bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer (LARC) with or without oxaliplatin (OX): Individual patient data (IPD) meta-analysis of three randomized controlled trials (RCTs) with subgroup analyses of age cohorts.
Authors: Fontana Elisa , Zichi Clizia , Smyth Elizabeth Catherine , Mauer Murielle E. , Roedel Claus , Fokas Emmanouil , Hofheinz Ralf Dieter , Arnold Dirk , Schmoll Hans-Joachim , Van Cutsem Eric , Haustermans Karin , Stein Alexander , Gerard Jean-Pierre , Conroy Thierry , Jouffroy-Zeller Claire , Moehler Markus H. , Lordick Florian , Ben-Aharon Irit , Di Maio Massimo ,   Adolescent and Young Adult Gastrointestinal Task Force, EORTC
Published: May 2020

4074

Background: Neoadjuvant CRT with fluoropyrimidine (FP) is standard treatment for LARC, which is increasing in younger patients (pts). RCTs examining the addition of OX are still controversial. A post hoc analysis of the CAO/ARO/AIO-04 trial showed significant benefit in pts < 60y. We hypothesised that younger pts with LARC might have improved outcomes with OX-CRT. Methods: Systematic review and IPD meta-analysis were performed. Data from 3 RCTs (CAO/ARO/AIO-04, ACCORD-12, PETACC-6) testing the addition of OX to standard FP-based CRT in LARC were available (of 9 RCTs identified). Primary endpoint: disease-free survival (DFS), secondary endpoints: pathologic complete response (pCR), overall survival (OS). Analyses were by intention to treat (ITT), stratified by trial. Age cut-offs were 60y and 50y. Given the focus on young age a multivariate analysis evaluating all possible confounders was not intended in the current work. Results: IPD from 2914 pts were included (48.5% of available literature). Median age was 63; 70% were male; 79% had a performance status = 0; 72% were stage ≥III. In ITT (Hazard Ratio [HR] 0.88, 95%CI 0.77-1.01, p = 0.06), DFS was not significantly improved by the addition of OX (Table). In < 60y (n = 1166, 40% total), DFS was significantly improved by OX (HR 0.77, 95%CI 0.62-0.96, p = 0.02). In < 50y (n = 350, 12% total) there was a numerically better DFS, although not significant (HR 0.73, 95%CI 0.49-1.08, p = 0.12). Interaction test between age and DFS was non-significant (60y p = 0.11; 50y p = 0.44). In ITT, OX increased pCR from 13% to 16% (Odds Ratio [OR] 1.28, 95%CI 1.04-1.57, p = 0.024 [stratified by trial]), without significant interaction with age (60y p = 0.11, 50y p = 0.74). No OS benefit was demonstrated (HR 0.97, 95%CI 0.82-1.15, p = 0.75). Conclusions: This first IPD meta-analysis of three RCTs evaluating the addition of OX to CRT did not show significant interaction of OX with age. However, we confirm a signal for DFS benefit in pts < 60y and a non-significant increment in DFS in < 50 y although this analysis may be underpowered. Stage-stratified analyses and feasibility/toxicity data in age cohorts will be presented. [Table: see text]
Tumor mutational load, microsatellite instability and actionable mutations in metastatic colorectal cancer: Results from the TRIBE2 study.
Authors: Antoniotti Carlotta , Marmorino Federica , Lonardi Sara , Corti Francesca , Rossini Daniele , Moretto Roberto , Ugolini Clara , Giordano Mirella , Tamburini Emiliano , Santini Daniele , Aprile Giuseppe , Bordonaro Roberto , Zucchelli Gemma , Fontanini Gabriella , Lenz Heinz-Josef , Falcone Alfredo , Korn Wolfgang Michael , Cremolini Chiara
Published: May 2020

4077

Background: In the TRIBE2 study molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD. We performed a comprehensive NGS analysis of samples from randomized patients in order to investigate the prognostic impact of tumor mutational load (TML), its additional value with respect to the assessment of microsatellite instability (MSI), and the overall prevalence of potentially actionable alterations. Methods: Tumor DNA was obtained from formalin-fixed, paraffin-embedded blocks from primary tumors of 296 (44%) out of 679 randomized patients and underwent NGS analysis using the Caris MI TumorSeek panel, assessing 592 genes. TML was defined low, intermediate or high if < 7, 7-16 or > 16 mutations/Mb were found. MSI status was determined both by NGS and by IHC. Results: TML and MSI were successfully determined by NGS in 224 (76%) cases. NGS and IHC results were concordant in 221 (99%) cases. TML was low, intermediate or high in 56 (25%), 157 (70%) and 11 (5%) cases, respectively. When compared with TML low and intermediate tumors, TML high were more frequently right-sided (p = 0.013), mucinous (p < 0.001) and MSI-high (p < 0.001). TML high tumors were MSI-high or MSS in 8 (73%) and 3 (27%) cases, respectively. Two out of 3 TML high and MSS tumours showed a pathogenic POLE mutation (p.S459F and p.P286R). The other TML high, MSS and POLE wt tumor was dMMR at IHC (loss of MSH6 expression) and showed a pathogenic MSH6 mutation (p.F1040fs). As compared with low and intermediate TML, high TML was associated with longer PFS (median PFS: 17.3 vs 10.6; HR: 0.54 [95%CI: 0.35-1.09], p = 0.098) and OS (median OS: not reached vs 23.7: HR: 0.45 [95%CI:0-28-1.13], p = 0.106). No interaction effect between TML and treatment arm was observed, and no difference between TML low and intermediate tumors was reported in terms of baseline characteristics and prognosis. Actionable alterations ( HER2 mutations [N = 2] and amplifications [N = 4], KRAS G12C [N = 10] and BRAF V600E mutation [N = 39]) were found in 55 (19%) out of 296 cases. No NTRK/ROS/ALK or MET amplification was found. Conclusions: TML high tumors are not limited to MSI-high ones but showed POLE or MSH6 somatic mutation and shower longer PFS and OS. No differences are reported between TML low and intermediate tumors. Molecular alterations predictive of benefit from targeted strategies currently available are detectable only in a small percentage of mCRCs.
Intra-tumoral microbes and overall survival in colorectal cancer patients.
Authors: Malalur Pannaga G. , Mo Xiaokui , Hoyd Rebecca , Carbone David Paul , Spakowicz Daniel
Published: May 2020

4083

Background: The presence of certain bacteria among or adjacent to tumor cells may contribute to colorectal cancer (CRC) development. However, the effect of the tumor microbiome on survival in CRC patients undergoing treatment is poorly understood. We hypothesize that intra-tumoral microbes correlate with overall survival (OS) in CRC patients. Methods: We obtained RNA-seq data from CRC tumor biopsies from patients treated at The Ohio State University Comprehensive Cancer Center as part of the Oncology Research Information Exchange Network (ORIEN). Reads were aligned to human and exogenous genomes using TopHat2 and Kraken2/Bracken, respectively. Results: The analyzed cohort included 99 CRC patients with an age range from 31-83 years, 62% female, and 44% with metastatic CRC. Therapies received prior to sample collection were grouped into chemotherapy with or without radiation (37%), antiVEGF/EGFR therapies (33%), no systemic therapy (23%), immunotherapy (3%); 3% were unknown. Overall, eleven bacteria were significantly associated with shorter OS, including a species in the genus Clostridium and Vibrio. Conversely, five other bacteria including several commensal gut microbes, were associated with longer OS. In patients who received chemotherapy with or without radiation (n = 38), several microbes were significantly associated with shorter OS, including a member of the genus Streptomyces. Only three bacteria were significantly associated with longer OS. In the patients who received antiVEGF/EGFR therapies (bevacizumab, cetuximab, panitumumab) (n = 33), several bacterial taxa were associated with shorter OS. In addition, bacteria including a member of the genera Bacillus and Staphylococcus were significantly associated with metastatic CRCs. (p < 0.05 for all, Fisher’s Exact tests). Conclusions: This study suggests that demonstrating the presence or absence of certain microbes in tumor biopsies could have important therapeutic implications for CRC patients. Only bacteria (no fungi, viruses, archaea, etc.) were found to significantly associate with OS across the entire cohort and within treatment subsets. The presence of bacteria was mostly, but not always, associated with worse OS. Antibiotics targeted towards bacterial species associated with negative outcomes could have the potential to improve OS in CRC patients.
Inpatient mortality, healthcare resource utilization, and complications of elective laparoscopic versus open colectomy in colon cancer patients: A nationwide inpatient sample analysis.
Authors: Vohra Ishaan , Katiyar Vatsala , Attar Bashar , Lingamaneni Prasanth , Moturi Krishna Rekha , Singh Sunny R K , Malapati Sindhu Janarthanam , Farooq Muhammad Zain , Gupta Shweta
Published: May 2020

4109

Background: Laparoscopic colectomy (LC) has become an accepted safe and alternative technique to open surgical colectomy (OC) as a treatment option for colon cancer. We compared inpatient mortality, hospital resource utilization and complications in patients who underwent LC vs OC. Methods: All patients with known diagnosis of colon cancer who underwent elective colonic resection were identified using Nationwide Inpatient Sample (NIS) 2017. Univariate and multivariate linear and logistic regression was performed to compare the outcomes of patients who underwent LC vs OC. Results: In our cohort, 171, 480 adult patients with colon cancer were identified. The number of males and females were equal. The mean age was 67.2 years. They were predominantly Caucasians (67.6%). OC was performed on 3,869 patients. Of 1,345 patients who underwent LC, 385 were converted to OC. As compared to OC, LC was associated with lower postoperative complications including anastomotic leak, stricture, intestinal obstruction(1% vs 10.8%, p<0.01), blood transfusion(2.2 % vs 11.2% p=0.01), malnutrition(0.2% vs 4.4% p=0.02), shock(0.7% vs 1.8%,p=0.04), ICU care(1.9% vs 5.3%), mean length of stay (5.9 days vs 8.7 days, p=0.01), lower hospital charge (88,642$ vs 106,315 $,p<0.01) and lower mortality(0.3% vs 1.9%(p=0.02). There was a trend towards decreased venous thromboembolism (0.3% vs 1.7 %, p=0.9) and post-operative ileus (0.1% vs 0.7% p=0.60) in LC as compared to OC. On multivariate analysis, independent predictors of undergoing LC were younger age, teaching and large bed-sized hospital and lower Charlson comorbidity index. Race, insurance status and income had no significant association with selection of operative approach (Table). Conclusions: In our cohort, laparoscopic colectomy was found to have better peri and post-operative clinical outcomes including decreased inpatient mortality and hospital resource utilization. It should be promoted as the curative surgical option for colon cancer whenever clinically indicated. [Table: see text]
Early ileostomy closure is safe and feasible during adjuvant chemotherapy after total mesorectal excision surgery for rectal cancer.
Authors: Gu Xiaodong , Zhou Minwei , Wang Zihao , Li Zhenyang , Yang Yi , Zang Yiwen , Zhou Yiming , Xiang Jianbin , Chen Zongyou
Published: May 2020

4111

Background: The aim of this study was to evaluate the comparative clinical and oncological outcomes of temporary ileostomy closure during or after adjuvant chemotherapy in patients with total mesorectal excision (TME) for rectal cancer. Methods: This randomized controlled trial investigated 87 patients (51 males, 36 females) with rectal cancer undergoing TME surgery with temporary ileostomy from January 2016 to December 2018. Patients were randomized divided into 2 groups: early group (43 patients, mean age: 60.35) who underwent stoma closure during adjuvant chemotherapy (3 months after primary surgery) and late group (44 patients, mean age 61.80) who underwent stoma closure after adjuvant chemotherapy (6 months after primary surgery). Both clinical and oncological outcomes were analyzed. Results: No significant differences were observed in operative time, blood loss, postoperative hospital stay, postoperative complications or hospital costs in ileostomy closure between the 2 groups. Stoma-quality of life (QOL) of patients in early group was significantly better than late group (52.02±5.68 vs 46.91±5.68, P <0.05). No significant difference in overall survival (P = 0.702) or progression-free survival (P = 0.638) was observed between the 2 groups. Conclusions: Ileostomy closure during adjuvant chemotherapy was clinically safe, and interruption of chemotherapy due to ileostomy closure did not change oncologic outcomes. Early ileostomy closure can improve QOL in those patients. Clinical trial information: NCT02665026 .
The landscape of MAP3K1/MAP2K4 alterations in gastrointestinal (GI) malignancies.
Authors: Stein Matthew K , Elliott Andrew , Hwang Jimmy J. , Lou Emil , Khushman Moh'd M. , Scott Aaron James , Marshall John , Sohal Davendra , Weinberg Benjamin Adam , Goldberg Richard M. , Salem Mohamed E. , Korn Wolfgang Michael , Grothey Axel
Published: May 2020

4113

Background: Inactivating alterations in MAP3K1/MAP2K4 occur in various solid tumors, sensitize cancer models to MEK inhibitors, and have co-mutation partners which may enable therapeutic targeting. Methods: We retrospectively reviewed 20290 GI malignancy patients (pts), comprised of 9986 colorectal carcinoma (CRC) and 10304 non-CRC, whose tumors were profiled with Caris Life Sciences from 2015-2019. Profiling included immunohistochemistry (IHC) with programmed death ligand-1 (PD-L1), next-generation sequencing (NGS), tumor mutational burden (TMB) and deficient mismatch repair or microsatellite instability-high status (dMMR/MSI-H). Results: MAP3K1/MAP2K4-alteration ( MAP3K1/MAP2K4-MT) was more frequent in CRC than non-CRC pts (2.0% v. 1.2%, p<0.0001), with truncating mutations representing the majority of lesions along both genes. While MAP3K1/MAP2K4-MT CRC pts were similar in age and gender to wild-type (WT), mutated non-CRC pts were older (median age 69 v. 65 years) and more likely female (51% v. 42%) compared to WT (both p<0.05). MAP3K1/MAP2K4-MT CRC (25% v. 7%) and non-CRC (30% v. 3%) were more frequently dMMR/MSI-H than WT pts (both p<0.0001). MAP3K1/MAP2K4-MT CRC cases were affiliated with higher TMB and similar rate of PD-L1 expression compared to WT. A higher rate of MAP3K1/MAP2K4-MT CRC pts were right-sided (36% v. 22%, p<0.0001) and transverse (8% v. 4%, p<0.05) compared to WT, whereas a higher frequency of WT cases were left-sided (20% v. 28%, p<0.05) and rectal (15% v 23%, p<0.05). Of microsatellite stable (MSS) CRC pts, those with MAP3K1/MAP2K4-MT were more likely PIK3CA (26% v. 17%) and APC (85% v. 78%) and less-likely TP53 (64% v. 77%) co-mutated versus WT MSS pts (all p<0.05); no difference was seen in BRAF V600E, ERBB2/ ERBB3 or KRAS co-mutation rate in MSS pts. In both all-comers and MSS CRC, MAP3K1/MAP2K4-MT pts were more frequently co-mutated than WT with ARID1A, POLE, ATM, BRCA2 and PIK3R1 (all ≥7% of MAP3K1/MAP2K4-MT pts, p<0.0001). A higher frequency of all-comer non-CRC GI malignancy pts with MAP3K1/MAP2K4-MT were co-mutated with PIK3CA (13% v. 6%), ERBB2/ERBB3 (8% v. 3%) or APC (13% v. 5%) compared to WT (all p<0.01). For MSS non-CRC GI cases, ARID1A (50% v. 30%) and SMAD4 (21% v. 12%) were more frequently co-mutated in MAP3K1/MAP2K4-MT versus WT pts (all p<0.05). Conclusions: Truncating MAP3K1/MAP2K4 alterations occur in nearly 2% of GI malignancy pts and are more commonly associated with dMMR/MSI-H than WT. Potentially targetable co-mutation partners implicated in MAPK and PI3K pathways as well as POLE, BRCA2 and ATM warrant further evaluation.
SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA).
Authors: Sohal Davendra , Duong Mai T. , Ahmad Syed A. , Gandhi Namita , Beg Muhammad Shaalan , Wang-Gillam Andrea , Wade James Lloyd , Chiorean Elena Gabriela , Guthrie Katherine A , Lowy Andrew M. , Philip Philip Agop , Hochster Howard S.
Published: May 2020

4504

Background: Clinical outcomes after curative treatment of resectable PDA remain suboptimal. To assess the potential of early control of systemic disease with multiagent peri-op CTx, we conducted a prospective trial in the National Clinical Trials Network. Methods: S1505 was a randomized phase II trial of peri-op CTx (12 weeks pre-, 12 weeks post-op) with either mFOLFIRINOX (Arm 1) or Gem/nabP (Arm 2). Eligibility required confirmed tissue diagnosis of PDA, ECOG PS 0 or 1, and resectable disease per Intergroup criteria. Primary outcome was 2-year overall survival (OS), using a “pick the winner” design; for 100 eligible patients (pts), accrual up to 150 pts was planned to account for cases deemed ineligible at central radiology review. We previously presented data on eligibility (ASCO 2019 abstr 4137). Here we present the final efficacy and toxicity results for the eligible pts. Results: From 2015 to 2018, 147 pts were enrolled; there were 102 eligible pts; 55 in Arm 1; 47 in Arm 2. For Arms 1 and 2 respectively: median age, 66 (44-76) and 64 (46-76) years; males, 36 (65%) and 24 (51%); and ECOG PS 0, 34 (62%) and 31 (66%) pts. Treatment details are shown in Table. For Arm 1 and Arm 2, respectively: Two-year OS was 41.6% and 48.8%; median OS was 22.4 months and 23.6 months. Neither arm’s 2-year OS estimate was statistically significantly higher than the a priori threshold of 40% (p=0.42 in Arm 1 and p=0.12 in Arm 2). Median disease-free survival (DFS) after resection was 10.9 months in Arm 1 and 14.2 months in Arm 2 (p=0.87). Conclusions: We have demonstrated: 1) two-year OS of 41.6% (median 22.4 months) with mFOLFIRINOX and 48.8% (median 23.6 months) with Gem/nabP for all eligible pts starting treatment for resectable PDA; 2) post-resection DFS of 10.9 months and 14.2 months, respectively; 3) adequate safety and high resectability rates with peri-op CTx; 4) little evidence that either regimen improves OS compared with the historical standard. Clinical trial information: NCT02562716 . [Table: see text]
Apatinib as second-line therapy in Chinese patients with advanced hepatocellular carcinoma: A randomized, placebo-controlled, double-blind, phase III study.
Authors: Li Qiu , Qin Shukui , Gu Shanzhi , Chen Xiaoming , Lin Lizhu , Wang Zishu , Xu Aibing , Chen Xi , Zhou Cuncai , Ren Zhenggang , Yang Lin , Xu Li , Bai Yuxian , Chen Lei , Li Jun , Pan Hongming , Cao Bangwei , Fang Weijia , Yan Ping , Jin Chunlei
Published: May 2020

4507

Background: Chinese patients (pts) account for more than 50% of hepatocellular carcinoma (HCC) cases in the world and have special features in etiology, biological behavior, treatment strategy and prognosis. The aim of this study was to evaluate the efficacy and safety of apatinib, an inhibitor targeting vascular endothelial growth factor receptor-2, in Chinese pts with pretreated advanced HCC. Methods: In this randomized, placebo-controlled, double-blind, phase 3 trial done in 31 sites in China, pts with HCC who had received at least one line of systemic therapy (including sorafenib and oxaliplatin-based chemotherapy, which is another first-line standard-of-care in China) and had Child-Pugh liver function class A or B ≤7 points were enrolled. The pts were randomly assigned (2:1) to receive 750 mg apatinib orally once daily or placebo and stratified by ECOG performance status (0 or 1), previous sorafenib treatment (yes or no), and extrahepatic spread and/or macrovascular invasion (yes or no) in 28-day treatment cycles. The primary endpoint was overall survival (OS). Results: Between Apr 01, 2014 and May 03, 2017, 393 pts were randomized and received at least one dose of study treatment (261 in apatinib arm and 132 in placebo arm). The median OS was significantly longer with apatinib than that with placebo (8.7 months [95% CI 7.5-9.8] vs 6.8 months [95% CI 5.7-9.1]; hazard ratio 0.785 [95% CI 0.617-0.998]; p=0.0476). Pts in the apatinib arm also had prolonged median progression free survival (PFS) compared with those in the placebo arm (4.5 months [95% CI 3.9-4.7] vs 1.9 months [95% CI 1.9-2.0]; hazard ratio 0.471 [95% CI 0.369-0.601]; p˂0.0001). The objective response rate was 10.7% (95% CI 7.2-15.1) with apatinib versus 1.5% (95% CI 0.2-5.4) with placebo. Treatment-related adverse events (TRAEs) were reported in 250 (97.3%) pts in the apatinib arm and 92 (70.8%) pts in the placebo arm. The most common TRAEs of grade 3 and 4 were hypertension (71 [27.6%] pts in the apatinib arm vs 3 [2.3%] pts in the placebo arm), hand-foot syndrome (46 [17.9%] vs 0), decreased platelet count (34 [13.2%] vs 1 [0.8%]), and decreased neutrophil count (27 [10.5%] vs 0). 24 (9.3%) pts with apatinib and 13 (10.0%) pts with placebo died due to adverse events, and none were deemed treatment-related by investigators. Conclusions: Apatinib significantly prolonged OS and PFS in Chinese pts with pretreated advanced HCC, and was well tolerated with a manageable safety profile. Clinical trial information: NCT02329860 .
Phase III APACT trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P + Gem) versus gemcitabine (Gem) alone for patients with resected pancreatic cancer (PC): Outcomes by geographic region.
Authors: Reni Michele , Riess Hanno , O'Reilly Eileen Mary , Park Joon Oh , Hatoum Hassan , Saez Berta Laquente , Salminen Tapio , Oettle Helmut , Lopez Rafael , Dowden Scot D. , Karthaus Meinolf , Tabernero Josep , Van Cutsem Eric , Philip Philip Agop , Goldstein David , Berlin Jordan , Tempero Margaret A.
Published: May 2020

4515

Background: The APACT trial was one of the largest and most geographically diverse trials of adjuvant chemotherapy for resected PC, allowing for comparison of outcomes by geographic region. In this analysis, we report updated overall survival (OS) results for the intent-to-treat (ITT) population and examine outcomes by geographic region. Methods: Treatment-naive patients with histologically confirmed PC, macroscopic complete resection, Eastern Cooperative Oncology Group performance status 0 or 1, and carbohydrate antigen 19-9 < 100 U/mL were eligible. Stratification factors were resection status (R0/R1) and lymph node status (positive/negative). Treatment was initiated ≤ 12 weeks postsurgery. Patients received nab-P 125 mg/m2 + Gem 1000 mg/m2 or Gem 1000 mg/m2 on days 1, 8, and 15 of six 28-day cycles. The primary endpoint was disease-free survival by independent review. Secondary endpoints were OS and safety. Results: The updated OS analysis (data cutoff date, January 2020) revealed a median OS of 41.8 months with nab-P + Gem compared with 37.7 months with Gem alone (hazard ratio [HR] 0.81; 95% CI, 0.68 - 0.97; nominal P = 0.047; Table). In each geographic region, the median OS with nab-P + Gem was numerically longer than with Gem alone. Conclusions: The updated OS analysis of the ITT population supports the previously reported trend favoring nab-P + Gem. The geographic regional analyses reveal numerically longer OS with nab-P + Gem vs Gem alone and variable outcomes by region; however, the differences do not support the trend observed in the ITT population, potentially due to limited sample sizes. Registration: EudraCT (2013-003398-91). Clinical trial information: NCT01964430 . [Table: see text]
Neoadjuvant chemotherapy plus surgery for high-risk advanced gastric cancer: Long-term results of KDOG1001 trial.
Authors: Hosoda Kei , Azuma Mizutomo , Katada Chikatoshi , Ishido Kenji , Niihara Masahiro , Ushiku Hideki , Sakuraya Mikiko , Washio Marie , Wada Takuya , Watanabe Akinori , Koizumi Wasaburo , Tanabe Satoshi , Yamashita Keishi , Hiki Naoki
Published: May 2020

4521

Background: In the phase 2, open-label, KDOG1001 (UMIN000003642) study, neoadjuvant chemotherapy (NAC) with docetaxel, cisplatin, and S-1 (DCS), followed by gastrectomy with D2 lymph node dissection for high-risk advanced gastric cancer showed feasibility of DCS therapy with an enough R0 resection rate of 90%. Here we present long-term results after a minimum follow-up of 3 years. Methods: Patients with bulky node metastasis (bulky N), linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) received up to four 28-day cycles of DCS neoadjuvant chemotherapy (docetaxel at 40 mg/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 lymphadenectomy. This analysis presents the final preplanned assessment of outcomes after 3 years. Primary endpoint was R0 resection rate. Secondary endpoints included overall survival (OS), progression free survival (PFS), completion rate of the protocol treatment, and pathological response rate (pRR) of DCS NAC. Results: Of 40 patients enrolled from May 2010 through January 2017, 7 (17.5%) had bulky N, 18 (45.0%) had type 4, and 16 (40%) had large type 3 with 1 (2.5%) having both large type 3 and bulky N2. All included patients underwent preoperative DCS chemotherapy followed by surgery with D2 lymphadenectomy with 32 (80%) completed postoperative S-1 therapy for 1 year. After a median follow-up for surviving patients of 67 mo (range, 36 mo to 110 mo) at the last follow-up in January 2020, 3-year OS was 78% [95% confidence interval (CI) 62–88%], while 3-year PFS was 63% (95% CI 47–76%). Completion rate of the protocol treatment was 62.5% (25/40) with pRR of 57.5% (23/40). In bulky N2, 3-y OS was 86% and 3-y PFS was 71% with pRR of 100%. In type 4, 3-y OS was 67% and 3-y PFS was 50% with pRR of 44%. In large type 3, 3-y OS was 88% and 3-y PFS was 75% with pRR of 56%. Patients with type 4 had significantly worse OS and PFS than those with the other types [HR 7.20 (95% CI 2.23–32.21) and HR 3.00 (95% CI 1.21–8.19)]. Conclusions: Preoperative chemotherapy with up to four cycles of DCS followed by gastrectomy plus adjuvant S-1 therapy is a promising treatment strategy for patients with bulky node metastasis, type 4 and large type 3 gastric cancers. For type 4 cancer, further improvement of treatment strategy is needed. Clinical trial information: 000003642 .
HX008, an anti-PD1 antibody, plus irinotecan as second-line treatment for advanced gastric adenocarcinoma: A phase II clinical trial.
Authors: Song Yan , Li Ning , Mu Lan , Zhang Shu , Fan Qingxia , Liang Xinjun , Yin Xianli , Zhuang Zhixiang , Liu Yunpeng , Zhang Jingdong , Kou Xiaoge , Zhong Haijun , Huang Jing
Published: May 2020

4524

Background: Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We investigated HX008, an Anti-PD1 Antibody, with irinotecan in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and/or fluoropyrimidine. Methods: This study is a multicenter, open, phase II clinical study of recombinant humanized anti-pd-1 monoclonal antibody HX008 injection plus Irinotecan that was conducted at 11 hospitals in China. Eligible patients are adults with histologically confirmed advanced gastric or gastro-oesophageal junction cancer. Subjects participating in this study are required to submit a archived tumor tissue specimen or newly obtained biopsy of tumor lesions at the site of no previous radiotherapy and peripheral blood (2mL) for detection of PD-L1 and MSI/MMR expression. The samples will be tested for expression of PD-L1 and MMR by immunohistochemistry (IHC) in the central laboratory, and MSI levels will be determined by polymerase chain reaction (PCR) and gel electrophoresis. Subjects received PD-1 monoclonal antibody HX008 at 200mg (d1, intravenous drip, once every 3 weeks) plus irinotecan at 160mg/m2 (d1, intravenous drip, 60 ~ 120min, once every 2 weeks). Response was assessed every 6 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. Primary endpoints was objective remission rate (ORR). Results: Between October 2018 and September 2019, a total of 58 patients with advanced gastric or gastro-oesophageal junction cancer were enrolled in this study. Median (range) age was 61 (27-71) years, and most patients were male (72.4%). Among 53 patients who were evaluated, 15 (28.3%) experienced objective response and 22 (41.5%) experienced stable disease (SD). The median progression free survival (PFS) was 5.4 months, the one-year survival rate was 71.3%. The most common treatment-related adverse events of grade 3 or 4 included neutropenia(31.0%), anemia(15.5%), loss of appetite (6.9%), vomiting(5.2%), nausea(3.4%), diarrhea (1.7%) and fatigue (1.7%). There were no treatment-related deaths. Conclusions: HX008 injection plus Irinotecan demonstrated promising activity and manageable safety in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Clinical trial information: NCT03704246 .
The association of tissue tumor mutational burden (tTMB) using the Foundation Medicine genomic platform with efficacy of pembrolizumab versus paclitaxel in patients (pts) with gastric cancer (GC) from KEYNOTE-061.
Authors: Shitara Kohei , Özgüroğlu Mustafa , Bang Yung-Jue , Di Bartolomeo Maria , Mandalà Mario , Ryu Min-hee , Vivaldi Caterina , Olesinski Tomasz , Chung Hyun Cheol , Muro Kei , Van Cutsem Eric , Kobie Julie , Cristescu Razvan , Aurora-Garg Deepti , Lu Jia , Shih Chie-Schin , Adelberg David , Cao Z. Alexander , Fabrizio David , Fuchs Charles S.
Published: May 2020

4537

Background: KEYNOTE-061 (NCT02370498) was a randomized, open-label, phase 3 study of pembrolizumab vs paclitaxel in pts with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma with tumor progression after first-line therapy (N = 592). In this analysis, we evaluated tTMB using FoundationOne CDx (F1CDx; Foundation Medicine) in pts with gastric or GEJ cancer in KEYNOTE-061. Methods: In pts with evaluable F1CDx tTMB data (n = 204), we analyzed the association of tTMB with confirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) within each treatment arm using one-sided (pembrolizumab) and two-sided (paclitaxel) Wald test nominal P for logistic regression (ORR) and Cox proportional hazards regression (PFS; OS) adjusted for ECOG performance status; significance was prespecified at 0.05. The clinical utility of tTMB was assessed using the prespecified cutoff of 10 mut/Mb for F1CDx. Clinical data cutoff: Oct 26, 2017. Results: tTMB was positively associated with ORR ( P < 0.001; AUROC, 0.68), PFS ( P < 0.001), and OS ( P = 0.003) with pembrolizumab but not paclitaxel (ORR, P = 0.047; AUROC, 0.30; PFS, P = 0.605; OS, P = 0.084). Pt outcomes by tTMB cutoff are reported in the Table; prevalence of TMB ≥10 mut/Mb was 17%. In pts with microsatellite stable disease-only, HRs (95% CI) by treatment arm for OS by F1CDx cutoff were 0.40 (0.14-1.17) for tTMB ≥10 mut/Mb (n = 21) vs 0.97 (0.70-1.34) for tTMB <10 mut/Mb (n = 168). Conclusions: In this exploratory analysis from KEYNOTE-061, tTMB as determined by F1CDx demonstrated a positive association with clinical outcomes with pembrolizumab, but not paclitaxel, in pts with GC; these findings are consistent with those reported with whole exome sequencing. Pembrolizumab demonstrated an OS benefit vs paclitaxel in the subgroup with tTMB ≥10 mut/Mb, which remained when pts with microsatellite instability-high disease were excluded. Clinical trial information: NCT02370498 . [Table: see text]
PILGRIM: Phase III clinical trial in evaluating the role of hyperthermic intraperitoneal chemotherapy for locally advanced gastric cancer patients after radical gastrectomy with D2 lymphadenectomy(HIPEC-01).
Authors: Cui Shu-zhong , Liang Han , Li Yong , Zhou Yanbing , Tao Kaixiong , Zhou Zhiwei , Li Guoxin , Li Peiyu , Zhou Baojun , Yao Hongliang , Peng Zheng , Xiong Bin , Pang Minghui , Cai Shirong , Li Yong , Wan Jin , Liang Bin , Lei Ziying , Wang Jiping ,   Chinese Peritoneal Oncology Study Group
Published: May 2020

4538

Background: Gastric cancer remains the 3rd leading cancer related death worldwide due to early disease recurrence. We hypothesize that hyperthermic intraperitoneal chemotherapy (HIPEC) may effectively prevent local regional recurrence for locally advanced gastric cancer patients who received curative intent surgery. Methods: Pathology proven gastric cancer patients with clinical T3/T4NxM0 disease are eligible for the study and will be randomized to either control group, who will receive standard radical gastrectomy and D2 lymph node dissection or HIPEC group, who will receive the same surgery and HIPEC with paclitaxel x 2 within the first week after surgery. All patients will receive either XELOX or SOX adjuvant chemotherapy. The primary end point is overall survival. Results: 648 patients from 16 high volume gastric medical centers were enrolled between May, 2015 and March, 2019. 331 and 317 patients were randomized to control and HIPEC groups respectively. The median follow-up time is 12.1 months. The common grade 3/4 toxicities ( > 5%) in control and HIPEC groups are anemia 6% vs. 4.1%, intraabdominal infection 5.4% vs. 3.8%, pneumonia 9.7% vs. 9.8%, fever 10.6% vs. 11.4% and hypoalbunemia 15.1% vs. 16.7% respectively. All three perioperative death (within 30 days after surgery) occurred in control group. One patient died from duodenum stump leak which led to multiple organ failure. One patient died from anastomotic led to intraabdominal infection and shock. The 3rd death was suicide caused by severe depression. At the time of this report, the number of event has not reached for final efficacy analysis. Conclusions: It is safe to administer HIPEC to patients received radical gastrectomy with D2 lymph node dissection within one week of surgery. The primary analysis will be expected in one year. Clinical trial information: NCT02356276 .
Durvalumab following multimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Updated survival and early translational results from Big Ten Cancer Research Consortium Study.
Authors: Mamdani Hirva , Schneider Bryan J. , Kasi Pashtoon Murtaza , Abushahin Laith I. , Birdas Thomas J. , Kesler Kenneth , Burney Heather , Perkins Susan , Jalal Shadia Ibrahim
Published: May 2020

4572

Background: Concurrent chemoradiation(CRT) followed by esophagectomy is a standard of care for locally advanced esophageal(LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients(pts) experience disease relapse within the 1st yr after treatment(tx) completion. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown radiation +/- chemotherapy upregulates PD-1/PD-L1 pathway. Methods: We conducted a phase II trial evaluating safety and efficacy of PD-L1 inhibitor durvalumab(durva) in pts with LA-EAC and GEJ adenocarcinoma who had residual disease in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: Initially 24 pts were enrolled, study was expanded to enroll additional 13 pts. Median age: 61yrs (range, 43-73). 31 received carbo/paclitaxel and 6 received cis/5-FU concurrently with RT. 24(64.9%) pts had positive lymph nodes(LN) at the time of surgery following CRT: N3(n = 3,8.1%), N2(n = 10, 27%), N1(n = 11,29.7%).17 pts relapsed: 11 on tx, 6 had late relapses. 3/5 late relapses were locoregional and were re-treated with chemo-RT. Remaining relapses were systemic with lung and LN being the most common sites. 2 of 3 pts who developed grade 3 irAEs are alive and disease free at 17 and 23 mo. RFS/OS:1 yr- 79.2%/95.5%, 2yr-55.5%/67.4%. 20/37 pts have HER-2 status available: 5/6 HER2 positive pts had disease relapse, 1 is undergoing tx. Molecular profiling is available on 8 relapsed pts: all were microsatellite stable with low TMB and PD-L1 < 10% CPS. Mutations in DNA repair genes ( ARID1A, ATM, ATR, CHEK2), and PIK3CA E542K were more prevalent among late relapsing pts. Circulating tumor cells (CTCs) analysis is available for 10/37 pts. 4/5 pts where CTCs increased from C1 to C4 had disease relapse. Molecular profiling of the remaining pts and correlation of PD-L1 expression, TMB, specific genes mutations, CTCs, and Immunoscore with outcomes with durva is being evaluated will be presented at the meeting. Conclusions: Adjuvant durva following trimodality therapy for LA-EAC and GEJ adenocarcinoma improved 1-yr RFS to 79.2% compared to historical rate of 50%.2-yr RFS and OS data are encouraging in this high risk pt population. HER-2 positivity may be associated with lack of benefit from durva. Mutations in DNA repair genes are prevalent in pts with delayed relapse. Rise in CTCs during durva tx may be an early marker of disease relapse. Clinical trial information: NCT02639065 .
A multicenter nonrandomized controlled trial to evaluate the efficacy of surgery versus radiofrequency ablation for small hepatocellular carcinoma (SURF cohort trial).
Authors: Tateishi Ryosuke , Hasegawa Kiyoshi , Kawaguchi Yoshikuni , Takayama Tadatoshi , Izumi Namiki , Yamanaka Naoki , Kudo Masatoshi , Shimada Mitsuo , Inomata Masafumi , Kaneko Shuichi , Koike Kazuhiko , Omata Masao , Makuuchi Masatoshi , Matsuyama Yutaka , Kokudo Norihiro
Published: May 2020

4581

Background: In parallel with a multicenter randomized controlled trial that reported an equal recurrence-free survival (RFS) of early-stage hepatocellular carcinoma (HCC) patients who underwent either surgery (SUR) or radiofrequency ablation (RFA), we also enrolled HCC patients who fulfilled the enrollment criteria but did not give consent to participate in the RCT. Methods: All patients gave informed consent to participate in this study. Inclusion criteria were as follows: primary HCC with less than or equal to 3 tumors, each measuring 3 cm or smaller; without vascular invasion or extrahepatic metastasis; Child-Pugh score of 7 or less; and ages between 20 and 79 years. The feasibility for both treatments was confirmed by a joint chart review by surgeons and hepatologists. The primary endpoint was RFS and overall survival. A pre-specified interim analysis was performed to compare RFS. Results: Between April 2009 and August 2015, 740 patients (371 in SUR, 369 in RFA) were enrolled from 49 participating hospitals in Japan. The SUR group had significantly fewer patients with chronic hepatitis C (56.6% vs. 69.4%), higher median value of platelet count (145 vs. 120 × 109/L), and more patients with > 2 cm tumors (49.9% vs. 27.9%); most patients had a single tumor (91.1% vs. 88.3%). During the median follow-up period of 5 years, tumor recurrence was observed in 192 of SUR and 218 of RFA with 3-year RFS being 66.0% and 61.7%, respectively ( P = 0.091). In subgroup analysis, RFS was significantly better in SUR in patients with ≤ 2 cm tumors (62.9% vs. 51.7% in 3 years; hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.56-0.93; P = 0.014), whereas the difference was not significant in those with > 2 cm tumors (52.7% vs. 46.4%; HR 0.85, 95% CI 0.63-1.18; P = 0.34). The adjusted HR for RFS using inversed probability of treatment weighting was 0.89 (95% CI, 0.72-1.10; P = 0.287). Conclusions: The imbalance in patient characteristics reflected a real-world practice. Factors related to background liver disease rather than tumor characteristics might have a larger impact on the recurrence in early HCC. Clinical trial information: C000001796 .
Genome-wide plasma cell-free DNA methylation profiling to identify high-performing biomarkers for early detection of hepatocellular carcinoma.
Authors: Yang Xin-Rong , Huang Ao , Wang Yuying , Peng Jiaxi , Jiang Ruijingfang , Li Zhilong , Jie Yuan , Fan Jia , Zhou Jian
Published: May 2020

4600

Background: Hepatocellular carcinoma (HCC) represents the second most common cause of cancer deaths worldwide. □-fetoprotein (AFP) is the most common serological test used for screening and diagnosis of HCC. However, it is widely recognized that AFP has lower sensitivity with sub-optimal specificity. Tumor-originated circulating cell-free DNA (cfDNA) provides new opportunity for non-invasive detection of liver cancer. Methods: HCC-specific differentially methylated regions (DMRs) were identified by whole genome bisulfite sequencing (WGBS) in 44 pairs of HCC tissues and adjacent tissues. We then performed methylome profiling on cfDNA from HCC patients and healthy individuals by targeted bisulfite sequencing covering genome-wide CpG islands, shelves, and shores. We employed machine learning approaches to build diagnostic models based on cfDNA regional methylation level to classify the plasma of HCC (n = 140) from that of healthy individuals (n = 84). Further analyses were performed in the validation cohort, including 155 HCC patients, and a control group with 96 healthy individuals, 21 chronic hepatitis B infection (CHB)/liver cirrhosis (LC) patients and 34 patients with benign hepatic lesions (BHL). Area under the receiver operating characteristic curve (AUC-ROC) was used to evaluate diagnostic performance. Results: A random forest classifier achieved an AUC of 0.97 (sensitivity: 92.9%; specificity: 89.4%) with 10-fold cross-validation using a panel of 39 DMR markers. The AUC of the diagnostic panel was 0.93 (sensitivity: 81.3%; specificity: 90.7%) in validation cohort, and it performed equally well in detecting BCLC stage 0+A (AUC = 0.90; sensitivity: 74.7%) and AFP negative (AUC = 0.92; sensitivity: 79.4%) HCC, as well as differentiating HCC from CHB/LC and BHL. Based on these results, we have further developed a small targeted bisulfite sequencing panel covering 127 CpG sites for non-invasive diagnosis of HCC. The panel had similar performance in training and validation cohorts, an AUC of 0.96 (sensitivity: 90.7%, specificity: 88.2%) in the training set, and 0.91 (sensitivity: 80.0%, specificity: 88.7%) in the validation set. Conclusions: Our diagnostic panel with 39 DMR markers showed high sensitivity and specificity in HCC diagnosis as well as surveillance in high-risk populations for developing HCC. More importantly, simple diagnostic model show similar diagnostic performance for early HCC diagnosis, which was easily to transfer to clinical application in the future.
Health-related quality-of-life results from SANET-ep: A phase III study of surufatinib versus placebo for advanced extrapancreatic neuroendocrine tumors.
Authors: Bai Chunmei , Xu Jianming , Shen Lin , Li Jie , Zhou Zhiwei , Chi Yihebali , Li Zhiping , Xu Nong , LI Enxiao , Liu Tianshu , Bai Yuxian , Yuan Ying , Li Xingya , Wang Xiuwen , Chen Jia , Ying Jieer , Li Jing , Fan Songhua , Peng Mengye , Su Weiguo
Published: May 2020

4613

Background: In the phase 3 study (SANET-ep, NCT02588170), surufatinib significantly prolonged progression free survival compared with placebo in patients with progressive, well-differentiated advanced extrapancreatic neuroendocrine tumors (epNETs) (ESMO 2019 Abs. LBA76). Here, we report the results of health-related quality-of-life (HRQoL) from this study. Methods: Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo, 300 mg, orally, once daily, until disease progression or intolerable adverse events. Patient-reported outcome questionnaires, including the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the QLQ-G.I.NET-21, were collected at baseline, Day 15 of the first cycle (28 Days/cycle), and Day 1 of every cycle thereafter and at discontinuation. Time until definitive deterioration (TUDD) was defined as time from randomization to deterioration of 10 points in domain score compared with baseline score (without subsequent observations of deterioration of less than 10 point or any improvement as compared to baseline score), or death due to any cause. TUDD and mean change from baseline based on a longitudinal repeated measures analysis of each domain were analyzed retrospectively. Significance testing was at two-sided 0.05 without adjustment for multiplicity. Results: Of 198 pts randomized (surufatinib n = 129; placebo n = 69), 197 (99.5%) patients completed HRQoL questionnaires at baseline. The questionnaire compliance rate was >90% for most on-treatment assessments. The TUDD was significantly longer in the surufatinib arm versus the placebo arm in the dyspnea domain (hazard ratio [HR] 0.52, p = 0.0103) and social function scale (HR 0.58, p = 0.0222), while the TUDD of diarrhea was significantly shorter in the surufatinib arm compared to placebo (HR 2.68, p = 0.0074). There was no significant difference of TUDD in the remaining domains of QLQ-C30 and G.I.NET-21. There was also no significant difference of the mean change of scores from baseline by repeated measures in the domains between the two arms except diarrhea (increase of 14.0 points [95% CI 9.6, 18.4] in the surufatinib arm versus 2.1 points [95% CI -4.1, 8.4] in the placebo arm, p = 0.0007). Conclusions: Treatment with surufatinib resulted in superior efficacy, acceptable toxicity, while generally maintaining HRQoL, which support surufatinib as a treatment option in this patient population that was previously treated with available therapies for epNETs. Clinical trial information: NCT02588170 .
Circulating tumor DNA is prognostic and potentially predictive of eryaspase efficacy in patients with advanced pancreatic adenocarcinoma.
Authors: Bachet Jean-Baptiste , Blons Helene , Hammel Pascal , El Hariry Iman , Portales Fabienne , Mineur Laurent , Metges Jean-Philippe , Mulot Claire , Bourreau Camille , Cain Jason , Cros Jerome , Laurent-Puig Pierre
Published: May 2020

4617

Background: Eryaspase is composed of L-asparaginase encapsulated in erythrocytes. It has demonstrated significant efficacy in combination with chemotherapy in a randomized phase 2 trial in second-line in patients with advanced pancreatic adenocarcinoma. We assessed, in this study, the prognostic and predictive value of circulating tumor DNA (ctDNA) in plasma samples of patients included in the eryaspase phase 2 trial. Methods: Samples prospectively collected pre-treatment at each 28-day cycle were centrally analyzed by next-generation sequencing (BPER method). Prognostic values of baseline ctDNA and ctDNA early changes between day 0 and 28 were assessed in both arms combined on objective response rate (ORR), progression free survival (PFS) and overall survival (OS). We conducted interaction test between ctDNA positivity and treatment arm, and the predictive value of ctDNA for eryaspase efficacy was investigated. Results: Patients with at least one available plasma sample have been included (n = 122/141). The presence of ctDNA at baseline was identified in 68% (77/113) of patients and was an independent negative prognostic factor for OS (4.6 vs 8.8 months; p = 0.0025) and PFS (1.6 vs 3.3 months; p = 0.00043). Early change in ctDNA levels was assessed by separating patients into three categories (one without detectable ctDNA, and two according to radio median value between day 0 and day 28) that were significantly correlated with ORR, PFS and OS. A significant interaction was observed between the presence of ctDNA and eryaspase efficacy. In patients with ctDNA detectable at baseline, eryaspase was associated with better PFS (HR = 0.53; 95% CI: 0.3-0.94) and OS (HR = 0.52; 95% CI: 0.29-0.91). Conclusions: We confirm from a prospective randomized trial that 1/ the presence of ctDNA at baseline is a major prognostic factor, 2/ the early change of ctDNA correlates with treatment outcome and 3/ the ctDNA could be a predictive biomarker of eryaspase efficacy. Clinical trial information: NCT02195180 .