bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concurrent chemoradiotherapy with 3-weekly versus weekly cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: A phase 3 multicentre randomised controlled trial (ChiCTR-TRC-12001979).
Authors: Liang Hu , Xia Wei-Xiong , Lv Xing , Sun Rui , Zeng Qi , Li Si-Wei , Mo Hao-Yuan , Han Fei , Luo Dong-Hua , Ye Yan-Fang , Yang Jing , Ke Liang-Ru , Guo Ling , Chen Ming-Yuan , Cao Ka-Jia , Zhao Chong , Mai Hai-Qiang , Qian Chao-Nan , Guo Xiang , Yanqun Xiang 
Published: September 2018

6006 Background: In intensity-modulated radiotherapy (IMRT) era, concurrent chemoradiotherapy (CCRT) with either every three week (ETW) or once a week (OAW) cisplatin is accepted practice for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, ETW and OAW were never prospectively compared in phase 3 clinical trials. This study is to assess the efficacy and toxicity profiles of CCRT with ETW versus OAW schedule of cisplatin. Methods: We conducted an open-label phase 3 multicentre randomised controlled trial in an endemic area. Patients with stage II-IVB NPC were randomly assigned to receive either cisplatin 100 mg/m² every 3 weeks for 2 cycles or cisplatin 40 mg/m² weekly up to 6 cycles concurrently with IMRT. IMRT in both groups was given as 2.19-2.34 Gy per fraction with five daily fractions per week for 6-7 weeks to a total dose of 68-70 Gy to the primary tumor and 62-68 Gy to the involved neck area. The primary endpoint was failure-free survival. Intention-to-treat population was adopted for efficacy analyses. Results: Of the 526 eligible patients, 267 were assigned to OAW arm, and 259 to ETW arm. Two arms were well-balanced in all prognostic factors. No difference was observed in overall tumor response between OAW and ETW (99.6% vs 98.9%, P = 0.624). After a median follow-up of 17.5 months (range 1.6-64.1), estimated 2 year failure-free survival rate was 92% (95% CI 87.7-96.3) in OAW and 88.3% (95% CI 83.2-93.4) in ETW (hazard ratio 1.056, 95% CI 0.58-1.92). The grade 3 or 4 toxicities were similar between two arms, but leucopenia and thrombocytopenia were significantly higher in OAW compared with ETW (24.8% vs 15.9%, P = 0.015 and 5.2% vs 1.1%, P = 0.01, respectively). Stomatitis (35.2% vs 32.6%, P = 0.576), leucopenia and nausea/vomiting (11.2% vs 12.5%, P = 0.684) were the most commonly observed grade 3 or 4 toxicities during both OAW and ETW arms. Conclusions: Weekly regimen of cisplatin as CCRT shows similar treatment efficacy but increased toxic effect of leucopenia and thrombocytopenia compared with 3-weekly schedule in LANPC. Longer follow-up is needed to fully assess prognosis and late toxicities. Clinical trial information: ChiCTR-TRC-12001979.
Phase III randomized trial comparing weekly versus three-weekly (W3W) cisplatin in patients receiving chemoradiation for locally advanced head and neck cancer.
Authors: Noronha Vanita , Joshi Amit , Patil Vijay Maruti , Agarwal Jaiprakash , Laskar Sarbani Ghosh , Budrukkar Ashwini Narsingrao , Murthy Vedang , Gupta Tejpal , D'Cruz Anil , Pai P. S. , Chaturvedi Pankaj , Chaukar Devendra , Pande Nikhil , Chandrasekharan Arun , Talreja Vikas , Vallathol Dilip , Manjrekar Aparna , Mathrudev Vijayalakshmi , Maske Kamesh , Prabhash Kumar 
Published: September 2018

6007 Background: Chemoradiation (CRT) with cisplatin 100mg/m2 given 3-weekly is the standard of care in locally advanced head and neck squamous cell cancer (HNSCC). Substituting low dose weekly cisplatin has pharmacological rationale due to lower toxicity and enhanced radiosensitization but has never been compared to 3-weekly cisplatin. Methods: Phase III non-inferiority trial (CTRI/2012/10/003062) in patients with Stage III or IV (non-metastatic) HNSCC planned for radical CRT. Pts were stratified for T-category, N-category and intent of therapy (adjuvant versus definitive) and centrally randomized 1:1 to cisplatin 30mg/m2 weekly or 100mg/m2 3-weekly concurrently with radiotherapy. Primary endpoint was locoregional control (LRC); secondary endpoints included toxicity, compliance, response, progression-free survival and overall survival. The upper boundary of non-inferiority margin was set at 15%, assuming LRC of 60% with power 80% and alpha 0.05. Results: 300 pts were randomized,150 to each arm; median age 44 years (range: 25-67), males 89%; 71% were smokeless tobacco users. 61% were T4, 71% > N2. 93% pts received CRT as adjuvant therapy for high-risk disease; indication was perinodal extension in 84%, close/ positive margins 8%. Median total treatment time was 86 days (IQR: 79-95). Median RT dose was 60 Gy (IQR 60-60 Gy) using shrinking field technique. In the weekly arm, 133 pts (88.7%) received > 6 cycles; 14 (9%) required dose reduction, median cumulative cisplatin dose 210 mg/m2 (IQR 180-210). In the 3-weekly arm, 143 pts (95%) received > 2 cycles, median cumulative cisplatin dose 300 mg/m2 (IQR 200-300); 12 (8%) required dose reduction. At a median follow up of 20 months (range: 1-49), locoregional relapses (LRR) occurred in 42.2% pts in the weekly arm and 29.6% pts in the 3-weekly arm, leading to an absolute difference in LRR of 12.7% (95%CI:1.89-23.41), p=0.035 by Gray’s test, HR-1.58 (95%CI:1.02-2.46). Acute > grade 3 toxicity occurred in 85.3% pts in 3-weekly arm and 70.7% pts in weekly arm, p=0.002; 30.7% pts in the 3-weekly arm and 14% patients in the weekly arm required hospitalization for management of toxicity, p=0.001. Conclusions: 3-weekly cisplatin leads to 42% relative reduction in locoregional recurrence; it is superior to weekly cisplatin and should be the preferred regimen in CRT for HNSCC. Clinical trial information: CTRI/2012/10/003062.
Neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV negative head and neck squamous cell carcinoma (HNSCC).
Authors: Uppaluri Ravindra , Zolkind Paul , Lin Tianxiang , Nussenbaum Brian , Jackson Ryan S , Rich Jason , Pipkorn Patrik , Paniello Randal , Thorstad Wade , Michel Loren , Mudianto Tenny , Oppelt Peter John , Wildes Tanya Marya , Dunn Gavin P , Piccirillo Jay F , Kallogjeri Dorina , Rodig Scott , Hagemann Ian S. , Chernock Rebecca , Adkins Douglas 
Published: September 2018

6012 Background: Pembrolizumab has efficacy in metastatic HNSCC. We hypothesized that treatment intensification in surgically resectable HPV-negative, Stage III/IV HNSCC with neoadjuvant plus post-operative adjuvant (POA) pembrolizumab would be safe and reduce 1-year locoregional recurrence/distant metastases (LRR/DM) from 35% (historical: Cooper and Bernier NEJM 2004) to 15%. Methods: Phase II trial where all eligible patients received 1 dose of pembrolizumab (200 mg) prior to surgery and only those with high-risk pathologic features (HRPF: extracapsular extension/positive margin) were given POA cisplatin and radiation followed by pembrolizumab. PD-L1 staining was assessed by immunohistochemistry (9A11 antibody). Results: The study continues to enroll. Characteristics of 21 enrolled patients (pts) were median age 59 (32-87) yrs, tobacco use 81% (17 pts), clinical T2 (n = 2), T3 (n = 1), T4 (n = 18), and cN0/1 (n = 8), cN2 (n = 13). Preliminary analyses revealed five important findings: 1) No serious study drug-related AEs or unexpected surgical delays/complications, 2) No LRR/DM events in the first 10 patients with > 1-year follow-up after surgery 3) HRPF rate of 38% (95% CI: 18%-62%) (expected: 80%), 4) 43% of pts (95% CI: 22%-66%) with pathologic treatment response to neoadjuvant pembrolizumab (definition: tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in > 10% of tumor area), and 5) 48% of pts (95% CI:26%-70%) with clinical-to-pathologic downstaging. Pathologic treatment effect (TE) in ≥ 70% of the resected tumor or lymph node tissue area occurred in 6/21 pts (29%). Baseline tumor biopsies were PD-L1 positive ( > 1% of tumor cells) in 11/19 (58%) evaluable samples and in 7/8 (88%) evaluable pathologic responders. A significant correlation existed between baseline PD-L1 expression on tumor cells and pathologic treatment effect in the tumor (correlation coefficient: 0.72 and p = 0.0005). Conclusions: Neoadjuvant and adjuvant pembrolizumab was safe and well tolerated. We observed several lines of evidence supporting an anti-tumor effect in these pts with a single dose of pre-operative pembrolizumab. Further evaluation of this strategy is warranted. Clinical trial information: NCT02296684.
Correlation of constitutive PD-1 resistance in HNC with GM-CSF expression and presence of myeloid derived suppressor cells (MDSCs).
Authors: Seiwert Tanguy Y. , Bao Riyue , Tan Y-H Carol , Acharya Rajesh , Brisson Ryan J. , Kochanny Sara , Arshad Saba , Zuo Zhixiang , Saloura Vassiliki , Agrawal Nishant , Gooi Zhen , Blair Elizabeth A. , Lingen Mark W. , Vokes Everett E. , Gajewski Thomas , Savage Peter A , Khattri Arun 
Published: September 2018

6049 Background: PD-1 checkpoint blockade is active in head and neck squamous cell carcinomas (HNC) with a response rate of ~18% and significant impact on survival. However, only a subset of patients benefits (Seiwert, Lancet Oncol). Biomarkers such as PD-L1 IHC and the Interferon-Gamma gene expression profile (INF-G GEP) identify inflamed tumors with a higher chance of response (~35-40%). However, it remains unclear why the majority of INF-G inflamed tumors still do not respond, or how to overcome constitutive resistance. Methods: 50 anti-PD-1 treated recurrent/metastatic HNC patients were included. Tumor RNA was analyzed using a 638-gene immune panel on the Nanostring nCounter. HPV status was assessed by HPV E6/E7 mRNA. T-cell inflamed phenotype was calculated using the 6-gene INF-G GEP (geometric mean) using both a low (6) and a high cutpoint. Differential gene expression was determined between inflamed-benefitting (IB) patients (defined as OS ≥ 250days), and inflamed-non-benefitting (INB) patients. Candidate biomarkers were evaluated in the entire cohort. Results: CD8 correlated highly with INF-G GEP (R = 0.80), suggesting T cell-driven inflammation. Comparing inflamed benefitting with inflamed non-benefitting tumors, the most differentially expressed gene was CSF-2, encoding GM-CSF, with 4-fold higher expression in inflamed non-benefitting (INB) tumors (with both cutpoints). In the overall anti-PD-1 treated cohort of 50 patients, CSF-2/GM-CSF correlated strongly with poor overall survival (P = 0.02), outperforming both HPV status, or PD-L1 expression in cox PH multivariate analysis. GM-CSF expression has been linked to myeloid derived suppressor cells (MDSC); MDSC marker CD34, as well as JAK2/IL10 were significantly elevated in inflamed non-benefitting (INB) tumors. There was no difference in M2 macrophage marker CD163 between the two groups. Conclusions: Constitutive resistance to PD-1 checkpoint blockade in inflamed HNC associates with expression of GM-CSF and Myeloid Derived Suppressor Cell (MDSC) markers. Strategies to deplete MDSCs, such as chemotherapy, should be considered in combination or sequentially with anti-PD-1.
Immunogenicity results using human papillomavirus (HPV) specific DNA vaccine, INO-3112 (HPV16/HPV18 plasmids + IL-12) in HPV+ head and neck squamous cell carcinoma (HNSCCa).
Authors: Aggarwal Charu , Cohen Roger B. , Morrow Matthew P , Kraynyak Kimberly , Bauml Joshua , Weinstein Gregory S. , Boyer Jean , Yan Jian , Mangrolia Drishty , Oyola Sandra , Duff Susan , Weiner David B. , Csiki Ildiko , Bagarazzi Mark L. 
Published: September 2018

6073 Background: Oropharyngeal HNSCCa is frequently associated with HPV. We hypothesize that immunotherapy with INO-3112 will generate immune responses in patients (pts) with HPV+ HNSCCa. Methods: This Phase I/IIa trial included pts with p16+ locally advanced HNSCCa, ECOG PS 0-1. INO-3112 was delivered IM along with electroporation with the CELLECTRA device, Q3 weeks x 4 doses. Cohort 1 (C1) pts received INO-3112 pre and post-surgery; Cohort 2 (C2) pts received INO-3112 post cisplatin-based definitive chemoradiation. 1° and 2° endpoints were safety and immune responses. Pre- and post INO-3112 tissue samples (C1) were assessed for tumor infiltrating lymphocytes (TILs). Peripheral immune responses were assessed by ELISA for HPV16/18 specific antibody levels, and by IFNɤ ELISpot for antigen specific response, at each dose visit and q3 months (mos). Results: As of 08/2016, 22 pts were treated, completing accrual. C1: n = 6, C2: n = 16; 20 male, median age 57.5 years (32-76); base of tongue = 10, tonsil = 12; never smoker = 10. All pts are alive, median follow up is 15.9 mos (1-26). INO-3112 was well-tolerated with no related Grade 3-5 AEs. In 5 C1 pts post immunotherapy, increase in CD8+ infiltration into tumor was noted in 2 pts (1.6-3.6 fold) and decrease in FoxP3+ was noted in the other 3 (1.8-2.1 fold). This resulted in positive shift in CD8+/FoxP3+ ratio in neoplastic tissue in 4/5 pts. Peak mean/median antibody responses to HPV16 E7 and HPV18 E7 antigens for 19 evaluable pts were 1:1235/1:150 and 1:2853/1:450, respectively. As compared to baseline, 18 evaluable pts showed elevated HPV16/HPV18 specific T cell activity (by IFNɤ ELISpot), with peak mean/median responses of 179.99/68.33 SFU per 106 PBMC (HPV16) and 107.18/53.3 SFU per 106 PBMC (HPV18). Persistent cellular responses > 100 SFU/106PBMC were noted out to 12 mos. 3 pts have progressed; 1 pt received Nivolumab for progressive disease, and remains in CR. Conclusions: These data show that INO-3112 generates HPV-specific peripheral humoral and cellular immune responses that may persist out to 12 months and influences the composition of CD8+ and FoxP3+ immune infiltration into tumor tissue in HPV+ HNSCCa. Clinical trial information: NCT02163057.
Assessment of established patient reported outcomes (PROs) instruments measuring toxicities and quality of life (QOL) for patients (pts) with head and neck cancer (HNC) treated on ECOG 1308 and 2399 studies.
Authors: Cmelak Anthony , Flamand Yael , Li Shuli , Marur Shanthi , Murphy Barbara A. , Cella David , Forastiere Arlene A. , Burtness Barbara 
Published: September 2018

6074 Background: HPV HNC pts are younger and have a higher cure rate than smoking-related pts, and therefore carry treatment toxicities longer. Dose deintensification and conformal RT may result in decreased toxicity. We report the impact of these techniques on patient outcomes in E2399 and E1308 as measured through PROs. Methods: Longitudinal data on acute and late toxicities were recorded prospectively at baseline, post-treatment, and at 6, 12, 24 and 30 months in HPV+ pts on E1308 and HIV+/- pts on E2399 using the following measures: E1308: FACT-HN, KATZ Index of Independence (ADL), Brief Fatigue Index (BFI), Instrumental Activities of Daily Living (IADL), and the Vanderbilt Head and Neck Symptom Survey Version 2 (VHNSS V2); on E2399: FACT-HN. We correlated acute and late toxicities with de-escalation of RT dose (69.3Gy to 54Gy) on E1308, and with IMRT (E1308) vs. conformal RT (E2399). Results: 38 pts on E1308 completed 12 mo VHNSS V2; 32 received low dose IMRT and 6 standard dose, and 56 E2399 pts completed 12 mo FACT-HN. Items from the VHNSS V2 showed that difficulty eating solids (40% vs. 89%, p = 0.011) and improved nutrition (10% vs 44%, p = 0.025) were statistically improved at 12 months by lowering IMRT dose from 69.3Gy to 54Gy. The FACT-HN showed an improvement in eating solids at 12 mo when comparing low dose IMRT vs. 3DRT (65% vs. 33% had no or minimal solid food problems, p = 0.057). No other statistically significant reductions in toxicity were noted on any of the other PRO instruments. Conclusions: Both FACT-HN and VHNSS V2 demonstrated an improvement in eating solids by reducing IMRT dose. FACT-HN demonstrated that IMRT is associated with an improvement in eating solids when compared to 3DRT. Analyses are exploratory and need to be validated using randomized data.Future studies should stress accurate and complete PRO data. The KATZ, BFI, and IADL were not sensitive to detecting differences in toxicities from IMRT dose reduction on E1308. The VHNSS V2 and FACT-HN instruments corroborated specific toxicities both by RT technique as well as IMRT dose, and will therefore be utilized in future ECOG-ACRIN HNC studies. Clinical trial information: NCT01084083.
Phase II study: Induction chemotherapy & transoral surgery as definitive tx for locally advanced oropharyngeal squamous cell carcinoma (OPSCC)—A novel approach.
Authors: Siegel Robert S. , Rafei Hind , Joshi Arjun , El-Shami Khaled , Taheri Reza , Guebre-Xabiher Hiwot , Sadeghi Nader 
Published: September 2018

6078 Background: The standard of care for OPSCC includes chemoradiation (CRT) or surgery with adjuvant radiation (RT). However, RT is associated with significant life long morbidity. We assessed the efficacy of a two-drug induction regimen, followed by transoral robotic assisted surgery (TORS) & neck dissection for locally advanced OPSCC. Methods: This is an IRB approved single-arm phase II study for untreated stage III or IVA OPSCC patients (pts) with an ECOG < 2 and GFR > 50 cc. Induction chemotherapy consisted of cisplatin 75 mg/m2 and taxotere 75 mg/m2 every 21 days for 3 cycles. Tumor shrinkage was examined after each cycle. If the primary tumor was > 80% smaller, pts underwent TORS and neck dissection(s). At post-op visits, flexible laryngoscopy, blood work, and imaging with PET/CT and/or MRI were done. Short and long term toxicity, progression-free survival (PFS) and overall survival (OS), and quality of life (QOL) were evaluated. Results: Nineteenpts were treated and 14 are available for analysis. Thirteen were male, 12 were Caucasian, 2 were African-American, and 13 were HPV+. Median age at diagnosis was 57. Tumors involved the tonsil (11 pts) and base of tongue (3 pts). Three pts were stage III, and 11 were stage IVA. Tumor size was reduced on average by 58%, 84% and 92% after the 1st, 2nd and 3rd induction cycles respectively. Pathologic complete remission of primary disease occurred in 11 pts and in 7 pts with cervical lymph node disease. Four pts were given dose-reduced chemo and one pt was changed to carboplatin per protocol because of renal dysfunction. In addition, adverse events included three patients with grade I fatigue, neuropathy or nausea. Pre vs post tx QOL scores were not significantly different. At a mean follow-up (f/u) of 13 months (range 2.5 to 19.7), 13 pts are alive and well. Three pts recurred, and were treated with salvage CRT. One pt died of metastatic disease. Conclusions: Cisplatin + Taxotere is an effective induction tx for OPSCC, Induction tx followed by transoral & neck resections without RT is a promising tx model for OPSCC. It appears effective while avoiding adverse effects of RT. Longer f/u is required to assess its true efficacy. Clinical trial information: NCT02760667.
Cognitive technology addressing optimal cancer clinical trial matching and protocol feasibility in a community cancer practice.
Authors: Beck J. Thaddeus , Vinegra Michael , Dankwa-Mullan Irene , Torres Adam , Simmons Courtney C , Holtzen Helen , Urman Alexandra , Roper Nancy , Norden Andrew D , Rammage Melissa , Hancock Steven , Lim Kyungae , Rao Prasanna , Coverdill Sadie , Roberts Louisa , Williamson Paul , Howell Mickey , Chau Quincy , Culver Kenneth W. , Sweetman Robert William 
Published: September 2018

6501 Background: IBM Watson for Clinical Trial Matching (CTM) is a cognitive computing solution that uses natural language processing (NLP) to help increase the efficiency and accuracy of the clinical trial matching process. This solution helps providers locate suitable protocols for their patients by reading the trial criteria and matching it to the structured and unstructured patient characteristics when integrated with the Electronic Medical Record (EMR). It is also designed to determine which sites have the most viable patient population and identify inclusion and exclusion criteria that limit enrollment. Methods: This project was a collaboration among Highlands Oncology Group (HOG), Novartis and IBM Watson Health to explore the use of CTM in a community oncology practice. HOG is in Northeast Arkansas and has 15 physicians and 310 staff members working across 3 sites. During the 16-week pilot period, data from 2,620 visits by lung and breast cancer patients were processed by the CTM system. Using NLP capabilities, CTM read the clinical trial protocols provided by Novartis, and evaluated the patient data against the protocols’ inclusion and exclusion criteria. Watson excluded ineligible patients, determined those that needed further screening, and assisted in that process. Feedback on the user experience was also obtained. Results: In an initial pre-screening test, the HOG clinical trial coordinator (CTC) took 1 hour and 50 minutes to process 90 patients against 3 breast cancer protocols. Conversely, when the CTM screening solution was used, it took 24 minutes. This represents a significant reduction in time of 86 minutes or 78%. Watson excluded 94% of the patients automatically, providing criteria level evidence regarding the reason for exclusion, thus reducing the screening workload dramatically. Conclusions: IBM Watson CTM can help expedite the screening of patient charts for clinical trial eligibility and therefore may also help determine the feasibility of protocols to optimize site selection and enable higher and more efficient trial accruals.
Changes in stage at diagnosis of screenable cancers after the Affordable Care Act.
Authors: Han Xuesong , Lin Chun Chieh , Jemal Ahmedin 
Published: September 2018

6521 Background: Extensive evidence links inadequate insurance with later stage at cancer diagnosis, particularly for cancers that can be detected by screening. The Affordable Care Act (ACA) implemented in 2014 has substantially increased insurance coverage for Americans 18-64 years old. This study aims to examine any changes in stage at diagnosis after the ACA for the following cancers for which screening is recommended for individuals at risk: female breast cancer, colorectal cancer, cervical cancer, prostate cancer, and lung cancer. Methods: We used National Cancer Data Base, a nationally hospital-based cancer registry capturing 70% new cancer cases in the US each year, to identify nonelderly cancer patients with screening-appropriate age who were diagnosed during 2013-2014. The percentage of stage I disease was calculated for each cancer type before (2013 Q1-Q3) and after (2014 Q2-Q4) the ACA. 2013 Q4-2014 Q1 was excluded as a washout/phase-in period. Prevalence ratios (PR) and 95% confidence intervals (CI) were calculated using log-binomial models controlling for age, race/ethnicity and sex if applicable. Results: 121,855 female breast cancer patients aged 40-64 years, 39,568 colorectal cancer patients aged 50-64 years, 11,265 cervical cancer patients aged 21-64 years, 59,626 prostate cancer patients aged 50-64 years, and 41,504 lung cancer patients aged 55-64 years were identified. After the implementation of the ACA, the percentage of stage I disease increased statistically significantly for female breast cancer (47.8% vs. 48.9%; PR = 1.02 [95%CI 1.01-1.03]), colorectal cancer (22.8% vs. 23.7%; PR = 1.04 [95%CI 1-1.08]), and lung cancer (16.6% vs. 17.7%; PR = 1.06 [95% CI 1.02-1.11]). A shift to stage I disease was also observed for cervical cancer (47.2% vs. 48.7%; PR = 1.02 [95% CI 0.98-1.06]) although not statistically significant. In contrast, the percentage of stage I decreased for prostate cancer (18.5% vs. 17.2%; PR = 0.93 [95%CI 0.9-0.96]) in 2014. Conclusions: The implementation of the ACA is associated with a shift to early stage at diagnosis for all screenable cancers except prostate cancer, which may reflect the recent US Preventive Services Task Force recommendations against routine prostate cancer screening.