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Yusupbekov Abrorjon Axmedjanovich, MD, DSc, deputy director of the Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan Usmanov Bekzod Baymatovich, MD, Ph D., senior researcher of thoracic oncology department Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan E-mail: [email protected] Khairutdinov Rafik Vakhidovich, MD, DSc, senior researcher of thoracic oncology department Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan Tuychiev Otabek Dilshodovich, MD, Resident of masters program of thoracic surgery Tashkent Medical Academy
MODERN VIEWS IN DIAGNOSTICS AND TREATMENT OF ESOPHAGEAL CANCER (LITERATURE REVIEW)
Abstract. Esophageal cancer (EC) has one of the leading positions in the structure of malignant diseases and holds even higher position on the aggressiveness of the process. This article briefly analyzes the current state of the EC problem, evaluates the modern aspects of early diagnosis, prognosis and complex treatment.
Keywords: esophagus cancer, squamous cell carcinoma, adenocarcinoma, fast track method, multimodal approach.
Epidemiology
EC is one of the most unfavorable diseases of the upper gastrointestinal tract (GIT). Quiescent initial stages of the disease significantly complicates early diagnosis and thereby worsens the outcome [12]. In the 2018, EC and cardioesophageal junction (KEJ) occupies the 9th place in the structure of new incidents of malignant tumors worldwide, accounting for 572,034 registered cases, and 6th in the structure of mortality among all cancers, killing 508,585 people annually (almost 1 person per minute) [7]. For comparison, it is equal to 600 air crashes with the maximum number of aircraft seats per year. According to statistical data, EC develops significantly more often in males than in females (70% of new incidents developed in men), and persons over 70 years old make up about 40% of the total number of cases, while the peak incidence is between 50-60 years old [34]. However, these figures vary by geographic region. For example, the highest incidence was found in Eastern Asia, Eastern and Southern Africa, while the lowest rate belongs to Central America [7; 12]. The index of aggressiveness of the EC in 2018 was 88%. Despite the intensive development of medicine, the presented figures are growing every year. So, if in 2008
identified new cases were 482300, by 2018, 572034 cases of EC were registered around the world. The increase in incidence over the past 10 years is 18% [12; 34].
Despite the widespread tendency to increase the incidence of EC (WHO 2018), according to Tillashaykhov M. N. et al. (2019) in Uzbekistan there was a decrease in this number. So if in 2008 the number of new incidents of the EC was 991 cases, in 2018 this figure is equal to 782 cases, decreasing for 26%. At the same time, the death rate also decreased, from 669 deaths in 2008 to 603 mortal cases in 2018. However, it should be noted, that the aggressiveness index for a given period increased from 67.5% to 77.1%.
The worldwide increase in the incidence rate is due to a number of factors and, first of all, to the low efficiency of treatment of patients with EC compared with distal forms of GIT cancer, which is explained by the later diagnosis of the disease and features of EC progression. All this, in turn, requires addressing the development ofmodern methods for early diagnosis ofEC [34].
Histology
As it is known, two most frequent types of malignant tumors of the esophagus (90-95%) are distinguished,
depending on the type of cells from which they develop. Squamous cell carcinoma (SCC), which is the most common form of EC, mainly found in upper and middle sections of esophagus. Adenocarcinoma (AC) of the esophagus, the second most common tumor of the organ. It is usually found in lower part of esophagus, at the junction with the stomach and develops from glandular (secretory) cells, the source of which can be the esophageal glands or metamorphosed, under the regurgitation of gastric juice, cells of the lower part of esophageal mucosa (gastroesophageal reflux disease (GERD) and, as its consequence, Barrett's esophagus (BE)). It should be emphasized that these two main histological forms of EC have different clinical manifestations and, accordingly, different outcomes of special treatment [12]. Rare forms of malignant tumors of the esophagus include: choriocarcinoma, lymphoma, melanoma.
Recently, there has been a growth trend ofAC of esophagus in Western countries. Currently, in the US, the frequency of AC has increased manyfold, while the number of patients with SCC of the esophagus has decreased slightly. The increase ofAC in the United States at the beginning of the twenty-first century is 463% compared with 1975-1979's of last century [2]. Among all registered cases in the period of 2009-2013, 61.79% were AC and 32.8% SCC of the esophagus [36].
Genetic features
The identification of genetic changes associated with EC can play an enormous role in understanding the gist of pathology and develop molecular-based treatment. An expanded analysis of the entire genome showed that 83% of patients with SCC of the esophagus contain a mutation in the TP53 genome. In addition, in 46.4% of patients, have increased activity of the cell cycle regulatory gene CCND1. Epigenome changes such as DNA overmetilation also plays a role for early diagnosis of AC, and its increased degree means a negative prognosis [19; 36].
Risk factors and etiology
The risk factors and etiology of EC have regional features and depend on the histological type. According to demographics, people of the white race have 5 times more risk of EC than black and white Hispanics. Smoking is considered one of the main direct risk factors for SCC, while it is an indirect risk ofAC (through GERD and BE). Alcohol, transforming under the influence of alcohol dehydrogenase on acetaldehyde, acts as a mutagenic factor for the DNA of the squamous epithelium. Therefore, alcohol is considered a risk factor mainly for SCC. GERD, subsequently causing BE, is considered to be a precancerous condition [6]. The presence of BE increases the risk of AC of esophagus 40 times. However, only 5% of patients with EC have a history of BE. Some sources report about the role of obesity in the AC of the esophagus, but this
factor is not directly correlates with AC of the esophagus, but leads to GERD and through it may increase the risk of the disease [6]. There are also report showing the role of some regional behavioral addictions to certain foods and beverages that increase the risk of EC. Hot tea in many parts of Asia, Paraguayan tea (ilex of Paraguay), and chewable types of tobacco, in particular betel, are directly correlated with the EC [8; 12; 15].
Although a huge amount of research has been done on risk factors, neither of them is considered to be the etiological cause of the EC and, separately, seldom cause this pathology. The combination of these factors may increase the risk of EC occurrence for many times.
Screening and diagnostics
Timely diagnosis of both EC and other cancers is the whole ballgame when it comes to oncology [30]. Stage I and II of EC are asymptomatic, and, therefore, early diagnosis is difficult.
Despite the widespread expansion of EC, up to date there are no standardized screening methods. Pinnerua-Gonzalez et al. (2019), suggest using toluidine blue in combination with Lugol's solution. In high-risk groups, white light esophagosco-py is performed, sequentially esophageal mucosa sprayed with toluidine blue and Lugol solution from the esophagogastric junction, after which biopsies are taken from suspicious sites (uptake dye areas with toluidine and less-intense stained with Lugol solution) and examined by morphologists. According to the results presented by the authors, when detecting AC, the sensitivity and specificity of the method are 100% and 85.7%, respectively [32]. Also, chromoendoscopy with Lugol solution is considered the standard method for early diagnosis of esophageal SCC in Japan. The sensitivity and specificity for SCC are 91.9% and 94.0%, respectively [38].
However, Pam Harris (2018) and other North American scientists do not share the opinion of their southern colleagues and do not consider esophagogastroscopy as a screening method. "Endoscopy is not a screening method, you only do it for symptoms" emphasizes Stefan Meltzer (2018), a professor oncologist at the Medical School of the John Hopkins University. For effective screening, they offered a new device called "Eso-phaCap". This capsule-shaped device, measuring 16x9 mm, is attached to a thin catheter with a diameter of 2.16 mm. In the stomach, the gelatin cover of the capsule dissolves within 3 minutes and an internal polyurethane sponge, which, when pulled back, collects samples from a pathological focus located in the wall of the esophagus. The obtained sample, laden with DNA material that is subsequently extracted using a new technique known as methylation on beads (MOB). MOB identifies DNA methylation biomarkers - CCNA1 and VIM. The diagnostic accuracy of the method is 86.7%. The sensitivity and specificity
of this method for determining BE is 78.6% and 92.8%, respectively. The method does not require endoscopist specialization and special training, and it can be performed on outpatient departments for people at risk [28; 29].
However, according to reference data, even despite the presence of numerous screening methods, nowadays there is no consensus about the routine feasibility of any method for the risk group.
Modern methods of diagnosis of EC include imaging and endoscopic methods. It is not difficult to determine whether there is cancer or not, but the exact staging of the process requires careful approach [37].
Esophagogastroscopy with a biopsy from a pathological focus gives accurate information about the process localization, its type of growth, the nature of the tumor surface, its length and performed biopsy, provides information about the cell type and degree of differentiation (G) of the tumor [6; 19]. For early diagnosis, a magnifying endoscopy is also used with a narrow band imaging (NBI), which makes it possible to clearly visualize the microvascular structure of the mucosal layer and submucosa. The device uses a narrow spectrum of light with a magnitude of 410-430 nm (for the mucous membrane) and 540 nm (for the submucosa). According to Masayuki Watanabe et al. (2018), the method determines surface SCC in 97% of cases, while in traditional endoscopy, the sensitivity is 55% [38].
In addition, modern endoscopic ultrasound is highly sensitive for determining the depth of tumor invasion into the esophagus layers, adjacent structures (cT) and metastases in regional lymph nodes (cN). Also, the ability to perform fine needle aspiration from local lymph nodes under the control of endosonography provides additional information about the state of lymphogenous dissemination. It is these characteristics, that make this type of examination an integral part of the diagnosis of EC [21].
Not a few important stage of diagnosis is, of course, imaging methods. Computed tomography (CT) and positron emission tomography with 18F-fluoro-2-deoxy-glucose (FDG-PET/CT) are at the forefront of staging, mainly for cN and cM [36]. CT scan provides a detailed overview of the organs of the chest, abdomen and their pathological changes. CT with contrast enhancement allows to more accurately assess the intactness of adjacent main vessels. Although this plays an important role in determining the volume of the operation, CT scan as well as FDG-PET/CT have a disadvantage in setting up the initial stages of invasion (cT) [21]. FDG-PET/CT would seem indispensable for the diagnosis of distant metastases (cN and cM), but a large number of false-positive results lead to unnecessary examinations and thus an increase in the cost of diagnosis and treatment in general
[36]. In this regard, the routine use of PET/CT in oncological practice is limited. In the CIS countries for the diagnosis of tumors of the esophagus contrast x-ray of the esophagus is used. This method provides information about the existence of the process, its form, and the longitudinal length. Due to low specificity, radiography is rarely used in the developed countries [19; 21].
Among the non-invasive diagnostic methods are ultrasound of the abdominal cavity, pleural cavity and peripheral lymph nodes. Ultrasound together with body CT and Endo-ultrasound in the vast majority of cases can limit the indications for PET / CT, presenting all the necessary data. If the process is located in the upper and middle parts of the esophagus, bronchoscopy is additionally performed to exclude involvement of the respiratory tract in the process and, if necessary, to obtain biopsy from the focus [19].
Treatment
Endoscopic treatment: Accurate staging of the disease is very important for choosing an appropriate treatment method or a combination of them. In addition to the exact stage of the process, the functional state, nutritional status of the patient and comorbidities are assessed [12]. In modern oncology, an integrated approach to treatment is commonly accepted. Treatment is strictly depends on the stage of EC. When the tumor is located in the mucosa and submucosa (T1a-T1b), endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) with radiofrequency ablation are performed. ESD compared with EMR has a high percentage of complete removal of the tumor (92.7 versus 52.7%) and less frequencies of local recurrence (0.3 versus 11.5%), respectively. Complications of this procedure can be stenosis (5%) and esophageal perforation (less than 1%), which can also be eliminated endoscopically [27]. ESD is the standard of treatment for high-grade dysplasia and cancer in the T1-N0M0 stage, and the T1bN0M0 stage is considered a relative indication for this procedure [27; 38]. However, diagnosing patients at an early stage is considered a rarity, moreover, an accurate determination of the cT degree is difficult and this increases the risk of incomplete removal of tumor cells. Therefore, some surgeons intend to perform resection of the esophagus in the initial stages rather than endoscopic treatment [19].
Surgery: Surgical treatment of EC is recognized as the central part of the complex therapy of early stages of EC. It basically means subtotal esophageal resection (ER). With the first successfully performed transthoracic ER (V. D. Do-bromyslov in 1900 and F. Torek in 1913) more than a hundred years have passed and the surgery of the esophagus has undergone significant changes. Today, for cancer of the thoracic esophagus, two main types of simultaneous interventions have been widely recognized - subtotal ER through
a two-zone (abdominal-thoracic) access with anastomosis formation in the dome of the right pleural cavity (Lewis' operation) or through a three-zone (abdominal, thoracic and cervical) access formation of anastomosis on the neck (McKeown's operation). There is also a transhiatal (abdominoservical access) ER developed by W. Denk in 1913, however, the method is not sufficiently adequate from the point of radically oncological view, due to the absence of a visual lymph node dissection from the chest [9, 38]. Although this approach has its supporters, in favor of its low traumatism. Due to the volume of open ER, the frequency of complications after surgery is high. According to R. V. Khayruddinov et al. (2006), after 286 surgeries, following complications were noted - transplantat necrosis (0.7%), pneumonia (7%), partial anastomosis leak (8.75%), wound suppuration (9.44%), exudative pleurisy (5, 6%), myocardial infarction (0.7%), arrosive bleeding (0.7%), purulent mediastinitis (3.5%), insufficiency of esopha-goenteroanastomosis (0.7%), cardiovascular insufficiency (2.8%), acute respiratory failure (1.7%), pulmonary edema (0.7%), pleural empyema (1%). A total number of complications 124 (43.4%), 31 (11%) of which were mortality cases [16]. Such frequency of postoperative complications led to the introduction of minimally invasive techniques to modern surgical oncology. The minimally invasive techniques of the presented operations were widely distributed among the developed countries of the western hemisphere and eastern Asia [36]. Minimally invasive resection of the esophagus (MIRE) in the early twentieth century was considered risky and had many intraoperative and postoperative complications. But recent studies have shown that these concerns were related to technical deficiencies and the limited experience of surgeons [21]. Today, minimally invasive methods of esophageal cancer surgery are generally recognized and are widely used by experienced thoracic surgeons in specialized centers [1; 19]. One of the biggest investigations, devoted to MIRE, belongs to Luketich et al. (2012). Based on MIRE performed on 1011 patients, the authors showed a clear example of the feasibility of MIRE with the formation of an anastomosis either in the pleural cavity or in neck, depending on the localization process [19; 20]. Concerns about interventions in chest shifted Japanese scientists to improve the mini-invasive trans-hiatal ER. During the laparoscopic stage, the en block of the lymph nodes is removed from the middle and lower third of the mediastinum; the lymph nodes from the upper mediastinum are removed through mediastinoscopy from a single port on the left neck [31]. The results of such operations strictly depend on the annual volume of operations performed by a single surgeon [38]. Minimally invasive surgical techniques can affect the patient's surgical status, postoperative complications (64.4% after open RP and 35.9% after MIRP), quality of life,
but have no effect on the overall survival of esophageal cancer patients [1; 5; 21].
Lymphadenoectomy in oncology is an inseparable part of the operation. The volume of lymph node dissection has been at the center of discussion for many years, although recent publications by Western scientists show that the removal of all regional lymph nodes compared to the tailored lymph node dissection does not significantly affect the overall survival of patients [18; 19; 22].
Despite the relentless improvement of surgical methods and the rational choice of the operation volume, postoperative changes in the patient's body significantly affect the quality of life of patients with EC. Frequently encountered are reflux, eating problems, malabsorption, dysphagia and others. Recovery after surgery and return to social life, often, is long [10; 23]. Chinese scientists were among the first in the world to solve this problem using the enhanced recovery after surgery technique (ERAS) on the esophagus. Li Yin is one of the founders of the fast track method for operable patients with EC, creating their own technique of forming esophagogastros-tomy (Li's anastomosis) [39].
Multimodality approach: The vast majority of patients are treated with locally advanced EC. The strategy of treatment in such cases is debatable among advanced thoracic cancer centers in developed countries. A multimodal approach for the treatment of EC is a key point of therapy [24]. Western scientists use the tactics of neo-adjuvant chemo-radiotherapy followed by surgery [4]. For squamous cancer, carboplatin + paclitaxel is used in conjunction with radiotherapy (41.4 Gy in 23 fractions) and subsequent surgery (CR0SS2012) [4; 14; 30]. For adenocarcinoma, neoadjuvant chemotherapy with a cisplatin + 5 fluorouracil regimen and subsequent surgery (OEO2, FNCLCC / FFCD) [3; 11; 13]. Opponents of this tactic (MAGIC) conduct various studies comparing the tactics of neoadjuvant chemoradiotherapy + surgery with the tactics of perioperative chemoradiotherapy + surgery and show that there are no significant differences between overall survival of the given approaches [3]. In consideration of the general condition deterioration of some patients [25] and the need for re-staging (additional costs) after neoadjuvant che-motherapyy and radiotherapy, the latter group of scientists prefer to resect the esophagus first, and initiate chemoradio-therapy next [6; 19].
Palliative treatment: With the invasion of tumor to adjacent structures or presence of distant metastases, the radical nature of therapy is excluded and in such cases, approach will be palliative. The goal of palliative therapy is to alleviate the symptoms of the disease, improve the quality of life of patients and prolong the patient survival. The dominant symptom in EC is dysphagia. Endoscopic stenting, with a self-expanding
stent followed by brachytherapy, is used to expand the lumen of the esophagus [19; 33]. This tactic for local therapy is considered optimal. There are stents with an iodine (125) seeds that act locally on the process [40]. The use of such stents for patients with an unresectable tumor prolongs the median survival [33].
Systemic palliative treatment involves chemotherapy. To date, there are no randomized 3rd phase studies associated with palliative therapy for esophageal squamous cell carcinoma and data are extrapolated from the esophageal AC [19]. Platinum-containing and fluoropyrimidine medicines are considered the first line chemotherapy, and in cases of satisfactory condition of patients, a third component (epi-rubicin or docetaxel) may be include [14]. Targeted therapy is used, once the chemotherapy failures. For esophageal AC, overexpression of the HER2 (Human Epidermal growth factor receptor 2) makes it possible to use trastuzumab together with chemotherapy, which prolongs the average survival rate up to 16 month versus 11.8 months for patients who received chemotherapy alone [26]. HER2 is the only oncological marker for EC, against which immunotherapy may signifi-
cantly affect the overall survival of patients [19; 26]. In addition, according to Lagergen et al. (2017) its overexpression occurs in 59.6-76% of patients with esophageal SCC [19]. Studies are also underway on the effect of immunotherapy (nivolumab, pembrolizumab) against the Programmed death ligand 1 (PD-L1). An increase of PD-L1 protein is found in 43.7% of patients with esophageal SCC. D. Kollmann et al. (2017) suggest, that 12-month survival in patients, who receive immunotherapy with chemotherapy, regardless of the histological type, is 43%, versus 20% in those who received only chemotherapy [17; 35].
Conclusion
EC remains a significant cause of death from cancer worldwide. A "innocuous" onset, aggressive growth, rapid spread and high resistance to antitumor therapy make the disease insidious. The lack of available standardized screening methods, specific tumor markers and effective treatment strategy, including the extensional nature of the radical surgery for EC, which consists of the stages of resection and reconstruction, indicates the presence of an "underwater part of an iceberg" called EC.
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