With the increase in endoscopic procedures for SESCC, the number of high risk patients with recurrence requiring adjuvant treatment is also expected to increase, and the choice of adjuvant treatment, e.g., esophagectomy or CRT, is becoming a major clinical issue. Compared to surgery, CRT is less invasive, but it also has the drawback of frequent local recurrence. Combined ESD and CRT provide a higher local control rate than definitive CRT alone [18–20], and theoretically fewer cardiopulmonary AEs occur because the appropriate irradiation dose can be delivered after the histopathological findings are confirmed. Our study observed no significant differences in prognosis between the esophagectomy and CRT groups despite the large number of elderly patients in the CRT group. Thus, the safety of CRT was also acceptable.
The efficacy of adding CRT after ESD has been shown in many published reports [2–4, 11, 21]. However, few reports have directly compared the outcomes of surgical treatment and CRT after ESD, and most were small retrospective studies with short follow-up periods [9, 13, 22]. Tanaka et al. investigated 52 cases of ESD combined with CRT for SESCC with submucosal invasion (19 esophagectomy, 33 CRT) and reported that the 3-year DFS of CRT was comparable to that of surgery (87.4% and 100%, respectively) [9]. Ikeda et al. reviewed 43 patients with clinically suspected SESCC treated with ESD [13], 15 of whom underwent adjuvant surgery, 11 underwent adjuvant CRT/radiotherapy, and 17 were followed up without adjuvant treatments. During the follow-up period of 36 months, the DFS of the adjuvant therapy groups was higher than that of the follow-up group without adjuvant treatment (p = 0.04), but there was no significant difference between the adjuvant CRT/radiotherapy and surgery groups (69% and 86%, respectively). Koterazawa et al. investigated 59 patients (28 esophagectomy, 31 CRT) who developed SESCC after noncurative ESD [22]. During a median follow-up of 45 months in the esophagectomy group and 41 months in the CRT group, there were no significant differences (p = 0.46) in OS between the two groups. These findings are similar to our findings, and adjuvant CRT after noncurative ESD may be a realistic treatment option for high-risk SESCC.
A systematic review by Lima [2] reported that patients who underwent ESD followed by CRT/radiotherapy demonstrated recurrence rates ranging from 0–27.2% and lymph node recurrence was the most common failure pattern (0–18.2% of patients). In our study, only one (3%) patient had lymph node recurrence, which occurred outside the irradiation field. Although we used a smaller irradiation field than in previous reports [9, 19, 22–24] to reduce AEs, our clinical results did not appear to be inferior to those of previous reports. One reason for this may be the chemotherapeutic regimen. We used a more potent chemotherapy regimen (5-FU 1000 mg/m2 on days 1–4 and 29–32 and CDDP 75 mg/m2 on days 1 and 29 [i.e., FP1000/75]) compared to previous studies (5-FU 700 mg/m2 on days 1–4 and 29–32 and CDDP 70 mg/m2 on days 1 and 29 [i.e., FP700/70]) [9, 19, 22–24]. Ikawa et al. evaluated 96 patients treated with adjuvant CRT using FP700/70 following ESD for SESCC [24]. Nine (9%) patients developed lymph node recurrence, and the majority of the recurrence involved the elective nodal irradiation field. Tanaka et al. investigated 33 patients with SESCC treated with ESD and CRT [9]. Concurrent chemotherapy was administered in various regimens, with FP700/70 as the basic regimen. No lymph node recurrence was observed in all 9 patients in the high-dose FP (1000/100 or 800/80) group, but it was observed in 4 of 24 (17%) patients in the nonhigh-dose FP group. An intensified chemotherapy regimen may play an important role in controlling potential lymph node metastasis.
Our study suggests that combining reduced field irradiation and intensified chemotherapy (FP1000/75) does not increase the risk of lymph node recurrence outside the irradiation field. In addition, cardiac- and lung-associated AEs at grades ≥ 2 were observed in only one (3%) patient (grade 3 congestive heart failure), which is a low frequency than noted in published studies [11, 23]. In particular, in cases where the primary tumor was located in the middle or lower esophagus, the reduced irradiation field may have provided safety.
In 2018, we published a preliminary report focusing on the feasibility and toxicity of adjuvant CRT after ESD and compared it to the outcomes of adjuvant surgery [12]. However, this study included only squamous cell carcinoma, had a larger sample size (N = 60) and longer follow-up (median, 4.9 years), and described more mature toxicity results and clinical data. We concluded that CRT remains an appropriate option for high-risk SESCC treated with ESD. To the best of our knowledge, this is the largest study directly comparing the efficacy of CRT and esophagectomy as adjuvant treatment after ESD.
This study has several limitations, which include its retrospective, single-institution design, and insufficient patient numbers. A multicenter randomized controlled trial is ongoing in China to compare the efficacy and safety of CRT and esophagectomy for high-risk SESCC after ESD [25], and the results are expected shortly.