Importance of early detection of esophageal cancer before the tumor progresses too much for effective treatment

Abstract

This editorial comments on an article by Qu et al published in the World Journal of Gastrointestinal Oncology. It focuses on the importance of early detection of esophageal cancer, including recurrence or secondary malignancy after chemoradiotherapy (CRT). Endoscopic resection is the first choice for treatment for esophageal cancer remaining within the mucous membrane, while surgery or radical CRT are treatment options for advanced stages depending on the patient’s general condition and desire. Although these treatments are potentially curative, they are more invasive than endoscopic resection. Early-stage esophageal cancer is often asymptomatic and difficult to detect. Uniform periodic endoscopy is unrealistic. Although less burdensome tests exist, including liquid biopsy and urinary biomarkers, these have not yet been widely used in clinical practice. Early detection is important after radical CRT because the local recurrence rate is higher than that after surgery. However, endoscopic resection or photodynamic therapy is indicated if detected in the early stages, and positive results have been reported. Early detection of esophageal cancer is crucial. Endoscopy is the main diagnostic method; however, new and less burdensome methods should be established to ensure early treatment for patients with esophageal cancer.

Key Words: Esophageal neoplasms; Screening; Endoscopy; Prognosis; Endoscopic mucosal resection; Endoscopic submucosal dissection; Photodynamic therapy

Core Tip: Surgery and chemoradiotherapy (CRT) for esophageal cancer are more invasive than endoscopic resection. However, early esophageal cancer is often asymptomatic and difficult to detect at an early stage. Uniform periodic endoscopy is unrealistic. This is a challenging problem. Regular endoscopy after CRT is also important, and if detected early, a complete cure can be expected with less burdensome endoscopic treatment. Currently, endoscopy is the main diagnostic method, but the hope is that new and less burdensome diagnostic methods will be established to ensure early treatment.

INTRODUCTION

Esophageal cancer has a poor prognosis and is the sixth leading cause of mortality (544000 deaths annually) globally. For instance, esophageal cancer was responsible for one out of every 18 cancer deaths in 2020[1]. Esophageal cancer is the most common malignancy in Eastern Asia, including China and Japan, with an age-standardized rate of 12.2 per 100000 person-years. This can partly be explained by varying distributions of the two main histologic subtypes of esophageal cancer, namely adenocarcinoma (AC) and squamous cell carcinoma (SCC). The latter histologic subtype is linked to tobacco smoking, heavy alcohol consumption, air pollution, and diet. SCC is the most common, accounting for > 90% of all esophageal cancer cases in high-risk regions. Other contributors to the high incidence observed in some countries remain to be elucidated[2]. The prognosis of SCC and AC differs slightly. The five-year overall survival (OS) rate for patients with SCC and AC was 21.1% and 24.2%, respectively, in 2010. After 1985, the OS rates for AC increased compared to SCC[3]. If patients with stage 1 esophageal cancer do not receive any treatment, the five-year OS rate is only ≤ 10%. Additionally, advanced stages show poorer prognoses[4].

Treatment for esophageal cancer varies depending on the disease progression. Endoscopic resection is recommended for esophageal cancer that remains within the mucosa without lymph node metastasis. In contrast, surgery with or without preoperative chemotherapy or chemoradiotherapy (CRT) is recommended for patients with more advanced-stage and resectable esophageal cancer. Radical CRT is a treatment option if preserving the esophagus is desirable or if surgery is difficult for any reason, such as older age and comorbidities. Radical CRT is indicated for cases of unresectable esophageal cancer[5-8]. Although concurrent chemotherapy is preferred, radiation therapy alone may be curative[9]. Treatment with immune checkpoint inhibitors is indicated as a postoperative treatment after preoperative CRT followed by surgery, and its results are improving[10]. However, patients find themselves with fewer options as the disease progresses towards the discovery stage. This editorial focuses on the importance of early detection of esophageal cancer, including recurrence or secondary malignancy after CRT.

IMPACT OF EARLY DETECTION ON INITIAL TREATMENT

At an early stage, when esophageal cancer remains within the mucous membrane, endoscopic resection, such as endoscopic mucosal resection or endoscopic submucosal dissection, is the first choice for treatment because it requires local excision and imposes the least burden on the patient’s body[5-7]. Surgery requires the removal of the esophagus, resulting in a loss of function. However, with CRT, the esophagus is retained but does not possess the same function as before. Although the decline in quality of life diminishes compared to surgery, especially in terms of loss of appetite and diarrhea, it is not completely eliminated[11]. Proton beam therapy reduces the total toxicity burden by more than half compared to intensity-modulated radiotherapy[12] but is more invasive than endoscopic resection.

The five-year OS rate after endoscopic resection is 87.2%, which is considered a good rate, and is based on actual clinical data, including cases ineligible for clinical trials[9]. Completing the treatment with less invasive methods is important; however, the disease is often asymptomatic in the early stages[2], and detecting the cancerous lesion in a state that can be resected endoscopically without some kind of examination is challenging. The report by Wei et al[13] serves as proof of this concept. In their study, the reduction in cumulative mortality in the intervention and control groups was 3.35% and 5.05%, respectively (P < 0.001)[14]. However, the mortality rate reduction due to intervention is not robust, and routine endoscopy for uniform screening is difficult to recommend in practice. If less invasive tests, such as liquid biopsy and urinary biomarkers are established as previous studies[14-16] and Qu et al[17] said, identifying separate groups for which endoscopy should be performed may be possible, allowing the realization of more realistic screening methods.

IMPORTANCE OF REGULAR ENDOSCOPY AFTER CRT FOR EARLY DETECTION

Early detection is important for initial treatment and recurrence or secondary malignancy after radical CRT. Local recurrence is inevitably more common after CRT than after surgery, posing a significant problem. A clinical trial revealed that the local recurrence rate within the irradiation field was 15.1% in stage 1[18] and increased to 32% in stage 2/3[19]. Even in rigorous clinical trials, the incidence of treatment-related death after salvage surgery was 4%[19]. In a systematic review, the treatment-related death rate after salvage surgery for recurrence after CRT was reported at 10.3%[20]. After salvage surgery, the three-year OS was only 33.5%, and 9.6% of patients experienced grade 3 toxicities, including anastomosis leak[18].

In contrast, the five-year OS rate was 49.1%, with no severe toxicity after salvage endoscopic mucosal resection for recurrence after CRT[21]. Photodynamic therapy, which is considered more useful than endoscopic resection, is indicated if local recurrence occurs without lymph node metastasis and the invasion of the muscularis mucosae. This treatment’s local complete response rate is 58.4%, and the five-year OS rate is 35.9%[22]. This treatment is less invasive than salvage surgery; however, the tumor must be detected early before its progression. Sudo et al[23] reported that 93% of cases of local recurrence after radical CRT were diagnosed within three years. The annual odds of a secondary malignancy diagnosed using endoscopy did not decrease over time. These results indicate the need to exercise caution during the first three years after radical CRT; however, even after three years, regular endoscopy is necessary to detect secondary malignancy before it advances.

CONCLUSION

Early detection of esophageal cancer is crucial. Endoscopy is the main diagnostic method; however, new and less burdensome diagnostic methods should be established to ensure early treatment for patients with esophageal cancer.