HPV-positive Oropharyngeal Carcinoma Research Articles

MR radiomics unveils neoadjuvant chemo-responsiveness with insights into selective treatment de-intensification in HPV-positive oropharyngeal carcinoma

BackgroundAccurate prediction of neoadjuvant chemotherapy (NAC) response allows for NAC-guided personalized treatment de-intensification in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). In this study, we aimed to apply baseline MR radiomic features to predict NAC response to help select NAC-guided de-intensification candidates, and to explore biological underpinnings of response-oriented radiomics. MethodsPre-treatment MR images and clinical data of 131 patients with HPV-positive OPSCC were retrieved from Fudan University Shanghai Cancer Center. Patients were divided into training cohort (n = 47), validation cohort 1 (n = 49) from NAC response-adapted de-intensification trial (IChoice-01, NCT04012502) and real-world validation cohort 2 (n = 35). NAC prediction model using linear support vector machine (SVM) was built and validated. Subsequent nomograms combined radiomics and clinical characteristics were established to predict survival outcomes. RNA-seq and proteomic data were compared to interpret the molecular features underlying radiomic signatures with differential NAC response. FindingsFor NAC response prediction, the fusion model with both oropharyngeal and nodal signatures achieved encouraging performance to predict good responders in the training cohort (AUC 0·89, 95% CI, 0·79-0·95) and validation cohort 1 (AUC 0·71, 95% CI, 0·59-0·83). For prognosis prediction, radiomics-based nomograms exhibited satisfactory discriminative ability between low-risk and high-risk patients (PFS, C-index 0·85, 0·76 and 0·83; OS, C-index 0·79, 0·76 and 0·87, respectively) in three cohorts. Expression analysis unveiled NAC poor responders had predominantly enhanced keratinization while good responders were featured by upregulated immune response and oxidative stress. InterpretationThe MR-based radiomic models and prognostic models efficiently discriminate among patients with different NAC response and survival risk, which help candidate selection in HPV-positive OPSCC with regard to personalized treatment de-intensification.

MR radiomics and neoadjuvant chemo-responsiveness with insights into selective treatment de-intensification in HPV-positive oropharyngeal carcinoma.

6085 Background: In HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), patients with good response to neoadjuvant chemotherapy (NAC) exhibit superior prognosis. Accurate prediction of NAC response allows for NAC candidate selection and personalized treatment de-intensification in HPV-positive OPSCC. In this study, we aimed to apply baseline magnetic resonance (MR) radiomic features to predict NAC response and prognosis. Methods: Pre-treatment MR images and clinical data of 131 patients with HPV-positive OPSCC were retrieved from Fudan University Shanghai Cancer Center. Radiomic features of both oropharyngeal lesions and metastatic nodes were extracted on T2WI and contrast-enhanced T1WI sequence. Patients were divided into training cohort (n=47), prospective validation cohort (n=49) and real-world validation cohort (n=35). Following radiomic feature selection, a linear support vector machine (SVM) model was built and validated for NAC response prediction. Nomograms that combined radiomics and clinical characteristics were then developed to predict survival outcomes. The performance of response models was assessed by the area under the curve (AUC), accuracy, sensitivity, specificity and prognostic models were measured by C-index. RNA-seq and proteomic data were further leveraged and compared to interpret the molecular features underlying radiomic signatures with differential NAC response. Results: For NAC response prediction, the fusion model with both oropharyngeal and nodal radiomic signatures on multi-sequence MR images achieved encouraging performance to predict good responders in the training cohort (AUC 0.89, 95% CI, 0.79-0.95) and prospective validation cohort (AUC 0.71, 95% CI, 0.59-0.83). For prognosis prediction, radiomics-based nomograms exhibited satisfactory discriminative ability between low-risk and high-risk patients in training cohort and two validation cohorts (PFS, C-index: 0.85, 0.76 and 0.83; OS, C-index: 0.79, 0.76 and 0.87). An exploratory analysis in the prospective validation cohort showed that de-intensified radiotherapy after NAC in low-risk patients yielded 100% in both PFS and OS. Furthermore, expression analysis unveiled distinct molecular phenotypes in relation to NAC response, where poor responders had predominantly enhanced keratinization while good responders were featured by stronger innate and adaptive immune response. Conclusions: The MR-based radiomic models and subsequent prognostic models efficiently discriminate among patients with different NAC response and survival risk. This study provides a new strategy for patient selection in HPV-positive OPSCC that are suitable for personalized de-intensification. Integration of radiomics in future trials is warranted.

270 Radiologic diagnosis of Extranodal Extension (ENE) in patients with HPV-positive oropharyngeal cancer: consensus diagnosis and influence on prognosis

Tumor often progresses through the weakest part of any surrounding tissues. The extent of tumor invasion depends on: a. Aggressiveness of the tumor cells (e.g. number and invasive character of stem cells), b. robustness of the surrounding tissues and their composition (e.g. vessels), and c. time to allow the tumor to proliferate. The lymph node (LN) capsule comprises dense connective tissue stroma and collagenous fibers, and is a natural barrier that generally prevents further tumor progression. Permeation of tumor through the nodal capsule into surrounding tissues is termed “extranodal extension”. The idiosyncratic and inconsistent mechanism of ENE is imprecisely understood, but it is thought to be due to either tumor cell proliferation that outpaces the capacity of nodal capsular expansion (“ruptures” the LN capsule), or factors within the tumor or tumor microenvironment that facilitate the “breach” of the capsule. The latter might explain ENE in small LNs, or a “neglected” tumor (lengthy intranodal tumor growth with eventual “rupture” through an expanded nodal capsule). Several biomarkers (e.g. podoplanin) that are often associated with tumor aggressiveness have been reported to have a high expression in ENE+ LN. ENE represents a spectrum of tumor nodal invasion. The early sign of ENE can only be visible under the microscope (pathologic ENE); when ENE progresses further, the radiographic signal changes become apparent, making it visible on imaging (iENE). Most advanced ENE causes emergence of clinical surrogates (e.g. peau d'orange, or a “fixed” nodal mass), rendering it detectable by regular clinical examination (ENEc). iENE has been reported to be one of the strongest anatomic prognostic factors for overall survival (mainly due to increased risk of distant metastasis) in HPV-positive oropharyngeal carcinoma (HPV+ OPC), and is able to identify a subgroup of stage I disease with poor prognosis. Several deintensification trials (NRG-HN002, ORATOR, ORATOR2, E3311) have excluded HPV+ OPC with some form of iENE from trial enrolment. Several authors have proposed that iENE be included in future clinical N classification for HPV+ OPC. However, adoption of iENE in clinical care remains challenging because it is not a well-defined radiologic feature among the radiology community. Various definitions / descriptions of iENE have been used in literature. There is also insufficient awareness of the prognostic importance of this parameter in head and neck oncology community. The international iENE Expert Panel was convened under the HNCIG comprised expert internationally renowned neuroradiologists and clinicians. Several rounds of Delphi process were conducted to consolidate iENE definition. The consensus recommendations on the terminology and diagnostic criteria for iENE were generated. The experts in the consensus process recognized the following as criteria for the diagnosis of iENE: clear evidence of irregular or indistinct nodal margin/border; extension into perinodal fat; extension into adjacent structures, and conglomerate/matted/coalescent nodes. These recommendations have been endorsed by 19 national organisations, representing 34 countries. With increased awareness and consolidated definition as well as training, iENE could become an important baseline factor for risk stratification and staging in HPV+ OPC.

The Prognostic and Predictive Value of Pre-Treatment Total Lymphocyte Count in HPV+ Oropharyngeal Carcinoma Receiving Definitive (Chemo-) Radiation

Evidence of prognostic importance of pre-radiotherapy (RT) total lymphocyte counts (TLC) and interaction with addition of cisplatin (CRT) in HPV-positive oropharyngeal carcinoma (HPV+OPC) is conflicting. Recent data suggest patients with high TLC may not benefit from the addition of chemotherapy (Price et al, JCO 2022). We assess the prognostic and predictive value of TLC in a large single center HPV+OCP cohort. All HPV+OPC patients treated at a single academic center with definitive RT/CRT between 2005-2018 were included. Pre-treatment TLC up to 6 weeks prior to RT start were considered. Multivariable analysis (MVA) was applied to assess the prognostic importance of TLC (continuous variable), adjusted for age, gender, performance status, TNM-8 stage, and smoking status in the CRT and RT subgroups. The actuarial rates of locoregional control (LRC), distant control (DC), and overall survival (OS) were calculated using Kaplan-Meier and competing risk methods, stratified by low vs high TLC (determined using Contal and O'Quigley method for optimal cutoff). Among 1153 eligible patients, 707 (61%) were treated with CRT. Median age was 59.7 (range 22.7-92.2) years. 526 patients were (46%) TNM-8 stage I, 366 (32%) stage II and 261 (23%) stage III. Median TLC was 1.6 x 109/L (range 0.1-8.5). Median follow-up was 5.5 years. On MVA, TLC was prognostic for patients receiving CRT (OS [adjusted hazard ration (aHR) 0.55 (0.38-0.79), p = 0.002], DC [aHR 0.57 (0.37-0.88), p = 0.011], LRC [aHR 0.57 (0.36-0.89), p = 0.014]) but not RT (OS [aHR 1.04 (0.82-1.31), p = 0.74], LRC [aHR 1.26 (0.86-1.85), p = 0.23], DC [aHR 0.87 (0.64-1.19), p = 0.4)]. The optimal TLC cut-off for OS with CRT was 1.9 x 109/L. Low vs high TLC patients receiving CRT had significantly inferior 5-year DC (87% vs 93%, p = 0.017) and OS (84% vs 90%, p = 0.026). The benefit of higher TLC was most evident in stage II disease (table 1). CRT vs RT improved OS for stage II/III disease at high and low TLC. Pre-treatment TLC is prognostic in a large cohort of HPV+OPC patients receiving CRT but not RT alone. Further investigation of the interaction of cisplatin and immune response during RT is warranted. The omission of chemotherapy based on TLC is not supported.

Research Progress on Human Papillomavirus-Associated Oropharyngeal Cancer

HPV-positive oropharyngeal carcinoma is classified as a distinct clinical entity that differs substantially from other types of head and neck tumors in terms of epidemiology, morphology, molecular and clinical features, treatment, and prognosis. The research progress in the above aspects is mainly reviewed.

De-escalated radiation for human papillomavirus virus-related oropharyngeal cancer: evolving paradigms and future strategies.

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma has increased dramatically in recent years reaching epidemic-like proportions. Data has emerged not only showing that these cancers are a unique entity with distinct molecular characteristics but that they also have a significantly improved prognosis as a result of their exquisite radiosensitivity compared to their HPV-negative counterparts. This, it has been increasingly suggested that these tumors can be targeted with de-escalated approaches using reduced doses of radiation. The overriding goal of de-escalation is to maintain the high cure and survival rates associated with traditional approaches while reducing the incidence of both short- and long-term toxicity. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, prospective studies have now been published demonstrating that de-escalated radiation can successfully maintain the high rates of cure and preserve quality of life for appropriately selected patients with this disease. However, these studies have been complicated by such factors as the relatively limited sample sizes, as well as the variability in treatment, inclusion criteria, and follow-up. As the data continues to mature on de-escalation, it is unquestionable that treatment paradigms for this disease will evolve. The ongoing quest to define a standard regimen comprises the subject of this review.

Reduced-dose radiation in human papillomavirus-associated oropharyngeal carcinoma can improve outcome: a systematic review and meta-analysis.

Despite its effectiveness, the standard course of chemoradiation for the treatment of human papillomavirus (HPV)-related oropharyngeal carcinoma (OPC) results in considerable treatment-related adverse effects. Studies proved that HPV-positive OPC is very sensitive to radiotherapy. Using de-escalation therapy as a new strategy is critical to maintaining positive outcomes while alleviating side effects. However, some studies hold that reduced dose causes insufficient effect on tumor killing. We conducted this systematic review and meta-analysis of survival and adverse reactions in patients with HPV-related OPC by retrospective analysis and evaluated the therapeutic effect of reducing the radiation dose. Data were double-selected and extracted by searching seven electronic databases, Original studies in all language treated HPV-associated OPC with reduced-dose and standard-dose therapies were included. Overall survival (OS), progression-free survival (PFS), and incidence rates of adverse events were obtained by pooling analyses. Statistical analyses were performed using RStudio Version 1.1.383 (RStudio, Boston, MA, USA) via the Meta-Analysis R Package (metafor). Heterogeneity was evaluated using the I2 statistic and the Cochran Q test. We used Stata (version 15.0) for forest graph. Thirteen studies were included in this meta-analysis, involving a dose range of 66-70 Gy for the standard treatment regimen and <66 Gy for the reduced-dose group. There was no significant difference in the age of the patients in the standard and the reduced treatment groups (60.9±5.9 vs. 58.6±2.4 years). Nine studies were included as standard cohort and thirteen studies were enrolled as reduced-dose cohort. The 2- and 3-year overall survival rates in the reduced-dose group (95.66% and 91.51%, respectively) were superior to those in the standard-dose group (88.36% and 87.46%, respectively). There was no significant difference in PFS between the two groups. A systematic review of articles on dose reduction and the standard dose was also conducted. The most common complication in reduced-dose radiation was oral mucositis (36.4%), followed by decreased white blood cell (WBC) count (30.5%) and dry mouth (29.1%). Reducing the radiation dose in patients with HPV-related OPC substantially alleviates the treatment toxicities and optimizes the quality of life of patients while at the same time maintaining favorable oncologic outcomes.

Surgical clinical trials for HPV-positive oropharyngeal carcinoma.

The treatment of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) continues to evolve as multiple ongoing and recently completed clinical trials investigate the role of surgery, radiation therapy, chemotherapy, and immunotherapy. Current trials are investigating transoral robotic surgery (TORS) in treatment de-escalation protocols in an effort to optimize quality of life, while maintaining historical survival rates. The advantage of TORS is its minimally invasive approach to primary resection of the tumor as well as valuable pathologic staging. The ORATOR trial reported poorer quality of life in patients treated with TORS compared to primary radiotherapy though this was not a clinically meaningful difference. The recently published ECOG 3311 trial showed that surgery can be used to safely de-escalate the adjuvant radiation dose to 50 Gy in intermediate-risk patients. In this review, we summarize and discuss the past and current clinical trials involving surgery in the treatment of HPV-positive OPSCC.

The Prognostic Value of Radiological Extranodal Extension in HPV-Positive Oropharyngeal Carcinoma Treated by (Chemo-)Radiation

<h3>Purpose/Objective(s)</h3> In HPV-positive (HPV+) oropharyngeal carcinoma (OPC), N-status is defined exclusively by size and laterality of lymph node metastasis. In HPV-unrelated head and neck cancers, extranodal extension has already been included in the clinical N-categories of the TNM-staging system. There is emerging evidence that the presence of radiological extranodal extension (rENE) impacts prognosis and survival for HPV+ OPC. The hypothesis of this study is that the presence of rENE in node positive HPV+ OPC is associated with worse outcome, and rENE may be used to improve prognostication. <h3>Materials/Methods</h3> Consecutive patients treated by definitive radiation or chemoradiation (organ-preservation), using IMRT, for node-positive HPV+ OPC between 2009 and 2018 were retrospectively registered. Baseline diagnostic MRI or CT scans (acquired <60 days of start of treatment) were retrospectively scored for the presence of rENE by two experienced head and neck radiologists, according to previously described methods (<i>Huang et al., JCO 2021</i>) and with scoring for level of certainty for the presence of rENE (<i>Panicek et al., AJR 2016</i>). Outcome measures included Overall Survival (OS), Disease Free Survival (DFS), Locoregional Control (LRC) and Distant Control (DC); each were stratified for rENE status. Multivariate analysis for OS was used to investigate the independent prognostic value of rENE. <h3>Results</h3> This cohort consisted of 111 patients with node-positive HPV+ OPC, treated by organ-preservation. Median age was 62.8 years, gender was male in 78% and female in 22% of cases, median number of pack years of smoking was 15 (range 0-113). T-stage (according to TNM-8) was as follows: T1 in 21, T2 in 34, T3 in 21 and T4 in 35 cases. N-stage consisted of: N1 in 66 cases, N2 in 11 cases and N3 in 1 case. TNM-group staging was stage I in 48, stage II in 27 and stage III in 36 cases. rENE was present (rENE+) in 39 cases (35%) and absent (rENE-) in 72 cases (65%). Median follow-up of all patients was 57 months (range 2-156); median follow-up of patients alive at last follow-up was 63 months (range 31-156). Patients with rENE+ had inferior 5-year OS compared to those with rENE-: 57% vs. 76% (Log-rank p-value = 0.018), inferior 5-year DFS (51% vs. 71%, p-value = 0.016), and inferior 5-year DC (81% vs. 91%, p-value = 0.11) but there was no meaningful difference in 5-year LRC (86% vs. 90%, p-value =0.49). In multivariate analyses, the following factors were independently associated with OS: N-stage (N2 vs. N1, HR 2.66, p-value = 0.01), age (HR 1.05, p-value = 0.005), smoking pack years (HR 1.02, p-value = 0.035) and rENE (HR 2.38, p-value = 0.024). <h3>Conclusion</h3> rENE is indeed an important prognostic factor in a contemporary single-institutional cohort of patients with HPV+ OPC, and is independent of N-stage. rENE may potentially be used to further refine the TNM staging system.

New progress in diagnosis and treatment of HPV-positive oropharyngeal carcinoma

In recent years, the incidence of oropharyngeal carcinoma （OPC） is increasing, while the better prognosis of patients with Human papillomavirus （HPV） positive oropharyngeal carcinoma has been confirmed in a number of studies. There are a variety of detection methods for HPV-associated oropharyngeal carcinoma. Including P16 immunohistochemistry, Polymerase Chain Reaction （PCR） or In situ hybridization （ISH） detection of HPV DNA, HPV RNA, Revers transcriptase Polymerase Chain Reaction （RT PCR） was used to detect HPV RNA. The better prognosis of patients with HPV-positive oropharyngeal carcinoma has led to the emergence of a large number of degraded treatment trials. The traditional P16 test has certain limitations in the diagnosis of patients with HPV-positive oropharyngeal carcinoma. It is necessary to combine with other detection methods to accurately screen out patients with HPV-positive oropharyngeal carcinoma and better apply to degraded therapy. In this article, we will briefly introduce the trend of HPV-associated oropharyngeal carcinoma, the detection methods and the new progress of degraded treatment trials.

2011–2021 rising prevalence of HPV infection among oropharyngeal carcinoma in France

BackgroundThe objective of our study was to investigate changes over the past decade in patient age and the prevalence of HPV in the population of patients with oropharyngeal carcinoma (OPC) treated at our center.MethodsWe performed a retrospective cohort study of patients treated at our cancer center for OPC between 2011 and 2021. Tissue biopsies were assessed for HPV status based on p16 staining for all patients.ResultsThere were 1,365 treated patients. The proportion of p16-positive patients increased from 43% in 2011 to 57.3% in 2021 (p = 0.01). The sex ratio was 3.6 M/1F for p16-positive and 3.7 M/1F for p16-negative patients (p = 0.94). The mean age increased from 60.2 y in 2011 to 63.6 y in 2021. The mean ages were 61.9 y for p16-positive and 61.7 y for p16-negative patients (p = 0.71), but there was a broader age distribution for the p16-positive patients (p = 0.03). The proportion of patients older than 70 y increased from 11% in 2011 to 28.2% in 2021, and this aging was similar between p16-positive (30.7% in 2021) and p16-negative (26.3% in 2021) patients. The 2-year and 5-year OS rates were 73.7% and 56.5% for the entire cohort. p16-positive patients had 2-year and 5-year OS rates of 86.8% and 77.4%, respectively, whereas p16-negative patients had 2-year and 5-year OS rates of 63.9% and 40.5%.ConclusionsAssessment of the change over the past decade in the population of patients with OPC at our center showed that HPV-positive OPC now appear to have overtaken HPV-negative cases in France, with 57.3% in 2021, and showed significant aging, with almost thirty percent of patients now older than 70 years. Those combined changes emphasize some of the challenges to be addressed in future OPC management.

Adjuvant Radiotherapy in Surgically Treated HPV-Positive Oropharyngeal Carcinoma with Adverse Pathological Features.

Simple SummaryHuman papillomavirus-positive oropharyngeal carcinoma (HPV-OPC) is being increasingly treated with upfront surgery. Whether patients require further “adjuvant” treatment, such as radiation, depends on microscopic “adverse features” identified on pathological analysis of the resected tumor specimen. Current guidelines recommend adjuvant radiotherapy for HPV-OPC tumors that demonstrate adverse features. In the present study, we demonstrate that adjuvant radiotherapy is associated with improved overall survival in patients with early-stage HPV-OPC who were found to have adverse pathological features. However, the rate of patients with adverse feature positive HPV-OPC who did not receive adjuvant radiotherapy significantly increased during the study period, from 10% in 2010 to 17% in 2017.Purpose: HPV-positive oropharyngeal carcinoma (HPV-OPC) is increasingly treated with primary surgery. The National Comprehensive Cancer Network (NCCN) recommends adjuvant therapy for surgically treated HPV-OPC displaying adverse pathological features (AF). We evaluated adjuvant radiotherapy patterns and outcomes in surgically treated AF-positive HPV-OPC (AF-HPV-OPC). Methods: The National Cancer Database was interrogated for patients ≥ 18 years with early-stage HPV-OPC from 2010 to 2017 who underwent definitive resection. Patients that had an NCCN-defined AF indication for adjuvant radiotherapy were assessed, including positive surgical margins (PSM), extranodal extension (ENE), lymphovascular invasion, and level 4/5 cervical lymph nodes. Overall survival (OS) was evaluated using Cox proportional hazards models and Kaplan–Meier analysis in whole and propensity score matched (PM) cohorts. Results: Of 15,036 patients meeting inclusion criteria, 55.7% were positive for at least one AF. Presence of any AF was associated with worse OS (hazard ratio (HR) = 1.56, p < 0.001). In isolation, each AF was associated with worse OS. On PM analysis, insurance status, T2 category, Charlson-Deyo comorbidity score, ENE (HR = 1.81, p < 0.001), and PSM (HR = 1.58, p = 0.002) were associated with worse OS. Median 3-year OS was 92.0% among AF-HPV-OPC patients undergoing adjuvant radiotherapy and 84.2% for those who did not receive adjuvant radiotherapy (p < 0.001, n = 1678). The overall rate of patients with AF-HPV-OPC who did not receive adjuvant radiotherapy was 13% and increased from 10% in 2010 to 17% in 2017 (ptrend = 0.007). Conclusions: In patients with AF-HPV-OPC, adjuvant radiotherapy is associated with improved survival. In the era of de-escalation therapy for HPV-OPC, our findings demonstrate the persistent prognostic benefit of post-operative radiotherapy in the setting of commonly identified adverse features. Ongoing clinical trials will better elucidate optimized patient selection for de-escalated therapy.

Use of positron emission tomography/ computed tomography in the initial staging of head and neck squamous cell carcinoma: Accuracy in evaluation of the primary site of the tumor, metastases to cervical lymph nodes, and distant metastases.

Our study aimed to evaluate the use of positron emission tomography/computed tomography (PET/CT) in the initial staging of head and neck squamous cell carcinoma (HNSCC), including assessment of local and distant spread of the disease. We also aimed to compare the accuracy of PET/CT in the evaluation of human papillomavirus (HPV) positive and HPV-negative oropharyngeal carcinoma. This single-center, prospective study was conducted between August 2016 and September 2021. A total of 198 patients with HNSCC who underwent PET/CT within the primary staging were included. We compared PET/CT results with histological findings. We calculated the accuracy, sensitivity, specificity, and positive and negative predictive values to assess the primary tumor, cervical lymph nodes, and distant metastases. PET/CT showed a high success rate (32%) in revealing the primary site of carcinoma of unknown primary (CUP). The accuracy of PET/CT in displaying the primary tumor, cervical lymph node metastases, and distant metastases was 89.4%, 85.4%, and 87.4%, respectively. The method provided high sensitivity but lower specificity in all three areas. Specifically, PET/CT showed low specificity in the assessment of small tumors (75%), metastatic involvement of cervical lymph nodes (69.6%), and HPV-positive oropharyngeal carcinoma (55.6%). The high accuracy of PET/CT to identify distant metastases and whole-body staging in one diagnostic step accelerated primary staging and resulted in earlier commencement of therapy. However, it also led to an overestimation of clinical findings and thus to extensive surgical treatment, especially in patients with small tumors, metastatic involvement of cervical lymph nodes, and HPV- positive oropharyngeal carcinoma. PET/CT is also useful for CUP diagnostics.

Events prediction after treatment in HPV-driven oropharyngeal carcinoma using machine learning

ObjectivesOur objective was to develop a predictive model using a machine learning signature to identify patients at high risk of relapse or death after treatment for HPV-positive oropharyngeal carcinoma. Materials and methodsPre-treatment variables of 450 patients with HPV-positive oropharyngeal carcinoma treated with a curative intent comprised clinical items, imaging parameters and histological findings. The events considered were progression or residual disease after treatment, the recurrent disease after a disease-free interval and death. The endpoints were the prediction of events and progression-free survival. After feature Z-score normalisation and selection, random forest classifier models were trained. The best models were evaluated on recall, the F-score, and the ROC AUC metric. The clinical relevance of the best prediction model was evaluated using Kaplan–Meier analysis with a log-rank test. ResultsThe best random forest model predicted the 5-year risk of relapse-free survival with a recall of 79.1%, an F1-score of 81.08%, and an AUC of the ROC curve of 0.89. The models performed poorly for the prediction of specific events of progression only, recurrence only or death only. The clinical relevance of the model was validated with a 5-year relapse-free survival of high-risk patients versus low-risk patients of 23.5% and 80%, respectively (p < 0.0001). ConclusionPatients with HPV-driven oropharyngeal carcinoma at high risk of relapse-free survival could be identified with a predictive machine learning model using patient data before treatment.

Pharmacodynamic and therapeutic pilot studies of single-agent ribavirin in patients with human papillomavirus–related malignancies

ObjectivesRibavirin inhibits eukaryotic translation initiation factor 4E (eIF4E), thereby decreasing cap-dependent translation. In this two-part study, we assessed the pharmacodynamic effects and therapeutic potential of ribavirin in human papillomavirus (HPV)–related malignancies. MethodsIn the pharmacodynamic study, ribavirin (400 mg BID for 14 days) was evaluated in 8 patients with HPV-positive localized oropharyngeal carcinoma with phosphorylated-eIF4E (p-eIF4E) ≥ 30%. In the therapeutic study, ribavirin (1400 mg BID in 28-day cycles, continuously dosed) was evaluated in 12 patients with recurrent and/or metastatic HPV-related cancer. Dose interruptions or reductions were allowed according to prespecified criteria. Toxicities were assessed in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4; response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Patients remained on study until disease progression or unacceptable toxicity. ResultsSix patients were evaluable in the pharmacodynamic study: 4 had decreased p-eIF4E after 14 days of ribavirin. In the therapeutic study, 12 patients were evaluable for toxicity, and 9 were evaluable for response. Among these, median follow-up was 3.5 months, and best overall response was stable disease in 5 patients and progression of disease in 4 patients. Median progression-free survival was 1.8 months. The most common treatment-related adverse events (grade > 2) were anemia, dyspnea, and hyperbilirubinemia. All patients had anemia (grades 1–3), with 33% having at least 1 dose reduction. ConclusionOral ribavirin decreases p-eIF4E levels and is well-tolerated. However, a clear signal of efficacy in patients with recurrent and/or metastatic HPV-related cancers was not observed. (NCT02308241, NCT01268579)

Patterns of disease events and causes of death in patients with HPV-positive versus HPV-negative oropharyngeal carcinoma

Background and purposeThere have been no studies to date of patterns of events after oropharyngeal squamous cell carcinoma (OPC) treatment comprising disease progression immediately after treatment or after a disease-free interval (DFI), and causes of death, according to HPV status. Materials and methodsPatients with a T1-4, N0-3, M0 OPC who completed treatment in a curative intent at our center between 2011 and 2020 were analyzed. A DFI was defined as the absence of the disease confirmed by both physical and radiological evaluation. ResultsWe analyzed 888 patients, of who 451 were p16-positive and 437 were p16-negative. The 5-year survival rates were 82.4% vs. 44%, respectively (p < 0.0001, HR 0.24). The rates of disease progression at the end of the treatment without a DFI were 7.8% vs. 21.1% in the p16-positive vs. the p16-negative patients (p < 0.0001, OR 0.38). The 5-year competing risks of disease recurrence after a DFI were 5.6% vs. 20.5%, respectively (p < 0.0001, HR 0.26). Patients who were p16-positive had a lower risk of death from OPC disease (p < 0.0001, HR 0.23). The 5-year competing risks of a second primary cancer during follow-up were 16.1% vs. 49.9% (p = 0.0002) in the p16-positive vs. the p16- negative patients. Patients who were p16-positive had a lower risk of death from intercurrent causes (p < 0.0001, HR 0.17). ConclusionClinical trials and medical interventions dedicated to each category of events and causes of death are needed to improve survival in HPV-positive and HPV-negative OPC patients.

Unfinished Business in Classifying HPV-Positive Oropharyngeal Carcinoma: Identifying the Bad Apples in a Good Staging Barrel.

This commentary highlights three important findings in the study by Vijayvargiya et al, published in this journal, involving 9554 oropharyngeal cancer patients from the SEER database. Firstly, there is improved performance in outcome prediction with TNM-8 in HPV+ OPC. However, heterogeneity exists, especially in TNM-8 stage I disease, and there is need for ongoing improvement in risk stratification. Several anatomical and non-anatomical prognostic factors have been proposed. Among them, radiologic extranodal extension has emerged as one of the promising parameters to be considered for future staging. These baseline prognostic factors should address sensitivity, specificity, and diagnostic accuracy to serve different clinical needs. Secondly, cure is possible for some patients presenting with M1 disease. Optimal management of such patients remains to be explored, and clinical trials targeting de novo M1 disease should be encouraged to optimize outcomes for this subset. Finally, methodologies to address missing tumor HPV status in historical cohorts have been discussed, including using baseline demographics and clinical characteristics, as well as statistical procedures such as multiple imputation.

Evaluation of Substantial Reduction in Elective Radiotherapy Dose and Field in Patients With Human Papillomavirus–Associated Oropharyngeal Carcinoma Treated With Definitive Chemoradiotherapy

Several de-escalation strategies for human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC) have focused on deintensifying gross disease treatment. Reduction of radiotherapy dose and target volume to subclinical regions may achieve good clinical outcomes with favorable patient quality of life (QOL). To determine outcomes from a systematic approach of reducing radiotherapy dose and target volume to the elective treatment regions in patients with HPV-associated OPC undergoing concurrent chemoradiotherapy (CCRT). This retrospective cohort study included 276 consecutive patients with HPV-positive OPC receiving CCRT from March 1, 2017, to July 31, 2019. Data were analyzed from February 23 to September 13, 2021. Elective nodal and subclinical regions received 30 Gy of radiotherapy in 15 fractions, followed by a cone down of 40 Gy in 20 fractions to gross disease for a total dose of 70 Gy. The high retropharyngeal nodal basins in the node-negative neck and bilateral levels IB and V basins were omitted. Patients were followed up to evaluate locoregional control as the primary outcome and distant metastasis-free survival, progression-free survival, and overall survival as secondary outcomes. Quality-of-life data were obtained at each visit when feasible. Among the 276 patients included in the analysis, the median age was 61 (range, 36-87) years; 247 (89.5%) were men; and 183 (66.3%) had less than 10 pack-years of smoking history. Most patients (251 [90.9%]) were White. Overall, 87 (31.5%) had cT3-cT4 disease and 65 (23.5%) had cN2-cN3 disease per the 8th edition of the American Joint Committee on Cancer Staging Manual. One hundred seventy-two patients (62.3%) completed 300-mg/m2 high-dose cisplatin therapy. During a median follow-up of 26 (range, 21-32) months, 8 patients developed locoregional recurrence, including 7 at the primary site or gross nodes that received a total dose of 70 Gy and 1 with a persistent node not previously identified as gross disease that received a total dose of only 30 Gy. The 24-month locoregional control was 97.0%; progression-free survival, 88.0%; distant metastasis-free survival, 95.2%; and overall survival, 95.1%. During treatment, 17 patients (6.2%) required a feeding tube. At 24 months, most of the QOL composite scores (jaw-related problems, pain, social contact, eating, speech, and swallow) were comparable or superior to baseline measures except for senses, dry mouth, muscular tension, and cognitive functioning, which improved over time but remained marginally worse than baseline. This cohort study found that the evaluated de-escalation strategy for elective regions showed favorable clinical outcomes and QOL profiles. Long-term follow-up data will help affirm the efficacy of this strategy as a care option for treating HPV-associated OPC with primary CCRT.

Clinical Validity of a Prognostic Gene Expression Cluster-Based Model in Human Papillomavirus-Positive Oropharyngeal Carcinoma.

PURPOSEUnder common therapeutic regimens, the prognosis of human papillomavirus (HPV)–positive squamous oropharyngeal carcinomas (OPCs) is more favorable than HPV-negative OPCs. However, the prognosis of some tumors is dismal, and validated prognostic factors are missing in clinical practice. The present work aimed to validate the prognostic significance of our published three-cluster model and to compare its prognostic value with those of the 8th edition of the tumor-node-metastasis staging system (TNM8) and published signatures and clustering models.METHODSPatients with HPV DNA-positive OPCs with locoregionally advanced nonmetastatic disease treated with curative intent (BD2Decide observational study, NCT02832102) were considered as validation cohort. Patients were treated in seven European centers, with expertise in the multidisciplinary management of patients with head and neck cancer. The median follow-up was 46.2 months (95% CI, 41.2 to 50), and data collection was concluded in September 2019. The primary end point of this study was overall survival (OS). Three-clustering models and seven prognostic signatures were compared with our three-cluster model.RESULTSThe study population consisted of 235 patients. The three-cluster model confirmed its prognostic value. Two-year OS in each cluster was 100% in the low-risk cluster, 96.6% in the intermediate-risk cluster, and 86.3% in the high-risk cluster (P = .00074). For the high-risk cluster, we observed an area under the curve = 0.832 for 2-year OS, significantly outperforming TNM 8th edition (area under the curve = 0.596), and functional and biological differences were identified for each cluster.CONCLUSIONThe rigorous clinical selection of the cases included in this study confirmed the robustness of our three-cluster model in HPV-positive OPCs. The prognostic value was found to be independent and superior compared with TNM8. The next step includes the translation of the three-cluster model in clinical practice. This could open the way to future exploration of already available therapies in HPV-positive OPCs tailoring de-escalation or intensification according to the three-cluster model.

P-71 Incidence of contralateral neck failure (CNF) after long-term follow-up in HPV positive oropharyngeal carcinoma treated with unilateral neck irradiation with or without primary surgery

P-71 Incidence of contralateral neck failure (CNF) after long-term follow-up in HPV positive oropharyngeal carcinoma treated with unilateral neck irradiation with or without primary surgery