Papillomavirus-associated Oropharyngeal Squamous Cell Carcinoma Research Articles

A Descriptive Study of Quality of Life Following Neoadjuvant Chemotherapy and Transoral Robotic Surgery for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

Patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with radiation-based therapy suffer from short- and long-term toxicities that affect quality of life (QOL). Transoral robotic surgery (TORS) has an established role in the management of early OPSCC but adjuvant treatment is often indicated postoperatively due to the high incidence of nodal metastasis associated with advanced human papillomavirus (HPV)-related OPSCC. To overcome the need for adjuvant radiation therapy (RT), neoadjuvant chemotherapy followed by TORS and neck dissection (ND) is proposed. This study aimed to assess if QOL in HPV-associated OPSCC receiving neoadjuvant chemotherapy followed by TORS and ND returns to baseline within 12 months of completing treatment. A 12 month longitudinal study was carried out at McGill University Health Centre in Montreal, Canada, among a convenience sample of patients with American Joint Committee on Cancer Seventh Edition stage III and IVa HPV-related OPSCC who were treated with neoadjuvant chemotherapy followed by TORS and ND. QOL data were obtained pretreatment and at 1, 3, 6, and 12 months following treatment completion using the European Organisation for Research and Treatment of Cancer Core and Head and Neck extension modules. Paired t tests and mixed models for repeated measures analysis were used to assess changes in QOL from baseline to 12 months postoperatively and over time, respectively. Nineteen of 23 patients (median age 58 years) who received the study treatment fulfilled the eligibility criteria. OPSCC subsites were palatine tonsil (n = 12) and base of tongue (n = 7). All 19 patients were treated per protocol and none required adjuvant RT as per pathology review and protocol requirements at a postoperative multidisciplinary team tumor board discussion. No significant differences were found when comparing 12 month QOL follow-up scores to pretreatment scores in measures that would likely be affected by RT [eg, swallowing (P = .7), social eating (P = .8), xerostomia (P = .9)]. In HPV-related OPSCC, neoadjuvant chemotherapy followed by TORS and ND as definitive treatment is associated with excellent QOL outcomes. Postoperative QOL scores returned to baseline by 3 months and were maintained for all measures, indicating a return to normal function.

A Longitudinal Study Evaluating Sexual Health Outcomes and Prioritization in Patients Undergoing Chemoradiation for Human Papillomavirus-Associated Oropharyngeal Cancer

PurposeThe primary objectives were to describe the longitudinal course of sexual health in people undergoing curative (chemo)radiotherapy ([C]RT) for human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPVOPSCC) and identify factors associated with higher sexual satisfaction 12 months after [C]RT. MethodsEligible participants from three sites were recruited to a prospective observational study between October 2020 and November 2021. Measures of sexual health (QLQ-SHQ22), treatment outcome priorities (Chicago priorities scale), quality of life (QLQ-C30), symptom burden (MDASI-HN), emotional distress (PROMIS), and facial appearance and appearance distress (FACE-Q) were administered before, at the end and three and 12 months after [C]/RT. ResultsOf 128 eligible participants, 100 were recruited; sexual health measure data was available for 89 of 98 patients alive at 12 months. Mean sexual satisfaction scores were 51.8 (SD=26.6) before [C]RT. Mixed model results indicated a clinically significant reduction in sexual satisfaction by the end of (-25.4, 95% CI -30.7 to -20.2) and three months after [C]RT (-12.2, -17.3 to -7.0), but not 12 months after [C]RT (-3.8, 95% CI -9.0 to 1.4). Of 13 treatment outcome priorities, ‘keeping sexual function’ had a median rank of 10 and 9 before and 12 months after [C]RT, respectively; 24% and 26% identified it as a top priority at these times. Cohabiting, having a sexual partner, being sexually active, higher global health status, lower sexual health issues, lower depression, and considering sexual function a top priority were associated with higher sexual satisfaction scores 12 months after [C]RT. ConclusionsWhile affected acutely by [C]RT, average sexual satisfaction returns to near pre-treatment levels after 12 months. Sexual function is considered a ‘top’ survivorship priority by approximately one-quarter of HPVOPSCC patients.

Survival and Swallowing Function after Primary Radiotherapy versus Transoral Robotic Surgery for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma

Introduction: The aim of this study was to investigate the impact of primary transoral robotic surgery (TORS) versus radiotherapy (RT) on progression-free survival (PFS), overall survival (OS), and 1-year swallowing function for patients with early-stage HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: Patients with stage I-II (AJCC 8th Ed.) HPV-associated OPSCC treated with TORS followed by risk-adapted adjuvant therapy or (chemo)radiotherapy between 2014 and 2019 were identified. PFS, OS, and swallowing outcomes including gastrostomy tube (GT) use/dependence, and Functional Oral Intake Scale (FOIS) change over 1 year were compared. Results: One hundred sixty-seven patients were analyzed: 116 treated with TORS with or without adjuvant RT and 51 treated with RT (50 chemoRT). The RT group had more advanced tumor/nodal stage, higher comorbidity, and higher rates of concurrent chemotherapy. There were no differences in 3-year PFS (88% TORS vs. 75% RT) or OS (90% vs. 81%) between groups, which persisted after adjusting for stage, age, and comorbidity. GT use/dependence rates were higher in the RT group. Mean (SD) FOIS scores in the TORS group were 6.9 (0.4) at baseline and 6.4 (1.0) at 1 year, compared with 6.7 (0.6) and 5.6 (1.7) for the RT group. Only clinical nodal stage was found to be significantly associated with FOIS change from baseline to 1 year. Conclusion: There were no differences in PFS or OS between patients treated with primary TORS or RT for early-stage HPV-associated OPSCC. Clinical N2 status is associated with FOIS change at 1 year and may be the major factor affecting long-term swallowing function, irrespective of primary treatment modality.

Selective Treatment Deintensification by Reducing Radiation Dose and Omitting Concurrent Chemotherapy Based on Response to Induction Chemotherapy in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma: A Single-Arm, Phase 2 Trial (IChoice-01)

To demonstrate the feasibility of deintensification regimen in the light of the response to induction chemotherapy (IC) in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Patients with p16+ OPSCC, T1-2/N1-3M0 (excluding T1N1M0 with single and ≤3 cm lymph node) or T3-4N0-3M0 were enrolled between January 2019 and July 2021. All patients received 2 cycles of IC with docetaxel 75 mg/m2 dL and cisplatin 75 mg/m2 dL every 3 weeks. Those with major responses (≥50% decrease in both primary and lymph nodes) to IC entered the deintensification cohort (cohort D), in which intensity modulated radiation therapy alone was given to a reduced dose of 60 Gy/30 fractions. Those who failed to meet major responsesentered the concurrent chemoradiotherapy cohort (cohort C), where the dose was simultaneously integrated boosted to a standard 70 Gy/35 fractions to nonmajor response sites, concurrently with cisplatin 80 mg/m2 dL,22. Patient-reported swallow function was documented using the MD Anderson Dysphagia Inventory. The primary endpoint was 2-year progression-free survival (PFS) using Simon's 2 stage design. A total of 26 of 48 (54.2%) participants met the criteria to enter cohort D and 22 of 48 (45.8%) patients entered cohort C. With a median follow-up time of 29.7 months (6.9-48.0 months), 2-year PFS and OS rates were 85.4% and 93.6%, respectively for all enrolled patients. In cohort D, 2-year PFS and OS rates were both 100%. Grade 3 and 4 IC-related toxicities included leukopenia/neutropenia occurring in 41.7% and hyponatremia in 4.2% of patients. A higher incidence of grade 3 and 4 mucositis (61.9% vs 23.1% P=.022) was observed in cohort C. Consistent decline in longitudinal MD Anderson Dysphagia Inventory scores were observed at month 3 after radiation therapy between cohorts and both were found to recover to baseline at month 12. Selective radiation therapy dose reduction and concurrent chemotherapy removal based on IC response in HPV+OPSCC was feasible and promising. Further study of this strategy to balance efficacy and toxicity is warranted in a prospective controlled trial.

Association of Core Biopsy With Extranodal Extension in Surgically Treated Human Papillomavirus–Associated Oropharyngeal Squamous Cell Carcinoma

Extranodal extension (ENE) is an adverse feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and is an indication for adjuvant treatment escalation. Preoperative core needle biopsy (CNB) may cause lymph node capsule disruption related to ENE development; however, evidence regarding this association in OPSCC is lacking. To assess whether preoperative nodal CNB is associated with presence of ENE in final pathology findings among patients with HPV-associated OPSCC targeted for primary surgical resection. This retrospective cohort study was conducted at a single academic tertiary care center from 2012 to 2022. All patients with OPSCC treated with transoral robotic surgery were assessed for eligibility, and primary surgical patients with HPV-associated OPSCC and node-positive disease confirmed on neck dissection were included in analyses. Data were analyzed from November 28, 2022, to May 21, 2023. Preoperative nodal CNB. The primary outcome was presence of ENE in final pathology findings. Secondary outcomes included adjuvant chemotherapy and recurrence rates. Outcomes of interest were investigated against patient demographic, clinical, and pathologic features. Of 106 patients (mean [SD] age, 60.2 [10.9] years; 99 [93.4%] men) included in analyses, 23 patients (21.7%) underwent CNB. Mean (range) preoperative node size was 3.0 (0.9-6.0) cm. Pathologic node class was pN1 in 97 patients (91.5%) and pN2 in 9 patients (8.5%). A total of 49 patients (46.2%) had ENE identified in final pathology analysis. Of 94 patients who received adjuvant therapy, 58 (61.7%) underwent radiation therapy and 36 (38.3%) underwent chemoradiation therapy. There were 9 recurrences (8.5%). In univariate analysis, CNB was associated with ENE (odds ratio [OR], 2.70; 95% CI, 1.03-7.08), but there was no association in a multivariable model including pN class and preoperative node size (OR, 2.56; 95% CI, 0.97-7.27). Compared with pN1 class, pN2 class was associated with ENE (OR, 10.93; 95% CI, 1.32-90.80). There were no associations of ENE with preoperative node size, presence of cystic or necrotic nodes, fine needle aspiration, tobacco or alcohol exposure, pathologic T class, prior radiation, or age. Furthermore, use of CNB was not associated with macroscopic ENE, adjuvant chemotherapy, or recurrence. This cohort study of patients with HPV-associated OPSCC found that preoperative nodal CNB was strongly associated with ENE in final pathology, supporting the possibility of an artifactual ENE component in this population.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis

18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation. This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months. There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P=.018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P=.037) compared with patients receiving standard CRT. Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption.

Patient-Reported Symptom Severity, Health-Related Quality of Life, and Emotional Distress Trajectories During and After Radiation Therapy for Human Papillomavirus–Associated Oropharyngeal Cancer: A TROG 12.01 Secondary Analysis

This secondary analysis of clinical trial TROG 12.01, involving patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma, aimed to identify patient-reported outcome (PRO) trajectories before, during, and after chemoradiotherapy. Head and neck cancer symptom severity (HNSS) and interference (HNSI), generic health-related quality of life (HRQL), and emotional distress were assessed with the MD Anderson Symptom Inventory-Head and Neck, Functional Assessment of Cancer Therapy-General, and Hospital Anxiety and Depression Scale questionnaires, respectively. Latent class growth mixture modeling (LCGMM) was used to identify distinct underlying trajectories. Baseline and treatment variables were compared between trajectory groups. The LCGMM identified latent trajectories for all PROs: HNSS, HNSI, HRQL, anxiety, and depression. Four HNSS trajectories (HNSS1-4) were identified, distinguished by differences in HNSS at baseline, during the peak of treatment symptoms, and during early and intermediate recovery. All trajectories were stable beyond 12 months. The reference trajectory (HNSS4, n=74) score was 0.1 (95% confidence interval [CI], 0.1-0.2) at baseline, peaking at 4.6 (95% CI, 4.2-5.0), with rapid early recovery (1.1; 95% CI, 0.8-2.2) and gradual improvement to 12 months (0.6; 95% CI, 0.5-0.8). Patients in HNSS2 (high baseline, n=30) reported higher baseline scores (1.4; 95% CI, 0.8-2.0) but were otherwise similar to HNSS4. Patients in HNSS3 (low acute, n=53) reported reduced acute symptoms (2.5; 95% CI, 2.2-2.9) with stable scores beyond 9 weeks after chemoradiotherapy (1.1; 95% CI, 0.9-1.4). Patients in HNSS1 (slow recovery, n=25) had slower recovery from an acute peak of 4.9 (95% CI, 4.3-5.6) to 0.9 (95% CI, 0.6-1.3) at 12 months. Age, performance status, education, receipt of cetuximab, and baseline anxiety varied between trajectories. The other PRO models demonstrated clinically relevant trajectories, with distinct associations with baseline factors. LCGMM identified distinct PRO trajectories during and after chemoradiotherapy. These and their associations with variations in the characteristics and treatment factors of patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma provide clinically relevant insights into identifying patients who may require increased support before, during, or after chemoradiotherapy.

Risk Stratification for Oropharyngeal Squamous Cell Carcinoma Using Texture Analysis on CT - A Step Beyond HPV Status.

Background and Purpose: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasingly prevalent. Despite the overall more favorable outcome, the observed heterogeneous treatment response within this patient group highlights the need for additional means to prognosticate and guide clinical decision-making. Promising prediction models using radiomics from primary OPSCC have been derived. However, no model/s using metastatic lymphadenopathy exist to allow prognostication in those instances when the primary tumor is not seen. The aim of our study was to evaluate whether radiomics using metastatic lymphadenopathy allows for the development of a useful risk assessment model comparable to the primary tumor and whether additional knowledge of the HPV status further improves its prognostic efficacy. Materials and Methods: 80 consecutive patients diagnosed with stage III-IV OPSCC between February 2009 and October 2015, known human papillomavirus status, and pre-treatment CT images were retrospectively identified. Manual segmentation of primary tumor and metastatic lymphadenopathy was performed and the extracted texture features were used to develop multivariate assessment models to prognosticate treatment response. Results: Texture analysis of either the primary or metastatic lymphadenopathy from pre-treatment enhanced CT images can be used to develop models for the stratification of treatment outcomes in OPSCC patients. AUCs range from .78 to .85 for the various OPSCC groups tested, indicating high predictive capability of the models. Conclusions: This preliminary study can form the basis multi-centre trial that may help optimize treatment and improve quality of life in patients with OPSCC in the era of personalized medicine.

Disparities in survival outcomes among Black patients with HPV-associated oropharyngeal cancer.

Patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma(HPV-OPSCC) have a favorable prognosis and excellent overall survival (OS), and studies have demonstrated these findings in cohorts of predominantly White patients. Racial/ethnic (R/E) minorities, particularly Black patients, with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared with White patients. In this study, we aimed to determine if Black patients with HPV-OPSCC have a similar favorable prognosis to the White population. This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database from 2010 to 2016. We identified patients with Stage I-IV HPV- OPSCC who were treated with radiation, surgery, chemotherapy, or a combination of modalities. Patient outcomes were stratified by R/E groups including White Versus Black patients. The main outcome in this study was OS. Analyses for proportions of categorical variables were performed using a χ2 or Fisher's exact test. Univariate and multivariate time-to-event survival analyses were performed using Kaplan-Meier product limit estimates and log-rank test to test the differences between strata. A Cox proportional hazards regression model was used to assess the association between covariates and risk of death (OS).We identified 9256 OPSCC patients who met inclusion criteria and were treated between 2010 and 2016, of which 7912 were White (85.5%) and 1344 were Black (14.5%). A total of 1727 were HPV-OPSCC, of which 1598 were White (92.5%) and 129 (7.5%) were Black. By race, the 5-year OS for White versus Black OPSCC patients was 42% versus 23%, respectively (log-rank, p < 0.0001). Among HPV-positive OPSCC patients, the 5-year OS for White versus Black patients was 65% versus 39% (log-rank, p < 0.0001). Among HPV-negativepatients, the 5-year OS for White versus Black patients was 36% versus 13% (log-rank, p < 0.0001). On multivariate analysis, after accounting for age, sex, insurance status, income, Charlson-Deyo score, receipt of surgery, distance from facility, and total treatment time, Black race trended toward, but was not associated with worse survival. Hazard ratio(HR:1.24, 95% confidence interval[CI] 0.85-1.81, p = 0.255). This national cohort study of OPSCC patients demonstrates that Black patients with HPV-OPSCC have a poor prognosis and OS similar to HPV-negative White patients. This may be partly due to socioeconomic barriers such as insurance and income. Further work is needed to better understand the specific drivers of inferior survival outcomes in this specific patient population.

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification.

There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients. We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes. A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR=9.0, 95% CI: 3.2-25.5, P=3.6×10-5) and mixed (HR=6.4, 95% CI: 2.2-18.7, P=0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30Gy radiation. With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned. CIHR, European Union, and the NIH.

241P P16 IHC stain is an useful marker for predicting outcome of oropharyngeal cancer in Taiwan

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) is well known to have a relatively indolent behavior, and it should be staged separately. P16 is a useful surrogate marker for HPV status in OP region. However, the low prevalence of HPV infection in Taiwan (lower than 30%) may cause increased possibility of false positive for p16 staining. This study is aimed to determine the concordance of p16 IHC stain and HPV RNA ISH in Taiwan population.

Diagnostic Delay in Human Papillomavirus Negative Oropharyngeal Squamous Cell Carcinoma.

Failure to recognize symptoms of non-human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV(-)OPSCC) at presentation can delay diagnosis and treatment. We aim to identify patient factors and provider practice patterns that delay presentation and care in HPV(-)OPSCC. Retrospective review at a tertiary care center. Patients with HPV(-)OPSCC receiving treatment from 2006 to 2016. Patients were excluded if their date of symptom onset or diagnosis was unknown after thorough review of the electronic medical record or their tissue was not tested for HPV or p16. Clinical data, workup, and care timelines were abstracted. Univariate and multivariable linear regressions were performed to determine associations between patient and provider factors and delays in care. Of 70 included patients, 52 (74%) were male and mean age was 60.5 (SD=9.0). Median time to diagnosis was 69 days (IQR=32-127 days), with a median latency of 30 days (IQR=12-61 days) from symptom onset to first presentation and 19.5 days (IQR=4-46 days) from the first presentation to diagnosis. Most patients visited at least 2 providers (n=52, 74%) before diagnosis. Evaluation by 3 or more providers prior to diagnosis was associated with significant delays in diagnosis of nearly a year (357.7 days, p < 0.001) and being treated or prescribed analgesia prior to diagnosis was significantly associated with delays in diagnosis (p=0.004) on univariate regression analysis. Delays in care related to evaluations by multiple providers and misdiagnosis prolonged time to diagnosis in HPV(-)OPSCC. Improved patient and provider education is necessary to expedite the diagnosis of HPV(-)OPSCC. 4 Laryngoscope, 133:1394-1401, 2023.

PET/CT versus triple endoscopy in initial workup of HPV+ oropharyngeal squamous cell carcinoma.

Synchronous primary tumors (SPTs) are detected via triple endoscopy or positron emission tomography/computed tomography (PET/CT). Patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) lack risk factors for SPTs. We performed a single institution retrospective review of the efficacy of triple endoscopy and PET/CT in HPV+ OPSCC patients. Sixty-five HPV+ OPSCC patients underwent triple endoscopy and PET/CT. Patients were white (n=48, 72.7%), male (n=53, 81.5%), mean 58.7 ± 8.1 years old. SPT was detected in 1 (1.5%) patient via PET/CT. No SPTs were detected on triple endoscopy. PET/CT had 100% and 95.3% sensitivity and specificity, respectively. PET/CT positive predictive value (PPV) and negative predictive value (NPV) were 25.0% and 100%, respectively. Triple endoscopy specificity and NPV was 90.2% and 93.2%, respectively. PET/CT is superior to triple endoscopy in ruling out SPTs. With negative PET/CT, only direct laryngoscopy with biopsy may be necessary.

Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer.

New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1copy/mL by POD 1 (n=8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350copies/mL) and remained elevated until adjuvant treatment (n=3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n=9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1mm (P=.0481) and with increasing lymph nodes involved (P=.0453) and were further associated with adjuvant treatment received (P=.0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2months earlier than clinical detection. POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.

Impact of Smoking and Primary Tumor Subsite on Recurrence in HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

To describe risk of recurrence and recurrence characteristics between ever- and never-smoking patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) when stratified by primary tumor subsite. Retrospective observational study. Tertiary care center. Retrospective chart review of 171 patients with HPV+ OPSCC with primary treatment between 2008 and 2019. Five-year recurrence-free survival and risk of recurrence were evaluated through Kaplan-Meier curves with log-rank test and Cox proportional hazards models, respectively. Of 171 patients with HPV+ OPSCC, 81.9% were male, and the average age was 63.9 years. Eighty patients (46.8%) had a smoking history (average, 17.7 pack-years), including 4 current smokers. Recurrence occurred in 31 patients (18.1%), 19 of whom were ever smokers. The recurrence rate for ever smokers with primary base of tongue (BOT) cancer was 41.7%, while 5.1% of never smokers with BOT primaries had recurrence. For primary tonsillar disease, 9.1% of ever smokers had recurrence versus 19.2% of never smokers. Five-year recurrence-free survival for BOT primaries was lower in ever smokers than never smokers (P = .001) but did not differ between ever and never smokers for tonsillar primaries (P = .215). In multivariable analysis across this period, ever-smoking status was associated with higher risk of recurrence than never-smoking status in BOT primaries (adjusted hazard ratio, 7.36; 95% CI, 1.61-33.68; P = .010) but with lower risk of recurrence after tonsillar primaries (adjusted hazard ratio, 0.23; 95% CI, 0.06-0.89; P = .033). Smoking may uniquely interact with tumor subsites within the oropharynx to influence recurrence risk. Understanding the association between smoking and HPV+ OPSCC recurrence could lead to personalized, evidence-based treatments to improve oncologic outcomes.

Increased rate of recurrence and high rate of salvage in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma with adverse features treated with primary surgery without recommended adjuvant therapy.

Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS). Three-hundred and sixty-four patients with treatment-naïve, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared. The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P < .001). Despite increased LRF, avoiding PORT was not associated with increased 3-year distant metastasis rates (8% vs 4%, P = .56) or worse 3-year survival (95% vs 98%, P = .34). Recurrences in the surgery alone cohort varied between local and regional sites and were often successfully salvaged. Patients with HPV-associated OPSCC who do not receive indicated PORT have an increased risk of LRF but similar survival due to high salvage rates.

Locoregional and distant recurrence for HPV-associated oropharyngeal cancer using AJCC 8 staging.

The objective of this study is to evaluate locoregional and distant failure for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) using American Joint Committee on Cancer eighth edition (AJCC 8) staging. Retrospective cohort study of 457 patients with HPV+OPSCC, treated with platinum-based chemoradiation from 2002 to 2018, followed for a median of 4.3years. Time to locoregional failure (TTLRF) and distant failure (TTDF) were estimated by Kaplan-Meier method. Log-rank, recursive partitioning analysis (RPA), and multivariable Cox proportional hazards were used to evaluate associated factors and stratify risk. Rates of five-year locoregional control (LRC) and distant control (DC) were 92% (95% CI, 90-95%) and 89% (95% CI, 85-92%), respectively. Smoking, T4, N3, and stage III were associated with significantly worse TTLRF. RPA identified three distinct locoregional failure groups: cT1-3 and<19 pack-years vs. cT1-3 with≥19 pack-years vs. cT4 (five-year LRC: 97% vs. 90% vs. 82%, P<.0001). The only factor associated with significantly worse TTDF was smoking status, while stage was not correlated. RPA identified two prognostic groups: former or never smokers vs. current smokers (five-year DC: 92% vs. 77%, P=.0003). In the largest evaluation of HPV+OPSCC after platinum-based chemoradiation using AJCC 8, risk for locoregional recurrence was stratified by smoking, T category, N category, and overall stage. Risk of distant recurrence was only stratified by smoking status and not related to stage. This has implications for surveillance and clinical trial design.

Human papillomavirus oropharynx carcinoma: Aggressive de-escalation of adjuvant therapy.

Aggressive dose de-escalated adjuvant radiation therapy (RT) in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC). Patients with HPV(+)OPSCC on a phase II clinical trial of primary surgery and neck dissection followed by dose de-escalated RT (N = 79) were compared with a cohort of patients who received standard adjuvant therapy (N = 115). Local recurrence-free, regional recurrence-free, distant metastases-free survival, and progression-free survival (PFS) were assessed. Of 194 patients, 23 experienced progression at a median of 1.1 years following surgery (interquartile range [IQR] 0.7-2.0; range 0.3-5.4); 10 patients in the de-escalated cohort and 13 patients in the standard cohort. The 3-year PFS rate for the de-escalated cohort was 87%, and in the standard cohort was 90% (hazard ratio [HR] 1.18, 95% confidence interval (CI) [0.50-2.75]). Patients with HPV(+)OPSCC who undergo surgical resection and neck dissection and meet criteria for adjuvant therapy can undergo aggressive dose de-escalation of RT without increasing risk of progression locally, regionally or at distant sites.

Socioeconomic and Racial Disparities and Survival of Human Papillomavirus–Associated Oropharyngeal Squamous Cell Carcinoma

To investigate differences in epidemiology of oropharyngeal squamous cell carcinoma (OPSCC) with regards to human papillomavirus (HPV), race, and socioeconomic status (SES) using the National Cancer Database (NCDB). Population-based cohort study. Racial and socioeconomic disparities in survival of OPSCC have been previously acknowledged. However, the distribution of HPV-related cancers and its influence on survival in conjunction with race and SES remain unclear. All patients with OPSCC in the NCDB with known HPV status from 2010 to 2016 were included. Differences in presentation, HPV status, treatment, and outcomes were compared along racial and socioeconomic lines. Univariable and multivariable Cox regression survival analyses were performed. In total, 45,940 patients met criteria. Most were male (38,038, 82.8%), older than 60 years (23,456, 51.5%), and white (40,156, 87.4%), and lived in higher median income areas (>$48,000, 28,587, 62.2%). Two-thirds were HPV positive (31,007, 67.5%). HPV-negative disease was significantly more common in lower SES (<$38,000, 2937, 41.5%, P < .001) and among blacks (1784, 55.3%, P < .001). Median follow-up was 33 months. Five-year overall survival was 81.3% (95% CI, 80.5%-82.1%) and 59.6% (95% CI, 58.2%-61.0%) in HPV-positive and HPV-negative groups, respectively. In univariable and multivariable analyses controlling for HPV status, age, stage, and treatment, black race (hazard ratio [HR], 1.22; 95% CI, 1.11-1.34; P < .001) and low SES (HR, 1.58; 95% CI, 1.45-1.72; P < .001) were associated with worse survival. Significant differences in HPV status exist between socioeconomic and racial groups, with HPV-negative disease more common among blacks and lower SES. When controlling for HPV status, race and SES still influence outcomes in oropharyngeal cancers.

Machine Learning Prediction of Extracapsular Extension in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

To determine whether machine learning (ML) can predict the presence of extracapsular extension (ECE) prior to treatment, using common oncologic variables, in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Retrospective database review. National Cancer Database study. All patients with HPV-associated OPSCC treated surgically between January 1, 2010, and December 31, 2015, were selected from the National Cancer Database. Patients were excluded if surgical pathology reports did not include information regarding primary tumor stage, number of metastatic regional lymph nodes, size of largest metastatic regional lymph node, and tumor grade. The data were split into a random distribution of 80% for training and 20% for testing with ML methods. A total of 3753 adults with surgically treated HPV-associated OPSCC met criteria for inclusion in the study. Approximately 38% of these patients treated with surgical management demonstrated ECE. ML models demonstrated modest accuracy in predicting ECE, with the areas under the receiver operating characteristic curves ranging from 0.58 to 0.68. The conditional inference tree model (0.66) predicted the metastatic lymph node number to be the most important predictor of ECE. Despite a large cohort and the use of ML algorithms, the power of clinical and oncologic variables to predict ECE in HPV-associated OPSCC remains limited.