Our study found that IOV in target volume delineation in dRT for thoracic esophageal cancer existed in routine delineating practice, and the contouring consistency could be improved using contouring protocol and delineation atlas, which laid the foundation of multi-center studies of dRT for esophageal cancer.
According to the RG data, the consistency in delineation of GTV-T is generally high with basic DSC above 0.75; no obvious IOV existed among clinicians and centers regardless of the location of the primary lesion. As also reported by Nowee et al. 26, GTV delineation consistency seemed difficult to further improved.
For GTV-N, although PET-CT, EUS, and other auxiliary examinations were provided to help diagnose metastatic lymph nodes, and the contouring protocol was applied to improve its consistency in diagnosis, its DSC value was generally lower than 0.70. The possible reasons for these results are: first, there is no clear standardized definition of metastatic lymph nodes in esophageal cancer, which may have resulted in instances of either missed or over contoured GTV-N. Second, some clinical studies 27–29 have shown that a large proportion of metastatic lymph nodes diagnosed by preoperative imaging is clinically over- or under-estimated compared with the postoperative pathological results. As reported by Mantziari et al. 30 in a study of 193 patients with esophageal cancer (clinical stage: T3N0), though the patients were enrolled into the single surgery group, pathological N0 cases accounted for only 35.8%, which indicated that more than 60% cases were under-estimated in the clinical assessment. Finally, according to the analysis by Gockel 31, there was a 27–55% rate of lymph node metastasis when the primary lesion invades the submucosa. In addition, the lymph node metastasis in esophageal cancer is very extensive. For the cases receiving three-field lymph node dissection, as reported by Isono 32, the rate of metastases in cervical nodes was 27.5% among patients with middle thoracic esophageal cancer. Therefore, it is challenging to assess lymph node metastasis in clinical practice. We reviewed the multi-center target volumes and found that variance in GTV-N is mainly due to the first reason, that is, clinicians’ cautious overestimation of suspected metastasis in lymph nodes. In reality, the introduction of protocol allows clinicians to comprehensively combine multiple diagnostic methods for judgment, which may be the reason for the increased consistency of GTV-N.
The CTV field mainly relies on clinical examinations that mainly serves to provide a reference for clinicians by improving the accuracy of judgment of metastatic lymph nodes and determination of the range of radiation treatment. In the RG, IOV in CTV were observed among branch-centers. However, for those cases with relatively limited and proven range of lymph node metastasis, the IOV was relatively small regardless of the study group, which indicates that radiation oncologists reached an agreement in delineation of such target volumes. However, in case 3, with relatively more extensive lymph node metastasis, the IOV in target volume delineation becomes an issue. The efficacy of involved field irradiation (IFI) versus elective nodal irradiation (ENI) is still debatable 33–35, and a meta-analysis 36 shows that there is no survival difference between IFI and ENI. Thus, more prospective, comparative studies should be conducted for validation. Our study suggests that regardless of the location of the primary lesion, the consistency of delineating CTV was significantly improved according to the requirements of the protocol. Therefore, the findings of this multi-center study are important because it emphasizes that a different center could achieve a more consistent target volume delineation.
A similar observation has been documented for other tumors such as nasopharyngeal, cervical, pulmonary, and gastric carcinomas 9,20,37,38. Factors accounting for the variance in GTV-N and CTV definition in this study were similar to those found by Weiss et al., 39 who suggested that causes are multifactorial, including image- and observer-related factors. A previous study 8 suggested that refined contouring guidelines should be provided to better reduce the IOV. Accordingly, the present protocol proposed a consensus on involved lymph nodes and strict definition in the expansion criteria of CTV, leading to higher consistency in delineation of GTV-N and CTV. According to an investigation on head and neck cancers by Peters et al. 11, protocol compliance did improve the radiotherapy quality assurance to achieve optimal treatment outcomes in the combined modality (chemoradiotherapy) treatment.
To our best knowledge, this is a minority of multicenter study of the variability in the target volumes of dRT for thoracic esophageal cancer, including 16 centers throughout China. Besides, we investigated IOV with respect to both volume and spatial relationship. In addition, unlike the previous trials that included dummy runs for QA analysis 10,40, our study showed, similar to Spoelstra et al., 20 that IOV both before and after using the protocol was used to evaluate its efficiency.
Our study explored the variability in target volumes of dRT for thoracic esophageal cancer and compensated for the gap in this field. Furthermore, our study enforced that a contouring protocol could contribute to the consistency of target volumes, making the results of multi-center studies more reliable. Except the protocol, the improvement in the contouring consistency depends on advances in diagnostics. The department of imaging diagnosis in our center indicated that combining both the lymph node size and axial ratio relationship could improve the sensitivity in diagnosis41. Besides, the addition of PET-CT and EUS will further increase the accuracy of N-stage 42,43, thereby improving the consistency of target volumes definition.
One limitation of our study is that the results were based on the combination of multiple modality examinations, while patients could only receive several of them in clinical practice, which could result in more striking contouring variance. In addition, we did not ask participating centers to design treatment plans for their target volumes, and therefore variances in dosimetric parameters could not be evaluated. Instead, we planned to further assess the variability in treatment plans designed for dRT of esophageal cancer and evaluate the impact of the dose-restriction protocol on dose–volume histogram parameters.