bluuebunny/crossref_metadata_2025_split huggingface dataset:
Doublet (FOLFOX or FOLFIRI) versus triplet (FOLFOXIRI) backbone chemotherapy regimen as first-line treatment of metastatic colorectal cancer: A meta-analysis and systematic review.
Authors: Jindal Vishal , Gupta Ruby , Sahu Kamal Kant , Rahi Mandeep Singh , Stender Michael J. , Jaiyesimi Ishmael A. 
Published: June 2021

3593 Background: Doublet chemotherapy FOLFOX and FOLFIRI are standard for first‐line treatment of metastatic colorectal cancer (mCRC). Recently, use of triplet chemotherapy FOLFOXIRI has shown an increased anti-cancer activity but still there is uncertainty regarding first line backbone chemotherapy. Therefore, we conducted this metanalysis to determine the efficacy, safety and outcome of triplet vs doublet chemotherapy. Methods: The study protocol was published at PROSPERO (CRD42020166745) and prepared as per PRISMA guidelines. Total 10 studies were included, with sample size of 1536 participants in triplet arm and 1535 participants in doublet arm. The primary outcome is Response rate (RR) and secondary outcomes are Progression-free survival (PFS), Overall survival (OS), post chemotherapy radical (R0) surgical resection rate of metastases. Quantitative synthesis was performed using “R” statistical package. Dichotomous outcomes were summarized using odds ratio (OR) and time to event data was summarized using hazard ratio (HR). Results: A total of 678 articles were retrieved. The Medline article search gave a result of 271 article, Embase 296, the Cochrane Library 100 and Clinical tral.gov 11, when searched through April 2020. Total 10 studies were included. All the studies were randomized, open-label, multicenter study. Out of the 10 trials 5 each were phase II and phase III studies. The pooled odds ratio for RR was 1.66 (95% CI 1.42 to 1.93) and PFS was (HR, 0.70; 95% CI, 0.63–0.78) in favor of triplet chemotherapy. There was significant improvement in radical resection (R0) of metastases (OR 1.59; 95% CI, 1.27–1.98) in triplet arm. Triplet arm was also associated with increased toxicity especially neurological events 2.51(0.88-7.16), diarrhea 2.40(1.74-3.31), neutropenia, 2.23(1.71-2.90) and thrombocytopenia 1.94(1.05-3.59). Conclusions: Findings in this meta-analysis showed that FOLFOXIRI significantly improves the PFS, RR, OS, and R0 resection rate of overall metastases over the doublet chemotherapy. The incidence of fatal adverse events was found to be more in triplet chemotherapy compared to doublet therapy. Therefore, we concluded that with moderate evidence FOLFOXIRI provide clinically meaningful efficacy benefit at cost of increased toxicity.[Table: see text]
Long-term outcome of a phase III trial on neoadjuvant chemoradiation with capecitabine and irinotecan in patients with locally advanced rectal cancer: Updated results of the CinClare trial.
Authors: Zhu Ji , Sun Xinchen , Liu Anwen , Zhu Yaqun , Zhang Tao , Liu Luying , Jia Jianhui , Tan Shisheng , Wu Junxin , Wang Xin , Zhou Juying , Yang Jialin , Zhang Chen , Zhang Hongyan , He Xinjia , Cai Gang , Zhang Wei , Cai Sanjun , Zhang Zhen 
Published: June 2021

3603 Background: Adding UGT1A1-guided irinotecan to capecitabine-based neoadjuvant chemoradiotherapy (CRT) significantly increased the pathological complete response (pCR) rate nearly doubling [J Clin Oncol. 2020 Dec 20;38(36):4231-4239]. Here, results of long-term outcome are reported. Methods: Eligible patients with clinical stage II/III rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomized to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by a cycle of oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with *1*1 or 65 mg/m2 for patients with *1*28, followed by a cycle of irinotecan and capecitabine. Surgery was scheduled for 8 weeks after completion of CRT. Five cycles of adjuvant XELOX chemotherapy were administered regardless of the pathologic result. Patients were stratified by UGT1A1 genotype (*1*1 vs. *1*28) clinical T stage (cT3 vs. cT4) and tumor distance from the anal verge (≤5 cm vs. > 5 cm). The primary end point of pCR was reached. Survival time was calculated from the date of randomization to the date of event or the last follow-up. Secondary endpoints were defined as local failure for local control (LC), tumor recurrence or death from any cause for disease-free survival (DFS), and death from any cause for overall survival (OS). Results: Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). A total of 311 patients underwent surgery and pCR was achieved in 80 patients, another 10 patients undergo a watch-and-wait approach after achieving cCR. With a median follow-up time of 48 months (Q25-Q75, 41-55 months), 57 deaths (33 and 24), 17 local failures (11 and 6) and 69 distant metastases (37 and 32) were observed, respectively. Overall, the 4y LC rate were 93% and 96% in control and experimental groups, with estimated LC HR of 0.53 (95% confidence interval [CI], 0.20-1.43), the 4y DFS rates were 69% and 74% (HR = 0.74, 95% CI 0.49-1.10), and the 4y OS were 80% and 85%, (HR = 0.70, 95% CI 0.42-1.19), respectively. In the subgroup analysis, irinotecan showed a significant improvement in DFS (HR = 0.77, 95% CI 0.61-0.98) and OS (HR = 0.71, 95% CI 0.51-0.98) in UGT1A1 *1*1 patients. Conclusions: The addition of irinotecan to standard capecitabine-based CRT had a tendency towards improving LC, DFS, and OS, but without reaching statistical significance. UGT1A1 *1*1 patients seem to benefit the most from irinotecan. Molecular studies and subsequent therapies should be considered. Clinical trial information: NCT02605265.
Influence of preoperative chemoradiation on tumor-infiltrating lymphocytes in locally advanced rectal cancer: The STAR-01 cohort.
Authors: Negri Francesca , Gnetti Letizia , Bottarelli Lorena , Campanini Nicoletta , Negru Maria Emanuela , Bergamo Francesca , Siena Salvatore , Frisinghelli Michela , Petric Marija , Chiaulon Germana , Smiroldo Valeria , Corsi Domenico C. , Vita Giulia Anna Carmen , Silini Enrico Maria , Azzoni Cinzia , Gaiani Federica , Laghi Luigi , de'Angelis Gian Luigi , Boni Luca , Aschele Carlo 
Published: June 2021

3611 Background: Preoperative chemoradiotherapy may increase antitumor immunity through enhancing T-cell activation and tumor infiltration. These effects could possibly sensitize tumors to immunotherapies, including checkpoint inhibitors. We explored whether preoperative chemoradiation for locally advanced rectal cancer induces immunologic changes and if the post-operative biological parameters are associated with tumor regression grade (TRG sec. Ryan –AJCC Eight ed.). Methods: The multicenter STAR-01 study compared a standard preoperative chemoradiotherapy regimen (50.4 Gy in 28 daily fractions with concomitant infused fluorouracil at the dose of 225 mg/m2/d) with the same regimen plus oxaliplatin given weekly at the dose of 60 mg/m2 in patients with locally advanced rectal cancers. Paired pre- and post-operative specimens were available for 58 patients from this trial and were analyzed by immunohistochemistry. The immunoistochemical analysis was performed with a panel of immune cells and associated factors as CD3, CD20, CD4/CD8, PD1. The pattern of tumor infiltrating lymphocytes (TILs) and related infiltrating lymphocytes (RILs) was also evaluated. Response to pre-operative chemoradiotherapy was assessed according to TRG. Results: After therapy we observed a decreased CD4/CD8 ratio (p < 0.001) and reduced expression level of CD20 (p < 0.001). The expression level of CD3+ and PD-1+ cells after therapy did not change significantly. The relative increase of lymphocytes CD8+ inside CD4/CD8 ratio evaluated on post-operative samples was significantly associated with TRG 0 (p < 0.001). Conclusions: Our data suggest that chemoradiation may induce an enrichment of CD8+ T lymphocytes and this translates in better response to chemoradiation. The new frontier of best treatment could be the use of specific immune cells (T lymphocytes) to trigger the system's immune response against disease.
Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): Expanded efficacy and safety analyses from CheckMate 577.
Authors: Kelly Ronan Joseph , Ajani Jaffer A. , Kuzdzal Jaroslaw , Zander Thomas , Van Cutsem Eric , Piessen Guillaume , Mendez Guillermo , Feliciano Josephine Louella , Motoyama Satoru , Lièvre Astrid , Uronis Hope Elizabeth , Elimova Elena , Grootscholten Cecile , Geboes Karen Paula , Zhang Jenny , Soleymani Samira , Lei Ming , Singh Prianka , Cleary James M. , Moehler Markus H. 
Published: June 2021

4003 Background: In CheckMate 577 (NCT02743494), NIVO demonstrated a significant and clinically meaningful improvement in disease-free survival (DFS; primary endpoint) vs placebo (PBO) and was well tolerated in patients (pts) with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease. Median DFS doubled with NIVO vs PBO (22.4 vs 11.0 months; HR 0.69; 96.4% CI 0.56–0.86; P = 0.0003). Serious treatment-related adverse events (TRAEs) and TRAEs leading to discontinuation were reported for < 10% of pts with NIVO and 3% with PBO. Methods: Pts were randomized 2:1 to NIVO 240 mg or PBO Q2W for 16 weeks, followed by NIVO 480 mg or PBO Q4W. Here, we present additional efficacy, safety, and quality-of-life (QoL) data from CheckMate 577. Results: 794 pts were randomized (NIVO, 532; PBO, 262). Distant recurrence was reported for 29% vs 39% and locoregional recurrence for 12% vs 17% of pts in the NIVO vs PBO groups, respectively. Median distant metastasis-free survival was 28.3 vs 17.6 months with NIVO vs PBO (HR 0.74; 95% CI 0.60–0.92). Median progression-free survival 2 (PFS2; time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier) was not reached with NIVO vs 32.1 months with PBO (HR 0.77; 95% CI 0.60–0.99). TRAEs with potential immunologic etiology (select TRAEs; sTRAEs) reported for NIVO are presented in the table. Results for the FACT-ECS and FACT-G7 showed similar trends for QoL improvement from baseline for NIVO and PBO during treatment and maintained benefit post-treatment. Conclusions: Adjuvant NIVO demonstrated clinically meaningful efficacy, an acceptable safety profile, and maintained QoL, providing further support for its use as a new standard of care for pts with resected EC/GEJC who received neoadjuvant CRT with residual pathologic disease. Clinical trial information: NCT02743494. [Table: see text]
Multicenter, randomized phase II study of neoadjuvant pembrolizumab plus chemotherapy and chemoradiotherapy in esophageal adenocarcinoma (EAC).
Authors: Shah Manish A. , Almhanna Khaldoun , Iqbal Syma , Thakkar Prashant , Schneider Bryan J. , Yantiss Rhonda , Wu Yiru , Futamura Emma , Port Jeffrey L. , Spinelli Cathy , Sarkar Sandipto , Christos Paul J. , Brar Gagandeep , Betel Doron , Sanfilippo Nicholas J. , Altorki Nasser K. 
Published: June 2021

4005 Background: Recent transformative studies in the treatment of EAC support adjuvant nivolumab for patients with residual disease following neoadjuvant chemoradiotherapy (CRT) (Checkmate 577) and pembrolizumab (P) with chemotherapy in untreated metastatic disease (Keynote 590). We hypothesized that pre-operative P combined with CRT can further improve outcomes in patients with locally advanced EAC. Methods: Patients with cT3-4Nx or T2N1 M0 EAC or gastroesophageal junction (GEJ) adenocarcinoma eligible for curative surgery were randomized (1:1) to receive either full-dose paclitaxel (T)/ carboplatin (C) or T/C + P induction therapy. All patients then received CRT with weekly T/C, RT 41.4Gy in 23 fractions, and P every 3 weeks. Following resection, patients received P for one year. The primary endpoint is rate of major pathologic response (MPR), defined as pathologic complete response or near complete response ( < 10% residual cancer), with 80% power and 0.1 one-sided significance level to detect the difference between a MPR proportion of 30% (historical control) and an alternative hypothesis of 47% (with preoperative P). Tissue was collected for tumor immune microenvironment (TIME) analysis including bulk and single cell RNA(scRNA) expression analysis, DNA sequencing, and flow cytometry. Results: From 8/4/17 to 10/26/20, 40 patients were enrolled: median age 68 [38-81], male 32, esophagus/GEJ type I (n = 16), GEJ II/III (n = 24). CRT was well tolerated, with no grade 3-4 adverse events attributed to P. Notable toxicity included grade 3-4 pneumonitis (13%), anastomotic leak (13%), infection (35%). In 31 evaluable patients to date, the MPR rate was 50.0% (95% CI, 32.7%-67.3%). 1-yr disease free survival was 100% for patients with MPR vs. 31.8% without MPR, p = 0.002. Esophageal/GEJ type I cancers had a significantly higher MPR rate when compared with GEJ type II/III (76.9% vs 37.5%, p = 0.03). scRNA seq on > 100,000 tumor cells revealed EAC/GEJ type I had higher infiltration of activated dendritic cells (p = 0.12), whereas GEJ tumors have significantly higher infiltration of activated B cells (p = 0.02). Conclusions: The addition of P to preoperative CRT for EAC is safe and associated with a significantly higher MPR rate compared to historical data. We found MPR to be significantly enriched in EAC/GEJ type I tumors compared with GEJ II/III, associated with important differences in the baseline tumor immune microenvironment. Clinical trial information: NCT02998268.
IDH1 and IDH2 Driven Intrahepatic Cholangiocarcinoma (IHCC): A comprehensive genomic and immune profiling study.
Authors: Makawita Shalini , Borad Mitesh J. , Carapeto Fernando , Kwong Lawrence , Bekaii-Saab Tanios S. , Murugesan Karthikeyan , Ross Jeffrey S. , Danziger Natalie , Israel Mason A. , McGregor Kimberly , Janku Filip , Javle Milind M. 
Published: June 2021

4009 Background: IDH1/2 genetic aberrations (GA) occur in 20% of IHCC cases and may be specifically targeted by IDH inhibitors. The genomic and immunologic profile of IHCC with IDH1/2 GA remains undefined. IDH1 mutations impair DNA damage repair (DDR), loss of heterozygosity (LOH) and may represent a biomarker for DDR in these patients. Methods: Comprehensive genomic profiling (CGP) was performed in 3,067 cases of advanced stage IHCC using a hybrid capture-based FDA-approved assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression in tumor cells (Dako 22C3) was measured by immunohistochemistry (IHC). Genomic LOH (gLOH) was assessed for samples meeting quality criteria. Densities of tumor associated immune cells and immune-checkpoint markers expressed in epithelial malignant cells and in the tumor microenvironment of 100 surgical samples from 96 patients were evaluated by IHC using digital image analysis of 14 markers (CD3, CD4, CD8, CD68, PD1,PD-L1, B7-H4, B7-H3, IDO1, ICOS, VISTA, OX40, TIM3, LAG3). Tissue microarrays were generated for multiplex immune panel analysis. A p value < 0.05 was considered statistically significant. Results: 426 (14%) of IHCC were IDH1+ and 125 (4%) were IDH2+ (Table) and were mutually exclusive. All IDH1 GA occurred at the R132 locus and included R132C (69%) and R132L/G/S/H/F (16%/7%/4%/3%/ < 1%) and 119Q ( < 1%) and IDH2 GA at R172 (94.4%) and R140 (6.6%). IDH1+ and IDH2+ IHCC had fewer co-occurring targetable GA than IDH1/2 wildtype (WT, IDHwt) cases including FGFR2 rearrangements (RE) (P <.0001), ERBB2 (P =.0009) and BRAF (P =.04). Median gLOH were not significantly different between IDH1+ IDH2+ IHCC vs. IDHwt IHCC (p = 0.37). Potential biomarkers of immune checkpoint inhibition (ICI) response including MSI High, TMB > 10 mut/Mb, and PD-L1 positivity were more frequent in IDHwt IHCC than IDH1+ IHCC. 29/96 (30%) surgical patients were positive for IDH1/2 mutation though mutational status did not confer a statistically significant difference in the 14 immune biomarker panel expression. Conclusions: CGP reveals significant differences in GA between IDH1+, IDH2+ and IDHwt IHCC consistent with IDH1 and IDH2 being driver oncogenes for IHCC. Immune biomarker expression and gLOH did not differ significantly between IDH mutated and WT cases.[Table: see text]
Camrelizumab combined with FLOFOX as neoadjuvant therapy for resectable locally advanced gastric and gastroesophageal junction adenocarcinoma: Updated results of efficacy and safety.
Authors: Liu Ying , Han Guangsen , Li Hongle , Zhao Yuzhou , Li Zhi , Zhuang Jing , Wang Gangcheng , Li Baodong , Wang Jinbang , Li Zhimeng , Xia Qingxin , Zhang Chengjuan , Yu Juan , Li Ke , Xu Shuning , Qiao Lei , Kuang Gaizhen , Li Danyang 
Published: June 2021

4036 Background: Although anti-PD-1 antibody in combination with chemotherapy has shown promising antitumor activity in advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), the evidence of neoadjuvant therapy for locally advanced GC/GEJC is limited. Camrelizumab combined FOLFOX as neoadjuvant therapy for resectable locally advanced GC/GEJC was a prospective, single-arm, phase 2 study we conducted. Here, we updated the results of efficacy and safety of this study. Methods: Patients confirmed by endoscopic ultrasonography (EUS) and imaging with clinical stage≥T2 and/or positive lymph nodes were enrolled. They received 4 cycles of camrelizumab (200mg ivgtt on day1, q2w) plus FOLFOX (oxaliplatin 85mg/m2 ivgtt, LV 200mg/m2 ivgtt, 5-Fu 400mg/m2 iv followed by 2.4mg/m2 CIV 46 hours on day 1, q2w) as neoadjuvant therapy. Then patients without disease progression evaluated by imaging underwent gastrectomy of D2 lymph node dissection. The primary endpoint was pCR, the secondary endpoints were R0 resection rate and safety. Results: Between Jul 24 2019 and Nov 30 2020, 49 patients were enrolled. The median age was 57 years (29-72 years). All patients completed 4 cycles treatment. Unfortunately, 2 of them were confirmed PD by imaging. In addition, two patients refused gastrectomy and withdrew from the study. Eventually, 45 patients underwent gastrectomy, of which 3 patients had intraperitoneal metastases during the operation. A total of 42 patients were evaluable, all of them gained R0 resection (100%), 4 patients (10%) achieved pCR and 10 patients (24%) reached TRG1. Among the patients experienced pCR, one of them was Her-2 positive, one was MSI-H, the rest two of them were PD-L1-positive (CPS≥10). The most common ≥grade 3 adverse events (AEs) were neutropenia (35%) and leukopenia (16%). Only 1 patient (2%) experienced grade 3 immune-related AEs of alanine aminotransferase and aspartate aminotransferase increase. No serious AEs resulted in termination of treatment or death. Conclusions: Camrelizumab combined with FOLFOX was an effective and safe neoadjuvant therapy strategy for patients with resectable locally advanced GC/GEJC. Furthermore, the analysis of biomarkers with clinical benefits is undergoing. Clinical trial information: NCT03939962. [Table: see text]
A prospective, phase II, single-arm study of neoadjuvant/conversion therapy with camrelizumab, apatinib, S-1 ± oxaliplatin for locally advanced cT4a/bN+ gastric cancer.
Authors: Li Song , Yu Wenbin , Xie Fei , Liu Zhimin , Lv Weiwei , Shi Duanbo , Yu Dexin , Wei Meng , Wang Jiaqian , Zhao Yongtian , Chen Cheng , Zhao Zhikun , Gao Jing , Sheng Lei , Liu Lian 
Published: June 2021

4061 Background: The prognosis of cT4a/bN+ gastric cancer (GC) is poor due to low R0 resection rate and frequent recurrence. We evaluated the feasibility, safety, and efficacy of a combination of immunotherapy, anti-angiogenesis, and chemotherapy for neoadjuvant/conversion treatment of cT4a/bN+ GC. Methods: Patients with T4a/bN+ GC were enrolled to receive camrelizumab (200mg d1), apatinib (250mg d1-14), S-1 (50mg bid d1-10) ± oxaliplatin (85 mg/m2 d1) for at least 2 cycles, followed by re-evaluation and operation. Peri-treatment samples were collected for whole-exome, transcriptome, and T cell receptor (TCR) sequencing. Pathological response (PR) and its relationship with genomic biomarkers are primary endpoints. Results: 25 patients were enrolled, with median age 63 (48-70), 19 male, 11 cT4aN2-3 and 14 cT4bN2-3. The radiological response (RR) rate of the treatments was 33.3% (8/24), and tumor down-staging rate 79.2% (19/24). 24 patients completed re-evaluation, with 3 failed conversion, 2 refused surgery, and 1 postponed surgery for immune-related pneumonia. Among the 18 patients with R0 resection, 3 got complete PR (CPR), 2 major PR (MPR, ≤10% residual cancer cells), and 3 partial PR (11̃49% residual cancer cells), with a PR rate of 44.4% and MPR+ (MPR & CPR) rate of 27.8%. 62.5% patients with PR and 83.3% patients with RR overlapped with each other. At a median of 12.5 (3.4-19.5) months of follow-up, 13 of 17 patients (76.5%) with R0 resection were recurrence-free. No ≥3 toxicity was found. Besides high microsatellite instability, tumor mutation/neoantigen burden (TMB/TNB), mutation signatures (“DNA damage repair” and “DNA mismatch repair”) and related gene mutations (BRCA2, PRKDC, ATM, POLD1, POLE), several novel driver mutations (SSPO, TRPS1, and DOCK2) and copy number variants (DUSP15 loss, FDFT1 gain, and RBBP8NL loss) were related to MPR+ GC. The combination therapy decreased TMB/TNB, facilitated infiltration of active immune cells (CD4+ memory T, CD8+ T, activated and plasmacytoid dendritic cells, and M1 macrophage), and specifically boosted TCR clonality in MPR+ patients. Besides, numbers of mesenchymal stem cells decreased in MPR+ but increased in MPR- GC after the treatment. Conclusions: Combination of camrelizumab, apatinib, S-1 ± oxaliplatin is feasible, safe, and efficient in neoadjuvant/conversion therapy for cT4a/bN+ GC. It may remodel immune microenvironments and induce anti-tumor immune responses. Clinical trial information: NCT03878472. [Table: see text]