Esophagogastric cancer accounts for the second most common cause of cancer-related mortality worldwide. Significant efforts have been made to detect these malignancies at an earlier stage through the implementation of screening programs in high-risk individuals using advanced diagnostic techniques. Endoscopic management techniques, such as endoscopic mucosal resection and endoscopic submucosal dissection, have consistently demonstrated excellent outcomes in the management of these lesions. These techniques are associated with a lower risk of morbidity and mortality when compared with traditional surgical management.
Key points
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Endoscopic management of early esophagogastric cancer is largely dependent on patient factors, the degree of tumour extent and level of medical expertise available.
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Endoscopic mucosal resection is a well-established therapeutic modality in the treatment of early esophageal cancer, early gastric cancer and Barrett esophagus with high-grade dysplasia.
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Ablative therapies are used independently or in combination with endoscopic mucosal resection in the treatment of Barrett esophagus, with or without dysplasia.
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Endoscopic submucosal dissection is superior to other endoscopic treatment modalities in achieving en-bloc or complete resection in tumours greater than 2 cm.
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Endoscopic submucosal dissection has similar outcomes to surgery with respect to the management of esophageal squamous cell carcinoma and early gastric cancer.
Introduction
Esophagogastric cancers remain some of the most difficult cancers to treat, accounting for approximately 16% of cancer-related mortality worldwide. The emergence of advanced diagnostic techniques—including high-resolution, high-definition white light endoscopy; chromoendoscopy; and narrow band imaging—in addition to the implementation of screening programs in certain high-risk individuals has been largely responsible for the early detection of premalignant and malignant lesions. Traditionally, the gold standard treatment of esophagogastric cancer has been surgery, even at the earliest stages of malignancy. These procedures, however, are associated with increased rates of treatment-related morbidity and mortality. Over the past decade, minimally invasive endoscopic management has become a viable alternative to surgical treatment. Ultimately, the mode of management is determined by local factors, including a patient’s age, comorbidities, and personal preference as well as the level of available medical expertise. This review discusses some of the major modes of endoscopic management pertaining to early esophageal and gastric cancer, including its techniques, indications and surrounding controversies.
Introduction
Esophagogastric cancers remain some of the most difficult cancers to treat, accounting for approximately 16% of cancer-related mortality worldwide. The emergence of advanced diagnostic techniques—including high-resolution, high-definition white light endoscopy; chromoendoscopy; and narrow band imaging—in addition to the implementation of screening programs in certain high-risk individuals has been largely responsible for the early detection of premalignant and malignant lesions. Traditionally, the gold standard treatment of esophagogastric cancer has been surgery, even at the earliest stages of malignancy. These procedures, however, are associated with increased rates of treatment-related morbidity and mortality. Over the past decade, minimally invasive endoscopic management has become a viable alternative to surgical treatment. Ultimately, the mode of management is determined by local factors, including a patient’s age, comorbidities, and personal preference as well as the level of available medical expertise. This review discusses some of the major modes of endoscopic management pertaining to early esophageal and gastric cancer, including its techniques, indications and surrounding controversies.
Early esophageal cancer
Esophageal cancer typically occurs in 2 histologic forms: squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma is the predominant form of esophageal cancer in Asia and much of the world. Its major risk factors include alcohol and tobacco abuse. Squamous cell carcinoma can develop anywhere in the esophagus but often occurs proximally. Adenocarcinoma is the leading type of esophageal cancer in most Western countries. This is due to the high incidence of Barrett esophagus, a premalignant condition involving replacement of the squamous epithelium in the distal esophagus of any length with columnar epithelium with identifiable intestinal metaplasia on histopathologic assessment.
Early esophageal cancers are classified as low-grade and high-grade intraepithelial neoplasia (dysplasia) and as adenocarcinoma contained within the mucosa. This definition is sometimes extended to include superficial submucosal involvement. Endoscopic therapy has become an integral part of the multidisciplinary management of early esophageal cancer. These approaches include endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), radiofrequency ablation (RFA), photodynamic therapy (PDT), cryotherapy and argon plasma coagulation (APC).
Initial Assessment
The UK National Institute for Health and Care Excellence guidelines recommend that endoscopic procedures (1) need to be carefully considered in high-volume tertiary referral centers with access to a surgeon, (2) should be performed by appropriately trained staff, and (3) must be managed by a multidisciplinary team to optimize patient care. For the best outcomes, patients suitable for endoscopic therapy must be carefully selected to avoid inadequate treatment of advanced cancers. An important aspect of choosing an appropriate management strategy is the accurate assessment of disease extent. It is important to carefully assess the depth of invasion, tumor grade, and degree of lymphovascular invasion to determine the stage of esophageal cancer. Submucosal involvement is the most important prognostic determinant for early esophageal cancer because the presence of lymphatic vessels within the submucosa facilitates dissemination of malignant cells. Modalities, such as endoscopic ultrasound, and histopathologic examination through biopsy and EMR have been shown to accurately predict lymph node involvement.
Endoscopic Mucosal Resection In Early Esophageal Cancer
EMR was first described in 1973 as a novel treatment of colorectal polyps. It has evolved into an effective diagnostic and treatment option for both early esophageal and gastric cancers. According to recently modified guidelines published by the Japanese Esophageal Society, lesions confined to the mucosal epithelium or lamina propria of the mucosal layer are rarely associated with lymph node metastasis. As such, EMR is suitable to treat these lesions. Lesions reaching the muscularis mucosae or slightly infiltrating the submucosa (up to 200 μm, T1b-SM1) are amenable to EMR but may carry a risk of lymph node metastasis. Therefore, these cases represent relative indications to performing EMR; 50% of lesions invading deeper (greater than 200 μm) into the submucosa (T1b-SM2) are associated with the presence of nodal metastases and should be treated in the same manner as advanced cancers (ie, cancer exceeding the muscularis propria) with esophagectomy.
The literature describes 3 major EMR techniques, including the inject, lift, and cut method; the cap-assisted EMR method; and EMR with ligation. EMR typically involves the injection of normal saline, which may be mixed with dilute adrenaline to allow for a bloodless endoscopic view, and a dye to better identify the target lesion. This submucosal injection both cushions and isolates the tissue before removal of the lesion with a snare. This also reduces the risk of thermal injury, perforation, and hemorrhage as well as facilitating en bloc resection. The cap-assisted technique is frequently used to excise early esophageal cancers ( Fig. 1 ). After submucosal injection, a cap mounted on the head of the endoscope is placed over the target lesion, which is subsequently suctioned into the cap. The snare, placed in the cap, is then closed around the base and diathermy is used to complete the excision. The banding method, or EMR ligation, is also commonly used. It involves using a band ligation device. The inject, lift and cut method is safe and straightforward but is more frequently used to manage colonic lesions. Larger lesions exceeding 2 cm are not excluded from EMR, although they may require piecemeal resection. Piecemeal resection is associated with tumor recurrence and should be performed with meticulous attention to avoid any residual islands of tissue being left behind.
Endoscopic mucosal resection in barrett esophagus
Endoscopic therapy is not recommended for the treatment of Barrett esophagus without dysplasia. It is the treatment of choice, however, for Barrett esophagus with high-grade dysplasia (HGD) and early mucosal cancer. Visible nodules or lumps in metaplastic Barrett esophagus have a high incidence of invasive cancer. Tissue sampling with biopsies from these lesions tends to underestimate the degree of dysplasia. Multiple studies have shown that EMR leads to better interobserver agreement with respect to the degree of dysplasia and can lead to clarification of the final histologic stage when compared with biopsy specimens. Follow-up of a seminal study conducted by Pech and colleagues found that the rates of recurrence and metachronous neoplasia range from 0% to 30%. Bleeding and stricture formation were the most common complications, which both could be dealt with endoscopically. Bleeding can occur in up to 12% of patients whereas perforation may occur in up to 2.3%. Early intervention demonstrated a higher remission rate and faster response time for small and low-grade cancers removed with EMR. A prospective study was conducted in 64 patients with early carcinoma or HGD who were grouped as low-risk or high-risk based on their stage, size and grade of cancer. These results demonstrated a higher complete remission rate for the low-risk group (97%). The mean follow-up period of 12 months revealed a 14% rate of recurrence for metachronous neoplasia. In a case series, recurrences of dysplasia or carcinoma were reported in 12% to 21% of patients after a mean follow-up period of 43 to 63 months. These cases were amenable to repeat endoscopic management. The risk of recurrence was higher in patients with long segment Barrett esophagus, patients with multifocal neoplasia, patients who underwent piecemeal resection and patients who needed a longer period to achieve complete remission. Another study assessed the role of endoscopy in esophageal adenocarcinomas limited to the upper third of the submucosa. The main outcomes included complete endoluminal remission in 87% and long-term remission in 84% of cases. Lymph node metastasis was ultimately found in only 1.9%, and metachronous neoplasia in 19% of cases. With the low rate of lymph node metastasis and an estimated 5-year survival rate of 84%, endoscopic therapy was thought preferable for small, low-risk esophageal cancers with SM1 involvement.
Endoscopic mucosal resection in squamous cell carcinoma
Lymphovascular invasion occurs earlier in squamous cell carcinoma. Lesions confined to the epithelium and lamina propria have up to a 5.6% risk of lymph node metastasis. Nodal metastases occur in up to 18% of patients with muscularis mucosae involvement and up to 53% of patients with SM1 involvement. A Japanese study reported on the outcomes of EMR in superficial esophageal cancer in 396 patients at 80 institutions. En bloc resection rates of 64.3% were achieved in tumors measuring less than 1 cm in diameter and 36.5% in those less than 2 cm in diameter. Patients with submucosal cancers showed significantly worse 5-year survival rates than those with mucosal cancers. In another prospective case series by Pech and colleagues, a total of 179 resections were performed (mean number of resections ± SD per patient, 2.8 ± 1.8); 11 of 12 patients (91.7%) with high-grade intraepithelial neoplasia and 51 out of 53 patients (96.2%) with mucosal cancer achieved a complete response during a mean follow-up period of 39.3 ± 22.8 months. Recurrence of malignancy after achieving a complete response was observed in 16 patients (26%), but these patients all achieved complete response after further endoscopic treatment. Independent risk factors for tumor recurrence included multifocal carcinoma (relative risk 4.1, P = .018). The 7-year survival rate calculated for all groups was 77%. Ciocirlan and colleagues performed a retrospective cohort study of 51 patients with early squamous cell carcinoma or HGD. These results demonstrated a complete local remission rate of 91% and a 5-year survival rate of 58%, mandating the need for close endoscopic surveillance after EMR.
Hence, patients with squamous cell carcinoma confined to the superficial mucosa (m1 and m2) may be candidates for EMR. Tumors that have invaded into the deep mucosa or submucosa, however, should be referred for surgical resection.
Ablative therapies
Ablative therapies have become one of the most important endoscopic modalities in the management of Barrett esophagus. They can be used independently or in combination with EMR in the treatment of Barrett-related dysplasia or early adenocarcinoma. A concerning factor for ablative therapies is the risk of recurrence from buried glands where neosquamous epithelium overgrows ablated tissue, potentially masking residual metaplastic or dysplastic tissue.
Radiofrequency ablation
RFA devices deliver alternating currents of electromagnetic waves at high frequency to physically destroy premalignant or malignant tissue. This technique is completed via catheters with inflatable balloons along guidewires or plates, which are attached to the tip or instrumental channel of an endoscope. The American College of Gastroenterology guidelines recommend that in subjects with EMR specimens demonstrating HGD or intramucosal carcinoma, endoscopic ablative therapy for the remaining Barrett esophagus should be performed. Given the costs and side-effect profile associated with PDT, RFA seems the preferred modality of ablative therapy for most patients. This is supported by a large body of data demonstrating its safety and efficacy. RFA is highly effective in the complete eradication of intestinal metaplasia and dysplasia, which has been confirmed by multiple studies, including the landmark Ablation of Intestinal Metaplasia Containing Dysplasia trial. In another European multicenter study, focal EMR followed by RFA was found safe and highly effective for the eradication of early Barrett-related adenocarcinoma as well as complete resection of the entire Barrett segment, correlating with success rates of approximately 90%. During a median follow-up of 27 months, the recurrence rate of neoplasia or visible Barrett mucosa remained at less than 10%. Common side effects included dysphagia, stricture formation, bleeding, and, rarely, perforation.
Photodynamic therapy
PDT involves the application of a photosensitizing agent, such as oral 5-aminolevulinic acid or intravenous sodium porfimer. When these photosensitizing agents are exposed to a specific wavelength of light, they produce a form of oxygen that can destroy nearby cells. PDT may be used as an alternative treatment option for Barrett esophagus with dysplasia. In a prospective, double-blind, randomized trial, PDT was compared with a placebo therapy in patients with low-grade dysplasia in Barrett esophagus. In the group exposed to PDT, 89% of patients responded with neosquamous epithelium in the treated area and no further development of dysplasia. Comparatively, no epithelial response was detectable in 67% of patients in the placebo group. Although this technique is effective, it is expensive and has unfavorable side effects, including stricture formation, skin photosensitivity, vomiting and chest pain.
Cryotherapy
Cryotherapy involves snap freezing of the surface epithelium, by using either liquid nitrogen or rapidly expanding carbon dioxide, which is released at high velocity, leading to immediate apoptosis. Cell injury occurs during reperfusion by the generation of free radicals in the frozen tissue as it is reoxygenated. Johnston and colleagues described the use of cryotherapy in 11 patients with Barrett esophagus. Histologic reversal of Barrett esophagus was identified in 78% of patients (n = 9) after a 6-month follow-up period without any major complications. Several other small studies have shown benefit with cryotherapy, particularly with patients excluded from surgery or who have failed other endoscopic treatments. Longitudinal studies are further required to determine the durability of benefits from cryotherapy at any stage of Barrett esophagus.
Argon plasma coagulation
APC causes thermal injury to the mucosa through energy delivery from ionized argon plasma via monopolar electrocautery. It is a recognized technique in the treatment of nondysplastic Barrett esophagus. Success rates of 70% to 86% have been reported when used in isolation for the eradication of Barrett esophagus with or without HGD. APC can lead to complications, however, such as postprocedural chest pain, ulceration, bleeding and stricture development. Buried glands may also occur in up to 30% of cases, which is considerably more common compared with other ablative therapies. Since the development of RFA, it has been used less frequently in the management of nondysplastic Barrett esophagus.
Endoscopic Submucosal Dissection In Early Esophageal Cancer
ESD was pioneered in Japan in the 1990s to overcome the shortfalls of endoscopic management for early gastric cancer (EGC). It is an advanced endoscopic technique, which first involves marking the target lesion with several vertical and lateral markings around its margin. The submucosa is then lifted with an injection solution similar to that used in EMR. The mucosa is then incised using a range of electrocautery knives. This allows for direct dissection of the submucosal layer until complete removal of the target lesion is achieved ( Fig. 2 ). The advantage of ESD is its ability to achieve en bloc margin-negative resection of tumors greater than 2 cm. It also reduces the need for piecemeal resection, which is associated with high rates of local recurrence. Due to the narrow lumen of the esophagus, which is prone to stricture formation, the Japanese Esophageal Society developed absolute and relative indications for performing ESD. Absolute indications include T1a esophageal carcinomas involving the epithelium or lamina propria and less than two-thirds of the circumference of the esophagus. Relative indications include esophageal carcinomas involving the muscularis mucosae or less than 200 μm of the submucosa. Most of the published literature stems from Japanese centers, given the high incidence of squamous cell carcinoma. Results of a recent survey suggested that only 12 of 340 published articles were reported from Western countries. Studies have still shown that the incidence of lymph node metastasis with T1a esophageal adenocarcinoma may be up to 2.6%, which is comparatively less than the mortality rate after esophagectomy. Therefore, it seems reasonable to consider ESD in the management of early esophageal cancer.
Related posts:
Advances in Esophageal and Gastric Cancer
Gastric and Esophageal Cancer 2017
The Asian Perspective on the Surgical and Adjuvant Management of Esophagogastric Cancer
Controversies and Consensus in Preoperative Therapy of Esophageal and Gastroesophageal Junction Cancers
Radiation Therapy for Locally Advanced Esophageal Cancer
Issues in the Management of Esophagogastric Cancer in Geriatric Patients
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