Primary Oropharyngeal Cancer Research Articles

Trends and predictors of unplanned hospitalization among oral and oropharyngeal cancer patients; an 8-year population-based study

PurposeThe incidence of oral cancers, particularly HPV-related oropharyngeal cancer, is steadily increasing worldwide, presenting a significant healthcare challenge. This study investigates trends and predictors of unplanned hospitalizations for oral cavity cancer (OCC) and oropharyngeal cancer (OPC) patients in the province of Alberta, Canada. MethodsThis retrospective, population-based, cohort study used administrative data collected from all hospitals in the province. Using the Alberta Cancer Registry (ACR), a cohort of adult patients diagnosed with a single primary OCC or OPC between January 2010 and December 2017 was identified. Linking this cohort with the Discharge Abstract Database (DAD), trends in hospitalizations, primary diagnoses, and predictors of unplanned hospitalization (UH) and 30-day unplanned readmission were analyzed. ResultsOf 1,721 patients included, 1,244 experienced 2,228 hospitalizations, with 48 % being categorized as UH. The UHs were significantly associated with a higher mortality rate, 18.5 % as compared to 4.6 % for planned, and influenced by sex, age groups, comorbidities, cancer types, stages, and treatment modalities. The rate of UH per patient decreased from 0.69 to 0.54 visits during the study period (P = 0.02). Common diagnoses for UH were palliative care and post-surgical convalescence, while surgery-related complications such as infection and hemorrhage were frequent in 30-day unplanned readmissions. Predictors of UH included cancer stage, material deprivation, and treatment, while cancer type and comorbidity predicted readmissions. ConclusionThe rate of UHs showed a noteworthy decline in this study, which could be a result of enhanced care coordination. Furthermore, identified primary diagnosis and predictors associated with UHs and readmissions, provide valuable insights for enhancing the quality of care for cancer patients.

Investigation of somatic mutation profiles and tumor evolution of primary oropharyngeal cancer and sequential lymph node metastases using multiregional whole-exome sequencing.

Lymph node (LN) metastasis is an important factor in determining the treatment and prognosis of oropharyngeal squamous cell carcinoma (OPSCC). Here, we compared the somatic mutational profiles and clonal evolution of primary and metastatic LNs using multiregion sequencing of human papilloma virus (HPV)-positive OPSCC and HPV-negative OPSCC. We performed high-depth whole-exome sequencing (200×) of 76 samples from 18 patients with OPSCC (10 HPV-positive and 8 HPV-negative), including 18 primary tumor samples, 40 metastatic LN samples, and 18 normal tissue samples. Among 40 metastatic LNs, 22 showed extranodal extension (ENE). Mutation profiles of HPV-positive OPSCC and HPV-negative OPSCC were similar to those reported previously. Somatic mutations in CDKN2A and TP53 were frequently detected in HPV-negative OPSCC. Somatic mutations in HPV-positive OPSCC samples showed APOBEC-related signatures. Somatic mutations from metastatic LNs showed a different pattern than the primary tumor. Somatic mutations acquired in the WNT pathway during metastasis showed a significant relationship with ENE. Clonal evolution analysis of primary and metastatic LNs showed that, in some cases, each metastatic LN originated from a different primary tumor sub-clone.

Concurrent Weekly Cisplatin and Simultaneous Integrated Boost-IMRT in Locally Advanced Head and Neck Squamous Cell Carcinoma-An Institutional Experience.

Introduction Concurrent chemoradiation with weekly cisplatin in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is widely practiced in India. Radiation with simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) has the advantage of executing IMRT in single phase with better dose distribution. Material and Methods 150 patients with LA-HNSCC treated between April 2015 and December 2019 were retrospectively evaluated. All patients received 70Gy in 33 to 35 fractions with SIB-IMRT and concurrent weekly cisplatin at a dose of 40 mg/m 2 . Treatment compliance and toxicities were assessed. Overall survival (OS) was evaluated using Kaplan-Meier estimates; univariate and multivariate analysis of prognostic factors were also evaluated. Results Median age was 58.5 years. Forty-five percent had primary oropharyngeal cancer. Sixty-two percent had T3 disease, 41% had N2 disease, and 51% had stage IV disease. All patients received 70Gy dose of RT. Median chemotherapy cycles were six, 84.7% received 200 mg/m 2 . Acute grade 2 xerostomia was seen in 79%, grade 3 neutropenia, mucositis and pharyngitis were seen in 11, 15, and 21%, respectively. Complete response was seen in 66.6%. At median follow-up of 21.4 months (3-71) OS was 60% and median OS was 33.2 months. Estimated 2 and 3 year OS was 56 and 48%. On univariate analysis, absence of node, N0-N1, stage III, cisplatin use, dose per fraction 2.12Gy ,and complete response showed good OS ( p <0.05). On multivariate analysis dose per fraction 2.12Gy and complete response showed good OS ( p <0.05). Conclusion Definitive chemoradiation with weekly cisplatin and SIB-IMRT in LA-HNSCC is well tolerated with good clinical outcomes.

Abstract 901: Quality of life among oropharyngeal cancer survivors

Abstract Purpose: Oropharyngeal cancer incidence continues to increase in the United States. Studies on the quality of life (QOL) experienced by oropharyngeal cancer patients usually assessed QOL one year after diagnosis instead of in the long term, and most were hospital-based. The aim of this study is to assess oral health and QOL in oropharyngeal cancer survivors in a population-based cohort over a long term follow-up. Methods: First primary oropharyngeal cancer patients, with confirmed cancer diagnosis from 1996 to 2016 were identified in the Utah Cancer Registry. Between January and May of 2019, the patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30), Quality of Life Questionnaire Head and Neck Cancer Module (EORTC QLQ-H&amp;N35) and Oral Health Impact Profile-14 (OHIP-14) questionnaire. Adjusted linear regression was used to assess associations between each dependent variables and QoL scores. The global health mean score ranges from 0 to 100; &amp;gt;70 is considered a high level of functioning and &amp;lt;70 is associated with lower level of symptomology based on previous studies. The OHIP-14 score ranges from 0 to 56; &amp;lt;9 is considered better functioning for oral health. Results: Among 262 oropharyngeal cancer survivors, 84.0% were male, 74.7% were sixty and older at cancer diagnosis, 21.8% were overweight (µ=26.5 (sd=4.9) kg/m2). More than half of participants had seen a dentist within the last 6 months (65.8%) and were former smokers (51.1%). The global QoL means scores for 1996-2000, 2001-2005, 2006-2010, and 2011-2016 were 77.5 (sd=16.3), 73.4 (sd=17.6), 67.3 (sd=24.1), and 73.4 (sd=20.4). Both the global QoL mean score (72.0 (sd=20.8)) and the OHIP-14 mean score (13.2 (sd=13.9)) were fairly high. Similarly, individual QoL physical, role, emotional, cognitive, and social mean scores from the QLQ-30 were also fairly high, ranging from 77.8 to 85.9. From the EORTC H&amp;N35 symptomatology scale, the highest symptom related mean scores were observed for weight gain (85.8 (sd=35.0)), pain-killers use (64.4 (sd=48.0)), and dry mouth (61.7 (sd=35.6)). Higher global QoL mean scores were seen with higher education (postgraduate vs technical school, 81.9 (sd=19.3) vs 67.9 (sd=22.4)), higher income ($100,000+ vs less than $25,00, 76.4 (sd=17.3) vs 60.2 (sd=24.6)), younger age (&amp;lt;40 vs &amp;gt;70, 87.5 (sd=17.7) vs 71.9 (sd=2.6)), and BMI (&amp;lt;18.5 vs 18.5-24.9, 45.8 (sd=26.7) vs 74.8 (sd=20.2)). Conclusion: Global QoL improvement suggests adaptability to a new normal among this group of U.S. oropharyngeal cancer survivors when compared to previous studies which were largely based on a shorter follow-up time. Oral health-related quality of life was marginally poor in our study, suggesting needed improvement in patient management overtime, with worse improvement in physical discomfort and physical disability scores across all demographic patient characteristics except with distant stage and recurrence. Citation Format: Alzina Koric, Marcus Monroe, Seungmin Kim, Esther Chang, Qingqing Hu, Siqi Hu, Mia Hashibe. Quality of life among oropharyngeal cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 901.

Endoscopic video-assisted transoral (EVAT) surgery of the oropharynx: clinical, oncological and functional outcomes.

Transoral surgery for suspected or proven oropharyngeal malignancies has increased significantly with the practice of transoral laser microsurgery (TLM) and transoral robotic surgery (TORS). An accepted alternative technique is endoscopic video-assisted transoral (EVAT) surgery. Our aim is to review the clinical, oncological and functional outcomes of this technique at our institution. 56 consecutive patients undergoing EVAT surgery as part of their cancer work up or treatment were reviewed, focusing on clinical, oncological, and functional outcomes. Patients had primary oropharyngeal cancer or carcinoma of unknown primary (CUP) staged between T0-T3 and N0-N3. EVAT surgery identified a primary in 47.1% of CUP with p16 positive disease. Major haemorrhage occurred in 1.8%, with eight post-operative complications. 8.9% of patients developed locoregional recurrence. Mean MD Anderson Dysphagia Inventory score was 76.4 following EVAT surgery, 68.8 after EVAT surgery + radiotherapy and 67.1 after EVAT surgery + chemoradiotherapy CONCLUSION: Early clinical, oncological and functional outcomes following EVAT surgery are comparable to TLM and TORS. 4 (case series).

HPV-Related Oropharyngeal Cancer and Biomarkers Based on Epigenetics and Microbiome Profile.

H uman papillomavirus (HPV) is considered the main cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC), and soon, the global burden of HPV-related OPSCC is predicted to exceed that of cervical cancer. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new promising targeted therapies and immunotherapy approaches. Epigenetic and microbiome-based exploration of biomarkers has gained growing interest with a view to the primary oropharyngeal cancer (OPC) screening. Understanding the role of the epigenetic mechanism and the changes that occur during pathogenesis shows appreciable progress in recent years. The different methylation status of DNA and miRNAs demonstrates the value of possible biomarkers discriminating even in different stages of dysplasia. Through whole-genome bisulfite sequencing, differentially methylated regions (DMRs) hold the key to recover missing information. O n the other hand, the microbiota investigation signifies a new biomarker approach for the evaluation of OPC. Along with known cofactors playing a major role in microbiota differentiation, HPV-related cases must be explored further for better understanding. The dynamic approach of the shotgun metagenomic sequencing will robustly fill the gap especially in species/strain level and consequently to biomarker detection. The constantly growing incidence of HPV-related OPC should lead us in further investigation and understanding of the unique features of the disease, more accurate diagnostic methods, along with the development and implementation of new, targeted therapies. This paper comprehensively reviews the significance of biomarkers based on epigenetics and microbiome profile in the accuracy of the diagnosis of the HPV-related cancer in the oropharynx.

Multidisciplinary Treatment for Triple Primary Cancers-Esophageal, Oropharyngeal and Renal Cancer: A Case Report

Multidisciplinary Treatment for Triple Primary Cancers-Esophageal, Oropharyngeal and Renal Cancer: A Case Report

Rate of Second Primary Head and Neck Cancer With Cannabis Use.

ObjectiveTo determine whether there is an association between cannabis use and developing a second primary cancer in head and neck cancer patients, as well as determining the prevalence of cannabis use amongst head and neck cancer patients.Study designThis retrospective cohort study investigated patients from the Hamilton Region Head and Neck Cancer Database who were enrolled prospectively between 2011 and 2015, with follow-up data up to November 2018. Patients were contacted to confirm current cannabis and tobacco smoking status.SettingAll patients were enrolled from a single tertiary cancer center in Hamilton, Ontario.Subjects and methodsConsecutive patients with a newly diagnosed head and neck cancer were prospectively enrolled between 2011 to 2015. Cannabis users and controls were compared using standard modes of comparison. The odds ratio from a multivariable logistic regression model was then determined.ResultsA total of 513 patients were included in this study: 59 in the cannabis group and 454 in the control group. In terms of baseline characteristics, there was no significant difference between cannabis users and controls except that cannabis users were more likely to develop primary oropharyngeal cancer (p=0.0046). Two of 59 (3.4%) cannabis users developed a second primary cancer, in comparison to 23 of 454 (5.1%) non-cannabis users. The odds ratio for cannabis use on the second primary cancer was 0.19 (95% CI [0.01-3.20], p=0.25).ConclusionThis study suggests that cannabis use behaves differently than tobacco smoking, as the former may not be associated with field cancerization.

Two cases of glottic closure for refractory aspiration pneumonia after vertical partial laryngectomy

Vertical partial laryngectomy is a well-established surgical procedure for early glottic cancers with acceptable functional and oncological outcomes. However, on a long-term basis, aspiration might be a serious problem with aging. Here we presented two cases of refractory aspiration pneumonia after vertical laryngectomy. Case 1: A 76-year old gentleman with a past history of malignant lymphoma treated by chemotherapy and radiotherapy had glottic cancer, which was treated by repeated vertical partial laryngectomies. Although glottic caner had been well controlled, he started to suffer from refractory aspiration pneumonia. Since his cervical skin was very thin and hard and his general condition was poor, we employed modified Kano's method for glottic closure. Case 2: A 87-year old Japanese male had a past history of glottic cancer treated by radiotherapy and vertical partial laryngectomy. He was repeatedly hospitalized for severe aspiration pneumonia. At the age of 87, he had second primary oropharyngeal cancer. Kano's method was simultaneously performed at the time of resection of oropharyngeal cancer. Postoperative courses were uneventful without sign of leakage in both cases. The patients started oral intake 2 weeks after the surgery. They have been alive without aspiration pneumonia and takes normal diet.

Epidemiology of human papillomavirus-related oropharyngeal cancer in a classically low-burden region of southern Europe

The incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing in some regions. Nevertheless, the epidemiology of this disease has not been extensively investigated in southern Europe. We conducted a retrospective cohort study of patients diagnosed with primary oropharyngeal cancer from 1991 to 2016. Cancer tissues underwent histopathological evaluation, DNA quality control, HPV-DNA detection and p16INK4a immunohistochemistry. Data were collected from medical records. Factors associated with HPV positivity and time trends were evaluated with multivariable Bayesian models. The adjusted prevalence of HPV-related cases in 864 patients with a valid HPV-DNA result was 9.7%, with HPV-DNA/p16INK4a double positivity being considered. HPV-related oropharyngeal cancer was likely to occur in non-smokers and non-drinkers, to be located in the tonsil or diagnosed at advanced stages. Time-trend analysis showed an increasing risk of HPV-related oropharyngeal cancer in the most recent periods (5-year period increase of 30%). This increase was highest and with a clear increasing trend only in the most recent years (2012–2016). The prevalence of HPV-related oropharyngeal cancer started to sharply increase in the most recent years in our setting, as occurred two decades ago in areas where most oropharyngeal cancer cases are currently HPV-related. Our results provide a comprehensive assessment of the epidemiological landscape of HPV-related oropharyngeal cancer in a region of southern Europe.

Transoral robotic surgery for squamous cell carcinoma of the oropharynx in a primarily human papillomavirus-negative patient population

Transoral robotic surgery (TORS) is one of the main treatment options for non-locally advanced primary oropharyngeal cancer in the United States. However, its use is more limited in countries with a low incidence of human papillomavirus (HPV), such as Spain, in patients with advanced disease, and as salvage surgery. To shed light on the use and potential benefit of TORS in Spanish patients, we analyzed the functional and oncologic outcomes of TORS as both primary and salvage surgery in a primarily HPV-negative population which is representative of oropharyngeal squamous cell carcinoma (OPSCC) patients in Spain. This is a retrospective analysis of prospectively collected data on OPSCC patients treated with TORS at our center between February 2017 and February 2019. Fifty-four OPSCC patients were included; 79.6% were males and 80.5% were HPV negative. Median age was 62years. Primary surgery was performed on 73.7% (48.1% stage I-II; 51.9% stage III-IV) and salvage surgery on 25.9% of patients. Positive margin rates were 4.3% for T1-2 and 25.8% for T3-4. None of the stage I-II patients and 27.7% of stage III-IV patients required adjuvant treatment. Reconstructive surgery was performed in 19.2% of all patients. Normal swallowing was achieved in 92.7% of patients at 6months after surgery. 1- and 2-year survival rates for all patients were 94.5% and 89%, respectively. The overall complication rate was 16.1%. Bleeding occurred in 11.5% of patients. Longer hospitalization time was associated with surgical complications (P = 0.03) and reconstructive surgery (P = 0.03) but not with salvage surgery. TORS is a safe and effective treatment for HPV-negative T1-2 OPSCC patients. The positive margin rate was worse in T3-4 patients, indicating the need for careful patient selection in this subgroup.

National treatment trends in human papillomavirus-positive oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC) is associated with dramatically improved survival in comparison with HPV-negative OPC and can be successfully treated with surgical and nonsurgical approaches. National treatment trends for OPC were investigated with the National Cancer Data Base (NCDB). The NCDB was reviewed for primary HPV-mediated OPC in 2010-2014. Multivariable regression was used to identify predictors of both nonsurgical therapy and receipt of adjuvant chemoradiation (CRT). There were 13,363 patients identified with a median age at diagnosis of 58years. The incidence of triple-modality treatment (surgery with adjuvant chemotherapy) decreased from 23.7% in 2010 to 16.9% in 2014 (R2 =0.96), whereas the incidence of nonsurgical treatment increased from 63.9% to 68.7% (R2 =0.89). Hospitals in the top treatment volume quartile (quartile 1 [Q1]; n=29) had a lower rate of positive margins (16.3%) than bottom-quartile centers (n=741; rate of positive margins, 36.4%; P<.001); Q1 hospitals used surgical therapy significantly more. Independent predictors of nonsurgical therapy included older age, advanced disease, lower hospital volume, and living closer to the hospital or outside the Pacific United States. In surgically treated patients, younger age, lower hospital volume, nodal disease, positive surgical margins, and extranodal extension (ENE) also predicted more adjuvant CRT use. The use of upfront surgical treatment decreased from 2010 to 2014. Hospital volume shows a strong, inverse correlation with the rate of positive surgical margins. The upfront treatment strategy is predicted not only by staging but also by patient-, geographic-, and hospital-specific factors. Lower hospital volume remains independently associated with increased triple-modality therapy after adjustments for positive margins, ENE, and pathologic staging.

Abstract 4946: Comprehensive molecular profiling reveals distinct immunemicroenvironment subtypes of oropharyngeal cancers

Abstract Background The oropharyngeal cancer (OPC) constitutes a distinct clinical subset of head and neck squamous cell carcinoma with high prevalence of HPV-associated tumorigenesis. However, the relationship between tumor molecular types and immune microenvironment has not been systematically delineated in OPCs. In this study, we classified the OPCs into three different molecular subtypes regarding their immunological character by comprehensive molecular profiling by RNA-seq and multiplexed immunohistochemistry (IHC). Methods The 37 surgically resected primary OPC tumors were analyzed, and the HPV status was evaluated by p16 IHC. The transcriptome profiling of tumors by RNA-seq classified OPCs into three molecular subtypes based on t-SNE plotting. The immune microenvironment of each subtype was investigated using VECTRA spectral imaging system in terms of CD8 T cell and macrophage infiltration patterns, as well as T cell exhaustion maker expressions. The 10 OPC patients treated with anti-PD-1/PD-L1 blockade were also classified into three subtypes and their therapy response was compared. Results We divided OPCs into Immune-rich (IR), mesenchymal (MS), and classical (CL) subtypes by RNA-seq clustering analysis. All IR type tumors were HPV-positive, whereas most CL types (7 out of 8) were HPV-negative. MS type showed mixed HPV status (HPV-positive in 5/14). The IR type showed favorable prognosis compared with poor prognosis of CL type, and MS type showed intermediate survival outcome. The IR type tumors showed high enrichment of adaptive immune response, T cell exhaustion, and cell cycle gene signature implying their highly immunogenic properties. The multiplexed IHC confirmed plenty of PD-1+CD8 T cells and type I macrophages infiltrating tumor nest in IR types. The MS type was characterized by upregulation of muscle, extracellular matrix, and TGF-β signatures with scant CD8 T cell signature expression. The IHC analysis of MS type showed exclusion of CD8 T cells from tumor nest that might be related to their high TGF-β-response signature (TBRS) score. CL types were related to high xenobiotic catabolism signatures, and showed low level of CD8 T cell infiltrations with focal CD73 expression. Among 10 OPC patients with anti-PD-1/PD-L1 blockade treatment, the IR type patients showed durable therapy response (3 of 4 patients), whereas CL type patients showed early progression on the treatment (3 of 4 patients). Conclusions Our comprehensive analysis reveals that OPCs can be classified into three distinct subtypes based on their immune microenvironment properties. The three molecular subtypes showed distinct therapy response on anti-PD-1/PD-L1 blockade. These findings are pertinent to develop predictive markers on immunotherapy and to design combination immunotherapy strategies in OPC patients. Citation Format: Min Hwan Kim, Jae-Hwan Kim, Dong Min Jung, Jae Woo Choi, Soo Jin Heo, Kyoung-Ho Pyo, Min Hee Hong, Byoung Chul Cho, Hye Ryun Kim. Comprehensive molecular profiling reveals distinct immunemicroenvironment subtypes of oropharyngeal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4946.

CT assessment of tumor heterogeneity and the potential for the prediction of human papillomavirus status in oropharyngeal squamous cell carcinoma.

The aim of this study is to find a correlation between tumoral heterogeneity of squamous cell carcinoma of the oropharynx and human papillomavirus (HPV) status and to determine whether analysis of texture features of primary lesion on contrast-enhanced CT (CECT) images can be useful in predicting the HPV positivity. Fifty patients with diagnosis of oropharyngeal carcinoma and pre-treatment CECT were included; tumoral heterogeneity of each lesion was evaluated by extracting quantitative texture parameters of first and higher orders. T test and logistic regression were conducted to evaluate the effects of different textural characteristics. There were 35 HPV+ and 15 HPV- lesions. Statistically significant (p < 0.05) differences were seen in multiple higher-order extracted parameters. The logistic regression model correctly classified lesions with an accuracy of 95.2%. CT texture analysis of primary oropharyngeal cancer may be used as a tool for predicting the HPV status.

Patients with a history of cervical cancer are at an increased risk of developing primary anal or oropharyngeal cancer

Patients with a history of cervical cancer are at an increased risk of developing primary anal or oropharyngeal cancer

Radiobiological Analysis for Osteoradionecrosis in Patients Treated With IMRT for Head and Neck Cancer: A Department of Veterans Affairs Experience

Previous publications by our group regarding osteoradionecrosis (ORN) induced by head and neck (H&N) radiation therapy (RT) have focused on the total physical dose deposited at the lesion site within the mandible. Furthermore, there seems to be a volume effect predicting increasing chance of ORN with a larger proportion of mandible receiving higher total dose. As with most published results, a relatively scarce number of cases limits the validity of findings, and biological consequence of spatial variation of dose per fraction is often ignored. In this study, we have pooled cases of ORN from two Veteran Affairs (VA) radiation oncology facilities, and analyze the pattern of failure based on the concept of biologically effective dose (BED). Ten patients treated with H&N radiation therapy were identified to have ORN (median time from RT completion to diagnosis of ORN was 6 months; range: 3.2 to 52.8 months). All were male veterans, with median age of 63.5 when receiving initial treatment. Five had primary oropharyngeal cancer, 3 had oral cavity cancer, and 2 were treated for unknown H&N primary. All ORN sites were localized toward the posterior portion of the mandible or retromolar area. Concurrent platinum-based chemotherapy was given to 5 patients and Cetuximab to 3. One had salvage mandibulectomy before developing ORN, the other had partial glossectomy before being treated with hypofractionated RT along with Cetuximab. Dosimetric outcomes were analyzed retroactively for 8 cases with available detailed treatment plans, using BED and linear-quadratic equivalent dose based on 2-Gy per fraction (LQED2). The average LQED2 based on the prescribed fractionation scheme was 69.3±1.4 Gy (BED of 115.6±2.4 Gy3). At the ORN lesion site, the average LQED2 was 76.0±4.1 Gy (BED of 126.7±6.8 Gy3), representing a 9.7% increase over the prescribed dose. For the entire mandible (average total volume of 74.0±14.5 cc), the average percent volumes receiving minimal LQED2 of 70 (V70) Gy (corresponding to BED of 116.7 Gy3) was 12.4±15.5%, corresponding to an absolute mandibular volume of 8.3±10.1 cc. Thus, while the mandible might be considered as a serial organ as far as ORN is concerned, it might be associated with a moderate volume effect. ORN can result from increased LQED2 or BED which may not be conspicuous from a dosimetric plan based solely on physical dose display. This study demonstrates the utilization of radiobiologically sound dosimetry which clinicians can use to quantify risk of late complications due to the “double trouble” arising from altered fractionation schemes. For the mandible, DVH guidelines based on BED or LQED2 might be better representations to predict true incidence of ORN, and useful when constructing the dose-response relation as a normal-tissue complication probability (NTCP) curve.

Second Primary Malignancies in Head and Neck Cancer Patients Treated With Definitive Radiation Therapy

Second primary malignancy (SPM) may occur after initial primary head and neck cancer treatment. The risk of SPM in head and neck cancer patients treated with definitive radiation therapy has not been well documented. This study evaluated the prevalence and outcome of SPM in patients with head and neck cancer treated with definitive radiation therapy. Eligible patients include those with histologically confirmed mucosal head and neck cancer treated with definitive radiation therapy between 2000 and 2010, with at least 6 months of follow-up. Age, tobacco smoking status (dichotomized by < or ≥10–pack-year cigarettes), primary site, and mode of detection of SPM were recorded. p16 data was not routinely collected until after 2010. SPM was defined as an invasive solid cancer at a non-contiguous site diagnosed at least 6 months after completion of radiation therapy. Clinical data was collected and the Kaplan-Meier method was used to estimate overall survival. This study included 1583 patients. Median age was 55 years. The median overall survival was 98 (range: 6-199) months. The majority of patients had primary oropharyngeal cancer (82.1%), followed by nasopharyngeal cancer (5.5%). A total of 133 (8.4%) patients developed an SPM, with 116 patients diagnosed with SPM at least 2 years posttreatment. The median time to develop an SPM was 72 months. 49.6% of SPMs were within the head and neck or thoracic region – 37 mucosal head and neck carcinomas, 2 head and neck sarcomas and 27 esophageal/ lung carcinomas. Patients with SPM were dichotomized into 2 groups: <10-pack-year smoking (23 non- and 17 former smokers) and ≥10-pack-year smoking (44 current and 49 former smokers). In those with SPM, 70% of patients had ≥10-pack-year smoking comprising 93% of thoracic and 64% of head and neck SPMs. The risk of SPM increased exponentially with time with overall rates at 2, 5, 10, and 15 years were 0.2%, 1.2%, 8.5% and 35.1%. SPM rates were higher in patients with ≥10-pack-year smoking than those with <10-pack-year: 2 years (0.4% vs 0%), 5 years (1.5% vs 0.9%), and 10 years (12.4% vs 4.8%). A total of 105 patients (79%) had subsequent curative intent therapy. Five-year overall survival from diagnosis of SPM was 46%. The majority of SPMs in head and neck cancer patients treated with radiation therapy were in those with a smoking history of ≥10-pack-years, reflecting the same risk factors for mucosal head and neck cancer. Nearly 1 in 2 patients with SPMs were salvaged successfully underscoring the importance of regular clinical surveillance for SPMs, especially of head and neck and thoracic regions.

Double positivity for HPV-DNA/p16ink4a is the biomarker with strongest diagnostic accuracy and prognostic value for human papillomavirus related oropharyngeal cancer patients

BackgroundThe etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. MethodsWe conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16INK4a/pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC. Results788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16INK4a, HPV-DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16INK4a, respectively. Being non-smoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub-sites and treatments was observed. Double positivity for HPV-DNA/p16INK4a showed strongest diagnostic accuracy and prognostic value. ConclusionsDouble positivity for HPV-DNA/p16INK4a, a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients’ classification and handling and also suggest that not all the HPV-related OPC behave similarly.

Cause-specific mortality in HPV+ and HPV- oropharyngeal cancer patients: insights from a population-based cohort.

Identifying the causes of death in head and neck cancer patients can optimize follow‐up and therapeutic strategies, but studies in oropharyngeal squamous cell carcinoma (OPSCC) patients stratified by HPV status are lacking. We report cause‐specific mortality in a population‐based cohort of patients with OPSCC. Patients who had been diagnosed with OPSCC (n = 1541) between 2000 and 2014 in eastern Denmark were included in the study. Causes of death were collected through medical files and the Danish National Cause of Death registry. Deaths were grouped as (1) primary oropharyngeal cancer, (2) secondary malignancies, (3) cardiovascular and pulmonary disease, or (4) other/unspecified. The cumulative incidence of death and specific causes of death were determined using risk analysis. At follow‐up, 723 (47.5%) patients had died. The median time to and cause of death were determined: oropharyngeal cancer (n = 432; 1.00 year), secondary malignancies (n = 131; 2.37 years), cardiovascular and pulmonary causes (n = 58; 3.48 years), and unspecified causes (n = 102; 3.42 years). HPV/p16 status was the strongest predictor of improved survival across all causes of death. The only cause of death to decrease in incidence over the 2 years after treatment was death from OPSCC. HPV/p16 positivity was an independent factor for improved survival across all causes of death in patients with OPSCC. In addition, both HPV‐positive and HPV‐negative OPSCC patients faced high 5‐ and 10‐year mortality rates. Implementing secondary screening and prevention strategies for late toxicity and mortality are major goals in managing the treatment of these patients.

What should we expect from robotic surgery for second primary oropharyngeal cancer?

The outcomes of second primary oropharyngeal cancer (SPOPC) may not be determined by oropharyngeal cancer but from the other index cancer as well. The management of (SPOPC) remains inconclusive and limited. Transoral robotic surgery (TORS) to maximize the functional outcomes without reducing oncologic effect is suggested as the primary treatment for selected oropharyngeal cancer. This study aimed to evaluate the feasibility and outcomes of TORS for the management of SPOPC. Patients who underwent TORS from January 2011 to June 2015 at a tertian referral center in Taiwan were recruited. Loco-regional status, overall survival (OS), disease-specific survival (DSS), and postoperative functional status were evaluated. Fifteen patients received TORS for SPOPC with curative intent, including eleven with tongue-base carcinomas, and four with tonsil carcinomas. One case was terminated because of inadequate exposure and the other 14 cases were completed with negative pathologic margins. Two-year OS and DSS were 53 and 77%, respectively. Patients with SPOPC occurring within 6months had poorer outcomes (p=0.044). The median time to feeding-tube removal was 5days, and one patient had long-term gastric-tube dependence. Patients of age <65years with synchronous SPOPC and esophageal cancer as the other index cancer were significant worse in oncologic outcomes. We concluded that TORS is a feasible alternative treatment in selected patients with SPOPC. Patients with metachronous T1-2 SPOPC without an esophageal primary can achieve excellent survival after TORS, while TORS can maximize functional preservation with limited destruction in patients with low life expectancy.