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A retrospective study comparing definitive chemoradiotherapy vs. chemoradiotherapy followed by surgery in T4 esophageal squamous cell carcinoma patients who were downstaged after neochemoradiotherapy

A retrospective study comparing definitive chemoradiotherapy vs. chemoradiotherapy followed by... Background: The outcome of patients with T4 esophageal squamous cell carcinoma (ESCC) is extremely poor. Two distinct therapeutic options are currently available for T4 esophageal cancers: neochemoradiotherapy followed by surgery (CRT-S) and definitive chemoradiotherapy (D-CRT ). This study aimed to investigate the clinicopathologic char - acteristics of T4 ESCC in Chinese patients and compare the survival between the two therapeutic options. Methods: We retrospectively analyzed 125 patients with clinically unresectable T4 ESCC in Tianjin Medical University Cancer Institute and Hospital from January 2010 to December 2020. Overall survival (OS), progression-free survival (PFS) and associated factors were analyzed. Results: A total of 106 of 125 T4 ESCC patients were downstaged of the tumor by neoadjuvant CRT. Among 106 patients, 32 patients underwent CRT-S, and 74 patients underwent D-CRT. Patients in the CRT-S group had a higher OS (20.4 months vs. un-reached median OS, p = 0.037) and PFS (8.6 months vs. 21.0 months, p = 0.008) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor of PFS. After propensity score matching (PSM), 50 patients (CRT-S = 25; D-CRT = 25) were matched. Among these 50 patients, patients in the CRT-S group had a higher OS (15.6 months vs. un-reached median OS, p = 0.025) and PFS (7.2 months vs. 18.8 months, p = 0.026) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor for PFS. Conclusion: We demonstrated that CRT-S was superior to D-CRT for T4 ESCC patients who were downstaged by neo-CRT with respect to longer OS and PFS. Randomized controlled trials involving large population samples are needed to define the standard treatment for T4 ESCC. Zhang Tian and Guo Zhoubo have contributed equally to this work *Correspondence: wczhang@tmu.edu.cn; pangqingsong@tjmuch.com Key Laboratory of Cancer Prevention and Therapy, Department of Radiation Oncology, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huanhu West Road, Hexi District, Tianjin, China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Radiation Oncology (2022) 17:148 Page 2 of 12 Keywords: Esophageal squamous cell carcinoma, T4, Neo-chemoradiotherapy followed by surgery, Definitive chemoradiotherapy Introduction EUS showed invasion of the trachea, bronchus, aorta, Esophageal squamous cell carcinoma (ESCC) is one of pleura, pericardium, and/or other peripheral organs; 2) the leading causes of cancer-related mortality worldwide, EBUS showed invasion of the trachea and/or bronchus; with a high prevalence in Asia [1, 2]. The outcome of 3) bronchoscopy showed protrusion of the esophageal patients with T4 esophageal cancer, defined as a tumor tumor into trachea and/or bronchi or abnormal tracheal that invades neighboring structures (e.g., aorta, tra- mucosa; and 4) if the patient could not undergo EUS, chea, bronchus, and lung), is extremely poor [3]. Despite adjacent organ invasion was defined by CT or positron advances in surgical treatment, these tumors are usually emission tomography (PET)-CT. Generally, invasion of considered inoperable; however, surgery alone has not the peripheral organs was diagnosed based on the loss of improved the prognosis of patients with T4 esophageal fat planes between the esophagus and peripheral organs. tumors [4, 5]. Invasion of the aorta was defined as > 90 degrees of the Two distinct therapeutic options are currently available aorta surrounded by tumor in more than one CT slice. for T4 esophageal cancers: chemoradiotherapy followed Invasion of the pericardium was defined as the disap - by surgery (CRT-S), which comprises esophagectomy pearance of the fat line at the focus level and local peri- following downstaging of the tumor by CRT, and defini - cardial thickening. tive chemoradiotherapy (D-CRT), which is designed to The following clinicopathologic parameters for each avoid esophagectomy by using maximum doses of irra- patient were also collected: sex, age at diagnosis, smok- diation [4, 6]. Until now, D-CRT has been the standard ing history, drinking history and TNM stage in line with alternative curative management for patients with locally the 8th edition of the esophageal cancer staging system. advanced disease who are not eligible for or refuse sur- The PFS and OS of patients diagnosed from January 2010 gery [7]. To our knowledge, there is little information on to December 2020 were recorded based on a follow-up the differences in the clinical outcomes of patients with clinic visit or a telephone call. T4 ESCC who undergo D-CRT and those who receive CRT-S. In this study, we discuss these two treatment Treatment and response modalities. Patients received conventional fraction radiotherapy using a 6 MeV linear accelerator. The radiation dose was Methods calculated by intensity-modulated radiotherapy (IMRT). Patients All plans were based on 3- or 5-mm CT scan images We retrospectively enrolled patients with ESCC who had obtained in the treatment position before radiotherapy. been treated with CRT from January 2010 to December The gross tumor volume (GTV) included the esopha - 2020 at our center, including 8 cases from a single-arm, geal tumor found under CT and esophageal endoscopy single-center, investigator-initiated, exploratory, phase and the enlarged locoregional lymph nodes found by II clinical study (ClinicalTrials.gov NCT04137679) at CT before treatment. GTV also included distant lymph Tianjin Medical University Cancer Institute & Hospital nodes with metastasis for patients with cervical or in Tianjin, China. The inclusion criteria were as follows: abdominal distant lymph node metastases. The clinical (1) squamous cell histological type; (2) staged as unre- target volume (CTV) was added to the esophageal tumor sectable T4 disease by a multidisciplinary team based on 5–6  mm laterally and 2–3  cm in the cephalo–caudal biopsy and imaging pretreatment examination data; (3) direction, and CTV also includes positive lymph nodes downstaged to T3 or lower T stage by neoadjuvant CRT; and its drainage area. The planning target volume (PTV) (4) without distant organ metastases; and (5) Eastern was added to the CTV 5 mm in the cephalo–caudal and Cooperative Oncology Group (ECOG) performance sta- lateral directions. Cone-beam computed tomography tus (PS) of ≤ 1. All patients were staged according to the (CBCT) was used to guarantee the treatment position 8th edition of the American Joint Committee on Cancer during the whole radiotherapy process once a week. The (AJCC) staging manual. induction and concurrent chemotherapy with radiation Adjacent organ invasion was diagnosed by esopha- included cisplatin, 5-FU or taxane-based regimens. The geal endoscopy ultrasound (EUS), endobronchial ultra- patients’ response to treatment was assessed by CT scan, sonography (EBUS), bronchoscopy, and/or computed endoscopy and upper gastrointestinal contrast in accord- tomography (CT) according to the following criteria: 1) ance with Response Evaluation Criteria in Solid Tumors Zhang  et al. Radiation Oncology (2022) 17:148 Page 3 of 12 1.1 (RECIST 1.1) criteria and the method reported in our neochemoradiotherapy. Of the whole 106 cases, 8 cases previous study [8]. were from a single-arm, single-center, investigator-initi- Patients in the CRT-S group received a 40-Gy radia- ated, exploratory, phase II clinical study (ClinicalTrials. tion dose (2 Gy once daily in 20 fractions, 5 days a week) gov NCT04137679) at Tianjin Medical University Can- and were scheduled to undergo resection 4–6 weeks after cer Institute & Hospital in Tianjin, China. The choices having completed induction chemoradiation. Patients in of the 8 patients were randomly made according to the the D-CRT group received a 60-Gy radiation dose (2 Gy random system. For the rest of the 98 cases, doctors pro- once daily in 30 fractions, 5  days a week). An intensity- vided the two possibilities of treatment ways equally and modulated radiotherapy dose planning system was used. patients and doctors made the final decision together. Of the 106 downstaged T4 stage patients, 32 patients Propensity score matching analysis received surgery after neo-CRT, and 74 patients received In this study, propensity score matching (PSM) was used D-CRT (Fig.  1). These patients had a median follow- to reduce bias due to an imbalance in observed variables up duration of 17.3  months (range: 2.6–90.6  months). between the CRT-S and D-CRT groups. Three baseline The cohort consisted mostly of males, 92 male patients characteristics (sex, T-stage and segment) were selected (86.8%) and only 14 female patients (13.2%). The major - as covariates in the PSM model, and the match tolerance ity of enrolled patients had upper (36; 34.0%) or middle was set to 0.01. Propensity scores of individuals were cal- (42; 4.0%) thoracic ESCC. In comparison with the D-CRT culated with logistic regression analysis (SPSS version group, the CRT-S group had a lower proportion of T4b 22.0, Chicago, IL), and then, the optimal 1:1 matching stage (p = 0.063), and more patients were in the middle between CRT-S and D-CRT patients was produced based or lower segment (p < 0.001). No other significant differ - on propensity scores. After matching, the distribution ences were found between the patients in the CRT-S and of the remaining observed variables was similar in the D-CRT groups with respect to age, sex, smoking history, CRT-S and D-CRT groups. drinking index, Karnofsky Performance Status (KPS) score, N stage or weight loss (Table 1). Statistical analysis Among all 106 patients, treatment (p = 0.037, Fig.  2A), Pearson’s χ test was used to investigate the correlations age (p = 0.009, Fig.  2B), and drinking index (p = 0.007, between 2 categorical variables. PFS and OS distribution Fig.  2C) were significantly associated with overall sur - was analyzed using the Kaplan–Meier method, and log- vival (OS); treatment (p = 0.008, Fig.  3A), age (p = 0.020, rank tests were employed for comparison of PFS or OS Fig. 3B), and drinking index (p = 0.025, Fig. 3C) were sig- between 2 categories in univariate analysis. Multivariate nificantly correlated with progression-free survival (PFS). survival analysis was conducted using Cox proportional In multivariate analysis incorporating treatment, age hazards regression to identify independent prognostic and drinking index, drinking index (hazard ratio = 0.473, factors. Data were statistically analyzed using SPSS 22.0 95% confidence interval: 0.268–0.836, p = 0.010) was an (Abbott Laboratories, North Chicago, IL, USA). Statisti- independent predictor for OS. In multivariate analy- cal significance was set at p < 0.05. sis incorporating treatment, age and drinking index, treatment (hazard ratio = 0.459, 95% confidence inter - Ethics statement val: 0.242–0.869, p = 0.017) and drinking index (haz- This study was approved by the institutional review board ard ratio = 0.569, 95% confidence interval: 0.351–0.924, at Tianjin Medical University. Written informed consent p = 0.022) were independent predictors for PFS (Tables 2 was obtained from each patient to allow their biologi- and 3). cal samples to be genetically analyzed. The experimental After propensity score matching (PSM), 50 patients protocol of this study was performed strictly in accord- (CRT-S = 25; D-CRT = 25) were matched, and Table  1 ance with the guidelines. shows the patients’ characteristics. No significant dif - ferences between the CRT-S and D-CRT groups were Results observed in terms of either T stage or segment. Among From January 2010 to December 2020, 125 T4 ESCC these 50 patients, treatment (p = 0.025, Fig.  4A), age patients were treated with CRT in our center; of these, (p = 0.001, Fig.  4B), KPS score (p = 0.039, Fig.  4C) and 106 patients were down staged to T3 or lower T stage. smoking index (p = 0.039, Fig.  4D) were significantly The patients’ demographics and tumor characteris - associated with OS; treatment (p = 0.026, Fig.  5A), age tics are listed in Table  1. After multi-disciplinary treat- (p = 0.001, Fig.  5B), smoking index (p = 0.016, Fig.  5C) ment (MDT) of department of radiation oncology and and smoking status (p = 0.036, Fig.  5D) were signifi - department of esophageal cancer, all patients were suit- cantly correlated with worse progression-free survival able for surgery or definitive chemoradiotherapy after (PFS). In multivariate analysis incorporating treatment, Zhang et al. Radiation Oncology (2022) 17:148 Page 4 of 12 Table 1 Comparison of clinical characteristics between ESCCs undergoing CRT-S and D-CRT before and after PSM Characteristics Before PSM After PSM Total CRT-S D-CRT P Total CRT-S D-CRT P N. of patients 106 32 74 50 25 25 Age, years ≤ 60 53 12 41 0.091 26 11 15 0.258 > 60 53 20 33 24 14 10 Sex Male 92 30 62 0.164 46 23 23 1.000 Famale 14 2 12 4 2 2 KPS score > 80 75 21 54 0.552 34 17 17 0.431 ≤ 80 23 5 18 11 4 7 Unknown 8 6 2 5 4 1 Smoking status Ever 76 26 51 0.191 12 6 6 1.000 Never 29 6 23 38 19 19 Smoking index < 850 96 30 66 0.461 47 24 23 0.552 ≥ 850 10 2 8 3 1 2 Drinking index > 4500 38 13 25 0.714 22 9 13 0.295 refere ≤ 4500 62 16 46 23 13 10 Unknown 6 5 3 2 T stage T4a 55 21 34 0.063 28 14 14 1.000 T4b 51 11 40 22 11 11 N stage N0 15 3 12 0.423 4 0 4 0.210 N1 43 13 30 21 11 10 N2 33 13 20 19 11 8 N3 15 3 12 6 3 3 Segment Cervical 13 1 12 < 0.001 2 1 1 1.000 Upper 36 5 31 10 5 5 Middle 42 16 26 32 16 16 Lower 14 10 4 6 3 3 Yes 42 15 27 0.315 18 12 6 0.077 Weight loss No 64 17 47 32 13 19 PSM propensity score matching; ESCC esophageal squamous cell carcinoma; CRT-S chemoradiotherapy followed by surgery; D-CRT definitive chemoradiotherapy; KPS Karnofsky Performance Status 62.5% (20/32). No additional treatment was given in the age, KPS score, and smoking index, the KPS score (haz- non-R0 resected group after surgery until progression. ard ratio = 0.310, 95% confidence interval: 0.100–0.960, In the CRT-S group, most cases occurred with distant p = 0.042) was an independent predictor for OS. In mul- metastasis (8/32, 25.0%), and only one case occurred tivariate analysis incorporating treatment, age, smoking with local progression (1/32, 3.1%). In the D-CRT status and smoking index, treatment (hazard ratio = 0.488, group, most cases had local progression (27/74, 36.5%), 95% confidence interval: 0.238–0.997, p = 0.049), age and the distant metastasis rate was 16.2% (12/74, (hazard ratio = 0.372, 95% confidence interval: 0.176– 0.785, p = 0.009) and smoking status (hazard ratio = 2.864, p < 0.001, Table  4). In the CRT-S group, leukocytope 95% confidence interval: 1.081–7.589, p = 0.034) were nia incidence was 28.1%, neutrophilic granulopenia independent predictors for PFS (Tables 2 and 3). incidence was 18.8% and thrombocytopenia incidence For the D-CRT group, the complete response (CR) was 12.5%. Three cases (9.4%) experienced anastomotic rate was 20.3% (15/74) and partial response rate (PR) leakage, two cases occurred post thoracotomy pulmo- rate was 79.7% (59/74). No additional treatment was nary infection, and one of them died of complications given in the non-CR group until progression. For the after the operation. In the D-CRT group, leukocyto- CRT-S group, the CR rate was 12.5% (4/32), PR rate penia incidence was 41.4%, neutrophilic granulopenia was 87.5% (28/32). The R0 resection rate was 93.75% incidence was 24.5%, and thrombocytopenia incidence (30/32) and R1 resection rate was 6.25% (2/32). The was 28.7%. Six cases (6.4%) had esophageal fistula, and PCR rate was 37.5% (12/32) and non-PCR rate was two cases (2.1%) had massive hemorrhage (Table 5). Zhang  et al. Radiation Oncology (2022) 17:148 Page 5 of 12 ESCC patients from 2010 to 2020 (n=701) Restagingbased on 8th Excluded edition of the AJCC Patients of T1-3 and staging manual patients with distant metastasis (n=576) Patients of T4 stage (n=125) Patients were assessed Excluded whether down-staged Patients notdown- afterneo-CRT staged afterneo-CRT (n=19) Patients assignedaccording to thetreatment methods (n=106) Patients undergoing Patients undergoing D- iCRT-S (n=32) CRT (n=74) Patients includedinthe Patients included in the analysis (n=25) analysis (n=25) Fig. 1 CONSORT diagram. Flow chart of patient inclusion into the study Fig. 2 Overall survival (OS) of patients before PSM. A Kaplan–Meier survival curves for OS analyses of patients between the CRT-S and D-CRT groups. B Kaplan–Meier survival curves for OS analyses of patients of different age groups. C Kaplan–Meier survival curves for OS analyses of patients of different drinking index groups. OS: overall survival; PSM: propensity score matching; CRT-S: chemoradiotherapy followed by surgery; D-CRT: definitive chemoradiotherapy Discussion found that patients in the CRT-S group had longer overall In the present study, we retrospectively investigated the survival (OS, not available vs. 20.37 months) and progres- clinical characteristics and prognosis of patients with T4 sion-free survival (PFS, 21.0 vs. 8.6 months) than those in stage ESCC who were downstaged after neo-CRT. We the D-CRT group. In addition, treatment option was an Zhang et al. Radiation Oncology (2022) 17:148 Page 6 of 12 Fig. 3 Progression-free survival (PFS) of patients before PSM. A Kaplan–Meier survival curves for PFS analyses of patients between the CRT-S and D-CRT groups. B Kaplan–Meier survival curves for PFS analyses of patients of different age groups. C Kaplan–Meier survival curves for PFS analyses of patients in different drinking index groups. PFS: progression free survival; PSM: propensity score matching; CRT-S: chemoradiotherapy followed by surgery; D-CRT: definitive chemoradiotherapy Table 2 Univariate and multivariate analysis for OS before and after PSM Characteristics Before PSM After PSM Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis P HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) Treatment CRT-S 0.037 0.487 0.065 0.477 0.025 0.416 0.059 0.411 D-CRT 0.244–0.972 0.214–1.046 0.188–0.921 0.163–1.033 Age, years ≤ 60 0.009 0.485 0.101 0.606 0.001 0.280 0.061 0.417 > 60 0.278–0.848 0.332–1.103 0.125–0.629 0.167–1.041 Sex Male 0.417 0.704 0.238 0.321 Famale 0.300–1.650 0.044–2.364 KPS score > 80 0.146 0.599 0.039 0.334 0.042 0.310 ≤ 80 0.297–1.206 0.113–0.992 0.100–0.960 Smoking status Ever 0.681 1.137 0.092 2.420 Never 0.617–2.095 0.837–6.998 Smoking index < 850 0.203 1.667 0.039 3.377 0.380 1.780 ≥ 850 0.751–3.700 0.984–11.587 0.491–6.453 Drinking index > 4500 0.007 0.464 0.010 0.473 0.072 0.485 ≤ 4500 0.263–0.819 0.268–0.836 0.217–1.085 T stage T4a 0.642 1.138 0.211 1.599 T4b 0.660–1.961 0.761–3.363 N stage N0 0.334 1.251 0.431 1.164 N1 0.925–1.691 0.710–1.909 N2 N3 Segment Cervical 0.959 0.929 0.177 0.903 Upper 0.677–1.275 0.476–1.711 Middle Lower Weight loss Yes 0.487 1.217 0.490 0.750 No 0.698–2.122 0.330–1.705 PSM propensity score matching; CRT-S chemoradiotherapy followed by surgery; D-CRT definitive chemoradiotherapy; KPS Karnofsky Performance Status.HR hazard radio; CI confidence interval Zhang  et al. Radiation Oncology (2022) 17:148 Page 7 of 12 Table 3 Univariate and multivariate analysis for PFS before and after PSM Characteristics Before PSM After PSM Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis P HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) Treatment CRT-S 0.008 0.463 0.017 0.459 0.026 0.463 0.049 0.488 D-CRT 0.258–0.831 0.242–0.869 0.231–0.929 0.238–0.997 Age, years ≤ 60 0.020 0.570 0.119 0.671 0.001 0.312 0.009 0.372 > 60 0.354–0.920 0.406–1.108 0.151–0.642 0.176–0.785 Sex Male 0.142 0.561 0.121 0.236 Famale 0.257–1.227 0.032–1.727 KPS score > 80 0.149 0.647 0.056 0.422 ≤ 80 0.357–1.174 0.170–1.050 Smoking status Ever 0.088 1.603 0.036 2.664 0.034 2.864 Never 0.927–2.771 1.027–6.914 1.081–7.589 Smoking index < 850 0.056 1.956 0.016 4.079 0.224 2.203 ≥ 850 0.969–3.948 1.174–14.169 0.616–7.881 Drinking index > 4500 0.025 0.579 0.022 0.569 0.113 0.565 ≤ 4500 0.357–0.938 0.351–0.924 0.276–1.157 T stage T4a 0.169 1.386 0.117 1.172 T4b 0.868–2.215 0.866–3.385 N stage N0 0.224 1.197 0.323 1.014 N1 0.913–1.568 0.644–1.594 N2 N3 Segment Cervical 0.815 0.885 0.427 1.022 Upper 0.672–1.164 0.581–1.798 Middle Lower Weight loss Yes 0.757 0.927 0.800 0.913 No 0.575–1.495 0.450–1.852 PSM propensity score matching; CRT-S chemoradiotherapy followed by surgery; D-CRT definitive chemoradiotherapy; KPS Karnofsky Performance Status.HR hazard radio; CI confidence interval independent predictor for PFS. In the present report, the able to undergo resection and numerically prolong sur- median OS of the CRT-S group was not available at the vival, but patient selection remains paramount [18, 19]. data cutoff (37.6  months median follow-up time). How - The median OS in the CMT, RT and surgery-based ther - ever, our findings showed that the 24-month OS rate was apy groups was 6.0, 12.7, and 43.9  months (P < 0.001), 69.4%. respectively. Nonsurgical treatment was associated with The therapeutic strategy for locally advanced inoper - poorer OS (P < 0.05). A similar problem also existed in able ESCC is controversial because the outcome differs a study from Japan. A small sample study from Japan among institutions [3, 6, 9–12]. For locally advanced reported that the OS of T4b EC patients who under- inoperable ESCC, although concurrent chemoradio- went DCF-RT was 50% at 3 years compared to 37.5% for therapy (CCRT) is recommended [13–15], neo-CRT is all T4b patients [18]. The mean interval was 17  months usually performed [10, 16]. Real-world data reported compared to 14.3  months for all included T4b patients. neoadjuvant chemoradiotherapy (44.9%) and definitive The 5-year survival rate was 19% in the D-CRT group [20, chemoradiotherapy (36.0%); however, 27.9% of patients 21]. undergoing neoadjuvant chemoradiotherapy did not However, some studies showed negative results. receive planned esophagectomy [17]. In retrospective A study from Japan enrolled 71 patients with T4 EC studies of T4b EC, patients who underwent surgical- with tracheobronchial invasion (TBI); 58 underwent based therapy had the longest median OS. However, the dCRT, and 13 underwent iCRT-S. There was no signifi - grouping was not random. Well-selected responders to cant difference between the dCRT and iCRT-S groups. chemotherapy (CMT) and/or radiotherapy (RT) may be Clinical LN negativity and later treatment period were Zhang et al. Radiation Oncology (2022) 17:148 Page 8 of 12 Fig. 4 Overall survival (OS) of patients after PSM. A Kaplan–Meier survival curves for OS analyses for patients between the CRT-S and D-CRT groups. B Kaplan–Meier survival curves for OS analyses of patients of different age groups. C Kaplan–Meier survival curves for OS analyses of patients of different KPS groups. D Kaplan–Meier survival curves for OS analyses of patients of different smoking index groups. OS: overall survival; PSM: propensity score matching; CRT-S: chemoradiotherapy followed by surgery; D-CRT: definitive chemoradiotherapy; KPS: Karnofsky Performance Status significantly good prognostic factors for T4 EC with were observed in the patient characteristics. Although we TBI [10]. The median survival times (MSTs) of patients acknowledge the limitations of retrospective studies, sur- with locally advanced esophageal cancer with adjacent gery after neo-CRT may probably improve survival and organ invasion after definitive CRT, bypass surgery plus decrease recurrence compared with D-CRT for locally CRT and CRT followed by esophagectomy were 10.4, advanced inoperable ESCC patients who are downstaged 11.0 and 16.4  months, respectively; MST did not differ after neo-CRT. significantly between patients [22]. To our knowledge, The first failure sites were categorized as local, regional our study is the first to compare CRT-S and D-CRT in nodal, or distant. In previous studies of locally advanced locally advanced inoperable ESCC patients who were esophageal cancer patients who underwent chemoradia- downstaged after neo-CRT. The choice of the 8 patients tion followed by esophagectomy, the rates were 4.5–67% from a single-arm, single-center, investigator-initiated, local, 10–57.9% regional nodal, and 21–32% distant fail- exploratory, phase II clinical study (ClinicalTrials.gov ures [23–26]. Local failure was correlated with fewer NCT04137679) was randomly made according to the lymph nodes (LNs) assessed and close/positive mar- random system. For the rest of the 98 cases, doctors pro- gins. Regional nodal failure was correlated with fewer vided the two possibilities of treatment ways equally and LNs assessed and larger pretreatment tumor size. Dis- patients and doctors made the final decision together. It tant recurrence was correlated with higher pathologic is a basic principle to respect the patients right of con- nodal stage, ulceration, perineural invasion, residual dis- sent. After propensity score matching (PSM), no signifi - ease, and higher posttreatment PET SUV max. Patients cant differences between the CRT-S and D-CRT groups with a pathologic complete response were less likely Zhang  et al. Radiation Oncology (2022) 17:148 Page 9 of 12 Fig. 5 Progression-free survival (PFS) of patients after PSM. A Kaplan–Meier survival curves for PFS analyses of patients between the CRT-S and D-CRT groups. B Kaplan–Meier survival curves for PFS analyses of patients of different age groups. C Kaplan–Meier survival curves for PFS analyses of patients of different smoking index groups. D Kaplan–Meier survival curves for PFS analyses of patients of different smoking status groups. PFS: progression free survival; PSM: propensity score matching; CRT-S: chemoradiotherapy followed by surgery; D-CRT: definitive chemoradiotherapy Table 4 Type of first progression in CRT-S and D-CRT group a high pathological complete response (pCR) rate (37.5%, 12/32), fewer lymph nodes (N0, 23/32; N1, 3/32; N2, Type of first progression CRT-S (n = 32) D-CRT (n = 74) P 4/32; N3, 0/32), high negative margin rate (32/32, 100%) Local recurrence 1 27 < 0.001 and high R0 resection rate (30/32, 93.75%) [24]. In the Regional lymph node 6 19 D-CRT group, the distant metastasis rate was only 16.2% metastasis (12/74). Most patients in the D-CRT group had local Distant metastasis 8 12 progression (27/74, 36.5%), 6 of whom were complicated Stable 17 16 with esophageal fistula, and 2 of whom had massive hem - CRT-S chemoradiotherapy followed by surgery; D-CRT definitive orrhage (Table 5). Our data indicated that CRT-S reduced chemoradiotherapy the local recurrence rate and the incidence of esophageal fistula (P = 0.097) and massive hemorrhage (p = 0.348), which was partially consistent with previous studies [3, to experience distant recurrence [24]. In our study, all 27]. cases were evaluated as down staged to operable by CT, In a randomized study comparing D-CRT and CRT-S endoscopy and upper gastrointestinal contrast. Most for patients with locally advanced operable esophageal cases in the CRT-S group had distant metastasis (8/32, carcinoma, preoperative chemoradiotherapy improved 25.0%), and the local progression rate was 3.1% (1/32). survival among patients with potentially curable esoph- The low local progression rate may be partially related to ageal or esophagogastric junction cancer. The regimen Zhang et al. Radiation Oncology (2022) 17:148 Page 10 of 12 Table 5 Treatment-related adverse events Adverse events CRT-S, n (%) D-CRT, n (%) P Anastomotic leakage 3 (9.4) / / Post thoracotomy pulmonary infection 2 (6.3) / / Operative mortality 1 (3.1) / / Esophageal fistula 0 (0) 6 (6.4) 0.097 Massive hemorrhage 0 (0) 2 (2.1) 0.348 Radiation esophagitis Grade 1 10 (31.3) 14 (14.9) 0.080 Grade 2 10 (31.3) 13 (13.8) Grade 3 0 (0) 5 (5.3) Grade 4 0 (0) 0 (0) Total 20 (62.5) 32 (34.0) Leukocytopenia Grade 1 0 (0) 3 (3.2) 0.038 Grade 2 9 (28.1) 26 (27.7) Grade 3 0 (0) 10 (10.6) Grade 4 0 (0) 0 (0) Total 9 (28.1) 39 (41.4) Neutrophilic granulopenia Grade 1 2 (6.3) 12 (12.8) 0.580 Grade 2 3 (9.4) 6 (6.4) Grade 3 1 (3.1) 4 (4.3) Grade 4 0 (0) 1 (1.1) Total 6 (18.8) 23 (24.5) Anemia Grade 1 18 (56.3) 35 (34.0) 0.759 Grade 2 3 (9.4) 10 (10.6) Grade 3 0 (0) 1 (1.1) Grade 4 0 (0) 0 (0) Total 21 (65.6) 46 (48.9) Thrombocytopenia Grade 1 3 (9.4) 20 (21.3) 0.087 Grade 2 0 (0) 3 (3.2) Grade 3 1 (3.1) 4 (4.3) Grade 4 0 (0) 0 (0) Total 4 (12.5) 27 (28.7) Hypoalbuminema Grade 1 12 (37.5) 14 (14.9) 0.382 Grade 2 0 (0) 2 (2.1) Grade 3 0 (0) 0 (0) Grade 4 0 (0) 0 (0) Total 12 (37.5) 16 (17.0) CRT-S chemoradiotherapy followed by surgery; D-CRT definitive chemoradiotherapy was associated with acceptable adverse event rates [28– the D-CRT group. Although there were no differences 30]. Some studies discussed the therapeutic options of of statistics in neutrophilic granulopenia incidence T4b EC; although CRT-S improved the survival rate, (p = 0.58), thrombocytopenia incidence (p = 0.087) perioperative complications were also increased. Anas- and radiation esophagitis incidence (p = 0.080) in the tomotic leakage after surgery was 25%, the recurrent CRT-S and D-CRT group, grade 3 radiation esophagi- laryngeal nerve paralysis rate was approximately 50% tis incidence was lower in the CRT-S group than the [21], the reoperation rate was approximately 7.7% [23], D-CRT group. In the CRT-S group, anastomotic leak- and the operative mortality was 5–23.4% [25]. In the age, post thoracotomy pulmonary infection and opera- present study, all adverse events were no more than tive mortality were lower than those in previous reports grade 3 and manageable. Leukocytopenia incidence in patients with advanced ESCC (Table  5) [20, 21, 23, (p = 0.038) in the CRT-S group was lower than those in 25]. Zhang  et al. Radiation Oncology (2022) 17:148 Page 11 of 12 Research Center for Cancer, Tianjin Medical University Cancer Institute Conclusions and Hospital, Huanhu West Road, Hexi District, Tianjin, China. K ey Laborator y In conclusion, the present study has demonstrated that of Cancer Prevention and Therapy, Department of Nutrition Therapy, National CRT-S was superior to D-CRT for T4 ESCC patients Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Can- cer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. who were downstaged by neo-CRT with respect to Key Laboratory of Cancer Prevention and Therapy, Department of Esophageal longer OS and PFS. However, the present study did Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research have several limitations. First, this was a retrospec- Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. Division of Life Sciences and Medicine, Department of Radia- tive study from a single institution. Second, half of the tion Oncology, The First Affiliated Hospital of USTC, University of Science patients included in the study were staged as T4 by CT and Technology of China, Hefei, Anhui, China. imaging and not by endoscopy. Furthermore, the num- Received: 29 January 2022 Accepted: 7 August 2022 ber of patients included in the study was small. Ran- domized controlled trials involving large population samples are needed to define the standard treatment for T4 esophageal cancer. References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. https:// doi. org/ 10. 3322/ caac. 21551. Abbreviations 2. Liang H, Fan JH, Qiao YL. Epidemiology, etiology, and prevention of ESCC: Esophageal squamous cell carcinoma; CRT-S: Neo-chemoradiotherapy esophageal squamous cell carcinoma in China. Cancer Biol Med. followed by surgery; D-CRT : Definitive chemoradiotherapy; OS: Overall 2017;14(1):33–41. https:// doi. org/ 10. 20892/j. issn. 2095- 3941. 2016. 0093. survival; PFS: Progression free survival; GTV: Gross tumor volume; CTV: Clinical 3. Makino T, Doki Y. Treatment of T4 esophageal cancer: Definitive chemo- target volume; PTV: Planning target volume; CBCT: Cone-beam computed radiotherapy vs chemo-radiotherapy followed by surgery. Ann Thorac tomography; ECOG: Eastern cooperative oncology group; PS: Performance sta- Cardiovasc Surg. 2011;17(3):221. https:// doi. org/ 10. 5761/ atcs. ra. 11. 01676. tus; AJCC: American joint committee on cancer; EUS: Esophageal endoscopy 4. Akutsu Y, Matsubara H. Chemoradiotherapy and surgery for T4 esopha- ultrasound; EBUS: Endobronchial ultrasonography; CT: Computed tomog- geal cancer in Japan. Surg Today. 2015;45(11):1360–5. https:// doi. org/ 10. raphy; CMT: Chemotherapy; RT: Radiotherapy; CCRT : Concurrent chemora- 1007/ s00595- 015- 1116-4. diotherapy; PET: Positron emission tomography; IMRT: Intensity-modulated 5. Zhong H, et al. T4 esophageal cancer treated with radical resection. Pan- radiotherapy; RESIST: Response evaluation criteria in solid tumors; MDT: Multi- minerva Med. 2019;61(4):509–11. https:// doi. org/ 10. 23736/ s0031- 0808. disciplinary treatment; TBI: Tracheobronchial invasion; PSM: Propensity score 19. 03622-x. matching; PCR: Pathological complete response; KPS: Karnofsky Performance 6. Makino T, et al. Treatment and clinical outcome of clinical T4 esophageal Status; CR: Complete response; PR: Partial response; LN: Lymph node; SUV: cancer: a systematic review. Ann Gastroenterol Surg. 2019;3(2):169–80. Standardized uptake value. https:// doi. org/ 10. 1002/ ags3. 12222. 7. Ajani JA, et al. Esophageal and esophagogastric junction cancers, version Acknowledgements 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc We thank for the surgery support of Dr. Jiang Hongjing and Dr. Tang Peng. Netw. 2019;17(7):855–83. https:// doi. org/ 10. 6004/ jnccn. 2019. 0033. 8. Qian D, et al. Tumor remission and tumor-infiltrating lymphocytes during Author contributions chemoradiation therapy: predictive and prognostic markers in locally TZ and ZG designed this study and wrote the main manuscript. XC and DQ advanced esophageal squamous cell carcinoma. Int J Radiat Oncol Biol analyzed the data. JD performed nutrition guidance to patients. HJ and PT Phys. 2019;105(2):319–28. https:// doi. org/ 10. 1016/j. ijrobp. 2019. 06. 079. performed some of the surgical operations. WZ and QP designed and directed 9. Stahl M, et al. Chemoradiation with and without surgery in patients the overall project. All authors reviewed the manuscript. with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23(10):2310–7. https:// doi. org/ 10. 1200/ JCO. 2005. 00. 034. Funding 10. Yamaguchi S, et al. Long-Term outcome of definitive chemoradio - This study was funded by Chinese National Key Research and Development therapy and induction chemoradiotherapy followed by surgery for T4 Project (No. 2018YFC1215601 to Wang Ping), the Natural Science Foundation esophageal cancer with tracheobronchial Invasion. Ann Surg Oncol. of China (82102835 to Zhang Tian, 82102840 to Chen Xi) and Tianjin Key Medi- 2018;25(11):3280–7. https:// doi. org/ 10. 1245/ s10434- 018- 6656-6. cal Discipline (Specialty) Construction Project ( TJYXZDXK-009A). 11. Fujita H, et al. Prospective non-randomized trial comparing esophagec- tomy-followed-by-chemoradiotherapy versus chemoradiotherapy-fol- Availability of data and materials lowed-by-esophagectomy for T4 esophageal cancers. J Surg Oncol. 2005. Not appilicable. https:// doi. org/ 10. 1002/ jso. 20259. 12. Fujita H, et al. Esophagectomy: is it necessary after chemoradiotherapy for a locally advanced T4 esophageal cancer? Prospective nonran- Declarations domized trial comparing chemoradiotherapy with surgery versus without surgery. World J Surg. 2005;29(1):25–30. https:// doi. org/ 10. 1007/ Ethics approval and consent to participate s00268- 004- 7590-2. The study was approved by the ethics committee of Tianjin Medical University 13. Lyu J, et al. Outcomes of concurrent chemoradiotherapy versus chemo- Cancer Institute and Hospital (E2019308). Written informed consent for scien- therapy alone for stage IV esophageal squamous cell carcinoma: a tific usage of clinical data was obtained from all patients. retrospective controlled study. Radiat Oncol. 2018;13(1):233. 14. Ohkura Y, et al. Prognostic factors and appropriate lymph node dissec- Consent for publication tion in salvage esophagectomy for locally advanced T4 esophageal Not applicable. Cancer. Ann Surg Oncol. 2019;26(1):209–16. https:// doi. org/ 10. 1245/ s10434- 018- 7074-5. Competing interests 15. Matsuda S, et al. Definitive chemoradiotherapy with simultaneous inte - The authors declare no competing interests. grated boost of radiotherapy dose for T4 esophageal cancer-will it stand for a standard treatment? J Thorac Dis. 2019;11(12):5682–4. https:// doi. Author details org/ 10. 21037/ jtd. 2019. 12. 59. Key Laboratory of Cancer Prevention and Therapy, Department of Radia- 16. Akiyama Y, et al. Safety of thoracoscopic esophagectomy after induction tion Oncology, National Clinical Research Center for Cancer, Tianjin’s Clinical chemotherapy for locally advanced unresectable esophageal squamous Zhang et al. Radiation Oncology (2022) 17:148 Page 12 of 12 cell carcinoma. Asian J Endosc Surg. 2020;13(2):152–9. https:// doi. org/ 10. 1111/ ases. 12731. 17. Hsu PK, et al. Treatment patterns and outcomes in patients with esopha- geal cancer: an analysis of a multidisciplinary tumor board database. Ann Surg Oncol. 2021. https:// doi. org/ 10. 1245/ s10434- 021- 10568-z. 18. Cushman TR, et al. Management of unresectable t4b esophageal cancer: practice patterns and outcomes from the national cancer data Base. Am J Clin Oncol. 2019;42(2):154–9. https:// doi. org/ 10. 1097/ coc. 00000 00000 19. Nakamura T, et al. Chemoradiotherapy with and without esophagec- tomy for advanced esophageal cancer. Hepatogastroenterology. 2006;53(71):705–9. 20. Anderegg MCJ, et al. Feasibility of extended chemoradiotherapy plus surgery for patients with cT4b esophageal carcinoma. Eur J Surg Oncol. 2020;46(4Pt A):626–31. https:// doi. org/ 10. 1016/j. ejso. 2019. 10. 023. 21. Hashimoto M, et al. Induction chemoradiotherapy including doc- etaxel, cisplatin, and 5-fluorouracil for locally advanced esophageal cancer. Esophagus. 2020;17(2):127–34. https:// doi. org/ 10. 1007/ s10388- 019- 00709-5. 22. Hamai Y, et al. Treatment outcomes and prognostic factors for thoracic esophageal cancer with clinical evidence of adjacent organ invasion. Anticancer Res. 2013;33(8):3495–502. 23. Morita M, et al. Clinical significance of chemoradiotherapy and surgical resection for cT4 esophageal cancer. Anticancer Res. 2012;32(8):3275–82. 24. Shaikh T, et al. Patterns and predictors of failure following tri-modal- ity therapy for locally advanced esophageal cancer. Acta Oncol. 2016;55(3):303–8. https:// doi. org/ 10. 3109/ 02841 86x. 2015. 11102 52. 25. Garg PK, et al. Preoperative therapy in locally advanced esophageal can- cer. World J Gastroenterol. 2016;22(39):8750–9. https:// doi. org/ 10. 3748/ wjg. v22. i39. 8750. 26. Sugimura K, et al. Long-term results of a randomized controlled trial com- paring neoadjuvant Adriamycin, cisplatin, and 5-fluorouracil vs docetaxel, cisplatin, and 5-fluorouracil followed by surgery for esophageal cancer (OGSG1003). Ann Gastroenterol Surg. 2021;5(1):75–82. https:// doi. org/ 10. 1002/ ags3. 12388. 27. Mori K, et al. Esophageal cancer patients’ survival after complete response to definitive chemoradiotherapy: a retrospective analysis. Esophagus. 2021;18(3):629–37. https:// doi. org/ 10. 1007/ s10388- 021- 00817-1. 28. van Hagen P, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–84. https:// doi. org/ 10. 1056/ NEJMo a1112 088. 29. Kim JH, et al. Preoperative hyperfractionated radiotherapy with concur- rent chemotherapy in resectable esophageal cancer. Int J Radiat Oncol Biol Phys. 2001;50(1):1–12. https:// doi. org/ 10. 1016/ s0360- 3016(01) 01459-6. 30. Zhang ZX, et al. Randomized clinical trial on the combination of preop- erative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)–report on 370 patients. Int J Radiat Oncol Biol Phys. 1998;42(5):929–34. https:// doi. org/ 10. 1016/ s0360- 3016(98) 00280-6. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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A retrospective study comparing definitive chemoradiotherapy vs. chemoradiotherapy followed by surgery in T4 esophageal squamous cell carcinoma patients who were downstaged after neochemoradiotherapy

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Abstract

Background: The outcome of patients with T4 esophageal squamous cell carcinoma (ESCC) is extremely poor. Two distinct therapeutic options are currently available for T4 esophageal cancers: neochemoradiotherapy followed by surgery (CRT-S) and definitive chemoradiotherapy (D-CRT ). This study aimed to investigate the clinicopathologic char - acteristics of T4 ESCC in Chinese patients and compare the survival between the two therapeutic options. Methods: We retrospectively analyzed 125 patients with clinically unresectable T4 ESCC in Tianjin Medical University Cancer Institute and Hospital from January 2010 to December 2020. Overall survival (OS), progression-free survival (PFS) and associated factors were analyzed. Results: A total of 106 of 125 T4 ESCC patients were downstaged of the tumor by neoadjuvant CRT. Among 106 patients, 32 patients underwent CRT-S, and 74 patients underwent D-CRT. Patients in the CRT-S group had a higher OS (20.4 months vs. un-reached median OS, p = 0.037) and PFS (8.6 months vs. 21.0 months, p = 0.008) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor of PFS. After propensity score matching (PSM), 50 patients (CRT-S = 25; D-CRT = 25) were matched. Among these 50 patients, patients in the CRT-S group had a higher OS (15.6 months vs. un-reached median OS, p = 0.025) and PFS (7.2 months vs. 18.8 months, p = 0.026) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor for PFS. Conclusion: We demonstrated that CRT-S was superior to D-CRT for T4 ESCC patients who were downstaged by neo-CRT with respect to longer OS and PFS. Randomized controlled trials involving large population samples are needed to define the standard treatment for T4 ESCC. Zhang Tian and Guo Zhoubo have contributed equally to this work *Correspondence: wczhang@tmu.edu.cn; pangqingsong@tjmuch.com Key Laboratory of Cancer Prevention and Therapy, Department of Radiation Oncology, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huanhu West Road, Hexi District, Tianjin, China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Radiation Oncology (2022) 17:148 Page 2 of 12 Keywords: Esophageal squamous cell carcinoma, T4, Neo-chemoradiotherapy followed by surgery, Definitive chemoradiotherapy Introduction EUS showed invasion of the trachea, bronchus, aorta, Esophageal squamous cell carcinoma (ESCC) is one of pleura, pericardium, and/or other peripheral organs; 2) the leading causes of cancer-related mortality worldwide, EBUS showed invasion of the trachea and/or bronchus; with a high prevalence in Asia [1, 2]. The outcome of 3) bronchoscopy showed protrusion of the esophageal patients with T4 esophageal cancer, defined as a tumor tumor into trachea and/or bronchi or abnormal tracheal that invades neighboring structures (e.g., aorta, tra- mucosa; and 4) if the patient could not undergo EUS, chea, bronchus, and lung), is extremely poor [3]. Despite adjacent organ invasion was defined by CT or positron advances in surgical treatment, these tumors are usually emission tomography (PET)-CT. Generally, invasion of considered inoperable; however, surgery alone has not the peripheral organs was diagnosed based on the loss of improved the prognosis of patients with T4 esophageal fat planes between the esophagus and peripheral organs. tumors [4, 5]. Invasion of the aorta was defined as > 90 degrees of the Two distinct therapeutic options are currently available aorta surrounded by tumor in more than one CT slice. for T4 esophageal cancers: chemoradiotherapy followed Invasion of the pericardium was defined as the disap - by surgery (CRT-S), which comprises esophagectomy pearance of the fat line at the focus level and local peri- following downstaging of the tumor by CRT, and defini - cardial thickening. tive chemoradiotherapy (D-CRT), which is designed to The following clinicopathologic parameters for each avoid esophagectomy by using maximum doses of irra- patient were also collected: sex, age at diagnosis, smok- diation [4, 6]. Until now, D-CRT has been the standard ing history, drinking history and TNM stage in line with alternative curative management for patients with locally the 8th edition of the esophageal cancer staging system. advanced disease who are not eligible for or refuse sur- The PFS and OS of patients diagnosed from January 2010 gery [7]. To our knowledge, there is little information on to December 2020 were recorded based on a follow-up the differences in the clinical outcomes of patients with clinic visit or a telephone call. T4 ESCC who undergo D-CRT and those who receive CRT-S. In this study, we discuss these two treatment Treatment and response modalities. Patients received conventional fraction radiotherapy using a 6 MeV linear accelerator. The radiation dose was Methods calculated by intensity-modulated radiotherapy (IMRT). Patients All plans were based on 3- or 5-mm CT scan images We retrospectively enrolled patients with ESCC who had obtained in the treatment position before radiotherapy. been treated with CRT from January 2010 to December The gross tumor volume (GTV) included the esopha - 2020 at our center, including 8 cases from a single-arm, geal tumor found under CT and esophageal endoscopy single-center, investigator-initiated, exploratory, phase and the enlarged locoregional lymph nodes found by II clinical study (ClinicalTrials.gov NCT04137679) at CT before treatment. GTV also included distant lymph Tianjin Medical University Cancer Institute & Hospital nodes with metastasis for patients with cervical or in Tianjin, China. The inclusion criteria were as follows: abdominal distant lymph node metastases. The clinical (1) squamous cell histological type; (2) staged as unre- target volume (CTV) was added to the esophageal tumor sectable T4 disease by a multidisciplinary team based on 5–6  mm laterally and 2–3  cm in the cephalo–caudal biopsy and imaging pretreatment examination data; (3) direction, and CTV also includes positive lymph nodes downstaged to T3 or lower T stage by neoadjuvant CRT; and its drainage area. The planning target volume (PTV) (4) without distant organ metastases; and (5) Eastern was added to the CTV 5 mm in the cephalo–caudal and Cooperative Oncology Group (ECOG) performance sta- lateral directions. Cone-beam computed tomography tus (PS) of ≤ 1. All patients were staged according to the (CBCT) was used to guarantee the treatment position 8th edition of the American Joint Committee on Cancer during the whole radiotherapy process once a week. The (AJCC) staging manual. induction and concurrent chemotherapy with radiation Adjacent organ invasion was diagnosed by esopha- included cisplatin, 5-FU or taxane-based regimens. The geal endoscopy ultrasound (EUS), endobronchial ultra- patients’ response to treatment was assessed by CT scan, sonography (EBUS), bronchoscopy, and/or computed endoscopy and upper gastrointestinal contrast in accord- tomography (CT) according to the following criteria: 1) ance with Response Evaluation Criteria in Solid Tumors Zhang  et al. Radiation Oncology (2022) 17:148 Page 3 of 12 1.1 (RECIST 1.1) criteria and the method reported in our neochemoradiotherapy. Of the whole 106 cases, 8 cases previous study [8]. were from a single-arm, single-center, investigator-initi- Patients in the CRT-S group received a 40-Gy radia- ated, exploratory, phase II clinical study (ClinicalTrials. tion dose (2 Gy once daily in 20 fractions, 5 days a week) gov NCT04137679) at Tianjin Medical University Can- and were scheduled to undergo resection 4–6 weeks after cer Institute & Hospital in Tianjin, China. The choices having completed induction chemoradiation. Patients in of the 8 patients were randomly made according to the the D-CRT group received a 60-Gy radiation dose (2 Gy random system. For the rest of the 98 cases, doctors pro- once daily in 30 fractions, 5  days a week). An intensity- vided the two possibilities of treatment ways equally and modulated radiotherapy dose planning system was used. patients and doctors made the final decision together. Of the 106 downstaged T4 stage patients, 32 patients Propensity score matching analysis received surgery after neo-CRT, and 74 patients received In this study, propensity score matching (PSM) was used D-CRT (Fig.  1). These patients had a median follow- to reduce bias due to an imbalance in observed variables up duration of 17.3  months (range: 2.6–90.6  months). between the CRT-S and D-CRT groups. Three baseline The cohort consisted mostly of males, 92 male patients characteristics (sex, T-stage and segment) were selected (86.8%) and only 14 female patients (13.2%). The major - as covariates in the PSM model, and the match tolerance ity of enrolled patients had upper (36; 34.0%) or middle was set to 0.01. Propensity scores of individuals were cal- (42; 4.0%) thoracic ESCC. In comparison with the D-CRT culated with logistic regression analysis (SPSS version group, the CRT-S group had a lower proportion of T4b 22.0, Chicago, IL), and then, the optimal 1:1 matching stage (p = 0.063), and more patients were in the middle between CRT-S and D-CRT patients was produced based or lower segment (p < 0.001). No other significant differ - on propensity scores. After matching, the distribution ences were found between the patients in the CRT-S and of the remaining observed variables was similar in the D-CRT groups with respect to age, sex, smoking history, CRT-S and D-CRT groups. drinking index, Karnofsky Performance Status (KPS) score, N stage or weight loss (Table 1). Statistical analysis Among all 106 patients, treatment (p = 0.037, Fig.  2A), Pearson’s χ test was used to investigate the correlations age (p = 0.009, Fig.  2B), and drinking index (p = 0.007, between 2 categorical variables. PFS and OS distribution Fig.  2C) were significantly associated with overall sur - was analyzed using the Kaplan–Meier method, and log- vival (OS); treatment (p = 0.008, Fig.  3A), age (p = 0.020, rank tests were employed for comparison of PFS or OS Fig. 3B), and drinking index (p = 0.025, Fig. 3C) were sig- between 2 categories in univariate analysis. Multivariate nificantly correlated with progression-free survival (PFS). survival analysis was conducted using Cox proportional In multivariate analysis incorporating treatment, age hazards regression to identify independent prognostic and drinking index, drinking index (hazard ratio = 0.473, factors. Data were statistically analyzed using SPSS 22.0 95% confidence interval: 0.268–0.836, p = 0.010) was an (Abbott Laboratories, North Chicago, IL, USA). Statisti- independent predictor for OS. In multivariate analy- cal significance was set at p < 0.05. sis incorporating treatment, age and drinking index, treatment (hazard ratio = 0.459, 95% confidence inter - Ethics statement val: 0.242–0.869, p = 0.017) and drinking index (haz- This study was approved by the institutional review board ard ratio = 0.569, 95% confidence interval: 0.351–0.924, at Tianjin Medical University. Written informed consent p = 0.022) were independent predictors for PFS (Tables 2 was obtained from each patient to allow their biologi- and 3). cal samples to be genetically analyzed. The experimental After propensity score matching (PSM), 50 patients protocol of this study was performed strictly in accord- (CRT-S = 25; D-CRT = 25) were matched, and Table  1 ance with the guidelines. shows the patients’ characteristics. No significant dif - ferences between the CRT-S and D-CRT groups were Results observed in terms of either T stage or segment. Among From January 2010 to December 2020, 125 T4 ESCC these 50 patients, treatment (p = 0.025, Fig.  4A), age patients were treated with CRT in our center; of these, (p = 0.001, Fig.  4B), KPS score (p = 0.039, Fig.  4C) and 106 patients were down staged to T3 or lower T stage. smoking index (p = 0.039, Fig.  4D) were significantly The patients’ demographics and tumor characteris - associated with OS; treatment (p = 0.026, Fig.  5A), age tics are listed in Table  1. After multi-disciplinary treat- (p = 0.001, Fig.  5B), smoking index (p = 0.016, Fig.  5C) ment (MDT) of department of radiation oncology and and smoking status (p = 0.036, Fig.  5D) were signifi - department of esophageal cancer, all patients were suit- cantly correlated with worse progression-free survival able for surgery or definitive chemoradiotherapy after (PFS). In multivariate analysis incorporating treatment, Zhang et al. Radiation Oncology (2022) 17:148 Page 4 of 12 Table 1 Comparison of clinical characteristics between ESCCs undergoing CRT-S and D-CRT before and after PSM Characteristics Before PSM After PSM Total CRT-S D-CRT P Total CRT-S D-CRT P N. of patients 106 32 74 50 25 25 Age, years ≤ 60 53 12 41 0.091 26 11 15 0.258 > 60 53 20 33 24 14 10 Sex Male 92 30 62 0.164 46 23 23 1.000 Famale 14 2 12 4 2 2 KPS score > 80 75 21 54 0.552 34 17 17 0.431 ≤ 80 23 5 18 11 4 7 Unknown 8 6 2 5 4 1 Smoking status Ever 76 26 51 0.191 12 6 6 1.000 Never 29 6 23 38 19 19 Smoking index < 850 96 30 66 0.461 47 24 23 0.552 ≥ 850 10 2 8 3 1 2 Drinking index > 4500 38 13 25 0.714 22 9 13 0.295 refere ≤ 4500 62 16 46 23 13 10 Unknown 6 5 3 2 T stage T4a 55 21 34 0.063 28 14 14 1.000 T4b 51 11 40 22 11 11 N stage N0 15 3 12 0.423 4 0 4 0.210 N1 43 13 30 21 11 10 N2 33 13 20 19 11 8 N3 15 3 12 6 3 3 Segment Cervical 13 1 12 < 0.001 2 1 1 1.000 Upper 36 5 31 10 5 5 Middle 42 16 26 32 16 16 Lower 14 10 4 6 3 3 Yes 42 15 27 0.315 18 12 6 0.077 Weight loss No 64 17 47 32 13 19 PSM propensity score matching; ESCC esophageal squamous cell carcinoma; CRT-S chemoradiotherapy followed by surgery; D-CRT definitive chemoradiotherapy; KPS Karnofsky Performance Status 62.5% (20/32). No additional treatment was given in the age, KPS score, and smoking index, the KPS score (haz- non-R0 resected group after surgery until progression. ard ratio = 0.310, 95% confidence interval: 0.100–0.960, In the CRT-S group, most cases occurred with distant p = 0.042) was an independent predictor for OS. In mul- metastasis (8/32, 25.0%), and only one case occurred tivariate analysis incorporating treatment, age, smoking with local progression (1/32, 3.1%). In the D-CRT status and smoking index, treatment (hazard ratio = 0.488, group, most cases had local progression (27/74, 36.5%), 95% confidence interval: 0.238–0.997, p = 0.049), age and the distant metastasis rate was 16.2% (12/74, (hazard ratio = 0.372, 95% confidence interval: 0.176– 0.785, p = 0.009) and smoking status (hazard ratio = 2.864, p < 0.001, Table  4). In the CRT-S group, leukocytope 95% confidence interval: 1.081–7.589, p = 0.034) were nia incidence was 28.1%, neutrophilic granulopenia independent predictors for PFS (Tables 2 and 3). incidence was 18.8% and thrombocytopenia incidence For the D-CRT group, the complete response (CR) was 12.5%. Three cases (9.4%) experienced anastomotic rate was 20.3% (15/74) and partial response rate (PR) leakage, two cases occurred post thoracotomy pulmo- rate was 79.7% (59/74). No additional treatment was nary infection, and one of them died of complications given in the non-CR group until progression. For the after the operation. In the D-CRT group, leukocyto- CRT-S group, the CR rate was 12.5% (4/32), PR rate penia incidence was 41.4%, neutrophilic granulopenia was 87.5% (28/32). The R0 resection rate was 93.75% incidence was 24.5%, and thrombocytopenia incidence (30/32) and R1 resection rate was 6.25% (2/32). The was 28.7%. Six cases (6.4%) had esophageal fistula, and PCR rate was 37.5% (12/32) and non-PCR rate was two cases (2.1%) had massive hemorrhage (Table 5). Zhang  et al. Radiation Oncology (2022) 17:148 Page 5 of 12 ESCC patients from 2010 to 2020 (n=701) Restagingbased on 8th Excluded edition of the AJCC Patients of T1-3 and staging manual patients with distant metastasis (n=576) Patients of T4 stage (n=125) Patients were assessed Excluded whether down-staged Patients notdown- afterneo-CRT staged afterneo-CRT (n=19) Patients assignedaccording to thetreatment methods (n=106) Patients undergoing Patients undergoing D- iCRT-S (n=32) CRT (n=74) Patients includedinthe Patients included in the analysis (n=25) analysis (n=25) Fig. 1 CONSORT diagram. Flow chart of patient inclusion into the study Fig. 2 Overall survival (OS) of patients before PSM. A Kaplan–Meier survival curves for OS analyses of patients between the CRT-S and D-CRT groups. B Kaplan–Meier survival curves for OS analyses of patients of different age groups. C Kaplan–Meier survival curves for OS analyses of patients of different drinking index groups. OS: overall survival; PSM: propensity score matching; CRT-S: chemoradiotherapy followed by surgery; D-CRT: definitive chemoradiotherapy Discussion found that patients in the CRT-S group had longer overall In the present study, we retrospectively investigated the survival (OS, not available vs. 20.37 months) and progres- clinical characteristics and prognosis of patients with T4 sion-free survival (PFS, 21.0 vs. 8.6 months) than those in stage ESCC who were downstaged after neo-CRT. We the D-CRT group. In addition, treatment option was an Zhang et al. Radiation Oncology (2022) 17:148 Page 6 of 12 Fig. 3 Progression-free survival (PFS) of patients before PSM. A Kaplan–Meier survival curves for PFS analyses of patients between the CRT-S and D-CRT groups. B Kaplan–Meier survival curves for PFS analyses of patients of different age groups. C Kaplan–Meier survival curves for PFS analyses of patients in different drinking index groups. PFS: progression free survival; PSM: propensity score matching; CRT-S: chemoradiotherapy followed by surgery; D-CRT: definitive chemoradiotherapy Table 2 Univariate and multivariate analysis for OS before and after PSM Characteristics Before PSM After PSM Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis P HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) Treatment CRT-S 0.037 0.487 0.065 0.477 0.025 0.416 0.059 0.411 D-CRT 0.244–0.972 0.214–1.046 0.188–0.921 0.163–1.033 Age, years ≤ 60 0.009 0.485 0.101 0.606 0.001 0.280 0.061 0.417 > 60 0.278–0.848 0.332–1.103 0.125–0.629 0.167–1.041 Sex Male 0.417 0.704 0.238 0.321 Famale 0.300–1.650 0.044–2.364 KPS score > 80 0.146 0.599 0.039 0.334 0.042 0.310 ≤ 80 0.297–1.206 0.113–0.992 0.100–0.960 Smoking status Ever 0.681 1.137 0.092 2.420 Never 0.617–2.095 0.837–6.998 Smoking index < 850 0.203 1.667 0.039 3.377 0.380 1.780 ≥ 850 0.751–3.700 0.984–11.587 0.491–6.453 Drinking index > 4500 0.007 0.464 0.010 0.473 0.072 0.485 ≤ 4500 0.263–0.819 0.268–0.836 0.217–1.085 T stage T4a 0.642 1.138 0.211 1.599 T4b 0.660–1.961 0.761–3.363 N stage N0 0.334 1.251 0.431 1.164 N1 0.925–1.691 0.710–1.909 N2 N3 Segment Cervical 0.959 0.929 0.177 0.903 Upper 0.677–1.275 0.476–1.711 Middle Lower Weight loss Yes 0.487 1.217 0.490 0.750 No 0.698–2.122 0.330–1.705 PSM propensity score matching; CRT-S chemoradiotherapy followed by surgery; D-CRT definitive chemoradiotherapy; KPS Karnofsky Performance Status.HR hazard radio; CI confidence interval Zhang  et al. Radiation Oncology (2022) 17:148 Page 7 of 12 Table 3 Univariate and multivariate analysis for PFS before and after PSM Characteristics Before PSM After PSM Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis P HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) Treatment CRT-S 0.008 0.463 0.017 0.459 0.026 0.463 0.049 0.488 D-CRT 0.258–0.831 0.242–0.869 0.231–0.929 0.238–0.997 Age, years ≤ 60 0.020 0.570 0.119 0.671 0.001 0.312 0.009 0.372 > 60 0.354–0.920 0.406–1.108 0.151–0.642 0.176–0.785 Sex Male 0.142 0.561 0.121 0.236 Famale 0.257–1.227 0.032–1.727 KPS score > 80 0.149 0.647 0.056 0.422 ≤ 80 0.357–1.174 0.170–1.050 Smoking status Ever 0.088 1.603 0.036 2.664 0.034 2.864 Never 0.927–2.771 1.027–6.914 1.081–7.589 Smoking index < 850 0.056 1.956 0.016 4.079 0.224 2.203 ≥ 850 0.969–3.948 1.174–14.169 0.616–7.881 Drinking index > 4500 0.025 0.579 0.022 0.569 0.113 0.565 ≤ 4500 0.357–0.938 0.351–0.924 0.276–1.157 T stage T4a 0.169 1.386 0.117 1.172 T4b 0.868–2.215 0.866–3.385 N stage N0 0.224 1.197 0.323 1.014 N1 0.913–1.568 0.644–1.594 N2 N3 Segment Cervical 0.815 0.885 0.427 1.022 Upper 0.672–1.164 0.581–1.798 Middle Lower Weight loss Yes 0.757 0.927 0.800 0.913 No 0.575–1.495 0.450–1.852 PSM propensity score matching; CRT-S chemoradiotherapy followed by surgery; D-CRT definitive chemoradiotherapy; KPS Karnofsky Performance Status.HR hazard radio; CI confidence interval independent predictor for PFS. In the present report, the able to undergo resection and numerically prolong sur- median OS of the CRT-S group was not available at the vival, but patient selection remains paramount [18, 19]. data cutoff (37.6  months median follow-up time). How - The median OS in the CMT, RT and surgery-based ther - ever, our findings showed that the 24-month OS rate was apy groups was 6.0, 12.7, and 43.9  months (P < 0.001), 69.4%. respectively. Nonsurgical treatment was associated with The therapeutic strategy for locally advanced inoper - poorer OS (P < 0.05). A similar problem also existed in able ESCC is controversial because the outcome differs a study from Japan. A small sample study from Japan among institutions [3, 6, 9–12]. For locally advanced reported that the OS of T4b EC patients who under- inoperable ESCC, although concurrent chemoradio- went DCF-RT was 50% at 3 years compared to 37.5% for therapy (CCRT) is recommended [13–15], neo-CRT is all T4b patients [18]. The mean interval was 17  months usually performed [10, 16]. Real-world data reported compared to 14.3  months for all included T4b patients. neoadjuvant chemoradiotherapy (44.9%) and definitive The 5-year survival rate was 19% in the D-CRT group [20, chemoradiotherapy (36.0%); however, 27.9% of patients 21]. undergoing neoadjuvant chemoradiotherapy did not However, some studies showed negative results. receive planned esophagectomy [17]. In retrospective A study from Japan enrolled 71 patients with T4 EC studies of T4b EC, patients who underwent surgical- with tracheobronchial invasion (TBI); 58 underwent based therapy had the longest median OS. However, the dCRT, and 13 underwent iCRT-S. There was no signifi - grouping was not random. Well-selected responders to cant difference between the dCRT and iCRT-S groups. chemotherapy (CMT) and/or radiotherapy (RT) may be Clinical LN negativity and later treatment period were Zhang et al. Radiation Oncology (2022) 17:148 Page 8 of 12 Fig. 4 Overall survival (OS) of patients after PSM. A Kaplan–Meier survival curves for OS analyses for patients between the CRT-S and D-CRT groups. B Kaplan–Meier survival curves for OS analyses of patients of different age groups. C Kaplan–Meier survival curves for OS analyses of patients of different KPS groups. D Kaplan–Meier survival curves for OS analyses of patients of different smoking index groups. OS: overall survival; PSM: propensity score matching; CRT-S: chemoradiotherapy followed by surgery; D-CRT: definitive chemoradiotherapy; KPS: Karnofsky Performance Status significantly good prognostic factors for T4 EC with were observed in the patient characteristics. Although we TBI [10]. The median survival times (MSTs) of patients acknowledge the limitations of retrospective studies, sur- with locally advanced esophageal cancer with adjacent gery after neo-CRT may probably improve survival and organ invasion after definitive CRT, bypass surgery plus decrease recurrence compared with D-CRT for locally CRT and CRT followed by esophagectomy were 10.4, advanced inoperable ESCC patients who are downstaged 11.0 and 16.4  months, respectively; MST did not differ after neo-CRT. significantly between patients [22]. To our knowledge, The first failure sites were categorized as local, regional our study is the first to compare CRT-S and D-CRT in nodal, or distant. In previous studies of locally advanced locally advanced inoperable ESCC patients who were esophageal cancer patients who underwent chemoradia- downstaged after neo-CRT. The choice of the 8 patients tion followed by esophagectomy, the rates were 4.5–67% from a single-arm, single-center, investigator-initiated, local, 10–57.9% regional nodal, and 21–32% distant fail- exploratory, phase II clinical study (ClinicalTrials.gov ures [23–26]. Local failure was correlated with fewer NCT04137679) was randomly made according to the lymph nodes (LNs) assessed and close/positive mar- random system. For the rest of the 98 cases, doctors pro- gins. Regional nodal failure was correlated with fewer vided the two possibilities of treatment ways equally and LNs assessed and larger pretreatment tumor size. Dis- patients and doctors made the final decision together. It tant recurrence was correlated with higher pathologic is a basic principle to respect the patients right of con- nodal stage, ulceration, perineural invasion, residual dis- sent. After propensity score matching (PSM), no signifi - ease, and higher posttreatment PET SUV max. Patients cant differences between the CRT-S and D-CRT groups with a pathologic complete response were less likely Zhang  et al. Radiation Oncology (2022) 17:148 Page 9 of 12 Fig. 5 Progression-free survival (PFS) of patients after PSM. A Kaplan–Meier survival curves for PFS analyses of patients between the CRT-S and D-CRT groups. B Kaplan–Meier survival curves for PFS analyses of patients of different age groups. C Kaplan–Meier survival curves for PFS analyses of patients of different smoking index groups. D Kaplan–Meier survival curves for PFS analyses of patients of different smoking status groups. PFS: progression free survival; PSM: propensity score matching; CRT-S: chemoradiotherapy followed by surgery; D-CRT: definitive chemoradiotherapy Table 4 Type of first progression in CRT-S and D-CRT group a high pathological complete response (pCR) rate (37.5%, 12/32), fewer lymph nodes (N0, 23/32; N1, 3/32; N2, Type of first progression CRT-S (n = 32) D-CRT (n = 74) P 4/32; N3, 0/32), high negative margin rate (32/32, 100%) Local recurrence 1 27 < 0.001 and high R0 resection rate (30/32, 93.75%) [24]. In the Regional lymph node 6 19 D-CRT group, the distant metastasis rate was only 16.2% metastasis (12/74). Most patients in the D-CRT group had local Distant metastasis 8 12 progression (27/74, 36.5%), 6 of whom were complicated Stable 17 16 with esophageal fistula, and 2 of whom had massive hem - CRT-S chemoradiotherapy followed by surgery; D-CRT definitive orrhage (Table 5). Our data indicated that CRT-S reduced chemoradiotherapy the local recurrence rate and the incidence of esophageal fistula (P = 0.097) and massive hemorrhage (p = 0.348), which was partially consistent with previous studies [3, to experience distant recurrence [24]. In our study, all 27]. cases were evaluated as down staged to operable by CT, In a randomized study comparing D-CRT and CRT-S endoscopy and upper gastrointestinal contrast. Most for patients with locally advanced operable esophageal cases in the CRT-S group had distant metastasis (8/32, carcinoma, preoperative chemoradiotherapy improved 25.0%), and the local progression rate was 3.1% (1/32). survival among patients with potentially curable esoph- The low local progression rate may be partially related to ageal or esophagogastric junction cancer. The regimen Zhang et al. Radiation Oncology (2022) 17:148 Page 10 of 12 Table 5 Treatment-related adverse events Adverse events CRT-S, n (%) D-CRT, n (%) P Anastomotic leakage 3 (9.4) / / Post thoracotomy pulmonary infection 2 (6.3) / / Operative mortality 1 (3.1) / / Esophageal fistula 0 (0) 6 (6.4) 0.097 Massive hemorrhage 0 (0) 2 (2.1) 0.348 Radiation esophagitis Grade 1 10 (31.3) 14 (14.9) 0.080 Grade 2 10 (31.3) 13 (13.8) Grade 3 0 (0) 5 (5.3) Grade 4 0 (0) 0 (0) Total 20 (62.5) 32 (34.0) Leukocytopenia Grade 1 0 (0) 3 (3.2) 0.038 Grade 2 9 (28.1) 26 (27.7) Grade 3 0 (0) 10 (10.6) Grade 4 0 (0) 0 (0) Total 9 (28.1) 39 (41.4) Neutrophilic granulopenia Grade 1 2 (6.3) 12 (12.8) 0.580 Grade 2 3 (9.4) 6 (6.4) Grade 3 1 (3.1) 4 (4.3) Grade 4 0 (0) 1 (1.1) Total 6 (18.8) 23 (24.5) Anemia Grade 1 18 (56.3) 35 (34.0) 0.759 Grade 2 3 (9.4) 10 (10.6) Grade 3 0 (0) 1 (1.1) Grade 4 0 (0) 0 (0) Total 21 (65.6) 46 (48.9) Thrombocytopenia Grade 1 3 (9.4) 20 (21.3) 0.087 Grade 2 0 (0) 3 (3.2) Grade 3 1 (3.1) 4 (4.3) Grade 4 0 (0) 0 (0) Total 4 (12.5) 27 (28.7) Hypoalbuminema Grade 1 12 (37.5) 14 (14.9) 0.382 Grade 2 0 (0) 2 (2.1) Grade 3 0 (0) 0 (0) Grade 4 0 (0) 0 (0) Total 12 (37.5) 16 (17.0) CRT-S chemoradiotherapy followed by surgery; D-CRT definitive chemoradiotherapy was associated with acceptable adverse event rates [28– the D-CRT group. Although there were no differences 30]. Some studies discussed the therapeutic options of of statistics in neutrophilic granulopenia incidence T4b EC; although CRT-S improved the survival rate, (p = 0.58), thrombocytopenia incidence (p = 0.087) perioperative complications were also increased. Anas- and radiation esophagitis incidence (p = 0.080) in the tomotic leakage after surgery was 25%, the recurrent CRT-S and D-CRT group, grade 3 radiation esophagi- laryngeal nerve paralysis rate was approximately 50% tis incidence was lower in the CRT-S group than the [21], the reoperation rate was approximately 7.7% [23], D-CRT group. In the CRT-S group, anastomotic leak- and the operative mortality was 5–23.4% [25]. In the age, post thoracotomy pulmonary infection and opera- present study, all adverse events were no more than tive mortality were lower than those in previous reports grade 3 and manageable. Leukocytopenia incidence in patients with advanced ESCC (Table  5) [20, 21, 23, (p = 0.038) in the CRT-S group was lower than those in 25]. Zhang  et al. Radiation Oncology (2022) 17:148 Page 11 of 12 Research Center for Cancer, Tianjin Medical University Cancer Institute Conclusions and Hospital, Huanhu West Road, Hexi District, Tianjin, China. K ey Laborator y In conclusion, the present study has demonstrated that of Cancer Prevention and Therapy, Department of Nutrition Therapy, National CRT-S was superior to D-CRT for T4 ESCC patients Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Can- cer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. who were downstaged by neo-CRT with respect to Key Laboratory of Cancer Prevention and Therapy, Department of Esophageal longer OS and PFS. However, the present study did Cancer, National Clinical Research Center for Cancer, Tianjin’s Clinical Research have several limitations. First, this was a retrospec- Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. Division of Life Sciences and Medicine, Department of Radia- tive study from a single institution. Second, half of the tion Oncology, The First Affiliated Hospital of USTC, University of Science patients included in the study were staged as T4 by CT and Technology of China, Hefei, Anhui, China. imaging and not by endoscopy. Furthermore, the num- Received: 29 January 2022 Accepted: 7 August 2022 ber of patients included in the study was small. Ran- domized controlled trials involving large population samples are needed to define the standard treatment for T4 esophageal cancer. References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. https:// doi. org/ 10. 3322/ caac. 21551. Abbreviations 2. Liang H, Fan JH, Qiao YL. 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Int J Radiat Oncol Biol Phys. 2001;50(1):1–12. https:// doi. org/ 10. 1016/ s0360- 3016(01) 01459-6. 30. Zhang ZX, et al. Randomized clinical trial on the combination of preop- erative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)–report on 370 patients. Int J Radiat Oncol Biol Phys. 1998;42(5):929–34. https:// doi. org/ 10. 1016/ s0360- 3016(98) 00280-6. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Journal

Radiation Oncology – Springer Journals

Published: Aug 23, 2022

Keywords: Esophageal squamous cell carcinoma; T4; Neo-chemoradiotherapy followed by surgery; Definitive chemoradiotherapy

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