Management of Oral Manifestations of Herpes Simplex Virus, Varicella Zoster Virus, and Human Papillomavirus.

Human herpes virus is a family of DNA viruses that includes herpes simplex virus (HSV) and varicella zoster virus (VZV). HSV-1 and HSV-2 are fairly common and result in oral and genital lesions. Recurrent infections of herpes include lesions on the lips resulting in pain and possibly societal stigma, making adequate treatment of these conditions crucial. VZV is the cause of chicken pox and shingles. Acyclovir and other nucleoside analogues have been the gold standard of treatment for HSV and VZV, but newer, more effective treatments are being developed, which is beneficial regarding the issue of resistance to standard antivirals. Human papillomavirus (HPV) is also a DNA virus with different subtypes that result in four common oral benign lesions. The significance and treatments of HSV, VZV, and HPV are discussed, along with certain developing treatments of herpes labialis (HSV).

De-Escalated Therapy and Early Treatment of Recurrences in HPV-Associated Head and Neck Cancer: The Potential for Biomarkers to Revolutionize Personalized Therapy.

Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the most common HPV-associated cancer in the United States, with a rapid increase in incidence over the last two decades. The burden of HPV+ HNSCC is likely to continue to rise, and given the long latency between infection and the development of HPV+ HNSCC, it is estimated that the effect of the HPV vaccine will not be reflected in HNSCC prevalence until 2060. Efforts have begun to decrease morbidity of standard therapies for this disease, and its improved characterization is being leveraged to identify and target molecular vulnerabilities. Companion biomarkers for new therapies will identify responsive tumors. A more basic understanding of two mechanisms of HPV carcinogenesis in the head and neck has identified subtypes of HPV+ HNSCC that correlate with different carcinogenic programs and that identify tumors with good or poor prognosis. Current development of biomarkers that reliably identify these two subtypes, as well as biomarkers that can detect recurrent disease at an earlier time, will have immediate clinical application.

Prognostic and therapeutic potential of STAT3: Opportunities and challenges in targeting HPV-mediated cervical carcinogenesis.

Cervical cancer (CaCx) ranks as the fourth most prevalent cancer among women globally. Persistent infection of high-risk human papillomaviruses (HR-HPVs) is major etiological factor associated with CaCx. Signal Transducer and Activator of Transcription 3 (STAT3), a prominent member of the STAT family, has emerged as independent oncogenic driver. It is a target of many oncogenic viruses including HPV. How STAT3 influences HPV viral gene expression or gets affected by HPV is an area of active investigation. A better understanding of host-virus interaction will provide a prognostic and therapeutic window for CaCx control and management. In this comprehensive review, we delve into carcinogenic role of STAT3 in development of HPV-induced CaCx. With an emphasis on fascinating interplay between STAT3 and HPV genome, the review explores the diverse array of opportunities and challenges associated with this field to harness the prognostic and therapeutic potential of STAT3 in CaCx.

Three-dimensional chromatin analysis reveals Sp1 as a mediator to program and reprogram HPV-host epigenetic architecture in cervical cancer.

Human papillomavirus (HPV) is predominantly associated with HPV-related cancers, however, the precise mechanisms underlying the HPV-host epigenetic architectures in HPV carcinogenesis remain elusive. Here, we employed high-throughput chromosome conformation capture (Hi-C) to comprehensively map HPV16/18-host chromatin interactions. Our study identified the transcription factor Sp1 as a pivotal mediator in programming HPV-host interactions. By targeting Sp1, the active histone modifications (H3K27ac, H3K4me1, and H3K4me3) and the HPV-host chromatin interactions are reprogrammed, which leads to the downregulation of oncogenes located near the integration sites in both HPV (E6/E7) and the host genome (KLF5/MYC). Additionally, Sp1 inhibition led to the upregulation of immune checkpoint genes by reprogramming histone modifications in host cells. Notably, humanized patient-derived xenograft (PDX-HuHSC-NSG) models demonstrated that Sp1 inhibition promoted anti-PD-1 immunotherapy via remodeling the tumor immune microenvironment in cervical cancer. Moreover, single-cell transcriptomic analysis validated the enrichment of transcription factor Sp1 in epithelial cells of cervical cancer. In summary, our findings elucidate Sp1 as a key mediator involved in the programming and reprogramming of HPV-host epigenetic architecture. Inhibiting Sp1 with plicamycin may represent a promising therapeutic option for HPV-related carcinoma.

Mapping the research landscape of HPV-positive oropharyngeal cancer: a bibliometric analysis.

OBJECTIVE: The aim of the study is to evaluate the scientific interest, the collaboration patterns and the emerging trends regarding HPV+ OPSCC diagnosis and treatment. MATERIALS AND METHODS: A cross-sectional bibliometric analysis of articles reporting on HPV+ OPSCC within Scopus database was performed and all documents published up to December 31th, 2022 were eligible for analysis. Outcomes included the exploration of key characteristics (number of manuscripts published per year, growth rate, top productive countries, most highly cited papers, and the most well-represented journals), collaboration parameters (international collaboration ratio and networks, co-occurrence networks), keywords analysis (trend topics, factorial analysis). RESULTS: A total of 5200 documents were found, published from March, 1987 to December, 2022. The number of publications increased annually with an average growth rate of 19.94%, reaching a peak of 680 documents published in 2021. The 10 most cited documents (range 1105-4645) were published from 2000 to 2012. The keywords factorial analysis revealed two main clusters: one on epidemiology, diagnosis, prevention and association with other HPV tumors; the other one about the therapeutic options. According to the frequency of keywords, new items are emerging in the last three years regarding the application of Artifical Intelligence (machine learning and radiomics) and the diagnostic biomarkers (circulating tumor DNA). CONCLUSIONS: This bibliometric analysis highlights the importance of research efforts in prevention, diagnostics, and treatment strategies for this disease. Given the urgency of optimizing treatment and improving clinical outcomes, further clinical trials are needed to bridge unaddressed gaps in the management of HPV+ OPSCC patients.

A bioconvergence study on platinum-free concurrent chemoradiotherapy for the treatment of HPV-negative head and neck carcinoma.

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is characterized by high rate of recurrence, resulting in a poor survival. Standard treatments are associated with significant toxicities that impact the patient's quality of life, highlighting the urgent need for novel therapies to improve patient outcomes. On this regard, noble metal nanoparticles (NPs) are emerging as promising agents as both drug carriers and radiosensitizers. On the other hand, co-treatments based on NPs are still at the preclinical stage because of the associated metal-persistence.In this bioconvergence study, we introduce a novel strategy to exploit tumour chorioallantoic membrane models (CAMs) in radio-investigations within clinical equipment and evaluate the performance of non-persistent nanoarchitectures (NAs) in combination with radiotherapy with respect to the standard concurrent chemoradiotherapy for the treatment of HPV-negative HNSCCs. A comparable effect has been observed between the tested approaches, suggesting NAs as a potential platinum-free agent in concurrent chemoradiotherapy for HNSCCs. On a broader basis, our bioconvergence approach provides an advance for the translation of Pt-free radiosensitizer to the clinical practice, positively shifting the therapeutic vs. side effects equilibrium for the management of HNSCCs.

Immunotherapy that leverages HPV-specific immune responses for precancer lesions of cervical cancer.

Cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN), are caused by high-risk human papillomavirus (HPV) viral infection and are highly susceptible to host immunity targeting of HPV viral proteins, which include both foreign antigens and cancer antigens expressed by tumors. Immunotherapy that induces Th1 immunoreactivity against viral proteins is expected to take advantage of this immunological regression mechanism. However, although cancer immunotherapies for cervical cancer and CIN have been developed over the past several decades, none have been commercialized. Most of these immunotherapies target the viral cancer proteins E6 and E7, which are generally the same. The reasons for the underdevelopment of HPV-targeted immunotherapy differ depending on whether the target is invasive cancer or CIN. We here summarize the developmental history of cancer immunotherapy for CIN and discuss strategies for solving the problems that led to this underdevelopment. We note that CIN is a mucosal lesion and propose that inducing mucosal immunity may be the key.

Overall survival, disease-free survival and quality of life in patients affected by HPV mediated p16+ oropharyngeal squamous cell carcinoma treated with upfront trans-oral robotic surgery vs radiotherapy or chemoradiotherapy.

PURPOSE: Treatment de-intensification for p16 + oropharyngeal squamous cell carcinoma (OPSCC) is an area of active research to reduce the side effects and improve patients' quality of life (QoL). In this paper we evaluated the Overall Survival (OS), the Disease-Free Survival (DFS) and the QoL of patients affected by p16 + OPSCC according to their prognostic stage group (PSG) and different treatments. METHODS: Patients were selected retrospectively through our Electronic Tumor Board Database according to prespecified inclusion criteria. Basic data of eligible patients were recorded and analyzed. Then, OS and DFS were evaluated according to the PSG and the treatments performed. Patients alive completed three questionnaires: the QoL Questionnaire Core 30 (QLQ-C30), the QoL Questionnaire Head & Neck 43 (QLQ-HN43) and the MD Anderson Dysphagia Inventory (MDADI) questionnaire. RESULTS: Sixty-one patients were included in this study. Eight patients died from the disease and the remaining 53 patients completed the 3 questionnaires. Fifteen (25%) patients were treated with upfront surgery, 6 (10%) patients with definitive radiotherapy and 40 (65%) patients with concomitant chemoradiotherapy. Comparing the DFS and the OS of PSG I patients by the different treatments performed, no statistically significant difference was identified. Patients treated with upfront surgery showed better outcomes in some aspects of their QoL. CONCLUSION: For p16 + OPSCC PSG I patients, upfront surgery can be considered a valid alternative to radiotherapy or chemoradiotherapy while maintaining a comparable DFS and OS and giving patients better results in terms of specific aspects of their QoL.

Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Treatment Modality Impact on Patient-Reported Quality of Life in Human Papilloma Virus-Associated Oropharyngeal Carcinoma.

OBJECTIVE: To prospectively compare the impact of treatment modality on patient-reported quality of life (QOL) in human papillomavirus-associated oropharynx squamous cell carcinoma (HPV + OPSCC). STUDY DESIGN: Prospective cohort study. SETTING: Academic medical center. METHODS: One hundred one patients with American Joint Committee on Cancer (AJCC) 8th edition T1-3 N0-2 HPV + OPSCC completed the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire and Head and Neck Module pretreatment and 3-month and 1-year posttreatment. Mean score changes were compared to published minimal clinically important differences. RESULTS: Patients underwent surgery alone (SA: N = 42, 42%), surgery with adjuvant radiation (S-RT: N = 10, 10%), surgery with adjuvant chemoradiation (S-CRT: N = 8, 8%), definitive radiation (RT: N = 11, 11%), or definitive chemoradiation (CRT: N = 30, 30%). SA, S-[C]RT, and [C]RT patients all reported clinically significant difficulty with sense of taste/smell persisting at 1 year. S-[C]RT and [C]RT patients reported statistically and clinically significant worse salivary dysfunction and problems with social eating at 1 year than SA. S-[C]RT patients reported statistically and clinically significant worse fatigue and head and neck pain compared to [C]RT and SA patients at 3 months, but normalized at 1 year. S-CRT compared to S-RT had statistically and clinically worse physical and role functioning and swallowing difficulties at 3 months but this difference was resolved by 1-year posttreatment. CONCLUSION: HPV + OPSCC patients after SA report the lowest posttreatment QOL impact, whereas after S-CRT report the highest symptom burden. Careful selection for definitive surgery is important given the possibility of adjuvant CRT. Patients can experience persistent sense taste and smell difficulties at 1 year with all treatment modalities. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1687-1695, 2024.

Translational research in head and neck cancer: Molecular and immunological updates.

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis. Each year, approximately 880,000 patients are newly diagnosed with HNSCC worldwide, and 450,000 patients with HNSCC die. Risk factors for developing HNSCC have been identified, with cigarette smoking, alcohol consumption, and viral infections being the major factors. Owing to the prevalence of human papillomavirus infection, the number of HNSCC cases is increasing considerably. Surgery and chemoradiotherapy are the primary treatments for HNSCC. With advancements in tumor biology, patients are eligible for novel treatment modalities, namely targeted therapies, immunotherapy, and photoimmunotherapy. Because this area of research has rapidly progressed, clinicians should understand the basic biology of HNSCC to choose an appropriate therapy in the upcoming era of personalized medicine. This review summarized recent developments in tumor biology, focusing on epidemiology, genetic/epigenetic factors, the tumor microenvironment, microbiota, immunity, and photoimmunotherapy in HNSCC, as well as how these findings can be translated into clinical settings.

A comparison of timing and patterns of treatment failure, and survival outcomes after progression between HPV+ and HPV- patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas.

BACKGROUND: We aimed to analyze and compare the timing and patterns of treatment failure, and survival after progression between HPV-positive (HPV+) and HPV-negative (HPV-) patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas (OPSCC). METHODS: A retrospective review was performed of all patients undergoing primary chemoradiation for OPSCC between 2008 and 2021. Demographic and clinical data were collected. Kaplan-Meier estimates for overall survival (OS), and time to recurrence/metastases (TTR) were compared using the log-rank test, with Cox regression used for multivariable modeling comparing HPV+ and HPV- patients. RESULTS: HPV- patients developed recurrence or metastases at earlier time points than HPV+ patients (8.8 vs. 15.2 months, p < 0.05), due to earlier local/locoregional recurrence and distant metastases, but not isolated regional recurrences. HPV- distant metastases exclusively occurred in a single organ, most commonly the lungs or bone, while HPV+ metastases frequently had multi-organ involvement in a wide variety of locations (p < 0.05). Once progression (recurrence/metastases) was diagnosed, HPV+ patients experienced superior survival to HPV- patients on univariate and multivariate analysis, largely due to improved outcomes after treatment of local/locoregional recurrences (p < 0.05). There were no differences in survival after isolated regional recurrences or distant metastases. CONCLUSION: HPV+ OPSCC patients relapse later compared to HPV- patients in local/locoregional and distant sites. HPV+ patients with local/locoregional recurrence experience superior survival after recurrence, which does not hold true for isolated regional recurrences or distant metastases. These data can be useful to inform prognosis and guide treatment decisions in patients with recurrent OPSCC.

Cervical cancer treatment update: A Society of Gynecologic Oncology clinical practice statement.

Cervical cancer is the most commonly diagnosed gynecologic cancer worldwide. Although the incidence has declined with increased screening and higher uptake of human papillomavirus (HPV) vaccination in high-income countries, this disease remains the second highest cause of cancer mortality among women in low- and middle-income countries. In this clinical practice statement, we describe therapies for cervical cancer by treatment setting, as well as quality of life, financial toxicity, and disparities associated with this disease. In addition to chemotherapy and radiation, therapeutic strategies for cervical cancer include immune checkpoint blockade, antiangiogenics, and antibody-drug conjugates. Optimal treatment for recurrent cervical cancer remains an area of unmet need, necessitating further exploration of rational and innovative treatment approaches, including cell and immune-based therapies. Importantly, development of effective therapies for cervical cancer must incorporate strategies to ensure universal equitable access to HPV vaccination, screening, and treatment. Important consequences of the disease and treatment that impact quality of life must also be addressed. Patients with cervical cancer are at increased risk for financial toxicity, which can lead to downstream detrimental effects on physical, financial, and career outcomes. Underrepresentation of racial and ethnic minorities in gynecologic oncology clinical trials highlights the urgent need for collaborative and focused initiatives to bridge the significant divide and alleviate inequalities in the prevention and treatment of cervical cancer.

Deciphering the role of HPV-mediated metabolic regulation in shaping the tumor microenvironment and its implications for immunotherapy in HNSCC.

Head and neck squamous cell carcinoma (HNSCC), as a complex and variable malignancy, poses a significant threat to human health. Since the intricate association between HPV and HNSCC emerged, its role within the TME has garnered extensive attention. HPV+HNSCC exhibits distinct immunological characteristics within the TME, intricately intertwined with mechanisms of immune evasion. HPV employs multifaceted pathways to intervene in metabolic regulation within the TME, exerting influence over immune cell functionality and neoplastic cell genesis. Furthermore, the heightened immune reactivity exhibited by HPV+HNSCC within the TME augments responses to immune interventions such as immune checkpoint inhibitors. Therefore, amidst the current limitations of therapeutic approaches, immunotherapy stands as a promising strategy to overcome the conventional confines of treating HNSCC. This article comprehensively outlines the impact of HPV on the inception and progression of HNSCC while discussing the amalgamation of metabolic regulation within the TME and immunotherapeutic strategies. By intervening in the reciprocal interactions between HPV and HNSCC within the TME, the potential to modulate the efficacy of immune-based treatments becomes evident. Concurrently, a synthesis of pertinent biomarker development is summarized. Such endeavors hold paramount significance for personalized therapeutic approaches and the more effective management of HNSCC patients.

The tumor microenvironment state associates with response to HPV therapeutic vaccination in patients with respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare, debilitating neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11 and characterized by growth of papillomas in the upper aerodigestive tract. There is no approved medical therapy, and patients require repeated debulking procedures to maintain voice and airway function. PRGN-2012 is a gorilla adenovirus immune-therapeutic capable of enhancing HPV 6/11-specific T cell immunity. This first-in-human, phase 1 study (NCT04724980) of adjuvant PRGN-2012 treatment in adult patients with severe, aggressive RRP demonstrates the overall safety and clinically meaningful benefit observed with PRGN-2012, with a 50% complete response rate in patients treated at the highest dose. Responders demonstrate greater expansion of peripheral HPV-specific T cells compared with nonresponders. Additional correlative studies identify an association between reduced baseline papilloma HPV gene expression, greater interferon responses and expression of CXCL9 and CXCL10, and greater papilloma T cell infiltration in responders. Conversely, nonresponders were characterized by greater HPV and CXCL8 gene expression, increased neutrophilic cell infiltration, and reduced T cell papilloma infiltration. These results suggest that papilloma HPV gene expression may regulate interferon signaling and chemokine expression profiles within the tumor microenvironment that cooperate to govern clinical response to therapeutic HPV vaccination in patients with respiratory papillomatosis.

Effect of distance of treatment center on survival for HPV-negative head and neck cancer patients.

BACKGROUND: In rural states, travel burden for complex cancer care required for head and neck squamous cell carcinoma (HNSCC) may affect patient survival, but its impact is unknown. METHODS: Patients with HPV-negative HNSCC were retrospectively identified from a statewide, population-based study. Euclidian distance from the home address to the treatment center was calculated for radiation therapy, surgery, and chemotherapy. Multivariable Cox proportional hazards models were used to examine the risk of 5-year mortality with increasing travel quartiles. RESULTS: There were 936 patients with HPV-negative HNSCC with a mean age of 60. Patients traveled a median distance of 10.2, 11.1, and 10.9 miles to receive radiation therapy, surgery, and chemotherapy, respectively. Patients in the fourth distance quartile were more likely to live in a rural location (p < 0.001) and receive treatment at an academic hospital (p < 0.001). Adjusted overall survival (OS) improved proportionally to distance traveled, with improved OS remaining significant for patients who traveled the furthest for care (third and fourth quartile by distance). Relative to patients in the first quartile, patients in the fourth had a reduced risk of mortality with radiation (HR 0.59, 95% CI 0.42-0.83; p = 0.002), surgery (HR 0.47, 95% CI 0.30-0.75; p = 0.001), and chemotherapy (HR 0.56, 95% CI 0.35-0.91; p = 0.020). CONCLUSION: For patients in this population-based cohort, those traveling greater distances for treatment of HPV-negative HNSCC had improved OS. This analysis suggests that the benefits of coordinated, multidisciplinary care may outweigh the barriers of travel burden for these patients.

Recurrent laryngeal papillomatosis: multimodal therapeutic strategies. Literature review and multicentre retrospective study.

Objectives: Recurrent respiratory papillomatosis (RRP) is a benign, rare disease caused by Human Papilloma Virus (HPV) that can be divided into juvenile and adult forms. The course of the disease is variable, but is usually more aggressive in the juvenile form. The standard surgical treatment is represented by CO2 laser resection, although photoangiolytic lasers represent a valid alternative. Adjuvant therapies have been proposed for disease control in case of frequent surgical resections or spreading into the lower airways. In recent years, the development of immunotherapy led to the use of bevacizumab either intratumorally or intravenously, but the most promising therapeutic development is represented by HPV vaccination. This paper aims to present a narrative review of the literature and the experience of three different University Centres in the treatment of RRP. Methods: A retrospective analysis of the clinical charts of all patients affected by laryngeal papillomatosis and treated in three different University Centres between 2002 and 2022 was performed. The following parameters were collected: sex, age at first evaluation, sites of larynx involved, HPV type, type of first surgical treatment, presence and number of recurrences, surgical treatment of recurrences, adjuvant therapies, side effects and status at last follow-up. Results: Seventy-eight patients were available for evaluation. Of these, 88% had adult onset RRP (Ao-RRP) and 12% juvenile onset RRP (Jo-RRP). The glottis was the most frequently involved subsite; all patients were submitted to surgical resection with CO2 laser under general anaesthesia. Recurrences appeared in 79% of the patients, the patients who did not recur were all adults. The mean number of recurrences was 9 (range 1-110). Recurrences were more frequent in children (M = 20; range 2-110) than adults (M = 5; range 1-21). Thirty-two (52%) of the 62 patients who recurred were re-treated with CO2 laser under general anaesthesia, while office-based treatment with a photoangiolytic laser was preferred in the remaining 30 (48%) patients. Adjuvant treatments were applied in 26 patients. The analysis of the course of the disease showed that in the 9 patients with Jo-RRP, 6 (67%) were free of lesions at the last follow-up, while the other 3 (33%) had papillomas. Of the 69 patients with Ao-RRP, 53 (77%) were alive and free of disease at the last visit, 14 (21%) were alive with disease, 1 (1%) was lost at follow-up and 1 (1%) died for other disease. Severe side effects were not observed except for 2 patients, who developed posterior glottic stenosis. Conclusions: Our results confirmed the literature review. RRP is a potentially aggressive disease, especially in juvenile onset. Surgical resection is still first-line treatment, but in case of multiple recurrences the use of adjuvant therapies must be taken into consideration.

De-Escalation Treatment for Human Papillomavirus-Related Oropharyngeal Cancer: Questions for Practical Consideration.

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC), which accounts for an increasing proportion of all head and neck cancers, represents a specific entity with distinct clinical and molecular characteristics. It is now firmly established that patients with HPV-positive oropharyngeal SCC have a significantly improved prognosis because this variant has exquisite radiosensitivity compared with HPV-negative oropharyngeal SCC; thus, it can be targeted with de-escalated approaches using reduced doses of radiation and/or chemotherapy. 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 high rates of cure and preserve the 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. How treatment paradigms will evolve, particularly in the era of precision medicine, is a provocative question and is the subject of this review.

The Current Role of Human Papillomavirus Circulating Tumor DNA in Oropharynx Cancer.

ABSTRACT: Human papillomavirus infection is currently implicated in the majority of oropharyngeal squamous cell carcinoma cases diagnosed in the United States. Circulating tumor DNA (ctDNA) has emerged as a potential biomarker for human papillomavirus-related oropharyngeal squamous cell carcinoma and has the opportunity to improve the diagnosis, treatment, and surveillance of patients with this disease. Changes in ctDNA levels during and after primary therapy may be related to disease response, which can possibly have implications for treatment intensification or de-escalation strategies. Further, ctDNA seems to be sensitive and specific for disease recurrence and may improve upon current methods for assessing both treatment response and failure. In this review, we examine the relevant literature on the use of ctDNA for oropharyngeal cancer treatment and surveillance and discuss current limitations and future directions for this promising biomarker.

Current Status of Human Papillomavirus-Targeted Therapies Development in Head and Neck Cancer.

PURPOSE: While the incidence of smoking-related head and neck squamous cell carcinoma (HNSCC) has been declining, that of human papillomavirus (HPV)-mediated HNSCC has rapidly increased in the past decades worldwide. Despite rapid advances in therapeutics for solid tumors with novel immunotherapy and targeted therapeutic agents, no breakthroughs have yet been made in the treatment of advanced HPV+ HNSCCs. This review aims to summarize the concepts and designs, early trial results, and future directions of various HPV-targeted experimental therapeutics for HPV+ HNSCC. MATERIALS AND METHODS: Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, a systemic literature search of PubMed was conducted for HPV-targeted therapeutics using the following search terms: HPV, head and neck squamous cell carcinoma, and therapy. For clinical trial data, publications, major oncology conference abstracts, and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov) information were reviewed. This review focused on the ones that are in the clinical stage and currently in active ongoing evaluation. The therapeutics not actively evaluated in HNSCC, in the preclinical stage, or terminated for further development were excluded. RESULTS: Diverse approaches are being actively explored to target HPV+ HNSCC, including therapeutic vaccines of various modalities, HPV-specific immune cell-activating agents, and adaptive cellular therapeutics. All these novel agents use immune-based mechanisms and target constitutively expressed oncogenic HPV E6 and/or E7 viral proteins. Most therapeutics demonstrated excellent safety but single-agent activities are only modest. Many are being tested in combination with immune checkpoint inhibitors. CONCLUSION: Our review summarized various novel HPV-targeted therapeutics that are in the clinical phase for HPV+ HNSCC. Early-phase trial data suggest the feasibility and promising efficacy. Further strategies, including selecting the optimal combination and understanding and overcoming resistant mechanisms, are warranted for successful development.