Multimodal image-guided volumetric modulated arc radiotherapy for postoperative esophageal cancer: A prospective randomized controlled trial

Abstract

BACKGROUND

Postoperative radiotherapy for esophageal cancer presents challenges in target delineation and normal tissue sparing because of surgical changes. Volumetric modulated arc therapy (VMAT) combined with multimodal image guidance may improve precision.

AIM

To evaluate the efficacy of multimodal magnetic resonance imaging (MRI)/computed tomography (CT)-guided VMAT compared with CT-guided radiotherapy in patients undergoing postoperative treatment for esophageal cancer.

METHODS

This prospective randomized controlled trial enrolled 65 patients with postoperative esophageal cancer, who were assigned to either an experimental group (MRI/CT-guided VMAT, n = 32) or a control group (CT-guided radiotherapy alone, n = 33). Dose distribution, dose-delivery accuracy, short-term efficacy, and adverse reactions were compared between groups.

RESULTS

The experimental group demonstrated a significantly lower mean daily dose deviation (difference between planned and delivered dose) than the control group (2.3% ± 0.5% vs 4.6% ± 0.7%, P < 0.01). The standard deviation of dose deviation was also significantly lower (1.1% ± 0.3% vs 2.4% ± 0.4%, P < 0.01). For short-term clinical outcomes at 6 months, the complete remission rate was significantly higher in the experimental group than in the control group (65.6% vs 36.4%, P < 0.05). Similarly, the overall response rate (complete remission + partial remission) was significantly higher in the experimental group (90.6% vs 69.7%, P < 0.05). Acute esophagitis (31.3% vs 54.5%, P < 0.05) and late cardiac injury (12.5% vs 27.3%, P < 0.05) were significantly lower in the experimental group.

CONCLUSION

Compared with conventional CT-guided radiotherapy, multimodal MRI/CT-guided VMAT significantly improves dose-delivery accuracy, short-term tumor control, and safety in postoperative radiotherapy for esophageal cancer.

Key Words: Multimodal imaging; Volumetric modulated arc therapy; Esophageal cancer; Postoperative radiotherapy; Image-guided radiotherapy

Core Tip: This prospective randomized controlled trial (n = 65) demonstrates that multimodal magnetic resonance imaging/computed tomography-guided volumetric modulated arc therapy significantly improves radiotherapy precision and safety compared with conventional computed tomography-guided radiotherapy alone in patients with postoperative esophageal cancer. The experimental group achieved a higher target dose coverage, lower dose deviation, better short-term tumor control, and reduced acute/late adverse reactions. Multimodal image-guided volumetric modulated arc therapy represents a preferred adjuvant radiotherapy strategy.

INTRODUCTION

Esophageal cancer is a common and highly lethal malignancy of the digestive system and is among the most frequent cancers of the gastrointestinal tract[1]. Although substantial advances have been made in diagnostic and therapeutic strategies in recent years, the overall prognosis for patients with esophageal cancer remains unfavorable. This outcome is largely attributable to the lack of noticeable early symptoms and the tumor's propensity for adjacent organ invasion and lymphatic spread[2]. Consequently, enhancing local tumor control and prolonging overall survival remain major objectives of clinical research in esophageal cancer, particularly in the postoperative adjuvant setting, where anatomical changes present additional challenges.

Radiotherapy is a key treatment modality for esophageal cancer, offering effective tumor cell destruction and volume reduction[3]. Volumetric-modulated arc therapy (VMAT) is an advanced intensity-modulated radiotherapy technique that delivers radiation continuously as the gantry rotates, providing improved dose conformity, reduced treatment time, and better sparing of at-risk organs than conventional fixed-field intensity-modulated radiation therapy[4]. However, conventional computed tomography (CT)-guided radiotherapy has limitations in terms of tumor targeting and dose allocation. Furthermore, it remains challenging to completely spare adjacent healthy tissues from radiation exposure, resulting in a high rate of radiation-induced adverse effects[5]. With ongoing advances in imaging technology, multimodal image-guided radiotherapy (IGRT) has attracted growing interest[6,7]. In particular, the integration of magnetic resonance imaging (MRI) with CT has shown clear benefits in tumor detection, tumor margin definition, and radiotherapy treatment planning.

In the postoperative setting, accurate localization of the tumor bed and residual disease is particularly difficult because of the use of surgical clips, tissue remodeling, and organ displacement. Multimodal imaging (MRI/CT) can address these challenges by providing complementary soft-tissue and anatomical information[8].

Currently, MRI is widely used in tumor diagnosis and therapy because of its excellent soft-tissue contrast and lack of ionizing radiation[9]. Numerous studies have indicated that MRI enables clearer identification of the interface between tumors and adjacent tissues, thereby enhancing the precision of tumor localization[10,11]. CT provides reliable anatomical data for radiotherapy planning because of its high spatial resolution and fast imaging speed[12,13]. Consequently, the integrated use of MRI and CT can leverage the complementary strengths of both imaging modalities, thereby improving the accuracy of radiation dose targeting and tumor control rates. However, research on the role of MRI/CT multimodal image guidance, specifically in radiotherapy for esophageal cancer, remains scarce, and there is a shortage of large-scale prospective randomized controlled trials.

In this prospective randomized controlled trial, we aimed to assess whether MRI/CT multimodal image guidance optimizes radiation dose within the treatment target compared with conventional CT guidance in postoperative esophageal cancer radiotherapy, and to evaluate its effect on clinical outcomes. Specifically, we compared dose distribution, local tumor control rate, long-term survival rate, and frequency of radiation-induced adverse events between the two groups. We also sought to investigate the potential mechanisms by which multimodal image guidance enhances radiotherapy outcomes, thereby providing a scientific rationale for clinical decision-making and optimizing therapeutic strategies.

MATERIALS AND METHODS

Study subjects

A total of 65 patients who underwent radical esophagectomy for esophageal cancer and subsequently received adjuvant radiotherapy between January 2020 and January 2023 were included in this study. All patients had pathologically confirmed esophageal cancer and had not received prior radiotherapy or chemotherapy. The inclusion criteria were as follows: (1) Eastern Cooperative Oncology Group performance status score of 0-2; (2) Age between 18 years and 75 years; (3) Voluntary participation in this study with the provision of written informed consent; and (4) An estimated survival time of more than 6 months. The exclusion criteria were as follows: (1) Severe hepatic, cardiac, or renal dysfunction; (2) Presence of other malignant tumors; and (3) Inability to tolerate MRI or CT examinations. Eligible patients were randomly assigned to either the control group (n = 33) or the experimental group (n = 32). This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Gansu Provincial Cancer Hospital. Written informed consent was obtained from all the participants.

Methods

The experimental group underwent VMAT planning guided by MRI/CT multimodal imaging. The procedures were as follows: (1) MRI: Before radiotherapy, patients underwent a 3.0 T MRI examination. The scanning range extended from the suprasternal notch to the inferior margin of the diaphragm. Axial T1-weighted imaging and T2-weighted imaging were performed. The slice thickness was 3-5 mm with an interslice gap of 1-2 mm. Patients fasted for 6 h before scanning; (2) CT imaging: Before radiotherapy, patients underwent 64-slice spiral CT. The scanning range was consistent with that of the MRI. The tube voltage was 120 kV, and the tube current was 150 mA. The slice thickness was 5 mm with an interslice gap of 5 mm. An intravenous iodine-based contrast agent was administered to improve the tissue contrast; and (3) Combined guidance: MRI and CT images were imported into the radiotherapy planning system for image fusion and tumor delineation. An individualized radiotherapy plan was formulated based on the fused image data. During treatment, patients were positioned on the treatment bed, and the treatment machine delivered high-energy radiation to the tumor according to the predefined radiotherapy plan. Precise targeting of the tumor was achieved by dynamically adjusting the irradiation dose and angles. During radiotherapy, clinicians regularly assessed the patient’s condition and physical responses. In addition, imaging modalities such as MRI and CT were used to monitor tumor changes and potential damage to the surrounding organs in real time. Based on these findings, the radiotherapy regimen was promptly modified to maintain both therapeutic efficacy and patient safety.

The control group underwent conventional CT-guided radiotherapy without MRI fusion. The procedures were as follows: (1) CT imaging: Before radiotherapy, each patient underwent a 64-slice spiral CT examination, and the scan range, equipment, and scanning parameters were identical to those used in the experimental group; and (2) Guided design: A standard radiotherapy plan was developed based on the CT image data, and dynamic multi-arc irradiation techniques were employed, whereby the treatment couch and linear accelerator rotated together to deliver radiation to the tumor from multiple directions, ensuring that the radiation dose was concentrated within the tumor area. Before each treatment fraction, IGRT technology was used to verify and correct patient positioning to ensure accurate treatment delivery.

Observation indicators

Assessment of radiation dose distribution: (1) Dose distributions within the tumor target volumes, including gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV), as well as in adjacent normal structures (e.g., lungs, heart, and spinal cord), were analyzed using a dose-volume histogram (DVH). Differences in dose coverage (D95%), maximum dose, and minimum dose delivered to the GTV, CTV, and PTV were compared between the two groups; and (2) Daily IGRT images were used to assess the consistency between the planned and delivered doses, and the mean and standard deviation of the dose deviation during radiotherapy were calculated.

Clinical efficacy: Short-term efficacy: Tumor response was assessed at 3 months, 6 months, and 12 months after radiotherapy using imaging modalities (CT and MRI) and endoscopy to assess the degree of tumor reduction and regression. The Response Evaluation Criteria in Solid Tumors 1.1 was used to record the number of cases of partial remission, complete remission, progressive disease, and stable disease.

Adverse reactions: (1) Acute adverse reactions: Acute adverse reactions, including esophagitis, pneumonia, and skin reactions, occurring during radiotherapy and within 3 months after treatment were recorded and graded according to the Common Terminology Criteria for Adverse Events version 5.0; and (2) Late adverse reactions: Late adverse reactions, including fibrosis, stenosis, and cardiac injury, occurring from 3 months after radiotherapy to the end of follow-up, were recorded and graded according to Common Terminology Criteria for Adverse Events version 5.0.

Statistical analysis

All statistical analyses were performed using SPSS version 25.0. Differences in radiation dose distribution between the two groups, including the tumor target areas and surrounding normal tissues, were compared using the independent-samples t-test. Differences in the incidence of adverse reactions and treatment efficacy were compared using the χ² test. A P-value of < 0.05 was considered statistically significant.

RESULTS

A comparison of the radiation dose distributions between the two groups is summarized in Table 1. The dose distribution in the experimental group for the tumor target areas (GTV, CTV, and PTV) and surrounding normal tissues was more favorable than that in the control group. Specifically, the dose coverage of the GTV, CTV, and PTV (D95%) in the experimental group was significantly higher than that in the control group, whereas the radiation doses received by the surrounding normal tissues (such as the lung V20/V30, heart V30/V40, and maximum spinal cord dose) were significantly lower than those in the control group (P < 0.01).

Table 1 Comparison of the radiation dose distribution between the two groups, mean ± SD.

Groups	GTV D95% (Gy)	CTV D95% (Gy)	PTV D95% (Gy)	Lung V20 (%)	Lung V30 (%)	Heart V30 (%)	Heart V40 (%)	Spinal cord Dmax (Gy)
Experimental group (n = 32)	55.8 ± 1.2	54.5 ± 1.3	50.2 ± 1.4	18.3 ± 3.2	12.1 ± 2.8	20.7 ± 3.1	12.3 ± 2.9	45.8 ± 1.6
Control group (n = 33)	52.3 ± 1.5	47.6 ± 1.7	47.6 ± 1.7	22.5 ± 3.7	15.4 ± 3.0	24.6 ± 3.5	15.7 ± 3.2	49.3 ± 1.8
t	10.368	18.340	6.719	4.888	4.581	4.750	4.484	8.276
P value	< 0.01	< 0.01	< 0.01	< 0.01	< 0.01	< 0.01	< 0.01	< 0.01

GTV: Gross tumor volume; CTV: Clinical target volume; PTV: Planning target volume; D95%: Differences in dose coverage; Dmax: Maximum dose.

A comparison of radiation dose deviations between the two groups is summarized in Table 2. Daily IGRT image analysis showed that the consistency between the planned and delivered doses was significantly higher in the experimental group than in the control group. The mean dose deviation was significantly lower in the experimental group than in the control group (2.3% ± 0.5% vs 4.6% ± 0.7%; P < 0.01). Similarly, the standard deviation of dose deviation was significantly higher in the experimental group than in the control group. (1.1% ± 0.3% vs 2.4% ± 0.4%; P < 0.01).

Table 2 Comparison of radiation dose deviation between the two groups, mean ± SD.

Groups	Mean dose deviation (%)	SD of dose deviation (%)
Experimental group (n = 32)	2.3 ± 0.5	1.1 ± 0.3
Control group (n = 33)	4.6 ± 0.7	2.4 ± 0.4
t	15.202	14.788
P value	< 0.01	< 0.01

A comparison of the short-term efficacy between the two groups is summarized in Table 3. At 3 months and 6 months after radiotherapy, the local control rate was significantly higher in the experimental group than in the control group. The proportion of complete remission in the experimental group was significantly higher than in the control group, whereas the proportions of partial remission, progressive disease, and stable disease were lower than those in the control group (P < 0.05).

Table 3 Comparison of short-term efficacy between the two groups, n (%).

Groups	3 months				6 months
	CR	PR	SD	PD	CR	PR	SD	PD
Experimental group (n = 32)	18 (56.3)	9 (28.1)	3 (9.4)	2 (6.3)	21 (65.6)	8 (25.0)	2 (6.3)	1 (3.1)
Control group (n = 33)	8 (24.2)	12 (36.4)	8 (24.2)	5 (15.2)	12 (36.4)	11 (33.3)	6 (18.2)	4 (12.1)
χ2	4.584		4.584		4.447		4.447
P value	< 0.05		< 0.05		< 0.05		< 0.05

CR: Complete remission; PR: Partial remission; SD: Stable disease; PD: Progressive disease.

A comparison of the acute adverse reactions between the two groups is summarized in Table 4. During radiotherapy and within 3 months of treatment, the incidence of acute adverse reactions was significantly lower in the experimental group than in the control group. The incidence rates of acute esophagitis, pneumonia, and skin reactions in the experimental group were lower than those in the control group (P < 0.05).

Table 4 Comparison of acute adverse reactions between the two groups, n (%).

Group	Acute esophagitis		Acute pneumonia		Skin reactions
	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4
Experimental group (n = 32)	9 (31.3)	2 (6.3)	7 (21.9)	1 (3.1)	8 (25.0)	1 (3.1)
Control group (n = 33)	18 (54.5)	5 (15.2)	15 (45.5)	4 (12.1)	14 (42.4)	4 (12.1)
χ2	8.125		7.099		4.670
P value	< 0.05		< 0.05		< 0.05

A comparison of late adverse reactions between the two groups is summarized in Table 5. From 3 months after radiotherapy to the end of the follow-up period, the incidence of late adverse reactions in the experimental group was lower than that in the control group. The incidence rates of fibrosis, stenosis, and cardiac injury in the experimental group were lower than in the control group (P < 0.05).

Table 5 Comparison of late adverse reactions between the two groups, n (%).

Group	Fibrosis		Stenosis		Cardiac injury
	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4
Experimental group (n = 32)	6 (18.8)	1 (3.1)	5 (15.6)	1 (3.1)	4 (12.5)	0 (0.0)
Control group (n = 33)	12 (36.4)	4 (12.1)	11 (33.3)	3 (9.1)	9 (27.3)	3 (9.1)
χ2	5.031		4.275		4.986
P value	< 0.05		< 0.05		< 0.05

DISCUSSION

Esophageal cancer is a common malignancy worldwide, particularly in China and other parts of Asia. According to recent epidemiological data, the incidence of esophageal cancer is increasing, especially among men. Despite continuous advancements in treatment strategies, including the combined use of surgery, radiotherapy, and chemotherapy, the prognosis of esophageal cancer remains poor, particularly in patients with locally advanced or advanced-stage disease.

Volumetric modulated arc therapy (VMAT) has emerged as an advanced radiotherapy technique that offers superior dose conformity and shorter treatment delivery times than conventional fixed-field intensity-modulated radiation therapy. However, the combination of VMAT and multimodal imaging guidance (MRI/CT) in patients with postoperative esophageal cancer has not been extensively studied. Currently, conventional radiotherapy for esophageal cancer relies primarily on CT guidance. However, owing to the complex anatomy of the esophagus and significant inter-individual anatomical variability, traditional CT-guided radiotherapy has limitations in tumor localization accuracy and in protecting surrounding normal tissues. These limitations may increase the incidence of adverse reactions during radiotherapy, thereby affecting treatment efficacy and patients’ quality of life.

This present study aimed to investigate the application of MRI/CT multimodal IGRT in the treatment of postoperative esophageal cancer. Compared with conventional single CT-guided radiotherapy, multimodal image guidance combines the superior soft-tissue contrast of MRI with the precise anatomical information provided by CT, thereby improving tumor localization accuracy and radiation dose concentration, and consequently enhancing therapeutic efficacy.

The results of this study indicate that MRI/CT multimodal IGRT achieves a higher radiation dose concentration within the tumor target area and significantly reduces radiation exposure to the surrounding normal tissues. The dose coverage of the GTV, CTV, and PTV (e.g., D95%) in the experimental group was significantly higher than that in the control group, whereas the radiation dose to the surrounding normal tissues, including the lungs, heart, and spinal cord was significantly lower than that in the control group, indicating that the use of multimodal image guidance leads to more precise tumor targeting and better sparing of healthy tissues, thereby improving the overall treatment efficacy.

Regarding the regional control rate, the experimental group exhibited a significantly higher rate than the control group at both 3 months and 6 months after radiotherapy, which is consistent with the findings of Zhang et al[14], who reported that multimodal image guidance enhanced the local control rate in esophageal cancer. Furthermore, Gupta et al[15] showed that MRI-guided radiotherapy markedly improved the precision of tumor localization, which, in turn, led to better local control and patient outcomes.

MRI offers distinct benefits for identifying tumor tissue and defining tumor margins, particularly in cases where soft-tissue contrast is poor. When used together with CT imaging, MRI provides clearer tumor boundaries and more detailed information about adjacent healthy structures, thereby supporting precise radiotherapy planning. In the present study, the dose deviation observed in the experimental group was notably smaller than in the control group, suggesting that multimodal image guidance enables more accurate delivery of the intended treatment plan, thereby enhancing both the precision and efficacy of radiotherapy.

Moreover, the use of multimodal imaging guidance substantially lowered the frequency of both acute and late adverse events. During radiotherapy and within the first three months post-treatment, the experimental group showed markedly lower rates of acute esophagitis, pneumonia, and skin reactions compared with the control group, which aligns with the results reported by Palmer, who showed that multimodal imaging guidance effectively reduces radiation exposure to healthy tissues, thereby decreasing acute toxicities associated with radiotherapy[16]. From three months after radiotherapy through the end of the follow-up period, the experimental group also exhibited substantially lower rates of fibrosis, stenosis, and cardiac injury than the control group, further reinforcing the benefits of multimodal imaging guidance in minimizing radiotherapy-related complications.

This study had several limitations. First, the sample size was relatively small, and the findings require validation in larger multicenter cohorts. Second, the follow-up period (median, 12 months) was insufficient to assess long-term survival outcomes or late toxicities beyond one year. Third, this study was conducted in a single institution, which may limit its generalizability. Fourth, although randomization was performed, blinding of the treating physicians was not feasible because of the nature of the intervention. Fifth, we did not evaluate patient-reported outcomes, such as quality of life, which are increasingly recognized as important endpoints. Future research should address these limitations. Compared with earlier investigations, such as the Shi et al[17] multicenter study, which involved a larger cohort, multimodal IGRT has consistently shown distinct advantages across various tumor types, which is in line with our results and further indicates that future research should incorporate larger sample sizes to confirm the reliability of the findings.

Future studies should prioritize expanding the sample size and extending the duration of follow-up observations. Doing so would allow a thorough evaluation of the long-term efficacy and safety profile of multimodal IGRT in patients with esophageal cancer. Additionally, incorporating other sophisticated imaging technologies into radiation treatment protocols should be explored. For example, the fusion of positron emission tomography with MRI may be considered a means to further improve therapeutic outcomes while reducing unwanted side effects. According to a study by Li et al[18], positron emission tomography/MRI demonstrates significant potential for tumor diagnosis and treatment, as it provides highly accurate data on both the metabolic activity of cancer and its detailed anatomical structure. With ongoing advancements and continuous optimization of image-guidance methods and radiotherapy planning, the overall efficacy of radiation therapy for esophageal cancer is expected to be maximized. This, in turn, will contribute to an improved quality of life and better long-term prognosis for affected patients.

CONCLUSION

In summary, this prospective randomized controlled trial demonstrates that multimodal MRI/CT-guided VMAT radiotherapy significantly improved dose accuracy, target coverage, and short-term tumor control while reducing acute and late adverse reactions compared with conventional CT-guided radiotherapy in postoperative patients with esophageal cancer. These findings support the clinical implementation of multimodal image-guided VMAT as the preferred adjuvant radiotherapy strategy. Larger multicenter studies with extended follow-up are warranted to confirm the long-term survival benefits.