included. Skeletal muscle mass and density were measured on CT. Patients with high and low skeletal muscle mass and density were compared regarding overall survival (OS). Results: In total, 165 patients (75.8% males, median age 63) were included, from March 2012 to September 2017. Before radiotherapy, 26.7% patients had low skeletal muscle mass and 23.0% patients had low skeletal muscle density. After radiotherapy, 40.6% patients had low skeletal muscle mass and 30.3% patients had low skeletal muscle density.The median OS of high skeletal muscle mass and density group was significantly higher than that of low skeletal muscle mass and density group before radiotherapy (28.7 months vs 28.2 months, p = 0.041; 29.6 months vs 16.9 months, p = 0.025). The median OS of high skeletal muscle mass and density group was also significantly higher than that of low skeletal muscle mass and density group after radiotherapy (30.3 months vs 20.3 months, P = 0.012; 29.6 months vs 17.2 months, p = 0.018). Conclusions: Low skeletal muscle mass and density are associated with long-term outcome in patients undergoing radical radiotherapy. It is suggested that oncologists should pay more attention to the management of muscle mass and density of patients with esophageal cancer undergoing radiotherapy in order to improve their nutritional status and long-term survival.
Minimally invasive or open oesophagectomy for localized oesophageal cancer: Results of the ROMIO phase 3 randomized controlled trial.
Authors: Blazeby Jane M. ,   The ROMIO Group
Published: June 2021

e16057

Background: Patients with localised oesophageal adenocarcinoma or squamous cell cancer are frequently offered surgery, usually with neoadjuvant treatment. Whether minimally invasive surgical approaches are superior to standard open procedures in terms of patient recovery and survival benefit is unclear. Well-designed and well-conducted pragmatic trials are limited. The ROMIO study compared laparoscopic abdominal surgery and thoracotomy (LAO) with open oesophagectomy (OO), to test the hypothesis that LAO allows faster recovery than OO whilst maintaining the survival benefit of surgery. Methods: A pragmatic multi-centre randomised controlled trial (1:1 LAO vs. OO) was conducted in 9 major cancer centres in the UK. Included were patients with localised adenocarcinoma or squamous cell cancer selected by a multi-disciplinary team for oesophagectomy with or without neoadjuvant treatment. Surgery was quality assured by provision of a protocol, pre-operative video assessment of the 40 participating surgeons and intra-operative photographs of key agreed surgical components. The primary outcome was the physical function scale of the EORTC QLQ-C30 assessed during the first 3 months. Results: At enrolment to ROMIO 447 (85%) of 526 participants were male, mean age was 67 years (SD 9), 469 (89%) had an adenocarcinoma, 368 (70%) had a clinically staged T3 or T4a tumour, 295 (56%) had clinically positive nodes, and 438 (83%) underwent neoadjuvant treatment. 263 were randomly allocated to each of the two procedures, with 241 (92%) undergoing their allocated open surgery and 237 (91%) undergoing their allocated LAO (hybrid) surgery. Analyses are underway and this presentation will include the primary outcome measure and other short-term clinical outcomes including key complications and survival during the first 90 days (clinical data >95% complete). Conclusions: ROMIO is the largest multi-centre randomised controlled surgical trial of minimal access versus open surgical approaches for oesophageal cancer. The provision of a surgical quality assessment tool will supplement trial data to provide for the first-time evidence of surgical standards of both approaches. Clinical trial information: ISRCTN10386621.
Phase 2 study of zolbetuximab plus mFOLFOX6 in claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ): ILUSTRO cohort 2.
Authors: Klempner Samuel J , Lee Keun-Wook , Metges Jean-Philippe , Catenacci Daniel V.T. , Loupakis Fotios , Ilson David H. , Shah Manish A. , Shitara Kohei , Arozullah Ahsan , Park Jung Wook , Raizer Jeffrey J. , Bang Yung-Jue
Published: June 2021

e16063

Background: One accepted treatment for patients (pts) with advanced HER2-negative G/GEJ is mFOLFOX6 (5-FU, folinic acid, oxaliplatin). Despite treatment options, 5-year survival is poor, and limited biomarkers exist to inform treatment selection. Claudin 18.2 (CLDN18.2), a tight junction protein normally confined to gastric mucosa of healthy tissue, is often retained in G/GEJ. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cancer cell death via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Nonclinical results showed that cytotoxic chemotherapy increased CLDN18.2 expression, improving ADCC/CDC activity of zolbetuximab. Phase 2 results (NCT01630083, FAST) showed prolonged survival with zolbetuximab+EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. This study assessed antitumor activity and safety/tolerability of first-line zolbetuximab+mFOLFOX6 (Cohort 2 in NCT03505320) in G/GEJ with high CLDN18.2 expression. Methods: Cohort 2 of this multicohort study enrolled adult pts with metastatic or locally advanced unresectable G/GEJ. Patients had measurable disease (RECIST v1.1), HER2-negative disease, and high CLDN18.2 expression (≥75% of tumor cells demonstrating moderate-to-strong membranous staining by central IHC testing). Patients received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 3 then 600 mg/m2 Q3W. Zolbetuximab and mFOLFOX (Q2W from Cycle 1 Day 1) were administered in 42-day cycles. Key endpoints were safety/tolerability and objective response rate by independent central review (ORRICR RECIST v1.1). Results: As of Jan 26, 2021, Cohort 2 had enrolled 21 pts; median age was 63 years (range, 36-74), 57% were male, 43% were Asian, and 38% were white. Of 19 evaluable pts, 12 had confirmed partial responses; ORRICR was 63.2% (95% CI: 38.4-83.7) (Table). Median PFS was 13.7 months (95% CI: 7.4-not estimable); 12-month PFS rate was 58%. Common adverse events (AEs) were nausea (90.5%; grade 3, 4.8%) and vomiting (61.9%; grade 3, 9.5%). Common grade 3/4 AEs were decreased neutrophil count (33.3%) and neutropenia (28.6%). There were no fatal AEs. Conclusions: Results suggest promising antitumor activity with zolbetuximab+mFOLFOX6 in metastatic or locally advanced G/GEJ. The safety profile was manageable and no new safety signals were identified. Clinical trial information: NCT03505320. [Table: see text]
Chemothery (pacitaxol or irinotecan), plus apatinib and sintilimab as second-/third-line treatment for advanced gastric cancer.
Authors: Deng Ting , Zhang Le , Duan Jingjing , Li Hongli , Ge Shaohua , Bai Ming , Ning Tao , Yang Yuchong , Ji Zhi , Liu Rui , Wang Xia , Zhang Haiyang , Ba Yi
Published: June 2021

e16080

Background: Patients with advanced gastric or gastro-esophageal junction cancer have poor prognosis after progression on first-line chemotherapy. We investigated to combine second-line chemotherpy with third-line drugs, apatinib and anti-PD-1 antibody in these patients. Methods: This study is a single center, exploratory study in China. Eligible patients are adults with histologically confirmed advanced gastric or GEJ adenocancinoma, who were failure of first-line or second-line chemotherapy. Subjects receive chemotherapy, pacitaxol or iritecan (investigator choice), apatinib 250mg po qd, sintilimab 200mg ivd q3w. Response was assessed every 6 weeks. (RECIST version1.1) Primary endpoint was progression free survival (PFS). Results: Between May 30, 2019 and November 5, 2020, a total of 26 patients were enrolled in this study, and 4 (15.4%) patients were failure of second-line chemotherapy. There were 21 males and 5 females, and the median age was 61. The total number of treatment cycles was 140 and the median number was 5.5. Among 24 patients who were evaluated, partial response (PR) was obtained in 12 cases, stable disease (SD) in 8 cases and progressive disease (PD) in 4 cases. Objective response rate was 50.0%，and disease control rate was 83.3%. The median PFS was 7.06 months (95% CI 5.52-8.60), and the median overal survival has not yet been reached. The most common adverse events (AE) were leukopenia (61.5%), anemia (57.7%), neutropenia (53.8%), proteinuria (42.3%), alopecia (42.3%), hypothyroidism (38.5%), elevated alanine aminotransferase (34.6%), elevated aspartate aminotransferase (34.6%) and elevated alkaline phosphatase (34.6%), but most of them were grade 1 or 2, and the most common grade 3 or 4 treatment-related adverse events was neutropenia (11.5%). Conclusions: Chemotherapy, plus apatinib and sintilimab demonstrated promising activity and manageable safety profile as second- even third-line treatment in advanced gastric or GEJ cancer. Demographics and baseline characteristics.[Table: see text]
Transjugular intrahepatic portosystemic shunt plus sequential systemic therapy for advanced hepatocellular carcinoma with tumor thrombus-related symptomatic portal hypertension: A multicenter retrospective study.
Authors: Qiu Zhenkang , Wang Guobao , Zhang Fujun , Xue Jingbing , Yan Huzheng , Wang Guisong , Feng Kai , Wu Xuan , He Zhijiang , Jiang Weiwei , Yang Guang , Chen Zixiong , Gao Fei
Published: June 2021

e16116

Background: Portal vein tumor thrombus (PVTT) and symptomatic portal hypertension severely affect the survival and quality of life of hepatocellular carcinoma (HCC) patients. The aim of this study was to evaluate the clinical outcomes of the transjugular intrahepatic portosystemic shunt (TIPS) plus sequential systemic therapy in advanced HCC patients with tumor thrombus-related symptomatic portal hypertension. Methods: This multi-center retrospective study explored 142 advanced HCC patients with PVTT and symptomatic portal hypertension who received either TIPS plus sequential systemic therapy (group A) or only symptomatic and supportive treatment (group B) for from April 2016 to January 2020. The Kaplan-Meier method and log-rank test were performed to determine the survival differences of variables. Univariable and multivariable Cox proportional hazards regression analyses were used to identify prognostic factors of overall survival (OS). We used independent factors for the nomogram to predict OS. Results: The median OS of group A was significantly better than that of group B (7.6 [95% CI: 4.6, 10.6] vs. 4.5 [95% CI: 2.7, 6.4], months, P < 0.001). Multivariable analysis also showed that PVTT degree (I/II) (Hazard ratios [HR] = 0.679; 95% CI: 0.465, 0.994; P = 0.046), variceal bleeding (HR = 1.686; 95% CI: 1.059, 2.684; P = 0.028), Child-Pugh Class A (HR = 0.450; 95% CI: 0.272, 0.746; P = 0.002), and BCLC stage C (HR = 0.434; 95% CI: 0.222, 0.850; P = 0.015) were significant predictors of OS. These five indicators were included in the nomogram model to predict survival probabilities in 6- and 12-months OS. Conclusions: TIPS plus sequential systemic therapy is safe and feasible for the treatment of advanced HCC with tumor thrombus-related symptomatic portal hypertension.
A real-world study of camrelizumab in the treatment of hepatocellular carcinoma.
Authors: Zeng Yong-Yi , Guo Wu-hua , Zhang Zhibo , Shi Xi , Su Yongjie , Cai Qinghe , Peng Jianyang
Published: June 2021

e16121

Background: Programmed cell death protein‐1(PD-1) targeted immunotherapy is a promising treatment strategy for advanced hepatocellular carcinoma. Anti-PD-1 inhibitor camrelizumab showed antitumour activity in phase II studies of advanced hepatocellular carcinoma, with manageable toxicities. This study evaluates safety and efficacy of camrelizumab in patients with advanced hepatocellular carcinoma. Methods: This is a multicentre, real‐world trial done at thirty-three centres in Fujian Province, China. Eligible patients were aged 18 to 75 years was diagnosed by China Liver Cancer Staging(CNLC) 2019 clinical diagnostic criteria or with a histological or cytological diagnosis of advanced hepatocellular carcinoma, unresectable or had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were received camrelizumab 200 mg intravenously every 2 weeks plus other treatments, such as molecular targeted drug, transcatheyer artetial chemoembolization, radiotherapy and chemotherapy. The primary endpoints were progression-free survival. Safety was analysed in all treated patients. Follow-up is ongoing. Results: Between Mar 12, 2020, and Dec 25, 2020, 63 patients were screened for eligibility, of whom 41 eligible patients received camrelizumab were recruited and among whom 15 received apatinib, 16 received lenvatinib, 2 received sorafenib and 1 received regorafenib. Median followup was 5.28 months (IQR 1.63–10.20). Objective response was reported in 12 (29.3%; 95% CI 16.1–45.5) of 41 patients. Disease control was reported in 34 (82.9%; 95% CI 67.9–92.8) of 41 patients. The median PFS was not reached, and expected more than 9 months. Grade 3 or 4 treatment-related adverse events occurred in 21 (51.2%) of 41 patients; the most common were increased gamma-glutamyltransferase (15 [36.6%]) and increased aspartate aminotransferase (7 [17%]). One death was judged by the investigators to be potentially treatment-related (due to upper gastrointestinal bleeding). Conclusions: Camrelizumab showed promising efficacy and safety in pretreated Chinese patients with advanced hepatocellular carcinoma, and might represent a new treatment option for these patients. Clinical trial information: ChiCTR2000041405. Research Sponsor: Jiangsu Hengrui Medicine Co., Ltd. Clinical trial information: ChiCTR2000041405.
Molecular characteristics of patients with resectable hepatocellular carcinoma.
Authors: Zeng Daobing , Wang Menglong , Wu Jushan , Lin Dongdong , Guo Qingliang , Li Chuanyun , Zhang Haitao , Di Liang , Zhao Xiaofei , Ma Chao , Gao Daming , Liu Zhaobo , Fu Zhi , Sun Libo , Zhang Qikun , Li Guangming , Guo Rongyun , Wang Huina , Zhang Yanrui
Published: June 2021

e16140

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies and leading cause of cancer deaths worldwide. Biomarkers contribute to predict the response of targeted treatments and immunotherapy. Therapy directed toward homologous recombination deficiency (HRD) is now approved in ovarian and breast cancer, but the pattern of HRD is not clear in HCC. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. Thus, we aimed to analyze the molecular characteristics of resectable HCC, including HRR genes. Methods: Matched tumor/normal DNA from resectable HCC patients (N = 53) were analyzed by whole exome sequencing (WES) or Acornmed panel with 808 cancer-related genes. Results: Overall, 94.3% (50/53) patients exhibited genetic alterations. TP53, ARID1A, PTEN and NBPF1 were the most commonly mutated genes in resectable HCC. In addtion, 35.9% patinets harbored at least one HRR genes mutation. The frequently mutated genes were BRCA2 (4.4%), BRCA1(4.0%), ATM (3.9 %), and RAD50 (3.8%). Interesting, frequency of HRR genes mutation in the Chinese cohort was higher than that in TCGA (35.9 % vs 20.9%). Analysis of carcinogenic pathways shown that ERBB and PI3K-AKT signaling pathway were the common signaling pathway. In resectable HCC, 32.08% (17/53) patients disclosed high TMB (highest 25%). Further analysis found that PTEN mutations were remarkably associated with low TMB (p < 0.05). Conclusions: This study contributes to understand the molecular characteristics of patients with resectable HCC, which will be useful to guide personalized therapy and promote the clinical management in this population. Furthermore, the study suggested that it is feasibility for resectable HCC patients received PARP inhibitors, DNA-damaging chemotherapies, and immune checkpoint blockade therapy.
Impact of lenvatinib (LEN) dose-intensity and starting dose on survival among patients with advanced hepatocellular carcinoma (HCC): Results from a Canadian multicenter database (HCC CHORD).
Authors: Amaro Carla Pires , Allen Michael J , Knox Jennifer J. , Tsang Erica S. , Lim Howard John , Lee-Ying Richard M. , Chan Kelvin K. , Qian Jessica , Meyers Brandon M. , Thawer Alia , Al-Saadi Sulaiman Mohammed Saif , Hsu Tina , Ramjeesingh Ravi , Karachiwala Hatim , Abedin Tasnima , Tam Vincent C. ,   HCC CHORD Consortium
Published: June 2021

e16142

Background: The REFLECT trial established LEN as a first-line treatment option for HCC. However, decreased LEN exposure is common due to adverse events leading to dose reductions and treatment discontinuations. The aim of this study was to evaluate whether starting dose or dose-intensity of LEN affects survival. To our knowledge, this is the first study to examine dosing of LEN and survival in HCC patients treated outside of Asia. Methods: From July 2018 to December 2019, HCC patients treated with first-line LEN from 10 different Canadian cancer centers were included. Overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR) were retrospectively analyzed and compared across different mean dose-intensities (> 66.7% vs <=66.7%) and starting dose groups (Full vs reduced). Survival outcomes were assessed with Kaplan-Meier curves and Cox proportional hazards models. DCR and ORR were determined radiographically according to the treating physician´s assessment in clinical notes and not RECIST 1.1 or mRECIST. Results: A total of 173 patients were included. Median age was 67 years, 77% were men and 23% East Asian. The most frequent causes of liver disease were hepatitis C (38%) and B (20%). 56% of patients received localized treatment prior to LEN. Of those, 24% had TACE, 6% TARE and 8% had liver transplant. Before starting LEN 31% of patients were ECOG 0 and 57% were ECOG 1. Most patients were Child-Pugh A (81%) and BCLC stage C (73%). Main portal vein invasion was present in 15% of the patients. Median follow-up was 4.5 months. LEN was started at full dose in 54% of patients and 60% had a mean dose intensity greater than 66.7%. ORR, PFS and OS results and their comparison between the different starting dose and dose-intensities are shown in the table. In a multivariate model that adjusted for age, gender, stage, ECOG, Child-Pugh, BCLC, cirrhosis, liver etiology disease (hepatitis B, C and non-viral), presence of tumor thrombus, prior transplant and localized treatment, dose intensity (>66.7 vs <=66.7% [HR 0.70, 95% CI 0.42-1.18; p=0.18]) was not a predictor of survival. Conclusions: In HCC patients starting LEN at a reduced dose does not appear to compromise survival. LEN dose-intensity of > 66.7% was associated with improved survival, but not after controlling for potential confounders.[Table: see text]
Epigenomic analysis of biliary tract cancer identifies subtypes with different immune characteristics and clinical outcomes.
Authors: Qiu Zhiquan , Ji Jun , Xu Yu , Zhu Yan , Gao Chun-Fang , Wang Guoqiang , Li Chengcheng , Zhang Yuzi , Zhao Jing , Wang Chenyang , Wen Xiaofang , Zhang Zhou , Li Bingsi , Han-Zhang Han , Liu Hao , Cai Shangli , Zhang Zhihong , Li Bin , Jiang Xiaoqing
Published: June 2021

e16153

Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited treatment options. The epigenome-associated multi-dimensional studies for BTC are limited. Here, we proposed a DNA methylation-based classification scheme and investigated the associations between methylation and multi-dimensional data including clinicopathological features, genetic aberrations, and prognosis. Methods: Multi-dimensional data concerning mutation, DNA methylation, and clinical data from 105 BTC patients who received surgical resection (gallbladder cancer [GBC], n=48, cholangiocarcinoma [CCA], n=57) were analyzed. Differentially methylated blocks (DMBs) in GBCs and CCAs were identified by comparing tumors and adjacent tissues. Methylation-based subtyping was performed via non-supervised consensus clustering. Results: The differentially methylated blocks (DMBs) in GBCs and CCAs are highly overlapping. Based on the common DMBs of GBCs and CCAs, the classifier yielded high sensitivity of 95.2% and specificity of 96.0%. Hypomethylated genes were enriched in pathways of transmemberane receptor and ion binding, while hypermethylation occurred in genes concerning DNA binding transcription activity. By non-supervised clustering of common DMBs, 6 clusters with different degrees of methylation change were identified. Higher methylation alteration (cluster risk-high) was associated with more copy number variation and shorter OS. By LASSO regression, a 12-gene prognostic model was trained and validated (Table). As for immune characteristics, the methylation of CD8A gene was lower in the cluster risk-high group, and this association was validated in the TCGA-cholangiocarcinoma cohort. In addition, lower methylation change was associated with higher BCR/TCR diversity, immune cell infiltration, and PD-L1 and CTLA4 mRNA expression. Conclusions: In BTC, methylation patterns may serve as a robust indicator of immune-related features and prognosis. Our integrative analysis highlights the association between genomic and epigenomic features, and provides insights into the molecular heterogeneity, and the potential therapeutic significance in biliary tract malignancies. Included methylation sites in the LASSO model.[Table: see text]
Phase II study of lenvatinib in combination with GEMOX chemotherapy for advanced intrahepatic cholangiocarcinoma.
Authors: Shi Guo-Ming , Jian Zhou , Fan Jia , Huang Xiao-Yong , Wu Dong , Liang Fei , Lu Jia-Cheng , Yang Guo-Huan , Chen Yi , Ge Ning-Ling , Ji Yuan , Hou YY , Sun Hui-Chuan , Qiu Shuang-Jian , Ye Qing-Hai , Huang Xiao-Wu , Shi Ying-Hong , Gao Qiang , Yang Xin-Rong , Wang Zheng
Published: June 2021

e16163

Background: The prognosis of advanced intrahepatic cholangiocarcinoma (ICC) remains dismal with gemcitabine-based first-line chemotherapy. This study is to evaluate the safety and efficacy of lenvatinib in combination with gemcitabine and oxaliplatin (Gemox) chemotherapy in the advanced ICC. Methods: Locally advanced or metastatic ICC patients (pts) were given lenvatinib 12 mg/day (body weight ≥60 kg) or 8 mg/day (body weight <60 kg) oral administration, once daily. They also received 1g/m² gemcitabine on Day 1 and Day 8, and 85 mg/m² oxaliplatin Q3W by IV for 6-8 cycles. The primary outcome was objective response rate (ORR) and secondary outcomes included safety, disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). ORR, DCR and PFS were measured according to RECIST 1.1. Treatment would be terminated by confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. Results: From March 2020 to Sep. 2020, 30 pathologically-confirmed advanced ICC pts with a mean age of 59.2 (range, 33-74) years, including 14 women (46.7%), were enrolled at Zhongshan Hospital, Fudan University. At the end of last follow-up (February 10, 2021), the ORR was 30.0% (9/30; 95% CI: 14.7%-49.4%). The disease control rate (DCR) was 86.7% (26/30; 95% CI: 69.3%-96.2%). Median follow-up was 6.8 months. One pt with locally advanced disease was down-staged and then underwent resection. This patient remained disease-free survival at the end of last follow-up. 11 pts experienced disease progression and 8 pts have died. The median PFS and OS have not been reached. Median duration of response (DOR) has not been reached and responses were ongoing in 6/9 (66.7%) pts. 6-months OS rate was 92.6%. No grade 5 adverse event (AE) was observed in present study. 40.0% (12/30) of pts experienced grade 3 or higher AEs and 5 pts discontinued the treatment owing to fatigue (3 pts), jaundice (1 pt) and vomiting (1 pt). Conclusions: Addition of lenvatinib to Gemox chemotherapy provided modest efficacy with reasonable tolerability in advanced ICC patients. Clinical trial information: (NCT04361331). Clinical trial information: NCT04361331.