bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperprogressive disease (HPD) in head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint inhibitors (ICI).
Authors: Alfieri Salvatore , Ferrara Roberto , Calareso Giuseppina , Cavalieri Stefano , Platini Francesca , Mancinelli Moela , Resteghini Carlo , Orlandi Ester , Iacovelli Nicola Alessandro , Ferella Letizia , Piazza Cesare , Apollonio Giulia , Galbiati Donata , Bossi Paolo , Bergamini Cristiana , Locati Laura Deborah , Licitra Lisa F. 
Published: May 2019

6029 Background: HPD was described in 9% of cancer patients (pts) treated in phase I trials, in 13.8% of advanced non-small cell lung cancer and 29% of 34 HNSCC pts upon ICI. A better definition of the hallmarks and survival outcomes of HPD pts in a larger cohort of HNSCC is still lacking. Methods: We retrospectively analyzed all advanced HNSCC pts treated with ICI at our Institution between October 2014 and December 2018. Three scans, performed before ICI, at baseline and at first evaluation during ICI, were assessed according to RECIST 1.1. Tumor Growth Kinetics (TGK) pre- (TGKpre) and post-baseline (TGKpost) were measured as previously reported (Saâda-Bouzid E, Ann Oncol 2017). Pts were defined HPD if they had progression at first radiological evaluation and TGKpost/TGKpre ≥2. Correlation between HPD and clinical characteristics was performed by Fisher or t-student test. Median overall survival (mOS) and progression free survival (mPFS) were estimated using the Kaplan-Meier method and compared between HPD and non-HPD using the log-rank test. Results: Ninety pts were eligible: 18% were female, 4% had ECOG PS ≥ 2, 73% smoking history, 37% oropharyngeal cancer (61% HPV+), 65% locoregional disease (89% previously irradiated), 54% received combined immunotherapy, 75% in ≥ 2nd line. Two out of 90 pts had TGKpre = 0 and were not evaluable for TGK ratio. HPD was observed in 7.9% (7/88) of pts. HPD pts were significantly younger compared to non-HPD pts (median age 53 ± 3.7 vs 63.3 ± 0.9 years, p = 0.002) and had a significantly higher median neutrophil-lymphocyte ratio (NLR) (11.5 ± 3.5 vs 6.4 ± 0.4, p = 0.004). Overall, mOS and mPFS were 7.5 (95% CI: 4.2-10.8) and 2.2 months (95% CI: 0.9-3.4), respectively. At a median follow-up of 20.9 months (95% CI: 19-22.8), HPD pts had a significantly worse mPFS compared to non-HPD pts [1.8 (95% CI: 1.5-2.2) vs 3.5 (95% CI: 2.2-4.8) months; p = 0.001]. HPD correlated with a not significant trend in lower mOS compared to non-HPD group [3.7 (95% CI: 2.4-5.1) vs 8.3 (95% CI: 4.1-12.5) months; p = 0.348]. Three (43%) out of 7 HPD pts early switched to chemotherapy after PD to ICI having a mOS of 8.1 months (range 3.7-25.3). Excluding these 3 pts, HPD correlated with a significantly worse mOS compared to non-HPD [2.6 (95% CI: 1.9-3.3) vs 8.3 (95% CI: 4.1-12.5) months; p = 0.006]. Conclusions: HPD was identified in 7.9% of HNSCC and correlated with younger age and higher NLR. HPD pts who did not receive a subsequent treatment had poorer mPFS and mOS. The assessment of HPD in a control cohort of advanced HNSCC upon standard chemotherapy is ongoing.
Metformin treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients induces an anti-tumorigenic immune response.
Authors: Karivedu Vidhya , Yaniv Benyamin , Asman Melissa , Palackdharry Sarah , Gulati Shuchi , Jandarov Roman , Hashemi Sadraei Nooshin , Takiar Vinita , Wise-Draper Trisha Michel 
Published: May 2019

6037 Background: Metformin is a biguanide, widely used oral hypoglycemic agent. Metformin has also shown to inhibit tumor growth and progression in a wide variety of cancers including Head and Neck Squamous Cell Carcinoma (HNSCC). Metformin activates AMP protein kinase (AMPK) related pathways leading to inactivation of mammalian target of rapamycin (mTOR) and suppression of its downstream effectors. In addition, metformin is postulated to alter immune regulation in the tumor microenvironment leading to increased tumor cell killing. Here, we report our findings on the impact of metformin on T cells, NK cells and cytokines from patient peripheral blood mononuclear cells (PBMCs) from a phase I open-label single site dose escalation study combining metformin and chemoradiation (CRT) in HNSCC (NCT02325401). Methods: In this study, we evaluated the immune cell phenotypes and cytokine profiles of peripheral blood in patients before and after metformin treatment on trial by using flow cytometry and cytokine magnetic bead assays (Luminex). Cytokine profiles were further studied in co-culture experiments combining PBMCs, HNSCC cell lines, and metformin. Results: Patients who received metformin developed expanded NK cell populations, increased NKG2D expression, and a shift in their CD8+ T-cell memory phenotypes. Patient serum ELISA examination revealed increased anti-tumorigenic cytokine profiles. Metformin treatment of HNSCC cell lines in vitro as well as HNSCC PBMCs ex vivo resulted in downregulation of STAT3 compared to healthy controls. Downregulation of STAT3 may be a potential mechanism in which metformin stimulates NK cells. Conclusions: Here we show evidence that metformin treatment has a direct effect on the innate immune system in patients with HNSCC, inducing an anti-tumorigenic immune response suggesting that metformin continues to be a good candidate to yield improved clinical outcomes in patients with advanced stage HNSCC. Clinical trial information: NCT02325401.
Role of the oral and gut microbiota as a biomarker in locoregionally advanced oropharyngeal squamous cell carcinoma (ROMA LA-OPSCC).
Authors: Oliva Bernal Marc , Schneeberger Pierre H.H. , Taylor Rachel , Rey Victor , Hansen Aaron Richard , Taylor Kirsty , Bayley Andrew , Hope Andrew , Hosni Ali , Bratman Scott Victor , Ringash Jolie , Gilbert Ralph William , Weinreb Ilan , Perez-Ordonez Bayardo , Waldron John , Xu Wei , Guttman David , Siu Lillian L. , Coburn Bryan , Spreafico Anna 
Published: May 2019

6045 Background: The ROMA LA-OPSCC ( NCT03759730) study prospectively evaluated the oral and gut microbiota in a single-centre cohort of LA-OPSCC patients (pts) receiving chemoradiotherapy (CRT). Methods: LA-OPSCC pts treated with definitive CRT (IMRT plus single-agent cisplatin) were eligible. Oral swabs over the tumor site and stool samples were collected at baseline and end of CRT (EOT). Taxonomic profiles were generated by 16S rRNA sequencing. ANOSIM/Kruskal-Wallis tests were used to identify differences between baseline and EOT samples. Results: A total of 96 samples were collected from 24 evaluable pts (100% compliance). Baseline characteristics: median age = 61 (range, 50-71); smoking status current/former/never = 5/11/8; HPV+/- = 23/1; stage I/II/III/IVA = 7/7/9/1; use of antibiotics = 12 pts. In oral swabs, decreased Shannon diversity ( p< 0.01) and changes in abundance (adjusted p value: q< 0.05) of multiple taxa including Prevotella, Veillonella, and Streptococcuswere observed at EOT vs baseline. Stool diversity did not differ between baseline and EOT ( p= 0.42), but abundance of Ruminoccocus and Roseburia decreased ( q< 0.05). CRT-associated changes remained significant when controlled for stage, smoking, antibiotics, cisplatin dose and mucositis grade ( p< 0.01). In HPV+ pts, stage I-II baseline oral swabs had higher relative abundance of Clostridium IV ( p= 0.02) and Escherichia ( p= 0.04) than stage III, which had higher Fusobacterium ( p =0.03) and Gemella ( p< 0.01). Relative abundance of Actinobacteria (p < 0.01), Proteobacteria (p < 0.01) and Firmicutes (p = 0.03) was higher in stool from stage III pts . Akkermansia muciniphila was present in 57% of the stage I-II stool samples, and 11% in stage III ( p= 0.04). Conclusions: CRT in LA-OPSCC is associated with increases in potentially pathogenic genera in the oropharynx. HPV+ stage III disease was associated with higher Fusobacterium in the oropharynx, which has been implicated in tumor metastases, and with decreased prevalence of the immunotherapy-response-associated species Akkermansia in stool. These preliminary observations suggest an opportunity for the evaluation of IO based therapies or manipulation of the gut microbiota in this patient population. Clinical trial information: NCT03759730.
Impact of tobacco smoking on radiotherapy outcomes in 1875 HPV-positive oropharynx cancer patients.
Authors: Lassen Pernille , Huang Shao Hui , Su Jie , O'Sullivan Brian , Waldron John , Andersen Maria , Primdahl Hanne , Johansen Jorgen , Kristensen Claus , Andersen Elo , Alsner Jan , Lilja-Fisher Jacob , Bratman Scott Victor , Spreafico Anna , de Almeida John R. , Xu Wei , Overgaard Jens 
Published: May 2019

6047 Background: This study investigates the impact of smoking on radiotherapy (RT) outcome and survival in a population based cohort of HPV+ oropharynx cancer (OPC). Methods: We identified all OPC with positive p16 staining from 2007 –2015 who received curative IMRT according to approved guidelines in two oncology groups. Associations between smoking and locoregional control (LRC) and distant control (DC) were estimated by competing risk regression. Disease free survival (DFS) and overall survival (OS) were estimated by proportional-hazards regression model. Multivariable analyses (MVA) adjusted for age, gender, performance status (PS), T- and N-category, and treatment regimen. Results: A total of 1875 patients were included. Median age was 59.2 [31.3-86.8]; 79% (1481) were males; 96% (1651) had PS <2; 71% (1337) received concurrent chemo-radiotherapy (CRT) +/- hypoxic modification (Nimorazole); and 538 (29%) received RT alone +/- Nimorazole. 23% (425) were current smokers (at time of diagnosis) and 46% (853) were ex-smokers. Median smoking pack-years (PY) was 20.1 in the total cohort, and higher in current smokers vs ex-smokers (38 vs 20 PY, p<0.001). 63% of current smokers had >30 PYs. Median follow-up was 4.8 years. Actuarial 5-year univariate analysis showed that current smokers had a reduced probability of LRC (85% vs 92%, p=0.002), DC (88% vs 92%, p=0.046), DFS (69% vs 84%, p<0.001), and OS (73% vs 88%, p=<0.001) compared to never-smokers (n=567). Outcomes for ex-smokers and never-smokers were similar. In MVA current smoking retained strong independent significance for LRC (HR 1.73 [1.18-2.53]), DFS (1.79 [1.35-2.36]) and OS (2.06 [1.49-2.84]). However, DC was not significantly influenced by current smoking status (1.27 [0.83-1.95]). Similar observations were found for >30PY. Conclusions: Heavy lifetime and current smoking negatively impacts LRC and survival in HPV+ OPC. While smoking mediated hypoxia could interfere with RT efficacy, a putative impact on tumor biology remains uncertain in the absence of a detriment to distant metastasis risk. The findings support encouraging smoking cessation to improve therapeutic efficacy of RT and to avoid excess smoking related mortality.
Racial disparities in outcome among head and neck cancer patients in the United States: An analysis using SEER-Medicare linked database.
Authors: Suzuki Ikumi , Cullen Kevin J. , Mehra Ranee , Bentzen Søren , Goloubeva Olga G. 
Published: May 2019

6051 Background: Despite overall decline in cancer mortality, African Americans suffer from higher mortality in most cancer types including cancers of the head and neck. These differences likely result from a complex interplay of clinical and non-clinical factors. We aim to estimate disparities in overall survival across racial groups in HNSCC in the United States. Methods: This study used SEER-Medicare linked database. We identified all patients aged 66 years or older diagnosed with HNSCC as their first cancer from 1992 to 2011. We excluded those in HMO, diagnosed by death certificate or autopsy, non-SCC, unknown race, and missing month and/or year of diagnosis. Further exclusions included metastatic disease, salivary gland cancers, receiving no treatment in the first 180 days, and unknown stage. Analytic data set included oropharynx, oral cavity, nasopharynx, hypopharynx, and larynx. Primary treatment was defined as any treatment modality received within 180 days after diagnosis. Overall survival (OS) parameters were estimated across ethnic groups by the Cox regression model stratified by site and stage of cancer at diagnosis, adjusted for clinical and demographic characteristics, and propensity score weighted. Results: Our study population included 15, 547 patients. Median OS was 3.5 years (95% CI: 3.4-3.7) across all ethnic groups. African Americans (AA) had inferior outcome with median OS of 2.0 years (95% CI: 1.9-2.3) compared to 3.7 years (95% CI: 3.6-3.8) for Caucasian Americans (CA) (p < 0.0001). This difference was seen despite AA patients receiving comparable treatments and presenting at similar stage of disease, except for cancers of the oral cavity where AA were more likely to present with advanced disease (67% versus 47%; P < 0.001). The difference was most pronounced in the oropharynx where median OS was 1.9 years (95% CI: 1.7-2.1) for AA and 3.8 years (95% CI: 3.5-4.1) in CA (P < 0.0001). AA also had consistently worse OS over time from 1992 to 2011. This study clearly demonstrated AA have inferior outcomes despite similar treatments, comorbidities, age at diagnosis, stage at presentation, tumor location, year of diagnosis and sex. Conclusions: The current study demonstrates inferior overall survival for African American head and neck cancer patients independent of primary site and treatment modalities.
Safety of radiotherapy with concurrent and adjuvant MEDI4736 (durvalumab) in patients with locoregionally advanced head and neck cancer with a contraindication to cisplatin: NRG-HN004.
Authors: Mell Loren K. , Torres-Saavedra Pedro A. , Wong Stuart J. , Chang Steven , Kish Julie Ann , Minn Andy , Jordan Richard C. , Liu Tian , Truong Minh Tam , Bauman Julie E. , Powell Steven Francis , Khomani Abderrahim , Riaz Muhammad Kashif , Raben David , Le Quynh-Thu 
Published: May 2019

6065 Background: MEDI4736 (durvalumab), a PD-L1 inhibitor, has shown promising antitumor activity and safety in head and neck squamous cell carcinoma (HNSCC). A phase II/III trial with lead-in component was designed to evaluate the safety and efficacy of concurrent and adjuvant MEDI4736 with radiation therapy (RT) for HNSCC patients with a contraindication to cisplatin. Safety data for 10 patients on the lead-in study are reported. Methods: Eligible patients had previously untreated locoregionally advanced unresected SCC of the larynx, hypopharynx, oropharynx (OPX), oral cavity, or unknown head/neck primary (AJCC 7th stage III-IVB). Contraindications to cisplatin included renal or hearing impairment, age ≥ 70 with moderate or severe comorbidity/vulnerability to cisplatin, or age< 70 with severe comorbidity/vulnerability, based on 6 validated indexes. Intravenous MEDI4736 1500 mg was delivered at weeks -2, 2, 6, 10, 14, 18, and 22 with RT (70 Gy in 35 daily fractions weeks 1-7). The primary endpoint was dose-limiting toxicity (DLT), defined as a high-grade adverse event (AE; NCI CTCAE version 4.0) definitely/probably related to MEDI4736 up to 4 weeks following completion of RT; 0-2 DLTs in 8 evaluable patients was considered acceptable. Results: Characteristics of the 10 enrolled patients were: 30% age ≥ 70, 90% male, 100% Caucasian, 40% ECOG performance status 0, 60% modified Charlson Comorbidity Index ≥ 1, 60% >10 pack-years, 20% larynx, 60% p16+ OPX, 50% T3-4 and 80% N2-3 disease. All 10 patients had ≥ 2 contraindications to cisplatin. All 10 patients completed RT and were evaluable. 8 of 10 patients received all 7 doses of MEDI4736 and 1 patient is still on MEDI4736 after 6 doses. 1 patient received 2 doses then discontinued due to AE (diarrhea possibly related to MEDI4736). No DLTs were observed. No grade 4-5 AEs were observed. Grade ≥ 3 AEs possibly related to MEDI4736 were: diarrhea (n=1), nausea (1), and vomiting (1). No grade ≥ 3 AEs were rated as definitely or probably related to MEDI4736. Conclusions: MEDI4736 is safe and feasible to administer concurrently with RT for patients with HNSCC with a contraindication to cisplatin. Clinical trial information: NCT03258554.
Safety of nivolumab and ipilimumab in combination with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Authors: Johnson Jennifer Maria , Bar Ad Voichita , Lorber Emily , Poller Dawn , Luginbuhl Adam , Curry Joseph M. , Cognetti David M. , Keith Scott W. , Axelrod Rita Susan , Zinner Ralph , Rodeck Ulrich , Harshyne Larry , Argiris Athanassios 
Published: May 2019

6070 Background: Standard cisplatin-based chemoradiotherapy for LA SCCHN is associated with toxicity and less than desirable survival in high-risk patients (pts). The combination of the anti-PD1 antibody nivolumab (nivo) and the anti-CTLA-4 antibody ipilimumab (ipi) has been effective in melanoma and renal cell carcinoma and is under investigation in other solid tumors including SCCHN. Combining RT and immunotherapy (IO) has a strong preclinical rationale and is being evaluated in the clinic. This pilot trial combines IO and RT to build upon these observations. Methods: We enrolled previously untreated high-risk pts with AJCC 7th edition stage IVA-IVB SCCHN of the oral cavity, oropharynx (OP), hypopharynx, larynx. HPV+ OP tumors were T4, or N2c or N3 by AJCC 7th edition criteria. Nivo 3 mg/kg was administered every 2 weeks IV x 17 doses and ipi 1 mg/kg every 6 weeks x 6 doses beginning 2 weeks before IMRT 2 Gy/fraction/day given to total dose 70 Gy. The primary safety endpoint was acute in-field toxicity. Exploratory correlative studies include tumor PD-L1 expression, tumor immune bias, and exosome quantity and composition. The total sample size is 24 pts with 12 enrolled in the first stage and 12 in the expansion cohort. Results: A planned safety analysis was performed in the first 12 pts (8 OP; 1 hypopharynx; 3 larynx). No acute grade (G) 4 or dose-limiting toxicities were seen. Acute G 3 in-field toxicity occurred during RT in 50% of pts: dysphagia (4 pts), mucositis (3), odynophagia (2), hoarseness (1), dermatitis (1). 50% of pts had immune-related toxicity at any time. 3 pts discontinued treatment at > 3 months post RT: 1 for an immune-related cause (G 3 colitis that resolved with steroids), and 2 for non-immune-related causes (1 G 5 bleeding due to carotid rupture secondary to an in-field ulcer at 4 months post RT in a pt with complete response and 1 G 3 OP ulcer resolving with hyperbaric oxygen). 1 pt with a laryngeal primary developed a solitary lung metastasis vs new primary 6 months post RT. 10 of 12 pts are alive with no evidence of disease (follow up 7.2-18.4 months). Conclusions: Preliminary results with this non-platinum-containing RT plus IO regimen are encouraging. Longer follow-up is needed for assessment of late effects and efficacy. Enrollment is ongoing in the expansion cohort. This study is supported by BMS. Clinical trial information: NCT03162731.
Phase II study: Induction chemotherapy and transoral surgery as definitive treatment (Tx) for locally advanced oropharyngeal squamous cell carcinoma (OPSCC)—An update and retrospective review of non-study patients.
Authors: Siegel Robert S. , Joshi Arjun , Taheri Reza , Sadeghi Nader , Thakkar Punam , Vongpachith Anonglack , Goodman Joseph 
Published: May 2019

6072 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 (AJCC 7th edition) OPSCC patients (pts) with an ECOG < 2 and GFR > 50 cc. Induction cisplatin 75 mg/m2 and docetaxel 75 mg/m2 was administered every 21 days for 3 cycles. Patients then underwent TORS and neck dissection(s). At post-op visits, flexible laryngoscopy, blood tests, and imaging with PET/CT and/or MRI were done. Short and long term toxicity, progression-free survival, overall survival, and quality of life (QOL) were evaluated in all pts. Results: Twenty oropharyngeal pts were treated, 19 were male, 17 were Caucasian, and 19 were HPV+. Median age at dx was 57. Three pts were stage III, and 17 were stage IVA. Pathologic CR at the primary site occurred in 15 pts and CR among LN neck dissections occurred in 13 pts. Four pts were given dose-reduced chemo and 1 pt was changed to carboplatin per protocol because of renal dysfunction. Pre vs post tx QOL scores did not change. At a mean follow-up of 33 months (range 19.6 to 44.1), 18 pts are alive and NED. Three pts recurred a mean of 2.2 mos after surgery, and were treated with salvage CRT. Two pts died of metastatic disease, the third is alive and well. All 3 pts had positive LN (9 LN, 3 LN and 1 LN) at surgery. A fourth pt had 12 pos LN and received radiation. He has not recurred. A retrospective review of an additional 20 twenty pts treated in the same way, were also reviewed for efficacy. Mean age was 61.5. Two pts died of metastatic disease. Fourteen pts have been followed for > 7 mos, and their mean overall survival is 44 mos. Conclusions: Cisplatin + docetaxel followed by TORS & neck dissection(s) appears to be an effective model for the definitive treatment for OPSCC, while avoiding the adverse effects of RT.