Estimated projection of oral cavity and oropharyngeal cancer deaths in Spain to 2044

Oral cavity cancer (OCC) and oropharyngeal cancer (OPC) are two malignant tumours closely related through the narrow topographical boundary between the mouth and the oropharynx. Squamous cell carcinoma arising from the superficial epithelium of the oral cavity and oropharynx accounts for more than 90% of all cancers in this region. Recent evidence supports that these cancers could be considered two different diseases in terms of etiopathogenesis, treatment, and prognosis [1]. Although they classically share common non-genetic risk factors, such as tobacco and alcohol consumption, human papillomavirus (HPV) is currently recognized as a specific risk factor primarily for OPC.

OCC and OPC represent a growing health concern since, in 2018, they were estimated to cause 177,400 deaths (119,700 males, 7,700 females) and 51,000 deaths (42,100 males, 8,900 females) worldwide, respectively [2]. Considering all locations together, neoplasms of the oral cavity, oropharynx, and pharynx are the ninth leading cause of cancer death globally [3]. Available data on mortality rates due to OCC and OPC in Spain are scarce. It has been reported that the mortality rates of these two related cancers reached their highest values in the 1990s, when they began to fall and have stabilized to the present [4]. However, in the last two decades, while OCC mortality rates have decreased markedly in males, a slight increase has been observed in females. On the contrary, a steady increase in OPC mortality has been observed in both sexes over the last decade.

Knowledge of OCC and OPC mortality rates and trends in large populations is a powerful tool for the planning process of public health strategies and for defining future research priorities. The government mortality registry available in Spain provides a high quality data source that allows accurate mortality analysis. This reliable data can be used to make large-scale predictions, showing trends not observable in small studies or clinical trials. Very few studies have reported predictions of OCC and OPC mortality for the next several years, and to our knowledge, no study has ever been conducted comparing the estimated mortality projections for these two related cancers separately and in combination. In Spain there are no specific reports that predict the future trends of mortality due to OCC and OPC. Consequently, this study aimed to analyse the mortality rates in the last 40 years to generate a predictive model of OCC and OPC mortality in Spain up to 2044.

This study reports, for the first time, a prediction of the temporal trend of OCC and OPC mortality for the next 25 years in Spain, analysed by sex and age groups. The most relevant findings according to our prediction model indicated that OCC mortality rates will tend to decrease in males while there will be a slight increase in females, more evident in those > 65 years. Regarding OPC mortality rates, the model predicts a downward trend in males, except in those > 65 years. In this group mortality rates will rose until the period 2025–2029, when they will begin to stabilize and then decrease. In contrast, OPC mortality in females will remain stable, showing a gradual increase in females > 65 years until the end of the period.

The possible association with the main known risk factors should be considered to explain the variations detected in mortality trend rates between OCC and OPC when analysing them according to sex and age groups. Traditionally, the main non-genetic risk factors for these related cancers are smoking and alcohol consumption, with synergistic effects when their use is combined [8]. The legislative and cultural changes of the late 1990s plausibly favoured a reduction in the population's exposure to tobacco and alcohol, which resulted in a decrease in mortality rates in those cancers associated with these etiological factors, in particular for OCC [9]. The global prevalence of OCC could be reduced by 75% by limiting tobacco and alcohol consumption in the population and increasing public awareness of its prevention [10]. In our study, these trend changes seemed to be clearly more noticeable in males, since a stabilization and decrease in OCC mortality is expected until the end of the study period. However, OCC mortality in females will increase throughout the analysed period, especially in females > 65 years, which is probably explained by their incorporation into tobacco consumption that occurred in Spain during the last decades of the twentieth century. The traditional gender difference in the prevalence of smoking has narrowed in Spain, due to an increase in the prevalence of female smokers, especially in the younger age groups [11]. Nevertheless, alcohol consumption in Spanish society remains constant in both sexes [11]. In gross figures, the number of OCC deaths in males in the period 2040–2044 is expected to reach similar values to those of the period 1980–1984; instead, the number of deaths in females is projected to increase by 490% between the periods 1980–1984 and 2040–2044. Our projections indicate that at the end of the estimated period, OCC mortality will reverse the classic trend of epidemic behaviour that associated this specific type of cancer with males, tobacco, and alcohol consumption, since it is estimated that by then, more females than males will die from OCC.

Regarding OPC mortality, our findings suggested that it will increase steadily in females over the next 25 years, although it will tend to stabilize. However, in females > 65 years, this increase is projected to continue until the end of the period studied. Since HPV infection is a well-established risk factor for a high proportion of oropharyngeal squamous cell carcinomas [12], it seems reasonable to assume that this increase in mortality could correspond to an increase in the incidence of HPV infection. Although information on HPV status was not available in our INE data, a causal association has been reported in the literature, as up to > 80% of OPC patients are infected with HPV [13]. The potential beneficial effect of HPV vaccination on OPC mortality remains unknown, but it is speculated that raising the awareness of the population and health professionals [14] together with institutional HPV vaccination campaigns will modify this specific risk factor. This could be especially important in younger age groups, in which mortality will tend to stabilize or decrease gradually. The long-term benefits of the HPV vaccine will largely depend on the duration of its protection [15]. Extensive vaccination campaigns with prolonged protection for at least 30 years are likely to be required to assess whether HPV vaccination has a significant impact on OPC mortality. The results of our study suggested that the impact of current HPV vaccination on OPC mortality trends in patients > 65 years will be quite limited over the next 25 years, and therefore the reduction in OPC mortality due to HPV vaccination among older adults will take longer [16].

The gross death rate comparison between OCC/OPC is projected to be halved from 6.2 (period 1980–1984) to 3.1 (period 2040–2044). When OCC and OPC mortality rates are compared by sex up to 2044, estimated projection predicts a strong decline in male mortality and an increase in females for OCC. This trend was especially relevant in females > 65 years, and according to the model it will reverse the classic mortality trends of OCC between males and females. Likewise, OPC mortality rates in males are expected to decline at the end of the period, while in females they will stabilize, except in those > 65 years where mortality rates are expected to rise. Therefore, our findings emphasized the need to maintain educational interventions aimed at the entire population in the coming years, promoting smoking cessation and alcohol abstinence, vaccination against HPV, campaigns for early diagnosis of potential malignant lesions in the oral cavity and oropharynx, changes in lifestyle, preservation of oral hygiene and periodontal health [17], and high consumption of fruits and vegetables. Our predictive model indicated that these preventive programs should be intensified especially in females in the near future.

Few studies on a global and European scale predicted mortality for the coming years. Kujan et al. [18] reported a projection analysis for OCC-OPC between 2012 and 2030 using data from GLOBOCAN 2012, estimating that the global mortality rate will increase by 50%. Thus, the burden projected by OCC-OPC between 2012 and 2030 will rise from 145,353 to 220,627 (for both sexes). In our model, the number of deaths from OCC-OPC in the period 2015–2019 was 7,991 deaths, and in the period 2040–2044 an increase of 8,912 deaths is projected, which represents an increase of 11.5% in Spain. Smittenaar et al. [19] estimated cancer cases and deaths between 2015 and 2035 in the UK. They found that while death rates for most cancers are declining, there will be an accelerating average annual increase in oral cancer death rates (1.42% for males, 1.53% for females), due to the most pronounced changes in the > 75 years group. A similar pattern is found for oral, anal, and cervical cancers, leading to speculation that similarities between these cancers are particularly associated with HPV. The number of deaths from oral cancer is expected to rise by 2.97% in males and 3.09% in females between 2014 and 2035. A study conducted in China has also shown an upward trend in future mortality rates from OCC-OPC [20].

This study presented some limitations that must be addressed. First, death certificates may be affected by errors that can influence subsequent analysis of mortality rates. However, it can be established that there have been no recent changes in classification and staging in subsequent revisions of the ICD. Mortality registries are more reliable than incidence registries, since the data they provide are usually more complete, better compiled and, therefore, more contextually real. For this reason, mortality certificates are a frequent and important source of public health studies and provide a tool to reliably evaluate public health interventions. Mortality data are the only ones that allow evaluating such a long population series, and in the case of cancer, previous studies have demonstrated the quality of these data [21]. Second, mortality predictions are necessarily affected by changes in cancer diagnosis or treatment, so they should be interpreted with caution if new treatment modalities may emerge in the coming years. Nevertheless, mortality trends are unlikely to be influenced by changes in diagnosis and certification in the near future, as these cancers are relatively easy to detect. Third, the standardization of rates has been carried out using the European standard population of 2013, so our data are sufficiently reliable and comparable to allow us to infer mortality trends in most of the European population, at least in South/Mediterranean countries. Nonetheless, the information on death certificates is not homogeneous or consistent between countries. Consequently, to improve our ability to predict mortality trends in the future, it would be desirable for death certificates to be uniform in all countries.

This predictive model study provided a global view of OCC and OPC mortality trends up to 2044 in Spain. Our results have predicted future changes in mortality trends by sex, age, and topographic locations. Based on our findings, OCC mortality rates will tend to stabilize and decrease in males but will increase markedly in females > 65 years. However, OPC mortality rates will increase until the middle of the period in males and subsequently decrease, while in females > 65 years there will be an increase and stabilization until the end of the study period. The similarities and differences revealed by the mortality projections when comparing OCC and OPC can be explained by the variable influence on exposure to main known risk factors and the efficacy of the available therapeutic tools. Some of the risk factors involved can be prevented by campaigning for smoking cessation and alcohol abstinence. To the same extent that OCC mortality rates in males have declined in the last observed decades, there is still room to improve OCC mortality rates in females > 65 years in the future by strengthening campaigns against the risk factors mentioned above. OPC mortality in both sexes is going to become a growing health problem in the coming years. Vaccination campaigns for the prevention of HPV-associated malignant neoplasms could have a preventive effect on mortality trends that will have to be evaluated in future studies. Nevertheless, although the protective role of the HPV vaccine in the long-term prevention of these cancers is still unknown, the increase in mortality for OPC makes it advisable to conduct educational campaigns to inform the general population about HPV forms of transmission and its important etiopathogenic role in disease development. Our findings highlighted the importance of closely monitoring the mortality rates for both types of cancers by age group and sex, and the need to continue preventive measures against known risk factors.