bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cetuximab, docetaxel, and cisplatin (TPEx) as first-line treatment in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Final results of phase II trial GORTEC 2008-03.
Authors: Guigay Joel , Fayette Jerome , Dillies Anne-Francoise , Sire Christian , Kerger Joseph N. , Tennevet Isabelle , Machiels Jean-Pascal H. , Zanetta Sylvie , Pointreau Yoann , Bozec Le Moal Laurence , Brugel Ribere Lydia , Henry Stefanie , Temam Stéphane ,   GORTEC
Published: March 2020

5505 Background: Cetuximab in combination with platinum and 5FU (PFEx) has become a standard in first-line treatment of patients (pts) with R/M SCCHN. Cetuximab and taxane combinations have shown promising activity. This multicenter phase II study evaluates the efficacy and safety of cetuximab, docetaxel and cisplatin combination (TPEx) as first-line treatment in pts with R/M SCCHN. Methods: Pts were required to have WHO PS 0-1, no prior systemic therapy for R/M SCCHN, cumulative dose of cisplatin less than 300 mg/m² and no prior anti-EGFR therapy. Pts received docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and cetuximab (400 mg/m² on day 1 of cycle 1 then 250 mg/m² weekly), repeated every 21 days x 4 cycles then followed by cetuximab 500 mg/m² every 2 weeks (wks) as maintenance therapy until disease progression or unacceptable toxicity. G-CSF support with lenograstim 150 µg/m²/day was delivered after each cycle of chemotherapy. Response was assessed every 6 wks, according to RECIST. The primary endpoint was objective response rate (ORR) at 12 wks. Secondary endpoints were safety, best overall response, progression-free survival (PFS), overall survival (OS) and biomarkers. Results: 54 pts have been enrolled: 52 males, median age 57.8years (28-69), 12 (22.2%) oropharynx, 55% metastatic.48 pts could be evaluated for ORR at 12 wks: partial response, stable disease and progression were respectively found in 23 pts (PR 47.9%), 21 pts (SD 43.7%) and 4 pts (PD 8.3%). Best overall ORR was 54% (1 CR, 27 PR). The median PFS and OS were 7.1 and 15.3 months, respectively. The 1-year OS was 58.6%. Median PFS after start of maintenance therapy was 4.2 months. Toxicity was manageable with G-CSF support. Treatment related toxicities included G4 neutropenia (n=3). Grade 3 events were skin rash (n=5), hypersensitivity reaction (n=3), mucositis (n=1), fatigue (n=1) and febrile neutropenia (n=1). Alopecia was common. 1 toxic death was related to sepsis on feeding tube. Conclusions: Efficacy analysis demonstrates that TPEx regimen is effective and might be a relevant substitute for PFEx as first-line treatment in fit pts with R/M SCCHN.
Intra-arterial infusion of recombinant adenoviral human p53 gene combined chemotherapy for advanced oral cancer: A phase II double-blind randomized clinical trial.
Authors: Li Yi , Li Longjiang 
Published: March 2020

5507 Background: The p53 tumor suppressor gene has been shown as having multiple anti-tumor functions and being capable of enhancing the efficacy of chemo-therapy. This study is to investigates clinical outcomes of intra-arterial infusion ofrecombinant adenoviral human p53 gene (rAd-p53) combined with chemotherapy in treatment of advanced oral cancer. Methods: Ninety-nine patients with stage III or IV oral carcinoma, satisfying with the inclusion criteria, were randomly allocated to Group I (G1: n=35; rAd-p53 plus chemotherapy), Group II (G2: n=33; rAd-p53), or Group III (G3: n=31; chemotherapy). Intra-artery infusion of rAd-p53 were given through superficial temporal artery reverse intubation at a dose 1-4 ×1012 viral particles (VP) , once every 3 days for 6 times. Chemotherapy regimen consisted of oxaplatin 200 mg/m2 on day1, bleomycin 8 mg/m2 on day 2, 6, 8 and Methotrexate 30 mg/m2 on day1, 8, for squamous cell carcinoma (SCC), and oxaplatin 200 mg/m2 on day1, 5-Fu 200 mg/m2 on day1,3 and cyclophosphamide 400 mg/m2 on day2, 8 for adenoid cystic carcinoma (ACC). Results: The complete response rate (CR) in G1 (48.5%) was significantly higher than in G2 (16.7%) and G3 (17.2%). The overall response rates (RR) were 88.6%, 54.5%, and 51.6% for G1, G2 and G3, respectively. The 3-year overall survival (OS) of G1 (82.9%) was significantly higher than the patients in G2 (60.6%) and G3 (58.1%). All those patients receiving rAd-p53 had a self-limited fever. Positive Bax immunostaining was detected in all the patients receiving rAd-p53. Conclusions: Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent an alternative to the current standard treatment for the late stage oral carcinoma.
An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.
Authors: Schoffski Patrick , Elisei Rossella , Müller Stefan , Brose Marcia S. , Shah Manisha H. , Licitra Lisa F. , Jarzab Barbara , Medvedev Viktor , Kreissl Michael , Niederle Bruno , Cohen Ezra E. W. , Wirth Lori J. , Ali Haythem Y. , Hessel Colin , Yaron Yifah , Ball Douglas Wilmot , Nelkin Barry , Sherman Steven I. , Schlumberger Martin ,   EXAM Study Group
Published: March 2020

5508 Background: MTC arises from parafollicular cells of the thyroid gland, accounts for 5-8% of thyroid cancers and represents an unmet medical need. Cabozantinib (cabo) is an oral inhibitor of MET, VEGFR2, and RET. We conducted a phase III study of cabo vs placebo (P) in pts with progressive, unresectable, locally advanced or metastatic MTC. Methods: Eligible pts were required to have documented RECIST progression within 14 months of screening. The primary efficacy measure was progression-free survival (PFS) as assessed by an independent review facility (IRF) using RECIST. Secondary efficacy measures included objective response rate (ORR) and overall survival (OS). The study has 90% power to detect a 75% increase in PFS and 80% power to detect a 50% increase in OS. Tumor assessments occurred every 12 weeks. Crossover between treatment arms was not allowed. Results: Between Sept 2008 and Feb 2011, 330 pts (median age 55 yrs; 67% male; 96% measureable disease; RET mutation status: pos 48%; neg 12%; unknown 39%; prior TKI exposure: yes 21%, no 78%, unknown 2%) were randomized 2:1 to cabo (140 mg free base [175 mg salt form] qd; n=219) or P (n=111). The planned primary PFS analysis included events through the date of the 138th event. As of 15June2011, 44.7% of pts on cabo and 13.5% on P were still receiving study treatment. Statistically significant PFS prolongation of 7.2 mo was observed; median PFS for cabo was 11.2 mo vs 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p<0.0001). PFS results favored the cabo group across subset analyses including RET status and prior TKI use. ORR was 28% for cabo vs 0% for P (p<0.0001). An interim analysis of OS (44% of the 217 required events) did not show a difference between cabo and P. The most frequent grade ≥3 adverse events (cabo vs P) were diarrhea (15.9 vs 1.8%), palmar-plantar erythrodysesthesia (12.6 vs 0%), fatigue (9.3 vs 2.8%), hypocalcemia (9.3 vs 0%), and hypertension (7.9 vs 0%). Conclusions: This phase III study met its primary objective of demonstrating substantial PFS prolongation with cabo vs. P in a patient population with MTC and documented progressive disease in need of therapeutic intervention.
A phase II study of temsirolimus/sorafenib in patients with radioactive iodine (RAI)-refractory thyroid carcinoma.
Authors: Sherman Eric Jeffrey , Ho Alan Loh , Fury Matthew G. , Baxi Shrujal S. , Haque Sofia , Korte Susan H. , Smith-Marrone Stephanie , Xiao Han , Ghossein Ronald A. , Fagin James A. , Pfister David G. 
Published: March 2020

5514 Background: Sorafenib is an oral tyrosine kinase inhibitor of multiple targets, including RAF, VEGFR1, and VEGFR2. Published response rates with sorafenib in RAI refractory thyroid cancer have ranged from 11-23%. Temsirolimus is an intravenous inhibitor of mTOR; mutations in the PI3K/mTOR/AKT pathway occur late in thyroid cancer and may be associated with aggressive disease. Methods: The study was a single institution, phase II design. Primary objective was response rate. Eligible patients (pts) had progressive, RAI-refractory/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-medullary, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 200 mg orally twice a day and temsirolimus at 25 mg intravenously weekly. 38 patients were enrolled; 37 were eligible and 36 patients started treatment between 12/18/09 – 10/20/11. Data cutoff date is 1/19/12. Fourteen pts are still actively on study. Results: Of the 37 eligible pts, demographics: female-46%; median age-64 years (30-81); histology-papillary (23)/follicular (1)/Hürthle (5)/poorly differentiated (6)/anaplastic (2); prior systemic treatment (21); prior sorafenib (6). Grade 4-5 adverse events at least possibly related to drug: grade 5 – sudden death, NOS (1 pt): grade 4 – colonic perforation (1 pt). Evaluation of best response: partial (PR) (8, including 3 with anaplastic/poorly differentiated); stable disease (SD) (21); progression (1); inevaluable (7). The partial response rate was 38% in the cohort that previously did not receive any systemic treatment. There was no correlation of response to either BRAF (10) or RAS (5) mutational status. Median time on treatment is 203 days (range 14-638 days) at the cutoff date. For the 21 pts with SD, the maximum percentage shrinkage by RECIST criteria ranged from -2% to -35% (one patient with unconfirmed PR) with a median time on treatment of 203 days (range 39-503 days). Conclusions: The combination of sorafenib and temsirolimus shows promising results in a heavily pretreated population. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc.
Expression of p16, ERCC1, and EGFR amplification as predictors of responsiveness of locally advanced squamous cell carcinomas of head and neck (SCCHN) to cisplatin, radiotherapy, and erlotinib: A phase II randomized trial.
Authors: Austin Melissa , Schmidt Rodney , Parvathaneni Upendra , Bauman Julie E. , Hayes David N. , Papagikos Michael A. , Eaton Keith D. , Liao Jay Justin , Mendez Eduardo , Kurland Brenda F , Xiaoyu Shawn , Wallace Sarah G. , Martins Renato 
Published: March 2020

5515 Background: This study evaluated the expression of p16 and ERCC1 and EGFR amplification as predictive and prognostic factors in a recently completed phase II randomized trial comparing cisplatin (100 mg/m2 on d 1, 22, 43) with radiotherapy (70Gy) +/- erlotinib (150 mg/d during radiotherapy) in locally advanced SCCHN. p16 (HPV surrogate) is a known prognostic factor in oropharyngeal SCCHN, and high ERCC1 expression has been correlated with resistance to cisplatin. EGFR gene copy number may be prognostic in SCCHN and alter response to erlotinib. Methods: Pretreatment formalin-fixed, paraffin-embedded tumor tissue was available for 84/204 patients. EGFR copy number was assessed using Vysis LSI DNA probes, and immunohistochemistry was performed on Leica Bond III machines using Lab Vision ERCC-1 (8F1) and CINtec p16 antibodies. All assays were performed in accordance with manufacturer instructions; all studies were reviewed by a single Pathologist (MA) who was blinded to patient outcome. Logistic regression and Cox regression models fit a treatment arm by marker interaction and tested selected linear contrasts. Results: Efficacy analysis showed no difference in complete response rate (CRR) and progression-free survival (PFS) between treatment arms. However, PFS in both arms was better than historical comparisons, with only 46 events over a median follow-up of 23 months. Positivity in p16 was associated with greater CRR (OR 3.5, p=0.03) and longer PFS (HR=0.38; p= 0.07). The CRR effect was greater for the erlotinib arm (OR 8.1, p=0.01) than for Arm A (OR 1.5, p=0.56). The ERCC1 (+) rate was 46% (39/84).ERCC1 expression above the median was not associated with worse CRR (OR 0.69; p=0.46) or PFS (HR 0.99; p=0.98). Only 4 tumors showed EGFR amplification precluding further analysis. Conclusions: p16(+) tumors had a better outcome, similar to other recent trials, and erlotinib seemed to increase the CRR among p16(+) tumors. ERCC1 expression did not predict chemoradioresistance in this study. EGFR amplification was too rare in the tested population to assess predictive or prognostic value.
Genomic profiling of a clinically annotated cohort of locoregionally advanced head and neck cancers (HNC) treated with definitive chemoradiotherapy.
Authors: Seiwert Tanguy Y. , Keck Michaela K. , Zuo Zhixiang , Khattri Arun , Brown Christopher , Stricker Thomas , Rieke Damian , Lingen Mark W. , Cohen Ezra E. W. , White Kevin P. , Vokes Everett E. 
Published: March 2020

5517 Background: Recent advances in genomic technology and sequencing have allowed the near comprehensive characterization of genetic abnormalities in HNC, but their correlation with clinical outcome remains to be determined. We analysed a clinically annotated cohort of locoregionally advanced HNC for copy number changes and mutations and correlated with outcome in an exploratory fashion. Methods: 120 head and neck cancers (frozen tissue) and matching normal tissues/blood from patients with locoregionally advanced HNC treated with definitive chemoradiation +/- induction at the University of Chicago were obtained from our tissue bank. DNA, RNA, protein were extracted. Barcoded, multiplexed sequencing libraries for 500 head and neck cancer associated genes (Agilent capture) were built and sequenced on Illumina HiSeq next generation sequencers. 150 commonly copy number altered and HNC relevant genes were analysed for copy number alterations (CNA) using the Nanostring nCounter platform. Respective genetic aberrations in curated pathways were allocated to tumor subgroups. Exploratory analysis correlated data with induction response and progression free survival. Confirmatory HPV testing was performed using an E6, nested, multiplex PCR. Results: ≥80% of targeted sequences were successfully captured and sequenced. Commonly mutated genes included: TP53, CDKN2A, PIK3CA, NOTCH1. Of note PIK3CA mutations were enriched in HPV(+) tumors. Commonly copy number altered genes included amplifications of VEGF1, CCND1, MYC, EGFR, MDM4, CTTN, as well as PIK3CA, and deletions of CDKN2A, SUCLG2, FHIT, TGFBR2, PTPRD, IKBKG, TRAF6, and RASSF1. CCND1, and MYC were commonly co-amplified and correlated with poor progression free survival, representing a distinct HNC phenotype. Analysis for additional genes and influence on induction response will be presented. Conclusions: Targeted, medium throughput genomic profiling is feasible, and provides the majority of HNC specific genetic aberrations at a comparably low cost. Impact on outcome (CCND1/MYC amplification) and potential treatment targets (PIK3CA mutations in HPV(+) tumors) were identified.
Lenvatinib treatment of advanced RAI-refractory differentiated thyroid cancer (DTC): Cytokine and angiogenic factor (CAF) profiling in combination with tumor genetic analysis to identify markers associated with response.
Authors: Ball Douglas Wilmot , Sherman Steven I. , Jarzab Barbara , Cabanillas Maria E. , Martins Renato , Shah Manisha H. , Bodenner Donald , Newbold Kate , Licitra Lisa F. , Topliss Duncan , Allison Roger , Kadowaki Tadashi , Funahashi Yasuhiro , Matijevic Mark , Sachdev Pallavi , O'Brien James P. , Schlumberger Martin 
Published: March 2020

5518 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In a phase II study of lenvatinib, 58 patients (pts) with DTC were enrolled and a response rate of 50% was observed (Sherman, ASCO 2011). Methods: Pts received lenvatinib at a starting dose of 24 mg oral once daily in 28-day cycles. Serum was collected at baseline (BL), on day 8 and on day 36 and concentrations of 47 CAFs were measured using multiplex bead arrays and enzyme-linked immunosorbent assay (ELISA). 33 genes (443 mutations) were examined in archival tumor tissues (n=25). Association of baseline CAF, changes in CAF levels upon treatment and gene mutation status with treatment outcomes was investigated. Results: Combination of low baseline VEGF and ANG-2 (p=0.02 and HR=0.386) correlated with longer PFS. Both baseline and changes in CAF levels demonstrated an association with gene mutation status. High baseline levels of VEGF were observed in pts with wild type RAS and BRAF (p=0.035) whereas high baseline sTIE-2 levels associated with RAS mutation (p=0.023). Supporting pre-clinical mouse xenograft tumor model developed using ANG2-overexpressing human thyroid cancer cell line FTC-286 demonstrated reduced sensitivity to lenvatinib treatment. Increased levels of IL-10 and FGF-2 8-day post-treatment (8d post-tx) significantly associated with RAS (N- or K-) and BRAF mutation. Combination of gene mutation status with baseline CAF levels provided better prediction of longer PFS compared to gene mutation alone. Hierarchical clustering modeling using changes in CAF levels 8d post-tx with tumor shrinkage identified a set of CAFs that could predict two categories of lenvatinib response: longer PFS and greater tumor shrinkage or longer PFS in the absence of significant tumor shrinkage. Conclusions: CAF profiling identified potential predictive biomarkers of lenvatinib treatment outcomes in DTC. Combination of RAS and BRAF mutation with baseline VEGF and ANG-2 or treatment-associated changes in FGF-2 and IL-10 level correlated with lenvatinib treatment response.
New DNA methylation markers associated with oral cancer (OC) development (dvlpt).
Authors: Saintigny Pierre , Lang Wenhua , Jelinek Jaroslav , Pickering Curtis R. , Feng Lei , Frederick Mitchell J. , Zhang Li , Ren Henning , Lee J. Jack , Kim Edward S. , Fan You Hong , El-Naggar Adel K. , Hong Waun Ki , Myers Jeffrey , Papadimitrakopoulou Vassiliki , Issa Jean-Pierre , Lippman Scott Michael , Mao Li 
Published: March 2020

5524 Background: We have reported that DNA methyltransferase-3B (DNMT3B) gene expression is a strong predictor of OC dvlpt. Using high-throughput DNA methylation profiles of oral preneoplastic lesions (OPL), we identified 86 candidate genes that were hypermethylated in patients (pts) developing OC and suggested that a CpG island methylation phenotype may occur early during OC dvlpt. Our aim was to validate some of the candidate genes and to study the value of LINE1 repetitive element methylation, a surrogate of global DNA methylation, as biomarkers of risk to develop OC. Methods: Validation cohort included 40 pts with a median follow-up of 4.2 years, including 14 pts who developed OC. None of them were used in the discovery phase. Frozen OPL were collected prospectively and subject to DNA extraction. We performed a quantitative analysis of the degree of methylation of LINE1, and AGTR1, FOXI2, PENK, and HOXA9 promoters CpG sites using pyrosequencing. Results: The degree of methylation of AGTR1 (Mann-Whitney P<0.0001), FOXI2 (P=0.0002), PENK (P<0.0001), but not HOXA9 (P=0.0714) was significantly higher in pts who developed OC. On the contrary, LINE1 methylation was significantly lower in pts who developed OC (P<0.0001). The median percent of methylation was used to dichotomize the pts into high versus low methylation levels. Oral cancer-free survival (OCFS) was significantly worse in pts with high levels of AGTR1 (Log-rank P=0.0229), FOXI2 (P=0.0170), and PENK (P=0.0142) promoter methylation. No significant difference was found with HOXA9. A Methylation Index (MI) was developed by averaging the percent of methylation of AGTR1, FOXI2, and PENK promoters; pts with a high MI had a worse OCFS (P=0.0031). On the other hand, pts with low levels of LINE1 methylation had a significantly worse OCFS (P=0.0118). Finally, in 26 pts, a positive correlation was observed between DNMT3B gene expression levels and the MI (rho=0.65, P=0.0003); surprisingly, there was a negative correlation with LINE1 methylation (rho=-0.74, P<0.0001). Conclusions: AGTR1, FOXI2 and PENK promoter methylation may be associated with increased OC risk in pts with OPL and correlate with DNMT3B expression. Global DNA hypomethylation is an early event in OC dvlpt.
Effects of low-level laser therapy in the prevention and treatment of concurrent chemoradiotherapy induced oral mucositis: A triple-blind randomized controlled trial.
Authors: Saxena P.U. Prakash , Fernandes Donald Jerald , Gautam Ajay , Maiya Arun , Sharan Krishna 
Published: March 2020

5526 Background: Oral mucositis (OM) is the most cumbersome acute side effect of concurrent chemoradiotherapy (CCRT) for head and neck cancer (HNC). OM associated pain affects oral function also may lead to CCRT break. Several modalities have been tried to prevent and treat this complication but none has been proved successful till date. We used prophylactic Low Level Laser Therapy (LLLT) for the prevention and treatment of CCRT induced OM. Methods: In this triple blind study, 221 HNC patients scheduled to undergo CCRT were randomized into laser (n=111) and placebo (n=110) group. Laser group received LLLT (Helium Neon laser, λ=632.8nm, P=24m, W=3.0J/cm2) while placebo received sham treatment daily prior to radiation for 45days. Oral Mucositis (OM) (RTOG/EORTC Scale), oral pain (Visual Analog Scale - VAS), dysphagia (Functional Impairment Scale - FIS), weight loss, duration of analgesic use were assessed. Data was analyzed using frequencies and percentage, generalized estimating equations (GEE) and Odds ratio. Results: There was significant reduction in incidence of severe OM (F=16.64, degree of freedom df=8,876, p<0.0001) and its associated pain (F=25.06, df=8,876, p<0.0001) and dysphagia (F=20.17, df=8,876, p<0.0001) and loss of weight (F=87.56, df=8,876, p<0.0001) when compared between the Laser and placebo group. The duration of step III analgesia required was also significantly lower (p<0.001) in laser (3.2 ±1.4days) than placebo (6.7 ±2.6days) group. Conclusions: LLLT was able to decrease the incidence of CCRT induced severe OM its associated pain, dysphagia, weight loss and the duration of analgesic use. [Table: see text]