The Impact of the COVID-19 Pandemic on Oral and Oropharyngeal Cancer

To describe the global impact of COVID-19 on oral cancer incidence and prognosis and to inform strategies for early detection and prevention. There is international evidence of delayed diagnosis and more advanced oral tumours presenting during the pandemic. Lockdowns were also associated with delayed surgeries and compromised treatment. School closures during the pandemic resulted in a rapid decline of human papillomavirus (HPV) vaccine coverage among adolescents globally. There was a rise in risk factor uptake in the form of tobacco use and alcohol consumptions across many parts of the world to manage stress and boredom during the pandemic. The economic fallout from the pandemic is another barrier to dental access and therefore early cancer detection. The full impact of the pandemic on oral cancer incidence and mortality may not be seen for some time. Strategies aimed at prevention and early detection of oral cancer should be prioritised.


Introduction
Since its detection in December 2019, the SARS-CoV-2 virus rapidly spread across the world, and the associated coronavirus disease (COVID-19) placed extraordinary strain on the world's healthcare systems.As of 29 March 2023, there have been 761,402,282 confirmed cases of COVID-19 globally, including 6,887,000 deaths, reported to the World Health Organisation (WHO) [1].
On 23 March 2020, a national lockdown was announced in the UK, and the Chief Dental Officer (CDO) for England ordered the national cessation of all routine dental care.This resulted in general dental practitioners having to diagnose problems via telephone triage and manage using the 3A's (advise, analgesics, antibiotics), without having carried out any clinical examination or direct investigations.Face-toface services were permitted to resume on 08 June 2020 with an emphasis still being on delivering urgent-only care and minimising unnecessary footfall.Similar restrictions were enforced across the world.
Regular dental visits are fundamental to maintain oral health and to facilitate early detection of oral diseases such as oral cancer.It has been shown that early diagnosis and management of oral cancer is associated with higher survival rates and better quality of life [2].Substantial increases in the number of cancer deaths have been predicted because of diagnostic delays due to the COVID-19 pandemic in different parts of the world [3][4][5].However, this review will argue that the problem is much wider than this specific issue and that the pandemic has had other implications including a rising cost of living, backlogged healthcare systems and an increased uptake of cancer risk factors by the public.These consequences could dramatically change the future epidemiology of oral cancer.

Oral Cancer: a Background
Head and neck cancer (HNC) is the seventh most common cancer globally, accounting for more than 660,000 new cases and 325,000 deaths annually, with the highest incidence observed in South and Southeast Asia [6,7].Approximately, 90% of head and neck cancers are squamous cell carcinoma (SCC), which arise from the epithelial lining of the oral cavity, pharynx and larynx [6].The overall incidence of HNC continues to rise, with a predicted 30% increase annually by 2030 in both developed and developing countries [6,7].
Established risk factors for oral SCC include smoking, oral exposure to tobacco and alcohol consumption.However, patients can also present with no identifiable risk factors.Southeast Asia and Asia-Pacific regions have a particularly high incidence of oral cancer, associated with chewing of areca nut (betel quid), with or without tobacco [8].The synergistic consumption of alcohol and tobacco (both smoked and smokeless) significantly increases the risk of oral SCC [9].The increasing incidence of HNC has been attributed to a rise in oropharyngeal SCC caused by human papillomavirus (HPV) infection, particularly HPV type 16, thought to be sexually transmitted via oro-genital contact [10].The percentage of HNCs diagnosed as HPV-positive oropharyngeal cancers in the USA rose from 16.3% in the 1980s to more than 72.7% in the 2000s [11].Around 50% of UK oropharyngeal SCC cases are HPV positive [12], and it has been postulated that the incidence of HPV-positive oropharyngeal SCC will overtake oral SCC in European countries, including the UK, over the next 20 years [13].
Oral cancer has a notably high 5-year mortality rate of approximately 50%, with most cases being diagnosed at an advanced stage: III and IV accounted for 58.5% of HNCs in the UK [14].

Delayed Diagnosis
Before the COVID-19 pandemic, incidences of oral cancer were already increasing.Between 2011 and 2018, the UK Cancer Registry Data showed a 34% increase in total cases across the four nations (England, Scotland, Wales, Northern Ireland) [15].Data collected by the Oral Health Foundation from seven National Health Service (NHS) hospitals demonstrated that referrals for suspected oral cancers had dropped by one third since the start of the pandemic [15].Two hospitals in Wales recorded a 47% drop in referrals, the largest recorded in the UK, whilst Northern Ireland, England and Scotland saw figures decrease by 36%, 31% and 30%, respectively [15].There has also been international evidence of delayed diagnosis and more advanced disease at diagnosis; however, delays to definitive surgery were not observed in these studies [16,17].

Delayed Treatment
A study in Germany found a significantly longer treatment delay in 2020 (median 45 days) compared with 2010-2019 (median 35 days) for patients with oral SCC [18].A large international, prospective cohort study enrolling 20,006 adult patients from 466 hospitals in 61 countries with 15 cancer types (including head and neck), who had a decision for curative surgery during the COVID-19 pandemic, was followed up until the point of surgery or cessation of followup [19•].Of the 20,006 eligible patients awaiting surgery, 10% did not receive surgery after a median follow-up of 23 weeks, all of whom had COVID-19-related reasons for not proceeding with surgery [19•].Lockdowns of varying magnitude were found to influence treatment, with moderate lockdowns and full lockdowns being independently associated with non-operation [19•].In the UK, surgical capacity was even more constrained in the second wave (58% of prepandemic level) compared with the first wave (62%) despite the time to prepare the NHS strategic response [20].Half of HNC patients in the UK requiring surgery had significantly compromised treatments during the second wave: 28% were delayed, 10% received radiotherapy-based treatment instead of surgery and 12% received de-escalated surgery [20].Although survival data for patients treated within this period is currently unavailable, the number of mouth cancer deaths in the UK has worsened over a 10-year period, with 2020 and 2021 having more deaths recorded when compared with 2011 and 2016 [15].

Rise in Risk Factors
Emerging research indicates that tobacco use and alcohol consumption increased during the COVID-19 pandemic [21,22].A 2020 study found a global increase in electronic cigarette consumption and nicotine products [23].The most common reasons for increasing e-cigarette use were stress management (36.3%),managing boredom (18%) and having more time and flexibility (18%) [24].The percentage of young people in Britain between 11 and 17 years of age who have tried vaping or are current users has continued to steadily increase from before the pandemic [25].This is concerning given that the evidence suggests a strong association between e-cigarette use among non-smokers and subsequent smoking, which would increase the risk of oral cancer development [26].
A study of US adults during the pandemic showed that 60% of people reported increased alcohol consumption, 34.1% reported binge drinking and 7% reported extreme binge drinking [27].Reasons for increased drinking were similar for smoking and mainly included increased stress (45.7%), increased alcohol availability (34.4%) and boredom (30.1%) [27].Collectively, these studies indicate that stress during the pandemic was correlated with more significant increases in alcohol consumption and tobacco use.If these trends persist, we could expect to see even further increases in global oral cancer rates over the coming decades.However, there is currently insufficient data to illustrate whether these trends have continued post-pandemic.

Reduced Uptake of HPV Vaccinations
The first vaccine for the prevention of HPV-related disease was licensed in 2006 and was intended to be administered as a two-dose schedule before the onset of sexual activity [28••].The primary target group is girls aged 9-14 years for the prevention of cervical cancer.Secondary target populations include females aged ≥ 15 years and boys; however, it has been shown that achieving over 80% coverage in girls also reduces the risk of HPV infection for boys [28••].All HPV vaccines contain virus-like particles which induce an immune response with the aim of providing protection against high-risk HPV types 16 and 18; the former being most often implicated in the pathogenesis of oropharyngeal SCC.The vaccine has 93% effectiveness against oral HPV16 and HPV18 infection at 4 years following first vaccination [29].To date, 125 countries (64%) have introduced HPV vaccine in their national immunisation programme for girls and 47 countries (24%) also for boys [28••].
In some regions of the UK, one-dose vaccine coverage was as low as 67% during the pandemic due to school closures [30].The two-dose vaccination uptake also decreased from 84% before the pandemic to 57% meaning that 317,581 children went without a second HPV vaccine dose, whilst 147,337 were completely unprotected in 2020-2021 [30].Similarly, in Malaysia, it is estimated that around 225,000 female students either missed their vaccination or had incomplete doses of HPV vaccination in 2020 and 2021 [31].In the USA, child and teen HPV vaccination coverage reached a low of 23% of the previous years' rate [32].
Modelling analyses have postulated that delayed recovery of the HPV vaccine uptake during the COVID-19 pandemic could lead to between 600 and 6200 additional male oropharyngeal cancer cases by the year 2100 [33].Conversely, achievement and maintenance of 80% coverage among adolescents plus young adults could prevent an additional 142,000 male oropharyngeal cancer cases by the year 2100 [33].UK data collected on HPV vaccine coverage among year 10 students (14 and 15 years old) indicated improved coverage compared to when it was measured when students were in year 9 (13 and 14 years old) in the 2020 to 2021 academic year, suggesting local catch-up activities have been increasing coverage in those students who had missed vaccinations during the COVID-19 pandemic [34].Provided that catch-up programmes continue, and high coverage rates of 80% or greater are achieved, the future HPV-associated cancer burden will be substantially reduced.
Paradoxical to the delayed uptake of HPV vaccinations, one beneficial outcome of the COVID-19 pandemic is a gradual increasing positive attitude from adults regarding vaccinations [35].A key message throughout the pandemic was that vaccination would be the most effective tool in the fight against COVID-19.It is therefore not surprising that one study found the COVID-19 vaccine willingness and uptake rate to be 98.7% among its participants [35].With regard to HPV vaccines specifically, a study found that positive attitudes and interests in HPV vaccines increased, whilst a negative attitude was reduced toward HPV vaccination in the COVID-19 pandemic era [36].Respondents stated that transparency regarding the effectiveness and safety of the HPV vaccine was important when considering whether to accept vaccination [36].This is again unsurprising given that one of the main hindrances to vaccination is public fear due to uncertainty regarding side effects and long-term health consequences [35].

Dental Access
A backlog of patients caused by the pandemic coupled with a growing population and a dwindling NHS dental workforce has led to a crisis in dental access in the UK.According to one report, there were 2189 fewer dentists providing care by the end of January 2022 than there were at the end of 2020 [37].According to the British Dental Association (BDA), 75% of UK dentists are likely to reduce, or further reduce, their NHS commitment, 45% claim they will go fully private and 47% suggest they will either change career or seek early retirement [38].Every vacancy translates into thousands of patients unable to access care, and it has been indicated that an unmet need for dentistry in 2022 stood at over 11 million people [38].
Lack of dental access is a significant problem in countries with no public funding.A research study across eight countries showed that 68% of adults have avoided going to the dentist during the pandemic even when they had a dental problem [39].Unfortunately, this trend will likely continue due to a rising cost of living.Disruption to global supply chains because of the pandemic has partly contributed to the growing economic crisis.In 2022, inflation reached a high of 10.7% in the UK, 12.6% in Italy, 16% in Poland and over 20% in Hungary and Estonia [40].Findings from the Oral Health Foundation show that 23% of UK adults have avoided making an appointment at the dentist because of the rising cost of living [41].Similarly, more than 7% of people in Latvia, Portugal and Greece reported unmet needs for dental care in 2020, mainly for financial reasons [42].The rising cost of living is currently the most pressing concern for 93% of Europeans [43].
Higher levels of deprivation are associated with an increased risk of oral cancer; the rising cost of living disproportionately affects people on lower income, increasing the issue of health inequalities [44].These barriers to accessing dental care are a growing problem as routine examinations are a critical avenue for early diagnosis of oral cancer.A recent Cochrane Oral Health review highlighted that visual examination of the mouth by a health professional is the most effective method of detecting cancer, successful in 59 to 99% of cases [45].

Promoting Early Detection and Prevention of Oral and Oropharyngeal Cancer
Improving HPV Vaccine Uptake Uptake of HPV vaccinations within schools must increase in line with, and even beyond that of, pre-pandemic times.To help increase vaccination uptake, all parents of eligible school children should receive information about HPV and the HPV vaccination, including when and how their child's vaccinations will take place [40].This information must also be made available to children and young people who do not attend schools.The involvement of other health and social care providers who are in contact with these families may be required to help gain consent [40].Reasons for lack of vaccine uptake in certain regions of England include reduced consent return rates and reports of vaccine hesitancy [34].Fears surrounding vaccination can be allayed with adequate information on the safety and efficacy of the HPV vaccine.Incentives for returning consent forms may be successful for increasing vaccine uptake.
In a new position paper published in December 2022, the WHO updated its recommendations for the HPV vaccine and emphasised the importance of reversing the declines in coverage experienced during the pandemic [28••].Crucially, they stated that a single-dose schedule, referred to as an alternative, off-label single-dose schedule can provide a comparable efficacy and durability of protection to a two-dose regimen [28••].This optimization of the HPV schedule could offer countries the opportunity to expand the number of adolescents who can be vaccinated by alleviating the burden of the often complicated and costly follow-up required to complete the vaccination series [28••].

Improve Public Education and Awareness
There is generally a low level of public awareness of oral cancer including its signs, symptoms and risk factors.A study that aimed to explore the experiences of young oral cancer patients confirmed gaps in understanding and awareness of oral cancer [46].Although many patients had heard of oral cancer, they did not think their symptoms were indicative of the disease [46].
Promotion of oral cancer awareness can involve one-toone interventions, community-based initiatives, populationbased programmes and mass media campaigns.Small-scale localised programmes can be developed using educational materials such as posters and leaflets [47].However, such campaigns may only result in an increased awareness in the short term, and preferentially among those at low risk, without influencing any behavioural change.
Some nations, including the UK and Australia, have introduced national mouth cancer awareness programmes on an annual basis [48].These programmes often provide facts and figures about the disease, highlight signs, symptoms and risk factors.They also provide advice on self-examination and on visiting dental or medical practitioners if problems such as ulcers, lumps, red or mixed red-white patches of the oral mucosa persist for more than 3 weeks [47].During these periods, local activities such as providing opportunities for a free oral examination are encouraged, and these have proven to be successful in identifying cases of oral cancer [48].The aim of such activities is to reach groups at higher risk of oral cancer who are less likely to regularly attend the dentist and remove any financial barriers to access.However, it has been acknowledged that it is often lower risk patients who respond most to such programmes, and those at higher risk of developing cancer are still being missed [47,48].
One-off programmes targeting at-risk populations have also been carried out.One such example is the West of Scotland Cancer Awareness Project which targeted adults over 45 years of age from lower socio-economic groups over a 6-month period [49].Evaluation of this programme showed that many attending secondary care rapid access clinics during the campaign were from the target group, with good awareness of the campaign among these patients [49].However, a high proportion of benign lesions were observed, and 30% of referrals were deemed to be inappropriate [49].
Further work is required to identify appropriate approaches for raising awareness of oral cancer and its risk factors in high-risk communities, and the importance of psychosocial factors and understanding the barriers to attending health services should not be overlooked.

Training for Other Health Professionals
It is known that those at higher risk of developing oral cancer are less likely to engage with general dental services and less likely to attend routine dental appointments.These individuals, who are often smokers and heavy drinkers with multiple co-morbidities, are more likely to access primary medical care and community pharmacies.It has been shown that more patients referred to secondary care services for suspicious oral lesions first presented to their doctor (59%) rather than their dentist (29%) [50].
Renewal of knowledge in detection of oral cancer is a recommended annual topic for dental practitioners as part of their continued professional development.However, very little is taught about this disease in the wider healthcare setting, which is reflected in doctors' and pharmacists' selfreported lack of confidence and awareness of oral cancer risk factors and clinical appearance [50,51].Several studies have shown that, when trained, healthcare workers are equally able to examine the mouth and detect relevant lesions when compared to dental professionals [52][53][54].Additionally, it has been shown that non-dental healthcare workers would welcome an educational resource to support professional development surrounding oral cancer [51].

Screening and Routes to Diagnosis
Oral cancers are often late stage at diagnosis which is associated with poorer prognosis.Early detection is therefore crucial to improve overall survival.In the UK, the urgent cancer pathway known as the 2-week wait (2WW) was established in 2000 to reduce delays in diagnosis [55].A target of 14 days from the point of referral for suspected cancer symptoms to the point of first assessment by a hospital specialist was implemented.Despite the decline over time in emergency presentation and the increased use of 2WW, significant socio-demographic inequalities in routes to diagnosis have been shown [56].An alternative route to diagnosis for oral cancer could be via national screening programmes [57•].
Screening differs from one-off clinical examinations or case findings, as it is an ongoing process of examination applied to a defined population at set intervals [57•].
A key example is cervical cancer screening by means of a smear test offered to all women aged 25 to 64 every 3-5 years.A smear test (also known as Pap smear or Pap test) involves taking a sample of cells from the cervix and assessing for histopathological signs of potentially cancerous change.A smear test has 96.8% specificity but only 55.4% sensitivity [58].
Many countries set strict criteria for new screening programmes to be initiated, and one such criteria is that the diagnostic test is validated and has an acceptable level of sensitivity and specificity.At the present time, no test beyond conventional oral examination (COE) has been shown to be effective for the accurate detection of oral lesions in the context of a screening programme [59].A Cochrane review examined the potential of COE, vital rinsing, light-based detection, biomarkers and mouth self-examination (MSE) as methods for the detection of potentially malignant lesions and early mouth cancer in apparently healthy adults [45].The review concluded that COE had a satisfactory test performance with sensitivities and specificities similar to those reported for breast and cervical cancer screening programmes [45].However, a more important consideration is to determine whether a mouth cancer screening programme using COE achieves the aim of reducing mortality from oral cancer.This has only been evaluated by one study to date, which was a large cluster-randomised controlled trial carried out over a period of 15 years involving four rounds of screening, completed in 1998, 2002, 2004 and 2009 in Kerala, South India [60].This study was able to demonstrate a statistically significant 24% reduction in mortality for highrisk individuals who used tobacco and/or alcohol between the screened group and the control group.However, no significant difference in overall mortality rate was observed between the screened group and controlled group [60].
There is a consensus that national mouth cancer screening would only be cost-effective if it were targeted at high-risk individuals [60,61].Patients with oral potentially malignant disorders (OPMDs), such as leukoplakia, erythroplakia, proliferative verrucous leukoplakia, oral lichen planus, oral submucous fibrosis and palatal lesions in reverse smokers, have a higher risk of oral cancer compared to the general population [62].Recommendations for management of patients with oral epithelial dysplasia during pandemic outbreaks were published in the UK in response to the COVID-19 pandemic [63 ••].However, it is recognised that many oral cancers arise de novo and are not preceded by OPMDs, so focussing screening efforts solely on patients with OPMDs would miss many cases of oral cancer.
There is future potential for the use of population-wide or targeted screening in the form of the Galleri test.This is a blood test which can detect abnormal DNA methylation patterns associated with over 50 types of cancer, including oral cancer [64].Currently, there is a clinical trial underway in the UK to evaluate the efficacy of the Galleri test within the context of the NHS [65].However, at the present time, there are currently no molecular biomarkers or adjunctive tests validated for clinical use that could be used in national screening programmes.
A greater emphasis needs to be placed on prevention, increasing public awareness and early detection of oral cancer.It is vital that countries strengthen their HPV vaccination programmes, expedite implementation and reverse the declines in coverage [28••].Any future national awareness interventions should consider the social determinants of the disease and health behaviour theory [47].Oral cancer information and education should be routinely given to nondental health professionals including doctors, pharmacists, care home and nursing staff to facilitate early detection outside of a general dental practice setting [41].Finally, more research is needed to fully understand the potential of targeted screening programmes, ideally based on a molecular risk profile, with the aim of detecting and treating patients with oral cancer as early as possible, when survival and outcomes are best.

SARS-CoV-2 and Carcinogenesis
Several human viruses can induce carcinogenesis, including HPV, Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV) (also known as human herpesvirus 8 (HHV-8)), HIV, hepatitis B and C viruses and HTLV-1 [66].These viruses typically establish long-term relationships with their host, and this can lead to uncontrolled cell proliferation and cancer development.These viruses can induce carcinogenesis via dysregulation of tumour suppressor activities of key tumour suppressor genes (p53 and pRB), manipulation of host signalling pathways, including the DNA damage response, and manipulation of the host immune response [66].
Both p53 and pRB are widely recognised as important tumour suppressor genes, with p53 being the most frequently mutated gene in human cancer, with up to 85% of HNC displaying p53 mutations [68].Like HPV, the SARS-CoV-2 virus has been shown to inhibit both p53 and pRB, which suggests it may have oncogenic potential [69].Evidence for SARS-CoV-2 persistence is currently limited.Unless proven to be the case, the inability to establish a long-lasting infection would argue against its role in oncogenesis.Additional studies on the long-term effects of the virus are needed to shed light on such a possibility.
Although a direct carcinogenic role of SARS-CoV-2 remains unproven, SARS-CoV-2-encoded proteins can induce reactivation of major human oncogenic viruses including EBV and KSHV through manipulation of intracellular signalling pathways [70,71].Therefore, it may indirectly increase the risk of developing virus-associated cancers.There has been one reported case of fast progressing cervical dysplasia to invasive HPV-positive carcinoma, 3 months following COVID-19 disease [72].It was hypothesised that the immune system may have been exhausted by the concurring COVID-19 infection, which may have detracted from the immunological response to the HPVinfected cervical dysplasia, therefore facilitating rapid disease progression [72].Unsurprisingly, in this case, p53 expression decreased with progression of the dysplasia.
However, this was more likely attributable to the pathogenesis of HPV rather than SARS-CoV-2 as there was no evidence of direct cervical infection with SARS-CoV-2 (72).
Evidence of SARS-CoV-2 directly initiating carcinogenesis is not yet established, but further work in this area is justified given the findings of potential reactivation of HPV and its effect on suppression of tumour suppressor gene expression.

Conclusion
The global incidence of oral cancer has steadily increased whilst survival remains poor and unchanged over the past few decades.The disruption caused by the COVID-19 pandemic will likely accelerate these trends due to delays in diagnosis or compromised treatment.COVID-19 has provided us with a learning opportunity to help mitigate the risks to patients during any future epidemic or pandemic.Evidence for SARS-CoV-2 viral persistence and oncogenesis, direct or indirect, is not yet established, but additional studies on the long-term effects of the virus are needed to shed light on such a possibility.