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Abstract

Oropharyngeal carcinoma, a type of head and neck cancer (HNC), is an emerging malignancy associated with low survival rates. It typically affects older males and correlates with smoking, drinking, and lower socioeconomic conditions. Traditional treatments such as surgery have often yielded limited outcomes. However, recent insights, particularly those emphasized by Dr Teknos in his Keynote Conference at MedNews Week, have sparked a deeper exploration into alternative and more promising treatment methods. A comprehensive literature review was conducted to explore this subject further. One such approach, demonstrated by the UMCC 9921 trial, involves a comprehensive protocol starting with induction chemotherapy. This initial phase aims to reduce tumor burden and assess response to treatment. Based on the individual outcomes, patients then undergo concurrent chemoradiation or salvage surgery. This strategy has significantly improved survival rates, especially in human papillomavirus (HPV)-positive patients, showcasing the potential of tailored treatments. While these advancements are promising, long-term complications such as dysphagia and osteoradionecrosis remain a cause of concern. The rise of HPV-related head and neck squamous cell carcinoma has further changed how risk factors and treatment outcomes are viewed. HPV-positive cancers have unique characteristics and respond well to modern therapies. Researchers are investigating biomarkers such as circulating HPV DNA and immunoglobulin J polypeptide expression, which could provide valuable insights into disease progression and pave the way for more targeted and effective treatment strategies. In addition, the use of existing medications, such as fenofibrate, to combat HPV infections illustrates the resourcefulness in repurposing specific treatments. Challenges persist, especially in the need for reliable biomarkers for early disease progression detection and monitoring. Deeper insights into viral-host interactions shape promising immunotherapy strategies that could revolutionize treatment approaches. Collaborative efforts between researchers, healthcare providers, and policymakers play a vital role in translating these advancements into substantial clinical benefits, improving outcomes and quality of life for individuals affected by HPV-related diseases. While HPV-associated HNCs present significant challenges, continuous research and innovative treatments offer hope for a brighter future in combating this growing epidemic and improving patient care.

Keywords

biomarkers chemoradiation head and neck cancer HPV-positive immunotherapy induction chemotherapy oropharyngeal carcinoma

Introduction

Oropharyngeal carcinoma (OPC), commonly known as throat or tonsil cancer, represents a less common yet significant subset of cancers historically associated with poor survival rates.¹ Primarily located in the lymphoid tissue of the oropharynx, including the base of the tongue, tonsils, and soft palate, it predominantly affects older males with a history of smoking, alcohol consumption, malnutrition, edentulism, and lower socioeconomic status.² Typically, the diagnosed carcinoma manifests as keratinized squamous cell carcinoma (SCC), the predominant subtype within OPC cases.³ Distinctly, oropharyngeal cancers are categorized into human papillomavirus (HPV)-associated and non-HPV-associated types, with the latter primarily linked to environmental factors such as tobacco and alcohol usage.^4,5 HPV, primarily transmitted sexually but also through skin-to-skin contact and potentially vertical transmission during childbirth, presents a significant risk factor.^6,7 High-risk HPV strains, among which HPV 16 and HPV 18, are strongly implicated in oropharyngeal cancers, particularly HPV 16.⁸ While HPV-related OPC constitutes approximately 30% of cases,⁹ its prevalence highlights the need for extensive research. The anatomical overlap of HPV infections and OPC emphasizes the virus’ role in disease etiology. Risk factors include smoking, alcohol abuse, immunosuppression, nutritional deficiencies, poor oral hygiene, syphilis, previous radiation exposure, and HPV infection. As highlighted by Dr Teknos during his Keynote Conference at MedNews Week,^2,10–12 the historically low survival rates and limited efficacy of surgical interventions underscore the urgent need for alternative, nonsurgical treatment options.^13,14 This lecture was the rationale for the comprehensive literature review exploring these alternatives.

Recent studies have highlighted the imperative to explore innovative therapeutic strategies, particularly for HPV-positive head and neck cancers (HNCs), with the aim of improving patient outcomes and prognoses. This comprehensive analysis endeavors to address and examine the following crucial aspects: (i) the clinical implications of HPV-related OPC, (ii) the identification of its distinctive prognostic markers and biological characteristics in contrast to non-HPV-related variants, (iii) ongoing clinical studies, and (iv) emerging treatment modalities specifically designed for advanced-stage HPV-positive OPC (Figure 1).

Figure 1.

Illustrates the evolving attributes of old and new HPV-associated cancers, highlighting distinct clinical and molecular characteristics between the two subsets. “Old Cancers” represent classic head and neck cases, while “New Cancers” reflect post-shift etiologies.

Understanding stages, treatments, and complications of OPC

OPC initially presents a relatively low survival rate upon diagnosis. It spans various stages from 0 to 4 on the staging system, as summarized in Table 1.^15–17 Stage 0, also termed carcinoma in situ (CIS), indicates the presence of cancer cells without spreading and poses no significant current risk. This stage is often referred to as the precancer stage.¹⁸ Stage 1 signifies the beginning of invasiveness, with a tumor size of 2 cm or less and membrane penetration of 5 mm or less.¹⁹ Stage 2, which is slightly more invasive than stage 1, lacks indications of spread to the lymph nodes or other organs. Stage 2 tumors are either 2 cm or less in size with a depth of 5–10 mm or 2–4 cm in size with a depth of 10 mm or less.^20,21 Stage 3 may involve spreading to lymph nodes or other organs, although not universally. The classification of a cancer diagnosis as stage 3 requires adherence to specific parameters: (i) the tumor must be between 2 and 4 cm in size and penetrate more than 10 mm in depth without dissemination, (ii) the tumor must exceed 4 cm in size while remaining 10 mm or less in depth without dissemination, or (iii) the tumor may be of any size but must have spread to a single lymph node on the same side of the neck.²² Stage 4 represents the most advanced stage, subdivided further into three substages: 4a, 4b, and 4c, where stage 4a indicates cancer spreading into the surrounding structures of the mouth, with one lymph node presenting cancer 3 cm or less in size. It may also denote a cancer of any size that spreads to multiple lymph nodes, ranging from a diameter of 3–6 cm. Stage 4b signifies spreading into more areas of the mouth, neck, and jaw, or spreading to a lymph node that is 6 cm or larger. This may also indicate that the cancer has spread to the tissue around the lymph node. Finally, stage 4c indicates that cancer has metastasized to various sites such as the liver, brain, kidney, and skeletal system.²³

Table 1.

The table summarizes the key features of OPC stages, highlighting important clinical and pathological characteristics associated with each stage of the disease.

Cancer stage	Metastasis	Invasiveness
Stage 0 (Precancer)	Carcinoma in situ	–
Stage 1	Starts to become invasive	Size: ⩽2 cm Depth: ⩽5 mm
Stage 2	More invasive than Stage 1	Size: ⩽2 cm and Depth: 5–10 mm; or Size: 2–4 cm and Depth: ⩽10 mm
Stage 3	No spreading; or No spreading; or Spreading to one lymph node on the same side of the neck	Size: 2–4 cm and Depth: >10 mm; or Size: ⩾4 cm and Depth: ⩽10 mm; or Any size
Stage 4: Stage 4a Stage 4b Stage 4c	Surrounding structures of the mouth; or Multiple lymph nodes Mouth, neck, and jaw, or spreading to a lymph node; Spread to organs and bones	Size: ⩽3 cm; or Size: 3–6 cm Size: ⩾6 cm

OPC, oropharyngeal carcinoma.

Research indicates that patients diagnosed with stage 1 or stage 2 cancer, prior to lymph node involvement, exhibit an overall survival rate of approximately 70%. In contrast, when the disease progresses to stage 3 or stage 4, with lymph node metastasis, survival rates decline significantly to around 30%–40%.^24,25 These sobering statistics have compelled medical professionals to explore nonsurgical therapeutic alternatives aimed at enhancing patient outcomes.

The UMCC 9921 trial was initiated in response to these concerning survival figures. This clinical investigation centered on individuals with stage 3 and 4 OPC.²⁶ The protocol commenced with induction chemotherapy as the initial intervention. Patients demonstrating partial response subsequently received concurrent chemoradiation, a combined approach utilizing chemotherapy and radiation therapy. Conversely, those who did not respond underwent salvage surgery for the removal of treatment-resistant tumors.²⁷

Successful responders to induction chemotherapy witnessed complete tumor reduction, replaced by scar tissue, upon treatment completion. Tumor biopsies collected before treatment underwent testing for HPV positivity, identified through p16 staining, a tumor suppressor protein.²⁸

Following the trial, patients with a stage 3 or stage 4 prognosis achieved a 60% survival rate.²⁹ Nonsmokers exhibited better survival prospects than former smokers, and former smokers fared better than current smokers.³⁰ Notably, HPV-positive patients experienced better survival outcomes in younger patients than in geriatric patients.³¹ Studies have demonstrated that nonsmoking individuals with HPV positivity exhibit a survival rate of 93%, while their smoking counterparts show a decreased survival rate of 75%. Moreover, smokers who are HPV-negative experience a substantially lower survival rate of 30%.^32,33 These findings underscore the significant impact of HPV positivity on survival rates, especially when combined with nonsmoking habits. Post-trial survival outcomes doubled or even tripled those of other treatment methods, suggesting a substantial increase in survival odds for patients undergoing induction chemotherapy followed by concurrent chemotherapy.³⁴ While survival outcomes following induction therapy were remarkable, they do come with long-term complications for patients. For instance, studies have shown that many patients encounter difficulties in swallowing, leading to G-tube dependence during meals. Multiple studies have reported a varying dependency rate (14%, 31%, etc.) for G-tubes to aid in swallowing.^35–37 In addition, there have been cases of patients experiencing osteoradionecrosis, a condition where bone tissue dies due to inadequate blood supply, affecting approximately 5% of patients.^11,38,39 Furthermore, 14% of patients have been reported to develop neuropathy following chemotherapy treatment.^40,41 Although these complications affect a small proportion of the patient population, they have been deemed significant. However, they are considered a small trade-off for the substantial increase in survival outcomes compared with previous methods.

The favorable outcomes of this investigation underscore the necessity for continued research to enhance patient care. While cancer prognosis has markedly improved, the long-term effects of treatment can significantly compromise patients’ quality of life. Additional studies are essential, with a particular focus on post-treatment sequelae such as oral dryness, to identify effective strategies for alleviating this complication and minimizing reliance on gastrostomy tubes.

HPV-related oropharyngeal squamous cell carcinoma: clinical features, epidemiology, and public health implications

Recognized as a distinct entity within head and neck malignancies, HPV-related head and neck squamous cell carcinoma (HNSCC), primarily found in the oropharynx, particularly in the palatine and lingual tonsils, is increasingly common.^42,43 This subtype is characterized by poor differentiation under microscopic examination and is often described as basaloid. Notably, it tends to present with a small primary tumor and large neck metastases, which may manifest as a neck mass without apparent symptoms related to a primary tumor.^44,45 Unlike traditional HNC, HPV-related malignancies exhibit distinct clinical features and risk profiles.^46,47 Traditional risk factors, such as tobacco and alcohol use, do not reliably predict malignancy in HPV-positive patients. Instead, studies have shown that the number of oral sexual partners and lifetime marijuana use are closely correlated with the likelihood of HPV-related malignancies.^48,49

The demographic profile of patients with HPV-related oropharyngeal cancer differs markedly from that of classical HNC patients. Affected individuals are typically between the ages of 40 and 60, with a higher prevalence in males.⁵⁰ Sexual activity emerges as a primary risk factor, with many diagnosed patients consisting of having no prior history of smoking or alcohol use.^51,52 Epidemiological data suggest that HPV infections acquired in late adolescence or early adulthood may remain dormant for several decades before manifesting as malignancy, with triggers for activation still under investigation.⁵³ Approximately 10% of men and 3.6% of women had oral HPV.⁵⁴ In the United States, an estimated 80 million people are infected with HPV, and the incidence of HPV-related oropharyngeal cancer surpasses that of HPV-related cervical cancer.^25,55 This trend is particularly pronounced among middle-aged and increasingly older white men who bear the highest burden of oropharyngeal cancer.^56,57 Despite the promise of HPV vaccination to change the epidemiology of this disease, the current vaccination rates remain too low to significantly reduce disease transmission.⁵⁸ The prevalence of HPV-related HNC underscores its importance as a public health concern. HPV infections are common among various populations, including college students, adults, hospital patients, and those with HIV.⁵⁹

The incidence of SCC of the oropharynx has been increasing in epidemic proportions. Approximately 80% of oropharyngeal cancers in the United States are associated with HPV.⁶⁰ This site-specific increase in incidence is due to an increase in HPV-related squamous cell carcinoma, whereas the incidence of tobacco-related SCC is decreasing because public health efforts have successfully reduced the smoking rate in the United States from 40% in 1965 to 20%.⁶¹ This substantial decrease in smoking rate appears to have led to a dramatic reduction in the incidence of smoking-related cancers of the oral cavity, larynx, and hypopharynx.⁶² This shift in the etiology of oropharyngeal squamous cell carcinoma (OPSCC) has significant implications for public health strategies, diagnoses, and treatment approaches. HPV-related tumors are typically present in younger patients and are associated with distinct clinical and molecular features compared with tobacco-related tumors.

Understanding and addressing the rising incidence of HPV-related SCC is essential for effective cancer prevention and management.⁶³ As individuals age and their immune systems weaken, there is a heightened risk of HPV-related malignancy.⁶⁴ This underscores the importance of continued research and public health efforts aimed at prevention, early detection, and effective management of HPV-related HNCs such as HNSCC. The growing prevalence and distinct characteristics of HPV-related malignancies highlight the need for ongoing vigilance and concerted efforts to address this evolving public health challenge.

Unraveling HPV molecular strategies: from cellular hijacking to clinical implications

The intricate interplay between HPV and the host cell involves a strategic manipulation orchestrated by viral oncoproteins E6 and E7, serving as crucial orchestrators of cellular processes.^65,66 E6, analogous to a cunning technician, disrupts the cellular surveillance system governed by the tumor suppressor protein p53, akin to dismantling the brakes in a vehicle. This disruption impairs p53’s ability to enforce programmed cell death (apoptosis), thereby enabling infected cells to proliferate unchecked, despite inherent genomic aberrations.⁶⁷ Conversely, E7, analogous to a bold accelerator driver, is proactive by perturbing cell cycle regulation through its interactions with the retinoblastoma protein (pRb) and related pocket proteins. This interplay releases the inhibitory influence on E2F transcription factors, thereby promoting the transcription of genes involved in cell cycle progression and DNA synthesis. The resultant dysregulation of the cell cycle machinery fosters uncontrolled cellular proliferation, a hallmark of cancer progression.⁶⁸ Beyond this, HPV’s intricate subversion extends to manipulating the p300 transcription factor, a key player in activating the tumor suppressor protein p53.⁶⁹ By targeting p300 for degradation, E6 disrupts the acetylation process necessary for p53’s activation, compromising its ability to inhibit cell growth and promoting HPV-associated cancer progression.⁷⁰ Moreover, HPV-mediated inactivation mechanisms have significant clinical implications, particularly in the development and progression of specific HPV-associated cancers such as cervical, anal, and oropharyngeal cancers. Understanding these mechanisms is essential for devising targeted therapies that can improve patient outcomes and reduce the global burden of HPV-related illnesses.

Furthermore, HPV’s evasion of the host immune response poses challenges for immunotherapeutic approaches aimed at combating HPV-associated cancers. Strategies to overcome immune evasion mechanisms and enhance antitumor immunity hold promise for improving treatment efficacy and patient survival.^71,72 HPV-mediated inactivation also contributes to genomic instability, facilitating the acquisition of additional oncogenic mutations and tumor heterogeneity.^73,74 This genomic chaos not only fuels cancer progression but also poses challenges for targeted therapies and precision medicine approaches. In addition to genetic alterations, HPV oncoproteins modulate epigenetic mechanisms such as DNA methylation and histone modifications, further shaping the cellular phenotype and influencing treatment response. Targeting these epigenetic alterations presents new avenues for therapeutic intervention in HPV-associated cancers.⁷⁵ As researchers unravel the complexities of HPV-mediated inactivation, clinical trials investigate novel therapeutic strategies targeting these mechanisms.⁷⁶ Translational research aims to bridge the gap between bench and bedside, translating promising preclinical findings into effective treatments for patients with HPV-associated cancers.

Moreover, the global health impact of HPV-associated cancers cannot be overlooked, particularly in low- and middle-income countries with limited access to screening and vaccination programs. International collaborations and initiatives are, especially in this context, crucial for addressing disparities in HPV-related cancer prevention, diagnosis, and treatment on a global scale.⁷⁷ In this dynamic landscape, the exploration of repurposed medications such as fenofibrate highlights the potential for innovative approaches to combat HPV infections and associated cancers. By leveraging existing drugs with hidden antiviral properties, researchers can offer more targeted and effective treatments while minimizing the harsh side effects often associated with standard therapies.⁷⁸

In conclusion, the comprehensive understanding of HPV-mediated inactivation mechanisms and their clinical implications appears fundamental for advancing cancer research and improving patient outcomes worldwide. Through multidisciplinary collaboration and continued innovation, we hope to overcome the challenges of HPV-associated cancers and reduce their global burden on public health.

Innovations in treatment modalities and prognostic biomarkers for HPV-positive HNSCC

Concurrent cancer treatments such as chemotherapy and radiation therapy often burden patients with morbidity. Previous investigations suggested no disparity in chemotherapy symptoms between HPV-positive and HPV-negative cases, the TROG 0202 trial revealed noteworthy outcomes, particularly in the tirapazamine arm among p-16 negative patients.^79,80 Notably, this trial shed light on the divergence in radiation therapy dosages required for HPV-positive versus HPV-negative patients. HPV-positive HNSCC patients exhibited diminished necessity for aggressive chemoradiotherapy, with lower radiation doses proving efficacious. The inclusion of tirapazamine in the TROG 0202 phase III trial underscored increased radioresistance, highlighting its role as a radiosensitizer and prompting consideration for alternative treatment modalities to mitigate potential adverse effects in HPV-positive HNSCC patients.^79,81

One promising avenue entails gene therapy in targeting the p53 gene. HPV-positive patients manifest significantly more p53 mutations and abnormalities compared to their HPV-negative counterparts.⁸² Efforts have been directed at reinstating p53 function by introducing wild-type p53, with COTI-2 emerging as a notable candidate.⁸³ COTI-2, a third-generation thiosemicarbazone, exhibits a high affinity for p53 mutations, facilitating the restoration of misfolded p53 to a wild-type conformation critical for tumor suppression. Preclinical xenograft models demonstrate COTI-2’s ability to impede tumor growth, a pivotal factor in cancer prognosis.^83–87 In addition, comparative analyses indicate COTI-2’s superiority over traditional therapies like cetuximab and erlotinib in reducing cell proliferation across various cell lines.⁸⁷

Another avenue of p53-targeted therapy involves adenoviral vectors to augment wild-type p53 levels.⁸⁸ Gendicine (Ad-p53) utilizes adenoviral vectors to infect cancer cells, producing heightened TP53 gene transcript and subsequent elevation of wild-type p53 levels.⁸⁹ Studies affirm that increased wild-type p53 expression enhances malignant cells’ radiosensitivity, bolstering treatments’ efficacy.^90,91 Through the restoration of p53 function via COTI-2 or the inhibition of tumor growth with adenoviral particles, effective management of HPV-positive HNSCC can be realized.^83,92

An additional alternative treatment option is Transoral Robotic Surgery (TORS), a minimally invasive approach initially developed for OPSCC that has now extended its utility to encompass HNCs, including HNSCC.⁹³ Reports have demonstrated comparable 3-year treatment outcomes between radiotherapy and TORS for HPV-positive disease, with 95% and 98% rates, respectively.⁹⁴ Notably, TORS offers analogous efficacy to radiotherapy but with fewer concurrent symptoms, presenting a viable therapeutic avenue for HPV-positive HNSCC. TORS represents just one facet of the burgeoning landscape of robotic interventions showing promise in HNSCC treatment.^95,96

Recent research has highlighted the potential of specific HPV strains, particularly HPV-16 and HPV-33, as biomarkers for HNSCC.⁹⁷ The successful application of circulating HPV DNA (cHPV-DNA) as a biomarker in cervical cancer has led to its exploration in HNSCC.⁹⁸ Detection of HPV-16 and HPV-33 cHPV-DNA in early stage patients suggests their viability as biomarkers. While both strains show promise, HPV-16 is considered more significant due to its higher prevalence, enhancing its reliability as an indicator.^99,100 A study examining 97 plasma samples from HPV-positive OPSCC patients and 8 HPV-positive anal SCC patients revealed HPV16 ctDNA in 90 cases and HPV33 ctDNA in three cases, further supporting their potential as early stage cancer biomarkers.^100–102

Another significant biomarker in the context of HPV-positive HNSCC is immunoglobulin J polypeptide (IGJ), whose expression is heightened in the presence of HPV and offers insights into early disease-specific mortality prediction. Cox regression modeling has underscored IGJ’s capacity to accurately prognosticate disease-specific survival, with elevated IGJ levels correlating with more favorable clinicopathological characteristics such as smaller tumor size, lower tumor stage, and absence of lymph node metastasis. These favorable attributes contribute to an improved prognosis, highlighting IGJ’s potential utility as a biomarker. Notably, prognosis is influenced by a myriad of molecular factors and tumor size, further emphasizing the relevance of IGJ as a biomarker in clinical decision-making. The incorporation of IGJ expression levels into treatment planning holds promise for oncologists and clinicians, enabling tailored therapeutic approaches for patients with HPV-positive HNSCC.¹⁰³

HPV-negative HNSCC predominantly arises from external factors such as smoking and tobacco usage, in contrast to HPV-positive cases, which result from HPV infections, most commonly HPV-16.¹⁰⁴ Notably, HPV-positive HNSCC exhibits a markedly superior prognosis compared to HPV-negative counterparts, with a 5-year survival rate of 85.75% versus 11.15%, respectively.⁴ This discrepancy can be attributed to several factors: heightened responsiveness of HPV-positive patients to modern cancer treatments, earlier age at diagnosis, and typically lower disease stage upon presentation. For instance, HPV-positive cancer patients demonstrate a higher response rate to pembrolizumab, averaging 25%, compared to 14% in HPV-negative cases.¹⁰⁵ However, despite these favorable prognostic indicators, HPV-positive HNSCC poses challenges, such as a lower immune infiltrate in the tumor microenvironment, indicative of a less active immune response. Moreover, HPV-negative cancers entail an increased risk of second primary tumors, a rarity in HPV-positive cancer, complicating diagnosis and management.¹⁰⁶ Furthermore, when examining different HPV strains, HPV-33 presents a similarly grim prognosis to HPV-negative cancers due to its comparable immune response rates. Patients afflicted with HPV-33 are five times more likely to succumb to the disease than those with HPV-16, attributable to lower immune response rates and diminished CD8+ cytotoxic T-cell activity.¹⁰⁷

In conclusion, while HPV-positive HNSCC generally confers a more favorable prognosis than its HPV-negative counterpart, it is important to recognize its distinct challenges and features. Understanding the diverse implications of HPV strains and their associated immune responses is crucial for tailored treatment strategies and improved patient outcomes in the management of HNSCC.

Conclusion and future perspectives

OPC, particularly the HPV-related subtype, presents a multifaceted landscape of risk factors, treatment challenges, and promising advancements. Traditionally associated with low survival rates, especially in advanced stages,¹⁰⁸ recent research efforts, such as the UMCC 9921 trial highlighted by Dr Teknos,² have introduced novel treatment approaches that significantly improve survival outcomes, particularly in HPV-positive patients.¹⁰⁵ induction chemotherapy followed by standardized treatments has remarkably succeeded in reducing tumor burden and enhancing survival rates.

The epidemiological landscape of HPV-associated HNC is rapidly evolving, with millions of new infections reported annually.⁵² Between 1990 and 2022, there was a staggering 300% increase in the incidence of HPV infections, underscoring the urgent need for effective treatment strategies to address this growing epidemic.^2,108 As of August 2022, nearly 80%–90% of all oropharyngeal tumors are HPV-positive,¹⁰⁹ with a substantially improved prognosis for patients with HPV-positive tumors. Recurrent disease following treatment for HPV-positive OPSCC occurs less frequently than for HPV-negative disease.¹¹⁰ In the recent report of NRG Oncology RTOG 1016, approximately 24% of patients developed disease recurrence, with the pattern of recurrence roughly evenly divided between local-regional recurrences and distant metastases.²² While modern studies report progression-free survival rates between 64% and 78% and overall survival rates between 71% and 85%, details regarding salvage treatments remain sparse.¹¹¹

This surge in incidence has prompted a significant and necessary change in diagnosis, treatment, and prevention strategies. One of the key challenges in managing HPV-related diseases is the lack of reliable biomarkers, which play a crucial role in identifying high-risk individuals, predicting treatment responses, and tailoring personalized therapeutic interventions.⁹⁸ Efforts must therefore be intensified to identify reliable biomarkers for HPV infections to enhance patient outcomes and streamline treatment approaches.

Recent advancements in research have unraveled cell activation mechanisms as critical factors in developing immunotherapeutic strategies against HPV. Immunotherapy holds great promise in empowering the body’s immune system to identify and eradicate HPV-infected cells.¹¹² Understanding the interplay between viral oncoproteins and host immune pathways is pivotal in designing effective immunotherapeutic interventions to enhance antitumor immune responses and improve patient clinical outcomes. One such promising therapy entails the reactivation of the tumor suppressor protein p53, offering significant potential in restoring p53 function within HPV-infected cells. This intervention increases the rate of apoptosis and curbs uncontrolled cell proliferation, a hallmark of cancer progression.¹¹³ This targeted treatment approach represents a significant advancement in combating HPV-associated malignancies.

Besides the treatments mentioned in this study, alternative methods exist. A prominent example is treatment intensity reduction. HPV-positive HNSCC, compared to HPV-negative, has a higher sensitivity to radiotherapy and chemotherapy: a lower intensity will achieve the same effect as a higher intensity while minimizing toxicity.⁷⁹ Aggressive treatments should be avoided as often as possible, and aggressive chemoradiation can cause severe, long-lasting side effects. The study (NRG Oncology HNO2) shows clinical promise for reduced dose radiation therapy for OPSCC. In the study, researchers found that intensity-modulated radiation therapy (IMRT) had a better outcome than traditional treatment methods. The IMRT arm had fewer grade 3–4 acute symptoms than traditional treatment methods—indicating IMRT provides a better prognosis.¹¹⁴ Standard therapy for locoregionally advanced OPSCC includes a combination of 70 Gy of radiation therapy with some form of chemotherapy. Traditional treatment can be associated with severe short-term toxicities, and some patients can be better treated with IMRT.¹¹⁵ Therefore, besides the treatments mentioned in this study (i.e., TORS and p53 gene therapy), there are alternative therapies that can be used to improve the prognosis of HPV+ HNSCC.

Research endeavors continue to add clarity to the complexities of HPV infections and their interactions with the human immune system. Therefore, ongoing efforts are imperative to translate these findings into clinically viable solutions. During the JADPRO Live Virtual 2020, Casey Fazer-Posorske underscored the importance of a multidisciplinary approach in managing HNC.¹¹⁶ This collaborative model involves a coordinated effort among healthcare professionals, including head/neck surgeons, oncologists, radiologists, and others, to optimize outcomes and preserve quality of life through personalized treatment plans. Such collaborative efforts are especially vital when considering alternative therapies such as treatment de-intensification, which requires high-level coordination to balance efficacy and minimize toxicity. Another promising avenue of treatment is targeted cancer vaccines. Cancer vaccines have been used to treat other types of cancer: Provenge is used for prostate cancer.¹¹⁷ Recent studies have shown the practicality and effectiveness of cancer vaccines to treat HPV+ HNSCC. PDS Biotechnology evaluated Versamune HPV + pembrolizumab treatment in patients with HPV16+ HNSCC. They found that the treatment arm had superior survival outcomes to traditional immune checkpoint inhibitors (ICI). Furthermore, compared to ICI and pembrolizumab, the best overall response and progression-free survival rates show that combination therapy with Versamune has superior survival and response rates. To further the results and implications of this study, PDS Biotechnology has announced a two-part registrational study that will focus on measuring the efficacy of Versamune HPV + pembrolizumab + PDS01ADC as a first-line treatment for HPV+ HNSCC.¹¹⁸ PDS01ADC has shown promise in previous studies and is designed to enhance tumor targeting and immune response. The addition of PDS01ADC aims to further efficiency in subsequent trials—giving an example of future studies that can improve/alter the current treatment avenues for HPV+ HNSCC. Furthermore, future research should aim to optimize treatment de-intensification; for example, finding the optimal dose of radiation (in grays) for specific HNSCC (e.g., laryngeal and oropharyngeal), depending on the staging and depth of the cancer, can provide valuable insights for improving patient prognosis.¹¹⁹

Public health strategies aimed at promoting HPV vaccination, raising awareness about risk factors, and improving access to screening and treatment services are integral components of a comprehensive approach to combat HPV-related diseases. While several countries have demonstrated vaccine effectiveness, herd protection, and declines in targeted types post-vaccination, challenges such as type specificity, the need for pre-exposure administration, the three-dose schedule, and early adolescence target age group persist.¹²⁰

In conclusion, while the rise of HPV-associated HNC presents significant challenges, it also presents opportunities for breakthroughs in diagnosis and treatment. By harnessing advancements in biomarker discovery, immunotherapy, and targeted therapies such as p53 reactivation, we can aspire to not only stem the tide of this epidemic but also enhance the quality of life for those affected by HPV-related diseases.

Footnotes

Acknowledgements

We thank Theodoros N. Teknos for the opportunity to learn from a global Leader in Medicine. We are grateful to be part of MedNews Week.

Declarations

ORCID iDs

Viviana Cortiana

Soumiya Nadar

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Understanding and treating HPV-associated oropharyngeal carcinoma: insights from a MedNewsWeek Keynote lecture by Dr Theodoros N. Teknos and literature review

Abstract

Keywords

Introduction

Understanding stages, treatments, and complications of OPC

HPV-related oropharyngeal squamous cell carcinoma: clinical features, epidemiology, and public health implications

Unraveling HPV molecular strategies: from cellular hijacking to clinical implications

Innovations in treatment modalities and prognostic biomarkers for HPV-positive HNSCC

Conclusion and future perspectives

Footnotes

Acknowledgements

Declarations

ORCID iDs

References