- Results: P-spline regression revealed a dependence of patient outcomes on GTVp, with 30 cm 3 being an optimal cut-off for differences in overall and progression-free survival (OS, PFS). - GTVp ≥ 30 cm 3 was a negative independent prognostic factor for OS and PFS. - 30 cm 3 , no significant survival differences were observed among the 3 treatments. - For GTVp ≥ 30 cm 3 , the worst 5-year OS rate was experienced by those given surgery. - For patients with GTVp ≥ 30 cm 3 , radiotherapy plus surgery was more effective than either treatment alone.. - 420, Fuma Road, Fuzhou 350014, China Full list of author information is available at the end of the article. - Yet, while cancer of the upper third of the esophagus at the cer- vical and upper thoracic region is relatively rare (ac- counting for no more than 10% all cases) [2], radical esophagectomy is often precluded. - The guideline of the National Comprehensive Cancer Network (NCCN) provides no consensus regarding the optimal treatment of upper EC, although definitive radiotherapy is recommended for cervical EC [3]. - Clinical TNM staging was in accordance with the eighth edition of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging criteria for EC. - Chemotherapy treatments were platinum-based, and administered to of the patients, of whom 113 (30.5. - The main observational indexes of acute toxicities of radio- therapy were acute radiation-induced esophagitis and radiation-induced pneumonitis, which were evaluated based on the criteria of the Radiation Therapy Oncology Group [17].. - The clinical features and adverse effects of treatment of the different subgroups were compared with Pearson’s chi-squared or Fisher’s exact tests. - The 5-year OS rates of the S, RT, and RT + S groups were and 51.0%. - Ultimately, 319 patients died of the following: 105 of dis- tant metastasis. - To quantify the effect and optimal cutoff value of GTVp on OS and PFS, a multivariate Cox regression analysis was conducted using P-splines in smoothHR of the R software. - The model indicated that the risk (InHR) of abbreviated OS and PFS increased sharply when GTVp was more than 30 cm 3 (Fig. - These findings con- firmed a GTVp-dependent effect, and a GTVp of 30 cm 3 was an optimal cut-off volume for survival difference.. - Consequently, all patients could be stratified into 2 sub- groups based on a GTVp of less or greater than 30 cm 3. - 30 cm 3 and ≥ 30 cm 3 . - with GTVp ≥30 cm 3 had markedly poorer 5-year OS and PFS than did those with GTVp <. - 30 cm 3 (Fig. - 30 cm 3 and ≥ 30 cm 3 (Supplemental Table 1), and PSM was employed to calibrate the potential indication bias be- tween the 2 groups. - As the GTVp of the 3 treatment groups differed so greatly, the possibility of selection bias was considered (Supple- mental Table 1). - 30 cm 3 , the OS curves of the RT, S, and S + RT groups appeared to be identical and did not differ signifi- cantly (Fig. - The PFS curves of the 3 groups were comparable, expect with a border line difference between the RT and S groups (P = 0.053. - The PSM analysis revealed no marked difference among the various clinical features of the 79 patients in the RT group and the 79 patients in the S group (Supplemental Table 2). - It was observed that the OS and PFS curves of the RT and S groups overlapped, respect- ively (all P >. - For GTVp ≥30 cm 3 , the OS curves of the S + RT and RT groups were significantly better than that of the S group. - the 5-year OS rates of the S + RT and RT groups were 45.4 and 21.1%, respectively, while that of the S group was 14.1% (P = 0.009 and 0.031;. - Although the 5-year OS rate of the S + RT group was better than that of the RT, the difference did not reach statistical difference (P = 0.169). - In addition, the S + RT group showed markedly better distinction of PFS curves compared with the RT and S groups with the 5-year PFS being 42.8% cf. - 14.3% (P = 0.003 and P = 0.002, respect- ively), whereas the PFS curves of the RT and S groups almost overlapped (P = 0.504. - PFS curve of the S + RT group was significantly better than that of the RT or S groups. - the 5-year PFS rates of the S + RT group was 42.8%, whilst that of the RT and S groups were 21.1 and 14.1% (P = 0.003 and 0.002). - The PFS curves of the RT and S groups al- most overlapped (P = 0.504, Fig. - To compensate for the unbalanced baseline charac- teristics, 27 patients in the S + RT group and 27 in the RT group were selected for comparison of their PFS (Supplemental Table 3). - The PFS of the 2 groups remained statistically similar (Fig. - 30 cm 3 or GTV- p ≥ 30 cm 3 . - 30 cm 3 . - 4 Survival rates of patients with GTV-p ≥ 30 cm 3 . - Taken together, the S group experienced the worst OS, while the PFS of the S + RT was significantly better that of the RT group for patients with GTVp ≥30 cm 3. - The rates of complications of the S + RT and S groups were similar.. - The rate of acute radiation-induced esophagitis in the S + RT group (64.4%) was markedly lower than that of the RT group (22.0%, P <. - This study found that a GTVp of 30 cm 3 was the optimal cut-off for differences in survival, and GTVp. - ≥30 cm 3 was an independent negative risk factor of OS and PFS. - 30 cm 3 , no significant survival dif- ferences were observed among the 3 treatment groups (S, RT, and S + RT). - For patients with GTVp ≥30 cm 3 , 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 radi- ation side effects compared with the RT group. - In this study, we firstly confirmed the GTVp- dependent effect on survival, and determined that 30 cm 3 was the optimal cut-off point using P-spline regres- sion analyses. - 30 cm 3 and those with GTVp ≥30 cm 3 . - It was observed that patients with GTVp ≥30 cm 3 indeed experienced poorer OS and PFS rates. - 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.. - 30 cm 3 , there were no signifi- cant 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 cm 3 may result in a significantly better prognosis irrespective of the therapeutic methods. - It is noteworthy that and patients, Table 3 Surgical complications of the S and S + RT groups. - respectively, were included in the S and S + RT groups (Supplemental Table 1), which suggests that most of the patients with GTVp <. - 30 cm 3 were considered viable candidates for radical resection. - Even for the patients who did not undergo surgery, definitive radio- therapy was able to achieve good efficacy, because radio- resistant hypoxic and clonogenic tumor cells were negligible when the GTVp is less than 30 cm 3 . - 30 cm 3 , 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 cm 3 , the S group had the worst 5-year OS rate. - ≥30 cm 3 , 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 me- tastases may be detected in the RT group if it was given lymph nodal pathological examination. - Secondly, the RT group may have had lower PFS be- cause these patients were more prone to develop cervical lymph node metastases than the S + RT group. - In addition, patients who received definitive chemoradiotherapy experienced more cervical lymph node recurrences compared with those given radical esophagectomy for ESCC [24], 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 radiother- apy to radical surgery made loco-regional recurrence more unlikely. - Conse- quently, in the present study, the addition of radiother- apy to surgery was associated with preferable survival benefits in patients with GTVp ≥30 cm 3. - The S + RT group had no more surgical complications than did the S group. - In the present study, most radiotherapy treatments when given were delivered post- operatively (16.7% preoperatively), and the S + RT group did not have a significant rate of postoperative complica- tions. - Furthermore, the S + RT group showed a signifi- cantly lower rate of radiation side effects compared with the RT group, especially for acute radiation-induced esophagitis. - 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 Table 4 Radiation toxicity of the S and S + RT groups. - 30 cm 3 , no sig- nificant survival differences were observed among the RT, S, and S + RT treatment arms. - For ESCC GTVp ≥30 cm 3 , radiotherapy plus surgery was the most effective treatment. - Clinical characteristics of 306 patients in the RT and S groups before PSM, and 158 patients after PSM for GTV- p <. - 30 cm 3. - Clinical characteristics of 149 patients in the RT and S + RT groups before PSM, and 54 patients after PSM for GTV- p ≥ 30 cm 3. - 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