Abstract
Introduction: Laryngeal cancer (LC) is the most common malignancy in otolaryngology, comprising 30–40% of head and neck malignancies. With an increasing incidence worldwide over the past few decades, LC has resulted in substantial strain on the NHS. There have been notable advancements in the treatment of LC over the years, particularly with the adoption of non-surgical methods, which emerged after the 1991 study conducted by the Veterans Affairs. Nevertheless, there has been an increase in mortality rates for head and neck cancer by approximately 15% in the UK over the last decade. This study aimed to evaluate the survival outcomes of patients with LC in our population, considering both the disease stage and treatment modality applied. Methods: Retrospective data were collected from 2015 to 2019 for all patients who were diagnosed with primary LC at NHS Tayside. Univariate and multivariate analyses were performed to determine the factors associated with overall survival (OS) and disease-specific survival (DSS) in LC. Survival analysis using Kaplan-Meier curve was used to compare the treatment modalities in different stages of LC. Results: Patients with advanced LC (stages 3 and 4) had more than 5 times risk of mortality compared to patients with early LC (stage 1 and 2) (DSS: HR 6.10, 95% CI: 1.52–14.61, p = 0.016; OS: HR 5.52, 95% CI: 1.64–13.34, p = 0.017). In patients with stage 4 LC, laryngectomy provides better survival outcomes than chemoradiotherapy (DSS: p = 0.035; OS: p = 0.046). In addition, DSS was double, and OS was 3 times higher for patients who received adjuvant radiotherapy following laryngectomy compared to patients who underwent laryngectomy alone (DSS: p = 0.036; OS: p = 0.032). Conclusion: Our study supports that surgical treatment with adjuvant radiotherapy improves the survival outcomes of advanced LC and should be considered as first-line treatment in patients who are fit for surgery. More prospective studies are needed to determine the optimal treatment approach for advanced LC with consideration of organ function, patient quality of life, and treatment-related morbidity and mortality.
Introduction
Laryngeal cancer (LC) represents between 30% and 40% of malignancies affecting the head and neck region, making it the predominant malignancy encountered in otolaryngology worldwide [1]. LC can be categorized as supraglottic, glottic, and subglottic cancers, with squamous cell carcinoma being the most prevalent histological type. In 2020, there were 184,615 newly diagnosed cases of LC worldwide, with an incidence of 2.0 per 100,000 individuals, resulting in almost 100,000 deaths related to LC [2]. Furthermore, the incidence and prevalence have increased by 12.0% and 23.8%, respectively, over the past 3 decades [3]. This results in a substantial strain on the NHS as head and neck cancer incurred an estimated cost of GBP 309 million over a 5-year period from 2006 to 2011 [4]. Various factors, including specific substances or viruses, have been linked to the development of LC, although additional research is required to conclusively determine the potential risks of certain factors. Established risk factors for LC include tobacco and alcohol consumption, both of which exhibit a direct relationship with the likelihood of developing the disease [5].
Over the past few centuries, significant progress has been made in treatment of LC. The history of LC treatment began in 1837 with Trousseau’s introduction of tracheostomy to manage airway obstruction secondary to LC. The first long-term control of LC was through a laryngofissure performed by Sands in 1863 [6]. Ten years later, Billroth performed the first total laryngectomy [7]. Surgery was the sole option for treating LC until advancements in the 19th century, such as the introduction of endoscopic lasers by Strong and Jako [8], along with the adoption of radiotherapy shortly after the invention of X-rays, which expanded the treatment options available for managing early LC [9]. However, most patients with advanced LC were still managed with total laryngectomy. In 1991, a study published by a team of Veterans Affairs (VA) surgeons showed no difference in survival outcomes between patients receiving induction chemotherapy (IC) followed by radiotherapy and those receiving total laryngectomy followed by radiotherapy [10]. This development has paved the way for a non-surgical approach to treat locally advanced LC, allowing preservation of the larynx and achieving substantial long-term survival rates. Presently, in the UK, early LC is managed with radiotherapy or transoral laser microsurgery, whereas advanced LC is managed with non-surgical larynx preservation treatments, with concurrent chemoradiotherapy as the standard of care. Total laryngectomy may be appropriate, especially when tumour infiltration extends beyond the cartilage into the soft tissues of the neck [11].
The management of advanced LC presents considerable challenges. Total laryngectomy greatly affects patients’ quality of life and psychosocial factors. Some patients undergoing organ preservation therapies may experience chemotherapy-related toxicity, preventing the completion of treatment, and approximately one-third of patients ultimately experience local recurrence or distant metastasis [12]. In addition, despite the aforementioned recent advancements in LC management, mortality rates for head and neck cancer have increased by approximately 15% in the UK over the past decade [13]. This study aimed to evaluate the survival outcomes of patients with LC in our population, considering both the disease stage and treatment modality applied.
Methods
All adult patients aged over 16 years who underwent microlaryngoscopy or laser cordotomy between 2015 and 2019 were identified from the NHS Tayside ENT department local theatre list record. This was then narrowed down to the list of patients who were diagnosed with primary laryngeal squamous cell carcinoma. The date of diagnosis was decided as the date of the multidisciplinary team (MDT) meeting, which led to the diagnosis of LC. In total, 119 patients were included in the study. Anonymized patient demographics, MDT outcomes, treatment plans, follow-up appointment data, and causes of death were collected from the Clinical Portal (NHS Tayside online patient database). Number stage for statistical analysis was based on TNM staging reported in the MDT meeting outcome. OS was measured from the date of diagnosis to the date of death or the date of the last follow-up for surviving patients. DSS was measured from the date of diagnosis to the date of death related to LC, or the date of the last follow-up for surviving patients. Number stages 1 and 2 are considered as early LC, whereas number stages 3 and 4 are considered as advanced LC.
Statistical Analysis
Data were analysed using GraphPad Prism, version 10.2.2 (341). Categorical variables were presented as frequencies and percentages. Continuous variables were presented as mean and standard deviation.
Survival analysis was performed using Kaplan-Meier curve to compare the treatment modalities in different stages of LC, and log-rank test was used to determine if there was a significant difference in survival curves between patients in different groups. Statistical significance was set at p < 0.05.
Cox proportional hazard regression was used to perform univariate and multivariate analyses to determine the factors associated with OS and DSS in LC. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Variables with a significance level of p < 0.05 in the univariable model were included in the multivariable model, where a p value of <0.05 was considered statistically significant.
Results
A total of 119 patients diagnosed with LC between 2015 and 2019 were included in this study. The mean age of patients was 68.96 (standard deviation 10.87). Patient characteristics are shown in Table 1. In the univariate analysis (shown in Table 2), number stage, tumour stage, nodal stage, and disease recurrence/distant metastasis were associated with DSS and OS.
Clinical characteristics of patients
Clinical characteristic . | Frequency, n (%) . |
---|---|
Number stage | |
1 | 30 (25.2) |
2 | 18 (15.1) |
3 | 38 (31.9) |
4 | 33 (27.1) |
Nodal stage | |
0 | 86 (72.3) |
1 | 7 (5.9) |
2 | 22 (18.5) |
3 | 4 (3.4) |
Tumour stage | |
1 | 31 (26.1) |
2 | 20 (16.8) |
3 | 45 (37.8) |
4 | 23 (19.3) |
Treatment | |
Laser | 26 (21.8) |
Chemoradiotherapy/radiotherapy alone | 69 (58.0) |
Laryngectomy | 24 (20.2) |
Adjuvant therapy | |
No | 111 (93.3) |
Yes | 8 (6.7) |
Clinical characteristic . | Frequency, n (%) . |
---|---|
Number stage | |
1 | 30 (25.2) |
2 | 18 (15.1) |
3 | 38 (31.9) |
4 | 33 (27.1) |
Nodal stage | |
0 | 86 (72.3) |
1 | 7 (5.9) |
2 | 22 (18.5) |
3 | 4 (3.4) |
Tumour stage | |
1 | 31 (26.1) |
2 | 20 (16.8) |
3 | 45 (37.8) |
4 | 23 (19.3) |
Treatment | |
Laser | 26 (21.8) |
Chemoradiotherapy/radiotherapy alone | 69 (58.0) |
Laryngectomy | 24 (20.2) |
Adjuvant therapy | |
No | 111 (93.3) |
Yes | 8 (6.7) |
Univariable disease-specific and overall survival results for patient characteristics
Variables . | DSS . | OS . | ||
---|---|---|---|---|
HR (95% CI) . | p value . | HR (95% CI) . | p value . | |
Age | 0.853 | 0.952 | ||
≤70 (n = 64) | 1 | 1 | ||
>70 (n = 55) | 1.07 (0.54–2.1) | 1.02 (0.54–1.90) | ||
Number stage | <0.001 | <0.001 | ||
1/2 (n = 48) | 1 | 1 | ||
3/4 (n = 71) | 5.55 (2.345–14.30) | 5.27 (2.38–11.97) | ||
Nodal stage | <0.001 | <0.001 | ||
0/1 (n = 93) | 1 | 1 | ||
2/3 (n = 26) | 4.66 (2.35–9.12) | 4.12 (2.15–7.72) | ||
Tumour stage | 0.002 | 0.002 | ||
1/2 (n = 51) | 1 | 1 | ||
3/4 (n = 68) | 3.24 (1.54–7.64) | 3.39 (1.65–7.41) | ||
Treatment | 0.846 | 0.848 | ||
Chemoradiotherapy (n = 69) | 1 | 1 | ||
Surgery (n = 50) | 0.92 (0.42–1.96) | 0.93 (0.45–1.86) | ||
Adjuvant | 0.839 | 0.662 | ||
No (n = 111) | 1 | 1 | ||
Yes (n = 8) | 0.89 (0.21–2.48) | 0.7693 (0.18–2.13) | ||
Local recurrence/distant metastasis | 0.024 | 0.047 | ||
No (n = 79) | 1 | 1 | ||
Yes (n = 40) | 2.16 (1.09–4.20) | 1.71 (0.89–3.20) |
Variables . | DSS . | OS . | ||
---|---|---|---|---|
HR (95% CI) . | p value . | HR (95% CI) . | p value . | |
Age | 0.853 | 0.952 | ||
≤70 (n = 64) | 1 | 1 | ||
>70 (n = 55) | 1.07 (0.54–2.1) | 1.02 (0.54–1.90) | ||
Number stage | <0.001 | <0.001 | ||
1/2 (n = 48) | 1 | 1 | ||
3/4 (n = 71) | 5.55 (2.345–14.30) | 5.27 (2.38–11.97) | ||
Nodal stage | <0.001 | <0.001 | ||
0/1 (n = 93) | 1 | 1 | ||
2/3 (n = 26) | 4.66 (2.35–9.12) | 4.12 (2.15–7.72) | ||
Tumour stage | 0.002 | 0.002 | ||
1/2 (n = 51) | 1 | 1 | ||
3/4 (n = 68) | 3.24 (1.54–7.64) | 3.39 (1.65–7.41) | ||
Treatment | 0.846 | 0.848 | ||
Chemoradiotherapy (n = 69) | 1 | 1 | ||
Surgery (n = 50) | 0.92 (0.42–1.96) | 0.93 (0.45–1.86) | ||
Adjuvant | 0.839 | 0.662 | ||
No (n = 111) | 1 | 1 | ||
Yes (n = 8) | 0.89 (0.21–2.48) | 0.7693 (0.18–2.13) | ||
Local recurrence/distant metastasis | 0.024 | 0.047 | ||
No (n = 79) | 1 | 1 | ||
Yes (n = 40) | 2.16 (1.09–4.20) | 1.71 (0.89–3.20) |
DSS, disease-specific survival.
In multivariable analysis (shown in Table 3), all number stage, tumour stage, nodal stage, and disease recurrence/distant metastasis remained significantly associated with DSS and OS. Advanced number stage (3 and 4), advanced nodal stage (2 and 3), and advanced tumour stage (3 and 4) were associated with poor survival outcomes. Patients with advanced number stage (3 and 4) had more than 5 times the risk of LC death compared to patients with early clinical stages (1 and 2) (DSS: HR 6.10, 95% CI: 1.52–14.61, p = 0.016; OS: HR 5.52, 95% CI: 1.64–13.34, p = 0.017). Nodal stages 2 and 3 were associated with more than two times the risk of LC death than nodal stages 0 and 1 (DSS: HR 2.61, 95% CI: 1.3–5.69, p = 0.009; OS: HR 2.40, 95% CI: 1.2–4.74, p = 0.015). Tumour stages 3 and 4 were associated with more than two times the risk of LC death than tumour stages 1 and 2 (DSS: HR 2.54, 95% CI: 1.72–5.12, p = 0.039; OS: HR 2.12, 95% CI: 1.89–4.97, p = 0.043). Disease recurrence was also associated with higher risk of LC death (DSS: HR 2.46, 95% CI: 1.2–4.74, p = 0.009; OS: HR 1.93, 95% CI: 0.99–3.58, p = 0.048).
Multivariable disease-specific and overall survival results for patient characteristics
Variables . | DSS . | OS . | ||
---|---|---|---|---|
HR (95% CI) . | p value . | HR (95% CI) . | p value . | |
Number stage | 0.016 | 0.017 | ||
1/2 (n = 48) | 1 | 1 | ||
3/4 (n = 71) | 6.10 (1.52–14.61) | 5.52 (1.64–13.34) | ||
Nodal stage | 0.009 | 0.015 | ||
0/1 (n = 93) | 1 | 1 | ||
2/3 (n = 26) | 2.61 (1.3–5.69) | 2.40 (1.2–4.74) | ||
Tumour stage | 0.039 | 0.043 | ||
1/2 (n = 51) | 1 | 1 | ||
3/4 (n = 68) | 2.54 (1.72–5.12) | 2.12 (1.89–4.97) | ||
Local recurrence/distant metastasis | 0.009 | 0.048 | ||
No (n = 79) | 1 | 1 | ||
Yes (n = 40) | 2.46 (1.2–4.74) | 1.93 (0.99–3.58) |
Variables . | DSS . | OS . | ||
---|---|---|---|---|
HR (95% CI) . | p value . | HR (95% CI) . | p value . | |
Number stage | 0.016 | 0.017 | ||
1/2 (n = 48) | 1 | 1 | ||
3/4 (n = 71) | 6.10 (1.52–14.61) | 5.52 (1.64–13.34) | ||
Nodal stage | 0.009 | 0.015 | ||
0/1 (n = 93) | 1 | 1 | ||
2/3 (n = 26) | 2.61 (1.3–5.69) | 2.40 (1.2–4.74) | ||
Tumour stage | 0.039 | 0.043 | ||
1/2 (n = 51) | 1 | 1 | ||
3/4 (n = 68) | 2.54 (1.72–5.12) | 2.12 (1.89–4.97) | ||
Local recurrence/distant metastasis | 0.009 | 0.048 | ||
No (n = 79) | 1 | 1 | ||
Yes (n = 40) | 2.46 (1.2–4.74) | 1.93 (0.99–3.58) |
DSS, disease-specific survival.
Kaplan-Meier curves for DSS and OS of patients at different stages are presented in Figure 1a and b, respectively. The DSS and OS of patients have gradually decreased from number stage 1 to number stage 4 (p < 0.001). At 10 years follow-up, the OS of patients with stage 1 LC (67.7%) was almost double that of patients with stage 4 LC (35.8%).In early stages of LC, no significant difference in DSS (p = 0.207) and OS (p = 0.548) was observed between patients receiving laser surgery and radiotherapy (shown in Fig. 2a, b).
Survival of stage 1 and 2 LC according to treatment, laser (n = 26) versus radiotherapy (n = 22). a DSS. b OS.
Survival of stage 1 and 2 LC according to treatment, laser (n = 26) versus radiotherapy (n = 22). a DSS. b OS.
In stage 3 LC, although patients receiving concurrent chemoradiotherapy seemed to have higher survival rates (DSS and OS) than those who underwent laryngectomy and radical radiotherapy alone, independent analyses of the three treatments did not show statistically significant differences (p > 0.05) (shown in Fig. 3a, b). This was likely due to the limited number of patients in the laryngectomy (n = 5, 13.2%) and radiotherapy (n = 2, 5.3%) groups.
Survival of stage 3 LC according to treatment, chemoradiotherapy (n = 31) versus radiotherapy alone (n = 2) versus laryngectomy (n = 5). a DSS. b OS.
Survival of stage 3 LC according to treatment, chemoradiotherapy (n = 31) versus radiotherapy alone (n = 2) versus laryngectomy (n = 5). a DSS. b OS.
Patients who underwent laryngectomy in stage 4 LC were found to have better survival outcomes than those who received concurrent chemoradiotherapy (DSS, p = 0.035; OS, p = 0.046) (shown in Fig. 4a, b). The OS at 5 years follow-up was significantly higher in the laryngectomy group (56.3%) than that in the chemoradiotherapy group (36.3%).
Survival of stage 4 LC according to treatment, chemoradiotherapy (n = 14) versus laryngectomy (n = 19). a DSS. b OS.
Survival of stage 4 LC according to treatment, chemoradiotherapy (n = 14) versus laryngectomy (n = 19). a DSS. b OS.
Among the 24 patients with advanced LC who underwent primary laryngectomy, eight (33.3%) received adjuvant radiotherapy. The 5-year OS of patients receiving adjuvant radiotherapy (75.1%) was more than 3 times higher than that of their counterparts who underwent laryngectomy alone (23.1%) (p = 0.032) (shown in Fig. 5b).
Survival of patients receiving laryngectomy alone (n = 16) versus. laryngectomy with adjuvant therapy (n = 8). a DSS. b OS.
Survival of patients receiving laryngectomy alone (n = 16) versus. laryngectomy with adjuvant therapy (n = 8). a DSS. b OS.
Discussion
Our study highlights that factors such as number stage, tumour stage, nodal involvement, and local recurrence/distant metastasis after diagnosis play significant roles in determining both DSS and OS in patients with LC. The most prominent risk factor in our analysis was advanced number stage, which increased risk of disease-related death by 6-fold. Several previous studies have reported similar findings, where T3 and T4 LC, positive nodal status, and development of recurrence were associated with higher mortality [14, 15]. This finding suggests the importance of comprehensive staging and vigilant surveillance in optimizing outcomes for patients with LC.
In our survival analysis of early LC, we did not find a significant disparity in DSS and OS between patients who underwent laser surgery and those who underwent radiotherapy. This finding is consistent with other studies that reported no difference in DSS and OS between radiotherapy and laser surgery treatment groups when managing T1 and T2 glottic cancers [16‒18]. In addition, another meta-analysis by Campo et al. [19] showed no difference in local control for patients treated with radiotherapy and laser surgery. The lack of superior survival outcomes between laser surgery and radiotherapy implies a potential redirection of attention towards functional outcomes. A systematic review conducted by Boyle and Jones [20] indicated that radiotherapy yields superior voice outcomes, whereas laser surgery is more advantageous in terms of swallowing outcomes. This is further supported by a meta-analysis by Yang et al. [21], which demonstrated the association between radiotherapy and better voice recovery. Another crucial aspect to consider is patient preference, in order to foster a culture that encourages shared decision-making. A study conducted by Zahoor et al. [22] revealed that most patients expressed a preference for laser surgery over radiotherapy.
Partial laryngectomy is another treatment regime practiced outside the UK for early LC. Partial laryngectomy provides the benefits of maintaining some degree of organ function, leading to better quality of life [23], and leaving total laryngectomy as a salvage option if organ-preserving surgery fails [24]. Moreover, a few recent studies have shown evidence that T3 LC had no statistical difference in survival rate when treated with partial laryngectomy versus total laryngectomy [25, 26].
In terms of managing advanced LC, there has been a trend towards non-surgical approaches in recent years, partly influenced by the VA study in 1991, which demonstrated comparable survival outcomes and an excellent laryngeal preservation rate in the non-surgical treatment group who underwent induction fluorouracil (F) and cisplatin (P) followed by radiotherapy. Following this, several studies have been conducted, hoping to increase the efficacy of IC by adding docetaxel (T) to fluorouracil (F) and cisplatin (P). These include the TAX323 [27] and TAX324 [28] studies, which showed significantly improved survival in patients who received TPF compared to patients who received PF alone in their IC. While the GORETEC 2000-01 [29] did not show any survival benefit of TPF induction regimen, it has successfully achieved a higher larynx preservation rate of 74% at 5 years, compared to 58% of PF arm and the historical data of 64% in the VA larynx trial. RTOG 91-11 [30] has subsequently compared induction cisplatin plus fluorouracil followed by radiation, concurrent chemoradiation therapy with cisplatin, and radiation alone in treating locally advanced LC. Overall survival (OS) rates were consistent across all three groups; however, concurrent chemoradiation achieved the highest larynx preservation rate, with 88% preserved at 2 years, compared to 75% for IC and 70% for radiation alone. This significant benefit of concurrent chemoradiotherapy for larynx preservation continues at the 10-year follow-up, showing a 42% reduction in the risk of laryngectomy compared to IC followed by radiation. Since then, concurrent chemoradiotherapy became the new standard for laryngeal preservation therapy, yet the exploration of sequential therapy continues.
Several phase III trials have been conducted to evaluate the efficacy of adding IC to chemoradiotherapy, compared to chemoradiotherapy alone in head and neck squamous cell carcinoma (HNSCC). DeCIDE [31] and PARADIGM [32] trials were the earliest studies, and both failed to demonstrate survival benefit of sequential therapy. However, these interim results could have been biased as both trials were closed early due to slow accrual, leading to a much smaller sample sized than initially proposed. The DeCIDE trial demonstrated a statistically significant reduction in the risk of distant recurrence without locoregional recurrence for patients with N2C-N3 disease in the sequential approach arm. However, since platinum-based chemotherapy was only administered during IC and not during concurrent chemoradiotherapy, it is challenging to determine whether the observed benefits stemmed from the use of platinum-based chemotherapy or from the sequential approach itself. The only phase III trial, which demonstrated survival benefit of induction TPF followed by chemoradiotherapy, was done by Ghi et al. [33], showing not only improved OS and progression-free survival but also higher rate of complete response in IC arm. However, the risk of grade 3–4 neutropenia was also significantly higher. Luo et al. [34] has conducted a more recent phase II trial in 2022, looking specifically into hypopharyngeal cancer, which has the poorest prognosis in HNSCC. The intention behind this was to minimize the impact of other head and neck cancers with better prognoses on the results. Unfortunately, similar to the DeCIDE and PARADIGM trial, this study has failed to demonstrate survival benefit of induction TPF followed by chemoradiotherapy. In addition, the risk of grade 3–4 neutropenia was again higher in the IC arm (41.5%) than in the chemoradiotherapy only arm (6.7%). One thing to note is that HPV status of patients was unknown in all 4 trials, which may have influenced the outcome as HPV-related HNSCC has overall better prognosis as those patients are generally younger and respond better to treatments [35].
Cetuximab, an epidermal growth factor receptor inhibitor, is a frequently used targeted therapy in managing advanced LC, particularly for patients who are unsuitable for platinum-based chemotherapy [36]. However, it was once used as an alternative to CCRT since the landmark study by Bonner et al. [37] demonstrated that the combination of cetuximab with radiotherapy significantly improved OS and locoregional control for LC patients from 29.3 months to 49.0 months and 14.9 months to 24.4 months, respectively, compared to radiotherapy alone. Nevertheless, this took a turn after results of more studies comparing cetuximab with cisplatin in combination with radiotherapy became available. The meta-analysis by Li et al. [38], which included seven high-quality randomized controlled trials, found that patients treated with cetuximab and radiotherapy had lower locoregional control, OS, and progression-free survival compared to those received combination of cisplatin and radiotherapy. Researchers have also been exploring the potential role of cetuximab in treating HNSCC, testing its effectiveness in concurrent use with CCRT, as an induction therapy, and in the adjuvant setting. However, these efforts have not yielded successful outcomes thus far [39].
Although there has been advancement in non-surgical management of LC over the years, concerns have been voiced regarding non-surgical approaches to treating advanced LC, prompted by observed declines in survival rates and studies reporting improved survival outcomes among patients undergoing surgical interventions for advanced LC [40]. In the analysis of our patients with stage 4 LC, we demonstrated significantly superior outcomes in terms of DSS and OS in patients who were treated with laryngectomy compared to those who underwent chemoradiotherapy. This might be due to a higher rate of local recurrence or distant metastasis in the chemoradiotherapy group (45.5%) than in the laryngectomy group (25.0%). Our finding aligns with those from studies worldwide, which have shown enhanced survival rates among individuals with advanced LC primarily treated with laryngectomy, particularly in cases of T4 LC [41‒44]. In terms of patients with stage 3 LC, our study did not demonstrate a significant difference in survival outcomes between surgical and non-surgical treatments, likely due to the limited number of patients in the surgical arm.
Apart from a shift towards non-surgical management of advanced LC, there are other factors that might explain the increasing mortality rate in LC. Studies have demonstrated that despite the increasing number of reported deaths from LC, the age-standardized mortality rate has dropped by an average of approximately 1.5% per year, suggesting that the increasing number of deaths from LC might simply be due to increasing age at the time of diagnosis [45, 46]. In addition, Li et al. [47] reported an increasing proportion of stage 4 LC since 2004, which might in turn contribute to the increasing mortality rate in LC.
Our study also revealed that primary laryngectomy followed by adjuvant radiotherapy increased the survival rate of patients with LC. Our data showed that 5-year OS was 3 times higher and 5-year DSS was double for patients who received adjuvant radiotherapy post-laryngectomy compared to patients who underwent laryngectomy alone. This is in line with other recent studies that demonstrated the survival benefits of adjuvant radiotherapy [48‒50]. Another area of discussion regarding the survival rate of patients with LC is the comparison between primary total laryngectomy (PTL) and salvage total laryngectomy (STL). Although various comorbidity factors can have an effect, multiple studies have shown that patients who underwent primary total laryngectomy had better OS and DSS than those who initially received radiotherapy or chemoradiotherapy followed by STL [51‒53]. A recent study by Miśkiewicz-Orczyk et al. [54] compared the survival rates of patients who underwent STL after initial therapy with either radiotherapy or partial laryngectomy. This study revealed that regardless of the treatment the patient had prior to STL, their survival rate was lower than that of patients who underwent PTL.
The management of recurrent LC differs from the management of previously untreated LC due to factors like previous treatments, altered anatomy, and potentially more aggressive disease behaviours. Recurrent LC can be managed with several treatment options, including repeated radiotherapy, with or without chemotherapy and salvage surgery. In the recent years, immune checkpoint inhibitors like nivolumab and pembrolizumab, which target the PD-1 pathway, have also become viable options for treating recurrent and metastatic LC in patients with positive PD-1. These immunotherapies offer an additional option, particularly for patients who are not candidates for surgery or for whom other treatments have proven ineffective. Two phase III trials, Keynote 040 [55], and CheckMate 141 [56], demonstrated increase in survival rate of patients receiving immunotherapy, compared to standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). With nivolumab, the median OS was 7.5 months versus 5.1 months with standard monotherapy. Similarly, pembrolizumab’s median OS was 8.4 months whilst it was only 6.9 months with standard care. These findings became the basis to study the role of immunotherapy in adjuvant and neoadjuvant settings. A study by Wang et al. [57] demonstrated that pembrolizumab combined with chemotherapy as neoadjuvant therapy for resectable, locally advanced HNSCC produced strong tumour responses, enabling R0 resection with partial rather than total laryngectomy and achieving a high rate of laryngeal function preservation (90.9%). Moreover, this regimen did not cause any delay in surgery or compromise surgical safety, highlighting pembrolizumab’s potential in organ preservation strategies for LC.
In conclusion, the treatment of LC is continually advancing as ongoing research and emerging therapies provide new options. Innovations in surgery, radiation techniques, immunotherapy, and targeted therapies are enhancing patient outcomes and expanding treatment possibilities. This study suggests that surgical treatment with adjuvant radiotherapy improves the OS and DSS of patients with advanced LC and should be considered as first-line treatment for patients who are fit for surgery. More prospective studies are needed to determine the optimal treatment approach for advanced LC with consideration of organ function, patient quality of life, and treatment-related morbidity and mortality.
Statement of Ethics
All data used in this study were anonymized and de-identified. Therefore, the need for approval from the research Ethics Committee was not required as per local guideline. This study adheres to the principles lined in the Declaration of Helsinki. Due to the retrospective nature of this study and all data collected being anonymized, patient consent is not required as per local guidelines.
Conflict of Interest Statement
The authors have no conflict of interest to declare.
Funding Sources
Open access was provided by University of Dundee. The funder had no role in the design, data collection, data analysis, and reporting of this study.
Author Contributions
C.P.S., Y.S., and V.G. contributed equally to data collection and writing the manuscript. C.P.S. performed statistical analysis. J.J.M. contributed to writing and reviewing the manuscript. R.C. contributed to reviewing the manuscript. C.P.S. and Y.S. are both co-first authors.
Data Availability Statement
The data that support the findings of this study are not publicly available because of privacy reasons, but de-identified data will be available from the corresponding author upon reasonable request.