Advances in endoscopic equipment have contributed to the increased detection of early-stage esophageal carcinoma; in addition, the number of patients with superficial esophageal cancer treated by ER has also increased. According to the Registry of Esophageal Carcinomas in Japan, superficial esophageal cancer accounted for 22.7% of esophageal cancer patients treated in 2001 and 33.4% in 2011. In the same reports, 11.3 and 17.2% of patients with esophageal cancer were treated with ER in 2001 and 2011, respectively [1, 17]. Difficulty in the accurate diagnosis of the invasion depth by endoscopic examination and recently expanded indications for ESD, such as tumor of entire circumference or MM invasion, has caused an increase in the number of non-curative resections requiring additional treatment. This study retrospectively analyzed the efficacy and toxicity of salvage RT for superficial esophageal cancer with non-curative ER. The 5-year OS rate was 78% (95% CI, 64–91%), and only one patient died of primary esophageal cancer. Several reports have shown the 5-year OS rate of stage I esophageal cancer patients treated with esophagectomy of approximately 64–78% [7, 8, 18]. Our results and recent reports of definitive CRT for superficial esophageal cancer were comparable to these results [12,13,14]. Moreover, RT is less invasive compared to esophagectomy and has obvious advantages for organ preservation. Although previous reports showed RT alone was inferior to CRT in esophageal cancer, we did not observe a significant difference in OS between CRT and RT alone [12, 14, 19, 20]. We previously reported the long-term outcome of IBT in combination with EBRT for superficial esophageal cancer . In that report, the most common failure pattern was the primary site, and regional lymph node metastasis tended to occur more frequently in submucosal cases. Resection of the primary tumor by ER may have contributed to local control in the present study. In addition, our results showed good regional control in cases of RT alone. Our cases were clinically judged to be suitable for treatment with ER. Hence, the risk of regional lymph node metastasis might be lower than that of esophageal cancer clinically diagnosed with submucosal invasion with no indications for ER. Although CRT is standard therapy for esophageal cancer, our results suggest that RT alone after non-curative ER might be a worthwhile, less toxic treatment option for patients who are difficult to administer chemotherapy.
The optimal radiation field and efficacy of ENI for esophageal cancer remain controversial. Although a recent meta-analysis did not indicate the effectiveness of ENI, cases of locally advanced esophageal cancer were mainly included . Moreover, the most common failure pattern was local failure in advanced cases . These findings suggest that poor local control may affect the limited contribution of ENI. Furthermore, no multi-center randomized phase III trials have evaluated the effectiveness of ENI for early esophageal cancer. In this study, all patients received ENI and none experienced regional lymph node metastasis, even though they were at risk of subsequent lymph node metastasis. We believe that the use of ENI contributed to this high regional control rate. Early esophageal cancer can achieve high local control rate by CRT compared with advanced cases and higher local control could be expected after ER. Thus, the effectiveness of ENI for early esophageal cancer should be investigated focused on this cohort. The concern of RT with ENI is the increased risk of severe cardiopulmonary toxicities. In our study, grade 3 or worth cardiopulmonary toxicities were observed in six patients (16%), an occurrence rate we considered to be acceptable. However, it is important to reduce the irradiation dose to the heart as much as possible. Although we did not identify any factor associated with late cardiac toxicities, five of them were treated by anterior-posterior field. Recently, the use of multi-portal beams to reduce cardiopulmonary toxicities has become standard in esophageal cancer radiotherapy. Recent advanced techniques such as IMRT or proton therapy have the potential to reduce cardiopulmonary toxicities. Lin et al. reported the efficacy of IMRT for esophageal cancer patients. They observed a significantly higher cumulative incidence of cardiac-related deaths in the 3D-CRT group compared to that in the IMRT group . In addition, they also reported that the use of IMRT may be associated with reduced all-cause, cardiac-related, and other-cause mortality in elderly patients with esophageal cancer . Moreover, proton therapy can improve target coverage while reducing the irradiation dose to the surrounding normal tissue compared to photon therapy and proton therapy is expected to achieve high locoregional control and reduce RT-induced toxicity [25, 26].
One concern regarding toxicity in this treatment strategy is esophageal stenosis. In our study, although grade 2 esophageal stenosis was observed in seven patients (19%), they were manageable and severe stenosis was not observed. The reported occurrence rates of esophageal stenosis after ER were 68–94% for tumor circumferences ≥3/4 and were significantly higher in cases with tumor circumference < 3/4 [27,28,29]. In our study, a tumor circumference ≥ 3/4 was also significantly associated with esophageal stenosis: ≥ 3/4 in six patients and < 3/4 or unknown in one patient (p < 0.001). Therefore, the indication for ER should be judged carefully, especially in cases with tumor circumference ≥ 3/4 and high probability for the requirement of additional treatment at clinical diagnosis.
On the basis of the results of the Japan Clinical Oncology Group (JCOG) trial, 60 Gy is considered standard treatment for both locally advanced and early stage esophageal cancer in Japan [14, 30]. Owing to the lack of the evidence about RT after non-curative ER, we used the same protocol of definitive CRT in the current study. The JCOG 0508 trial is a phase II trial that evaluated the use of the combined ER and CRT for clinical stage I esophageal cancer. In JCOG 0508 trial, patients with clinical stage I submucosal (cSM1–2) esophageal cancer received diagnostic ER and selective CRT based on the histological status. Group A, defined as pathological mucosal invasion with negative resection margin and no LVI, received no additional treatment, while Group B, with pathological SM invasion with negative resection margin or pathological mucosal invasion with LVI, received prophylactic CRT (41.4 Gy) and Group C, with pathological SM invasion with positive resection margin, received definitive CRT (50.4 Gy). The 3-year OS rates were 90.7% for Group B and 92.6% in all patients . This result was comparable to that of surgery or CRT for clinical stage I esophageal cancer. Thus, a high dose such as 60 Gy, might not be needed for esophageal cancer after ER.
Metachronous esophageal cancer is a grave issue in patients who have undergone organ preservation treatment for esophageal cancer. The incidence rate of metachronous cancer after ER are 13–14.6% [32, 33]. In the present study, seven patients (19%) experienced metachronous cancer and the 5-year incidence rate was 13%. Five of the seven patients were successfully salvaged by ER. Therefore, the detection of metachronous cancers as superficial lesions by close endoscopic observation is important.
Esophageal cancer patients are at high risk for other malignancies such as head and neck, gastrointestinal, or lung cancers. In our cases, 15 patients (41%) experienced other malignancy after RT, and the most common cause of death was other malignancies. Early detection of other malignancies is also important after RT since patients with superficial esophageal cancer can expect long-term prognosis.
Our study was limited by its retrospective nature, small number of patients, and variety of RT methods and chemotherapeutic regimens. However, as there are few reports on the long-term results of salvage RT after non-curative ER for superficial esophageal cancer, we think that the results of this study are of great significance. Diagnostic ER and selective CRT based on histological status are likely to become the standard treatment strategy for submucosal esophageal cancer instead of surgery. Our results suggest that RT after ER is a safe and effective treatment while preserving organs and that a longer follow-up is required for the early detection of metachronous esophageal cancer and other malignancies.