Oesophageal and Esophagogastric Junctional Carcinoma- Management and Outcomes from an Academic Community Centre of Nepal

BACKGROUND Oesophageal and junctional cancer is an aggressive malignancy with poor prognosis even with multimodality treatment. The true nature of the presentation, management and its outcome is less known in our population. This study was done to provide clinicians with useful information about the disease epidemiology, stage of presentation and clinical picture of the disease in the setting of a developing country. All patients managed for oesophageal and esophagogastric junction (EGJ) tumours over six years were retrospectively studied for types and location of the tumour, treatments given and their outcomes. patients underwent surgery with curative intent. There was no operative mortality. The mean survival in patients undergoing surgery with curative intent was 26.9 months (range 4-60 months) while the mean survival in the remaining patients was only 11 months (range: 3-18 months). Squamous cell carcinoma is the predominant type and the middle and upper third are the most common locations of oesophageal carcinoma. Most of the patients present with advanced stage disease with poor survival.


B A C K G R O U N D
Oesophageal and esophagogastric junctional (EGJ) cancer represent the seventh most common cancer and the sixth most common cause of cancer death worldwide with dismal 5-year overall survival (12-20 %) [1,2] They usually present with progressive dysphagia, bleeding, weight loss and anorexia at an advanced stage of the disease. Oesophageal cancer is either squamous cell carcinoma or adenocarcinoma, predominantly seen in smokers. While EGJ cancers are adenocarcinomas seen in obese and alcoholics. EGJ adenocarcinoma is divided into 3 types as per the Siewert classification, which is based purely on the anatomic location of the epicentre of the tumour. Siewert type I tumours are defined as an adenocarcinoma of the lower oesophagus with the tumour epicentre located within 1 to 5 cm above the anatomic EGJ. Siewert type II tumours are defined as a true carcinoma of the cardia with the tumour epicentre located within 1 cm above and 2 cm below the EGJ. Siewert type III tumours are defined as a subcardial carcinoma with the tumour epicentre located between 2 and 5 cm below the EGJ, which infiltrates the EGJ and the lower oesophagus from below. EGJ tumours with epicentres located within 2 cm of the proximal stomach (Siewert types I and II) are staged as oesophageal adenocarcinoma. EGJ tumours with epicentres located >2 cm into the stomach (Siewert type III) are now staged using the gastric cancer staging system. [3] Diagnosis is established by endoscopy and biopsy, contrast-enhanced computed tomography (CT) chest and abdomen, endoscopic ultrasound and whole-body FDG-PET/CT scan. Surgery is a major component of the treatment of locoregional oesophageal and EGJ cancers. In recent years, improvements in imaging/staging techniques, patient selection, perioperative care, and surgical experience have led to a marked reduction in operative morbidity and mortality. Furthermore, randomized trials have shown that preoperative chemoradiation and perioperative chemotherapy have significantly improved survival in patients with resectable, locoregionally advanced oesophageal and EGJ cancers. [3,4] Several studies report a 5year survival rate of 30-40 % for patients with oesophageal and junctional cancer after surgery with curative intent in combination with completed chemoradiotherapy.
Currently, the standard treatment option for potentially resectable locally advanced disease is multimodal, which includes neoadjuvant chemoradiation and subtotal oesophageal and/or gastric resection. However, in routine clinical practice, the majority of the patients present in advanced stages precluding curative treatment. This accounts for approximately 50-70 %, including T4b disease and metastases. In this scenario, the overall survival without any form of treatment is poor. However, with definitive chemoradiotherapy, the 5-year survival reaches up to 20 %. The same is the scenario in Nepal, where the majority of our patients present with the advanced-stage disease often with significant weight loss and absolute dysphagia. [3,4] Those patients where curative intent resection cannot be done are subjected to palliative chemo/radiotherapy and/or palliative operations depending on the symptoms. Palliative operations include feeding jejunostomy or palliative total gastrectomy. Therefore, in this study, we analyzed the demographic characteristics, clinical presentation, management, perioperative outcomes and survival from a tertiary care centre in Nepal. This study was done to provide clinicians with useful information about the disease epidemiology, stage of presentation and clinical picture of the disease in the setting of a developing country.

ME T H O D S
This is a retrospective observational study of all patients diagnosed and managed for oesophageal and esophagogastric junctional (EGJ) carcinoma from January 2015 to December 2020 in the Department of Surgery. Our institution is an academic centre providing tertiary level healthcare services to around 2.5 million population of Eastern Nepal. According to the literature review, the incidence of oesophageal cancer in the nearby region was found to be 6.5 per 100,000 populations. According to the medical record section of our institution, it was found that 76 cases were treated for oesophageal cancer in the Department of Surgery. Hence, the total number of samples considered was 76 and the purposive sampling method was used for the analysis. The diagnosis of the disease was made based on the clinical details, esophagoscopy, and contrast computed tomography (CT) of the chest and abdomen and was confirmed by endoscopic biopsy ( Figure 1A). The further treatment decision was performed by a multidisciplinary team of gastrointestinal and thoracic surgeons, medical oncologists, and radiologists' centred on the patient's desire for the treatment. The patient's medical record was reviewed to collect the following data: demographics and clinical information (including dysphagia grade, weight loss, smoking and alcohol consumption), ASA grade, co-morbidity, location of the tumour on the oesophagus, histological type, clinical and pathological stage of the disease and the treatment received (curative vs. palliative). Operative outcomes including morbidity and 90-day mortality were recorded. Survival outcomes in patients undergoing surgery with curative intent and those in the palliative group were studied. The study was approved by the institute's ethics committee.

S t a t i s t i c a l A n a l y si s
Statistical analysis was performed with SPSS v 20.0 software for the descriptive statistical analysis by calculating the mean, median (range), and percentages. In the entire group (oesophageal + EGJ), only 10 (13.2 %) patients underwent surgery with curative intent-subtotal esophagectomy (7; 9.2 %) ( Figure 1B) and extended total gastrectomy (3; 3.9 %). Eighteen (23.7 %) patients required operative feeding jejunostomy as a palliative procedure, 26 (34.2 %) underwent definitive chemoradiotherapy due to the unresectable/metastatic or inoperable disease, and the remaining 20 (26.3 %) underwent best palliative treatment. All patients underwent transhiatal esophagectomy except one (laparoscopic transthoracic esophagectomy) ( Figure 1C). There was no operative mortality (in-hospital and 90-day) in the entire curative intent group. However, there were three major morbidities (chest infections in two patients, and esophagojejunal anastomotic leak in one patient), which were managed conservatively. The result is summarized in Table 1.

R E S U L T S
The median survival in patients undergoing surgery with curative intent was 26.9 months (range: 4-60 months). There was one patient who was surviving without disease for 5years. While the median survival in the remaining patients in the definitive chemoradiotherapy/palliative group was only 11 months (range: 3-22 months).

D I SC U S SI O N
This study reflects the experience of oesophageal cancer management in our population according to the available accepted treatment modalities. Studies have shown that more than half the cases are inoperable at the time of presentation, however, in our population this is even higher. [3,5,6] At initial presentations, more than two-thirds of patients were inoperable or were candidates for palliative treatment only; 22.9 % of patients were having metastasis and 52.6 % of patients were having the locally advanced unresectable disease. Only 18.4 % of patients presented with tumours that could be resected. Only 10 (13.2 %) patients were treated with curative intention after diagnosis. Seven underwent subtotal esophagectomy and three underwent extended total gastrectomy with no operative or 90-day mortality. In four patients with oesophageal tumours, despite the tumour being resectable on imaging, the patient was inoperable and opted for definitive chemoradiotherapy. A similar experience has been worldwide and in a study by Thakur et al. from our country, where the resectability rate was 25 %. [3,4] Late detection of the disease is the main reason as shown in our study.
The tumour location and histological types vary according to geography and race. Worldwide squamous cell carcinoma (SCC) is the predominant histological type of oesophageal cancer followed by adenocarcinoma. [7] In this study, the predominant histological type was SCC (63.15 %), similar to findings in other populations of this geographic region. [8,9] However, the incidence of adenocarcinoma has exceeded SCC in the USA and other western European countries. [10,11,12] Similarly, the location of the tumour has shifted to the lower third and GEJ with rise in adenocarcinoma in the western world. The predominant location of tumours is still the middle third followed by the lower third of the oesophagus in our population. Similar findings have been reported from our subcontinent with no significant temporal change in the number and proportion of adenocarcinoma and the location of oesophageal carcinoma. [8,9] The EGJ tumour comprised only 18.4 % of total cases and all of them were adenocarcinoma in our study.
The main associated risk factor was smoking (73.7 %) followed by alcohol consumption (26.3 %). The dietary habit of smoked and spicy food is common in our population which might have contributed to the development of oesophageal carcinoma. None of the patients with EGJ or lower esophageal tumour was having Barrett's oesophagus, however, all of them had a history of treatment for gastroesophageal reflux disease.
A total of 26 patients (34.2 %) underwent definitive concurrent chemoradiotherapy due to the unresectable/ metastatic or inoperable disease. Studies have shown similar or better results with concurrent chemoradiotherapy for nonsurgical management of the advanced disease. [13,14] Almost half of our patients were managed with palliative treatment; 18 (23.7 %) required operative feeding jejunostomy and 20 (26.3 %) underwent the best palliative medical treatment.
The median survival in the entire group with palliative and curative intent was 11 and 27 months respectively. This is in line with the study on our part where it was 8.5 and 25 months for palliative and curative intent respectively. Similarly, there was only 22 % of 5-year survival. [3,4] On the contrary, as per the CROSS trial, the overall median survival was 48.6 months with a 5-year survival of up to 40 % after receiving multimodality therapy. [15] L i m i t a t i o n s This is a single centre retrospective study in a communitybased hospital setup. Due to the lack of infrastructure and referral for radiotherapy to other centres, complete follow-up data is not available. However, it does provide a real-time scenario of management to patients of this aggressive disease.

C O N C L U S I O N S
SCC is still the most common type and middle and upper third are the most common locations of oesophageal carcinoma. Only 18 % of the tumour was resectable, while only 13 % received surgery with curative intent. More than two-thirds of our patients presented in advanced stage and required palliative treatment or definitive chemoradiotherapy. To improve its outcome, early screening (clinical and endoscopy) may help diagnose the disease at its early stage.

E t h i c a l A p p r o v a l
Ethical approval from IRC of BPKIHS, Dharan, Nepal.