Characteristics And Treatment Advances Of Cardia Cancer

The definitions of GCC vary domestically and internationally. Some studies abroad define GCC as occurring in the cardia mucosa 3 cm below and 2 cm above the gastroesophageal junction, while others describe type II tumors located 1 cm above and 2 cm below the gastroesophageal junction as “true GCC.” Existing data show that GCC is highly prevalent in regions with high rates of esophageal gastric cancer, with an epidemiological trend opposite that of esophageal gastric cancer, and the etiology may differ from that of esophageal gastric cancer. There may be two possible pathways for development: in high-risk areas, the pathway related to Helicobacter pylori infection (Hp), low acidity, and intestinal metaplasia-developing abnormalities-cancer may exist, while in low-risk areas, mucosal damage induced by reflux toxins, high acidity leading to intestinal metaplasia-developing abnormalities-cancer may occur.

The incidence of GCC in men and women increases with age, peaking at 55-69 years, and then gradually declining, while the incidence of non-GCC increases with age before 60 and remains stable. There is a significant gender difference in GCC, with a higher diagnosis rate of male CGA compared to females, with a male-to-female ratio of 3:1. The median overall survival for males is 3.871 years, while for females, it is 4.274 years. Gender is an independent prognostic factor for GCA patients, with female patients showing significantly better survival than male patients, and the independent prognostic factors differ between genders in GCA patients.

Hp infection is a major risk factor for non-GCC but does not increase the risk of GCC. Obesity and gastroesophageal reflux disease have been associated with an increased risk of GCC but are unrelated to non-GCC. Being overweight is associated with an increased risk of GCC, and higher body fat in late adolescence and early adulthood is related to the risk of malignancy in old age. Meta-analysis shows that higher body mass index (BMI) is associated with CGA risk but not with NCGA risk. In population-based studies, metrics like waist circumference and waist-to-hip ratio may be better cancer risk indicators than BMI. A meta-analysis indicates that individuals who exercise regularly have a 21% reduced risk of gastric cancer compared to those who do not, with NCGA (37% risk reduction) and CGA (20% risk reduction) both reporting this risk reduction. Smoking is associated with CGA, with higher risks in low, medium, and high-intensity smoking populations compared to NCGA. Low-grade chronic inflammation caused by diet may be related to the risk of GCC. Individuals with blood type B have a relatively increased risk of developing GCC.

With the passage of time and changes in lifestyle, the main pathogenic factors for gastric cancer are changing, such as the decline in Hp infection rates, changes in dietary structure (reduced salt intake, increased coffee and alcohol consumption, increased meat intake, prevalence of takeout and fast food), changes in behavioral factors (decrease in smoking, increase in obesity), occupational exposure, genetic factors, etc. Hp infection is correlated with precancerous lesions of GCC, and various clinical evidence should be collected during the early stages of lesions. Addressing factors such as Hp infection symptomatically will benefit the prognosis of this disease, while incorporating Hp infection testing into the early screening of GCC, as an auxiliary diagnostic means outside of upper gastrointestinal endoscopy, will help improve the detection rate of precancerous lesions of GCC.

Environmental factors are also closely related to the occurrence of GCC. Tobacco contains various carcinogens and free radicals, such as polycyclic aromatic hydrocarbons, benzopyrene, and nicotine, which can damage the cardia mucosa upon reaching it. Additionally, smoking can stimulate increased gastric acid secretion and reflux, causing direct damage to the cardia mucosa, thereby increasing the risk of GC carcinogenesis. Alcohol can inhibit the expression of antioxidants and cell protective enzymes and induce the expression of CYP2E1, leading to the production of reactive oxygen species, stimulating the absorption of chemical carcinogens and their metabolites, causing inflammatory responses, and directly damaging tight junctions between cells, leading to damage to the cardia mucosa. The mechanism by which high BMI causes GCC may involve abdominal pressure leading to ectopic and damaged lower esophageal sphincter, increased bile and pancreatic enzyme output, and the development of hiatal hernia, further contributing to the occurrence of GCC.

Genetic factors are also an important cause of GCC. Scholar Jiang Meihua’s research first reported that the heterozygous mutation at the NT5E 3’UTR rs6913634 polymorphic site increases the risk of gastric cancer and GCC in the local population, while the homozygous mutation at the miR-30a polymorphic site rs2222722, which binds to NT5E, increases the risk of GCC in the local population.

For early gastric cancer patients without lymph node metastasis, tumor location is not a predictor of overall survival. Therefore, the criteria for endoscopic resection of early non-cardia gastric cancer may apply to the treatment of early GCC. A thorough examination and necessary biopsies should be performed on the cardia of middle-aged and elderly patients. Once a high-grade intraepithelial neoplasia or early cancer diagnosis is confirmed, endoscopic submucosal dissection (ESD) should be the preferred treatment method for most cases. Endoscopic submucosal tunneling tumor resection can be performed on both cardia and non-cardia sites, and its efficacy is comparable to that of non-cardia sites. Irregular morphology is an independent risk factor for incomplete resection.

Some studies suggest that the best method for cardia tumors has not yet been fully determined, and the complication rate remains high, but significant progress has been made through minimally invasive techniques. Open surgery for GCC with abdominal approach allows for more thorough lymph node dissection, fewer postoperative pulmonary complications, and minimal impact on patient prognosis, with higher safety than thoracotomy. Japanese scholars recommend using the translingual approach for GCC rather than the left thoracoabdominal approach. The treatment strategy for gastric cancer surgery is shifting from “aggressive treatment to minimally invasive” and “to conservative treatment,” but this does not imply that the advantages of laparoscopic or robotic minimally invasive surgery (laparoscopic and robotic surgery) should be overlooked.

The basic principle of neoadjuvant chemotherapy is to shrink the tumor volume, downstage it, and kill dormant tumor cells by using chemotherapy drugs before surgery, which is expected to allow for more thorough surgical resection, reduce tumor recurrence rates, and prolong patient survival. In clinical practice, most patients diagnosed with GCC are already in advanced stages, making surgical cure impossible. New chemotherapy methods such as apatinib combined with chemotherapy, 5-fluorouracil sustained-release particles, oxaliplatin + tegafur (SOX regimen) combined with three-dimensional conformal radiotherapy have been shown to effectively improve the survival rate, quality of life, and prognosis of GCC patients compared to traditional chemotherapy drugs in clinical studies. Neoadjuvant chemotherapy has similar survival effects to neoadjuvant chemoradiotherapy for resectable GCC patients. Stenting under direct endoscopic vision and fluoroscopy for patients with advanced esophageal GCC has proven effective, with direct endoscopic procedures being simple and accurate. However, when the degree of stricture is severe, fluoroscopic operations may be considered. In patients with advanced GCC, placing a new type of fully covered radioactive stent is safe and effective, providing rapid relief of dysphagia and effectively preventing stent re-stenosis. The underestimation rate of GCC in predicting infiltration depth is significantly higher than that of non-GCC, so caution should be exercised when selecting ultrasound treatment methods for GCC. Two single marker prediction models for predicting the survival rates of GCC and non-GCC patients, based on genetic support vector machines and genetic algorithms-Cox methods, can provide more support for individualized treatment of GCC and non-GCC patients. The pathological response to neoadjuvant chemotherapy (new CTX) is a prognostic factor for many cancer types, and early prediction can help alter treatment. The response PET-CT after the first cycle of new CTX cannot accurately predict the overall pathological response. However, PET-CT reliably detects non-responders and identifies which patients should immediately undergo resection or receive modified multimodal treatment.

Early detection and accurate diagnosis of GCC through precise endoscopic examinations such as chromoendoscopy and indicative biopsies can improve the diagnosis rate of GCC. By utilizing chromoendoscopy, electronic chromoendoscopy, and endoscopic ultrasound to assess the extent and layers of GCC lesions, resection or cure can be achieved through ESD, surgical open surgery, etc., providing early enteral nutritional support. New chemotherapy drug combinations and stenting under direct endoscopic vision or fluoroscopy have been clinically confirmed for treating advanced GCC patients. Various intervention methods can enhance comprehensive treatment for GCC patients, improving quality of life and prognosis.

References (omitted)

This article cites: Meng Tong, Qin Ziwen, Chen Xing, et al. Characteristics and Treatment Advances of Cardia Cancer [J/CD]. Chinese Journal of Gastrointestinal Endoscopy, 2021, 8(2): 86-88.