Human Papillomavirus-associated Oropharyngeal Cancer Research Articles

Oncologic Outcomes Following Transoral Robotic Surgery for Human Papillomavirus–Associated Oropharyngeal Carcinoma in Older Patients

While early epidemiologic studies ascribed increases in the incidence of human papillomavirus-associated oropharyngeal cancers to middle-aged patients, recent analyses have demonstrated an increasing median age of diagnosis. Treatment of patients older than 70 years is controversial as their inclusion in the practice-defining clinical trials has been limited and the survival benefit conferred by chemotherapy may be outweighed by treatment toxic effects. To assess the oncologic outcomes of older adults with human papillomavirus-associated oropharyngeal cancer who underwent upfront transoral robotic surgery and pathologic characteristics-guided adjuvant therapy in a large cohort of patients with close follow-up. A retrospective cohort analysis was conducted in a tertiary care academic medical center between January 1, 2010, and December 30, 2017. Patients aged 70 years or older at time of diagnosis with biopsy-proven and surgically resectable p16-positive oropharyngeal cancers were included. Data analysis was conducted from March 1 to June 1, 2020. Transoral robotic surgery oropharyngeal resection and neck dissection with pathologic characteristic-guided adjuvant therapy. Three-year estimates of disease-specific survival, overall survival, and disease-free survival, as well as rates of adjuvant therapy (radiotherapy and chemoradiotherapy) and perioperative complications. Seventy-seven patients were included (median age, 73.0; interquartile range, 71.0-76.0; range, 70-89 years); of these, 58 were men (75.3%). Perioperative mortality was 1.3% and the rate of oropharyngeal hemorrhage was 2.6%. Twenty-seven patients (35.1%) underwent postoperative radiotherapy and 20 patients (26.0%) underwent postoperative chemoradiotherapy. The median length of follow-up was 39.6 (range, 0.1-96.2) months, and the 3-year estimates of survival were 92.4% (95% CI, 82.4%-96.9%) for disease-specific survival, 90.0% (95% CI, 79.4%-95.0%) for overall survival, and 84.3% (95% CI, 73.4%-91.0%) for disease-free survival. The findings of this cohort study suggest that transoral robotic surgery and pathologic characteristic-guided adjuvant therapy can provide beneficial survival outcomes, infrequent perioperative mortality, and, for most carefully selected older adults, obviate the need for chemotherapy.

The declining role of post-treatment neck dissection in human papillomavirus-associated oropharyngeal cancer

Background and purposeHuman papillomavirus-associated oropharyngeal cancer (HPV+ OPC) with regional lymph node metastases has a good prognosis following (chemo)radiation therapy (C/RT) but lymph nodes may remain detectable for several months. Delayed [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET) can identify patients who may avoid post-treatment neck dissection (PTND). We investigated the rate of PTND in HPV+ OPC treated with C/RT and delayed PET-directed management of the neck. Materials and methodsThis is a retrospective cohort study from a prospectively updated institutional database. Eligible patients were treated between January 2005 and July 2017 with a minimum of 18 months follow up, had node-positive, non-distant metastatic HPV+ OPC and were treated with RT (70 Gy/35#/5 per week) with concurrent Cisplatin or Cetuximab, or accelerated RT alone (68 Gy/34#/6 per week). The primary endpoint was rate of PTND. Secondary endpoints were locoregional failure free survival (LRFFS), regional failure free survival (RFFS), distant metastatic failure free survival (DMFFS), overall survival (OS) and oropharyngeal cancer-specific survival (CSS). Results418 patients were eligible. Nineteen patients (4.5%) received a PTND. None of the tested variables were associated with an increased risk of PTND. Five-year probabilities for LRFFS, RFFS, DMFS, OS and CSS were, 91.2% (95% CI 88.3–94.2), 93.4% (95% CI 90.8–96.0), 91.2% (95% CI 88.3–94.2), 86.4% (95% CI 83.0–90.1) and 90.2% (95% CI 87.1–93.4), respectively. ConclusionIn a large cohort with good median follow up and protocolized C/RT, delayed PET-directed management of the neck affords a lower rate of PTND than reported in historical series without compromising disease control and survival.

Identification of an excellent prognosis subset of human papillomavirus-associated oropharyngeal cancer patients by quantification of intratumoral CD103+ immune cell abundance.

Accurate prognostic stratification of human papillomavirus-associated oropharyngeal cancers (HPV+OPSCC) is required to identify patients potentially suitable for treatment deintensification. We evaluated the prognostic significance of CD103, a surface marker associated with tissue-resident memory T cells (TRMs), in two independent cohorts of patients with HPV+OPSCC. The abundance and distribution of CD103+ immune cells were quantified using immunohistochemistry in a cohort of 189 HPV+OPSCC patients treated with curative intent and correlated with outcome. Findings were then validated in an independent cohort comprising 177 HPV+OPSCCs using univariable and multivariable analysis. Intratumoral CD103+ immune cells were characterized by multispectral fluorescence immunohistochemistry and gene expression analysis. High intratumoral abundance of CD103+ immune cells using a ≥30% cut-off was found in 19.8% of tumors in the training cohort of HPV+OPSCC patients and associated with excellent prognosis for overall survival (OS) with adjusted hazard ratio (HR) of 0.13 [95% confidence interval (CI) 0.02-0.94, P = 0.004]. In the independent cohort of HPV+OPSCCs, 20.4% had high intratumoral CD103+ abundance and an adjusted HR for OS of 0.16 (95% CI 0.02-1.22, P = 0.02). Five year OS of patients with high intratumoral CD103 was 100% across both cohorts. The C-statistic for the multivariate prognostic model with stage and age was significantly improved in both cohorts with the addition of intratumoral CD103+ cell abundance. On the basis of spatial location, co-expression of CD8 and CD69, and gene expression profiles, intratumoral CD103+ cells were consistent with TRMs. Quantification of intratumoral CD103+ immune cell abundance provides prognostic information beyond that provided by clinical parameters such as TNM-staging, identifying a population of low risk HPV+OPSCC patients who are good candidates for trials of deintensification strategies.

Return to Work in Survivors of Human Papillomavirus–Associated Oropharyngeal Cancer: An Australian Experience

Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) commonly affects people of working age, yet there is limited data regarding the return-to-work experience in this cohort. This study aimed to investigate the proportion of survivors currently working after completion of radiation therapy and to explore potential facilitators and barriers to working after treatment. A cross-sectional, single-institutional study was undertaken at the Peter MacCallum Cancer Centre, a comprehensive cancer center in Melbourne, Victoria, Australia. Eligible participants were 18 to 65 years old at diagnosis, were employed at or within the 3 months before diagnosis, and had completed curative treatment for HPV-associated OPC ≥4 months before enrollment. Participants completed a paper-based survey to assess baseline demographics, employment status, and quality of life (QOL; Functional Assessment of Cancer Therapy Head and Neck). Open-ended questions explored factors affecting return to work. Associations between current employment status and various disease, treatment, and demographic variables and with QOL were examined. Free-text items were analyzed by summarizing content analysis. Of 93 participants approached, 68 responded (73.1%). Mean age was 54.1 years (range, 39-64 years), and 89.7% were male. Most participants (67.6%) had stage II disease and were treated with chemoradiation (85.3%). Mean time after treatment was 2.6 years (range, 0.3-9.1 years). Fifty-eight of 68 participants (85.3%) were working at enrollment; median time to return to work was 6.0 months (interquartile range, 4-10 months); 45 (77.6%) were in the same role and 35 (60.3%) worked the same number of hours. Ten participants were not working, 3 had retired, 5 reported persistent and significant treatment toxicity preventing employment. Survivors currently working reported higher physical, functional, and global QOL scores. Access to leave and support from treating doctors were facilitators for return to work, whereas fatigue was frequently reported as a barrier to returning to work. With time, the majority of participants with HPV-associated OPC will return to work after radiation therapy. Attention to symptom management and support from the workplace may enable more successful return to work.

Sexual Satisfaction and Relationship Status in Long-term Survivors of Human Papillomavirus-Associated Oropharyngeal Carcinoma

To characterize the long-term relationship and sexual satisfaction in human-papillomavirus-associated oropharyngeal cancer (HPVOPC) patients following radiotherapy (RT) or chemoradiotherapy (CRT). A cross-sectional study was undertaken at a high volume head and neck center in HPV OPC survivors ≥12 months from completion of radical CRT/RT. As part of a larger study, patients completed multiple questionnaires. We report the results of: (1) a survey developed specifically addressing sexual and relationship status; (2), EORTC global (QLQ-C30) and sexual health (QLQ-SHQ22) QOL (score 0-100, higher score reflects better QOL) and (3) symptom burden (MDASI-HN; 0-10; lower scores reflect lower toxicity). Sexual satisfaction is a multi-item functional scale from the SHQ22. Forty-seven patients were enrolled. Median assessment time was 2.9y (1-5.1y) following CRT/RT. Median age was 64 (range: 50-74); 89% were male and 83% were married/de facto relationship at diagnosis. Stage I, II and III were 55%, 19%, and 26%, respectively (AJCC8). Most received 70Gy/35# (94%) and CRT (81%). The median global QOL score was 83 (IQR 67-88). The median MDASI-HN total severity score was 1.8 (IQR 0.7–3.0). The median sexual satisfaction domain score was 42 (IQR 17-68). Although most (34/46; 74%) patients reported an active sex life as important, only 24% (11/47) reported being sexually active (‘quite a bit’ or ‘very much’). The majority of patients reported low levels (‘not at all’ or ‘little bit’) of satisfaction with their sex life (28/46; 61%), of sexual enjoyment (24/45; 53%), of satisfaction with intimacy (26/44; 59%), of sexual desire (23/46; 50%), ability to reach orgasm (21/43; 49%) and enjoyment from sex (22/46; 37%). However only 29% (13/44) and 17% (8/46) of patients felt treatment or a lack of energy, respectively, affected their sexual activity (‘quite a bit’ or ‘very much’). The sexual satisfaction functional domain score was most significantly driven by the items reporting level of sexual activity and satisfaction with intimacy or their sex life. The sexual satisfaction score did not correlate with quality of life or symptom burden (all r<0.2). Our developed survey found that while 47% (18/38) reported a negative change in their sexual relationship since treatment, most patients partnered at diagnosis reported no change in their general relationship status compared to before treatment (23/40; 57%); 32% (13/40) reported a positive change; only few reported a negative effect (4/40; 10%). Although the majority of HPVOPC survivors considered an active sex life important, only a minority were sexually active. Despite a high frequency of negative change in their sexual relationship and low levels of sexual satisfaction, only a minority ascribed this to treatment and only a few reported a negative change in their overall relationship.

Impact of Human Papillomavirus Infection And Tobacco Exposure On Oropharyngeal Squamous Cell Carcinoma Biology From A Radiomics Perspective

It is well-established that human papillomavirus-associated (HPV+) oropharyngeal cancers (OPC) have distinct biology and favorable clinical outcomes in contrast to HPV-negative (HPV-) OPC. Though HPV+ OPC is currently regarded as one disease entity, there is growing evidence that extensive tobacco exposure can alter tumor biology and clinical outcomes, including overall survival. We hypothesized that these changes in the underlying biology would generate alterations in tumor phenotypes that can be captured by radiomics analytics. Data for biopsy-proven OPC patients dispositioned to definitive (chemo)-radiotherapy at a single institution between 2005 and 2012 were evaluated (n=319). Eligibility criteria included: concordant HPV DNA and p16 status as well as reported baseline patient reported smoking status in pack-years (PY). A total of 197 radiomics features were extracted from the gross volumes of the primary tumors. Redundant (Spearman correlation > 0.8) features were eliminated, and the remaining 37 features were used for modeling. Ensembles of random forests were used to correct for the imbalanced class representation in the data (275 HPV+ and 34 HPV-). All the models were internally validated using bootstrapping. Two classifiers of HPV status were trained using only radiomics features and then radiomics features in addition to smoking pack-years. Three-hundred and nineteen OPC patients were included in the analysis. The radiomic feature only classifier of HPV status produced an AUC = 70.5 (95%CI: 61.2-79.7). Including smoking PYs improved the AUC to 73.7 (65.1-82.2). Pack-years were also predictive in the second model (mean-decrease in accuracy: 2.0). Excluding ≥10 PY smokers (n= 110) from the HPV+ cohort resulted in superior discrimination between HPV+ (the subset with smoking PY<10; n= 175) and HPV- tumors using the same radiomic classifier, i.e. the largest AUC, 76.9 (95%CI: 67.3-86.4). The shape feature sphericity was the most discriminating feature for all three models (mean-decrease in accuracy: 2.4, 2.4, and 3.4). Other discriminating radiomic features included: Grey Level Co-occurrence Matrix features (Information measure correlation 1 and maximum probability), and shape feature ‘Convexity’. The 8th Edition of the AJCC Staging Manual is applied to all HPV/p16+ OPC tumors regardless of tobacco exposure history, presuming similar biological behavior and homogeneous clinical outcomes. Our radiomic data strongly suggest that conflating HPV+ OPC patients with significant tobacco exposure (>10 pack years) with HPV+ OPC patients without tobacco exposure may in fact be incorrect. Additional studies are required to explore the mechanisms which underlie the differential radiomic signature generated by tobacco exposure in HPV+ OPC.

Dose to medium in head and neck radiotherapy: Clinical implications for target volume metrics.

Background and purposeIn radiotherapy dose calculation, advanced type-B dose calculation algorithms can calculate dose to medium (Dm), as opposed to Type-B algorithms which compute dose to varying densities of water (Dw). We investigate the impact of Dm on calculated dose and target coverage metrics in head and neck cancer patients.Methods and materialsWe reviewed 27 successfully treated (disease free at two-years post-(chemo)radiotherapy) human papillomavirus-associated (HPV) oropharyngeal cancer (ONC) patients treated with IMRT. Doses were calculated with Type-B and Linear Boltzman Transport Equation (LBTE) algorithms in a commercial treatment planning system, with the treated multi-leaf collimator patterns and monitor units. Coverage for primary Gross Tumour Volume (GTVp), high dose Planning Target Volume (PTV) (PTV_High), mandible within PTV_High (Mand ∩ PTV) and PTV_High excluding bone (PTV-bone) were compared between the algorithms.ResultsDose to 95% of PTV_High with LBTE was on average 1.1 Gy/1.7% lower than with Type-B (95%CI 1.5–1.9%, p < 0.0001). This magnitude was inversely linearly correlated with the relative volume of the PTV_High containing bone (pearson r = −0.81). Dose to 98% of the GTVp was 0.9 Gy/1.3% lower with LBTE compared with Type-B (95%CI 1.1–1.5%, p < 0.05). Dose to 98% of Mand ∩ PTV was on average 3.4 Gy/5.0% lower with LBTE than with Type-B (95%CI 4.6–5.4%, p < 0.0001).ConclusionIn OPC treated with IMRT, Dm results in significant reductions in dose to bone in high dose PTVs. Reported GTVp dose was reduced, but by a lower magnitude. Reduced coverage metrics should be expected for OPC patients treated with IMRT, with dose reductions limited to regions of bone.

Priorities of human papillomavirus-associated oropharyngeal cancer patients at diagnosis and after treatment

IntroductionLittle is known regarding how human papillomavirus-positive oropharyngeal cancer (HPV-OPC) patient goals change with treatment. This study evaluates whether patient ranking of non-oncologic priorities relative to cure and survival shift after treatment as compared to priorities at diagnosis. Materials and MethodsThis is a prospective study of HPV-OPC patient survey responses at diagnosis and after treatment. The relative importance of 12 treatment-related priorities was ranked on an ordinal scale (1 as highest). Median rank (MR) was compared using Wilcoxon matched-pairs signed-rank tests. Prevalence of high concern for 11 treatment-related issues was compared using paired t-test. The effect of patient characteristics on change in priority rank and concern was evaluated using linear regression. ResultsAmong 37 patients, patient priorities were generally unchanged after treatment compared with at diagnosis, with cure and survival persistently ranked top priority. Having a moist mouth uniquely rose in importance after treatment. Patient characteristics largely did not affect change in priority rank. Concerns decreased after treatment, except concern regarding recurrence. DiscussionTreatment-related priorities are largely similar at diagnosis and after treatment regardless of patient characteristics. The treatment experience does not result in a shift of priorities from cure and survival to non-oncologic domains over cure and survival. The rise in importance of moist mouth implies that xerostomia may have been underappreciated as a sequelae of treatment. A decrease in most treatment-related concerns is encouraging, whereas the persistence of specific areas of concern may inform patient counseling.

Which treatment strategies are the most promising for locally advanced resectable human papillomavirus-associated oropharyngeal cancers?

e17556 Background: The standard of care for oropharyngeal squamous cell carcinoma (OPSCC) is surgical (S) or non-surgical (NS) approach including chemoradiation (CRT). However, CRT is associated with significant long-term toxicity. Human papillomavirus (HPV) status are associated with improved prognosis for patients (pts) with OPSCC. The aim of this study was to explore the most promising treatment strategy with maintaining survival outcomes while improving QOL for locally advanced resectable HPV-positive OPSCC. Methods: A retrospective analysis of 96 pts with locally advanced resectable HPV-positive OPSCC in Shizuoka Cancer Center between 2004 and 2018 was performed. p16 immunohistochemistry was used to determine HPV tumor status. Clinical characteristics, acute and late toxicities, nutritional support, and survival were compared by treatment modalities. In pts who received S, surgical procedure and histological findings of the surgical specimens were additionally compared between pts who underwent upfront surgery (US) and those who did induction chemotherapy followed by surgery (ICT-S). Results: The median age was 62 years, with the majority having tonsil and base of the tongue as primary site. Thirty-six pts (38%) were current smokers, and 39 (41%) were former smokers. As an initial treatment, 62 (64.6%) and 34 (35.4%) pts underwent S and NS, respectively. Aspiration pneumonia more frequently occurred in NS (41.2%) than in S (8.1%) (p &lt; 0.01). Nutritional support by gastrostomy tube or total parenteral nutrition was required in 20 pts (58.8%) of NS, compared with 15 pts (24.2%) of S (p &lt; 0.01). S showed a trend toward longer overall survival (OS) than NS [HR = 0.204, p = 0.052], while progression free survival (PFS) was comparable between the groups. Of all S, 48 (50.0%) and 14 (14.6%) underwent US and ICT-S, respectively. Transoral surgery was performed in 78.6% of ICT-S, compared with 20.8% of US (p &lt; 0.01). Histological examination of the surgical specimens revealed that positive surgical margins, involvement of ≥ 2 regional lymph nodes, and positive extracapsular extension were present in 7.1, 35.7, and 35.7% of ICT-S, compared with 31.3, 58.3, and 45.8% of US, respectively (N.S.). Pathologic complete response in the primary site and lymph nodes occurred in 43 % of ICT-S. Both OS and PFS was comparable between the groups. Conclusions: Our results suggest the impact of surgical approach on reduced long-term toxicity for HPV-positive OPSCC. ICT followed by surgery might be promising novel treatment strategy.

Development and Assessment of a Novel Composite Pathologic Risk Stratification for Surgically Resected Human Papillomavirus–Associated Oropharyngeal Cancer

Human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a distinct form of head and neck squamous cell carcinoma (HNSCC) with its own American Joint Committee on Cancer staging system. However, pathologic risk stratification for HPV+ OPSCC largely remains based on the experience with HPV-unassociated HNSCC. To compare the survival discrimination of traditional pathologic risk stratification for both HPV+ OPSCC and HPV-unassociated HNSCC and derive a novel pathologic risk stratification system for HPV+ OPSCC with improved survival discrimination. In this retrospective cohort study, we used the National Cancer Database to identify 15 324 patients diagnosed with nonmetastatic HNSCC between January 1, 2010, and December 31, 2013, who were treated with upfront surgery and neck dissection. We compared traditional pathologic risk stratification for HPV+ OPSCC and HPV-unassociated HNSCC and then derived a novel pathologic risk stratification system. Analyses were performed from July 1, 2018, to January 31, 2019. Definitive primary surgical resection and neck dissection. Survival discrimination of pathologic risk stratification systems measured with concordance indices. This retrospective cohort study included 15 324 patients (10 779 men and 4545 women; mean [SD] age, 59.9 [11.8] years) with surgically treated nonmetastatic HNSCC. Separation of survival curves for HPV-unassociated HNSCC using traditional pathologic risk stratification (5-year overall survival for the low-, intermediate-, and high-risk groups) were 76.2%, 54.5%, and 40.9%, respectively. Separation curves for HPV+ OPSCC were 93.2%, 88.9%, and 83.7%, respectively. Human papillomavirus-unassociated HNSCC had a concordance index of 0.68, whereas HPV+ OPSCC had a concordance index of 0.58. A novel risk stratification system for HPV+ OPSCC that more closely fits actual survival rates for HPV+ OPSCC was derived. The system incorporated the composite number of pathologic adverse features. This composite risk stratification system was associated with an improved concordance index of 0.67 for HPV+ OPSCC. Adjuvant treatment with radiation was not associated with improved survival for patients categorized as low risk according to the new risk stratification system, but this treatment was associated with improved survival for patients in the intermediate- and high-risk groups. Traditional pathologic risk stratification shows poor survival discrimination for HPV+ OPSCC and classifies many patients with an excellent prognosis as high risk. We derived a novel composite pathologic risk stratification system for HPV+ OPSCC that may be associated with improved survival discrimination.

Human papillomavirus-associated oropharyngeal cancer: review of current evidence and management.

Oropharyngeal cancer (opc) has become the leading site for human papillomavirus (hpv)-associated cancers in humans. It is an epidemic that remains relatively unfamiliar to most physicians, potentially delaying diagnosis and treatment. Traditionally, cancers involving the head and neck have occurred in smokers and in those with a significant alcohol history. Typically, hpv-positive opc presents in a younger, healthier population with a different set of risk factors and good prognosis for survival. However, many head-and-neck cancer patients, including those with hpv-positive disease, develop lifelong disabilities because of the morbid nature of their treatments, and those patients have the highest level of unmet needs in studies spanning cancer sites. Knowledge of this epidemic, a high index of suspicion, and an understanding of how the tumours present in clinical practice can help physicians to make an early diagnosis, thus sparing the patient significant morbidity from treatments associated with more advanced disease stages. Furthermore, recognizing that these patients have distinct psychosocial needs and implementing a collaborative team approach is critical to providing optimal care and improving quality of life in the survivorship period.

Primary surgery for human papillomavirus-associated oropharyngeal cancer: Survival outcomes with or without adjuvant treatment

ObjectivesHuman papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a unique form of head and neck cancer with improved prognosis. We assessed survival for stage I patients with low- or intermediate-risk pathologic features with surgery alone compared with surgery with adjuvant radiation (RT) or chemoradiation (CRT). Materials and methodsWe identified patients with stage I HPV+ OPSCC (after restaging with 8th edition staging system) treated with surgery alone, adjuvant RT or CRT in the National Cancer Data Base from 2010 to 2013. We compared survival for low-risk patients (≤1 metastatic lymph nodes with no adverse features) and intermediate-risk patients (2–4 metastatic lymph nodes, microscopic extranodal extension (ENE) or lymphovascular invasion). ResultsWe examined 1677 patients with median follow-up of 43.9 months. In the intermediate-risk group, 4-year overall survival was 94.0% with surgery alone, 91.5% with adjuvant RT and 92.0% with adjuvant CRT (p = 0.72). There were similar rates of overall survival in the low-risk group. In multivariable models accounting for clinicopathologic differences the dose of adjuvant RT was not associated with mortality. On Cox proportional hazard modeling, adjuvant RT (HR 0.94; CI 0.43–2.08) or CRT (HR 0.96; CI 0.45–2.11) did not significantly improved survival compared with surgery alone in the intermediate-risk group (reference). Similar results were seen in the low-risk group. The composite number of pathologic risk features significantly improved risk stratification. ConclusionWe provide observational evidence that adjuvant RT or CRT does not provide a survival benefit for stage I HPV+ OPSCC with low- or intermediate-risk pathologic features.

Practice Patterns in Human Papilloma Virus-Associated Oropharyngeal Cancer and Strategies for Deintensification of Therapy: A Nationwide Survey of Radiation Oncologists

In the absence of large clinical trial results, practice patterns have varied as to utilization of deintensification strategies in human papilloma virus-associated oropharyngeal cancer (HPV-OPC) and as to up-front management of these malignancies. We hypothesized that there is substantial heterogeneity amongst radiation oncologists as to treatment recommendations for HPV-OPC. An institutional review board-approved survey was developed and distributed electronically through a third-party website. Survey questions focused on demographics of respondents, setting of clinical practice, region of practice, preferred deintensification strategies, recommendations based on extent of extracapsular extension (ECE) in resected HPV+ nodes, institutional use of transoral robotic surgery (TORS), and 2 clinical vignettes highlighting controversial cases. A Pearson’s correlation test was utilized for statistical analysis. A total of 111 radiation oncologists (105 attendings/practicing physicians, 6 residents) responded (100 complete, 11 partial) to the survey. Respondents identified their current positions as at major academic hospitals (40.5%), non-academic hospitals (27.9%), satellite/community sites of major academic facilities (17.1%), and private practices (14.4%). Respondents were divided as to the “ideal” form of deintensification in HPV-OPC. While 40.6% felt that chemoradiation (ChemoRT) with reduced RT dose to 60 Gy best served patients, 35.9% preferred TORS followed by adjuvant therapy as indicated. The remaining practitioners selected altered fractionation RT (AFX-RT) (60 Gy/5 weeks, 10.4%), induction chemotherapy followed by ChemoRT (4.7%), or other (8.5%). Respondents were more likely to recommend TORS with neck dissection in HPV-OPC than in HPV-negative disease regardless of radiographic lymph node size (47.5% vs 40.6%) or with nodes <6 cm (21.8% vs 16.8%); nodes <3cm (25.7% vs 38.6%). There was also significant consideration of omission of chemotherapy in postoperative patients with HPV-OPC and minimal ECE (<2mm) (31.7%), while 64.4% still regularly prescribe ChemoRT. Others (3.8%) consider RT alone regardless of ECE extent. In a patient with cT2N2aM0 HPV-OPC of the base of tongue, preferred respondent up-front approaches were ChemoRT (55%), TORS with adjuvant therapy as indicated (37%), AFX-RT (6%), and other (2%). In a patient with pT1N1MX HPV-OPC of the tonsil after TORS (3mm margin, no ECE/LVSI/PNI), practitioners were evenly split as to whether to offer adjuvant RT: observation 51%, RT 47%, other 2%. Optimal management and therapy deintensification strategies for patients with HPV-OPC remain controversial. Forthcoming clinical trial data should substantially inform therapeutic recommendations and practice guidelines.

Human Papillomavirus-Associated Oropharyngeal Cancer: Patterns of Nodal Disease.

To characterize patterns of neck lymph node (LN) metastases in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma, represented by p16 positivity (p16+OPSCC). Case series with chart review. Tertiary care center. Neck dissection (ND) specimens of nonirradiated p16+OPSCC patients were analyzed for frequencies of clinically evident and occult LNs by neck level. Local, regional, and distant recurrences were reviewed. Seventy p16+OPSCC patients underwent primary site transoral robotic surgery and 82 NDs of varying levels. Metastatic pathologic LNs were found at the following frequencies: 0% (0/28) in level I, 75.6% (62/82) in level II with 57.4% (35/61) in level IIA and 13.1% (8/61) in level IIB, 22.0% (18/82) in level III, 7.0% (5/71) in level IV, and 6.3% (1/16) in level V. The level V LN was clinically evident preoperatively. Five of 21 (23.8%) elective NDs contained occult LNs, all of which were in level II and without extranodal extension. Twenty-seven (38.6%) patients underwent adjuvant radiation; 19 (27.1%) patients underwent adjuvant chemoradiation. With a mean follow-up of 29 months, 3 patients had developed recurrences, with all but 1 patient still alive. All patients who recurred had refused at least a component of indicated adjuvant treatment. For p16+OPSCC, therapeutic NDs should encompass any levels bearing suspicious LNs and levels IIA-B, III, and IV, while elective NDs should be performed and encompass at least levels IIA-B and III. These selective ND plans, followed by indicated adjuvant treatment, are associated with a low nodal recurrence rate.

Improved outcomes in PI3K-pathway-altered metastatic HPV oropharyngeal cancer.

While it has been recognized that human papillomavirus-associated (HPV-associated) oropharyngeal cancer (OPC) portends an improved prognosis, distinct patterns of disease recurrence have emerged. Molecular characterization of this subset of HPV patients remains unexplored. We evaluated 52 metastatic HPV+ OPC patients from our institution and paired massively parallel sequencing data with clinical parameters and survival outcomes in 81% of patients. Genomic data were then compared with 2 molecularly defined, curable HPV+ cohorts. Metastatic HPV+ OPC patients with pulmonary-only metastases demonstrated worse outcomes. Nonexclusive somatic alterations in KMT2D and PIK3CA were most frequent, with PRKDC alterations occurring at higher frequency when compared with all sequenced HPV+ OPC patients. PI3K pathway alterations were associated with improved outcomes among metastatic HPV+ OPC patients. We demonstrate subtle differences in the mutational landscape between curable and metastatic HPV+ OPC populations, with a trend towards more frequent DNA repair protein alterations in the latter. We demonstrate improved outcomes when PI3K pathway alterations are present in these patients. We provide molecular insights for this important HPV+ subgroup that have significant therapeutic implications.

Radiographic Imaging Does Not Reliably Predict Macroscopic Extranodal Extension in Human Papilloma Virus-Associated Oropharyngeal Cancer

Background: Radiographic concern for lymphatic extranodal extension (ENE) impacts upfront management decisions for patients with human papilloma virus (HPV) oropharyngeal squamous cell carcinoma (OPSCC). Therefore, we set out to evaluate the accuracy of preoperative contrast-enhanced computed tomography (CECT) to predict major ENE (> 2 mm). Methods: Twenty-seven consecutive patients with HPV-associated OPSCC who presented at our institutional multidisciplinary tumor board were staged radiographically with positron emission tomography (PET/CT) and CECT, and underwent primary transoral robotic resection and neck dissection. CECT imaging results were correlated with pathologic ENE (pENE). Results: CECT specificity for all pENE was 69 and 75% for radiologist 1 and 2, respectively. For pENE > 2 mm, the sensitivities were 88 and 100%, but specificities were 52.6 and 63.2%. Positive predictive values (PPV) were 43.8 and 53.3%; negative predictive values were 90.9 and 100%. On logistic regression analysis, only size ≥3 cm (OR 4.7–5.4, p < 0.02, 95% CI 1.3–44.0) demonstrated significant correlation with major ENE > 2 mm. Conclusions: Preoperative imaging for HPV-associated OPSCC had a PPV for pENE > 2 mm of 44–55%, based on any interruption in the capsule or invasion into the perinodal fat. The PPV is low and equipoise in treatment decision making for patients with HPV-associated OPSCC may require other imaging characteristics.

Postoperative (chemo) radiation in patients with squamous cell cancers of the head and neck \u2013 clinical results from the cohort of the clinical cooperation group \u201cPersonalized Radiotherapy in Head and Neck Cancer\u201d

BackgroundPostoperative (chemo) radiation improves tumor control and survival in high-risk patients with head and neck squamous cell carcinoma based on established risk factors. The clinical cooperation group “Personalized Radiotherapy in Head and Neck Cancer” focuses on the identification and validation of new biomarkers, which are aimed at eventually stratifying and personalizing the therapy concept. Hence, we reviewed all patients with head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx, treated with postoperative (chemo) radiation from 06/2008 until 06/2015 at the Department of Radiation Oncology in the University Hospital, LMU Munich. Here we report the clinical results of the cohort, laying the foundation for further research within the framework of a clinical cooperation group.MethodsPatient data were retrospectively (until 2013) and prospectively (from 2013) collected and analyzed for outcome and treatment failures with regard to previously described and established risk factors.ResultsWe identified 302 patients (median follow-up 45 months, average age 60.7 years), having received postoperative (chemo)radiation (median 64 Gy). Chemotherapy was added in 58% of cases, mostly Cisplatin/5- Fluorouracil in concordance with the ARO 96–3 study. The 3-year overall survival, local, locoregional and distant failure estimates were 70.5, 9.7, 12.2 and 13.5%, respectively. Human papillomavirus-associated oropharyngeal cancer was associated with a significant improved overall survival, locoregional, distant and overall tumor control rates in multivariate analysis. Additionally, in multivariate analysis, for local failure, resection status and perineural invasion, for locoregional and distant failure extracapsular extension and for overall survival the presence of nodal disease were significant adverse factors. Moreover, 138 patients have been treated in concordance with the ARO 96–3 protocol, corroborating the results of this study.ConclusionsOur cohort represents a large unselected cohort of patients with head and neck squamous cell carcinoma treated with postoperative (chemo)radiation. Tumor control rates and survival rates are consistent with the results of previously reported data.

A cross-sectional survey of awareness of human papillomavirus-associated oropharyngeal cancers among general practitioners in the UK

ObjectivesTo examine the level of awareness of the link between human papillomavirus (HPV) and oropharyngeal cancer (OPC) and epidemiological trends in HPV-related OPC among general practitioners (GPs) in the UK.DesignCross-sectional...

Treatment deintensification to surgery only for stage I human papillomavirus-associated oropharyngeal cancer.

6003Background: Human papillomavirus-associated (HPV+) oropharyngeal cancer (OPC) is an emerging entity with improved prognosis and distinct staging system. We assessed if deintensificaiton to surgery only decreased survival for stage I patients at low or intermittent risk compared with surgery with adjuvant radiation (RT) or chemoradiation (CRT). Methods: From the National Cancer Data Base (2010-2014), we identified patients with stage I HPV+ OPC (after restaging with eighth edition guidelines) treated with surgery only or with adjuvant RT or CRT. We compared survival for low risk patients (≤1 metastatic lymph nodes with no adverse features) and intermediate risk patients (2-4 metastatic lymph nodes, microscopic extranodal extension (ENE) or lymphovascular invasion). We excluded high risk patients with positive margins or macroscopic ENE. Results: We identified 2,463 patients with median follow-up of 44.3 months. In the low risk group 4-year overall survival was 93.0% with surgery only versus 95.6% with ...

Impact of Routine Surveillance Imaging on Detecting Recurrence in Human Papillomavirus–Associated Oropharyngeal Cancer

The utility of routine surveillance neck and chest imaging after definitive (chemo)radiation therapy (CRT) for oropharyngeal cancer (OPC) in patients (pts) with human papillomavirus (HPV)–associated disease—with their excellent outcomes, unique patterns of failure and lower risk of second aerodigestive primary tumors (SPT)—is unknown. This study examines the utility of surveillance imaging in detecting locoregional (LRF) and distant failures (DF) as well as SPT. From an IRB-approved database, we identified all HPV+ OPC pts who received definitive CRT between 2004 and 2015 whose initial posttreatment imaging was not suspicious for disease recurrence (DR). CT Neck and either CXR or CT chest were obtained variably in follow up (f/u) based on provider preference and clinical concern. Each image interpretation was coded: 0 (negative), 1 (likely reactive), 2 (suspicious for disease) or 3 (recurrent disease). DR included the first event of biopsy proven LRF and/or DF and were back dated to the first date of image interpretation ≥2. The Mann-Whitney test/Chi-square was used to determine differences in baseline characteristics between G1 and G2. Fine & Gray regression was used to determine if there was an association between imaging frequency and DR and imaging frequency and diagnosis of a SPT. 225 pts were eligible for this study; 30% had T3-T4 disease and 90% had ≥ N2 disease. All received CRT with most receiving IMRT (80%) and concurrent cisplatin (63%). Median age was 58.5, median f/u was 40.8 m (range [R]: 5.7 – 108.7). 64% met annual chest screening criteria for lung cancer. A median of 6 scans were obtained in f/u (R: 2-22) with a mean of 1.94 s/y (R: 0.5-6.5). Two groups were defined based on image frequency: pts with <2 scans/year (s/y) (123; 55% - Group 1 [G1]) and pts with ≥ 2 s/y (102; 45% - Group 2 [G2]). Pts in G2 were more likely to have ≥ N2b disease (85% vs. 72%; p=0.04), be current/recent smokers (46% vs 29%; p=0.04), and had a higher mean pack-year history (23 vs. 15; p=0.03). A total of 21 failures were observed, 7 LRF and 15 DF. 6 of the 7 LRF occurred within 24 m of treatment completion; 14 of 15 DF occurred within 36 m of treatment completion. Regression analysis showed G2 pts had a significantly increased risk of DR compared to G1 pts (HR 10.3; p=0.002). Five SPT were found (2 lung, 2 esophagus, and 1 oropharynx) between 4.5 to 159 m post-CRT. HPV+ OPC pts have low overall failure rates minimizing the utility of surveillance imaging. Most LRF were found within 2 years post-CRT and DF found within 3 years post-CRT. The frequency of imaging during this time should be modified based on known risks of DR. After these time points, surveillance imaging should be continued only in pts who fit lung cancer screening guidelines.