Reduction in Chemotherapy Relative Dose Intensity Decreases Overall Survival of Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Esophageal Carcinoma

Reduction in Chemotherapy Relative Dose Intensity Decreases Overall Survival of Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Esophageal Carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Reduction in Chemotherapy Relative Dose Intensity Decreases Overall Survival of Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Esophageal Carcinoma Li Jiang, Jie Zhu, Xue Chen, Yi Wang, Lei Wu, Gang Wan, Yongtao Han, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3974394/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Aug, 2024 Read the published version in BMC Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Background Many patients undergo dose reduction or early termination of chemotherapy to reduce chemoradiotherapy-related toxicity, which may increase their risk of survival. However, this strategy may result in underdosing patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This study aimed to analyze the relationship between the relative dose intensity (RDI) and survival outcomes in patients with LA-ESCC. Methods This retrospective study assessed patients with LA-ESCC (cT2N + M0, cT3-4NanyM0) receiving neoadjuvant chemoradiotherapy (NCRT) with curative-intent esophagectomy. The patients received 2 courses of paclitaxel plus carboplatin (TC) combination radiotherapy prior to undergoing surgery. During NCRT, RDI was computed, defined as the received dose as a percentage of the standard dose, and the incidence of dose delays was estimated (≥ 7 days in any course cycle). The best RDI cutoff value (0.7) was obtained using ROC curve. The Kaplan-Meier survival curves were compared using the log-rank test, the treatment effect was measured using hazard ratios (HR) and 95% confidence intervals (CI). Results We included 132 patients in this study, divided into RDI < 0.7 and RDI ≥ 0.7 groups using cut-off value of 0.7. RDI grade was an independent prognostic factor for OS. Baseline demographic and clinical characteristics were well balanced between the groups. There was no evidence that patients with RDI < 0.7 experienced less toxicity or those with RDI ≥ 0.7 resulted in more toxicity. However, patients with RDI < 0.7 who were given reduced doses had a worse overall survival [HR 2.058, 95% CI 1.13–3.74, P = 0.015]. The risk of a lower RDI increased with a longer dose delay time (P < 0.001). Conclusion The RDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival. Esophageal cancer (ESCC) Locally advanced esophageal cancer (LA-ESCC) Neoadjuvant chemoradiotherapy (NCRT) Paclitaxel plus carboplatin regimen (TC) Relative dose intensity (RDI) Adverse events (AEs) Overall survival (OS) Figures Figure 1 Figure 2 Introduction Esophageal cancer ranks as the eighth most common form of malignancy and the sixth leading cause of cancer-related deaths globally [ 1 ]. In Asian countries, notably China and Japan, esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype, with locally advanced disease being the most prevalent stage among newly diagnosed patients [ 2 ]. Neoadjuvant chemoradiotherapy (NRCT) has become established as the standard treatment approach for non-metastatic but locally advanced esophageal squamous cell carcinoma (LA-ESCC) with curative intent [ 3 – 5 ]. Since the publication of the CROSS trial, the paclitaxel plus carboplatin (TC) chemotherapy regimen has been extensively utilized in neoadjuvant chemoradiotherapy for LA-ESCC [ 6 ]. The TC regimen has gained considerable popularity owing to its minimal toxicity. Our retrospective analysis demonstrated that the TC regimen is a safe and effective (equivalent) alternative to the paclitaxel plus cisplatin (TP) regimen for NCRT in patients with LA-ESCC [ 7 ]. Over the past decade, the focus of NCRT is the efficacy and safety of different chemotherapy regimens [ 7 , 8 ]; however, little research has been conducted on chemotherapy dose in NCRT for patients with LA-ESCC. Relative dose intensity (RDI) has recently emerged as an important measure that reflects the tolerability and degree of adherence to chemotherapy regimens [ 9 ]. RDI is defined as the ratio of the received dose intensity to the prescribed dose intensity, measured as the amount of drug delivered per unit time [ 10 ]. Clinical evidence suggests that improved outcomes can be achieved by using standard chemotherapy regimens in a dose-dependent manner. Patients who receive higher dose intensities tend to experience improved overall survival (OS), progression-free survival (PFS), and disease-free survival compared to those who receive lower dose intensities than planned [ 11 ]. RDI less than 85% is considered to be a clinically significant reduction from standard or planned therapy [ 12 ]. However, dose delays and reductions are common methods for mitigating chemotherapy-induced side effects. Despite the fact that maintaining RDI is important to achieve improved outcomes, a substantial proportion of patients are administered less than 85% of the recommended dose, and research indicates that less than half of patients receive the 85% suggested RDI dose [ 13 ]. Sufficient chemotherapy dose improves the clinical outcomes of various malignancies [ 14 , 15 ]. However, few studies have explored the optimal strategy for the dose intensity of NCRT chemotherapy in patients with LA-ESCC. To explore the rationale for chemotherapy RDI in ESCC, we retrospectively analyzed the survival and toxicity of TC chemotherapy regimens with different dose intensities as neoadjuvant treatment for patients with resectable LA-ESCC. Method Patients We conducted a retrospective review of patients with LA-ESCC who underwent NCRT followed by surgery at Sichuan Cancer Hospital and Institute between May 2017 and June 2021. Inclusion criteria were as follows: (1) A resectable LA-ESCC (cT1-2N + M0 or cT3–cT4NanyM0) as determined by the American Joint Committee on Cancer 8th edition [ 16 ]; (2) a score of 0 or 1 on the new Eastern Cooperative Oncology Group (ECOG) performance scale [ 17 ]; (3) following NCRT, resectional surgery was performed on patients; and (4) administration of TC chemotherapy regimen. Exclusion criteria were as follows: (1) prior treatment for primary tumors or nodes; (2) non-squamous cell carcinomas (including adenocarcinoma or small cell carcinoma); (3) patients who received chemotherapy alone, radiotherapy alone, or no treatment prior to surgery; and (4) patients did not complete standard chemotherapydue to personal reasons. The Institutional Review Board of Sichuan Cancer Hospital approved this retrospective study. Chemoradiotherapy regimens The chemotherapy regimen consisted of a paclitaxel dose of 135 mg/m 2 (day 1), while carboplatin administered at an area under the curve of AUC = 4 mg/mL/min (day 1) at weeks one and four, spanning two cycles. Chemotherapy dosages and any necessary adjustments were determined under the supervision of medical oncologists. The delineation of the gross tumor volume (GTV) was based on clinical imaging modalities such as esophagoscopy, computed tomography (CT), and positron emission tomography-CT. The clinical target volume (CTV) encompassed the GTV plus a 2–3 cm margin in the cranial-caudal direction and a 0.5 cm margin in the transverse plane, ensuring that the CTV boundary did not extend beyond anatomical constraints such as blood vessels. The median total radiotherapy dose was 40 Gy (2.0 Gy/fraction). Concurrently, intensity-modulated radiotherapy commenced with the initial chemotherapy cycle and continued for five days a week for 4–5 weeks of radiotherapy. Calculation of relative dose intensity and dose delay Dose intensity was defined as the amount of drug (paclitaxel at 135 mg/m 2 and carboplatin at AUC = 4) delivered to a patient within a week of treatment. The achieved dose intensity was determined as the total dose of the individual drug received in the first four cycles for each individual agent per body surface area divided by the number of days from the beginning (cycle 1, day 1) to the end (cycle 4, day 21) of treatment for every patient. The RDI of nab-paclitaxel was calculated for each patient using the following equation: actual dose intensity/standard dose intensity. The actual dose intensity was calculated by dividing the total dose delivered by the total chemotherapy duration. Average dose-intensity values for each individual drug and 95% confidence intervals (CIs) will not be detailed in this article. Statistical distributions of the RDI and treatment duration are provided. Dose delay was defined as the delay in the next treatment cycle by ≥ 7 days. Efficacy evaluation Effectiveness was evaluated through key metrics, including the pathological complete response (pCR) rate, R0 resection rate, OS, and PFS. pCR was defined as the absence of any residual invasive tumor in the surgical resection specimen (GR0). R0 was defined as microscopically negative surgical margins. Defined the quality of resection (R) using the surgical and pathological report, resection status was characterized as R0, R1 (microscopic tumor at any margin), and R2 (macroscopically incomplete resection). OS was calculated from the date of neoadjuvant therapy initiation to the date of death from any cause, or censored until the date of last follow-up. PFS was calculated from the start date of therapy to the date of progression or death, whichever is earlier. Statistical analysis Statistical analyses were performed using the R software (R version 4.0.3; http://www.R-project.org , The R Foundation). The best RDI cut-off value of 0.7 was obtained using the Cox proportional hazard model according to OS. Meanwhile, LA-ESCC patients were classified into the RDI < 0.7 group and RDI ≥ 0.7 group based on the optimal cutoff from the receiver operating characteristic (ROC) curve analysis. Survival times were analyzed by Kaplan-Meier survival analysis using a log-rank test for curve comparisons. Continuous variables are presented as mean (SD) if normally distributed or median (interquartile range [IQR]) if not normally distributed. Categorical variables are expressed as counts (percentages). Comparisons were made using two-tailed unpaired Student's t-tests and p values < 0.05 were considered statistically significant. Survival benefits were measured using hazard ratios (HR) and its 95% CI. Result Population characteristics Among 321 eligible patients, 132 met the inclusion criteria. The median RDI was 0.74 (range 0.45–1.05). The ROC curve revealed 0.7 as the optimal cutoff value for the RDI. RDI was < 0.7% in 38.6% of the patients. Patients were split into two groups, with RDI < 0.7 and RDI ≥ 0.7 levels, according to the best cut-off value. A total of 132 patients were randomly assigned between July 7, 2017, and June 21, 2021, to the RDI < 0.7 (n = 51) or RDI ≥ 0.7 (n = 81) groups. Baseline characteristics (Table 1 ) were well balanced between the two groups. The majority of patients were ≤ 65 years (RDI < 0.7 group, 70.6%; RDI ≥ 0.7 group, 72.4%). There were more males than females (84.8% versus 15.2%), with a mean age of 59.9 ± 6.9 years. According to the TNM stage, most patients (73.9%) were classified as stage III. Table 1 Patient characteristics. Variables Total (n = 132) RDI < 0.7 (n = 51) RDI ≥ 0.7 (n = 81) P Age, years, n(%) 0.779 < 65 95 (72.0) 36 (70.6) 59 (72.8) ≥ 65 37 (28.0) 15 (29.4) 22 (27.2) Sex, n (%) 0.174 Male 112 (84.8) 46 (90.2) 66 (81.5) Female 20 (15.2) 5 (9.8) 15 (18.5) BMI Grade, n (%) 0.763 14 45 (34.1) 17 (33.3) 28 (34.6) ECOG, n (%) 1 0 120 (90.9) 46 (90.2) 74 (91.4) 1 12 ( 9.1) 5 (9.8) 7 (8.6) Smoking, n (%) 0.098 Yes 87 (65.9) 38 (74.5) 49 (60.5) No 45 (34.1) 13 (25.5) 32 (39.5) Drinking, n (%) 0.157 Yes 86 (65.2) 37 (72.5) 49 (60.5) No 46 (34.8) 14 (27.5) 32 (39.5) Tumor location, n (%) 0.173 Uper 23 (17.4) 5 (9.8) 18 (22.2) Midle 45 (34.1) 18 (35.3) 27 (33.3) Lower 64 (48.5) 28 (54.9) 36 (44.4) Clinical T stage, n (%) 0.075 T2 6 ( 4.5) 0 (0) 6 (7.4) T3 109 (82.6) 44 (86.3) 65 (80.2) T4a 11 ( 8.3) 3 (5.9) 8 (9.9) T4b 6 ( 4.5) 4 (7.8) 2 (2.5) Clinical N stage, n (%) 0.202 N0 3 ( 2.3) 1 (2) 2 (2.5) N1 44 (33.3) 12 (23.5) 32 (39.5) N2 68 (51.5) 29 (56.9) 39 (48.1) N3 17 (12.9) 9 (17.6) 8 (9.9) Stage, n (%) II 5 ( 3.8) 1 (2) 4 (4.9) 0.566 III 96 (72.7) 36 (70.6) 60 (74.1) IVA 31 (23.5) 14 (27.5) 17 (21) BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group performance. Independent prognostic factor for OS and PFS To study the prognosis-related factors, univariate and multivariate independent prognostic Cox analyses was performed. Univariate and multivariate analyses demonstrated that RDI grade was an independent prognostic factor for OS (HR = 0.513, 95% CI = 0.284–0.926, P = 0.027). None of the other factors such as age, sex, or ECOG score were independent predictors (P > 0.05) (Table 2 ). Supplementary Table 1 shows the univariate analysis for PFS. The results demonstrated that neither RDI nor other clinical characteristics were associated with PFS. Table 2 Univariate and multivariate Cox hazard regression analysis of OS. Characteristics Univariate analysis Multivariate analysis Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value Age < 65 Reference ≥ 65 0.86 (0.43,1.7) 0.658 0.71 (0.33, 1.54) 0.383 Sex Male Reference Female 1.1 (0.49,2.47) 0.815 1.5 (0.4, 5.6) 0.545 BMI Grade 14 0.44 (0.13,1.54) 0.201 0.38 (0.09, 1.54) 0.175 ECOG 0 Reference 1 1.9 (0.74,4.86) 0.18 1.51 (0.55, 4.14) 0.423 Smoking Yes Reference No 1.1 (0.58,2.08) 0.763 1.05 (0.28, 3.87) 0.943 Drinking Yes Reference No 1.18 (0.63,2.24) 0.602 1.43 (0.42, 4.96) 0.568 Tumor location Uper Reference Midle 1.64 (0.69,3.89) 0.258 1.42 (0.53, 3.75) 0.485 Lower 0.87 (0.36,2.09) 0.752 0.58 (0.2, 1.67) 0.309 Clinical T stage T2 Reference T3 1.21 (0.29,5.05) 0.795 0.76 (0.16, 3.51) 0.722 T4a 1.81 (0.37,8.99) 0.466 1.3 (0.24, 6.97) 0.76 T4b 2.71 (0.45,16.36) 0.278 1.3 (0.17, 9.72) 0.796 Clinical N stage N0 Reference N1 1.08 (0.14,8.14) 0.941 0.54 (0.07, 4.52) 0.572 N2 0.71 (0.09,5.35) 0.742 0.28 (0.03, 2.39) 0.243 N3 2.48 (0.32,19.5) 0.388 1 (0.11, 8.95) 0.999 Dose delay No Reference Yes 1.16 (0.63,2.13) 0.632 RDI RDI < 0.7 Reference RDI ≥ 0.7 2.1 (1.16,3.81) 0.015 0.4 (0.201, 0.793) 0.005 BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group performance; RDI: Relative dose intensity. Toxicity of concurrent chemoradiotherapy As shown in Table 3 , all patients completed chemotherapy; of these, 23 patients received a second cycle of chemotherapy by adjusting the dose, which was compared to the first cycle of chemotherapy. No significant differences in second-cycle dose reductions were observed between the two groups (P = 0.374), mainly because the patients could not tolerate chemoradiotherapy-related adverse events (AEs). Table 3 Grade 3 and higher chemoradiotherapy relative adverse events. Variables Total RDI < 0.7 RDI ≥ 0.7 p (n = 132), n (%) (n = 51), n (%) (n = 81), n (%) Dose adjustment 23 (17.4) 7 (13.7) 16 (19.8) 0.374 Hematologic 38 (28.8) 11 (21.6) 27 (33.3) 0.118 Leukopenia 34 (25.8) 12 (23.5) 22 (27.2) 0.642 Anemia 0( 0) 0(0) 0 (0) 1 Thrombocytopenia 1 ( 0.8) 1 (2) 0 (0) 0.386 Neutropenia 29 (22.0) 9 (17.6) 20 (24.7) 0.341 Non-hematologic 21(15.9) 8 (15.7) 13 (16) 0.956 Nauseau 8 ( 6.1) 2 (3.9) 6 (7.4) 0.484 Vomiting 4 ( 3.0) 1 (2) 3 (3.7) 1 Esophagitis 3 ( 2.3) 1 (2) 2 (2.5) 1 Febrile neutropenia 1 ( 0.8) 1 (2) 0 (0) 0.386 Radiation pneumonitis 1 ( 0.8) 1 (2) 0 (0) 0.386 Acute AEs (occurring within 3 months of NCRT) during chemoradiotherapy were graded according to the Common Terminology Criteria for Adverse Events version 4.0. The severity of RT-induced esophagitis and pneumonitis was graded according to the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring criteria [ 18 ]. Hematologic and non-hematologic AEs of grade ≥ 3 were observed in 39 (29.5%) and 21 (15.9%) patients, respectively, in the intention-to-treat population (Table 4 ). Patients treated with RDI ≥ 0.7 (33.3%) had a higher incidence tendency to hematologic grade ≥ 3 AEs than those in the TC (23.5%) group, but the difference was not statistically significant (P = 0.229). There was no evidence that patients with RDI ≥ 0.7 experienced more toxicity or that patients with RDI 0.05). All the AE grades are presented in Supplementary Table 2. Table 4 Pathological findings and surgical outcomes. Variables Total (n = 132) RDI < 0.7 (n = 51) RDI ≥ 0.7 (n = 81) p Perineural invasion, n (%) 0.526 Negative 20 (15.2%) 9 (17.6%) 11 (13.6%) Positive 112 (84.8%) 42 (82.4%) 70 (86.4%) Lymphovascular invasion, n (%) 0.732 Negative 14 (10.6%) 6 (11.8%) 8 (9.9%) Positive 118 (89.4%) 45 (88.2%) 73 (90.1%) Resection margins, n (%) 0.287 R0 126 (95.5%) 48 (94.1%) 78 (96.3%) R1 4 ( 3.0%) 1 (2%) 3 (3.%7) R2 2 ( 1.5%) 2 (3.9%) 0 (0%) pCR, n (%) 0.951 Yes 41 (31.1%) 16 (31.4%) 25 (30.9%) No 91 (68.9%) 35 (68.6%) 56 (69.1%) TRG, n(%) 0.307 TRG 1a 52 (39.4%) 20 (39.2%) 32 (39.5%) TRG 1b 30 (22.7%) 8 (15.7%) 22 (27.2%) TRG 2 41 (31.1%) 20 (39.2%) 21 (25.9%) TRG 3 9 ( 6.8%) 3 (5.9%) 6 (7.4%) Postop.T, n (%) 0.82 T0 82 (40.8) 21 (42) 61 (40.4) T1-2 64 (31.8) 17 (34) 47 (31.1) T3-4 55 (27.4) 12 (24) 43 (28.5) Postop.N, n (%) 0.097 N0 140 (69.7) 40 (80) 100 (66.2) N+ 61 (30.3) 10 (20) 51 (33.8) pCR: Pathologic complete remission; TRG: Tumor regression grade. Surgical and pathological outcomes Among the 51 patients in the RDI < 0.7 group, 48 (96%), 1 (2%), and 2 (3.9%) achieved R0, R1, and R2 resections, respectively. Eighty-seven patients (96.6%) in the RDI ≥ 0.7 group achieved R0 resection, and 3 patient (3.4%) achieved R1 resection. Overall, 66 of 201 patients achieved pCR (33.3%). The pCR rate did not differ significantly between the lower- and higher-RDI groups (31.4% vs. 34.5%, P = 0.708). No statistically significant intergroup differences were noted in perineural invasion, lymphovascular invasion, resection margins, or pCR rates (all P > 0.05) (Table 4 ). The postoperative complications were not significantly different between the two groups (Supplementary Table 3). The pathological response was assessed using the tumor regression grade (TRG) of the Becker criteria. As shown in the Supplementary Table 3, 52 (39.4%), 30 (22.7%), 41 (31.1%), and 9 (6.8%) patients had no residual tumor (TRG 1a), 50% residual tumor per tumor area (TRG 3), respectively. The differences in the TRG scores between the two groups were not statistically significant (P = 0.31). Survival The median follow-up was 37.29 months in the censored patients. OS and PFS for recurrence in patients grouped according to various average RDI are shown in Figs. 1 and 2 . OS was significantly higher in the high group than in the low group when the RDI cut-off points of 0.7 was used. The 3- and 5-year OS was 77.9% (95% CI = 0.691–0.878) and 63% (95% CI = 0.511–0.776) in the RDI ≥ 0.7 group, 57.7% (95% CI = 0.446–0.746) and 51.9% (95% CI = 0.373–0.722) in the RDI < 0.7 group, respectively. The 5-year PFS was 51.1% (95% CI = 0.4-0.654) in the higher RDI group and 46.7% (95% CI = 0.343–0.635) in the lower RDI group, respectively. Patients with RDI < 0.7 who were given reduced doses had a worse OS (HR 1.947, 95% CI 1.079–3.542, P = 0.015) and a slightly worse PFS (HR 1.471, 95% CI 0.883–2.45, P = 0.14). Correlation analyses of RDI and patient characteristics We further explored the association between RDI and patients’ clinical characteristics. As shown in Supplementary Table 4, dose delay was the only factor associated with an RDI < 0.7. The mean delay time was 3.8 ± 0.8. The RDI < 0.7 group average dose-delay time was 4.3 ± 0.9, and 60.8% patients experienced dose-delay. The RDI ≥ 0.7 group average dose-delay time was 3.5 ± 0.6 (Supplementary Table 3). Fifty-one percent patients in the RDI < 0.7 group and 12.3% in the RDI ≥ 0.7 group experienced dose-delay (P < 0.001). Patient clinical characteristics such as age, sex, body mass index (BMI), tumor location, and tumor stage were not significantly associated (Table 1 ). In addition, no correlation was found between the RDI and chemoradiation-related AEs such as leukopenia, anemia, neutropenia, nausea, and vomiting (all P > 0.05) (Table 3 ). There was no statistical correlation between the RDI and other surgical and pathological outcomes, such as R0 resection rate, TRG grade, pCR rate, perineural invasion, and lymphovascular invasion (Table 4 ). Discussion Previously, our research group assessed whether the TC regimen was superior to the TP regimen, and demonstrated that the TC regimen was a safe and equivalent alternative to the TP regimen for NCRT in patients with LA-ESCC [ 7 ]. To further explore the effects of the chemotherapy dose, we analyzed 132 patients with complete TC regimen chemotherapy doses and grouped them using a cutoff RDI of 0.7. Our study indicated that patients who received higher doses did not experience more toxicity and those who received lower doses experienced less toxicity. Patients who were administered reduced doses had a worse OS (HR 1.947, 95% CI 1.079–3.542, P = 0.015) and a slightly worse PFS (HR 1.471, 95% CI 0.883–2.45, P = 0.14). The two groups showed no significant differences in perineural invasion, lymphovascular invasion, or resection margins. The relationship between the RDI and short-term efficacy was further analyzed. Dose-delay was the only factor associated with low RDI. To the best of our knowledge, this is the first study to compare the chemotherapy RDI in patients with LA-ESCC undergoing NCRT. The importance of RDI in advanced unresectable solid tumors has been well recognized in recent years [ 11 , 19 ]. A recent meta-analysis evaluated the impact of the RDI on survival in adult patients with solid tumor cancer receiving non-adjuvant-based chemotherapy regimens. Significantly shorter OS at RDI < 80% vs. ≥ 80% and < 85% vs. ≥ 85% was observed upon meta-analysis of four carboplatin-based studies for breast, non-small cell lung, or ovarian cancer, and three FOLFOX-/FOLFIRI-/FOLFIRINOX-based studies for colorectal or pancreatic cancer [ 11 ]. The results suggested longer OS with RDI ≥ 80% or ≥ 85% for both regimens, indicating longer OS with higher-RDI in advanced solid tumors. In our study, the best cut-off value of RDI calculated using the ROC curve was 70%, which was used as the criterion for subgrouping. The RDI ≥ 0.7 group had significantly higher OS than the RDI < 0.7 group. Cox regression analysis further confirmed that the RDI was an independent prognostic factor affecting survival. Therefore, it can be preliminarily deduced that an RDI of 70% can satisfy the balance of survival benefits. Patients with lower-RDI who were administered reduced doses had worse OS (P = 0.024). Thus, the results of the current study, as well as earlier studies, suggest that maintaining the RDI has a positive impact on survival. Considering patient tolerance, continuation of chemotherapy, and the reduction of chemotherapy-related side effects, dose reduction is commonly used in clinical practice for patients with LA-ESCC receiving NCRT. At present, studies on RDI chemotherapy in NCRT for LA-ESCC are scarce. The impact of the average RDI in neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-NAC) for resectable LA-ESCC has shown that an average RDI of ≥ 80% improved prognosis in patients receiving DCF-NAC for ESCC [ 20 ]. To explore whether the same results were obtained when neoadjuvant radiation was added, we retrospectively analyzed 132 patients with LA-ESCC who underwent radical esophagectomy and lymphadenectomy after NCRT. Our findings indicated that when combined with neoadjuvant chemotherapy and radiotherapy, in patients who had reduced RDI > 30%, chemotherapy not only led to significantly worse OS, but also could not decrease the risk of hematologic and non-hematologic AEs. Several factors are associated with chemotherapy RDI. Schraa et al. found that RDI < 85% was predicted by patients’ age, febrile neutropenia, and hypersensitivity reactions to taxanes in patients with breast cancer receiving adjuvant chemotherapy treatment [ 21 ]. A multicenter analysis in the United States demonstrated that malnutrition was an independent predictor of chemotherapy dose reduction due to toxicity [ 22 ]. Ilana et al. retrospectively analyzed 237 patients with breast cancer and found that the RDI was not associated with BMI (P = 0.71) or pCR (P = 0.31); however, fewer dose delays were associated with pCR (P = 0.02) [ 23 ]. In our study, we performed a univariate logistic regression model correlation analysis to explore the association between the RDI and patients’ clinical characteristics. Our results showed that 36 (27.3%) patients experienced dose delays due to personal reasons, whether initiated by the patient or the physician. Dose delay was the only factor associated with RDI 0.05). Thus, avoiding dose delays can effectively avoid dose intensity reduction. RDI is a crucial metric for assessing the intensity of chemotherapy. Management of chemotherapy time and avoidance of dose delay across treatment modalities could contribute to the maintenance of a higher RDI and benefit survival in patients with LA-ESCC for NCRT. The chemotherapy dose can be appropriately reduced to ensure the safety profile of NCRT. However, we do not support the policy of reducing chemotherapy doses > 30% in patients with LA-ESCC. Dose reductions or delays in the administration of chemotherapy owing to toxicity, or with the intention of avoiding toxicity, lead to a reduction in the dose intensity of treatment and may decrease its therapeutic effect. Avoiding toxicity can cost them months (if not years) of survival. This study has some limitations. First, this was a retrospective cohort study with potential selection bias compared to prospective randomized controlled studies. In addition, the follow-up duration was relatively short and the median OS was not reached. Moreover, in our cohort, episodes of AEs were underreported, given that this information was not prospectively gathered and that these mild events would not have warranted intervention or a change in treatment. Further large prospective studies with a systematic evaluation of the chemotherapy RDI in patients with LA-ESCC undergoing NCRT are needed. Conclusion RDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival. List Of Abbreviations AEs adverse events CI confidence interval CT computed tomography CTV clinical target volume DCF NAC-neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil ESCC esophageal squamous cell carcinoma GTV gross tumor volume HR hazard ratio ROC receiver operating characteristic LA ESCC-locally advanced esophageal squamous cell carcinoma NRCT neoadjuvant chemoradiotherapy OS overall survival pCR pathological complete response PFS progression-free survival RDI relative dose intensity TC paclitaxel plus carboplatin TP paclitaxel plus cisplatin TRG tumor regression grade Declarations Acknowledgements We thanked Professor Jinyi Lang and Professor Tao Li, Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China for their general support. Ethics approval and consent to participate According to the ethical guide-lines of the Helsinki Declaration and was approved by the institutional review board of Sichuan Cancer Hospital & Institute. Written informed consents were obtained from all patients prior to treatment. Consent for publication All patients in the study provided written informed consent. Availability of data and materials All data generated and analyzed in this study are included in this published article. Funding This work was supported by the Science and Technology Department of Sichuan Province (2020YFH0169, 2023YFS0488 and 2023YFQ0055), Sichuan Province Clinical Key Specialty Construction Project. Competing interests The authors declare no confict of interest. Authors' contributions Li Jiang: Data collection, statistics, original draft. Jie Zhu: Conceptualization, review and editing the manuscript. Yi Wang: conducted the data analysis and developed the tracking and data collection programs. Xue Chen, Lei Wu, Gang Wan: data collection. Yongtao Han, Xuefeng Leng, Lin Peng: Executed esophagectomy. Qifeng Wang, Lin Peng and Jun Zhang: Monitor the clinical trial. Author details 1 Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China; 2 Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China. 3 Department of Oncology, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China; References Uhlenhopp DJ, Then EO, Sunkara T, Gaduputi V. Epidemiology of esophageal cancer: update in global trends, etiology and risk factors. Clin J Gastroenterol. 2020;13:1010–21. https://doi.org/10.1007/s12328-020-01237-x . Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137–50. https://doi.org/10.1200/JCO.2005.05.2308 . Lordick F, Mariette C, Haustermans K, Obermannová R, Arnold D. Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v50–7. https://doi.org/10.1093/annonc/mdw329 . Kuwano H, Nishimura Y, Oyama T, Kato H, Kitagawa Y, Kusano M, et al. Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus April 2012 edited by the Japan Esophageal Society. Esophagus. 2015;12:1–30. https://doi.org/10.1007/s10388-014-0465-1 . Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Corvera C, Das P, et al. Esophageal and esophagogastric junction cancers, version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17:855–83. https://10.6004/jnccn.2019.0033 . Eyck BM, Van Lanschot JJB, Hulshof MCCM, van der Wilk BJ, Shapiro J, van Hagen P, et al. Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial. J Clin Oncol. 2021;39:1995–2004. https://doi.org/10.1200/JCO.20.03614 . Jiang L, Zhu J, Chen X, Wang Y, Wu L, Wan G, et al. Safety and efficacy of paclitaxel plus carboplatin versus paclitaxel plus cisplatin in neoadjuvant chemoradiotherapy for patients with locally advanced esophageal carcinoma: a retrospective study. Radiat Oncol. 2022;17:218. https://doi.org/10.1186/s13014-022-02190-4 . Honing J, Smit JK, Muijs CT, Burgerhof JGM, de Groot JW, Paardekooper G, et al. A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients. Ann Oncol. 2014;25:638–43. https://doi.org/10.1093/annonc/mdt589 . Weycker D, Barron R, Edelsberg J, Kartashov A, Lyman GH. Incidence of reduced chemotherapy relative dose intensity among women with early-stage breast cancer in US clinical practice. Breast Cancer Res Treat. 2012;133:301–10. https://doi.org/10.1007/s10549-011-1949-5 . Longo DL, Duffey PL, DeVita VT Jr, Wesley MN, Hubbard SM, Young RC. The calculation of actual or received dose intensity: a comparison of published methods. J Clin Oncol. 1991;9:2042–51. https://doi.org/10.1200/JCO.1991.9.11.2042 . Nielson CM, Bylsma LC, Fryzek JP, Saad HA, Crawford J. Relative dose intensity of chemotherapy and survival in patients with advanced stage solid tumor cancer: a systematic review and meta-analysis. Oncologist. 2021;26:e1609–18. https://doi.org/10.1002/onco.13822 . Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol. 2003;21:4524–31. https://doi.org/10.1200/JCO.2003.05.002 . Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332:901–6. https://doi.org/10.1056/NEJM199504063321401 . Liu J, Yang Y, Liu Z, Fu X, Cai X, Li H, et al. Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma. J Immunother Cancer. 2022;10:e004291. https://doi.org/10.1136/jitc-2021-004291 . Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681–92. https://doi.org/10.1016/S1470-2045(11)70142-5 . Marano L, D’Ignazio A, Cammillini F, Angotti R, Messina M, Marrelli D, et al. Comparison between 7th and 8th edition of AJCC TNM staging system for gastric cancer: old problems and new perspectives. Transl Gastroenterol Hepatol. 2019;4:22. https://doi.org/10.21037/tgh.2019.03.09 . Sok M, Zavrl M, Greif B, Srpčič M. Objective assessment of WHO/ECOG performance status. Support Care Cancer. 2019;27:3793–8. https://doi.org/10.1007/s00520-018-4597-z . Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European-organization-for-research-and-treatment-of-cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31:1341–6. https://doi.org/10.1016/0360-3016(95)00060-C . Denduluri N, Lyman GH, Wang Y, Morrow PK, Barron R, Patt D, et al. Chemotherapy dose intensity and overall survival among patients with advanced breast or ovarian cancer. Clin Breast Cancer. 2018;18:380–6. https://doi.org/10.1016/j.clbc.2018.02.003 . Shiraishi O, Kato H, Momose K, Hiraki Y, Yasuda A, Shinkai M, et al. Impact of relative dose intensity of docetaxel, cisplatin, and 5-fluorouracil neoadjuvant chemotherapy on survival of esophageal squamous cell cancer patients. Oncology. 2023;101:203–12. https://doi.org/10.1159/000528937 . Schraa SJ, Frerichs KA, Agterof MJ, Hunting JCB, Los M, de Jong PC. Relative dose intensity as a proxy measure of quality and prognosis in adjuvant chemotherapy for breast cancer in daily clinical practice. Eur J Cancer 2017 Oxf Engl;79:152–7. https://doi.org/10.1016/j.ejca.2017.04.001 . Klute KA, Brouwer J, Jhawer M, Sachs H, Gangadin A, Ocean A, et al. Chemotherapy dose intensity predicted by baseline nutrition assessment in gastrointestinal malignancies: a multicentre analysis. Eur J Cancer. 2016;63:189–200. https://doi.org/10.1016/j.ejca.2016.05.011 . Usiskin I, Li F, Irwin ML, Cartmel B, Sanft T. Association of relative dose intensity with BMI and pathologic complete response in patients treated with neoadjuvant chemotherapy for breast cancer. Breast Cancer Res Treat. 2021;186:191–7. https://doi.org/10.1007/s10549-020-05994-8 . Additional Declarations No competing interests reported. Supplementary Files Supplementarytables.docx Cite Share Download PDF Status: Published Journal Publication published 02 Aug, 2024 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 16 Apr, 2024 Reviews received at journal 12 Apr, 2024 Reviewers agreed at journal 07 Apr, 2024 Reviews received at journal 25 Mar, 2024 Reviewers agreed at journal 17 Mar, 2024 Reviewers invited by journal 07 Mar, 2024 Editor invited by journal 07 Mar, 2024 Editor assigned by journal 06 Mar, 2024 Submission checks completed at journal 06 Mar, 2024 First submitted to journal 20 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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03:35:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3974394/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3974394/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-024-12724-6","type":"published","date":"2024-08-02T15:57:36+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":52450659,"identity":"ee13ed28-c374-4901-8bd7-75f4607d676a","added_by":"auto","created_at":"2024-03-11 19:08:08","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":205811,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOS curve of two RDI groups.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3974394/v1/5bee0e70f2857988f7604b60.jpeg"},{"id":52450644,"identity":"3e95e42c-bd9f-4d72-843d-23a4849d3222","added_by":"auto","created_at":"2024-03-11 19:07:59","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":222459,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePFS curve of two RDI groups.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3974394/v1/0f97b9b8b5854ace7b7f1e1c.jpeg"},{"id":61794279,"identity":"6231b3a8-68f1-409a-907c-4d9ea5546dc5","added_by":"auto","created_at":"2024-08-05 16:18:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1354037,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3974394/v1/3d3f240a-9f7b-47a3-9319-881b95663b1f.pdf"},{"id":52450650,"identity":"76883a8a-ec0b-4e0c-8012-b7c268490ea0","added_by":"auto","created_at":"2024-03-11 19:08:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29005,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-3974394/v1/9c80b2a36481026e53df46f5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Reduction in Chemotherapy Relative Dose Intensity Decreases Overall Survival of Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Esophageal Carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEsophageal cancer ranks as the eighth most common form of malignancy and the sixth leading cause of cancer-related deaths globally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In Asian countries, notably China and Japan, esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype, with locally advanced disease being the most prevalent stage among newly diagnosed patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Neoadjuvant chemoradiotherapy (NRCT) has become established as the standard treatment approach for non-metastatic but locally advanced esophageal squamous cell carcinoma (LA-ESCC) with curative intent [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince the publication of the CROSS trial, the paclitaxel plus carboplatin (TC) chemotherapy regimen has been extensively utilized in neoadjuvant chemoradiotherapy for LA-ESCC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The TC regimen has gained considerable popularity owing to its minimal toxicity. Our retrospective analysis demonstrated that the TC regimen is a safe and effective (equivalent) alternative to the paclitaxel plus cisplatin (TP) regimen for NCRT in patients with LA-ESCC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Over the past decade, the focus of NCRT is the efficacy and safety of different chemotherapy regimens [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]; however, little research has been conducted on chemotherapy dose in NCRT for patients with LA-ESCC.\u003c/p\u003e \u003cp\u003eRelative dose intensity (RDI) has recently emerged as an important measure that reflects the tolerability and degree of adherence to chemotherapy regimens [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. RDI is defined as the ratio of the received dose intensity to the prescribed dose intensity, measured as the amount of drug delivered per unit time [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Clinical evidence suggests that improved outcomes can be achieved by using standard chemotherapy regimens in a dose-dependent manner. Patients who receive higher dose intensities tend to experience improved overall survival (OS), progression-free survival (PFS), and disease-free survival compared to those who receive lower dose intensities than planned [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. RDI less than 85% is considered to be a clinically significant reduction from standard or planned therapy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, dose delays and reductions are common methods for mitigating chemotherapy-induced side effects. Despite the fact that maintaining RDI is important to achieve improved outcomes, a substantial proportion of patients are administered less than 85% of the recommended dose, and research indicates that less than half of patients receive the 85% suggested RDI dose [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSufficient chemotherapy dose improves the clinical outcomes of various malignancies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, few studies have explored the optimal strategy for the dose intensity of NCRT chemotherapy in patients with LA-ESCC. To explore the rationale for chemotherapy RDI in ESCC, we retrospectively analyzed the survival and toxicity of TC chemotherapy regimens with different dose intensities as neoadjuvant treatment for patients with resectable LA-ESCC.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e We conducted a retrospective review of patients with LA-ESCC who underwent NCRT followed by surgery at Sichuan Cancer Hospital and Institute between May 2017 and June 2021. Inclusion criteria were as follows: (1) A resectable LA-ESCC (cT1-2N\u0026thinsp;+\u0026thinsp;M0 or cT3\u0026ndash;cT4NanyM0) as determined by the American Joint Committee on Cancer\u003csup\u003e8th\u003c/sup\u003e edition [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]; (2) a score of 0 or 1 on the new Eastern Cooperative Oncology Group (ECOG) performance scale [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]; (3) following NCRT, resectional surgery was performed on patients; and (4) administration of TC chemotherapy regimen. Exclusion criteria were as follows: (1) prior treatment for primary tumors or nodes; (2) non-squamous cell carcinomas (including adenocarcinoma or small cell carcinoma); (3) patients who received chemotherapy alone, radiotherapy alone, or no treatment prior to surgery; and (4) patients did not complete standard chemotherapydue to personal reasons. The Institutional Review Board of Sichuan Cancer Hospital approved this retrospective study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eChemoradiotherapy regimens\u003c/h2\u003e \u003cp\u003eThe chemotherapy regimen consisted of a paclitaxel dose of 135 mg/m\u003csup\u003e2\u003c/sup\u003e (day 1), while carboplatin administered at an area under the curve of AUC\u0026thinsp;=\u0026thinsp;4 mg/mL/min (day 1) at weeks one and four, spanning two cycles. Chemotherapy dosages and any necessary adjustments were determined under the supervision of medical oncologists. The delineation of the gross tumor volume (GTV) was based on clinical imaging modalities such as esophagoscopy, computed tomography (CT), and positron emission tomography-CT. The clinical target volume (CTV) encompassed the GTV plus a 2\u0026ndash;3 cm margin in the cranial-caudal direction and a 0.5 cm margin in the transverse plane, ensuring that the CTV boundary did not extend beyond anatomical constraints such as blood vessels. The median total radiotherapy dose was 40 Gy (2.0 Gy/fraction). Concurrently, intensity-modulated radiotherapy commenced with the initial chemotherapy cycle and continued for five days a week for 4\u0026ndash;5 weeks of radiotherapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCalculation of relative dose intensity and dose delay\u003c/h2\u003e \u003cp\u003eDose intensity was defined as the amount of drug (paclitaxel at 135 mg/m\u003csup\u003e2\u003c/sup\u003e and carboplatin at AUC\u0026thinsp;=\u0026thinsp;4) delivered to a patient within a week of treatment. The achieved dose intensity was determined as the total dose of the individual drug received in the first four cycles for each individual agent per body surface area divided by the number of days from the beginning (cycle 1, day 1) to the end (cycle 4, day 21) of treatment for every patient. The RDI of nab-paclitaxel was calculated for each patient using the following equation: actual dose intensity/standard dose intensity. The actual dose intensity was calculated by dividing the total dose delivered by the total chemotherapy duration. Average dose-intensity values for each individual drug and 95% confidence intervals (CIs) will not be detailed in this article. Statistical distributions of the RDI and treatment duration are provided. Dose delay was defined as the delay in the next treatment cycle by \u0026ge;\u0026thinsp;7 days.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy evaluation\u003c/h2\u003e \u003cp\u003eEffectiveness was evaluated through key metrics, including the pathological complete response (pCR) rate, R0 resection rate, OS, and PFS. pCR was defined as the absence of any residual invasive tumor in the surgical resection specimen (GR0). R0 was defined as microscopically negative surgical margins. Defined the quality of resection (R) using the surgical and pathological report, resection status was characterized as R0, R1 (microscopic tumor at any margin), and R2 (macroscopically incomplete resection). OS was calculated from the date of neoadjuvant therapy initiation to the date of death from any cause, or censored until the date of last follow-up. PFS was calculated from the start date of therapy to the date of progression or death, whichever is earlier.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using the R software (R version 4.0.3; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.R-project.org\u003c/span\u003e\u003cspan address=\"http://www.R-project.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, The R Foundation). The best RDI cut-off value of 0.7 was obtained using the Cox proportional hazard model according to OS. Meanwhile, LA-ESCC patients were classified into the RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 group and RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 group based on the optimal cutoff from the receiver operating characteristic (ROC) curve analysis. Survival times were analyzed by Kaplan-Meier survival analysis using a log-rank test for curve comparisons. Continuous variables are presented as mean (SD) if normally distributed or median (interquartile range [IQR]) if not normally distributed. Categorical variables are expressed as counts (percentages). Comparisons were made using two-tailed unpaired Student's t-tests and \u003cem\u003ep\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. Survival benefits were measured using hazard ratios (HR) and its 95% CI.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePopulation characteristics\u003c/h2\u003e \u003cp\u003eAmong 321 eligible patients, 132 met the inclusion criteria. The median RDI was 0.74 (range 0.45\u0026ndash;1.05). The ROC curve revealed 0.7 as the optimal cutoff value for the RDI. RDI was \u0026lt;\u0026thinsp;0.7% in 38.6% of the patients. Patients were split into two groups, with RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 and RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 levels, according to the best cut-off value.\u003c/p\u003e \u003cp\u003eA total of 132 patients were randomly assigned between July 7, 2017, and June 21, 2021, to the RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 (n\u0026thinsp;=\u0026thinsp;51) or RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 (n\u0026thinsp;=\u0026thinsp;81) groups. Baseline characteristics (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) were well balanced between the two groups. The majority of patients were \u0026le;\u0026thinsp;65 years (RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 group, 70.6%; RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 group, 72.4%). There were more males than females (84.8% versus 15.2%), with a mean age of 59.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9 years. According to the TNM stage, most patients (73.9%) were classified as stage III.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;132)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 (n\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 (n\u0026thinsp;=\u0026thinsp;81)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge, years, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.779\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95 (72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (70.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59 (72.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (29.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (27.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.174\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e112 (84.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (90.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66 (81.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBMI Grade, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.763\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 ( 3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18.5\u0026thinsp;\u0026le;\u0026thinsp;BMI\u0026thinsp;\u0026le;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e82 (62.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (64.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (60.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45 (34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eECOG, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e120 (90.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (90.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (91.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 ( 9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSmoking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e87 (65.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (74.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (60.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45 (34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (25.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDrinking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.157\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e86 (65.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (72.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (60.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46 (34.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTumor location, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUper\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMidle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45 (34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (35.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64 (48.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (54.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eClinical T stage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 ( 4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e109 (82.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (86.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 (80.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11 ( 8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6 ( 4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eClinical N stage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.202\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 ( 2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68 (51.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (56.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (48.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17 (12.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 ( 3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.566\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e96 (72.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (70.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (74.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI: Body mass index; ECOG: Eastern Cooperative Oncology Group performance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eIndependent prognostic factor for OS and PFS\u003c/h2\u003e \u003cp\u003eTo study the prognosis-related factors, univariate and multivariate independent prognostic Cox analyses was performed. Univariate and multivariate analyses demonstrated that RDI grade was an independent prognostic factor for OS (HR\u0026thinsp;=\u0026thinsp;0.513, 95% CI\u0026thinsp;=\u0026thinsp;0.284\u0026ndash;0.926, P\u0026thinsp;=\u0026thinsp;0.027). None of the other factors such as age, sex, or ECOG score were independent predictors (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Supplementary Table\u0026nbsp;1 shows the univariate analysis for PFS. The results demonstrated that neither RDI nor other clinical characteristics were associated with PFS.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate Cox hazard regression analysis of OS.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.86 (0.43,1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.658\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.71 (0.33, 1.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.383\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1 (0.49,2.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.815\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.5 (0.4, 5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.545\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18.5\u0026thinsp;\u0026le;\u0026thinsp;BMI\u0026thinsp;\u0026le;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.42 (0.13,1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.33 (0.08, 1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.131\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.44 (0.13,1.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.38 (0.09, 1.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9 (0.74,4.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.51 (0.55, 4.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1 (0.58,2.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.05 (0.28, 3.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.943\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrinking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.18 (0.63,2.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.602\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.43 (0.42, 4.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.568\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUper\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMidle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.64 (0.69,3.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.258\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.42 (0.53, 3.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.485\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.87 (0.36,2.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.752\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.58 (0.2, 1.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.309\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical T stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.21 (0.29,5.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.795\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.76 (0.16, 3.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.722\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.81 (0.37,8.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.24, 6.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT4b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.71 (0.45,16.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.17, 9.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.796\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical N stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08 (0.14,8.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.54 (0.07, 4.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.572\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.71 (0.09,5.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.742\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.28 (0.03, 2.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.243\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.48 (0.32,19.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (0.11, 8.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose delay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.16 (0.63,2.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.632\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRDI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1 (1.16,3.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.4 (0.201, 0.793)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI: Body mass index; ECOG: Eastern Cooperative Oncology Group performance; RDI: Relative dose intensity.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eToxicity of concurrent chemoradiotherapy\u003c/h2\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, all patients completed chemotherapy; of these, 23 patients received a second cycle of chemotherapy by adjusting the dose, which was compared to the first cycle of chemotherapy. No significant differences in second-cycle dose reductions were observed between the two groups (P\u0026thinsp;=\u0026thinsp;0.374), mainly because the patients could not tolerate chemoradiotherapy-related adverse events (AEs).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGrade 3 and higher chemoradiotherapy relative adverse events.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;132), n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;51), n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;81), n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose adjustment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.374\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (28.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (21.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (25.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (27.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.642\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0( 0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 ( 0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.386\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (22.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (17.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (24.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-hematologic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(15.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (15.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.956\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNauseau\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 ( 6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.484\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 ( 3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEsophagitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 ( 2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFebrile neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 ( 0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.386\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation pneumonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 ( 0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.386\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAcute AEs (occurring within 3 months of NCRT) during chemoradiotherapy were graded according to the Common Terminology Criteria for Adverse Events version 4.0. The severity of RT-induced esophagitis and pneumonitis was graded according to the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring criteria [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Hematologic and non-hematologic AEs of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 were observed in 39 (29.5%) and 21 (15.9%) patients, respectively, in the intention-to-treat population (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Patients treated with RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 (33.3%) had a higher incidence tendency to hematologic grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs than those in the TC (23.5%) group, but the difference was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.229). There was no evidence that patients with RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 experienced more toxicity or that patients with RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 resulted in less toxicity (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). All the AE grades are presented in Supplementary Table\u0026nbsp;2.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePathological findings and surgical outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;132)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 (n\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 (n\u0026thinsp;=\u0026thinsp;81)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePerineural invasion, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.526\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20 (15.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (17.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (13.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e112 (84.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (82.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (86.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eLymphovascular invasion, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.732\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (11.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (9.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e118 (89.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (88.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73 (90.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eResection margins, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.287\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e126 (95.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (94.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78 (96.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 ( 3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (3.%7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 ( 1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003epCR, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.951\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41 (31.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (30.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e91 (68.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (68.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56 (69.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTRG, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.307\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTRG 1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52 (39.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (39.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (39.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTRG 1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30 (22.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (15.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (27.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTRG 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41 (31.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (39.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (25.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTRG 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 ( 6.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePostop.T, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e82 (40.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (40.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64 (31.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 (31.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3-4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55 (27.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43 (28.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePostop.N, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e140 (69.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100 (66.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61 (30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51 (33.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003epCR: Pathologic complete remission; TRG: Tumor regression grade.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSurgical and pathological outcomes\u003c/h2\u003e \u003cp\u003eAmong the 51 patients in the RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 group, 48 (96%), 1 (2%), and 2 (3.9%) achieved R0, R1, and R2 resections, respectively. Eighty-seven patients (96.6%) in the RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 group achieved R0 resection, and 3 patient (3.4%) achieved R1 resection. Overall, 66 of 201 patients achieved pCR (33.3%). The pCR rate did not differ significantly between the lower- and higher-RDI groups (31.4% vs. 34.5%, P\u0026thinsp;=\u0026thinsp;0.708). No statistically significant intergroup differences were noted in perineural invasion, lymphovascular invasion, resection margins, or pCR rates (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The postoperative complications were not significantly different between the two groups (Supplementary Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eThe pathological response was assessed using the tumor regression grade (TRG) of the Becker criteria. As shown in the Supplementary Table\u0026nbsp;3, 52 (39.4%), 30 (22.7%), 41 (31.1%), and 9 (6.8%) patients had no residual tumor (TRG 1a), \u0026lt; 10% residual tumor per tumor area (TRG 1b), 10\u0026ndash;50% residual tumor per tumor area (TRG 2), and \u0026gt;\u0026thinsp;50% residual tumor per tumor area (TRG 3), respectively. The differences in the TRG scores between the two groups were not statistically significant (P\u0026thinsp;=\u0026thinsp;0.31).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSurvival\u003c/h2\u003e \u003cp\u003eThe median follow-up was 37.29 months in the censored patients. OS and PFS for recurrence in patients grouped according to various average RDI are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. OS was significantly higher in the high group than in the low group when the RDI cut-off points of 0.7 was used. The 3- and 5-year OS was 77.9% (95% CI\u0026thinsp;=\u0026thinsp;0.691\u0026ndash;0.878) and 63% (95% CI\u0026thinsp;=\u0026thinsp;0.511\u0026ndash;0.776) in the RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 group, 57.7% (95% CI\u0026thinsp;=\u0026thinsp;0.446\u0026ndash;0.746) and 51.9% (95% CI\u0026thinsp;=\u0026thinsp;0.373\u0026ndash;0.722) in the RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 group, respectively. The 5-year PFS was 51.1% (95% CI\u0026thinsp;=\u0026thinsp;0.4-0.654) in the higher RDI group and 46.7% (95% CI\u0026thinsp;=\u0026thinsp;0.343\u0026ndash;0.635) in the lower RDI group, respectively. Patients with RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 who were given reduced doses had a worse OS (HR 1.947, 95% CI 1.079\u0026ndash;3.542, P\u0026thinsp;=\u0026thinsp;0.015) and a slightly worse PFS (HR 1.471, 95% CI 0.883\u0026ndash;2.45, P\u0026thinsp;=\u0026thinsp;0.14).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation analyses of RDI and patient characteristics\u003c/h2\u003e \u003cp\u003eWe further explored the association between RDI and patients\u0026rsquo; clinical characteristics. As shown in Supplementary Table\u0026nbsp;4, dose delay was the only factor associated with an RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7. The mean delay time was 3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8. The RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 group average dose-delay time was 4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9, and 60.8% patients experienced dose-delay. The RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 group average dose-delay time was 3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6 (Supplementary Table\u0026nbsp;3). Fifty-one percent patients in the RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 group and 12.3% in the RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 group experienced dose-delay (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003ePatient clinical characteristics such as age, sex, body mass index (BMI), tumor location, and tumor stage were not significantly associated (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, no correlation was found between the RDI and chemoradiation-related AEs such as leukopenia, anemia, neutropenia, nausea, and vomiting (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There was no statistical correlation between the RDI and other surgical and pathological outcomes, such as R0 resection rate, TRG grade, pCR rate, perineural invasion, and lymphovascular invasion (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePreviously, our research group assessed whether the TC regimen was superior to the TP regimen, and demonstrated that the TC regimen was a safe and equivalent alternative to the TP regimen for NCRT in patients with LA-ESCC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. To further explore the effects of the chemotherapy dose, we analyzed 132 patients with complete TC regimen chemotherapy doses and grouped them using a cutoff RDI of 0.7. Our study indicated that patients who received higher doses did not experience more toxicity and those who received lower doses experienced less toxicity. Patients who were administered reduced doses had a worse OS (HR 1.947, 95% CI 1.079\u0026ndash;3.542, P\u0026thinsp;=\u0026thinsp;0.015) and a slightly worse PFS (HR 1.471, 95% CI 0.883\u0026ndash;2.45, P\u0026thinsp;=\u0026thinsp;0.14). The two groups showed no significant differences in perineural invasion, lymphovascular invasion, or resection margins. The relationship between the RDI and short-term efficacy was further analyzed. Dose-delay was the only factor associated with low RDI. To the best of our knowledge, this is the first study to compare the chemotherapy RDI in patients with LA-ESCC undergoing NCRT.\u003c/p\u003e \u003cp\u003eThe importance of RDI in advanced unresectable solid tumors has been well recognized in recent years [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A recent meta-analysis evaluated the impact of the RDI on survival in adult patients with solid tumor cancer receiving non-adjuvant-based chemotherapy regimens. Significantly shorter OS at RDI\u0026thinsp;\u0026lt;\u0026thinsp;80% vs. \u0026ge; 80% and \u0026lt;\u0026thinsp;85% vs. \u0026ge; 85% was observed upon meta-analysis of four carboplatin-based studies for breast, non-small cell lung, or ovarian cancer, and three FOLFOX-/FOLFIRI-/FOLFIRINOX-based studies for colorectal or pancreatic cancer [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The results suggested longer OS with RDI\u0026thinsp;\u0026ge;\u0026thinsp;80% or \u0026ge;\u0026thinsp;85% for both regimens, indicating longer OS with higher-RDI in advanced solid tumors. In our study, the best cut-off value of RDI calculated using the ROC curve was 70%, which was used as the criterion for subgrouping. The RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 group had significantly higher OS than the RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 group. Cox regression analysis further confirmed that the RDI was an independent prognostic factor affecting survival. Therefore, it can be preliminarily deduced that an RDI of 70% can satisfy the balance of survival benefits. Patients with lower-RDI who were administered reduced doses had worse OS (P\u0026thinsp;=\u0026thinsp;0.024). Thus, the results of the current study, as well as earlier studies, suggest that maintaining the RDI has a positive impact on survival.\u003c/p\u003e \u003cp\u003eConsidering patient tolerance, continuation of chemotherapy, and the reduction of chemotherapy-related side effects, dose reduction is commonly used in clinical practice for patients with LA-ESCC receiving NCRT. At present, studies on RDI chemotherapy in NCRT for LA-ESCC are scarce. The impact of the average RDI in neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-NAC) for resectable LA-ESCC has shown that an average RDI of \u0026ge;\u0026thinsp;80% improved prognosis in patients receiving DCF-NAC for ESCC [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. To explore whether the same results were obtained when neoadjuvant radiation was added, we retrospectively analyzed 132 patients with LA-ESCC who underwent radical esophagectomy and lymphadenectomy after NCRT. Our findings indicated that when combined with neoadjuvant chemotherapy and radiotherapy, in patients who had reduced RDI\u0026thinsp;\u0026gt;\u0026thinsp;30%, chemotherapy not only led to significantly worse OS, but also could not decrease the risk of hematologic and non-hematologic AEs.\u003c/p\u003e \u003cp\u003eSeveral factors are associated with chemotherapy RDI. Schraa et al. found that RDI\u0026thinsp;\u0026lt;\u0026thinsp;85% was predicted by patients\u0026rsquo; age, febrile neutropenia, and hypersensitivity reactions to taxanes in patients with breast cancer receiving adjuvant chemotherapy treatment [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A multicenter analysis in the United States demonstrated that malnutrition was an independent predictor of chemotherapy dose reduction due to toxicity [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Ilana et al. retrospectively analyzed 237 patients with breast cancer and found that the RDI was not associated with BMI (P\u0026thinsp;=\u0026thinsp;0.71) or pCR (P\u0026thinsp;=\u0026thinsp;0.31); however, fewer dose delays were associated with pCR (P\u0026thinsp;=\u0026thinsp;0.02) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In our study, we performed a univariate logistic regression model correlation analysis to explore the association between the RDI and patients\u0026rsquo; clinical characteristics. Our results showed that 36 (27.3%) patients experienced dose delays due to personal reasons, whether initiated by the patient or the physician. Dose delay was the only factor associated with RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7; BMI, pCR rate, TRG grade, and chemoradiation-related AEs were not significantly associated with RDI reduction (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Thus, avoiding dose delays can effectively avoid dose intensity reduction.\u003c/p\u003e \u003cp\u003eRDI is a crucial metric for assessing the intensity of chemotherapy. Management of chemotherapy time and avoidance of dose delay across treatment modalities could contribute to the maintenance of a higher RDI and benefit survival in patients with LA-ESCC for NCRT. The chemotherapy dose can be appropriately reduced to ensure the safety profile of NCRT. However, we do not support the policy of reducing chemotherapy doses\u0026thinsp;\u0026gt;\u0026thinsp;30% in patients with LA-ESCC. Dose reductions or delays in the administration of chemotherapy owing to toxicity, or with the intention of avoiding toxicity, lead to a reduction in the dose intensity of treatment and may decrease its therapeutic effect. Avoiding toxicity can cost them months (if not years) of survival.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, this was a retrospective cohort study with potential selection bias compared to prospective randomized controlled studies. In addition, the follow-up duration was relatively short and the median OS was not reached. Moreover, in our cohort, episodes of AEs were underreported, given that this information was not prospectively gathered and that these mild events would not have warranted intervention or a change in treatment. Further large prospective studies with a systematic evaluation of the chemotherapy RDI in patients with LA-ESCC undergoing NCRT are needed.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eRDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eclinical target volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDCF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNAC-neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eESCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eesophageal squamous cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egross tumor volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehazard ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ereceiver operating characteristic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eESCC-locally advanced esophageal squamous cell carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneoadjuvant chemoradiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003epCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epathological complete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRDI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erelative dose intensity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epaclitaxel plus carboplatin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epaclitaxel plus cisplatin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTRG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etumor regression grade\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thanked Professor Jinyi Lang and Professor Tao Li, Department of Radiation Oncology, Sichuan Cancer Hospital \u0026amp; Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China for their general support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the ethical guide-lines of the Helsinki Declaration and was approved by the institutional review board of Sichuan Cancer Hospital \u0026amp; Institute. Written informed consents were obtained from all patients prior to treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients in the study provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated and analyzed in this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Science and Technology Department of Sichuan Province (2020YFH0169, 2023YFS0488 and 2023YFQ0055), Sichuan Province Clinical Key Specialty Construction Project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no confict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLi Jiang: Data collection, statistics, original draft. Jie Zhu: Conceptualization, review and editing the manuscript. Yi Wang: conducted the data analysis and developed the tracking and data collection programs. Xue Chen, Lei Wu, Gang Wan: data collection. Yongtao Han, Xuefeng Leng, Lin Peng: Executed esophagectomy. Qifeng Wang, Lin Peng and Jun Zhang: Monitor the clinical trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003c/strong\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital \u0026amp; Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China; \u003csup\u003e2\u003c/sup\u003eDepartment of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital \u0026amp; Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China. \u003csup\u003e3\u003c/sup\u003eDepartment of Oncology, The Third People\u0026apos;s Hospital of Chengdu, Chengdu, Sichuan, China;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUhlenhopp DJ, Then EO, Sunkara T, Gaduputi V. 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Association of relative dose intensity with BMI and pathologic complete response in patients treated with neoadjuvant chemotherapy for breast cancer. Breast Cancer Res Treat. 2021;186:191\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10549-020-05994-8\u003c/span\u003e\u003cspan address=\"10.1007/s10549-020-05994-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Esophageal cancer (ESCC), Locally advanced esophageal cancer (LA-ESCC), Neoadjuvant chemoradiotherapy (NCRT), Paclitaxel plus carboplatin regimen (TC), Relative dose intensity (RDI), Adverse events (AEs), Overall survival (OS)","lastPublishedDoi":"10.21203/rs.3.rs-3974394/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3974394/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMany patients undergo dose reduction or early termination of chemotherapy to reduce chemoradiotherapy-related toxicity, which may increase their risk of survival. However, this strategy may result in underdosing patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This study aimed to analyze the relationship between the relative dose intensity (RDI) and survival outcomes in patients with LA-ESCC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study assessed patients with LA-ESCC (cT2N\u0026thinsp;+\u0026thinsp;M0, cT3-4NanyM0) receiving neoadjuvant chemoradiotherapy (NCRT) with curative-intent esophagectomy. The patients received 2 courses of paclitaxel plus carboplatin (TC) combination radiotherapy prior to undergoing surgery. During NCRT, RDI was computed, defined as the received dose as a percentage of the standard dose, and the incidence of dose delays was estimated (\u0026ge;\u0026thinsp;7 days in any course cycle). The best RDI cutoff value (0.7) was obtained using ROC curve. The Kaplan-Meier survival curves were compared using the log-rank test, the treatment effect was measured using hazard ratios (HR) and 95% confidence intervals (CI).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe included 132 patients in this study, divided into RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 and RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 groups using cut-off value of 0.7. RDI grade was an independent prognostic factor for OS. Baseline demographic and clinical characteristics were well balanced between the groups. There was no evidence that patients with RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 experienced less toxicity or those with RDI\u0026thinsp;\u0026ge;\u0026thinsp;0.7 resulted in more toxicity. However, patients with RDI\u0026thinsp;\u0026lt;\u0026thinsp;0.7 who were given reduced doses had a worse overall survival [HR 2.058, 95% CI 1.13\u0026ndash;3.74, P\u0026thinsp;=\u0026thinsp;0.015]. The risk of a lower RDI increased with a longer dose delay time (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe RDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival.\u003c/p\u003e","manuscriptTitle":"Reduction in Chemotherapy Relative Dose Intensity Decreases Overall Survival of Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Esophageal Carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-11 19:06:19","doi":"10.21203/rs.3.rs-3974394/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-16T12:57:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-12T06:49:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7a51bdcc-091b-4cac-a6eb-daf12dad8181","date":"2024-04-08T01:05:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-25T18:15:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ebe789cd-874c-4e58-8612-d4f0746c5cf8","date":"2024-03-17T05:37:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-07T13:37:52+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-03-07T13:22:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-06T14:19:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-06T14:19:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-02-21T02:29:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c32ae10f-8f67-4e71-90ca-bd439078236e","owner":[],"postedDate":"March 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T16:13:40+00:00","versionOfRecord":{"articleIdentity":"rs-3974394","link":"https://doi.org/10.1186/s12885-024-12724-6","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2024-08-02 15:57:36","publishedOnDateReadable":"August 2nd, 2024"},"versionCreatedAt":"2024-03-11 19:06:19","video":"","vorDoi":"10.1186/s12885-024-12724-6","vorDoiUrl":"https://doi.org/10.1186/s12885-024-12724-6","workflowStages":[]},"version":"v1","identity":"rs-3974394","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3974394","identity":"rs-3974394","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}