To our knowledge, the present study comprised the largest cohort of patients with upper ESCC to investigate the significance of GTVp for prognosis and indication of treatment. This study found that a GTVp of 30 cm3 was the optimal cut-off for differences in survival, and GTVp ≥30 cm3 was an independent negative risk factor of OS and PFS. For GTVp < 30 cm3, no significant survival differences were observed among the 3 treatment groups (S, RT, and S + RT). For patients with GTVp ≥30 cm3, the S + RT and RT groups both experienced significantly better OS than did the S group, while the PFS of the S + RT group was superior to that of the RT. In addition, the S + RT group had a significantly lower rate of radiation side effects compared with the RT group. These findings indicate that GTVp was predictive for prognosis and treatment in patients with upper ESCC.
In this study, we firstly confirmed the GTVp-dependent effect on survival, and determined that 30 cm3 was the optimal cut-off point using P-spline regression analyses. GTVp was then found to be an independent prognostic factor for OS and PFS. Recently, several studies have reported a close association between survival outcome and tumor volume in EC [19, 20], but the optimal cut-off points of GTVp varied among studies. Créhange et al.  initially found that the optimal cut-off point for differences in OS was 100 cm3. Chen et al.  reported that 20 cm3 and 40 cm3 were useful cut-off points for OS differences, based on clinical experience. Using receiver operating characteristic (ROC) curve analysis, Chen et al.  identified 39.41 cm3 as a cut-off to predict survival differences, while Chen et al.  suggested a cut-off of 28 cm3. The above postulated cut-off values were based either on clinical experience or ROC analysis, and limited by considering only associations between the continuous variable and survival endpoints. In the present study, multivariate Cox regression analysis using P-splines in smoothHR was conducted to determine the optimal cutoff value, which should be more valid because it is based on an association between the continuous variable and survival rates.
To further verify the prognostic value of GTVp, PSM analysis was employed to calibrate the potential indication bias between patients with GTVp < 30 cm3 and those with GTVp ≥30 cm3. It was observed that patients with GTVp ≥30 cm3 indeed experienced poorer OS and PFS rates. In addition, multivariate Cox proportional hazards regression showed that GTVp (HR [hazard ratio] for OS 1.682; HR for PFS 1.673) was more prognostic than T stage (HR for OS 1.245; HR for PFS 1.214). Therefore, GTVp is an important risk factor that independently influences patient outcomes, outside of clinical TNM stage.
An increasing number of studies have indicated that TNM stage may not be sufficient to determine prognosis, as it does not consider GTV that differs between T or N stage [10, 22]. Larger GTVp is understood to represent greater tumor load, a higher percentage of tumor radioresistant hypoxic cells and clonogenic cells, and greater risk to organs surrounding the tumor, which results in poor survival . Furthermore, GTVp should be included in the staging system as an indicator of patients’ prognosis [9, 10]. Taken together, GTVp showed a powerful prognostic value that may make up for the deficiency of the TNM stage, and should be part of a personalized treatment strategy for upper ESCC.
As GTVp in the present study was markedly different among the S, RT, and S + RT groups, the 3 treatment groups were further stratified by GTVp to explore prognostic effect. For GTVp < 30 cm3, there were no significant differences in OS and PFS among the treatments. This may be because of the lighter tumor burden and less tumor infiltration to adjacent anatomical structures, and GTVp < 30 cm3 may result in a significantly better prognosis irrespective of the therapeutic methods. It is noteworthy that 215 (54.3%) and 80 (20.2%) patients, respectively, were included in the S and S + RT groups (Supplemental Table 1), which suggests that most of the patients with GTVp < 30 cm3 were considered viable candidates for radical resection. Even for the 101 (25.5%) patients who did not undergo surgery, definitive radiotherapy was able to achieve good efficacy, because radioresistant hypoxic and clonogenic tumor cells were negligible when the GTVp is less than 30 cm3. Therefore, for patients with GTVp < 30 cm3, we suggest that surgery, or radiotherapy plus surgery, is preferred if the tumors are considered resectable, whereas definitive radiotherapy is best if the tumors are non-resectable.
For GTVp ≥30 cm3, the S group had the worst 5-year OS rate. The extent of tumor local invasion was larger, and most of these patients (81.4%) were staged as locoregional advanced disease. Thus, surgery may not be sufficient to control tumor development when GTVp is ≥30 cm3, and poor OS is the result.
Furthermore, the S + RT group had better 5-year PFS rates than did the RT group. This may be because, first, a more advanced N stage may have been a feature of the RT group. Although the imbalance in clinical characteristics between the RT and S + RT groups was compensated for by PSM, more numbers of positive locoregional nodal metastases may be detected in the RT group if it was given lymph nodal pathological examination. There is surgical data that the rates of positive locoregional nodal metastases in ESCC increase with each T stage, from a low of 31% for T1b, up to 100% for T4 .
Secondly, the RT group may have had lower PFS because these patients were more prone to develop cervical lymph node metastases than the S + RT group. It was reported that the most common nodal metastases in upper ESCC are cervical (49.5%) . In addition, patients who received definitive chemoradiotherapy experienced more cervical lymph node recurrences compared with those given radical esophagectomy for ESCC , which may be reflected the poorer 5-year PFS rates in the RT group of the present study.
Finally, perhaps the S + RT group had better 5-year PFS rates than the RT because the addition of radiotherapy to radical surgery made loco-regional recurrence more unlikely. Some studies showed that neoadjuvant chemoradiotherapy prior to surgery could result in lower risk of local recurrence and higher disease-free survival in patients with locally advanced ESCC [25, 26]. Consequently, in the present study, the addition of radiotherapy to surgery was associated with preferable survival benefits in patients with GTVp ≥30 cm3.
The S + RT group had no more surgical complications than did the S group. Postoperative complications that have been confirmed negative prognostic factors in EC include pneumonia, pyothorax, and chylothorax, and preoperative chemoradiotherapy was even reported to reduce the negative effect of postoperative complications on patient outcome . In the present study, most radiotherapy treatments when given were delivered postoperatively (16.7% preoperatively), and the S + RT group did not have a significant rate of postoperative complications. Furthermore, the S + RT group showed a significantly lower rate of radiation side effects compared with the RT group, especially for acute radiation-induced esophagitis. This may be because the radiation dose delivered during definitive radiotherapy was much higher than that of either the preoperative or postoperative radiotherapy.
Notably, there were some limitations in this study. Although the cohort was large, it was retrospective, with inevitable selection and confounding bias. A prospective, multicenter study is warranted. Furthermore, this study did not consider the GTV of lymph nodes, which may also influence survival . Because the selection of treatment was primarily based on T stage for non-metastatic ESCC as recommended by the NCCN guideline , we emphasized the prognostic and predictive effects of GTVp. Yet, the effects of the GTV of lymph nodes for upper ESCC are worthy of investigation. Finally, this analysis did not integrate other independent prognostic factors with GTVp, such as gender, cT stage, and LNM, which may improve the accuracy of prognosis and choice of treatment. Thus, a nomogram to predict the survival prognosis of patients with upper ESCC is needed.
In conclusion, GTVp is prognostic for OS and PFS in patients with upper ESCC. For GTVp < 30 cm3, no significant survival differences were observed among the RT, S, and S + RT treatment arms. For ESCC GTVp ≥30 cm3, radiotherapy plus surgery was the most effective treatment. These findings may help clinicians strategize individualized treatment for patients with upper ESCC.