Trends and Outcomes of Non-Small-Cell Lung Cancer in Omani Patients Experience at a university hospital

Objectives: The incidence of lung cancer in Oman has shown a gradual but definitive increase since 2002. This study aimed to evaluate the demographic and epidemiological characteristics and survival outcomes of patients with non-small-cell lung cancer (NSCLC) at a university hospital in Oman. Methods: This study was conducted from January to June 2016. A retrospective analysis was performed of consecutive patients diagnosed with NSCLC presenting to the Sultan Qaboos University Hospital (SQUH) in Muscat, Oman, between March 2000 and December 2015. Clinical features at presentation and prognostic and predictive markers were reviewed. Kaplan-Meir estimates were used to determine relapse-free survival, progression-free survival (PFS) and overall survival (OS). Results: A total of 104 patients presented to SQUH during the study period. The median age at diagnosis was 64 years. Overall, 62 patients (59.6%) had adenocarcinomas. Only 12 patients (11.5%) presented in the early stages (I or II) of the disease and the majority of patients had an Eastern Cooperative Oncology Group performance status of 1 (27.9%) or 2 (26.0%). The prevalence of epidermal growth factor receptor mutations was 27.9%. The median PFS for patients with advanced disease (stages III or IV) was five months and the median OS for all patients was seven months. After five years, 50.0%, 60.0%, 10.0% and 8.0% of patients with disease stages I, II, III and IV, respectively, were alive. Conclusion: Patients with NSCLC in Oman were found to present at an advanced stage. However, patient outcomes were similar to those reported in the USA.


L
ung cancer has recently been identified as the most frequently occurring cancer and leading cause of cancer-related deaths worldwide, with an age-standardised incidence and mortality rate among men alone of 33.8% and 29.2%, respectively. 1Globally, it remains the most common form of cancer in men, with high rates in Europe, the USA and Eastern Asia and lower rates in Africa. 1 Since 2002, the incidence of lung cancer in Oman has been steadily rising over time; according to the Ministry of Health, lung cancer was ranked as the sixth most common cancer among men in 2013 (6.2%) and was the second most frequent cause of hospitalbased cancer-related deaths (8.7%) following stomach cancer. 2However, there is as yet no information regarding prognostic markers, presenting features and treatment outcomes among Omani patients.
Lung cancer is associated with tobacco smoking and the risk of developing the disease increases with smoking duration and the number of cigarettes smoked; hence, lung cancer is considered to be a preventable disease. 3In the USA, the prevalence of heavy smoking (i.e.][6] In addition, the majority of smokers are male, with 13.4% of men smoking versus 0.5% of women. 6larmingly, waterpipe smoking has also become more popular in Oman recently, especially among younger individuals. 7,8he current study aimed to describe the demographic characteristics, clinicopathological features, management details and outcomes of patients with non-small-cell lung cancer (NSCLC) presenting at the Sultan Qaboos University Hospital (SQUH), a tertiary university hospital in Muscat, Oman.The results were subsequently compared with those of previous research from the USA regarding lung cancer-related outcomes. 9

Methods
This non-concurrent retrospective study was conducted from January to June 2016 and included consecutive patients diagnosed with NSCLC presenting to SQUH between March 2000 and December 2015.Clinical and demographic data were reviewed using the hospital's information system, including age, gender, race, weight loss, smoking habits, Eastern Cooperative Oncology Group (ECOG) performance status and the presence of any concurrent illnesses.Prognostic and predictive markers were also analysed, including histological subtype, tumour grade, disease stage, sites of metastasis, epidermal growth factor receptor (EGFR) mutation status, treatment offered, survival and the occurrence of side-effects.Tissue samples were sent abroad to a reference laboratory for EGFR and echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) genetic testing.Cancer stages were defined as per the International Staging Committee criteria of the International Association for the Study of Lung Cancer. 10The histology results of patients who were referred from other hospitals to SQUH after diagnosis were reviewed, although the majority of patients had been diagnosed at SQUH.All patients with incomplete electronic data and those who had received treatment and follow-up elsewhere (n = 7) or individuals diagnosed with small-cell lung cancer (n = 14) were excluded from the study.Data were analysed using the Statistical Package for the Social Sciences (SPSS), Version 20.0 (IBM Corp., Armonk, New York, USA).Relapse-free survival (RFS) was calculated as the period of time between the date of diagnosis until the date of documented relapse, while progression-free survival (PFS) was deemed to constitute the period of time between the date of diagnosis until the date of progression of the disease.Overall survival (OS) was measured as the period of time from the date of diagnosis to the date of death or until the last known date of follow-up as of June 2016.Kaplan-Meir estimates were used to determine RFS, PFS and OS and the log-rank test was used for the comparative analysis.The Cox regression model was used for the multivariate analysis and included all statistically significant variables indicated by the univariate analysis.A P value of ≤0.050 was considered statistically significant.
This study was approved by the Research & Ethics Committee of the College of Medicine & Health Sciences, Sultan Qaboos University (MREC #641).
-These findings may act as a reference regarding associated clinicopathological features for patients with NSCLC from Oman as well as other countries in the Gulf Cooperative Council region.
Application to Patient Care -Patient outcomes and survival rates are vital to help decide upon appropriate treatment regimens for patients with malignant disorders.
-The availability of these local data from Oman may serve as a benchmark regarding lung cancer survival rates and will help clinicians during the treatment decision-making process.

Results
A Patients who received first-line chemotherapy were treated with a median of four cycles (range: 1-6 cycles).Only seven patients received tyrosine-kinase inhibitors (TKIs) during the first line of chemotherapy, including erlotinib (n = 5), a combination of erlotinib and chemotherapy (n = 1) and gefitinib (n = 1).All of these patients experienced disease progression requiring second-line chemotherapy, except for one patient who died while receiving erlotinib.A total of 62 patients (59.6%) were treated with platinum doublets as first-line therapy.The first-line treatment regimens prescribed are shown in Table 2. Maintenance chemotherapy after induction therapy was offered to 11 patients who received a median of 14 maintenance cycles (range: 4-26 cycles) before progression.A median of three cycles of second-line chemotherapy was administered (range: 1-17 cycles).Docetaxel alone was administered to 10 patients in the second line, while five patients received pemetrexed or gemcitabine with platinum.The remaining patients were treated with other single agents or a combination of regimens.Of the 35 patients who received secondline chemotherapy, 19 (54.3%) also received thirdline chemotherapy.Docetaxel and erlotinib were the most commonly used third-line agents (21.1% each).Five patients (4.8%) were treated with five lines of chemotherapy.
In total, 83 patients (79.8%) died secondary to disease progression and eight (7.7%) died of nondisease-related causes.At the time of writing, five patients (4.8%) were alive and actively receiving treatment, three patients (2.9%) who had received adjuvant chemotherapy were in remission, one patient (1.0%) was alive on best supportive care and one patient (1.0%) was alive and diseased, but under active observation due to a bronchial carcinoid tumour.The status of the remaining three patients (2.9%) was unknown as they were lost to follow-up.According to gender, median PFS was 19.0 months in females versus 7.4 months in males and OS was 22.2 months in females versus 10.5 months in males.Median RFS among patients with early-stage disease (stage I or II) was 29 months (range: 1-74 months), while median PFS among patients with more advanced disease (stage III or IV) was five months (range: five days-97 months)     [Figure 1].The median OS for all patients was seven months (range: 7 days-123 months).At two and five years, OS was 96.0% and 7.0%, respectively.At two years, OS was 50.0%, 70.0%, 22.0% and 17.0% for patients with disease stages I, II, III and IV, respectively.After five years, 50.0%, 60.0%, 10.0% and 8.0% of patients with stages I, II, III and IV were still alive [Figure 2].On univariate analysis, females had a significantly higher median PFS rate (19.0 versus 7.4 months; P = 0.003) in comparison to males, although OS was not significantly different (19.0 versus 6.0 months; P = 0.055).Moreover, curative surgical resection, an early-stage diagnosis, never smoking, ECOG performance status, the absence of nodal involvement, the site of metastasis, chemotherapy approach, the number of cycles of chemotherapy administered, the presence of chemotherapy-associated side-effects and treatment response to first-line chemotherapy were also significantly associated with PFS (P <0.050 each).In addition, a younger age, curative surgical resection, an early-stage diagnosis, never smoking, ECOG performance status, weight loss, the absence of nodal involvement, the site of metastasis, chemotherapy approach, the number of chemotherapy cycles, receiving radiation therapy, treatment response to firstline chemotherapy and PFS were significant factors affecting increased OS (P <0.050 each) [Table 3].However, none of these factors were found to be statistically significant during the multivariate Cox regression analysis.

Discussion
In Oman, lung cancer is a major cause of cancerrelated deaths, warranting patient, physician and specialist awareness. 2While fewer patients are diagnosed with lung cancer in Oman as compared to neighbouring countries like the United Arab Emirates and Saudi Arabia, the age-standardised ratio for lung cancer is higher in Oman at 6.7 for males and 2.1 for females. 2 Nevertheless, the incidence of lung cancer in Oman is lower than in other nearby countries like Egypt, Kuwait and Jordan. 11,12The mean age of the patient population in the current study (64 years) was consistent with that reported in previously published research (59.2 years). 13Moreover, age was significantly associated with poorer survival in the current study; while age is reportedly not prognostic for survival, it is known to be a poor prognostic factor for toxicity to chemotherapy. 14 the present study, NSCLC was more frequent among men; the lower incidence among Omani women may perhaps reflect the cultural taboo of tobacco smoking in females.Women also showed superior median PFS and OS compared to men; this correlates favourably with Western findings reported by Wisnivesky et al. 15 A Norwegian study similarly reported that men with adenocarcinomas had a 24% higher risk of death than women. 16However, environmental exposure, genetic predisposition, hormonal factors and viral infections may all play a role in lung cancer among women and never smokers, both of whom have a higher prevalence of adenocarcinomas. 3,17Zang et al. found that the odds ratio for adenocarcinomas was higher among females due to their greater susceptibility to carcinogens, regardless of level of exposure to tobacco smoke. 18denocarcinoma subtypes are usually related to subpleural scars. 19While the incidence of SCC has decreased over the past few decades, that of adenocarcinomas has increased in both genders due to the introduction of filter vents that facilitate easier and deeper inhalation of tobacco-specific carcinogens. 3This was reflected in the current study in which a higher incidence of adenocarcinomas was observed in comparison to SCC.Additionally, according to the univariate analysis, never smokers in the present study had a significantly better PFS rate.Furthermore, the vast majority of smokers were male.Various carcinogens and cell signal pathways have been proposed to contribute to lung oncogenesis among never smokers. 4oss of body weight at presentation was associated with poorer survival in the present study, with almost half of the study sample losing >5% of their baseline weight; in addition, decreased ECOG performance status was associated with poor outcomes.Yang et al. also found that weight loss was associated with poorer survival. 20In a study of various chemotherapy regimens for patients with advanced NSCLC, Schiller et al. indicated that the absolute benefit of chemotherapy for one year and median OS varied inversely with poor ECOG performance status. 21ultiple concurrent illnesses were noted in the current study which is understandable considering the fact that most of the patients were quite elderly.However, the frequency of these variables was too low to predict survival.The severity or burden of comorbidity has been reported to have a clear relationship with poor survival in lung cancer; for example, the Charlson Comorbidity Index is associated with increasing toxicity to chemotherapy. 22,23Ethnicity has also been found to have an impact on survival; a recent article indicated that African Americans had poorer survival prospects even though Caucasians had a higher risk of developing lung cancer. 24Most patients in the current study were Omani, with eight patients originating from either Africa, Pakistan, the Philippines, India or Europe; unfortunately, due to the low number of expatriates, it was not possible to correlate race or ethnicity with survival.
The majority of patients in the current study were treated with platinum doublets.Bevacizumab could not be administered to many of the patients due to the presence of absolute or relative contraindications. 25t SQUH, anticancer therapy is customised based on the histological subtype of NSCLC; pemetrexed and platinum doublets with or without bevacizumab are usually prescribed for adenocarcinomas, while platinum and gemcitabine or nab-paclitaxel are prescribed for SCC and TKIs for patients with adenocarcinomas also harbouring EGFR mutations.Overall, EGFR mutations are present in 40-50% of East Asians and 10% of Caucasians. 26However, the exact incidence of these mutations in the GCC region is unknown; in the current study, it was observed that 27.9% of patients with adenocarcinomas had EGFR mutations in exons 19 or 21.As of late 2010, selected NSCLC patients at SQUH are treated with maintenance therapy.8][29][30][31] Several prognostic and predictive markers are also now available to guide oncologists in providing customised and individualised evidencebased care. 32major cause of death in the present study was either local progression leading to respiratory failure, progressive metastasis (i.e.leptomeningeal and brain metastases, liver failure, pulmonary parenchymal relapse or pleural effusion or both) or infections (i.e.pneumonia and sepsis).No deaths were attributable to venous thromboembolic phenomena or pulmonary embolisms, which may be due to the strict thromboprophylaxis policy implemented at SQUH.Survival outcomes were very poor for patients who were diagnosed NSCLC at a late stage, which constituted the vast majority of patients in the studied cohort.This incidence of advanced stage NSCLC is very similar to that reported by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute in the USA [Table 4]. 9 Advanced NSCLC has a median OS of 10 months. 32emetrexed and targeted agents have been reported to enhance survival to 12 months and beyond, while the benefits of post-progression bevacizumab are currently under investigation. 33In the current study, prolonged survival was observed in a few cases treated with either TKIs or maintenance therapy; these findings are in agreement with those from other studies. 34,35

Conclusion
In the current study, the majority of patients with NSCLC were found to present at an advanced stage.However, survival outcomes were similar to those reported by the SEER Program in the USA.To the best of the authors' knowledge, this study is the first to describe the trends and outcomes of patients with NSCLC in Oman.

Figure 1 :
Figure 1: Median (A) progression-free survival for all patients and (B) recurrence-free or progression-free survival according to stage among patients with non-small-cell lung cancer presenting to the Sultan Qaboos University Hospital, Muscat, Oman (N = 104).

Figure 2 :
Figure 2: Median overall survival for (A) all patients and (B) according to stage among patients with non-small-cell lung cancer presenting to the Sultan Qaboos University Hospital, Muscat, Oman (N = 104).

Table 1 :
Baseline clinical, demographic and pathological characteristics of patients with non-small-cell lung cancer presenting to the Sultan Qaboos University Hospital, Muscat, Oman (N = 104) The commonest site of metastasis was in the bone (19.2%).The clinical, demographic and pathological characteristics of the patients are presented in Table1.Only 12 patients (11.5%) presented with earlystage disease, including one patient (8.3%) at stage I and 11 patients (91.7%) at stage II.Of the patients of any size invading the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina or separate tumor in different ipsilateral lobe; N0 = absence of nodal involvement; N1 = metastasis to the ipsilateral hilar or peribronchial lymp nodes; N2 = metastasis to the ipsilateral mediastinal or carinal lymp nodes; N3 = metastasis to the contralateral hilar, mediastinal or supraclavicular lymp nodes; Nx = nodal involvement unknown.*Onradiology.e304| SQU Medical Journal, August 2017, Volume 17, Issue 3who presented with early-stage NSCLC, 10 (83.3%) underwent surgical resection.Seven patients received adjuvant chemotherapy, one patient was deemed unfit for chemotherapy and received adjuvant radiation therapy instead and two patients opted not to receive adjuvant therapy and later died due to progressive

Table 2 :
First-line treatment regimens among patients with non-small-cell lung cancer presenting at the Sultan Qaboos University Hospital, Muscat, Oman (N = 104)

Table 3 :
Univariate analysis of factors affecting recurrence-free survival, progression-free survival and overall survival among patients with non-small-cell lung cancer presenting to the Sultan Qaboos University Hospital, Muscat, Oman (N = 104) RFS = recurrence-free survival; PFS = progression-free survival; OS = overall survival, CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; N0 = absence of nodal involvement.

Table 4 :
9omparison of stage distribution and survival rates of patients with non-small-cell lung cancer in Oman and the USA Data sourced from the results of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for 2001-2008.9 *