Factors predicting early death in head and neck cancer

Head and neck cancer (HNC) ranks as the seventh most common cancer worldwide. Nearly 890,000 cases and 450,000 deaths were reported in 2020. The majority (90%) of HNC cases are head and neck squamous cell carcinoma (HNSCC), and over 60% of cases are diagnosed at advanced stages (III or IV). The global incidence of HNC is projected to increase by 30% by 2030, mostly driven by human papilloma virus (HPV)-induced oropharyngeal cancer. HNC reflects a heterogeneous group of malignancies. Diagnosis relies on clinical examination, biopsies with histopathological analyses, and various radiological investigations, including computer tomography, positron emission tomography/computed tomography, and magnetic resonance imaging (CT, PET/CT, and MRI, respectively). Key risk factors for HNC include tobacco use, alcohol consumption, and oncogenic HPV infection. HPV-positive HNC, which typically affects patients 10 years earlier than HNC caused by traditional risk factors, exhibits improved survival and higher sensitivity to radiotherapy. In Sweden, approximately 1,700 new HNC cases are reported annually. These patients have a 5-year relative survival rate of 67% and have shown a significant increase in incidence of 24% from 2008 to 2020. Treatment decisions are guided by the tumor/node/metastasis (TNM) classification system. Treatment regimens are determined at multidisciplinary board meetings. Surgery and radiotherapy with or without chemotherapy are the most common treatment options. Early-stage HNC is often managed with single-modality therapy, while advanced stages require combined modalities. The impact of treatment on functional and aesthetic outcomes necessitates early rehabilitation interventions and is a heavy burden for both patients and their families. Early identification of patients at risk of early death is of great importance. This thesis includes four papers with the aim of identifying HNC patients at risk of early death and the factors indicating increased risk of early death. Study I: a nationwide population-based study that was aimed at identifying patients at risk of early death, which was defined as death within six months of HNC diagnosis. The study sought to raise awareness of this vulnerable group with the aim of improving care strategies by identifying tumor-specific and patient-specific risk factors. It was found that older patients with hypopharyngeal cancer and poor general health (according to World Health Organization [WHO]) had the highest risk of early death. The results from study I (mainly WHO class) are now being utilized in multidisciplinary tumor board (MDTB) to enhance patient safety and decision-making for newly diagnosed cancers. Study II: a multicenter observational prospective study that examined the relationship between body composition (fat-free mass index [FFMI], body mass index [BMI)], and early death [between 6- and 12-months post-treatment]) in patients with head and neck squamous cell carcinoma. Measurements of body composition were obtained using bioimpedance analysis (BIA). Low FFMI was identified as an independent prognostic factor for early death. Weight loss six months before diagnosis statistically correlated to recurrence within a year. In study II, we showed that nutritional status is of relevance in the treatment decision process and that BIA can be an effective tool when predicting patients at risk of early death. Study III: explored potential variations in immunohistochemical biomarkers that were obtained from biopsies between individuals who died within six months of diagnosis and those surviving 24 months. High survivin expression emerged as an independent risk factor for early death and suggests its potential for risk stratification in combination with other markers. The expression of Ki-67 was significantly higher in the early death group and suggests that Ki-67 is a prognostic marker for early death in HNC. Trends in epidermal growth factor receptor (EGFR), carbonic anhydrase 9 (CA 9), and p16 suggest differences that warrant further investigation in a larger study. Study IV: a nationwide population-based study that focused on identifying HNC patients at risk of early death after curative treatment. The risk of early death significantly decreased from 4.7% to 2.5% during 2008 to 2020. Shorter times to treatment were noted for both surgical and oncological regimens (radiotherapy with or without chemotherapy). Increased risk of early death was associated with male gender, older age, advanced disease, higher WHO scores, and hypopharyngeal tumors. The implementation of standardized work-ups and treatment due to national guidelines most likely contributed to reducing early death in HNC patients. In conclusion, this thesis identifies key risk factors for early death in HNC thus enabling the clinician to identify patients at risk and provide the best individualized treatment options. Further studies on biomarkers, body composition, tumor- and patient-related factors could lead to an algorithm predicting 6- and 12-month mortality and aid early diagnostic and clinical decision-making by the MDTB.