bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bisphosphonates in the adjuvant setting of breast cancer therapy: Effect on survival—A systematic review and meta-analysis.
Authors: Vidal Liath , Ben-Aharon Irit , Rizel Shulamith , Yerushalmi Rinat , Sulkes Aaron , Stemmer Salomon M. 
Published: March 2020

548 Background: The role of bisphosphonates (BP) in the adjuvant setting in breast cancer has been evaluated in several studies, yielding inconsistent evidence. We performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluate the effects of BP treatment on survival in patients with early breast cancer in the adjuvant setting. Methods: RCTs that compared BP therapy in addition to the standard adjuvant therapy (cytotoxic or hormonal) with standard adjuvant therapy only were identified by searching the Cochrane Library, LILACS, MEDLINE databases and conference proceedings (12.2011). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled. All statistical tests were two-sided. Results: Thirteen trials met the inclusion criteria., among which are the two recently published abstracts of large scale RCTs (NSABP-B34, GAIN) evaluating a total of 15,762 patients. Ten trials reported the OS outcome. Meta-analysis revealed no statistically significant benefit for BP (HR 0.89, 95% CI = 0.79 to 1.01). Nine trials reported the DFS outcome. Meta-analysis revealed no statistically significant better DFS for the intervention (HR 0.95 (0.80-1.11)). Six trials reported DFS stratified upon menopausal status. Postmenopausal patients who were treated with BP therapy had statistically significant better DFS than the control group (HR 0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated with HR of OS (coefficient, -0.23; standard error, 0.144). BP therapy resulted in less fractures in the intervention arm, but higher incidence of osteonecrosis of the jaw and pyrexia. Conclusions: Our meta-analysis indicates a positive effect for adjuvant BP on survival outcomes only in postmenopausal patients with breast cancer. Meta-regression appraised the effect of confounders such as chemotherapy, showed a negative association between chemotherapy use and the effect of bisphosphonates on survival. Further large scale RCTs are warranted to unravel the specific subgroups and adjuvant treatments that would benefit from the addition of BP in the adjuvant setting.
DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Cohen Ezra E. W. , Karrison Theodore , Kocherginsky Masha , Huang Chao H , Agulnik Mark , Mittal Bharat Bhushan , Yunus Furhan , Samant Sandeep , Brockstein Bruce , Raez Luis E. , Mehra Ranee , Kumar Priya , Ondrey Frank G. , Seiwert Tanguy Y. , Villaflor Victoria Meucci , Haraf Daniel J. , Vokes Everett E. 
Published: March 2020

5500 Background: IC is associated with lower distant failure (DF) rates in SCCHN but an improvement in overall survival (OS) has not been validated. The goal of this trial was to determine whether IC prior to chemoradiotherapy (CRT) improves survival compared to CRT alone. Methods: In this phase 3, open-label trial, subjects with pathologically confirmed SCCHN; N2/N3 disease without metastases; no prior therapy; KPS ³ 70%; and intact organ function were randomized to CRT alone (CRT arm) [5 days of D (25 mg/m2), F (600 mg/m2), hydroxyurea (500 mg BID), and RT (150 cGy BID) followed by a 9 day break] or to 2 cycles of IC [D (75 mg/m2), P (75 mg/m2), F (750 mg/m2 day 1-5)] followed by the same CRT (IC arm). Primary endpoint was OS. Secondary endpoints included DF free survival, failure pattern, and recurrence-free survival (RFS). 280 subjects provided 80% power to detect a hazard ratio HR=0.5 for OS (a=0.05). Results: 280 subjects were accrued from 2004-09 with minimum follow-up 24 months. Of 142 patients randomized to IC, 91% received 2 cycles and 87% continued to CRT. Treatment adherence during CRT was high for docetaxel and hydroxyurea, but fewer than 75% of the patients received target dose of 5FU in both arms. RT was delivered without major deviations in 94% and 95% of patients on IC and CRT arms, respectively. The most common grade 3-4 toxicities during IC were febrile neutropenia (9%) and mucositis (8%), and during CRT (both arms combined) they were mucositis (45%), dermatitis (19%), and leukopenia (17%). Only grade 3-4 leukopenia and neutropenia rates were significantly higher in IC (p=0.002 and p=0.02, respectively). Table shows efficacy. Conclusions: High survival rates were observed in both arms. Further analysis and follow-up may provide insight into why the significant decrease in DF did not translate into improved OS. [Table: see text]
PD-1:PD-L1(B7-H1) pathway in adaptive resistance: A novel mechanism for tumor immune escape in human papillomavirus-related head and neck cancers.
Authors: Lyford-Pike Sofia , Peng Shiwen , Taube Janis M. , Westra William H. , Akpeng Belinda , Wang Hao , Drake Charles G. , Chen Lieping , Topalian Suzanne Louise , Pardoll Drew M. , Pai Sara I 
Published: March 2020

5506 Background: Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) are associated with a strong host immune response. Despite ample tumor infiltrating lymphocytes (TILs), the cancer is able to persist and grow. Here, we provide evidence for an adaptive immune resistance mechanism mediated through the PD-1:PD-L1 pathway. Methods: We evaluated the peripheral blood and tumor infiltrating lymphocytes for PD-1 expression using flow cytometry in HPV-HNSCC patients. We evaluted PD-L1 expression within the tumors using immunohistochemistry. We performed functional assays evaluating IFN-gamma secretion of PD-1+ and PD-1(-) CD8+ T cells isolated from the tumor microenvironment of PD-L1+ and PD-L1(-) HPV-related head and neck cancers. Results: We found the majority of CD8+ TILs in HPV-HNSCC express the PD-1 co-inhibitory receptor. We report a striking association between expression of its ligand PD-L1 on tumor cells and tumor associated macrophages, and the presence of TILs. Interestingly, membranous PD-L1 staining on tumor cells and CD68+ antigen presenting cells was geographically localized to the periphery of tumor nests and juxtaposed to fronts of infiltrating T cells. Functional assays demonstrated that PD-1-dependent T cell inhibition required expression of PD-L1 in the tumor microenvironment. Finally, we report localized expression of PD-L1 in the deep crypts of normal tonsils, the site of HPV infection and origin of HPV-HNSCC. Conclusions: Our findings support the role of the PD-1:PD-L1 interaction in creating an immune-privileged site for initial viral infection and subsequently adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.
Safety of everolimus for women over 65 years of age with advanced breast cancer (BC): 12.5-mo follow-up of BOLERO-2.
Authors: Pritchard Kathleen I. , Burris Howard A. , Rugo Hope S. , Gnant Michael , Baselga José , Piccart-Gebhart Martine J. , Noguchi Shinzaburo , Dakhil Shaker R. , Srimuninnimit Vichien , Puttawibul Puttisak , Osborne Karen , Mukhopadhyay Pabak , Taran Tanya , Sahmoud Tarek , Campone Mario , Hortobagyi Gabriel N. 
Published: March 2020

551 Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE); but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized, trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 mo median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients <65 (HR = 0.37; P < .05) or ≥65 years of age (HR = 0.56; P < .05). Adverse events (AEs) of special interest (all grades) occurring more frequently with EVE vs PBO (overall study population) included stomatitis (66.6% vs 11.3%), infections (50.4% vs 25.2%), rash (44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia (15.4% vs 2.5%). Elderly EVE-treated patients (≥65 years) had similar or marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis (14.6%), and hyperglycemia (12.5%) compared with the overall population. Grade 3/4 AEs in patients ≥70 years of age (n = 161) reported only among patients receiving EVE (n = 118) included fatigue (10.2%), anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea (6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). Conclusions: Adding EVE to EXE was well tolerated in the overall population and in elderly patients with advanced BC; grade 3/4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE.
Role of c-MET pathway in the outcome prediction of cetuximab-based therapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Authors: Casado Victoria , Arranz Juan Luis , Zazo Sandra , Martin Valades Jose Ignacio , Madoz Juan , Domine Manuel , Perez-Gonzalez Nuria , Lobo Francisco , Rincon Raul , Rubio Gustavo , Canadas Carmen , Leon Ana , Izarzugaza Yann , Campos Angel , Serrano Gloria , Carames Cristina , Rojo Federico , Garcia-Foncillas Jesus 
Published: March 2020

5520 Background: Activation of the c-MET oncogene promotes tumor growth, invasion and metastasis in several tumor types. In addition, c-MET has been reported in consort with EGFR and/or be activated as a compensatory pathway in the presence of EGFR blockade resulting a mechanism of acquired resistance to EGFR inhibitors in lung and colorectal carcinoma. We investigated the impact on cetuximab sensitivity of HGF, c-MET, c-MET activation and c-MET gene status in recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) patients. Methods: A single-institution retrospective analysis including 50 HNSCC patients was carried out. For each case, formalin-fixed tumor specimens were assayed for HGF, total and phosphorylated Y1234/35 c-MET (p-c-MET) by immunohistochemistry and c-MET gene by FISH. Overexpression criteria were defined by ROC curves for each protein and amplification was defined by >2 copies in at least two of the three studied tumor areas. Results were analyzed for association with clinico-pathological features and survival outcomes for cetuximab-treated patients (median follow-up 75 months). Results: c-MET overexpression was detected in 26 (52%) of patients, c-MET amplification in 15 (30%) and p-c-MET in 12 (24%). Amplification was associated with c-MET overexpression (p=0.004). HGF overexpression was observed in 8 (12%) associated with c-MET phosphorylation (p=0.001), suggesting a paracrine activation of receptor. No significant association with clinico-pathological parameters was detected. Log-rank test showed significantly worse outcome in c-MET overexpressing patients for progression-free (PFS) (p=0.002) and overall survival (OS) (p=0.045); p-c-MET was correlated with worse PFS (p=0.014) and OS (p<0.001). In multivariate logistic regression analysis, p-c-MET was an independent prognostic factor for PFS (HR 6.5; 95% CI 1.5-8.9). Conclusions: HGF/c-MET pathway correlated with worse outcome in cetuximab-based regimen treated HNSCC patients, acting as a resistance mechanism for EGFR inhibitors and supporting a dual blocking HGF/c-MET and EGFR pathways for treatment of these patients.
Outcomes of HIV patients treated with chemoradiotherapy (CRT) for squamous cell carcinoma of the head and neck (SCCHN).
Authors: Mourad Waleed Fouad , Hu Kenneth , Shourbaji Rania Ayman , Li Zujun , Culliney Bruce , Harrison Louis Benjamin 
Published: March 2020

5531 Background: SCCHN with HIV is a challenging clinical situation in the medical arena due to limited data. We report our outcomes and the impact of chemotherapy (CT) and HPV on this patient (pt) population Methods: This is a single institution retrospective study of 71 HIV pts with SCCHN treated from 1998-2011. The median age at RT and HIV diagnosis was 51 (32-72) and 34 (25-50) respectively. HIV duration was 11 yrs (6-20). Stage I-II, III and IV were 22, 27 and 51% respectively. Pts treated with RT alone were 37% and CRT 63% {CDDP 91%}. Fifty pts were on HAART during treatment and 50% of pts with SCC of the oropharynx were HPV+. Median dose of 70, 63 and 54 Gy were delivered at 1.8-2 Gy/fraction to gross disease, high and low risk neck respectively. Twelve pts (17%) underwent neck dissection for N3 Results: With a median follow up of 50 months (12-140) the median weight loss was 20 lbs (6-40). Acute skin desquamation and mucositis grades ≤ 2 and 3 were 76 and 24% respectively. Treatment breaks ≥ 10 and 5 days were 7 and 21% respectively. One pt died from induction CT, 1 was hospitalized for grade 4 mucositis and 1 developed osteoradionecrosis during CRT. Late dysphagia grades ≤ 2, 3 and 4 were 74, 15 and 11%. Late xerostomia grades ≤ 2 and 3 were 77 and 23% respectively. The median CD4 count and viral load before, during and after treatment were 370, 135, 100 and 0, 160, 260 respectively. Seven pts (10%) developed second primary malignancy. The 4 yr locoregional control (LRC) and overall survival (OS) were 69% and 55% respectively. Chi-square test shows significant relationship between LRC and RT duration, as well as between CT and lower CD4 counts and higher viral load (P=0.001). Positive trends were observed between (weight loss ≤10% and LRC) and (absence of second malignancy and OS) (P=0.271). There was no significant relationship between HPV +ve or CT on either LRC or OS. Conclusions: The addition of CT to RT yielded higher morbidity and mortality without clear benefit on LRC or OS. HIV per se seems to have a -ve impact on HPV +ve pts outcomes. Comparing observed rates of LRC and OS, our data show that RT±CT administered for HIV +ve pts with SCCHN appears to be less effective than HIV-ve pts. Larger size studies are warranted to optimize the management of this growing patient population.
Gingival cancer: 11 year follow-up at Karolinska University Hospital (2000-2010).
Authors: Simonoska Rusana 
Published: March 2020

5536 Background: In Sweden, approximately 500-600 cases of oral cancer are diagnosed every year. These include cancer of the gingiva, retromolar trigonum, bucca, hard palate, tongue and floor of the mouth. Each year, around 15 cases of gingival cancer (GC) are diagnosed in the Stockholm region. The goal of this study was to study the onset of symptoms, treatment, prognosis, and sequelae of GC in order to optimize the treatment. Methods: The study consists of a retrospective review of medical records of all diagnosed cases of GC in Stockholm region between 2000-2010, identified through the ENT-clinic Karolinska Hospital patient database. Results: Our retrospective study comprised 156 patients diagnosed with GC. The average age was 72 years sharing equally between the sexes, 50% were smokers. 98% had a squamous cell carcinoma (scc). Presenting symptoms were often lump or ulceration in the gums, pain, bleeding or discomfort/misfit of dentures. Around 30% had premalignant lessons in the oral cavity before diagnosis. 3/4-th of all GC was localized in the lower jaw. 66% of the GC-patients presented as aT4 cancer. At presentation, 26% had a regional metastasis and of those 90% had their primary tumor in the lower jaw. Six cases had bilateral neck disease. 81% of the patients with regional metastasis had low to medium grade of scc differentiation of the primary tumor. 84% of all patients with regional metastasis had a T4 primary tumor. Neck dissection was performed in 38% (n=59). Of these 35 cases where staging neck, i.e. N0 at presentation and in 7 cases (20%) a positive neck disease was found. The risk for second primary was 15%. The overall 5-year survival was 24%. Conclusions: Advanced age and high number of T4 cancer at diagnosis partly explains the poor survival statistics. Almost 30% of the patients in our material have had premalignant lessons in the oral cavity before the cancer diagnosis and are at high risk for new tumors (second primary); therefore patients with GC should be followed up for at least 5 years, possibly longer in the presence of premalignant lessons. GC of the lower jaw is more likely to metastasize than GC of the upper jaw. Due to 20% occult metastasis occurrence in the staging neck cases, we recommend staging neck dissection for patients with GC.
Efficacy of concurrent cetuximab (C225) versus 5-fluorouracil/carboplatin (5FU/CBDCA) or cisplatin (CDDP) with intensity-modulated radiation therapy (IMRT) for locally advanced head and neck cancer (LAHNSCC).
Authors: Shapiro Lauren Quinn , Sherman Eric Jeffrey , Koutcher Lawrence , Setton Jeremy , Zhang Zhigang , Shi Weiji , Rao Shyam S. , Fury Matthew G. , Wolden Suzanne L. , Kraus Dennis , Pfister David G. , Lee Nancy Y. 
Published: March 2020

5537 Background: We reported inferior outcomes for LAHNSCC patients (pts) that received concurrent C225 vs. high-dose CDDP with IMRT (IJROBP 2011; 81:915). Prior to FDA approval of C225 for LAHNSCC, non-CDDP candidates at our institution were treated with 5FU/CBDCA (JNCI 1999; 91:2081). The purpose of this study was to compare the outcomes of concurrent C225 vs. 5FU/CBDCA vs. CDDP with IMRT for LAHNSCC. Methods: Retrospective review of records was performed for pts treated at MSKCC with concurrent C225 (n=49) vs. 5FU/CBDCA (n=52) vs. high-dose CDDP (n=259) and IMRT from 11/02 to 04/08. Overall survival (OS), locoregional failure-free survival (LRFS), and late toxicity for all pts and oropharyngeal subset were obtained. Outcomes were analyzed using univariate/multivariate Cox proportional hazards model or competing-risks analysis. Multivariate OS analysis was confirmed by propensity score adjustment. Results: Pts were similar with regard to site, overall stage, and alcohol/tobacco history. Compared to pts treated with CDDP, those who received C225 or 5FU/CBDCA were older, with lower performance status, higher Charlson score, higher T stage, and worse renal function. With median follow-up of 53.1 months for survivors, the 4-year OS was 40.9% (95% CI 26.0-55.2%) for C225 vs. 70.2% (95% CI 55.5-80.9%) for 5FU/CBDCA vs. 86.9% (95% CI 82.0-90.6%) for CDDP. Compared with CDDP, C225 (hazard ratio [HR] 4.01, p<0.0001) but not 5FU/CBDCA (HR 1.54, p=0.15) was associated with worse OS on multivariate analysis. Propensity score analysis yielded a HR of 2.76 (p=0.01) for treatment with C225 vs. platinum-based chemotherapy. 4-year actuarial LRF for 5FU/CBDCA was similar to CDDP (9.7% vs. 6.3%, HR 1.51, p=0.42 by Gray’s method) and significantly lower than C225 (40.2%, HR 4.95, p=0.002). Late toxicity was as follows: C225 (6.1%) vs. CDDP (7.7%) vs. 5FU/CBDCA (21.2%). Conclusions: After adjusting for independent risk factors, there was no significant difference in OS or LRFS between 5FU/CBDCA and high-dose CDDP, but C225/RT resulted in significantly inferior OS and LRFS. Late toxicity was worst with 5FU/CBDCA.
Phase II trial of everolimus in patients with previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).
Authors: Varadarajan Prakash , Kotsakis Athanasios Panayotis , Martin Daniel , Gutkind Jorge Silvio , Gibson Michael K. , Argiris Athanassios 
Published: March 2020

5541 Background: The PI3K/Akt/mTOR pathway plays an important role in SCCHN pathogenesis and resistance to treatment. We conducted a phase II study of everolimus, an oral inhibitor of mTOR, in patients with refractory SCCHN. Methods: Patients with recurrent or metastatic SCCHN treated with at least 1 prior regimen, performance status (PS) 0-2, and adequate organ function, received everolimus 10 mg once daily orally. The primary endpoint was the disease control rate (DCR) defined as the proportion of patients with a complete response, a partial response, or stable disease. A two-stage design was followed. Cytokines were measured in plasma and serum at baseline and post treatment. Results: 9 patients were enrolled. Median age 63 years (range 51 - 82), Male/Female, 6/3, performance status 0/1/2, 2/5/1. Primary site: oropharynx (2), oral cavity (4), larynx (1), others (2). Median number of palliative therapies in the recurrent/metastatic setting prior to study was 1 (range 1- 4). Median number of cycles of everolimus delivered was 1 (range 1-5). No objective responses were seen. One patient had stable disease that lasted 6 months but all other patients had progression as best response. DCR was 11%. Median progression-free survival was 40 days. Four patients have died due to disease progression. Grade 3 adverse events were infrequent: pain (2 patients), anemia (2 patients), and 1 patient each with pruritus, hypertransaminasemia, hyponatremia, lymphopenia, and fatigue. No Grade 4 toxicities were reported. Biomarker analysis in 2 patients with available post treatment samples showed reduced plasma levels of VEGF-A, Gro-α, and IL-17, after everolimus treatment, but no reduction was observed in the plasma levels of IL-6 and IL-8, two cytokines often associated with SCCHN disease progression. Conclusions: Everolimus as monotherapy was well tolerated but did not have sufficient activity in this setting. This phase II study did not meet the predefined primary endpoint in the first stage of accrual.
Recurrent/metastatic salivary gland malignancies (RMSGM): Final report of 60 cases treated with cisplatin plus vinorelbine (DDP+VNB).
Authors: Pedani Fulvia , Airoldi Mario , Garzaro Massimiliano , Raimondo Luca , Carnio Simona , Fora Gianluca , Giordano Carlo , Pecorari Giancarlo 
Published: March 2020

5548 Background: RMSGM are not amenable to the usual treatment with surgery and post-operative radiotherapy. The role of chemotherapy (CT) for RMSGM is palliative only. VNB showed moderate activity in our experience (Bull Cancer 85:892;1998) and in a randomized phase II trial we had demonstrated that the DDP+VNB combination had a better outcome than VNB alone (Cancer 91:541; 2001). In this abstract we report the final results of this combination in 60 cases. Methods: From April 2001 to February 2009 , 60 cases with RMSGM were enrolled. All patients received the following regimen: DDP 80 mg/sm d.1 + VNB 25 mg/sm d. 1,8 every 3 weeks. The study foresees a maximum of 6 cycles. Results: Patients characteristics were as follows: 35 males (58%) and 25 females (42%).; median age: 56 yrs (range 20-68); median ECOG PS: 1 (0-2); histology: adenocarcinoma 15 (25%), adenoid cystic ca. 34 (57%), others 11 (18%); site of disease: local 30 (50%) , mts +/- local 30 (50%). Forty-two pts received DDP+VNB as first line CT (70%) while 18 pts (30%) had the combination as second-line CT (30%). After a median of 5 cycles of first line DDP+VNB responses were: 3 CR (7%), 10 PR (24%), 14 NC (33%) and 15 PD (36%). After a median of 4 cycles of second line CT responses were: 0 CR; 1 PR (5%), 6 NC (33%) 11 PD (62%). Median survival: 10 months (3-29) for first line CT ; 4 months (1-12) for second line CT. G3-4 toxicity: neutropenia (20%), anemia (12%), nausea/vomiting (12%) , peripheral toxicity (3%). Conclusions: DDP+VNB is an effective first line CT in RMSGM ; second line CT has a low palliative activity. Toxicity seems acceptable. This regimen could be suitable for an integration with new biologic target agents.