Pathophysiology and perioperative dystrophy of esophagus cancer: association with malnutrition

Introduction

Esophageal cancer (EC) is one of the most aggressive and lethal malignancies, and it accounts for a significant proportion of cancer-related deaths worldwide. Over the past three decades, remarkable advancements have been made in diagnostic techniques and pretreatment staging accuracy (1,2). However, the management of EC presents significant therapeutic challenges, particularly in relation to the role of radiotherapy, and debate continues as to the optimal treatment strategies. There is strong evidence that esophagectomy has better survival rates than non-surgical methods; thus, for localized, operable disease, esophagectomy remains the best treatment option (3). However, the novel approach of using multiple treatments together (e.g., administering chemotherapy and radiation before or during surgery) has changed the timing of surgery, increased the success of surgeries, and led to better treatment responses. Treatment decision making is complicated, and careful consideration of the tumor’s features, its level of advancement, and the patient’s other health issues is required to achieve the best results (3,4).

For patients with early stage cancers limited to the inner lining of the esophagus, treatment choices include endoscopic therapies and small surgical procedures (3-6). In the combined treatment of EC, doctors often use chemotherapy, radiation therapy, or a mixture of both [concomitant chemoradiotherapy (CRT)], either before surgery or as the main treatment to help relieve symptoms. Since the 1990s, numerous studies have examined whether multimodal approaches improve survival outcomes (6-8). Meta-analyses have reported inconsistent results; however, current research generally shows that combined-modality therapy provides a modest but significant survival benefit, particularly in patients with locally advanced disease (7,8). Currently, the role of minimally invasive esophagectomy (MIE) in this context remains unclear. For patients with advanced, untreatable disease, palliative treatments aimed at relieving symptoms (e.g., radiotherapy, endoscopic stenting, and other therapies) are very important for easing the problems caused by tumors (e.g., difficulty swallowing and blockages) (8,9).

Despite advancements in medical science (8,10), EC is more deadly than other types of malignancies. EC is primarily classified into two histological subtypes: esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EAC). ESCC usually occurs in the middle-upper region of the esophagus, while EAC usually occurs in the lower portion of the esophagus (11). Geographically, the incidence rates of less developed and more developed nations differ by a factor of two, with peak incidence rates observed in several Asian locations, such as China and Iran. While the prevalence of EAC has been increasing rapidly in the United States of America (USA) and Western Europe since the 1970s, the occurrence of ESCC has remained rather constant worldwide (12,13). According to USA population–based cancer registries, the incidence of EAC in white males quadrupled between 1976 and 1990. EAC, once a relatively rare malignancy, is currently the predominant subtype of EC in Western countries (Table 1). This shift suggests that there has been an epidemiological change in EC (14,15). The complicated design of the organ and the typically delayed onset of tumor-related symptoms are obstacles to successful therapy (16). Tumors can occur in both the upper body and the belly, and each type requires a different treatment approach. A definitive diagnosis of EC and an assessment of its dangerousness and functionality are all part of the diagnostic strategy (17).

Surgical therapy is explored for all patients, and includes various methods such as transthoracic or blunt transhiatal esophagectomy, classic open approaches, and minimally invasive approaches (18,19). The use of endoscopic procedures that can completely remove the cancer and save the organ calls into question the use of surgery in the treatment of early distal EC (20). The five-years survival rates of patients who receive surgery alone are fairly poor, ranging from 15% to 40%. Proposals for multimodal therapy, combining esophagectomy with neoadjuvant chemotherapy (NAC) or CRT, have emerged. However, the outcomes of these proposed therapies have been inconsistent (21,22). Along with developments in surgical care, definitive CRT has appeared as a treatment option for ESCC (23).

This article outlines previous research on the etiology, diagnosis, therapy, and epidemiology of EC. It details notable accomplishments and discusses contemporary debates as to the state of multimodal principles and appropriate therapy. Additionally, it notes the urgency of palliative care and the available solutions for patients with advanced, incurable tumors to alleviate their symptoms. A multidisciplinary strategy is necessary in the treatment of EC, as it is a clinically difficult condition. Even after receiving extensive therapy, patients may experience a significant decrease in their health-related quality of life (HRQoL) and a dismal outlook. In recent decades, the outlook has steadily improved in many nations (24-26). Endoscopic techniques are increasingly being used to treat early stage and premalignant esophageal tumors. Conventional treatment for localized ECs primarily includes chemotherapy, or CRT in addition to surgery. The practice of surgery is now more centralized and standardized. Palliative care has a number of different therapy options (27).

A poor prognosis, a significant reduction in HRQoL, and an unmet need for advanced therapeutic regimens are associated with EC (28). The usual treatment for a cure involves major surgery and chemotherapy (28). Nevertheless, the prognosis and survival rates of EC patients have improved recently. Most individuals contact a doctor after experiencing increasing dysphagia and uncontrollable weight loss. The two primary histological kinds of EC (i.e., ESCC and EAC) are overrepresented in older males (i.e., those aged 60 years or older) (29). The typical male/female ratios for ESCC and EAC are 3:1 and 6:1, respectively; however, regional variations in these ratios are common. EAC patients are generally more obese and have chronic gastro-esophageal reflux disease (GERD), while ESCC patients usually have a history of severe smoking and alcoholism (30,31).

Globally, the most prevalent type of EC is ESCC, which has high incidence rates in eastern Asia and southern Africa (31). The “EC belt”, which extends from north Iran through central Asia to north China, has the highest incidence of EC; approximately 90% of EC patients in this geographic region develop ESCC. Over the past 40 years, there has been a notable increase in the occurrence of EA throughout North America, Europe, and Australia, and while the incidence of ESCC has decreased in a majority of the locations, this trend appears to continue (31,32). In many Western nations, the rate of EAC has exceeded that of ESCC. In the past 10 years, the general five-year survival rate of EC patients has increased in many European, American, and Chinese nations from less than 5% in the 1960s to around 20% in the current decade. However, the prognosis of patients differs depending on their location. Tumor stage, tumor subsite and histology, comorbidities, patients’ performance state, and HRQoL are all considered prognostic variables (28-32).

Epidemiology of EC

Demographic patterns: globally, there were approximately 481,000 new cases of EC in 2008, making it the eighth most common cancer worldwide (33). Currently, EC is the sixth leading cause of cancer-related deaths, and almost 80% of these deaths occur in developing nations. It was estimated that there were 17,460 new cases of EC and 15,070 EC-related deaths in the USA in 2012, making it the seventh most deadly cancer in the USA (22). Between the highest-risk region, known as the “EC belt”, which includes central Asia and central China, and the lower prevalence regions, which include central USA and Africa, there is a 15-fold difference in the prevalence rates across the world (22,34-37).

The epidemiology of EC has changed significantly in the West, such that the formerly less common EAC is now more common than ESCC. This change has coincided with an increase in the incidence of known risks for EAC, including obesity and GERD, and with parallel decreases in alcohol and tobacco use, which are known risk factors for SCC (37). The prevalence of EAC in the USA increased from 3.6 cases per million (in 1973) to 25.6 cases per million (in 2006), indicating a significant rise in incidence. However, it appears that the annual growth rate of EAC incidence has decreased significantly, falling from an annual increase of 8.2% before 1996 to an annual increase of 1.3% in subsequent years (36).

Despite such improvements, there are still certain places in the industrialized world where males have elevated rates of ESCC (i.e., an incidence rate of approximately 11.8 per 100,000 people), including in the Calvados region of France and northern Italy (which has an incidence rate of approximately 7–9 per 100,000 people) (35). Moreover, researchers noted an increase in the prevalence of ESCC in the male populations of Denmark and the Netherlands from 1973 to 2005 (37). The incidence of ESCC varies greatly by gender, race, and ethnicity in the USA. For instance, data from the cancer registry indicate that the incidence of ESSC is five-fold higher in black men (10 per 100,000 people) than white men, although the incidence rates of both groups decreased by half between 1970 and 2000 (37). Regional differences in EC rates have been reported in China; for example, in the Hebei and Hunyuan counties, these rates range from 1.4 to 140 per 100,000, respectively. The prevalence of ESCC is also high in Iran where similar patterns of diverse regional distribution have also been observed (36,37). Currently, the prevalence rates differ significantly between the high-risk zones in Northwest Iran and the low-risk zones near the Persian Gulf coast. Data from Iranian cancer registries reveal an epidemiological change similar to that observed in Western nations over the previous few decades. Although the incidence rate of EAC continues to increase each year that of ESCC remains almost unchanged. Iranian experts attribute this tendency to simultaneous increases in the incidence of GERD and obesity, as well as socioeconomic status (8,13,35-38).

Compared to ESCC, there is less global variation in the rates of EAC; however, there are variations in the incidence rates between genders and races in the same geographic location (8). In the USA, the incidence of EAC is eight times higher in males than females, and nearly five times higher in white people than black people (3.7 vs. 0.8 per 100,000 of the population) (12). The illness mostly affects white men. In Europe, the male-to-female ratios are 2:1 in the Netherlands and 12:1 in France (13). Conversely, in Asia, with the exception of high-occurrence places, the male-to-female ratio for ESCC is 3:1, where the circulation is more uniform due to the same circulation of recognized risks for the illness (13,38).

The incidence of ESCC varies by gender, geography, and socioeconomic position in the USA, where it is increased in minorities and lower socioeconomic classes (14,38). Given its rapidly increasing occurrence, EAC prevalence rates should be analyzed over similar periods. Scotland had the highest recorded incidence rates in Europe between 1978 and 1995 where the incidence rates were 3.9 per 100,000 in men, and 1.1 per 100,000 in women. The mean incidence rates for men in other nations vary from 0.6 per 100,000 people in the Netherlands to 1.8 per 100,000 people in Iceland (37). EAC accounts for 1% of all digestive cancers in France and 5% in England; thus, this country, appears to be at medium risk. In France, it accounts for 64% of ECs in women and 25% of malignancies in men (14). In addition to variations in incidence based on the global region, other notable variations in incidence have been observed (17,36-39).

Initial reports from the United Kingdom (UK) and the US traced the increase in the occurrence of EAC back to the 1970s. Age-standardized incidence rates for males and females in England and Wales from 1996–2001 were 4.5 per 100,000 people and 0.9 per 100,000 people, respectively. There was an approximately five-fold increase over a 24-year period [1971–1995]. In England and Wales, the overall risk of acquiring EAC between the ages of 15 and 74 years has risen dramatically in consecutive birth cohorts, such that compared with males and females born in 1900, males and females born in 1940 had a 10- and 5-fold increased risk of EAC, respectively. A rise in occurrence was observed in France, Holland, and Australia around 15 years after it was observed in the US and UK. The incidence rates in France from 1996 to 2001 were 0.3 per 100,000 people for women and 3.3 per 100,000 people for males (35-38,40). In the last three decades, EAC has increased more rapidly in France than any other digestive cancer with an average 5-year variation of +68.1% in males and +97.4% in females. The rates of EAC were initially the same across different occupations, and while they have increased for everyone since 1995, the increase has been faster among people in higher social classes, likely reflecting changes in the risk factors (36-38).

Pathophysiology of EC

The squamous epithelial cells lining the inside of the esophagus are the source of esophageal cancer cells (ECCs). Repeated chemical or physical insults to the esophageal mucosa increase the risk of ECCs. In non-endemic locations, excessive alcohol use and cigarettes smoking are the major risk factors for ECCs. Carcinogens found in tobacco smoke include nitrosamines, acetaldehyde, and polycyclic hydrocarbons (40,41). Smoking is associated with a five- to nine-fold increased risk of ECCs; however, in endemic areas, the comparative risk is lower; for example in Linxian, China, the risk is 1.3-fold higher in smokers than non-smokers (41). Salivary products and oral bacteria oxidize acetaldehyde mediate the harmful effects of alcohol on the esophageal mucosal lining. Acetaldehyde exposure is higher in Asian people due to pharmacogenetic variations in alcohol metabolism. Alcohol consumption along with smoking raises the risk of oral squamous cell carcinoma (OSCC) (41-43). Eating fewer fruits and vegetables, and a lack of certain important nutrients such as vitamins A and E increase the risk of ECCs (41). Due to the correlation between these striking risk factors and a lower socioeconomic position, ECCs are more prevalent in economically challenged areas and populations. For example, in northern Iran, the frequency of ECCs varies by area, and one factor that may contribute to this variance is recurrent thermal damage from drinking hot liquids such as tea (42). Finally, human papillomavirus (HPV) infection may be linked to ECCs. However, according to data from The Cancer Genome Atlas (TCGA), the molecular profile of ECCs is consistent with HPV-negative SCC. Rather than indicating a causal relationship, the evidence suggests that HPV-associated ECCs may reflect the variability of HPV prevalence throughout the world.

Apart from rare familial instances, inherited genetic variations have no effect on the risk of ECC malignancy (42,43). A change in the RHBDF2 gene, which makes the iRHOM2 peptide, leads to tylosis, a condition that can be passed down in families. This condition is linked to both plantar and palmar hyperkeratosis, and by the time a person is 70 years old, their cumulative chance of having OSCC is 90%. Research (44,45) has shown that certain areas of chromosomes are linked to a 1.3- to 1.4-fold higher risk of OSCC. The specific areas linked to higher risk are the HLA class II region (6p21.32), 10q23 (which makes an enzyme called phospholipase Cε1 that is involved in cell growth, development, and death), 5q31.2 (which makes a protein that helps the body respond to infections), and 17p13.1 (which forms part of the sodium/potassium pump and is near the TP53 gene that produces p53 (44).

Environmental changes that affect the risk of ECCs might be influenced by differences in genes that help detoxify harmful substances. For example, lifestyle variables combined with functional variations in the enzymes’ alcohol dehydrogenase 1B and aldehyde dehydrogenase 2 increase the risk of ECCs in the people of Japan. ECCs progress from low- to high-grade basal-cell hyperplasia, and from dysplasia to cancer (in situ) (Figure 1). The invasive nature of ECCs has not been studied in detail, but a key characteristic is the failure of the TP53 gene and other genes that help control the cell cycle, such as the retinoblastoma (RB)-associated protein (from the RB1 gene) and cyclin-dependent kinase inhibitor 2A (CDKN2A). These alterations are already present in precursor lesions (43,44). Higher levels of CDKN2A and RB have been associated with the worsening of cancer from inflamed sores in the esophagus, and changes in p53 have been observed in esophageal tissues after dysplasia or ECCs (43).

Figure 1 Esophagus cancer gradings. N, node; T, tumor.

It is difficult to differentiate between dysplastic tissue and normal tissue for accurate risk assessment; however, by studying the genes that behave differently in ECCs and normal esophageal lining, two possible biomarkers have been discovered that could aid in the diagnosis of dysplasia or invasive ECCs in the future. Due to dysplasia, TNFAIP3 (for TNF-3) and CHN are more highly expressed in cancerous tissues than normal tissues (41-45). The transcriptome, epigenetic, and mutation features of ECCs have been studied using various large-scale sequencing methods and research techniques across different platforms. According to TCGA data, the most common places for point mutations and small insertions or deletions (indels) are TP, KMT2D (which makes lysine methyltransferase 2D, also called MLL2), and NFE2L2 (which makes nuclear factor 2-like 2). Conversely, TCGA data have frequently revealed amplifications in SOX2, TP63, and FGFR1, which encode SRY-box 2, tumor protein 63, and fibroblast growth factor receptor 1, respectively (44-46).

The regulation of cellular growth, tyrosine-kinase receptor signaling, and chromatin remodeling, as well as nascent signaling like the Hippo signaling pathways (YAP1 overexpression encrypts Yes-associated protein-1), or the obliteration of vestigial-like family member-4 (VGLL4), or encrypting the autophagy-related gene-7 (ATG7) are among the irregular expression levels that could be targeted in ECC treatment approaches. TCGA data revealed that 57% of tumors had extra copies of CCND1, which is the gene that makes cyclin D1, and 76% of tumors had CDKN2A problems, which reflects the findings of earlier studies. In 13% of tumors, the PIK3CA gene is active, and in 19% of tumors, the epidermal growth factor receptor (EGFR) signaling pathway is activated due to mutations or overexpression (43-47). Each of these pathways has been effectively targeted by tyrosine kinase inhibitors, which have now been approved for use in other types of tumors (46).

Perioperative dystrophy in EC

Once distinct indicators are reliably identified with the potential to progress into cancerous tissues and histological criteria are validated, restricted or extensive lacerations of the gastrointestinal mucosal lining are referred to as “pre-neoplastic”. A prospective study demonstrate a significantly increase risk of cancer development (47). Lesions that could become cancer display changes in the skin or tissue such as increased cell growth, a disorganized structure, and an unusual cell appearance (47,48). There is a considerable chance that such lesions, which begin as pre-neoplastic or normal epithelial lesions, may develop into cancer (Figure 2). Malignancy occurs when the cancer spreads into the mucosal lining, and as it progresses, there are changes at the molecular level in the stomach or esophageal mucosa (49). Certain genetic alterations in the metaplastic epithelium of the mucus lining next to the cancerous tissues can be detected early, and can even be detected in the absence of the disease. Benign neoplastic lesions of the columnar epithelium that are flat or depressed (non-polypoid) are called “dysplasia” in Western nations, while those that protrude (adenoma) are called “polypoid”. Conversely, both types of lesions are referred to as “adenoma” in Asian nations (50). Most pathologists now use the Vienna categorization, which has the following nine categories: Groups 1 (no signs of cancer) and 2 (uncertain signs of cancer), which comprise pre-neoplastic conditions; Groups 3 (low-grade cancer) and 4 (high-grade non-invasive or invasive cancer), which comprise neoplastic lesions; and Group 5, which comprises cancers that have spread into the submucosa (49-51). Under the Paris classification system, neoplastic lesions that emerge superficially during an endoscopy are classed as type 0, while “advanced” (non-superficial) malignancies are classified as types 1–5. Evaluating invasion in the submucosa is crucial for determining the risk of nodal metastasis, and assessing qualitative indicators of insignificant diagnosis, such as tumor grade, capillary incursion images, and tumor growth (50).

Figure 2 Mechanism of perioperative dystrophy in esophagus cancer. RB, retinoblastoma.

To ensure that endoscopic therapy is appropriate, the depth at which the tumor penetrates the muscularis mucosa (from the bottom) should be measured. For squamous stratified epithelium, the empirical cut-off limit of invasion is 200 mm, while for columnar epithelium, it is 500 mm. In the stomach, a superficial neoplastic lesion is also referred to as “early cancer”. The rate at which “early” cancer progresses to “advanced” cancer varies, and many “early” tumors may never become obvious, clinically noticeable lesions (50-52). This bias has a limited effect; in a study of 43 early cases of gastrointestinal cancers in Japan where treatment was delayed, 27 cases (63%) developed advanced gastric cancer after an average of 37 months (53). This suggests that the majority of “early” cancers discovered via screening will develop into more severe symptomatic illnesses.

Abnormal growths in the upper digestive system occur when there is ongoing inflammation in the inner lining or the layer just beneath it. Inflammation can be caused by various external toxic or infectious factors, such as dietary pollutants, alcohol, nicotine, nitrites, Helicobacter pylori (H. pylori) present in gastric juices, and possibly HPV infections affecting the esophagus (52,54). Additionally, there are endogenous processes at play, including bile and acid reflux from the duodenum and stomach. The phrase “indefinite for neoplasia” is appropriate given the ambiguity surrounding the difference of responsive cellular modifications and the initial fundamental transformations to cancer cells. Frequent changes in the TP53 gene, such as G:C to A:T shifts at the CpG site, are found in tumors of the stomach and esophagus, suggesting a link between ongoing irritation and cancer. Such types of mutations are quite common in esophageal and gastric lining globally, as well as in high-risk regions of Asia in squamous EC (54,55). Several factors associated with inflammation are overexpressed in columnar-lined EC as it progresses from metaplasia to neoplasia (Figure 2). Cyclo-oxygenase 2 (Cox-2) expression is commonly increased in EC and is significantly increased in columnar metaplasia. Cox-2 produces prostaglandin E2, which triggers the β-catenin growth-signaling pathway (54,55). Metaplasia often occurs alongside the activation of nuclear factor kB (NF-kB), which is the main regulator controlling Cox-2 expression. The distal esophagus’s surface and the stomach cardia’s distal to the Z line are exposed to acid in the esophagogastric area; the pH reaches its lowest point in the postprandial phase, 5 mm above the esophagogastric junction. Bile acids and salts, along with nitric oxide (NO) made from nitrite by bacteria in the mouth can also cause damage (54).

The process of cancer development in a stomach infected with H. pylori occurs in stages: first, the stomach lining changes to resemble the intestines (intestinal metaplasia); next, there is long-term inflammation (atrophic chronic gastritis); and finally, abnormal cell growth occurs (intraepithelial neoplasia). Additionally, atrophic gastritis increases the pH inside the stomach by changing nitrites (NO2) into NO, which is controlled by inducible nitric oxide synthetase (i-NOS). Antioxidants, such as ascorbic acid, prevent the chain reaction related to nitration, which leads to the luminal production of cancer-causing agents.

The most common molecular changes that occur during the development of changes in epithelial cells include changes in the TP53 gene (17p13), which makes the p53 protein, the shutdown of the P16/CDKN2A gene (9p22), which produces p16, increased levels of the CCND1 gene, which makes cyclin D1, and increased amounts of proto-oncogenes such as the EGF receptor or c-Myc. The inactivation of TP53, which is mostly caused by mis-sense mutations, causes the dysregulation of cellular growth control and programmed cell death (55,56). Changes in mutagenesis risk factors may account for the regional variances in TP53 mutations. TP53 mutations are prevalent (65–80%) in high-risk regions of Western Europe, including Northern Italy and Western France, and a significant fraction of the overall alterations occur at A:T. A process involving alcohol metabolites, including acetaldehyde, which has been shown to cause transformations at A:T base pairs in vitro, is compatible with this mutation. While TP53 mutations are common (50–75%) in high-risk areas of Asia, the main type of mutation is the change from G:C to A:T at methylated cytosines. In SSC, the TP63 gene is overexpressed, suggesting that it is also an early indication. The TP63 gene (3p28) encodes a protein required for the growth and discrimination of squamous epithelia (54,56,57).

Esophageal stem cells can turn into two types of cells, columnar or squamous, based on the levels of p63, which is not working properly. EC often occurs because there is an abnormal amount of growth factors that help blood vessels develop, such as vascular EGF. This leads to changes in the small blood vessel loops in the esophagus that can be seen with an endoscope. The expression of EGF factors is upregulated in the mesenchyme-epidermal interface (55,56). According to recent research, a tiny percentage of SCCs may carry mutations or gene amplifications that activate EGF receptors. The TP53 mutation, P16/CDKN2A hypermethylation, and CCND1 amplification, which reflect changes from normal cells to cancer cells, are very similar to those observed in the squamous epithelium. The p63 isoforms could possibly be involved (58). Compared to EAC that starts in the gastric cardia, EAC that starts in the esophagus more often has TP53 mutations and increased CK7 expression at the esophagogastric junction. Notably, EAC that starts in the gastric cardia is linked to a higher occurrence of MDM2 amplification, which helps to control the stability of the p53 protein (56,59,60).

Cancerous lesions in the epithelial layers progress slowly to high-grade cancer cells, following the same sequence as the transition from lasting atrophic inflammation of the gastric mucosa and intestinal metaplasia to neoplasia. Conversely, 80% of instances with high-intraepithelial neoplasia develop in to cancer within 6 months (61). As previously mentioned, the “intestinal” mutations that develop into cancerous tissues include those that affect mismatch repair genes (hMLH1), suppresser or directing genes (APC and TPp53), and oncogenes (K-ras and beta-catenin). APC gene (5q21) mutations are rare in malignant lesions; however, they often appear early in premalignant precursors. This suggests that other molecular components, such as MSI-H, are responsible for the advancement. In a recent investigation of stomach neoplastic lesions, the APC transformation was found in 77% of polypoid pre-cancerous cells, 74% of non-polypoid premalignant lesions, 4% of “intestinal” type cancers, and 5% of “diffuse” type cancers. The corporal transformation causing the “diffuse” form of gastric cancer is related to the directing gene (16q), which codes for the cell adhesion protein E-cadherin (61-64).

Even though it is rare, hereditary ESCC has been connected to palmoplantar keratoderma (tylosis), which is associated with a spot on chromosome 17p known as the TOC locus. Gene polymorphisms account for the greater alcohol sensitivity of the squamous epithelium in a significant proportion of the Asian population (50%) (61). Such individuals carry inefficient versions of alcohol or aldehyde dehydrogenase enzymes (ADH-2 or ALDH-2). Changes in the CYP2A6 gene in smokers might lead to the creation of cancer-causing nitrosamines (61,63-65). A “diffuse” type of hereditary gastric cancer that has been reported in New Zealand is caused by a germline alteration in the supervisory gene (16q) that codes for E-cadherin (66). Other genetic disorders include transmissible non-polyposis colon tumors and transmissible gastrointestinal polyposis (FAP (Familial adenomatous polyposis) and Peutz-Jeghers syndrome), which can also result in gastric cancer (sometimes known as the “intestinal type”). Variations in one or more genes related to H. pylori infection may affect the chance of developing sporadic stomach cancer (66). For instance, the immune response to the bacteria may be regulated by cytokines (interleukins) generated by the host’s epithelial cells; also, individuals with the blood group A phenotype have increased bacterial adherence to the stomach epithelium (66).

Association of EC with malnutrition: mechanisms and management

Research comparing preoperative parenteral nutrition (PN) as an adjuvant to oral feeding with no total parenteral nutrition (TPN) is incredibly limited. Compared to patients who received saline infusions only, those who received 1–1.5 weeks of PN before surgery had an encouraging N2 balance pre- and postsurgical intervention, including a decrease in wound contagion (67). However, hypercaloric and hyperproteic treatments are now considered outdated and unsuitable. Only a few studies have compared PN with enteral nutrition (EN), and regular formulas with immune-boosting mixtures (66,67). EN supplementation has been shown to lead to an increase in white blood cells and CD⁺ lymphocytes, supporting earlier PN findings, and to provide some benefits for metabolism and the immune system (66). Additionally, EN has been shown to enhance the quality of life and muscle function of patients. Lim et al. and Reynolds et al. (66,67) observed no difference between PN and EN; however, Aiko et al. reported a shorter hospital stay for EN (68).

The administration of immune-enriched mixtures during surgery was found to slightly beneficial but did not result in improved patient outcomes (69). The provision of pre-surgical PN support for patients undergoing EC surgery should be considered as part of their overall surgical care, even though there is no evidence that PN helps patients undergoing esophagectomy (69,70). However, “an absence of evidence of an effect is not evidence of absence of effect”. Research strongly suggests that initial EN, especially immune-enriched EN, is better for patients undergoing major surgery than PN or the usual isotonic fluid delivery (71).

The question arises as to whether a patient’s life routine is negatively affected by tube feeding. Studies have shown that 10% of patients with head and neck cancer ultimately require EN because their tumors make it difficult to eat, or because the long-term side effects of chemotherapy and radiotherapy greatly affect their ability to chew, swallow, eat, and enjoy life (72,73). Answering this question presents a few challenges. First, studies on this issue and the practice of tube feeding or percutaneous endoscopic gastrostomy (PEG) typically take into account various head and neck tumors not only EC. Further, the ailment itself, and the oncological therapy and its after effects can all affect patients’ quality of life (72). The majority of these individuals express discomfort in relation to experiences of gustatory deprivation connected to drinking liquids, savoring, mastication, and swallowing food, as well as exposure to foods that are banned, and unfulfilled cravings for certain foods, thirst, and dry mouth. Negative feelings related to a loss of social interactions, which are typically connected to sharing a meal with family and friends, is another factor. Recent research has revealed a negative correlation between changes in taste and fragrance and lower quality of life ratings (69,71,73). Additionally, because each person may be experiencing their illness at a different stage and because diagnoses are likely to fluctuate over time, evaluating the quality of life of these suffering individuals presents specific difficulties. Further, in a recent prospective study, minimal consistency was found in the quality-of-life ratings of terminally ill cancer patients and their primary family caregivers (74).

Some writers have disputed initial clinical research findings that patients receiving PEG feeding have a higher quality of life (74-78). One study compared the quality of life of three groups of patients following upper gastrointestinal tumor surgery; that is, those who did not receive a PEG as part of their treatment, those from whom a PEG was removed, and those who continued to have a PEG for a median duration of 34 months (73). The PEG-bearing individuals showed severe deficiencies in all aspects of quality of life compared to the non-PEG or PEG-removed individuals. Notably, interference with social activities, family life, romantic relationships, and interests (rather than pain or instances of tube obstruction or seepage) were the main PEG-related issues (75-79). A recent study examined the effect of home-based EN on the quality of life of patients with head and neck tumors, as well as the primary caretakers of these patients after an average of 19.2 months. A 27-item Satisfaction Profile Questionnaire was used to gauge the participants’ satisfaction with their social, psychological, physical, and sleep/eat/leisure functioning. Further, the participants were asked to list the five primary benefits and drawbacks of EN (80). The satisfaction profile scores of females were comparable to the normative standard scores, but the depression scores of males for physical working and sleep/eating/leisure were decreased. In terms of the main benefits of the EN, nearly 50% of the participants felt they had major restrictions on their independence, less than 33% reported some improvements in managing physical feelings and eating, and 25% were unhappy about losing their ability to eat normally (79). Overall, it appears that this patient group’s quality-of-life scores were somewhat below the average for men, and the drawbacks of their condition exceeded the benefits (as in Figure 3). These conclusions align with those of Roberge et al., who stated that after 28 days of tube feeding, symptoms and functional ratings remained the same or slightly improved (80), eating, sleeping, and physical and psychological functioning (79-84).

Figure 3 Marginal gains theory applied to perioperative nutritional therapy. Small gains acquired throughout the surgical continuum may result in clinically meaningful improvements in surgical outcomes.

The primary benefits identified by caregivers were related to their patients’ physical well-being (44%) and eating functional management (33%). Conversely, caregivers identified fewer drawbacks, such as autonomy limitations (27%) and therapy-related difficulties (23%). There appears to be a substantial disconnect between the viewpoints of patients and their caregivers in relation to the benefits and drawbacks of home EN for life quality (82). Overall, while patients acknowledged that PEG was a life-saving technique, they also found that tube feeding ultimately make difficult their lives, was linked to a significant treatment load, and ultimately did not improve their quality of life (84-87).

Nutritional assessment and interventions

On their initial visit, many EC patients have already experienced some passageway disturbance and loss of body weight. Thus, in addition to correctly staging the disease, a nutritional assessment needs to be performed to determine whether a nutritional intervention is necessary. The initial diagnosis and management approaches for EC are detailed in Figure 4 (88). SCC represents a large proportion of EC cases in Japan. NAC before surgery is the standard therapy for patients with stage II/III SCC. To preserve or enhance the patients’ overall health and ensure they undergo surgery in an excellent condition, the initiation of appropriate nutritional assistance in addition to NAC may be necessary (89). Before undergoing the surgical removal of the esophagus in conjunction with NAC, patients should undergo a nutritional evaluation. Advanced EC patients who have stenosis in the upper section of their esophagus should be considered at high risk of aspiration, and should continue their oral nutrition with caution. Such patients frequently require individualized meals of the right volume, texture, and substance, or their oral feeding may need to be restricted. It is crucial to assess the risk of bleeding while eating (90). Therefore, to implement prompt, adequate nutritional treatment, physicians should exchange evidence with other staff members, including the dietitians, nurses, and pharmacists who are responsible for the patient.

Figure 4 Diagnosis and treatment of esophageal cancer.

Based on previous reports, nutritional interference via EN or TPN should be initiated if the patient: (I) has experienced a weight loss ≥10%; (II) cannot adequately consume a rice gruel meal; (III) has a highly imbalanced diet; and/or (IV) eating carries a potential risk of bleeding or perforation. The blood albumin concentrations may not always be low in cases of desiccation in advanced-stage EC patients at the initial medical checkup. When treating patients who have previously experienced weight loss, optimal energy needs to be computed to enhance their nutritional status and ascertain the maximum quantity of energy that may be consumed orally (91-93). It can be calculated as follows: optimal energy = ideal body weight × 30 kcal/kg/day. Next, the area receiving artificial nourishment in the form of EN or TPN need to be excluded. Biological EN is believed to be a useful defense against microbial translocation and might aid in the management of infections. Thus, it is best to use EN for nutritional control, and to place a nasogastric pipe further into the stomach/intestine than the point of stenosis (94). Many physicians try to avoid TPN due to its potential for problems (95).

Occasionally, EN alone is insufficient to meet the nutritional needs of surgical patients. Consideration needs to be given to the hazards associated with aspiration, fixation-related skin conditions, and nasal catheter pain (96). Changes in the structure and function of the mucus lining in the intestine caused by TPN have been found to improve with combined nutritional therapy (CNT), which combines EN and PN, such that 10–15% of the total energy is provided via EN by managing certain nutrients like the Glutamine Fiber-Oligosaccharide enteral formula, and the remainder is provided by TPN. Thus, in patients with esophageal stenosis, CNT that comprises TPN and a small quantity of oral nutritional supplement may be appropriate.

As many patients have complex diabetes, preoperative nutritional management and blood glucose control with TPN and insulin may be safe in some cases. However, as preoperative therapy can alter the normal lifestyle of patients, revisions may need to be made to the nutritional support’s program, goal, and approach (97,98). A nutrition-support team or infection-control team, comprising dentists, nurses, dietitians, and pharmacists, should provide medical care facility-wide at the beginning of NAC. The nutritional status and danger of infections must also be regularly assessed throughout NAC. Research has shown that receiving nutritional guidance from a dietician during NAC reduces the incidence of postoperative problems after esophagectomy (99). In the future, we anticipate that complete team medical care will become even more crucial in promoting early recovery after EC surgery.

Following the advent of bioelectrical impedance analyses (BIAs), body composition analyzers are now more widely available, and such analyses can be completed rather fast (100). It has been proposed that having a low muscle mass before surgery, or changes in body composition after NAC, might help predict complications after EC surgery. However, further research is required to determine whether nutritional supplementation enhances skeletal muscle mass or similar characteristics, and lowers postoperative morbidity. Using body composition analysis, it is still unclear if nutritional intervention is necessary and when it is appropriate for preventing postoperative infection problems (101,102).

For over a decade, the post-surgical implementation of the immune-modulating diet (IMD), which is nearly interchangeable with the immune-enhancing diet (IED), has been eagerly awaited as a nutritional intervention strategy for averting surgical site infections. The European Society for Clinical Nutrition and Metabolism recommends an IED in the perioperative care of patients undergoing large gastrointestinal surgeries like esophagectomy. Western studies have shown that a preoperative IED enhances body defensive mechanisms and reduces the incidence of complications from post-surgical infections (99-103). However, no large-scale randomized controlled trial (RCT) of EC surgical patients has been conducted in Japan, and previous research has not shown that immune nutrition has a beneficial effect on lowering postoperative infection problems in esophageal surgery. Conducting a prospective, multicenter cooperative RCT is challenging, as different hospitals or surgeons adopt different perioperative care and surgical approaches (104). A single RCT of 53 people showed that using EN’s formula with eicosapentaenoic acid (EPA) before and after surgery helped patients maintain their weight after having their esophagus removed; however no significant difference was found in terms of the occurrence of major problems (105).

Preoperative IMD has been shown to lower the increase in tumor necrosis factor-alpha (TNF-α) levels of EC patients who had their esophagus removed by thoracoscopy, but it produced no noticeable change in the interleukine-6 (IL-6) or C-reactive protein (CRP) levels or the number of problems after surgery (104). Thus, immunological nutrition may be a viable intervention for early recovery. From a cost-effectiveness standpoint, there is presently inadequate data to support the widespread usage of IMD in patients undergoing EC surgery, although the procedure is now much safer than it was in the past. For high-risk patients who cannot initiate an IED or IMD before to surgery, IMD may be appropriate (104-106). Minimizing perioperative fasting is fundamental in the primary retrieval program; hence, certain precautions are advised to prevent interfering with these efforts (105).

Unlike colonic surgery, which can make it difficult for patients to eat after the operation, the ERAS^® program aims to help patients start eating again as soon as possible after an esophagectomy. However, due to the high risk of aspiration, it is often not safe to do start eating earliest. Further, because of the significant aspiration risk, it is frequently not feasible to do it safely. Further, it is doubtful whether individual patients would be able to consume sufficient energy in the initial stages following EC surgery, even if oral consumption could be accomplished (105-108). Thus, postoperative EN via a jejunostomy may be recommended immediately after the esophagus is removed, even for those who were malnourished before surgery or high-risk patients, like older adults, but patients should not be expected to consume food by mouth.

Several studies have shown that post-surgical early EN might aid in an early recovery following EC surgery (80,84,86). However, because there can be issues with jejunostomy after surgery, the placement of a jejunostomy during the surgery might make it more difficult to use this type of catheter for enteral feeding (109). Additionally, some medical professionals have contended that EN nourishing was never essential for MIE individuals, as adequate oral eating might be restarted promptly and securely following MIE. However, esophagectomy and reconstruction are quite invasive procedures, and major difficulties affecting postoperative oral intake can arise even with MIE (110). A recent RCT of patients receiving MIE showed that postoperative early EN (by jejunostomy) lowered the likelihood of postsurgical pneumonia from 30.4% to 12.5%. Depending on the operating technique or the post-surgical sequence at each hospital, enteral catheter feeding may not be necessary. Recently, it has been suggested that individuals should receive a standard formula with a progressively rising daily dose in clinical practice, and that pipe feeding should be initiated from postoperative days 1–3. As previously stated, it might take five to seven days to reach the desired consumption (111,112). The authors do not use standard TPN before an esophagectomy and usually start patients on catheter EN on the first day after surgery or as early as possible (Figure 5). Early EN with a low-fat elemental formula (ELENTAL^®) has been shown to aid recovery after esophagectomy and may also help prevent pneumonia and chyle leaks. Further, the pre-surgical administration of an EPA-enriched formula helps maintain lean body mass following an esophagectomy. However, a typical whole-protein formula is suitable for most patients following EC surgery (113-115).

Figure 5 An overview of the types, incidence, and risk factors of esophageal cancer, and the effect of nutrition therapy. An upward arrow “↑” indicates an increase. EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell cancer; GIT, gastrointestinal.

Patients with eating issues may require a change in the usual enteral formula, depending on the severity of their EC. A low-fat essential formula should both treat and prevent chyle leak. The authors often use a formula high in fat (Pulmocare^®-Ex) for patients who have pneumonia after surgery, and a low-potassium formula (RENALEN LP/MP^®) for patients with high potassium levels due to kidney failure. The wide range of postoperative courses following EC surgery suggests that these disease-specific equations might be helpful for tailored therapy (116-118). Water and various medications can also be administered through a feeding tube. Patients suffering from problems such as anastomotic seepage must be treated with TPN until the contagion is under control if no EN catheter has been implanted following the procedure. Next, through the anastomosis, a feeding line might be placed through the nasal cavity, at which point EN may begin. EN should then be used instead of TPN to promote an early cure and recovery. When TPN is required for infectious complications after esophagectomy, there is a risk of catheter-related bloodstream infections (73,87,99,117-119).

Conclusions

Precautions need to be taken to prevent the progress of catheter-related blood circulation infections in patients receiving TPN to manage infectious complications after esophagus removal; however, this may also lead to a reduced cure rate and response rate. ONS management is a straightforward process that could be implemented worldwide, but it may not be effective in the absence of rigorous dietician counseling. Only facilities with sufficient funding and an interest in the procedure can implement this kind of approach. Further, individuals with severe dysphagia brought on by their tumor or by toxicities due to chemotherapy/radiotherapy are not eligible for ONS. The use of a feeding tube with regular formula can help doctors ensure patients who cannot consume food orally (e.g., those experiencing a loss of appetite, painful swallowing, or sores) receive the right amount of nutrients. Depending on the facilities of individual institutions and the anticipated duration of the nutritional support, a nasogastric tube, PEG, or jejunostomy may be used. Improved rehabilitation strategies that emphasize smooth enteral feeding are promising in the field of EC surgical resection, and precautions against infection issues following surgery may be crucial. However, future research is likely to gather more scientific data. In older patients, multi-occupational team medical treatment, including perioperative cancer rehabilitation and mental/social support, may be crucial. Improved recovery programs that emphasize smooth enteral feeding are promising in the field of esophageal tumor surgery, and precautions against infection problems following surgery may be crucial. We intend to gather more scientific data soon. EAC will soon no longer be an uncommon type of cancer. In only one generation, the chance of acquiring EC has increased five-fold in women and 10-fold in men. To prevent EAC, the two independent risk factors of the disease (i.e., smoking and obesity) need to be addressed. Barrett’s esophagus is a pre-cancerous lesion; however, the likelihood of it getting worse has long been exaggerated. There is strong evidence from population-based research that a small percentage of people with Barrett’s esophagus will develop EC. The most certain marker of cancer risk is dysplasia. Routine monitoring is problematic in the absence of dysplasia, especially in women and patients aged under 50 years old. The present surveillance recommendations must be updated in light of the most recent population-based data.

Acknowledgments

We are grateful for the financial support from Gansu Provincial Natural Science Foundation (No. 22JR5RA647) and Longyuan Youth Innovation and Entrepreneurship Talent (Individual) Project (No. 211278291049).

Footnote

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-424/prf

Funding: This work was supported by Gansu Provincial Natural Science Foundation (No. 22JR5RA647) and Longyuan Youth Innovation and Entrepreneurship Talent (Individual) Project (No. 211278291049).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-424/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Esophageal cancer statistics. Cancer Research UK; 2020. Available online: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/oesophageal-cancer
2. van der Werf LR, Busweiler LAD, van Sandick JW, et al. Reporting National Outcomes After Esophagectomy and Gastrectomy According to the Esophageal Complications Consensus Group (ECCG). Ann Surg 2020;271:1095-101. [Crossref] [PubMed]
3. Garth AK, Newsome CM, Simmance N, et al. Nutritional status, nutrition practices and post-operative complications in patients with gastrointestinal cancer. J Hum Nutr Diet 2010;23:393-401. [Crossref] [PubMed]
4. Findlay M, Purvis M, Venman R, et al. Nutritional management of patients with esophageal cancer throughout the treatment trajectory: benchmarking against best practice. Support Care Cancer 2020;28:5963-71. [Crossref] [PubMed]
5. West MA, Wischmeyer PE, Grocott MPW. Prehabilitation and Nutritional Support to Improve Perioperative Outcomes. Curr Anesthesiol Rep 2017;7:340-9. [Crossref] [PubMed]
6. Filip B, Scarpa M, Cavallin F, et al. Postoperative outcome after oesophagectomy for cancer: Nutritional status is the missing ring in the current prognostic scores. Eur J Surg Oncol 2015;41:787-94. [Crossref] [PubMed]
7. Low DE, Allum W, De Manzoni G, et al. Guidelines for Perioperative Care in Esophagectomy: Enhanced Recovery After Surgery (ERAS(®)) Society Recommendations. World J Surg 2019;43:299-330. [Crossref] [PubMed]
8. Norman K, Stobäus N, Gonzalez MC, et al. Hand grip strength: outcome predictor and marker of nutritional status. Clin Nutr 2011;30:135-42. [Crossref] [PubMed]
9. Ordan MA, Mazza C, Barbe C, et al. Feasibility of systematic handgrip strength testing in digestive cancer patients treated with chemotherapy: The FIGHTDIGO study. Cancer 2018;124:1501-6. [Crossref] [PubMed]
10. Mendes J, Alves P, Amaral TF. Comparison of nutritional status assessment parameters in predicting length of hospital stay in cancer patients. Clin Nutr 2014;33:466-70. [Crossref] [PubMed]
11. Short MW, Burgers KG, Fry VT. Esophageal Cancer. Am Fam Physician 2017;95:22-8. [PubMed]
12. Lakenman P, Ottens-Oussoren K, Witvliet-van Nierop J, et al. Handgrip Strength Is Associated With Treatment Modifications During Neoadjuvant Chemoradiation in Patients With Esophageal Cancer. Nutr Clin Pract 2017;32:652-7. [Crossref] [PubMed]
13. Chen CH. Hand-grip strength is a simple and effective outcome predictor in esophageal cancer following esophagectomy with reconstruction: a prospective study. J Cardiothorac Surg 2011;6:98. [Crossref] [PubMed]
14. Thrift AP, Garcia JM, El-Serag HB. A multibiomarker risk score helps predict risk for Barrett's esophagus. Clin Gastroenterol Hepatol 2014;12:1267-71. [Crossref] [PubMed]
15. Bhat S, Coleman HG, Yousef F, et al. Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study. J Natl Cancer Inst 2011;103:1049-57. [Crossref] [PubMed]
16. Sato S, Nagai E, Taki Y, et al. Hand grip strength as a predictor of postoperative complications in esophageal cancer patients undergoing esophagectomy. Esophagus 2018;15:10-8. [Crossref] [PubMed]
17. van Egmond MA, van der Schaaf M, Klinkenbijl JH, et al. Preoperative functional status is not associated with postoperative surgical complications in low risk patients undergoing esophagectomy. Dis Esophagus 2017;30:1-7. [PubMed]
18. Drover JW, Cahill NE, Kutsogiannis J, et al. Nutrition therapy for the critically ill surgical patient: we need to do better!. JPEN J Parenter Enteral Nutr 2010;34:644-52. [Crossref] [PubMed]
19. Schier R, Levett D, Riedel B. Prehabilitation: The next challenge for anaesthesia teams. Eur J Anaesthesiol 2020;37:259-62. [Crossref] [PubMed]
20. Simard EP, Ward EM, Siegel R, et al. Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin 2012;62:118-28. [Crossref] [PubMed]
21. Pickens A, Orringer MB. Geographical distribution and racial disparity in esophageal cancer. Ann Thorac Surg 2003;76:S1367-9. [Crossref] [PubMed]
22. Bosetti C, Levi F, Ferlay J, et al. Trends in esophageal cancer incidence and mortality in Europe. Int J Cancer 2008;122:1118-29. [Crossref] [PubMed]
23. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. [Crossref] [PubMed]
24. Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop. Gastroenterology 2004;127:310-30. [Crossref] [PubMed]
25. Reid BJ, Barrett MT, Galipeau PC, et al. Barrett's esophagus: ordering the events that lead to cancer. Eur J Cancer Prev 1996;5:57-65. [Crossref] [PubMed]
26. Corley DA, Levin TR, Habel LA, et al. Surveillance and survival in Barrett's adenocarcinomas: a population-based study. Gastroenterology 2002;122:633-40. [Crossref] [PubMed]
27. Rubenstein JH, Morgenstern H, Appelman H, et al. Prediction of Barrett's esophagus among men. Am J Gastroenterol 2013;108:353-62. [Crossref] [PubMed]
28. Kubo A, Corley DA. Marked multi-ethnic variation of esophageal and gastric cardia carcinomas within the United States. Am J Gastroenterol 2004;99:582-8. [Crossref] [PubMed]
29. El-Serag HB, Mason AC, Petersen N, Key CR. Epidemiological differences between adenocarcinoma of the oesophagus and adenocarcinoma of the gastric cardia in the USA. Gut 2002;50:368-72. [Crossref] [PubMed]
30. Abrams JA, Fields S, Lightdale CJ, et al. Racial and ethnic disparities in the prevalence of Barrett's esophagus among patients who undergo upper endoscopy. Clin Gastroenterol Hepatol 2008;6:30-4. [Crossref] [PubMed]
31. Cook MB, Wild CP, Forman D. A systematic review and meta-analysis of the sex ratio for Barrett's esophagus, erosive reflux disease, and nonerosive reflux disease. Am J Epidemiol 2005;162:1050-61. [Crossref] [PubMed]
32. Kubo A, Corley DA. Marked regional variation in adenocarcinomas of the esophagus and the gastric cardia in the United States. Cancer 2002;95:2096-102. [Crossref] [PubMed]
33. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
34. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2016, National Cancer Institute. Bethesda, MD. Available online: https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER web site, April 2019. Accessed 23 February 2020.
35. Arnold M, Soerjomataram I, Ferlay J, et al. Global incidence of oesophageal cancer by histological subtype in 2012. Gut 2015;64:381-7. [Crossref] [PubMed]
36. Ferlay J, Ervik M, Lam F, et al. Global cancer observatory: cancer today. International Agency for Research on Cancer, Lyon, France. Available online: https://gco.iarc.fr/today. Accessed 05 March 2020.
37. Global Burden of Disease Cancer Collaboration. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol 2017;3:524-48. [Crossref] [PubMed]
38. Montgomery EA. Esophageal Cancer. In: Stewart BW, Wild CP (Eds) World Cancer Report 2014. World Health Organization. 2014 p 374-82.
39. Chen W, Zheng R, Zeng H, et al. Annual report on status of cancer in China, 2011. Chin J Cancer Res 2015;27:2-12. [Crossref] [PubMed]
40. Pandeya N, Olsen CM, Whiteman DC. Sex differences in the proportion of esophageal squamous cell carcinoma cases attributable to tobacco smoking and alcohol consumption. Cancer Epidemiol 2013;37:579-84. [Crossref] [PubMed]
41. Dong J, Thrift AP. Alcohol, smoking and risk of oesophago-gastric cancer. Best Pract Res Clin Gastroenterol 2017;31:509-17. [Crossref] [PubMed]
42. Bosetti C, Gallus S, Garavello W, et al. Smoking cessation and the risk of oesophageal cancer: An overview of published studies. Oral Oncol 2006;42:957-64. [Crossref] [PubMed]
43. Hardikar S, Onstad L, Blount PL, et al. The role of tobacco, alcohol, and obesity in neoplastic progression to esophageal adenocarcinoma: a prospective study of Barrett's esophagus. PLoS One 2013;8:e52192. [Crossref] [PubMed]
44. Cook MB, Kamangar F, Whiteman DC, et al. Cigarette smoking and adenocarcinomas of the esophagus and esophagogastric junction: a pooled analysis from the international BEACON consortium. J Natl Cancer Inst 2010;102:1344-53. [Crossref] [PubMed]
45. Liu J, Wang J, Leng Y, et al. Intake of fruit and vegetables and risk of esophageal squamous cell carcinoma: a meta-analysis of observational studies. Int J Cancer 2013;133:473-85. [Crossref] [PubMed]
46. World Cancer Research Fund/American Institute for Cancer Research. Diet, Nutrition, Physical Activity and Cancer: a Global Perspective. Continuous Update Project Expert Report 2018. Available online: https://dietandcancerreport.org. Accessed 24 Aug 2020.
47. Zhao Y, Guo C, Hu H, et al. Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis. Oncotarget 2017;8:10458-69. [Crossref] [PubMed]
48. Zgaga L, O'Sullivan F, Cantwell MM, et al. Markers of Vitamin D Exposure and Esophageal Cancer Risk: A Systematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev 2016;25:877-86. [Crossref] [PubMed]
49. Fritscher-Ravens A, Bohuslavizki KH, Brandt L, et al. Mediastinal lymph node involvement in potentially resectable lung cancer: comparison of CT, positron emission tomography, and endoscopic ultrasonography with and without fine-needle aspiration. Chest 2003;123:442-51. [Crossref] [PubMed]
50. Vickers J. Role of endoscopic ultrasound in the preoperative assessment of patients with oesophageal cancer. Ann R Coll Surg Engl 1998;80:233-9. [PubMed]
51. Kumbasar B. Carcinoma of esophagus: radiologic diagnosis and staging. Eur J Radiol 2002;42:170-80. [Crossref] [PubMed]
52. Dionigi P, Dionigi R, Nazari S, et al. Nutritional and immunological evaluations in cancer patients. Relationship to surgical infections. JPEN J Parenter Enteral Nutr 1980;4:351-6. [Crossref] [PubMed]
53. Takagi K, Yamamori H, Morishima Y, et al. Preoperative immunosuppression: its relationship with high morbidity and mortality in patients receiving thoracic esophagectomy. Nutrition 2001;17:13-7. [Crossref] [PubMed]
54. Sica GS, Sujendran V, Wheeler J, et al. Needle catheter jejunostomy at esophagectomy for cancer. J Surg Oncol 2005;91:276-9. [Crossref] [PubMed]
55. Groos S, Reale E, Hünefeld G, et al. Changes in epithelial cell turnover and extracellular matrix in human small intestine after TPN. J Surg Res 2003;109:74-85. [Crossref] [PubMed]
56. Senkal M, Zumtobel V, Bauer KH, et al. Outcome and cost-effectiveness of perioperative enteral immunonutrition in patients undergoing elective upper gastrointestinal tract surgery: a prospective randomized study. Arch Surg 1999;134:1309-16. [Crossref] [PubMed]
57. Heyland DK, Novak F, Drover JW, et al. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA 2001;286:944-53. [Crossref] [PubMed]
58. Tandon S, Batchelor A, Bullock R, et al. Peri-operative risk factors for acute lung injury after elective oesophagectomy. Br J Anaesth 2001;86:633-8. [Crossref] [PubMed]
59. Nakanishi K, Takeda S, Terajima K, et al. Myocardial dysfunction associated with proinflammatory cytokines after esophageal resection. Anesth Analg 2000;91:270-5. [PubMed]
60. Nakazawa K, Narumi Y, Ishikawa S, et al. Effect of prostaglandin E1 on inflammatory responses and gas exchange in patients undergoing surgery for oesophageal cancer. Br J Anaesth 2004;93:199-203. [Crossref] [PubMed]
61. Bartels H, Stein HJ, Siewert JR. Preoperative risk analysis and postoperative mortality of oesophagectomy for resectable oesophageal cancer. Br J Surg 1998;85:840-4. [Crossref] [PubMed]
62. Rindani R, Martin CJ, Cox MR. Transhiatal versus Ivor-Lewis oesophagectomy: is there a difference?. Aust N Z J Surg 1999;69:187-94. [Crossref] [PubMed]
63. Hooi JKY, Lai WY, Ng WK, et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017;153:420-9. [Crossref] [PubMed]
64. Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prev Res (Phila) 2008;1:329-38. [Crossref] [PubMed]
65. Nie S, Chen T, Yang X, et al. Association of Helicobacter pylori infection with esophageal adenocarcinoma and squamous cell carcinoma: a meta-analysis. Dis Esophagus 2014;27:645-53. [Crossref] [PubMed]
66. Lim ST, Choa RG, Lam KH, et al. Total parenteral nutrition versus gastrostomy in the preoperative preparation of patients with carcinoma of the oesophagus. Br J Surg 1981;68:69-72. [Crossref] [PubMed]
67. Reynolds AP, Kiely E, Meadows N. Manganese in long term paediatric parenteral nutrition. Arch Dis Child 1994;71:527-8. [Crossref] [PubMed]
68. Aiko S, Yoshizumi Y, Matsuyama T, et al. Influences of thoracic duct blockage on early enteral nutrition for patients who underwent esophageal cancer surgery. Jpn J Thorac Cardiovasc Surg 2003;51:263-71. [Crossref] [PubMed]
69. Sakurai Y, Masui T, Yoshida I, et al. Randomized clinical trial of the effects of perioperative use of immune-enhancing enteral formula on metabolic and immunological status in patients undergoing esophagectomy. World J Surg 2007;31:2150-7; discussion 2158-9. [Crossref] [PubMed]
70. Healy LA, Ryan A, Doyle SL, et al. Does Prolonged Enteral Feeding With Supplemental Omega-3 Fatty Acids Impact on Recovery Post-esophagectomy: Results of a Randomized Double-Blind Trial. Ann Surg 2017;266:720-8. [Crossref] [PubMed]
71. Soeters P, Bozzetti F, Cynober L, et al. Meta-analysis is not enough: The critical role of pathophysiology in determining optimal care in clinical nutrition. Clin Nutr 2016;35:748-57. [Crossref] [PubMed]
72. Eliasen M, Grønkjær M, Skov-Ettrup LS, et al. Preoperative alcohol consumption and postoperative complications: a systematic review and meta-analysis. Ann Surg 2013;258:930-42. [Crossref] [PubMed]
73. Oppedal K, Møller AM, Pedersen B, et al. Preoperative alcohol cessation prior to elective surgery. Cochrane Database Syst Rev 2012;CD008343. [Crossref] [PubMed]
74. Rubinsky AD, Bishop MJ, Maynard C, et al. Postoperative risks associated with alcohol screening depend on documented drinking at the time of surgery. Drug Alcohol Depend 2013;132:521-7. [Crossref] [PubMed]
75. Tønnesen H, Nielsen PR, Lauritzen JB, et al. Smoking and alcohol intervention before surgery: evidence for best practice. Br J Anaesth 2009;102:297-306. [Crossref] [PubMed]
76. Lauridsen SV, Thomsen T, Kaldan G, et al. Smoking and alcohol cessation intervention in relation to radical cystectomy: a qualitative study of cancer patients' experiences. BMC Cancer 2017;17:793. [Crossref] [PubMed]
77. Tønnesen H, Egholm JW, Oppedal K, et al. Patient education for alcohol cessation intervention at the time of acute fracture surgery: study protocol for a randomised clinical multi-centre trial on a gold standard programme (Scand-Ankle). BMC Surg 2015;15:52. [Crossref] [PubMed]
78. Sarin A, Chen LL, Wick EC. Enhanced recovery after surgery-Preoperative fasting and glucose loading-A review. J Surg Oncol 2017;116:578-82. [Crossref] [PubMed]
79. Steenhagen E. Enhanced Recovery After Surgery: It's Time to Change Practice! Nutr Clin Pract 2016;31:18-29. [Crossref] [PubMed]
80. Roberge C, Tran M, Massoud C, et al. Quality of life and home enteral tube feeding: a French prospective study in patients with head and neck or oesophageal cancer. Br J Cancer 2000;82:263-9. [Crossref] [PubMed]
81. Blank S, Nienhüser H, Dreikhausen L, et al. Inflammatory cytokines are associated with response and prognosis in patients with esophageal cancer. Oncotarget 2017;8:47518-32. [Crossref] [PubMed]
82. Nygren J, Thorell A, Ljungqvist O. Preoperative oral carbohydrate therapy. Curr Opin Anaesthesiol 2015;28:364-9. [Crossref] [PubMed]
83. Amer MA, Smith MD, Herbison GP, et al. Network meta-analysis of the effect of preoperative carbohydrate loading on recovery after elective surgery. Br J Surg 2017;104:187-97. [Crossref] [PubMed]
84. Torgersen Z, Balters M. Perioperative nutrition. Surg Clin North Am 2015;95:255-67. [Crossref] [PubMed]
85. Findlay JM, Gillies RS, Millo J, et al. Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines. Ann Surg 2014;259:413-31. [Crossref] [PubMed]
86. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2016;40:159-211. [Crossref] [PubMed]
87. Huddy JR, Huddy FMS, Markar SR, et al. Nutritional optimization during neoadjuvant therapy prior to surgical resection of esophageal cancer-a narrative review. Dis Esophagus 2018;31:1-11. [Crossref] [PubMed]
88. Markar SR, Naik R, Malietzis G, et al. Component analysis of enhanced recovery pathways for esophagectomy. Dis Esophagus 2017;30:1-10. [Crossref] [PubMed]
89. Sandrucci S, Beets G, Braga M, et al. Perioperative nutrition and enhanced recovery after surgery in gastrointestinal cancer patients. A position paper by the ESSO task force in collaboration with the ERAS society (ERAS coalition). Eur J Surg Oncol 2018;44:509-14. [Crossref] [PubMed]
90. Probst P, Ohmann S, Klaiber U, et al. Meta-analysis of immunonutrition in major abdominal surgery. Br J Surg 2017;104:1594-608. [Crossref] [PubMed]
91. Jager-Wittenaar H, Ottery FD. Assessing nutritional status in cancer: role of the Patient-Generated Subjective Global Assessment. Curr Opin Clin Nutr Metab Care 2017;20:322-9. [Crossref] [PubMed]
92. Hartwell JL, Cotton A, Rozycki G. Optimizing Nutrition for the Surgical Patient: An Evidenced Based Update to Dispel Five Common Myths in Surgical Nutrition Care. Am Surg 2018;84:831-5. [Crossref] [PubMed]
93. Soeters PB, Wolfe RR, Shenkin A. Hypoalbuminemia: Pathogenesis and Clinical Significance. JPEN J Parenter Enteral Nutr 2019;43:181-93. [Crossref] [PubMed]
94. Yoshida N, Baba Y, Baba H. Preoperative malnutrition and prognosis after neoadjuvant chemotherapy followed by subsequent esophagectomy. J Thorac Dis 2017;9:3437-9. [Crossref] [PubMed]
95. Baracos VE. Cancer-associated malnutrition. Eur J Clin Nutr 2018;72:1255-9. [Crossref] [PubMed]
96. Sealy MJ, Nijholt W, Stuiver MM, et al. Content validity across methods of malnutrition assessment in patients with cancer is limited. J Clin Epidemiol 2016;76:125-36. [Crossref] [PubMed]
97. Quyen TC, Angkatavanich J, Thuan TV, et al. Nutrition assessment and its relationship with performance and Glasgow prognostic scores in Vietnamese patients with esophageal cancer. Asia Pac J Clin Nutr 2017;26:49-58. [PubMed]
98. Evans DC, Martindale RG, Kiraly LN, et al. Nutrition optimization prior to surgery. Nutr Clin Pract 2014;29:10-21. [Crossref] [PubMed]
99. Gillis C, Carli F. Promoting Perioperative Metabolic and Nutritional Care. Anesthesiology 2015;123:1455-72. [Crossref] [PubMed]
100. Baracos VE, Martin L, Korc M, et al. Cancer-associated cachexia. Nat Rev Dis Primers 2018;4:17105. [Crossref] [PubMed]
101. Li S, Xie K, Xiao X, et al. Correlation between sarcopenia and esophageal cancer: a narrative review. World J Surg Oncol 2024;22:27. [Crossref] [PubMed]
102. Purcell SA, Elliott SA, Baracos VE, et al. Key determinants of energy expenditure in cancer and implications for clinical practice. Eur J Clin Nutr 2016;70:1230-8. [Crossref] [PubMed]
103. Viggiani MT, Lorusso O, Natalizio F, et al. Influence of chemotherapy on total energy expenditure in patients with gastrointestinal cancer: A pilot study. Nutrition 2017;42:7-11. [Crossref] [PubMed]
104. Cao DX, Wu GH, Zhang B, et al. Resting energy expenditure and body composition in patients with newly detected cancer. Clin Nutr 2010;29:72-7. [Crossref] [PubMed]
105. van der Schaaf MK, Tilanus HW, van Lanschot JJ, et al. The influence of preoperative weight loss on the postoperative course after esophageal cancer resection. J Thorac Cardiovasc Surg 2014;147:490-5. [Crossref] [PubMed]
106. Hynes O, Anandavadivelan P, Gossage J, et al. The impact of pre- and post-operative weight loss and body mass index on prognosis in patients with oesophageal cancer. Eur J Surg Oncol 2017;43:1559-65. [Crossref] [PubMed]
107. Wightman SC, Posner MC, Patti MG, et al. Extremes of body mass index and postoperative complications after esophagectomy. Dis Esophagus 2017;30:1-6. [Crossref] [PubMed]
108. Lunardi AC, Miranda CS, Silva KM, et al. Weakness of expiratory muscles and pulmonary complications in malnourished patients undergoing upper abdominal surgery. Respirology 2012;17:108-13. [Crossref] [PubMed]
109. Ligthart-Melis GC, Weijs PJ, te Boveldt ND, et al. Dietician-delivered intensive nutritional support is associated with a decrease in severe postoperative complications after surgery in patients with esophageal cancer. Dis Esophagus 2013;26:587-93. [Crossref] [PubMed]
110. Wischmeyer PE, Carli F, Evans DC, et al. American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Nutrition Screening and Therapy Within a Surgical Enhanced Recovery Pathway. Anesth Analg 2018;126:1883-95. [Crossref] [PubMed]
111. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 2019;48:16-31. [Crossref] [PubMed]
112. Prado CM, Purcell SA, Alish C, et al. Implications of low muscle mass across the continuum of care: a narrative review. Ann Med 2018;50:675-93. [Crossref] [PubMed]
113. Boshier PR, Heneghan R, Markar SR, et al. Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis. Dis Esophagus 2018; [PubMed]
114. Wagner D, DeMarco MM, Amini N, et al. Role of frailty and sarcopenia in predicting outcomes among patients undergoing gastrointestinal surgery. World J Gastrointest Surg 2016;8:27-40. [Crossref] [PubMed]
115. Mazzola M, Bertoglio C, Boniardi M, et al. Frailty in major oncologic surgery of upper gastrointestinal tract: How to improve postoperative outcomes. Eur J Surg Oncol 2017;43:1566-71. [Crossref] [PubMed]
116. Hodari A, Hammoud ZT, Borgi JF, et al. Assessment of morbidity and mortality after esophagectomy using a modified frailty index. Ann Thorac Surg 2013;96:1240-5. [Crossref] [PubMed]
117. Cederholm T, Jensen GL, Correia MITD, et al. GLIM criteria for the diagnosis of malnutrition - A consensus report from the global clinical nutrition community. Clin Nutr 2019;38:1-9. [Crossref] [PubMed]
118. Yu Z, Li S, Liu D, et al. Society for Translational Medicine Expert Consensus on the prevention and treatment of postoperative pulmonary infection in esophageal cancer patients. J Thorac Dis 2018;10:1050-7. [Crossref] [PubMed]
119. Asif A, Saleem S, Memon AAQ, et al. Significance Of Dietary Factors In Occurrence, Prevention And Treatment Of Esophageal Carcinoma. JPTCP 2023;30:676-97. [Crossref]

(English Language Editor: L. Huleatt)