bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network-meta-analysis of chemotherapy in nasopharyngeal carcinoma (MAC-NPC): An update on 8,221 patients.
Authors: Petit Claire , Lee Anne WM , Carmel Alexandra , Ng Wai Tong , Ma Jun , Chan Anthony TC , Hong Ruey-Long , Chen Ming-Yuan , Chen Lei , Zhu Guopei , Li Wen-Fei , Poh Sharon , Ngan Roger , Mai Hai-Qiang , Huang Pei-Yu , Zhang Li , Fountzilas George , Bourhis Jean , Pignon Jean-Pierre , Blanchard Pierre 
Published: May 2020

6523 Background: Based on an individual patient data (IPD) network meta-analysis (NMA) of 20 randomized trials and 5,144 patients (pts), the MAC-NPC collaborative group has shown that the addition of adjuvant chemotherapy (AC) to chemo-radiotherapy (CRT) achieved the highest survival benefit in nasopharyngeal carcinoma (NPC; Ribassin-Majed JCO 2017). Here, we updated the meta-analysis with the addition of 8 trials. Methods: Trials of Radiotherapy (RT) with or without chemotherapy (CT) in patients with non-metastatic NPC were identified and updated IPD obtained. Both Western and Chinese medical literatures were searched. Overall Survival (OS) was the main endpoint. Fixed and random-effects frequentist NMA models were applied, network heterogeneity and consistency were evaluated. P-score was used to rank the treatments. R software - netmeta package was used to perform the analyses. Treatments were grouped in the following categories: RT alone (RT), induction chemotherapy followed by RT (IC-RT), induction chemotherapy without taxanes followed by concomitant chemoradiotherapy (ICtax(-)-CRT), induction chemotherapy with taxanes followed by concomitant chemoradiotherapy (ICtax(+)-CRT), concomitant chemoradiotherapy (CRT), concomitant chemoradiotherapy followed by adjuvant chemotherapy (CRT-AC) and RT followed by adjuvant chemotherapy (RT-AC). Results: Overall 28 trials and 8,214 pts were included. Median follow-up was 7.2 years. There was no heterogeneity in the NMA. There was inconsistency in the main analysis, which disappeared after the exclusion of 2 outlier trials. ICtax(+)-CRT ranked the best treatment for OS with a P-Score of 91%. Hazard ratio [HR, 95% Confidence Interval] for ICtax(+)-CRT was 0.75 [0.59-0.96] compared to CRT and 0.92 [0.69-1.24] compared to CRT-AC (second best treatment in raking with a P-Score of 85%; see league table below). When the 2 types of IC were merged, CRT-AC ranked the first followed by IC-CRT with P-Scores of 93% and 86% respectively, with a HR of 0.97 [0.84-1.14] for CRT-AC vs. IC-CRT. Conclusions: This IPD NMA of the treatment of locally advanced NPC demonstrates that the addition of IC or AC to CRT improves disease control probability and survival over CRT alone. Data on progression-free survival, locoregional and distant control will be presented at the meeting. [Table: see text]
Association between calcitonin and efficacy of anlotinib in medullary thyroid carcinoma: An analysis based on the ALTER01031 trial.
Authors: Gao Ming , Chi Yihebali , Tang Pingzhang , Xu Zhengang , Zheng Xiangqian , Li Dapeng , Chen Xiaohong , Ge Minghua , Zhang Yuan , Guo Zhuming , Wang Jun , Chen Jie , Zhang Jiewu , Cheng Ying , Li Zhendong , Liu Hui , Qin Jianwu , Zhu Jingqiang , Cheng Ruochuan 
Published: May 2020

6526 Background: Calcitonin (Ct) is the most important biomarker for medullary thyroid carcinoma (MTC). In a randomized, placebo-controlled phase IIb trial (ALTER01031, NCT02586350) for MTC, anlotinib exhibited a strong capability not only in PFS prolongation but also in decreasing Ct level. This subanalysis explored the relationship between Ct level and anlotinib efficacy in this trial. Methods: Serum Ct of patients (pts) were tested at baseline and on week 6 (after 2 treatment cycles). Correlation between changes in Ct level and changes in target lesion diameters was explored. The influence of baseline Ct level on median PFS for anlotinib treated pts was estimated. Finally, pts in anlotinib arm were divided into two subgroups based on the percentage decline of Ct levels (> 50% vs. ≤50%) at week 6. Median PFS (mPFS), median OS (mOS) and objective response rate (ORR) of two groups were compared. Results: 86 of 91 enrolled pts (58 in anlotinib arm and 28 in placebo arm) were recorded their serum Ct levels at baseline and no significant difference was observed between two arms (7990.0 ng/L vs. 10891.5 ng/L, P = 0.192). After 2 treatment cycles, the Ct level decreased to 4597.5 ng/L in anlotinib arm (n = 50) while increased slightly in placebo arm (12640.0 ng/L, n = 24, P = 0.006). For 49 pts in anlotinib arm who had complete assessments at baseline and week 6, roughly linear relationship was observed between Ct levels (X-axis) and target lesion diameters (Y-axis) in percent changes from baseline to week 6 (y = 0.175x – 0.049; r = 0.352, P = 0.016, excluding 3 outliers). Pts with less baseline Ct level (≤ median value vs. > median value) did not show more PFS benefit (17.7 vs. 22.4 months, P = 0.802). However, after 2 treatment cycles, a trend of better survival and higher response was observed in pts with high percentage decline of Ct level (> 50%, n = 25) than those with low percentage decline (≤50%, n =25) although without statistical difference (data presented in the table below). Conclusions: In ALTER01031, anlotinib showed a strong capability in rapidly decreasing serum Ct. Lower baseline Ct level does not mean better prognosis while a rapid Ct decrease may predict improved survival and treatment response to MTC pts received anlotinib. Clinical trial information: NCT02586350 . [Table: see text]
A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients.
Authors: van Boxtel Wim , Uijen Maike , Driessen Chantal , Pegge Sjoert , Willems Stefan M. , Jonker Marianne , Dijkema Tim , van Engen - van Grunsven Ilse , Van Herpen Carla M.L.- 
Published: May 2020

6529 A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients. Background: Because c-MET and VEGFR are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in recurrent/metastatic (R/M) SGC pts. Methods: A single center, single arm, phase II study was conducted. Immunohistochemical c-MET positive (H-score ≥10) R/M SGC pts were included in 3 cohorts: adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), and other SGCs. Objective growth or complaints due to the disease were required before inclusion in the ACC and other SGC cohort. No prior systemic treatments were required. Pts started 60 mg cabozantinib tablets OD. Primary endpoint was the objective response rate (ORR). A Simon two-stage design was used. In case of ≥1 objective response in the first 9 pts/cohort, 8 additional pts would be included in the cohort. Results: In total 25 pts were included from Sep. 2018 until premature closure due to severe toxicity in Nov. 2019. Median age was 56 years (range 49-72), prior treatments included: primary tumor resection ( n=19), radiotherapy ≥50Gy ( n=24), systemic therapy ( n=10; adjuvant in 2 pts, palliative in 8 pts). Six pts had grade 3 ( n=4), grade 4 ( n=1), or grade 5 ( n=1) wound/fistula complications, occurring at a median of 7.2 mths on cabozantinib (range 2.1-12.8). This resulted in a severe wound complication rate of 32% in 19 pts on treatment for ≥2 mths. Remarkably, 4 out of 6 pts developed this complication in the area exposed to high-dose Rx; 2/4 had a pre-existing fistula in this area. Median interval between Rx and start of cabozantinib was 71.3 mths (range 10.6-94.7). Other grade ≥3 adverse events in >1 pt were: hypertension (5 pts), diarrhoea (2 pts) and dehydration (2 pts). Current median follow-up is 6.8 mths. The ORR was 6% (1/17 pts) in the ACC cohort, 20% (1/5 pts) in the SDC cohort, and 0% (0/3 pts) in other SGC pts; median PFS is 12.6 mths (95% CI 6.8 – 18.4 mths), 9.0 mths (insufficient events for 95% CI), and 6.9 mths (95% CI 0 – 15.2 mths), respectively. Median OS is not reached in any cohort. Conclusions: This phase II study on cabozantinib in R/M SGC pts demonstrated severe wound and fistula complications in 32% of pts on treatment for ≥2 mths, mostly (4/6 pts) within the radiotherapy field. Because of this toxicity the study was closed prematurely. Furthermore, cabozantinib showed minimal clinical activity in SGC pts. Research funding: Ipsen Pharmaceuticals Clinical trial information: NCT03729297 .
A phase I/Ib study of lenvatinib and cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Dunn Lara , Ho Alan Loh , Eng Juliana , Michel Loren S. , Fetten James Vincent , Warner Elizabeth , Kriplani Anuja , Zhi Wanqing Iris , Ng Kenneth K. , Haque Sofia , Pfister David G. , Sherman Eric Jeffrey 
Published: May 2020

6541 Background: Despite overexpression of EGFR in HNSCC, cetuximab monotherapy has limited benefit. Fibroblast growth factor receptor (FGFR) signaling is a known resistance mechanism to EGFR inhibition. Lenvatinib is a multi-targeted receptor tyrosine kinase inhibitor (RTKI) and has unique activity against FGFR 1,2,3, and 4. We are evaluating inhibition of EGFR and RTKs including FGFR through the combination of cetuximab and lenvatinib in patients (pts) with R/M HNSCC. Methods: In this phase I/Ib, single-institution study, pts with measurable disease per RECIST v1.1 that is incurable with surgery and radiation are eligible regardless of prior cetuximab therapy. The dose de-escalation phase included pts with HNSCC and cutaneous squamous cell carcinoma (cSCC) treated with standard cetuximab dosing and lenvatinib in 3 potential dose levels (DL): (0) 24mg, (-1) 20mg, (-2) 14mg oral daily in a standard 3+3 design. The primary objective was to determine the MTD of lenvatinib in combination with cetuximab. The expansion phase included an additional 5 pts with HNSCC treated at the MTD. Exploratory endpoints include ORR and PFS in HNSCC pts treated at the MTD. Results: 12 evaluable pts were treated on the dose de-escalation phase. There were no DLTs on DL 0; however, 3/6 pts were removed immediately following the 28-day DLT period due to toxicity that included extensive thrombotic events and athlerosclerotic disease. On DL -1, 0/6 pts (5 HNSCC/1 cSCC) had a DLT establishing lenvatinib 20mg daily as the MTD. 7 pts were enrolled onto the expansion phase; 4 are currently evaluable for response and 2 are unevaluable because of withdrawal due to a cetuximab reaction and required surgery. Of the 9 evaluable HNSCC pts treated with lenvatinib 20mg daily, 6 pts had a PR with a 67% ORR. For the 8 pts who have completed treatment, the median PFS is 3.6 months (range 1.6-10.4). Grade 3 AEs regardless of attribution included hypertension (3), oral mucositis (3) and oral cavity fistula (1). The most common AEs were acneiform rash (7), fatigue (6), and hypertension/hypothyroidism/oral mucositis (5 each). Conclusions: The MTD of lenvatinib 20mg daily with cetuximab appears to be active in R/M HSNCC with an impressive preliminary ORR, warranting further evaluation of the efficacy of this combination. Clinical trial information: NCT03524326 .
Radiomic response evaluation of recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC) patients receiving pembrolizumab on KEYNOTE-012 study.
Authors: Taylor Kirsty , Kazmierski Michal , Billfalk-Kelly Astrid , Khodakarami Farnoosh , Driscoll Brandon , Wang Lisa , Bratman Scott Victor , Haibe-Kains Benjamin , Siu Lillian L. 
Published: May 2020

6545 Background: Immunotherapy has become a standard of care in the treatment of R/M HNSCC, however only a subset of patients respond, highlighting the need for predictive and prognostic biomarkers. Radiomics is a non-invasive method to quantitatively analyze tumors through conventional imaging. Methods: The pre-treatment and first-on-treatment (after 8 weeks) computed tomography (CT) scans from 132 R/M HNSCC patients treated with single-agent Pembrolizumab (10mg/kg Q2W or 200mg Q3W IV) on the KEYNOTE-012 study were analyzed. Identified target lesions, per RECIST 1.1, were manually contoured, and radiomic features from the tumor and peritumoral region (3 mm expansion of the tumor) were extracted using PyRadiomics. All combinations of image filters and feature classes, not including shape descriptors of peritumoral region, were extracted. Feature space dimensionality was reduced by clustering features (hierarchical clustering using Pearson-based distance and complete linkage) and selecting the medoid of each cluster. Correlation with lesion-level response (LLR) at first-on-treatment CT and overall response (OR) was evaluated using concordance index (CI) with Benjamini-Hochberg multiple testing correction. Results: A total of 406 lesions were included (45 head & neck (HN), 207 lung, 57 liver, 86 lymph nodes (LN), 11 other). 3562 features were extracted from pre-treatment scans (2246 tumor, 1316 peritumor). Considering all lesion sites collectively, 27 of 110 feature clusters were significantly correlated with LLR (false discovery rate (FDR) < 0.05) but not with best overall RECIST response per patient on study. However, when grouped by organ, a number of feature cluster medoids were significantly associated (FDR < 0.05) with LLR (HN: 1, lung: 28, liver: 8, LN: 1) and OR (liver: 18). Feature clusters predictive of LLR and OR included descriptors of both tumor-specific and tumor/peritumoral gray-level intensity and texture (e.g. 74% tumor and 26% peritumoral features in clusters significantly associated with OR in liver). Conclusions: Tumor and peritumoral radiomic features at baseline correlate with LLR and OR to immunotherapy in R/M HNSCC. Despite significant heterogeneity in lesion site, both global and site-specific significant feature clusters could be identified.
Exome scale liquid biopsy characterization of putative neoantigens and genomic biomarkers pre- and post anti-PD-1 therapy in squamous cell carcinoma of the head and neck.
Authors: Abbott Charles , Bedi Nikita , Zhang Simo V , Li Robin , Pyke Rachel , Levy Eric , Chernock Rebecca , Mansour Mena , Sunwoo John B. , Colevas A. Dimitrios , Chen Richard , Boyle Sean Michael 
Published: May 2020

6557 Background: The reduced scope, and number of genes profiled by typical liquid biopsy panels can result in missed biomarkers including neoantigens, which may change with treatment, as well as potentially undetected resistance mechanisms and pathways beyond the scope of targets typically captured by panels. To address these limitations, we used a whole-exome scale liquid biopsy monitoring platform, NeXT Liquid Biopsy, to analyze head and neck squamous cell carcinoma (HNSCC) patients that have received anti-PD1 therapy. Presently, we sought to (1) monitor neoantigen changes in cfDNA as a complement to tumor biopsy-derived neoantigens, (2) compare the impact of tumor escape mechanisms, including HLA-LOH, on neoantigens identified in tissue and cfDNA and (3) to identify novel biological signatures that combine information from both solid tumor and liquid biopsies. Methods: Pre- and post-intervention matched normal, tumor and plasma samples were collected from a cohort of 12 patients with HNSCC. Following baseline sample collection all patients received a single dose of nivolumab, followed by resection approximately one month later when feasible, or a second biopsy where resection was impractical. Solid tumor and matched normal samples were profiled using ImmunoID NeXT, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale somatic variants were identified in cfDNA from plasma samples using the NeXT Liquid Biopsy platform. Data from these two platforms were compared with corresponding clinical findings. Results: Concordant somatic events were detected between plasma and tumor at pre- and post-treatment timepoints. Neoantigens predicted to arise from these somatic events were reduced in solid tumor post-treatment, but increased in cfDNA, when compared to pre-treatment timepoints. HLA LOH was identified in a number of subjects, likely resulting in reduced neoepitope presentation in those cases. Immune cell infiltration increased in the tumor following treatment, with no changes to the CD8+/Treg cell ratio, suggesting consistent immunoregulation. Conclusions: Exome-wide neoantigen burden was reliably predicted from cfDNA, providing additional insight complementing data from solid tumor. Analyzing HLA LOH, and neoantigen burden from both solid and liquid biopsies together over the course of treatment creates a more comprehensive profile of therapeutic response and resistance mechanisms in HNSCC patients missed with typical liquid biopsy panels.
Computerized features of spatial interplay of tumor-infiltrating lymphocytes predict disease recurrence in p16+ oropharyngeal squamous cell carcinoma: A multisite validation study.
Authors: Corredor Germán , Lu Cheng , Koyuncu Can , Bera Kaustav , Toro Paula , Fu Pingfu , Koyfman Shlomo A. , Chute Deborah , Adelstein David J. , Thorstad Wade , Bishop Justin A. , Faraji Farhoud , Lewis James , Madabhushi Anant 
Published: May 2020

6559 Background: While overall, patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis, subsets of patients experience disease recurrence (DR) and death despite aggressive multimodality treatment. Aside from routine staging criteria, there are no biomarkers of tumor behavior routinely employed in OPSCC to identify patients at higher risk of DR. In this study we sought to evaluate whether the interplay between tumor-infiltrating lymphocytes (TILs) & cancer cells, in both stromal and epithelial compartments from digitized H&E-stained slides, can predict DR in OPSCC patients. Methods: OPSCC resected specimens from 354 patients (66 with DR) were retrospectively collected from 3 different sites. 107 (16 DR) patients from site 1 formed the training set and 247 (50 DR) patients from sites 2 & 3 formed the independent validation cohort. Computerized algorithms automatically identified 4 types of nuclei (TILs & non-TILs in both stromal & epithelial regions), defined clusters for each nuclei type based on cell proximity, and used network graph concepts to capture measurements relating to the arrangement of these clusters. The top 10 features determined by a statistical selection method (LASSO) were used to train a Cox regression model that assigns a risk of DR to each patient on the training set. The median risk score was used as threshold for stratifying patients on the validation set into low and high-risk of DR. Survival analysis was used to evaluate the stratification given by the trained model. Results: Patients identified by the TIL interplay model as high risk for DR had statistically worse disease specific survival. Univariate analysis yielded an HR=2.49 (95% CI: 1.22-5.07, p=0.04) for site 2 and HR=3.62 (95% CI: 1.39-9.43, p=0.03) for site 3. Multivariate analysis controlling the effect of different clinical variables is shown in the attached table. Conclusions: We introduce a prognostic model based on the automated quantification of the interplay between tumor microenvironment cells that is able to help distinguish OPSCC patients with higher DR risk from those who will experience longer disease-free survival. [Table: see text]
Nivolumab (Nivo) and ipilimumab (Ipi) in combination with radiotherapy (RT) in high-risk patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Authors: Johnson Jennifer Maria , Bar Ad Voichita , Lorber Emily , Poller Dawn , Manukian Gregor , Luginbuhl Adam , Curry Joseph M. , Cognetti David M. , Keith Scott W. , Axelrod Rita Susan , Rodeck Ulrich , Harshyne Larry , Argiris Athanassios 
Published: May 2020

6577 Background: Immune checkpoint inhibitors (ICI) are the standard of care in recurrent/metastatic SCCHN but their role in the curative therapy setting with RT is under study. We evaluated the novel approach of combining Nivo, a PD-1 inhibitor, and Ipi, a CTLA-4 inhibitor, in lieu of chemotherapy, with concurrent RT in pts with high-risk LA SCCHN. Methods: We enrolled newly diagnosed, chemotherapy eligible pts with AJCC 7th edition stage IVA-IVB SCCHN of the oral cavity, oropharynx (OP), hypopharynx, and larynx. HPV+ OP were T4, N2c or N3 OP. Nivo (3 mg/kg every 2 weeks IV x 17 doses) and Ipi (1 mg/kg every 6 weeks x 6 doses) were administered starting 2 weeks prior to the start of RT. RT was prescribed to a dose of 70 Gy delivered in 2 Gy/fraction/day using VMAT. The primary objective was safety of combination ICI with RT. Secondary objectives included 1-year progression-free survival (PFS), overall survival, and correlative studies. Results: 24 pts were enrolled; median age of 60 (range 48-77); 20 were male; 16 oropharynx (14 HPV+), 2 hypopharynx, and 6 larynx; AJCC 7th edition stage IVA (23), IVB (1). Grade 3 acute in-field adverse events (AEs) occurred in 17/24 (71%) of patients during concurrent ICI-RT (9 mucositis, 6 dysphagia, 5 dermatitis, 4 odynophagia, 1 dysphonia); there were no grade 4/5 AEs during ICI-RT. During ICI maintenance 5 pts developed in-field ulcerations at the primary site detected at an average of 3 months post RT; 1 of them died of bleeding due to erosion into the carotid artery with no evidence of active cancer; 4 additional pts developed in-field necrosis. 7 pts discontinued ICI treatment at > 3 months post-RT: 1 due to immune AE, 5 due to in-field ulcerations, 1 due to persistent mucositis without ulceration. 4 pts (17%) had grade 3 immune AEs: 1 elevation of lipase, 1 colitis, and 2 rash. There were no grade 4/5 immune AEs. The median follow-up is 16 months (range, 6.3-30.6). 21 of 24 pts (87.5%) are alive with no evidence of disease progression. 2 pts recurred at distant sites: 1 had a solitary lung lesion at 11 months and was treated with RT; 1 in mediastinal lymph nodes at 9 months and was treated with chemo-RT. Locoregional control remains at 100%. Conclusions: RT plus dual ICI combination was feasible and resulted in no locoregional relapses so far in 24 high-risk LA SCCHN pts. Longer follow-up is needed to fully assess PFS and locoregional control as well as post-treatment in-field ulceration/necrosis that may be attributed to the potent radiosensitizing effect of dual PD-1 and CTLA-4 blockade. Clinical trial information: NCT03162731 .