Abstract
Background/Aim: To evaluate the toxic effects associated with various factors, including the presence or absence of concurrent chemotherapy with volume-modulated arc therapy (VMAT) and dose parameters for esophageal cancer (EC), and to assess the safety and feasibility of the VMAT protocol. Patients and Methods: Patients with EC who received definitive VMAT between December 2016 and December 2020 were retrospectively analyzed. VMAT plans were designed to deliver 60 Gy to the primary tumor, 54 Gy to high-risk sites, and 51.3 Gy to regional lymph node sites. Toxic effects were evaluated for esophagitis, neutropenia, esophageal stricture, pericardial effusion, radiation-associated pneumonia. Results: Forty-five patients received concurrent chemoradiotherapy (CCRT), while 29 were treated with radiation therapy (RT) alone. The following grade 3 complications were detected: Neutropenia in four patients (5.4%), esophagitis in two (2.7%), and esophageal stricture in one (1.4%). Grade 4 or more complications were not observed. The median age of the CCRT group (67 years) was significantly lower than that of the RT-alone group (77 years) (p<0.0001). The incidence of esophagitis was significantly higher in the CCRT group (75.5%) than in the RT group (48.3%) (p=0.033). The univariate analysis identified increasing mean dose to the pericardium as a significant risk factor for pericardial effusion, and CCRT and performance status ≥1 as significant for radiation-associated pneumonia. These factors were not significant in the multivariate analysis. Neutropenia and esophageal stricture were not associated with any factor examined. Conclusion: VMAT alone and in CCRT performed with our protocol was safe and feasible in patients with esophageal squamous cell cancer.
- Esophageal cancer
- squamous cell cancer
- VMAT
- toxic effects
- esophagitis
- radiation pneumonia
- esophageal stricture
- pericardial effusion
Esophageal cancer is the seventh most common malignant tumor worldwide and the sixth leading cause of cancer death (1). The two major histological subtypes of esophageal cancer are adenocarcinoma and squamous cell carcinoma (SCC), with SCC being predominant in Eastern Asian countries (2). Radiation therapy (RT) alone and concurrent chemoradiotherapy (CCRT) are effective treatment options for esophageal cancer (3). CCRT and surgery are recommended for the treatment of locally advanced SCC of the esophagus.
Important organs, such as the lungs and heart, are close to the esophagus. Unlike other areas of the gastrointestinal tract, the esophagus lacks a serosal layer and lymphatic spread of cancer is frequent. Therefore, a large planning target volume (PTV) is necessary to cover lymphatic spread in RT, which is delivered at a high dose to the lungs and heart. Therefore, toxic effects associated with irradiation of patients with esophageal cancer include esophagitis, neutropenia, esophageal stricture, pericardial effusion, and radiation-associated pneumonia.
Intensity-modulated radiation therapy (IMRT) may increase tumor coverage with smaller doses to the surrounding normal tissues of critical organs at risk. IMRT uses multiple beams at fixed angles, with beam-modifying devices to change the intensity of radiation across the field. This improves dose conformality with better dose escalations. Volume-modulated arc therapy (VMAT) is an advanced type of IMRT. It dynamically modulates the movement of the multileaf collimator and the angular dose rate. A highly conformal dose distribution with a shortened treatment time may be achieved using VMAT (4). To the best of our knowledge, some dosimetric studies have been conducted (5, 6); however, few clinical studies have examined the treatment of esophageal cancer using VMAT. Therefore, we performed VMAT by delivering 60 Gy to the gross tumor volume (GTV), 54 Gy to high-risk sites, and 51.3 Gy to the regional lymph nodes using the same protocol at a single institution. We investigated the toxicity of VMAT in relation to the presence or absence of concurrent chemotherapy, as well as various factors, including dose–volume parameters. We also examined the safety and feasibility of the VMAT protocol.
Patients and Methods
Patients. We retrospectively analyzed data from 74 patients with esophageal cancer treated with definitive VMAT at the Yokohama City University Medical Center between December 2016 and December 2020. All patients were pathologically diagnosed with SCC by endoscopic biopsy.
The clinical stage was assessed using endoscopy, chest and abdominal computed tomography (CT) and positron-emission tomography CT and classified based on the eighth edition of the Union for International Cancer Control TNM Malignant Tumor Classification (7). In consideration of the dose limitation of the stomach, patients with lower thoracic esophageal cancer with distal tumors located within 3 cm of the gastroesophageal junction were excluded from the analysis. RT alone was selected when CCRT-related toxicities were expected, particularly in elderly patients and patients with comorbidities.
Compliance with ethical standards. The present study was approved by the Institutional Committee at Yokohama City University (approval number: B170700047). The institutional formal consent of patients was obtained.
Treatment planning. The GTV consisted of the primary GTV (GTVp) and lymph node GTV (GTVn). The esophageal mass was depicted relative to that marked using endoscopic clipping prior to simulation CT. Contours were drawn with reference to the guidelines reported by Wu et al. (8). The clinical target volume to receive 60 Gy (CTV60) included GTVp and GTVn without margins. CTV54 was defined as GTVp with a 4-cm cranial margin, 3-cm caudal margin, and 1-cm radial margin along the esophagus. GTVn with a 1-cm margin was also included in CTV54. CTV51.3 was set within a range of 5 cm on the cranial side and 4 cm on the caudal side along the esophagus with reference to the lymph node region of the Japan Classification of Esophageal Cancer, 11th Edition (8, 9). Bilateral supraclavicular nodal sites were included for tumors above the level of the carina. The PTV was generated by expanding the circumference of the CTV by 0.5 cm in all directions. PTV54 was generated by removing PTV60. PTV51.3 was generated by excluding PTV60 and PTV54. To increase the dose-reporting accuracy for whole heart contours, we used the atlas proposed by Feng et al. (10). The pericardium was contoured with the heart serving as the inner boundary of the shell and extended three-dimensionally outwards by 5 mm. Dose distributions were calculated using Pinnacle 3 software (Philips, Amsterdam, the Netherlands). The maximum and mean doses for the PTV and at-risk organs were calculated from the dose–volume histogram. The PTV coverage goal was 95% of the prescription dose, which was 60 Gy for PTV60, 54 Gy for PTV54, and 51.3 Gy for PTV51.3. Normal tissue dose constraints included a spinal cord dose <44 Gy, pericardial dose V50 <17% (11), lung V30 <10%, V20 <18%, and gastric dose <50 Gy. Vx was the percentage volume receiving a dose greater than x Gy.
Treatment. The primary lesion and affected lymph nodes received 60 Gy in 2 Gy/fraction 5 days per week. VMAT was performed using two full arcs with 6-MV photons. During RT, all patients were immobilized in a supine position with vacuum immobilizers. Concurrent chemotherapy consisted of two cycles of combined 5-fluorouracil and cisplatin (700 mg/m2 5-fluorouracil and 70 mg/m2 cisplatin administered on days 1-4 and day 1, respectively) (12, 13).
Follow-up and statistical analysis. Evaluations after treatment were performed every 3 to 6 months, and comprised medical histories, physical examinations, laboratory tests, and CT or positron-emission tomography-CT. At each follow-up visit, treatment-related toxicities were assessed. The interval of toxic events was calculated from the start of RT to the time when the first adverse event was initially observed in various tests and physical examinations. The grade of all adverse events was determined using the Common Terminology Criteria for Adverse Events ver. 5.0. (14).
Toxicity was evaluated by the presence or absence of adverse events, not by their grade. Patients were classified by performance status (PS) into two groups, PS=0 and PS ≥1.
Overall survival (OS) was defined as the period from the date of RT completion to the date of death or final confirmation of survival and was calculated using the Kaplan–Meier method. A log-rank test was used to compare the two groups. Since esophagitis and neutropenia are adverse events that occur during RT, we performed statistical analyses using the chi-squared test. Other adverse events were analyzed using a Cox proportional hazards regression analysis. In all analyses, a two-tailed value of p<0.05 was considered to be significant. All statistical analyses were performed using the JMP pro version 15.0.0 software package (SAS Institute, Tokyo, Japan).
Results
Table I shows the clinical characteristics of patients and Table II shows the dose–volume parameters. The median age was lower by a decade for the CCRT group than that of the group treated with RT alone (p<0.0001). None of the other factors examined significantly differed between the two groups. The median follow-up of the study cohort was 13.5 months (range=1-52 months). One-year OS rates were 80% for the whole cohort of patients, 86% for the RT-only group, and 77% for the CCRT group. The two-year OS rate was 60% for the CCRT group (Figure 1).
Baseline clinical characteristics.
Median (range) PTV and dosimetric parameters.
Kaplan–Meier curves of overall survival in groups treated with volumetric-modulated arc therapy radiotherapy alone (RT) and with concurrent chemotherapy (CCRT). The RT-alone group was censored 20 months after treatment.
Table III shows the incidence of esophagitis, neutropenia, esophageal stricture, pericardial effusion, and radiation pneumonia by grade in the RT-alone and CCRT groups. Among these early and late complications, only esophagitis was associated with the use of CCRT (p=0.033). RT was paused for the following reasons: One patient in the CCRT group developed grade 3 esophagitis, while one in the RT alone group developed grade 3 thrombocytopenia. The patient with thrombocytopenia had the largest entire PTV (PTV60+PTV54+PTV51.3) in the RT-alone group (1,482.7 cc); the second largest entire PTV was 790 cc in the RT-alone group and the largest entire PTV was 838.8 cc in the CCRT group. The following grade 3 complications were noted: Neutropenia in four patients (5.4%), esophagitis in two (2.7%), and esophageal stricture in one (1.4%). Grade 4 or more complications were not detected.
Treatment-related toxicity.
The incidence of complications according to the prognostic factors listed in Table I and Table II was investigated in the CCRT group in comparison to the RT-alone group, and significant factors are shown in Table IV. Variables with p<0.05 in the univariate analysis were examined in the multivariate Cox analysis. Regarding esophagitis, a multivariate analysis was also performed for PTV60, which had the next lowest p-value (p=0.133). In the univariate and multivariate analyses, only chemotherapy was identified as a significant risk factor for esophagitis. None of the other factors examined in the univariate and multivariate analyses significantly affected the incidence of neutropenia. Factors related to pericardial effusion are also shown in Table IV. In the univariate analysis, i767ncreasing mean dose to the pericardium was identified as a significant risk factor for pericardial effusion. The multivariate analysis was also performed on the entire PTV volume, which had the next lowest p-value (p=0.062). None of the factors examined in the multivariate analysis significantly affected the incidence of pericardial effusion. CCRT and PS ≥1 were identified as significant risk factors for radiation-associated pneumonia in the univariate analysis, but not in the multivariate analysis.
Factors associated with esophagitis, pericardial effusion, and radiation pneumonia in univariate and multivariate analyses.
Discussion
Simultaneous integrated boost (SIB)-RT delivers dose-escalated RT to locally advanced esophageal cancer. The safety of IMRT with SIB has been demonstrated (15-18). We selected studies on IMRT with SIB for esophageal cancer for comparisons with the present results and summarized their findings in Table V. However, difficulties were associated with comparing the present results with these findings due to differences in treatment protocols and PTV. Regarding esophagitis, grade 2 and 3 esophagitis occurred in 71.1 and 4.4%, respectively, of patients in the CCRT-treated group (Table III). Concurrent chemotherapy has been reported to affect the incidence of esophagitis in patients with lung cancer (19). Although chemotherapy regimens differed from those in other studies, the lowest incidence of grade 3 esophagitis was noted in the present study. Most of our physicians preferred to prescribe anti-inflammatory analgesics for esophagitis at the onset of symptoms. Therefore, the incidence of grade 2 esophagitis was high. Regarding neutropenia, in comparison with the study reported by Xu et al. (18), our groups had a lower incidence of grade 2 and 3 neutropenia, and grade 4 or more neutropenia was not detected (Table III). Concerning esophageal stricture, Vlacich et al. (17) reported that the incidence of grade 3 or more esophageal stricture was 8% among patients who received CCRT. The doses delivered to GTV and at-risk sites were 60 and 54 Gy, respectively, in 30 fractions, which was similar to those of our protocol. Although 85% of their patients received higher doses of cisplatin (75 mg/m2) and 5-fluorouracil (1,000 mg/m2), drug regimens and doses were at the discretion of the attending medical oncologist. In the present study, all patients received the same drug regimens and doses, and grade 3 or more esophageal stricture occurred in only one patient in the group treated with RT alone. In the present study, no patient developed grade 3 or more radiation-associated pneumonia, and the incidence of grade 2 was lower than previously reported. The incidence of grade 1 radiation-associated pneumonia was high because we carefully reviewed the follow-up CT of all patients.
We previously investigated dose–volume parameters for the pericardium. We showed that pericardial V50 ≤17% was important to prevent the development of symptomatic pericardial effusion in patients with esophageal cancer treated with CCRT (11). We used this finding for dose constraints. Previously reported risk factors for grade 3 or more pericardial effusion were a mean pericardial dose >36.5 Gy and V45 >58% (20). In the report about these risk factors, irradiation was performed by three-dimensional conformal RT. Pericardial V40 >55.4% was also identified as a risk factor for grade 3 or more pericardial effusion (21) in a study in which irradiation was performed by IMRT. In the present study, the mean pericardial dose ranged between 0.3 and 32.5 Gy (median=17.8 Gy), pericardial V40 between 0 and 38.1% (median=16.3%), and pericardial V45 between 0 and 30.1% (median=13.0%), which were markedly lower than previously reported. Therefore, irradiation using our VMAT protocol reduced the dose delivered to the pericardium.
Regarding the relationship of radiation-associated pneumonia to lung V20 and the mean lung dose (MLD), La et al. reported no radiation-associated pneumonia occurred using a MLD 10.9 Gy and V20=16.5% (22). On the other hand, according to Xu et al. (18), grade 2 or more radiation-associated pneumonia was detected in 4.3% of patients with MLD of 13.4 Gy and V20 of 22.6%. In the present study, the median MLD was 10.1 Gy (range=6.2-13.5 Gy), median V20 was 17.3% (range=5.4-22.4%), and one patient developed grade 2 or more radiation-associated pneumonia (1.4%), values which were lower than previously reported.
The INT 0123 trial reported a negative finding for dose escalations for esophageal cancer with CCRT, namely, a higher radiation dose did not increase survival or local/regional control. Two-year OS rates were 31% for those treated with 64.8 Gy and 40% for those treated with 50 Gy. They concluded that the standard radiation dose for patients treated with CCRT should be 50.4 Gy (23).
In the INT 0123 trial, most patients were treated with two-dimensional RT. At least 54 to 60 Gy was required for the definitive treatment of unresected solid tumors (15). The survival of patients with locally advanced SCC of the esophagus was longer when treated with CCRT than with RT alone (3). In the present study, we conducted RT by delivering 60 Gy to the GTV and 51.3 Gy to regional nodes using VMAT. The 2-year OS rate of the CCRT-treated group was 60%. Previously reported 2-year OS rates for patients treated with CCRT in were 41.3% (15) and 48.6% (17) (Table V). Both studies delivered ≥60 Gy to the GTV and our present results were consistent with their 2-year OS rates.
Comparison of treatment protocols and incidence of adverse events with simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) studies.
In the present study, the incidence of each toxicity, particularly those of grade 3 or more, was lower than previously reported. Furthermore, RT was paused for one patient who developed grade 3 thrombocytopenia, and the PTV was the maximum possible. Irradiation of 60 Gy to the GTV, 54 Gy to high-risk sites, and 51.3 Gy to regional nodes by VMAT was safe and feasible when the entire PTV was ≤790 cc for treatment with RT alone and ≤838.8 cc for treatment with CCRT.
There were some limitations to this study, such as the use of retrospective data, the small sample size, the short follow-up period, and distal tumors located within 3 cm of the gastroesophageal junction being excluded. In the future, evaluation of various adverse events, including late complications in the heart, may contribute to the identification of risk factors for toxicity from VMAT.
In conclusion, the present study used VMAT to treat esophageal SCC. CCRT and RT alone by VMAT were safe and feasible for delivery of 60 Gy to the GTV, 54 Gy to high-risk sites, and 51.3 Gy to regional lymph nodes sites, thus warranting further study.
Footnotes
Authors’ Contributions
DS: Participated in the design of the study, writing-review, and editing. IO: Conceptualization, writing-review, and editing. SW: Data collection, writing-review, and editing. HM: Writing-review and editing. All Authors critically revised the article and approved the submitted version.
Conflicts of Interest
The Authors declare that there are no conflicts of interest regarding this study.
- Received March 6, 2023.
- Revision received March 20, 2023.
- Accepted March 22, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
