Oral cancer(OC) is one of the most commonly occurring malignancies in head and neck, depicted by diverse geographic distribution in its incidence and prevalence. In 2024, there will be an estimated number of 36620 newly diagnosed cases and 7930 estimated deaths in the United States(US) (1). Oral squamous cell carcinoma(OSCC) dominates all oral cancer cases. Behaviors identified as risk factors increase the likelihood of oral cancer, such as betel nut chewing, tobacco use, excessive alcohol consumption, and poor oral hygiene (2–6).

Due to early diagnosis and advances in treatment effectiveness, the number of cancer survivors is remarkably increasing. It is estimated that there are more than 300000 males survivors with a previous diagnosis of oral and pharynx cancer in US (7). Oral cancer and its treatments affect major structures involved in eating, swallowing, breathing, and communicating. Besides, non-cancer related comorbidity also complicates the survival of oral cancer patients. Therefore, understanding the real causes of death in oral cancer patients could help optimize health management and develop individual follow-up strategies.

Few studies have focused on the causes of death in oral cancer patients, especially for non-cancer related reasons. In this study, we provide a population-based analysis concentrating on each cause of death among oral cancer patients. We related different causes of death to time periods with respect to demographic and clinicopathological characteristics. Further, the risk of death from each cause in oral cancer was compared with that of the general population.

With improvements in early detection, anti-tumor treatments and supportive care, the number of oral cancer survivors is increasing. Understanding the real causes of death is vital for oral cancer patients to optimize follow-up strategies. In our study, we analyzed causes of death of 30538 patients diagnosed with oral cancer from 2004 to 2015 in SEER database. A total of 17654 patients died during follow-up period, and the mortality rate reached 57.81%. More than half of the deaths were causes by other types of cancer and non-cancer causes. Cancer-related causes were responsible for the majority of deaths in the initial phase after diagnosis. But with the extension of survival time, the percentage of non-cancer related deaths gradually increased.

Second primary cancer is a leading long-term cause of death for oral cancer survivors. Apart from oral and pharynx cancer, we observed 5145 deaths due to other malignant cancer, of which miscellaneous malignant cancer and respiratory system cancer were the most frequent. A previous study confirmed that patients with oral squamous cell cancer had an 85% excess risk of growing second primary cancer compared with the incidence rate in Finnish population (8). And respiratory organs, intrathoracic organs and digestive organs were the commonest site for second primary cancer (8). Another study indicated that oral cancer patients had a substantially higher risk for second primary hypopharyngeal and esophageal cancer and had poor prognosis (9). Besides, a population-based, retrospective study found a noteworthy increased rate of second primary cancer after treatment of oral squamous cell cancer, especially in head and neck region and in lungs (10). Several factors may influence the development of second primary cancer, such as gene mutations, environmental exposures, and living habits (11–14). Anti-tumor treatments also influence the development of second primary cancer, such as radiation exposure (15).

The most common non-cancer cause of death was cardiovascular disease. Cancers have been found to be strongly associated with cardiovascular disease (16, 17). A representative cohort study in Taiwan discovered that cancer patients had a significantly greater risk of fatal or non-fatal cardiovascular disease (18). Cardio-oncology was proposed to focus on diagnosis, treatment and prevention of cardiovascular consequences of cancer and its treatment. Betel quid chewing is one of the major factors of developing oral cancer. Previous studies concluded that betel quid chewers would experience much more incidence of cardiovascular disease (19–21). Besides, tobacco was recognized to be the risk factor for oral cancer and cardiovascular disease.

The risk of death from infectious diseases in oral cancer patients was significantly increased. Infection, a preventable cause, was thought to be related to the development of oral cancer (22–24). Among oral cancer survivors, as a consequence of disease and its treatments, infectious conditions of any nature, viral, bacterial, and fungal were frequent (25). Mouth infections can affect the prognosis of patients with oral cancer. Fungal were the most common opportunistic infections. Neutropenia caused by cancer and its treatments would promote the invasion of Candida species and lead to clinical debilitating infections (26). Besides, mucosal damage resulting from oral cancer increased the risk of infectious complications. Moreover, aspiration pneumonia and surgical site infection remained to be a critical problems for surgery-induced complications (27).

In addition, the risk of dying from stomach and duodenal ulcers in oral cancer patients was higher than the general population, especially in the first year of diagnosis. Radiotherapy is widely used for head and neck cancer patients. In 9388 head and neck cancer patients treated with radiotherapy, the percentage of comorbidity about peptic ulcer diseases was 6.8% (28). Besides, in 232 oral cancer patients post major surgical intervention with or without adjuvant therapy, peptic ulcer(8.6%) was the most common comorbidity (29).

Surgery is still the primary therapeutic option for oral cancer. The goal of surgery is complete resection of tumor with an adequate margin. Margin status diagnosis, significantly influences the occurrence of tumor and quality of life, should be accessed cautiously (30, 31). The surgical approach in oral cancer has evolved over the years. A retrospective study compared patients treated by invasive surgery with those treated by less invasive approach and concluded that the invasive approach does not correlate to better survival or locoregional control (32).

With the progress of radiation techniques, modern radiotherapy aims to improve therapeutic efficacy and side effects. Radiotherapy is recommended for parts of postoperative oral cancer patients or patients who are not suitable for surgery. Intensity-modulated radiotherapy(IMRT) or volumetric intensity-modulated arc therapy(VMAT), administering high doses of radiation to a small area of oral cavity of many critical structures, was reported to reduce radiation-related toxicity, such as xerostomia, dysphagia, severe mucositis (33–35). Besides, in head and neck cancers, IMRT and VMAT reduce the possibility of second primary cancer within the in-filed volume compared to conventional radiotherapy (35). Besides, the risk of radiation-induced carcinogenesis decreases for VMAT, as a result of the reduction of monitor unit and the whole-body integral dose (36).

Chemotherapy can be used as postoperative adjuvant therapy, primary treatment when surgery is not possible, concurrent chemoradiotherapy, or palliative therapy. Adverse effects vary depending on chemotherapeutic agents. Agents commonly used in oral cancer include cisplatin, 5-fluorouracil, docetaxel, paclitaxel and gemcitabine. Renal toxicity is a well-known adverse effect of cisplatin, and adequate hydration is required during cisplatin injection. Cardiotoxicity is a severe adverse effect of 5-fluorouracil following cancer treatment (37). Cetuximab, a monoclonal antibody against epidermal growth factor receptor(EGFR), has an established role in oral cancer. But cetuximab can cause severe skin, mucosal, gastrointestinal and kidney toxicity. New inhibitors like nimotuzumab, have been developed with higher EGFR affinity and fewer side effects (38).

However, our study has several limitations that should be addressed. First, our study was retrospective, and bias was inevitable, particularly in the selection of patients and the accuracy of recorded data. Second, the prevalence of oral cancer is depicted by diverse geographic disparity, with common occurrence in South Asia countries. But the majority participants in our study were white. Also, the study may not capture the full spectrum of oral cancer patients because of our exclusion criteria. Whether our finding can be applied to all oral cancer patients need further investigation. Furthermore, the administrative data in SEER database may not include detailed clinical information, such as comorbid states, treatment strategies and complications, which could be relevant to the outcomes in our study.

In conclusion, with the extension of survival, the number of oral cancer patients dying from non-cancer related causes increased. Cardiovascular disease was the most common non-cancer cause of death in oral cancer patients. Besides, the risk of dying from infections, cardiovascular disease or peptic ulcers was higher in oral cancer patients. Therefore, being aware of non-cancer risk factors and optimizing follow-up strategies are crucial to achieve longer survival time and better quality of life for oral cancer patients.

For oral cancer patients, our study highlighted that attention should be paid not only to anti-tumor therapy but also to the occurrence of other risks. As the survival time prolonged, the problem of second primary cancer and non-cancer related deaths emerged. Future studies are encouraged to explore second primary cancer of oral cancer survivors, particularly focusing on the prevention of second primary cancer. In addition, newly developing subjects, such as cardio-oncology, are required to research, treat and prevent non-cancer diseases for oral cancer patients. Furthermore, oral cancer patients in our study were diagnosed between 2004 and 2015 in SEER database. We need further research about causes of death for oral cancer patients diagnosed recently, due to the rapidly improved treatments.