Disease burden, risk factors, and trends of lip, oral cavity, pharyngeal cancers: A global analysis

Abstract Background Lip, oral and pharyngeal cancers make up a small percentage of total cancer cases worldwide and have reported lower rates of cancer‐related deaths globally in 2020, but their 5‐year survival rate in either early or advanced stages is different. The study evaluated the global incidence, mortality, risk factors, and temporal trends by age, gender, and geographical locations of lip, oral cavity, and pharyngeal cancer. Methods Incidence and mortality rates were extracted from Cancer Incidence in Five Continents (CI5) volumes I‐XI, the Nordic Cancer Registries (NORDCAN), the Surveillance, Epidemiology, and End Results (SEER) Program, and the WHO IARC mortality database. Joinpoint regression was used to calculate the Average Annual Percentage Change to examine trends. Results The highest incidence rates were found in Melanesia and South‐Central Asia and mortality rates were 8.2 and 7.5. Risk factors associated with incidence and mortality included HDI, tobacco use, alcohol consumption, poor diet, and chronic health conditions such as hypertension. Increasing trends of incidence and mortality were observed in females from Malta; males aged 50 and above from the United Kingdom, and females aged 50 and above from Slovakia reporting the largest increase. Conclusions Although global incidence and mortality trends reported an overall decrease, significant increases were found for older age groups and female subjects. Incidence increase may be due to the growing prevalence of lifestyle, metabolic risk factors, and HPV infections, especially in developed countries.


| INTRODUCTION
3][4] In the early stages, oral cancers are often asymptomatic but may eventually present as pain caused by lesions.Lesions may appear as white and red patches, referred to as leukoplakia and erythroplakia, respectively.Additional symptoms at later stages may include bleeding, loose teeth, difficulty wearing dentures, dysphagia, dysarthria, odynophagia, and the development of a neck mass.
In developed and developing countries, cancers of the lip, oral cavity, and pharynx variety have been shown to be associated with exposure to risk factors such as tobacco use, including chewing or smoking tobacco 5,6 ; consumption of alcohol 7 ; consumption of nitrosamine-rich foods 8 ; infection with human papillomavirus (HPV) 9 ; environmental exposures, for example, ultraviolet radiation (UVR) 10 ; dietary deficiencies due to a lack of fruit and non-starchy vegetables. 11hough previous studies have examined the epidemiological trends of lip, oral cavity, and pharyngeal cancers, they utilized data limited to specific regions and countries, 12,13 of lower quality, 14 or did not include analyses on age subgroups. 15An updated global assessment to examine the country-specific, sex-specific, and age-specific incidence and mortality rates using high-quality data would contribute toward a better understanding of the international differences in etiology, diagnosis, prognosis, and treatment.Additionally, this would inform the development of targeted interventions and disease prevention policies to reduce the overall burden of lip, oral cavity, and pharyngeal cancers.This study investigated the global incidence, mortality, risk factors, and temporal trends of lip, oral cavity, and pharyngeal cancers by age, sex, and geographical location.

| Data sources
To define the lip, oral cavity, and pharyngeal cancers, we used the International Classification of Diseases Version 10 (ICD-10) C00-14). 16Data were extracted from the Global Cancer Observatory (GLOBOCAN) database, developed by the International Agency for Research on Cancer, World Health Organization (IARC, WHO). 17The Gross Domestic Product (GDP) per capita and Human Development Index (HDI) for each country and region were retrieved from World Bank and United Nations.For the categorization of HDI rates, <0.550, 0.550-0.699,0.700-0.700,and ≥0.800 are considered low, medium, high, and very high.The WHO Global Health Observatory data repository was employed for the age-adjusted prevalence of smoking, alcohol drinking, unhealthy dietary, physical inactivity, hypertension, diabetes, and lipid disorders, at the country level. 180][21] The CI5 database contains cancer incidencerelated data drawn from global, regional, and national cancer registries including the percentage of cases officially registered, the frequency of cases microscopically recorded, and cancer incidence by age, primary tumor year, and geographical locations.The NORDCAN database and SEER program contain cancer-related statistics from the Nordic region and the United States, respectively.The WHO IARC mortality database contained cancer-related death data for each country and region chronic health conditions such as hypertension.Increasing trends of incidence and mortality were observed in females from Malta; males aged 50 and above from the United Kingdom, and females aged 50 and above from Slovakia reporting the largest increase.

Conclusions:
Although global incidence and mortality trends reported an overall decrease, significant increases were found for older age groups and female subjects.Incidence increase may be due to the growing prevalence of lifestyle, metabolic risk factors, and HPV infections, especially in developed countries.

K E Y W O R D S
burden, lip, oral cavity, pharyngeal cancer, risk factors, temporal trends and was used for conducting a mortality trend analysis. 22Collecting data on cancer-related deaths from national civil cancer registries on a local and national level with the registering system verified cancer deaths and their causes, which were then reported to the WHO annually.The weighted age-standardized rate (ASR) was generated using the Segi-Doll world reference population to transform all cancer incidence and mortality figures. 23,24Weighting was proportionate to the individuals in the standard population's corresponding age groups.

| Statistical analysis
Choropleth maps were constructed on the global incidence and mortality of lip, oral cavity, and pharyngeal cancers in 2020.To assess the relationships between GDP, HDI, risk factors, and lip and oral cavity incidence and mortality, a linear regression analysis was conducted using STATA 16.0 to generate the both beta coefficients (β) and the corresponding 95% CIs.The β estimates referred to the level of variation in ASR of incidence or mortality of lip, oral cavity, and pharyngeal cancers.To assess the temporal trend of incidence and mortality rates of all ages across gender (male and female) and geographical regions (Asia, Oceania, Northern America, Southern America, Northern Europe, Western Europe, Southern Europe, Eastern Europe), a logarithm transformation was performed on the incidence and mortality rates before carrying out the joinpoint regression analysis.The Average Annual Percentage Change (AAPC) and its 95% CI were calculated using joinpoint regression analysis software (Version 4.8.0.1-April 2020; Statistical Methodology and Applications Branch, Surveillance Research Program, National Cancer Institute).When conducting analysis on trends with transitions, AAPC is preferred over annual percentage change (APC) since the length of the time segment is considered and it does not assume linearity. 25This method has been used in previous studies to determine the epidemiological trend of other forms of cancer, with the outcome of positive or negative AAPC indicating an increasing or decreasing trend in cancer incidence or mortality, respectively. 26All p < 0.05 were considered statistically significant.

| Global incidence of lip, oral cavity, and pharyngeal cancer in 2020
In 2020, there were an estimated 747,316 newly reported cases of lip, oral cavity, and pharyngeal cancer with a global ASR of 8.1 new cases per 100,000 population (Figure 1).The region with the highest incidence was Melanesia (ASR = 19.8),followed by South-Central Asia (13.5),Central and Eastern Europe (10.3),Western Europe (10.0), and Australia and New Zealand (10.0).On the contrary, the lowest incidence was found in Central America (2.0),Western Africa (3.1),Western Asia (3.7), Northern Africa (ASR = 3.9), and Eastern Africa (4.3).The incidence rate of males (12.2) was almost 3 times that of females (4.3).Countries with medium HDI had the highest incidence (19.5), followed by those with very high HDI (13.1), high HDI (8.3), and low HDI (5.2).The incidence of lip, oral cavity, and pharyngeal cancer increased with age, with the highest incidence found among the 70-85+ age group (37.8,Table S1).

| Global mortality of lip, oral cavity, and pharyngeal cancer in 2020
In 2020, it was estimated that 367,285 lip, oral cavity, and pharyngeal cancer-related deaths were reported on a global scale (ASR = 3.9 death cases per 100,000 population).Similarly, Melanesia had the highest mortality (8.2), followed by South-Central Asia (7.5), South-Eastern Asia (5.8), Central and Eastern Europe (5.2), and Micronesia (4.1); while regions with the lowest mortality were Central America (0.90), Northern America (1.6),Western Asia (1.7), Australia and New Zealand (1.8), and Northern Africa (2.1).There was a threefold difference in the mortality between the two sexes (male ASR = 6.0, female ASR = 2.0).Populations with medium HDI had a significantly higher mortality of 7.3, while the other populations had mortality ranging from ASR 2.8 to 2.9.Similarly, the highest mortality was found among the 70-85+ age group (21.1).

| Temporal trends of lip, oral cavity, and pharyngeal cancer
The incidence and mortality trends of lip, oral cavity, and pharyngeal cancer for each country between 1980 and 2019 are shown in alphabetical order according to their continents in Figure S1, and the trend regression is presented in Figure S2.

| Summary of major findings
This study comprehensively analyses the disease burden, risk factors, and temporal epidemiological trends of lip, oral cavity, and pharyngeal cancer, using the most updated data retrieved from databases.Subgroups of regions, countries, sexes, and age groups have been included in a robust statistical analysis.We noted a significant geographical disparity in the incidence of the cancer.Higher lip, oral cavity, and pharyngeal cancer incidence and mortality were associated with higher HDI as well as prevalence of smoking, alcohol consumption, poor diet, and hypertension in males, while mortality was associated with a lower HDI, GDP, and prevalence of lifestyle and metabolic risk factors in females.There has been an overall decreasing trend in incidence for both male and female among Asian countries, while a general increasing trend in incidence was found in European countries, such trends were particularly evident in female aged 50 years old or above.For mortality, a decreasing trend was found among the male population in general while an overall increasing trend was observed for female.

| Explanations and comparisons with past literature
Lip, oral cavity, and pharyngeal incidence were found to be highest in Melanesia, South-Central Asia, Australia, and New Zealand, which supports past findings where overall incidence rates ranged from 0.5 to 21.2 in males and 0.5 to 12.0 per 100,000 persons in females. 27The increasing number of cases in European countries, with significant rises in developed countries, may be due to advancements in early cancer detection and increased exposure to risk factors.For instance, central and Eastern Europe and Western Europe incidence was significantly higher than the global average.This further reinforces evidence where the region previously reported a majority of newly diagnosed cases (19.2% worldwide) in 2012. 15In the present study, the highest mortality rates were found in the region of Melanesia, South-Central Asia, South-Eastern Asia, Central and Eastern Europe, and Micronesia, all of which are locations where high lip, oral cavity, and pharyngeal incidence rates have been reported. 28isk factor associations, such as high HDI, substance use, and chronic health conditions, reinforce findings from previous studies.The highest incidence and mortality of lip, oral cavity, and pharyngeal cancer were observed in medium HDI countries with the ASR being 19.5 and 7.3, respectively.Previously in 2012, countries with low HDI had a higher ASR of 4.4 for incidence compared to medium HDI countries (ASR = 2.2), and higher age-standardized mortality rates in low HDI countries (ASR = 3.3) than in medium HDI countries.(ASR = 2). 29ncidence and mortality rates are usually pronounced in low and medium HDI settings as rapid socio-economic development brings about the adoption of adverse lifestyle, behavioral, and environmental factors.Moreover, the existing healthcare infrastructure and medical interventions are ill-equipped to elevate the increasing burden of cancer. 30A review of the prevalence of substance usage in different regions found that tobacco smoking and alcohol consumption were primary risk factors for oral cavity cancer in Europe, North, and Latin America. 31Additionally, Melanesia, South-Central Asia, and South-Eastern Asia may be partially explained by the prevalence of betel quid chewing 32 while solar radiation in parts of Oceania, namely Australia and New Zealand, is the most pertinent risk factor associated with these regions. 15Non-starchy vegetables and fruit intake may act as a protective factor as dietary deficiencies and increased red meat consumption have been associated with 11%-15% of oral cavity and pharyngeal cancer cases. 31,33,34Hypertension is one of the most frequently reported comorbidities found for lip, oral cavity, and pharyngeal cancer, as both diseases share the same risk factors including sedentary lifestyle, unhealthy diet, obesity, alcohol use, and smoking. 35,36he global variation in lip, oral cavity, and pharyngeal cancer incidence and mortality trends may be reflective of the changing risk factor prevalence and population lifestyle of each region.The gradual decreasing trend in global incidence, particularly in males, mirrors the overall decline in tobacco use since 1990 (−27.2%, 95% CI: −26.0% to −28.3%). 37This is indicative of the effectiveness of interventions centered around substance use cessation and its importance in preventing the development of cancers. 38lthough majority of cases are found in people aged 50 and older, rising incidence trends in younger age groups within developed regions-Australia, Europe, and North America-have been thought to be associated with the spread of human papillomavirus (HPV) infection. 2,15,39or instance, HPV-associated oropharyngeal cancer has been increasing from 16% in 1984 to more than 70% in 2000 in the USA. 40An upward trend of cancer incidence and mortality in women was accompanied by a growing prevalence of smoking among females, with female smokers shown to be at an increased risk of developing oral cavity cancer compared to males. 2,28

| Limitations
There were some limitations in this study.First, the estimates of GLOBOCAN 2020, which were based on past data on incidence and mortality trends, did not take into account the influence of the COVID-19 pandemic.The incidence might have been overestimated as cancer diagnoses were expected to decline due to the pandemic.On the contrary, there might be an underestimation of the mortality because of late diagnosis and co-infection of COVID-19.Further, there is a possibility of the underreporting of incidence and mortality of lip, oral cavity, and pharyngeal cancers in developing countries due to the absence of well-established infrastructure and mechanisms for cancer reporting.Lastly, an analysis of the trends of different stages, subtypes, and categories of lip, oral cavity, and pharyngeal cancers was not conducted due to the limited availability of data.

| CONCLUSION
The incidence of lip, pharynx, and oral has been steadily increasing, especially in developed countries, female subjects, and older populations.While mortality decreased in males in the majority of the regions, overall rates have been increasing in female population.The rise in cases may be due to the improvement in disease detection and increased prevalence of its related lifestyle and metabolic risk factors.Lifestyle modifications are highly recommended to combat the risk posed by such factors by means of alcohol control, weight control, and increasing physical activity.As diagnosis in advanced stages worsens prognosis significantly, methods to enhance early detection and disease surveillance may improve overall treatment outcomes.Future research may look to explore the precipitating variables behind the epidemiologic trends which may provide more insight into the etiology and prognosis of lip, oral, and pharyngeal cancers.

F I G U R E 5
AAPC of LOCP cancers mortality for individuals of all ages.AAPC, annual percentage change; *p < 0.05.