Human Papillomavirus-negative Oropharyngeal Cancer Research Articles

Predictive potential of dynamic contrast-enhanced MRI and plasma-derived angiogenic factors for response to concurrent chemoradiotherapy in human papillomavirus-negative oropharyngeal cancer.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascularity, which depends on the process of angiogenesis and affects tumour response to treatment. Our study explored the associations between DCE-MRI parameters and the expression of plasma angiogenic factors in human papilloma virus (HPV)-negative oropharyngeal cancer, as well as their predictive value for response to concurrent chemoradiotherapy (cCRT). Twenty-five patients with locally advanced HPV-negative oropharyngeal carcinoma were prospectively enrolled in the study. DCE-MRI and blood plasma sampling were conducted before cCRT, after receiving a radiation dose of 20 Gy, and after the completion of cCRT. Perfusion parameters ktrans, kep, Ve, initial area under the curve (iAUC) and plasma expression levels of angiogenic factors (vascular endothelial growth factor [VEGF], connective tissue growth factor [CTGF], platelet-derived growth factor [PDGF]-AB, angiogenin [ANG], endostatin [END] and thrombospondin-1 [THBS1]) were measured at each time-point. Patients were stratified into responders and non-responders based on clinical evaluation. Differences and correlations between measures were used to generate prognostic models for response prediction. Higher perfusion parameter ktrans and higher plasma VEGF levels successfully discriminated responders from non-responders across all measured time-points, whereas higher iAUC and higher plasma PDGF-AB levels were also discriminative at selected time points. Using early intra-treatment measurements of ktrans and VEGF, a predictive model was created with cut-off values of 0.259 min-1 for ktrans and 62.5 pg/mL for plasma VEGF. Early intra-treatment DCE-MRI parameter ktrans and plasma VEGF levels may be valuable early predictors of response to cCRT in HPV-negative oropharyngeal cancer.

Rising incidence of HPV positive oropharyngeal cancer in Taiwan between 1999 and 2014 where betel nut chewing is common

BackgroundThe incidence of human papillomavirus (HPV) positive oropharyngeal cancer (OPC) is rising but HPV negative OPC is decreasing in Western countries. In Taiwan, the incidence of HPV negative OPC is common but the incidence of HPV positive OPC remains unknown. The objective of this study is to estimate the incidence trend and the survival of HPV positive OPC in Taiwan.MethodsBetween 1999 and 2014, primary tumor tissues from 425 incident OPCs were obtained from 5 medical centers in Taiwan. 408 OPCs were evaluated by the EasyChip HPV genotyping (King-Car, I-Lan, Taiwan) and 369 OPCs by p16 staining. The clinical data were retrospectively obtained from the medical records.ResultsIn our study, 29% of OPCs were HPV positive. The percentage of HPV positive OPC was stable from 1999 to 2014 (25% (1999–2002), 30% (2003–2006), 30% (2007–2010), 29% (2011–2014)). The estimated crude incidence rate of HPV positive OPC increased significantly from 0.62 (1999–2002), 1.06 (2003–2006), 1.52 (2007–2010) to 1.74 (2011–2014) per 100,000 person-year. The sensitivity and specificity of p16 staining for positive HPV infection were 92% and 91%, respectively. The 5-year overall survival rates for patients with HPV positive OPC and with HPV negative OPC were 67.8% and 49.0%, respectively (HR = 0.52 (0.35–0.76), p = 0.0005). Patients with HPV positive OPC but no betel nut/cigarette exposure had the best overall survival (5-year: 88.2%, p < 0.0001). Patients with HPV negative OPC and betel nut/cigarette exposure had the worst overall survival (5-year: 46.6%, p < 0.0001). Patients with HPV positive OPC but also with betel nut/cigarette exposure had poorer 5-year overall survival (48.3%, p < 0.01).ConclusionThe incidence of HPV positive OPC is increasing along with HPV negative OPC, which leads to stably low percentage of HPV positive OPC in Taiwan. HPV positive OPC may become an important head and neck cancer when the incidence of HPV negative OPC declines in the near future. P16 is a useful surrogate marker for HPV infection in OPC and a good prognostic indicator for treatment outcome of OPC. Patients with HPV positive OPC but no betel nut/cigarette exposure has an excellent prognosis. Betel nut/cigarette exposure significantly worsens the prognosis of HPV positive OPC.

Therapeutic efficacy of selective intraarterial chemoradiotherapy with docetaxel and nedaplatin for human papilloma virus-negative oropharyngeal cancer

ObjectiveHuman papilloma virus-negative oropharyngeal cancer has not achieved satisfactory outcomes compared with those of human papilloma virus-positive oropharyngeal cancer. This study evaluated the therapeutic efficacy of selective intraarterial chemoradiotherapy with the docetaxel and nedaplatin regimen for human papilloma virus-negative oropharyngeal cancer. MethodsTwenty-two consecutive patients with human papilloma virus-negative oropharyngeal cancer who had undergone selective intraarterial chemoradiotherapy were retrospectively analyzed. The primary tumor and whole neck were irradiated (50 Gy). Subsequently, the primary site and metastatic lymph nodes were boosted by 20 Gy. The intraarterial chemotherapy regimen comprised a combination of nedaplatin (80 mg/m2) and docetaxel (60 mg/m2), which was initially administered at the start of radiotherapy and was given every 4 weeks for three sessions. Each intraarterial dose of an anticancer agent was determined according to the percentage of the tumor volume supplied by the target artery to the total tumor volume, which was intraoperatively measured via cone-beam computed tomography. The outcome measures were locoregional control, disease-free survival, and overall survival rates and adverse events. Statistical analyses were performed using the Kaplan–Meier method. ResultsThe median follow-up period was 59 (range, 15–103) months. The T stage was T1/T2 in 5 patients (23%), T3 in 5 patients (23%), and T4 in 12 patients (54%). Cervical lymph node metastasis was staged as ≥N2c in 7 (32%) patients. Complete response was achieved in all patients at the first imaging examination after intraarterial chemoradiotherapy. The 5-year locoregional control, disease-free survival, and overall survival rates were 96% (95% confidence interval, 0.72–0.99), 91% (95% confidence interval, 0.68–0.98), and 100% (95% confidence interval, not available), respectively. Regarding serious acute adverse events, grade 4 laryngeal edema and leukopenia were observed in 1 (5%) and 11 patients (50%), respectively. No other serious acute adverse events were observed. ConclusionSelective intraarterial chemoradiotherapy with docetaxel and nedaplatin has the potential to achieve favorable locoregional control, disease-free survival, and overall survival rates in human papilloma virus-negative oropharyngeal cancer.

Race, not socioeconomic disparities, correlates with survival in human papillomavirus-negative oropharyngeal cancer: A retrospective study

PurposeInvestigate the impact of black versus white race, socioeconomic status (SES), and comorbidity burden on oropharyngeal cancer (OPC) survival. Materials and methodsThis study retrospectively analyzed patients diagnosed between 1991 and 2012 at an urban tertiary care center with a high volume of head and neck cancer referrals. Data gathered included demographics, human papilloma virus (HPV) status, follow-up time, comorbidities, smoking history, and overall survival. SES was extrapolated from the 2000 and 2010 censuses. Analysis of variance, chi-square tests, multivariable Cox proportional hazards models, Cox proportional hazards regression, Kaplan Meier curves and the log-rank test were utilized. ResultsOf 208 charts reviewed, 192 patients met inclusion criteria. Black patients had significantly (p < 0.001) poorer survival at 1, 2, and 5 years than white patients (5-year survival: 32% vs 64%); this discrepancy persisted in only HPV-negative disease (20% vs 50%). In the HPV-negative subgroup, there was no racial difference in treatment modality received, Charlson Comorbidity Index, and proportion receiving inadequate, noncurative or no treatment. Univariate analysis identified significant differences in median household income, education level, and stage at presentation between black and white subgroups. Multivariate analysis identified white race and HPV-positive status as independent predictors of overall survival, but SES and stage at presentation were not. ConclusionSES did not explain the greater survival in HPV-negative white versus black patients. This indicates that race is an independent predictor of survival; future studies should examine more accurate indicators of SES and genetic differences in tumors of black and white patients.

HPV driven squamous cell head and neck cancer of unknown primary is likely to be HPV driven squamous cell oropharyngeal cancer.

To compare risk factors and survival in people with oropharyngeal cancer (OPC) and cancer unknown primary (CUP). We recruited 5511 people with head and neck cancer between 2011 and 2014. We collected data on age, gender, smoking, sexual behaviour, treatment intent, stage, co-morbidity, p16 protein overexpression and biological samples. We assessed human papillomavirus (HPV) status using serological response and p16 immunohistochemistry. We followed up participants to identify those who had died. We used Cox proportional hazards regression models to estimate survival and adjust for confounders. Of the 4843 people with squamous cell cancer 196 had CUP - a prevalence of 4.0% (95% CI 3.5% to 4.6%). Of those people with OPC and CUP 69% (1150/1668) and 60% (106/178) respectively had HPV driven tumours. People with HPV driven tumours were likely to be younger, male, non-smokers, with higher stage disease, a history of oral sex and less co-morbidity. People with HPV negative CUP and HPV driven CUP had the survival of people with a stage II/III HPV negative OPC and a stage I/II HPV driven OPC respectively. The adjusted hazard ratio for HPV driven OPC and CUP compared with HPV negative OPC and CUP was 0.46 (95% CI 0.35 to 0.59) and 0.34 (95% CI 0.14 to 0.82) respectively. HPV driven CUP is likely to be HPV driven OPC. Identifying effective methods of detecting occult OPC could improve CUP management and allow the detection of early lesions in high risk groups.

The Effect of Human Papillomavirus E6 Oncogene on the Radiosensitivity of Non-Oropharyngeal Cancer Cells

Background:We have previously shown that stable transfection of the human papillomavirus (HPV) E6*I oncogene can sensitize two HPV negative oropharyngeal cancer (OSCC) cell lines to radiation. In the current study, we extended our work on OSCC to determine whether the HPV E6 oncogene can enhance the radiosensitivity of non-OSCC cell lines.Methods:Three non-OSCC cell lines (melanoma, colorectal adenocarcinoma and large cell lung cancer) were stably transfection with the HPV E6 oncogene (E6 total, E6*I and E6*II) and treated with different doses of radiation. Clonogenic assays were used to measure the radiation survival.Results:Following transfection, there was a reduction in the survival of the melanoma cell line after 2 Gy (SF2) from 0.401 (untransfected) to 0.219 (Melanoma-E6 total). This reduction was not evident at higher doses of radiation. There was no significant change in the SF2 of melanoma-E6*I (0.303) and melanoma-E6*II (0.414). The SF2 colorectal adenocarcinoma and large cell lung cancer cell lines did not change significantly after transfection.Conclusions: The radiosensitizing effect of HPV E6 oncogene is cell line specific. We found no clear evidence of a radiosensitising effect of E6 in these three non-OSCC cancer cell lines.

High-resolution microbiome profiling uncovers Fusobacterium nucleatum, Lactobacillus gasseri/johnsonii, and Lactobacillus vaginalis associated to oral and oropharyngeal cancer in saliva from HPV positive and HPV negative patients treated with surgery and chemo-radiation.

Microbiome studies show altered microbiota in head and neck squamous cell carcinoma (HNSCC), both in terms of taxonomic composition and metabolic capacity. These studies utilized a traditional bioinformatics methodology, which allows for accurate taxonomic assignment down to the genus level, but cannot accurately resolve species level membership. We applied Resphera Insight, a high-resolution methodology for 16S rRNA taxonomic assignment that is able to provide species-level context in its assignments of 16S rRNA next generation sequencing (NGS) data.Resphera Insight applied to saliva samples from HNSCC patients and healthy controls led to the discovery that a subset of HNSCC saliva samples is significantly enriched with commensal species from the vaginal flora, including Lactobacillus gasseri/johnsonii (710x higher in saliva) and Lactobacillus vaginalis (52x higher in saliva). These species were not observed in normal saliva from Johns Hopkins patients, nor in 16S rRNA NGS saliva samples from the Human Microbiome Project (HMP). Interestingly, both species were only observed in saliva from Human Papilloma Virus (HPV) positive and HPV negative oropharyngeal cancer patients. We confirmed the representation of both species in HMP data obtained from mid-vagina (n=128) and vaginal introitus (n=121) samples.Resphera Insight also led to the discovery that Fusobacterium nucleatum, an oral cavity flora commensal bacterium linked to colon cancer, is enriched (600x higher) in saliva from a subset of HNSCC patients with advanced tumors stages.Together, these high-resolution analyses on 583 samples suggest a possible role for bacterial species in the therapeutic outcome of HPV positive and HPV negative HNSCC patients.

A 5‑year update of patients with HPV positive versus negative oropharyngeal cancer after radiochemotherapy in Austria.

SummaryBackgroundAfter publishing promising results for the treatment of patients with human papilloma virus (HPV) positive oropharyngeal cancer with radiochemotherapy regarding 2‑year survival, we present an update of the disease-specific and disease-free survival after 5 years.Patients and methodsA total of 29 patients of which 18 were HPV negative and 11 HPV positive with squamous cell carcinoma of the oropharynx received radiation therapy with or without chemotherapy (cisplatin) or immunotherapy (cetuximab) between 2007 and 2009. At time of the present analysis, six patients are still alive including four with HPV positive and two with HPV negative oropharyngeal carcinoma, while 15 out of 16 patients with HPV negative tumors died and 1 died of another cause with evidence of disease.ResultsSince the 2‑year disease-specific survival of patients with HPV positive cancer of the oropharynx was published with 100% versus 30.4% in HPV negative tumors, we now present the 5‑year disease-specific survival after treatment, which was 85.7% in HPV positive versus 11.1% in HPV negative patients.ConclusionWe present the results of patients receiving radiochemo(immuno)therapy for oropharyngeal cancer regarding the HPV status, which is still promising.

The prognostic significance of hypoxia inducing factor 1-α in oropharyngeal cancer in relation to human papillomavirus status

This study examines the prognostic significance of hypoxia inducing factor-1α (HIF-1α) expression in relation to human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma (SCC). Clinical details on 233 oropharyngeal SCCs were extracted from institutional databases. Recurrence in any form or death from any cause was recorded for a median of 51 months after diagnosis. HIF-1α expression was evaluated by semiquantitative immunohistochemistry and HPV status was determined by HPV E6-targeted multiplex real-time PCR and p16 immunohistochemistry. Determinants of recurrence and mortality hazards were modeled using Cox regression with censoring at dates of last follow-up. The HIF-1α positivity rate was 58.8%. HIF-1α positivity was associated with higher T category (T3/T4 vs. T1/T2, 64.2% vs. 48.4%, p=0.001) and lower grade (Grade 1-2 vs. 3, 62% vs. 46.9%, p=0.001). There was no significant association between HIF-1α expression and HPV status. After adjustment for clinico-pathological variables, HPV status but not HIF-1α was a strong predictor of outcome. The combination of HPV and HIF-1α was not a prognostic variable but the worst outcomes were seen in those with HPV negative and HIF-1α positive cancers. There was no statistically significant evidence of an interaction between HPV and HIF-1α. The degree of hypoxia as measured by HIF-1α expression does not differ between HPV positive and HPV negative cancers. The role of hypoxia in HPV negative oropharyngeal cancer warrants further investigation.