Just because you can (and radiotherapy seems to be effective), doesn’t mean you should

Endoscopic therapy of early squamous cell cancer (SCC) has become the treatment of choice, including in the West. A major disadvantage of endoscopic therapy is the relatively high rate of recurrence, as the organ at risk is not removed. Back in the days when conventional endoscopic mucosal resection (EMR) with ligation devices or the cap technique was performed, recurrence rates were as high as up to 26 % [1]. The reason for this high recurrence rate was considered to be residual neoplastic tissue in the esophagus after piecemeal resection. Therefore, endoscopic submucosal dissection (ESD) was introduced as a method of achieving en bloc resection of the squamous cell neoplasia. The two main advantages of ESD are: 1) a very low risk of leaving residual neoplastic tissue behind when the margins of the resection specimen are tumor free; 2) the squamous cell neoplasia can be analyzed by a pathologist in order to confirm complete resection and to look for the presence of risk factors for lymphatic spread of the tumor, such as submucosal invasion, lymph vessel invasion, and poor differentiation grade. Retrospective studies comparing EMR with ESD in the treatment of early neoplastic squamous lesions have demonstrated that ESD has a significantly lower recurrence rate than EMR [2]. However, there is still a risk of recurrence after ESD. This led to the concept of additional treatment with radiotherapy or radiochemotherapy after ESD of SCCs.

“In the end, the question remains whether we should really advise our patients to undergo radiotherapy after ESD to reduce local recurrence, even though it has been shown to be effective in this study from China.”

In the current issue of Endoscopy, Zhang et al. report on their prospective randomized study, which included 70 patients with SCC limited to the mucosa (T1a) who underwent ESD [3]. In all patients, complete resection (R0) was confirmed by the pathologist. Patients were then randomized into a follow-up arm and an additional radiotherapy arm. Patients in the radiotherapy arm received a median dose of 59.4 Gy on the tumor bed but not including the regional lymph nodes. During a median follow-up of 35 months (range 6 – 50 months), there were three recurrences in the non-radiotherapy group and none in the radiotherapy group. Tumor-related death or distant metastasis were not observed. Surprisingly, radiotherapy had no influence on the stricture rate after ESD (nine patients with strictures in each group).

The concept in this study is new, as radiotherapy or radiochemotherapy is usually added after ESD in patients who have an increased risk of developing lymph node metastasis in order to reduce the risk for lymph node recurrence and to avoid surgery [4]. However, in this trial, the aim was to reduce the risk of local intraluminal recurrence only. The regional lymph nodes were explicitly spared during radiotherapy because only patients with mucosal SCC were included. There were only three patients with recurrence in the non-radiotherapy group and those were re-treated with ESD without any problems. Unfortunately, the authors did not provide any information about the characteristics of the recurrences and the second ESD procedure. It would have been very interesting to know whether the recurrence was a “real” recurrence detected at the scar of the previous ESD or whether it was a metachronous neoplasia at a different site. Local recurrence after R0 resection is quite rare but the risk for metachronous neoplasia in patients with SCC is relevant. In particular, patients with multiple Lugol-voiding lesions have an increased risk of developing a second cancer during follow-up [5] [6]. One possible explanation for this high rate of metachronous neoplastic lesions is a so-called “field cancerization” effect [7]. Early genetic events might lead to clonal expansion of preneoplastic daughter cells in the esophagus. Subsequent genomic changes in some of these cells drive them towards the malignant phenotype. Those transformed cells could be diagnosed histopathologically as neoplastic lesions leading to changes in cell morphology. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remains in the esophagus, demonstrating the concept of field cancerization. A possible explanation of the positive effect of radiotherapy might be the destruction of those daughter cells with genetic changes on their way to cancer or hidden neoplastic cells in Lugol-voiding lesions.

Radiotherapy seems to be effective in reducing the risk for local intraluminal recurrences after ESD of squamous cell neoplasia. The number needed to treat was 12 in the Zhang et al. study, which means that 12 patients would have to undergo radiotherapy with 59.4 Gy in order to prevent one local recurrence. We have to keep in mind that all recurrences that were reported in the study could be re-treated endoscopically. In the end, the question remains whether we should really advise our patients to undergo radiotherapy, even though it has been shown to be effective in this study from China. In addition, we have no information yet on whether the effect of radiotherapy is the same in Western patients.

Even after radiotherapy, we have to perform follow-up endoscopies in our patients. In the rare event of a local recurrence, ESD could be performed easily to achieve cure. However, performing ESD of a recurrence after radiotherapy is usually cumbersome due to submucosal fibrosis and might lead to a higher complication rate of endoscopic resection. Therefore, we should wait for more and larger prospective series before we perform radiotherapy after ESD in T1a SCC on a routine basis.

Publikationsverlauf

Artikel online veröffentlicht:
25. November 2020

• References

• 1 Pech O, May A, Gossner L. et al. Curative endoscopic resection in patients with early esophageal squamous cell carcinoma or high-grade intraepithelial neoplasia. Endoscopy 2007; 39: 30-35
• 2 Takahashi H, Arimura Y, Masao H. et al. Endoscopic submucosal dissection is superior to conventional endoscopic resection as a curative treatment for early squamous cell carcinoma of the esophagus (with video). Gastrointest Endosc 2010; 72: 255-264
• 3 Zhang Y, Liu L, Wang Q. et al. Endoscopic submucosal dissection with additional radiotherapy in the treatment of T1a early esophageal squamous cell carcinoma: a prospective randomized controlled trial. Endoscopy 2020; 52: 1066-1074
• 4 Minashi K, Nihei K, Mizusawa J. et al. Efficacy of endoscopic resection and selective chemoradiotherapy for stage I esophageal squamous cell carcinoma. Gastroenterology 2019; 157: 382-390
• 5 Muto M, Hironaka S, Nakane M. et al. Association of multiple Lugol-voiding lesions with synchronous and metachronous esophageal squamous cell carcinoma in patients with head and neck cancer. Gastrointest Endosc 2002; 56: 517-521
• 6 Katada C, Yokoyama T, Yano T. et al. Association between the findings of metachronous secondary primary malignancies and the number of Lugol-voiding lesions. Dis Esophagus 2020; DOI: 10.1093/dote/doz110.
• 7 Jaiswal S, Jaiswal S, Kumar R. et al. Field cancerization: concept and clinical implications in head and neck squamous cell carcinoma. J Exp Ther Oncol 2013; 10: 209-214