Introduction

Laryngeal cancer (LC) is a rare type of cancer that can involve different sub-anatomical regions of the larynx. It has variable presentation patterns and therapeutic approaches, besides differences in the epidemiological picture. For instance, the prevalence rate of primary glottic LCs is three times higher than supraglottic LC, while subglottic presentation is extremely rare (2% of all LCs) [1]. Furthermore, glottic tumors typically present at early stages as hoarseness; while supraglottic tumors are more commonly manifested later with a profound pain and difficult swallowing [2]. Distant metastasis can be present in approximately 10% of the cases and lymph nodes are involved in 25%-50% of the patients; whereas 66% of the patients would have localized lesions at diagnosis [1].

Recent global estimates show a significant decline of disease burden over the past two decades. In 2015, disability-adjusted life years (DALYs) were estimated to be 37.6 compared to 57.7 DALYs per 100,000 population in 1990 [3]. Such a pattern coincides with reduced smoking rates during the same period. Similarly, LCattributable mortality dropped from 1.70% to 1.53% between 1990 and 2015. Very recently, in 2019, according to data from the Surveillance, Epidemiology, and End Results (SEER) program and the American Cancer Society, the numbers of new cases and deaths due to LC in the United State were estimated to be 12,410 and 3,760, respectively [4,5]. Additionally, comparative analyses revealed higher incidence among males than females and among blacks than whites [1]. In Saudi Arabia, based on the Saudi Cancer Registry in 2016 (n=69), [6] the crude incidence rate of LC was 0.7 in males and 0.1 in females per 100,000 accounting for 1.20% of all cancers in both sexes.

As such, the variability in LC clinical characteristics coupled with its low incidence created multiple challenges related to treatment individualization, and yielded large gaps in the prospected outcomes. For instance, the United Kingdom National Multidisciplinary guidelines recommend radiotherapy coupled with transoral laser microsurgery (TLM) for supraglottic and glottic LC presenting at early stages (i.e., stage I or II), while a concurrent chemoradiotherapy is recommended as alternative for surgery. On the other hand, open surgery is indicated in selected patients [2]. Other recent recommendations indicated a single approach, whether radiotherapy or surgery in the early stages [7,8]. However, appropriate decision of treatment is usually based on meticulous discussions within multidisciplinary teams. Such uncertainty has been associated with conflicting outcomes regarding the efficacy and safety of surgical versus non-surgical modalities as well as survival outcomes following treatments.

Therefore, there is a requirement to assess the survival profiles of LC in different regions and settings. The variability of treatment opportunities and prognostic outcomes further supports this requirement. Given the scarcity of data from Saudi Arabia, providing insights into patients’ survival with respect to the heterogeneous clinical characteristics, low incidence, variable treatment recommendations, and the increasing trend of smoking would not only achieve significant benefits to healthcare planning, but will also help conduct future reliable research studies, such as meta-analyses. In this context, the present study aimed at analyzing the survival and disease-free survival in a tertiary care center located in the Western region of Saudi Arabia, and investigating the stage of the disease at diagnosis, the anatomic location, and the received treatment as factors and predictors of survival, besides other factors.

Methods

Design and Setting

This retrospective study was carried out at the Otolaryngology-Head and Neck Surgery Department of King Abdul-Aziz University Hospital (KAUH), Jeddah, Saudi Arabia.

Population

We included all patients aged 12 years and above, who were followed up at the participating center for malignant laryngeal cancer, which was diagnosed before 31 December 2017. Patients who had benign laryngeal tumor and those who were diagnosed after 31 December 2017 were excluded.

Data collection

Data collection was carried out between January and April 2019. It comprised the following: 1) Baseline demographic and clinical data including age at diagnosis, gender, nationality, smoking status, history of gastroesophageal reflux disease [GERD], alcohol, and family history of laryngeal cancer; 2) pathological characteristics including date of diagnosis, tumor site (glottic, subglottic, supraglottic, transglottic), histological type (carcinoma in situ, squamous cell carcinoma, etc.), grade (low versus high); 3) Management data including surgery (endoscopic resection, partial or total laryngectomy +/- lymph node resection), chemotherapy, radiation therapy, and combined therapy, with date of each procedure, where applicable, in addition to tracheotomy; 4) Outcomes including the occurrence and location of metastasis, relapse (recurrence or progression), and or death, and the date of each event, where available, and the date of last follow up were documented with the status at last follow up (alive without disease, alive with disease or deceased). Data was collected and processed with strict anonymity and confidentiality.

Outcome definition

Survival was defined as the time from diagnosis to last follow up or death; while disease-free survival was calculated as the time from diagnosis to relapse or death, whichever applicable, or to last follow up in case of no relapse or death.

Statistical methods

Statistical analysis was performed with the Statistical Package for Social Sciences version 21.0 for Windows (SPSS Inc., Chicago, IL, USA). Categorical variables are presented as frequency and percentage, while discrete variables are presented as mean ± standard deviation (SD) for normally distributed variables and median, 75^th centile (P75) for non-normally distributed ones. Kaplan-Meier survival analysis was carried out to explore survival (event=death) and disease-free survival (event=relapse or death) and their associated factors; results were presented as mean (95% confidence interval [95% CI]) survival with Log-rank level. Cox regression analysis was carried out using a multivariate model to explore independent factors of survival and disease-free survival; results were presented as odds ratio (OR) with 95% CI. A p value of ≤0.05 was considered to reject the null hypothesis.

Ethical consideration

The study was approved by the institutional review board of King Abdul-Aziz University.

Results

Baseline demographic and clinical characteristics Fifty patients were included. Mean (SD) age of the total population was 53.56 (16.22) years. Majority of the patients were males (43, 86.0%) and non-Saudi (31, 62.0%). Smoking was reported in 11 (22.0%) and GERD in 22 (44.0%). The most common tumor site was supraglottic (13, 26.0%) or transglottic (13, 26.0%), followed by glottic (12, 24.0%). Squamous cell carcinoma was the most frequent histological type diagnosed in 38 (76.0%) patients, and tumor grade was high in 12 (20.0%) of the cases. Notably, pathological data was missing in 5-12 (10.0%24.0%) cases (Table 1).

Table 1: Baseline demographic and clinical characteristics.

Management and outcomes

Majority of the patients underwent surgery (36, 72.0%), and the most common procedures included endoscopic resection (18, 36.0%), total laryngectomy (12, 24.0%) and regional lymph node resection (5, 10.0%). Further, 25 (50.0%) and 29 (58.0%) patients benefited from chemotherapy and radiotherapy, respectively. Overall, 15 (30.0%) patients benefitted from surgery combined with chemotherapy and radiotherapy; 7 (14.0%) from surgery plus radiotherapy, 6 (12.0%) from chemotherapy plus radiotherapy; while 14 (28.0%) benefitted from surgery only and five (10.0%) had no therapy. Mean and median time from diagnosis to treatment was 6.31 months and 1.25 months, respectively (Table 2).

Outcomes showed the rates of metastasis (12 patients, 24.0%) and relapse (16, 32.0%), including recurrence (5, 10.0%) and progression (12, 24.0%). At last follow up, 28 (56.0%) were alive without disease, 10 (20.0%) were alive with disease, and 12 (24.0%) were deceased; and death occurred after a median (P75) time = 18.75 (76.94) months. Further, 5-year survival rate was 24.0% (95%CI=13.1; 38.2%) (Table 2).

Table 2: Management and outcomes.

Survival and disease-free survival and their associated factors

Kaplan-Meier survival analysis showed mean (95% CI) survival time = 11.38 (4.95 – 17.80) years, and median (95% CI) survival time = 9.98 (6.57 – 13.39) years (Figure 1.a); while mean (95% CI) disease-free survival time was 8.64 (3.43 – 13.85) years and median (95% CI) disease-free survival time = 2.10 (0.00 – 6.34) years (Figure 1.b).

Patients who benefited from surgery achieved longer survival (mean survival=12.55 versus 4.26 years; p=0.043) and diseasefree survival (10.0 versus 2.36 years; p=0.044) compared to those who had no surgery, respectively. Further, survival was significantly reduced in case of relapse (mean=5.17 versus 13.73 years; p=0.049) or metastasis (5.83 versus 18.52 years; p=0.045); while disease-free survival was reduced among known smokers (mean=5.14 versus 7.25 years; p=0.050) compared to non-smokers. Of note, although not statistically significant, patients with subglottic (mean=1.52 years) and glottis and subglottic (3.90 years) tumor localizations survival achieved the least survival, compared to supraglottic (8.40 years) and transglottic (6.94 years) ones, p=0.733 (Table 3, Figure 2).

Kaplan-Meier survival analysis exploring factors of survival (event=death) and disease-free survival (event= relapse or death). CI: confidence interval; GERD: Gastroesophageal reflux disease; SCC: squamous cell carcinoma; CT: chemotherapy; RT: radiotherapy; * statistically significant result (p<0.05).

Table 3: Factors of survival and disease-free survival in laryngeal cancer.

Predictors of survival and disease-free survival

The multivariate Cox regression models for survival and disease-free survival, including the respective significant factors in Kaplan-Meier analysis, showed no statistical significance (Table 4).

Table 4: Predictors of survival and disease-free survival in laryngeal cancer.

Figure 1: Kaplan Meier survival (a) and disease-free survival (b) in laryngeal cancer.

Figure 2: Most significant factors of survival (panels a-d) and disease-free survival (panels e, f).