Esophageal cancer is the seventh most common malignancy and the sixth most common cause of death worldwide. It is estimated that 604,000 new cases and 554,000 deaths occurred in 2020 (1). Squamous cell carcinoma of the esophagus is common in East and Central Asia, and East and South Africa. Esophageal adenocarcinoma is common in North America and Europe (2). Multimodal approaches, including surgical resection and chemoradiotherapy, have been used as the standard treatment for non-early stage cancers with the potential for lymph node metastasis (3).

Concurrent chemoradiotherapy is recommended for definitive treatment for esophageal cancer (4). Radiotherapy alone and sequential chemoradiotherapy are performed for patients who cannot tolerate concurrent chemoradiotherapy due to old age or poor general condition (5).

Esophagitis, pneumonitis, cytopenia, and esophageal fistula are known as adverse events of chemoradiotherapy for esophageal cancer (6-9). However, it is not clear whether the wide irradiated field affects the incidence of these adverse events.

Irradiation field size and dose to the regional lymph node area vary widely (10,11). Recently, there is also a method of omitting prophylactic area irradiation by using multi-gate three-dimensional conformal radiotherapy (3D-CRT) or volumetric modulated arc therapy (VMAT) (12,13). The standard field of irradiation for lymph node area has not been established.

The purpose of this study was to clarify the relationship between the size of the irradiated field and suspension or discontinuation of radiotherapy, and between the regional lymph node area coverage of the irradiated field and new regional lymph node metastasis.

Patients and design. In this retrospective study, we reviewed the medical records of 289 consecutive patients who received definitive radiotherapy for esophageal cancer between January 2013 and December 2020 at Yokohama City University Medical Center. All patients had a definitive pathological diagnosis and were staged by the Union for International Cancer Control TNM classification 8th edition. The follow-up time was defined as the period between the first day of radiotherapy to the date of death or final confirmation of survival. The median follow-up of the study cohort was 18 months (range=2-98 months). Gastroscopy and computed tomography (CT) were performed for pretreatment staging on all patients. Evaluations after treatment were performed every 3 to 6 months, and comprised provisional medical history and physical examination, laboratory tests, gastroscopy and CT or positron emission tomography/CT. Risk factors for suspension or termination of radiotherapy were analyzed in all 289 patients. We excluded 14 patients with irradiation doses of less than 50 Gy who were not considered to have received definitive treatment, 6 with salvage surgery, and 11 with discontinuation of observation without judgment of therapeutic effects. Factors affecting new regional lymph node metastasis and survival were analyzed in the remaining 258 patients. Furthermore, we analyzed the factors that affect new regional lymph node metastasis and survival in 153 patients who were considered to have achieved a complete response (CR) clinically (Figure 1).

Data collection. Two hundred and nine patients were treated using 3D-CRT and the other 80 patients were treated using VMAT. During radiotherapy for simulation and treatment, all patients were immobilized in a supine position. Vacuum bags were used to improve position accuracy in many cases. Planning CT images of the entire chest were obtained using a Lightspeed RT Scanner (GE Healthcare, Chicago, IL, USA) with a 2.5-mm slice thickness under shallow breathing. The gross tumor volume (GTV) was defined as the primary lesion in the esophagus and clinically involved lymph nodes, and the clinical target volume (CTV) was defined as the micro-infiltrated area around the primary lesion and adjacent lymph node areas. The planning target volume (PTV) was set with an appropriate margin on the CTV. X-rays at 6 to 10 MV were used for treatment. Image-guided radiotherapy using cone-beam CT was performed during daily treatment for patients after 2016 as standard. Contouring of the GTV, CTV, PTV, and organs at risk, and setting of external beam fields were performed by radiation oncologists. Dose distributions were calculated using the Pinnacle 3 software program (Philips, Amsterdam, the Netherlands). All patients received definitive radiotherapy and there were no gross lesions outside the irradiated field. Radiotherapy was delivered five days per week. In the 3D-CRT patients, the daily dose ranged from 1.8 to 2.0 Gy. A prophylactic dose ranging from 39.6 to 54 Gy (median, 44.0 Gy) was delivered to regional lymph nodes and the total dose in those who completed the curative treatment ranged from 50 to 64 Gy (median, 59.4 Gy). In the VMAT patients, 2 Gy, 1.8 Gy, and 1.71 Gy were delivered to high-risk PTV, intermediate-risk PTV, and low-risk PTV, respectively, using the simultaneous integrated boost method with daily treatment. The total dose in those who completed the curative treatment was 50 to 60 Gy (median, 60 Gy). The proximal and distal sides of the primary esophageal lesion were determined where the cervical esophagus, upper thoracic esophagus, middle thoracic esophagus, lower thoracic esophagus, and abdominal esophagus were located. The regional lymph node area of group 1 was determined as the area with the highest probability of lymph node metastasis and group 2 was determined as the area with the next highest probability of lymph node metastasis depending on the primary site of esophageal cancer according to the Japanese Classification of Esophageal Cancer, 11th edition (14). Thereafter, it was determined whether group 1 or group 2 was completely included in the prophylactic irradiated field. In this study, "regional lymph nodes" were defined as the range of group 2.

Statistical analysis. Fisher’s exact test and the Mann–Whitney U-test were used to evaluate associations between the treatment and examined characteristics. Logistic regression analysis was used to analyze risk factors for suspension or discontinuation of radiotherapy. Time-to-event analyses were performed using Cox’s proportional hazards regression analysis. The Kaplan–Meier method was used to calculate the cumulative incidence of new regional lymph node metastasis, disease progression, disease-specific death, and mortality in the two groups. The Log-rank test was used to analyze the differences in these parameters between the two groups. For all analyses, a two-tailed p-value of <0.05 was considered significant. All statistical analyses were performed using the JMP pro version 15.0 software package (SAS Institute, Tokyo, Japan).

Ethical considerations. This retrospective research plan was approved by the institutional review board of Yokohama City University (approval number: B170700047), and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and relevant guidelines and regulations. All patients included in this study provided a treatment consent form.

Patients. This study included 222 males and 67 females, with a median age of 71 years. The pathological type was squamous cell carcinoma in 281 patients, adenocarcinoma in 6 patients, poorly differentiated carcinoma in 1 patient, and high-grade dysplasia in 1 patient. The therapeutic effects at the end of radiotherapy and chemotherapy were clinical CR in 153 patients and clinical non-CR in 125 patients. The remaining 11 patients were not evaluated for therapeutic effects. The detailed characteristics are presented in Table I.

Risk factors for suspension or discontinuation of radiotherapy. Of the 289 patients, 21 required suspension (delayed planned irradiation schedule) or termination (decrease from the scheduled number of irradiations) of radiotherapy for medical reasons. Eight patients had only suspension, 11 had only termination, and 2 had suspension and termination. The cause of suspension or termination is shown in Table II. The reasons for suspension or termination in 10 patients were clearly unrelated to radiotherapy such as aspiration pneumonitis, myocardial infarction, cerebral infarction, intestinal hemorrhage outside the irradiated field, intestinal perforation outside the irradiated field, and progression of the current disease. The reason for suspension or termination in 5 patients was esophageal fistula formation, all of which were T4b. The reason for suspension or termination in 5 patients was cytopenia. The reason for suspension or termination in 1 patient was fatigue.

Hemoglobin level, serum albumin level, performance status (PS), and stage were identified as significant risk factors for suspension or termination of radiotherapy for medical reasons in logistic univariate analysis, but the serum albumin level was the only risk factor in the multivariate analysis (Table III). The factors used in the multivariate analysis were not correlated. Next, we focused on suspension or termination due to cytopenia in 5 patients. The logistic univariate analysis did not detect any significant risk factors.

Regional lymph node area coverage of irradiated field and new regional lymph node metastasis. Of the 258 patients who received the curative dose (50 Gy or more), the 74 in whom group 2 was completely included in the irradiated field had a significantly lower rate of regional lymph node metastasis than the 184 in whom group 2 was not included or insufficiently included (Figure 2, p=0.0127). Furthermore, the 106 patients in whom group 1 was completely included in the irradiated field had a significantly lower rate of regional lymph node metastasis than the 152 in whom group 1 was not included or insufficiently included (Figure 3, p=0.0159).

In the Cox proportional hazards univariate analysis, group 1 or group 2 not being included or being inadequately included within the irradiated field was a significant risk factor for new regional lymph node metastases. In the multivariate analysis, group 2 not being included or being incompletely included within the irradiated field, and stage 3 or higher disease were risk factors for new regional lymph node metastases (Table IV). When multivariate analysis was performed using only these two factors, group 2 not being included or being incompletely included was the only significant risk factor for new regional lymph node metastases (risk ratio=0.2420188, 95%CI=0.073-0.798, p=0.0197).

Of the 153 patients who were clinically determined to have achieved CR, 18 had recurrence with regional lymph node metastasis. Of these, 3 had distant metastases found at the same time and 15 had recurrence of regional lymph node metastasis alone. Of these 15 patients, only 1 experienced relapse within the irradiated field, 12 had recurrence in the unirradiated part of group 1, and 2 had recurrence in the unirradiated part of group 2. The 46 patients in whom group 2 was completely included in the irradiated field had a significantly lower rate of recurrence of regional lymph node metastasis alone than the 107 patients in whom group 2 was not included or insufficiently included (Figure 4, p=0.0337). Moreover, the 63 patients in whom group 1 was completely included in the irradiated field had a significantly lower rate of recurrence of regional lymph node metastasis alone than the 90 patients in whom group 1 was not included or insufficiently included (Figure 5, p=0.0239).

In the Cox proportional hazards univariate analysis, group 1 not being included or being inadequately included within the irradiated field was a significant risk factor for the recurrence of regional lymph node metastasis alone (risk ratio=0.2109153, 95%CI=0.048-0.935, p=0.0405). The other factors, such as sex, age, stage, PS, hemoglobin level, serum albumin level, body mass index, and presence of concurrent chemotherapy, were not significant risk factors for the recurrence of regional lymph node metastasis alone.

Regional lymph node area coverage of the irradiated field and survival. Statistical analysis of 258 patients who received the curative dose (50 Gy or more) demonstrated no significant difference between patients in whom group 1 or 2 was completely included in the irradiated field and those in whom group 1 or 2 was not included or insufficiently included in overall survival (OS) (p=0.9401, 0.4627) and disease-specific survival (DSS) (p=0.5445, 0.6174).

Statistical analysis of the data of 153 patients who were clinically determined to have reached CR demonstrated no significant difference between the patients in whom group 1 or 2 was completely included in the irradiated field and those in whom group 1 or 2 was not included or insufficiently included in OS (p=0.5042, 0.5544) and DSS (p=0.7557, 0.7420).

In two-dimensional radiotherapy, a wide irradiation field including the area from the supraclavicular fossa to the entire mediastinum is used (15). As 3D-CRT and intensity-modulated radiation therapy (IMRT) are currently employed, the irradiation field is individualized according to the location of the primary lesion (16). However, an appropriate irradiation field has not yet been established from the viewpoint of adverse events and prophylactic irradiation that suppresses late lymph node metastasis.

Adverse events during radiotherapy may include those affected by the size of the irradiation field, such as cytopenia, general malaise, esophagitis, and gastritis, and those affected by the degree of cancer progression such as esophago-tracheal fistula, esophago-vascular fistula, and mediastinitis (9,17). The latter develops with a certain probability and is difficult to reduce by irradiation techniques, but the former may be reduced by appropriate setting of the irradiated field. Means for responding to adverse events, such as cytopenia, are evolving year by year and are standard for patients who have had adverse events (18-21). In addition, there is evidence that the extension of the overall treatment period leads to a decrease in the cure rate in radiotherapy for esophageal cancer (22). Therefore, this study focused on the suspension or termination and not the adverse event itself. Although no similar prior studies exist and cannot be compared, only 11 (3.8%) of the 289 patients in this study required suspension or termination due to radiation-related causes. Of these, there were 6 with in T4b disease in whom it was difficult to avoid suspension or termination due to esophageal vascular perforation, esophageal tracheostomy, and mediastinitis. Five patients required suspension or termination due to cytopenia, but as the wide irradiation field was not a risk factor, there was considered no reason to positively set a narrow irradiation field.

Radiotherapy for esophageal cancer has the problem that the CR rate of primary lesions and metastatic lymph nodes is low, and high-dose radiotherapy and IMRT are being tested to increase the CR rate (23,24). Conventionally, only elective nodal irradiation (ENI) was used in the setting of the irradiation field, but in recent years, involved-field radiation therapy (IFRT) has also been used. In IFRT, only the primary lesion and metastatic lymph nodes are irradiated, and prophylactic irradiation of regional lymph node area is not performed (13).

On the other hand, surgical data suggest that there is a risk of more extensive lymph node metastases. Pathological lymph node metastasis was found in 60% of patients who underwent surgery in clinically determined cases of T2-T3N0 (25). There is a high probability of upper mediastinal lymph node metastasis in 24% and perigastric lymph node metastasis in 16% of patients with cancer of the middle thoracic esophagus (26). The prognosis of three-field dissection was reported to be better than that of two-field dissection, but the irradiation field of radiotherapy and recommended dissection range for surgery do not match (27,28). However, unlike surgery, which is effective only on the site where the operation is performed, radiotherapy also irradiates the area around the irradiation target; therefore, the surrounding lymph node area is exposed to radiation (12).

In stage I cases, the rate of regional lymph node recurrence in the irradiated field was reported to be 1.5% and that out of the irradiated field was reported to be 4.4% (29). In advanced cases, the rate of regional lymph node recurrence in the irradiated field was reported to be 1% and that out of the irradiated field was reported to be 13% (30). In this study, the rate of regional lymph node recurrence in the irradiated field was 0.6% and that out of the irradiated field was 9.1%, which were considered reasonable compared with the previous study.

In past studies, there was no significant difference in OS or DSS between patients who received IFRT and those who received ENI in radiotherapy for esophageal cancer (31,32). In this study, the patients in whom group 1 or 2 was included in the irradiated field had a significantly lower rate of intraregional lymph node metastasis alone, but there was no difference in OS or DSS when comparing groups with or without the inclusion of group 1 or 2.

The regional lymph node recurrence rate reported in studies of radiotherapy for esophageal cancer was lower than the pathological lymph node metastasis rate reported in studies of surgery for esophageal cancer (25,26,29,30). However, in reality, the probability of lymph node metastasis should be the same at the same stage regardless of the treatment method. As the CR rate of primary lesions and metastatic lymph nodes is lower in radiotherapy than in surgery, the recurrence rate of regional lymph nodes alone and the effects of regional lymph node recurrence on OS are considered to be underestimated. Controlling regional lymph node metastasis may prolong OS if advances in radiotherapy technology increase the CR rate of primary lesions and lymph node metastases. In addition, the number of patients who will have to receive additional treatment, such as chemotherapy and surgery, is expected to decrease by reducing the rate of regional lymph node metastasis, which may improve the patient’s quality of life.

There are several limitations in this study. First, it was a single-center retrospective observational study. Second, the therapeutic effects were judged by CT or endoscopy, and pathological judgment was not always performed. In particular, the uncertainty of CR judgment may underestimate or overestimate the rate of regional lymph node recurrence alone.

In radiotherapy for esophageal cancer, a wide irradiated field was not a risk factor for suspension or discontinuation of radiotherapy. There was no difference in OS or DSS when comparing patients in whom group 1 or 2 was included in the irradiated field and those in whom group 1 or 2 was not included or insufficiently included. However, patients in whom group 1 or 2 was included in the irradiated field had a significantly lower rate of intraregional lymph node metastasis alone. Irradiation of the regional lymph node area should be considered to avoid additional treatment for new lymph node metastases.

All Authors report no conflicts of interest related to this study.

S.W. designed the study. S.W. and D.S. collected and analyzed the data. S.W. wrote the manuscript with support from I.O., and M.H., I.O., and M.H. supervised the study. All Authors discussed the results and contributed to the final manuscript.