Abstract
Background
Chemoradiotherapy is the standard treatment for esophageal cancer, but the optimal radiation dose remains undetermined. A dose of 50.4 Gy is commonly used in both neoadjuvant and definitive settings. This study evaluates the outcomes of using 50.4 Gy in neoadjuvant chemoradiotherapy (nCRT).
Methods
Patients with esophageal cancer who underwent nCRT with 50.4 Gy radiation followed by surgery between 2010 and 2023 were retrospectively analyzed. They were categorized as achieving pathological complete response (pCR patients) or not (non-pCR patients). Oncological outcomes, including overall survival (OS) and recurrence-free survival (RFS), were assessed.
Results
Among 258 patients treated with nCRT, 96.5% completed the treatment protocol, and 74.4% (n=192) proceeded to surgery. These 192 patients formed the analysis cohort. The overall complication rate was 70.3%, with 19.3% classified as major complications. The 30-day and 90-day postoperative mortality rates were both 0.5%. The pCR rate was 45%. Patients with pCR had a 3-year OS rate of 72.7% and a median survival of 125 months, whereas non-pCR patients had a 3-year OS rate of 49.6% and a median survival of 35 months (p=0.002). Additionally, pCR patients had a 3-year RFS rate of 62.0% and a median RFS of 68 months, compared to 33.6% and 20 months, respectively, for non-pCR patients (p<0.001).
Conclusion
This study reports the outcomes of using 50.4 Gy in nCRT for locally advanced esophageal cancer. The findings affirm the efficacy of 50.4 Gy neoadjuvant chemoradiotherapy in achieving favorable long-term outcomes, particularly among patients with complete pathological response.
Keywords: Definitive chemoradiotherapy, Esophageal neoplasms, Neoadjuvant chemoradiotherapy, Pathological complete response, Esophagectomy
Introduction
Neoadjuvant therapy benefits patients with locally advanced esophageal cancer, as demonstrated by clinical trials such as CROSS [1], CALGB 9781 [2], and OE05 [3], which compared it with upfront surgery. This strategy has become the standard of care. However, the optimal neoadjuvant regimen, particularly the choice of systemic treatment and radiotherapy dose, remains a matter of debate.
The current National Comprehensive Cancer Network guidelines [4] recommend neoadjuvant radiotherapy doses of 41.4–50.4 Gy. Lower doses, such as the 41.4 Gy used in the CROSS and SANO trials, have demonstrated significant benefits. In the CROSS trial, this dose was superior in the neoadjuvant chemoradiation–surgery strategy compared with surgery alone. Similarly, the SANO trial found that this approach enabled organ preservation with non-inferior overall survival (OS) in patients managed with active surveillance rather than surgery [5]. Conversely, a dose of 50.4 Gy is widely used in definitive chemoradiotherapy (dCRT). However, it remains unclear whether a higher dose in the neoadjuvant setting could improve pathological complete response (pCR) rates and survival outcomes, or whether it might adversely affect completion rates for chemoradiation.
In dCRT, studies such as that by Marker et al. [6] compared the outcomes of salvage esophagectomy following dCRT with those of planned surgical resection after neoadjuvant CRT (nCRT) and found comparable OS and disease-free survival (DFS). However, the dCRT group experienced a higher incidence of surgical complications. The JCOG 0909 study [7], along with the ongoing NEEDS trial, has further examined salvage esophagectomy after dCRT with 50–50.4 Gy radiation doses in patients with residual or recurrent locoregional esophageal cancer.
Although a 50.4 Gy dose is permitted in both neoadjuvant and dCRT settings, the outcomes of surgical resection following chemoradiotherapy (CRT) at this radiation level remain insufficiently defined. Therefore, this study aimed to evaluate the clinical outcomes of patients undergoing nCRT with a 50.4 Gy radiation dose followed by surgical resection for locally advanced esophageal cancer.
Methods
The Institutional Review Board (IRB) of Taipei Veterans General Hospital approved this study (IRB-TPEVGH no., 2024-11-008CC). The requirement for informed consent was waived due to the retrospective design, which involved the analysis of previously collected patient data.
Study population
Patient data were retrospectively obtained from a single- center esophageal cancer database maintained by a multidisciplinary tumor board. The study included patients diagnosed with esophageal cancer between 2010 and 2023 who underwent nCRT with a 50.4 Gy radiation dose followed by surgical resection.
Exclusion criteria included patients deemed unsuitable for neoadjuvant therapy; those with cT4b or cM1 disease; patients who underwent upfront surgery without prior CRT; those who received dCRT with or without subsequent salvage surgery; patients treated with nCRT at a radiation dose other than 50.4 Gy; those who failed to complete the planned nCRT regimen; and those who did not undergo the scheduled surgical resection after nCRT.
Eligible patients were categorized based on their pathological response to nCRT: those achieving pCR and those who did not (non-pCR).
Staging
Following the diagnosis of esophageal cancer, all patients underwent comprehensive staging, which included chest computed tomography (CT), upper gastrointestinal endoscopy with endoscopic ultrasound (EUS), and whole-body fluorodeoxyglucose positron emission tomography (FDG-PET/CT). The choice of treatment—upfront surgery, nCRT followed by surgery, or dCRT—was determined by a multidisciplinary tumor board based on staging results and the patient’s overall condition.
Neoadjuvant treatment
Chemotherapy and radiotherapy protocols were tailored by medical and radiation oncologists within the multidisciplinary team. The primary chemotherapy regimen consisted of a 4-day cycle of cisplatin, 5-fluorouracil, and leucovorin administered every 3–4 weeks for 2 cycles. Alternatively, some patients received weekly paclitaxel combined with cisplatin or carboplatin for 5–6 cycles, or other platinum-based chemotherapy regimens.
All patients received external beam radiotherapy delivered via intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). Target volumes were contoured slice by slice on treatment-planning CT images with a 5-mm slice thickness. The gross tumor volume encompassed the primary tumor and enlarged locoregional lymph nodes, as identified on CT or PET-CT. The clinical target volume included a radial margin of 5–7 mm around the gross tumor volume and a cranio-caudal margin of 3–5 cm, along with elective nodal regions determined by tumor location. Elective nodal regions comprised the supraclavicular fossa and paraesophageal regions for proximal thoracic tumors; paraesophageal regions for middle thoracic tumors; and paraesophageal, left gastric, and celiac axis regions for distal thoracic tumors. The planning target volume was defined as the clinical target volume plus 5–7 mm to account for respiratory motion and positioning variability. Radiation was delivered in daily fractions of 1.8 Gy to a total dose of 50.4 Gy. Dose constraints for organs at risk were as follows: heart mean dose <30 Gy, V40Gy ≤50%; lung V20Gy ≤25%, mean lung dose <20 Gy; and spinal cord maximum dose ≤45 Gy.
Surgical resection
Restaging was performed after completion of nCRT using chest CT, EUS, and FDG-PET/CT. Surgical resection was offered to patients demonstrating a favorable response to nCRT and was performed within 4–8 weeks of treatment completion.
The surgical procedures included McKeown esophagectomy, Ivor Lewis esophagectomy, or total gastrectomy, selected according to tumor location and histology. Reconstruction routes were determined by the surgical approach and surgeon preference: for McKeown esophagectomy, either the substernal or posterior mediastinal route was used; for Ivor Lewis esophagectomy, the posterior mediastinal route was standard; and for total gastrectomy, reconstruction was performed via an intra-abdominal approach. Anastomotic sites corresponded to the surgical method: cervical for McKeown, intrathoracic for Ivor Lewis, and intra-abdominal for total gastrectomy.
During the study period, minimally invasive esophagectomy was the standard approach at our institution. Conversion to open thoracotomy or laparotomy was occasionally necessary due to intraoperative bleeding, dense adhesions, or tumor invasion into adjacent vital structures.
Pathological evaluation
pCR was defined as the absence of residual tumor cells in both the primary site and regional lymph nodes (ypT0N0). Patients with residual pathological disease or positive resection margins were classified as non-pCR.
Outcomes
The primary outcomes were OS and recurrence-free survival (RFS). OS was defined as the time from curative surgery to the last follow-up or death from any cause. RFS was measured from the date of surgery to the date of cancer recurrence, death, or last follow-up without recurrence. Survival and recurrence data were collected up to October 2024. Recurrence was confirmed histologically by tissue biopsy or clinically by multidisciplinary review.
Statistical analyses
The Shapiro-Wilk test was used to assess the normality of continuous variables. Depending on distribution, comparisons were made using either the t-test or the Mann- Whitney U test. Categorical variables were analyzed using the Pearson chi-square or Fisher exact test, as appropriate.
Kaplan-Meier survival curves were generated for OS and RFS, and differences between groups were evaluated using the log-rank test. Statistical analyses were conducted with R software ver. 4.1.1 (http://www.r-project.org/). A p-value <0.05 was considered statistically significant.
Results
Treatment results of nCRT with 50.4 Gy radiation dose
During the study period, 258 patients were diagnosed with esophageal cancer and underwent nCRT with a radiation dose of 50.4 Gy, as illustrated in Fig. 1. Among them, 249 patients (96.5%) completed the full course of nCRT, while 9 patients did not.
Fig. 1.
Flowchart of treatment completion and pathological response in patients with esophageal cancer treated with neoadjuvant chemoradiotherapy (nCRT) at a dose of 50.4 Gy and subsequent surgical resection. pCR, pathological complete response.
In total, 192 patients (74.4%) completed both nCRT and surgical resection and were included in the final analysis. Of these, 87 patients (45.3%) achieved pCR, while the remaining 105 patients (54.7%) had residual disease. Interval metastasis was identified in 8.9% of patients, including 16 with distant disease detected during restaging who did not undergo surgery, and 7 with pathologically confirmed metastases (ypM1) at the time of resection.
Patient and tumor characteristics
The characteristics of these 192 patients are summarized in Table 1. The mean patient age was 60 years, and 84% were male. The majority (91.7%) had an Eastern Cooperative Oncology Group performance status of 0. Tumors were most commonly located in the lower esophagus (46.4%), followed by the middle (35.9%) and upper (17.7%) esophagus. Squamous cell carcinoma was the predominant histology (93.8%), with adenocarcinoma accounting for 4.7%, and the remainder comprising other malignancies. Most patients (71%) presented with clinical stage III disease.
Table 1.
Patient demographics, clinicopathological characteristics in esophageal cancer and recurrence patterns
| Characteristic | Overall | Non-pCR | pCR | p-value |
|---|---|---|---|---|
| No. of patients | 192 | 105 | 87 | |
| Age (yr) | 60.03±7.87 | 59.89±7.83 | 60.21±7.96 | 0.779a) |
| Sex | 0.447b) | |||
| Male | 162 (84.4) | 91 (86.7) | 71 (81.6) | |
| Female | 30 (15.6) | 14 (13.3) | 16 (18.4) | |
| ECOG | 0.056b) | |||
| 0 | 176 (91.7) | 94 (89.5) | 82 (94.3) | |
| 1 | 14 (7.3) | 11 (10.5) | 3 (3.4) | |
| 2 | 2 (1.0) | 0 (0.0) | 2 (2.3) | |
| Smoking | 0.118b) | |||
| No | 40 (20.8) | 17 (16.2) | 23 (26.4) | |
| Yes | 152 (79.2) | 88 (83.8) | 64 (73.6) | |
| Alcohol consumption | 0.732b) | |||
| No | 43 (22.4) | 25 (23.8) | 18 (20.7) | |
| Yes | 149 (77.6) | 80 (76.2) | 69 (79.3) | |
| Betel nuts | 1b) | |||
| No | 124 (64.6) | 68 (64.8) | 56 (64.4) | |
| Yes | 68 (35.4) | 37 (35.2) | 31 (35.6) | |
| Location | 0.514b) | |||
| Upper | 34 (17.7) | 16 (15.2) | 18 (20.7) | |
| Middle | 69 (35.9) | 37 (35.2) | 32 (36.8) | |
| Lower | 89 (46.4) | 52 (49.5) | 37 (42.5) | |
| Histology | 0.096b) | |||
| Squamous | 180 (93.8) | 95 (90.5) | 85 (97.7) | |
| Adenocarcinoma | 9 (4.7) | 7 (6.7) | 2 (2.3) | |
| Others | 3 (1.6) | 3 (2.9) | 0 (0.0) | |
| Clinical stage | ||||
| cT | 0.148b) | |||
| 1 | 3 (1.6) | 1 (1.0) | 2 (2.3) | |
| 2 | 19 (9.9) | 6 (5.7) | 13 (14.9) | |
| 3 | 167 (87.0) | 96 (91.4) | 71 (81.6) | |
| 4 | 3 (1.6) | 2 (1.9) | 1 (1.1) | |
| cN | 0.669b) | |||
| 0 | 21 (10.9) | 13 (12.4) | 8 (9.2) | |
| 1 | 78 (40.6) | 40 (38.1) | 38 (43.7) | |
| 2 | 71 (37.0) | 38 (36.2) | 33 (37.9) | |
| 3 | 22 (11.5) | 14 (13.3) | 8 (9.2) | |
| cM | NA | |||
| 0 | 192 (100.0) | 105 (100.0) | 87 (100.0) | |
| Clinical stage | 0.693b) | |||
| II | 31 (16.1) | 16 (15.2) | 15 (17.2) | |
| III | 137 (71.4) | 74 (70.5) | 63 (72.4) | |
| IV | 24 (12.5) | 15 (14.3) | 9 (10.3) | |
| Operation | 0.656b) | |||
| McKeown | 173 (90.1) | 94 (89.5) | 79 (90.8) | |
| Ivor-Lewis | 18 (9.4) | 10 (9.5) | 8 (9.2) | |
| Total gastrectomy | 1 (0.5) | 1 (1.0) | 0 (0.0) | |
| Pathological stage | ||||
| yp T stage | <0.001b) | |||
| 0 | 97 (50.5) | 10 (9.5) | 87 (100.0) | |
| 1 | 26 (13.5) | 26 (24.8) | 0 (0.0) | |
| 2 | 25 (13.0) | 25 (23.8) | 0 (0.0) | |
| 3 | 32 (16.7) | 32 (30.5) | 0 (0.0) | |
| 4 | 12 (6.2) | 12 (11.4) | 0 (0.0) | |
| yp N stage | <0.001b) | |||
| 0 | 148 (77.1) | 61 (58.1) | 87 (100.0) | |
| 1 | 33 (17.2) | 33 (31.4) | 0 (0.0) | |
| 2 | 8 (4.2) | 8 (7.6) | 0 (0.0) | |
| 3 | 3 (1.6) | 3 (2.9) | 0 (0.0) | |
| yp M stage | 0.017c) | |||
| 0 | 185 (96.4) | 98 (93.3) | 87 (100.0) | |
| 1 | 7 (3.6) | 7 (6.7) | 0 (0.0) | |
| Pathological grade | <0.001b) | |||
| Not accessed | 103 (53.6) | 16 (15.2) | 87 (100.0) | |
| Well | 2 (1.0) | 2 (1.9) | 0 (0.0) | |
| Moderate | 77 (40.1) | 77 (73.3) | 0 (0.0) | |
| Poor | 10 (5.2) | 10 (9.5) | 0 (0.0) | |
| Margin | 0.001b) | |||
| R0 | 177 (92.2) | 90 (85.7) | 87 (100.0) | |
| R1 | 8 (4.2) | 8 (7.6) | 0 (0.0) | |
| R2 | 7 (3.6) | 7 (6.7) | 0 (0.0) | |
| Lymphovascular invasion | <0.001b) | |||
| No | 166 (86.5) | 80 (76.2) | 86 (98.9) | |
| Yes | 26 (13.5) | 25 (23.8) | 1 (1.1) | |
| Perineural invasion | <0.001b) | |||
| No | 168 (87.5) | 81 (77.1) | 87 (100.0) | |
| Yes | 24 (12.5) | 24 (22.9) | 0 (0.0) | |
| Tumor regression grades | <0.001b) | |||
| Grade 0 | 95 (49.5) | 11 (10.5) | 84 (96.6) | |
| Grade 1 | 27 (14.1) | 27 (25.7) | 0 (0.0) | |
| Grade 2 | 60 (31.2) | 60 (57.1) | 0 (0.0) | |
| Grade 3 | 5 (2.6) | 5 (4.8) | 0 (0.0) | |
| NA | 5 (2.6) | 2 (1.9) | 3 (3.4) | |
| Extracapsular tumor extension | <0.001b) | |||
| No | 167 (87.0) | 80 (76.2) | 87 (100.0) | |
| Yes | 22 (11.5) | 22 (21.0) | 0 (0.0) | |
| NA | 3 (1.6) | 3 (2.9) | 0 (0.0) | |
| Patterns of recurrence | 0.002b) | |||
| No recurrence | 114 (59.4) | 51 (48.6) | 63 (72.4) | |
| Local | 18 (9.4) | 16 (15.2) | 2 (2.3) | |
| Distant | 33 (17.2) | 21 (20.0) | 12 (13.8) | |
| Both | 27 (14.1) | 17 (16.2) | 10 (11.5) |
Values are presented as mean±standard deviation or number (%).
pCR, pathological complete response; ECOG, Eastern Cooperative Oncology Group performance status; NA, not avialable.
a)By t-test. b)By chi-square test. c)By Fisher exact test.
Regarding surgical procedures, 90.1% underwent McKeown esophagectomy, 9.4% underwent Ivor Lewis esophagectomy, and 0.5% underwent total gastrectomy. No significant differences were observed between the pCR and non-pCR groups with respect to demographic variables, tumor characteristics, or surgical methods.
Postoperative morbidity and mortality
Following nCRT with a 50.4 Gy radiation dose and subsequent surgical intervention, both the 30-day and 90-day postoperative mortality rates were 0.5%. The overall complication rate was 70.3%. Anastomotic leakage was the most common complication, occurring in 18.8% of patients and classified as type I (3.6%), type II (10.9%), and type III (4.2%). Other frequent complications included pleural effusion requiring drainage (27.1%), vocal cord palsy confirmed clinically or via laryngoscopy (15.1%), and anastomotic stenosis requiring single or multiple dilatations (18.8%) (Table 2). Major complications (Clavien-Dindo grade ≥III) occurred in 19.3% of patients. These included injection laryngoplasty for vocal cord palsy (n=13), laparotomy for intestinal obstruction within 3 months post-surgery (n=2), wound debridement (cervical or abdominal), tracheostomy (one case due to pneumonia and 2 due to vocal cord palsy), thoracic duct ligation (n=2), and decortication with or without stent placement for thoracic anastomotic leakage, among others.
Table 2.
Postoperative complications (n=192)
| Complication | No. (%) |
|---|---|
| All complications | 135 (70.3) |
| Major complications (Clavien–Dindo grade ≥III) | 37 (19.3) |
| Pleural effusiona) | 52 (27.1) |
| Anastomotic stenosisb) | 36 (18.8) |
| Vocal cord palsyc) | 29 (15.1) |
| Anastomotic leakd) | 36 (18.8) |
| Type I | 7 (3.6) |
| Type II | 21 (10.9) |
| Type III | 8 (4.2) |
| Pneumonia | 19 (9.9) |
| Chylothorax | 12 (6.2) |
| Wound complicationse) | 12 (6.2) |
| Respiratory failure | 6 (3.1) |
| Gastrointestinal complicationsf) | 4 (2.1) |
| Postoperative bleedingg) | 2 (1.0) |
a)Pleural effusion requiring drainage. b)Narrowing at the anastomosis site necessitating 1 or more endoscopic balloon dilatations. c)Diagnosed based on clinical presentation or endoscopic findings. d)Categorized based on the Esophagectomy Complications Consensus Group (ECCG) classification. e)Include surgical site infection, wound dehiscence, and delayed wound healing requiring local wound care or surgical revision. f)Gastrointestinal complications including postoperative feeding jejunostomy-related intestinal obstruction, pancreatic leakage, or chyloascites, confirmed by imaging or reoperation. g)Postoperative bleeding requiring surgical re-exploration for hemostasis.
Survival analysis
Univariate and multivariate Cox regression analyses were performed to identify prognostic factors for OS (Fig. 2) and RFS (Fig. 3). Multivariate analysis showed that tumor location in the lower third of the esophagus was independently associated with improved OS (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.32–0.85; p=0.008) and RFS (HR, 0.51; 95% CI, 0.34–0.79; p=0.002) compared to tumors located in the upper or middle third. Achieving pCR independently predicted favorable OS (HR, 0.56; 95% CI, 0.34–0.93; p=0.024) and RFS (HR, 0.52; 95% CI, 0.33–0.81; p= 0.004). Conversely, the presence of distant metastases at pathological staging (ypM1) was an independent predictor of poorer RFS (HR, 3.73; 95% CI, 1.49–9.29; p=0.004) compared to patients without metastases (ypM0).
Fig. 2.
Forest plots illustrating prognostic factors for overall survival. (A) Univariable Cox regression analysis, displaying hazard ratios (HRs) with 95% confidence intervals (CIs) and associated p-values for clinical, pathological, and treatment-related variables. (B) Multivariable Cox regression analysis, showing adjusted HRs for variables identified as significant (p<0.1) in the univariable analysis. ECOG, Eastern Cooperative Oncology Group performance status; SCC, squamous cell carcinoma; PFL, cisplatin + 5-fluorouracil + leucovorin; pCR, pathological complete response.
Fig. 3.
Forest plots illustrate prognostic factors for recurrence-free survival. (A) Univariable Cox regression analysis, displaying hazard ratios (HRs) with 95% confidence intervals (CIs) and associated p-values for clinical, pathological, and treatment-related variables. (B) Multivariable Cox regression analysis, showing adjusted HRs for variables identified as significant (p<0.1) in the univariable analysis. ECOG, Eastern Cooperative Oncology Group performance status; SCC, squamous cell carcinoma; PFL, cisplatin + 5-fluorouracil + leucovorin; pCR, pathological complete response.
The median follow-up period was 26 months. pCR patients demonstrated significantly better OS than non-pCR patients (p=0.002). The 3-year OS rate for the pCR group was 72.7% (95% CI, 62.9%–83.9%) with a median survival of 125 months, compared to 49.6% (95% CI, 39.6%–62.2%) and a median survival of 35 months in the non-pCR group.
RFS was also significantly higher in the pCR group (p<0.001). The 3-year RFS rate was 62.0% (95% CI, 51.7%–74.3%) with a median RFS of 68 months in the pCR group, compared to 33.6% (95% CI, 24.9%–45.4%) and a median RFS of 20 months in the non-pCR group (Fig. 4).
Fig. 4.
Kaplan-Meier curves comparing overall survival (A) and recurrence-free survival (B) in pathological complete response (pCR, blue) and non-pCR (red) patients.
Recurrence patterns
During follow-up, recurrence occurred in 27.6% of pCR patients and 51.4% of non-pCR patients. The distribution of recurrence patterns differed significantly between groups (p=0.002). In pCR patients, the most common patterns were distant metastasis (13.8%) and simultaneous local and distant recurrence (11.5%), while isolated local recurrence occurred in only 2 patients (2.3%).
In non-pCR patients, the most frequent pattern was distant recurrence (20.0%), followed by local recurrence (15.2%) and simultaneous local and distant recurrence (16.2%) (Table 1).
Discussion
This study highlights the clinical outcomes of preoperative CRT with a 50.4 Gy radiation dose followed by surgery, showing a completion rate of 74.4% and a pCR rate of 45.3%. Median OS in patients achieving pCR (125 months) was significantly longer than in non-pCR patients (35 months). Similarly, median RFS was markedly greater in pCR patients (68 months) compared with non-pCR patients (20 months).
To contextualize these findings, we compared the outcomes of pCR patients in our cohort with patients who achieved clinical complete response (cCR) in other studies investigating preoperative CRT followed by active surveillance (Table 3). We also compared non-pCR patient outcomes with results from studies examining salvage surgery after dCRT for esophageal cancer (Table 4).
Table 3.
Outcomes of studies on complete responders to preoperative chemoradiation therapy followed by active surveillance in esophageal cancer
| Study | Study types | No. of patients | Histology | Chemotherapy | Radiation dose (Gy) | Outcomes | |
|---|---|---|---|---|---|---|---|
|
| |||||||
| After diagnosis/start of treatment | After surgery/active surveillance | ||||||
| This study | Retrospective cohort | 87a) | SCC (85); AC (2) | Primary PFL | 50.4 | 1-year OS (96.5%); 3-year OS (76.0%); mOS (129 m) | 1-year OS (90.6%); 3-year OS (72.7%); mOS (125 m); 1-year RFS (81.4%); 3-year RFS (62.0%); mRFS (68 m) |
| SANO [5] | Clinical trial (CRT + f/u vs. CRT + S) | 198b) | SCC (47); AC (147); other (4) | TC | 41.4 | NA | mOS (43 m); 2-year OS (74%); mDFS (35 m) |
| ESOPRESSO [8] | Clinical trial (CRT + f/u vs. CRT + S) | 18b) | SCC (18) | XP | 50.4 | mOS (not reached); mPFS (25.6 m) | 2-year DFS (42.7%); mDFS (21.7 m) |
| Jeong et al. [10] | Retrospective cohort (CRT + f/u vs. CRT + S) | 31b) | SCC (31) | XP | 54 | 2-year OS (61.3%); 2-year DFS (47.3%) | NA |
| Castoro et al. [23] | Retrospective cohort (CRT + f/u vs. CRT + S) | 38b) | SCC (38) | Primary FP | 45–50.4 | 5-year OS (57%) | 5-year DFS (34.6%) |
| van der Wilk et al. [9] | Retrospective cohort (CRT + f/u vs. CRT + S, matched) | 29b) | SCC (22); AC (7) | TC | 41.4 | 1-year OS (100%); 3-year OS (77%); mOS (not reached); 1-year PFS (100%); 3-year PFS (60%); mPFS (39.5) | NA |
Chemotherapy regimens: FP, 5-fluorouracil + cisplatin; PFL, cisplatin + 5-fluorouracil + leucovorin; TC, paclitaxel + carboplatin; XP, capecitabine + cisplatin.
SCC, squamous cell carcinoma; AC, adenocarcinoma; OS, overall survival; mOS, median overall survival; RFS, recurrence-free survival; mRFS, median recurrence-free survival; CRT, chemoradiotherapy; f/u, follow-up (active surveillance); S, surgery; NA, not available; mDFS, median disease-free survival; mPFS, median progression-free survival; DFS, disease-free survival; PFS, progression-free survival.
a)Number of pathological complete responders to chemoradiation therapy, followed by surgical resection. b)Number of clinical complete responders to chemoradiation therapy, managed with active surveillance without surgical intervention.
Table 4.
Outcomes of studies on salvage surgery following definitive chemoradiation therapy in esophageal cancer
| Study | Study type | No. of patientsa) | Histology | Chemotherapy | Radiation dose (Gy) | Salvage indicationsb) | Surgery | Outcomes | |
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| After diagnosis/enrollment | After surgery | ||||||||
| This study | Retrospective cohort | 105 (192) | SCC (95); AC (7); others (3) | Primary PFL | 50.4 | RES (pathology proved) (105) | E (85.7% R0) | 1-year OS (89.3%); 3-year OS (54.8%); mOS (40 m) | 1-year OS (79.8%); 3-year OS (49.6%); mOS (35 m); 1-year RFS (61.6%); 3-year RFS (33.6%); mRFS (20 m) |
| RTOG 0246 | Clinical trial (dCRT +-S) | 17 (41) | SCC/AC | PPF | 50.4 | RES (17) | SE | 1-year OS (88.2%); 3-year OS (47.1%) | NA |
| Markar et al. [6] | Retrospective cohort (nCRT +S vs. dCRT +S) | 234 (308) | SCC (144); AC (85); others (5) | FP | 50 (range, 25–75) | RES (234) | SE (86.3% R0) | NA | 3-year OS (39.1%); 3-year DFS (35.4%) |
| Miyata et al. [13] | Retrospective cohort (dCRT +S) | 116 (227) | SCC (116) | FP; TF | 56.8±5.6 | RES (116) | SE (83% R0) | NA | 3-year OS (33.7%); 5-year OS (28.0%) |
| Watanabe et al. [24] | Retrospective cohort (dCRT +S) | 43 (63) | SCC (63) | FP (51); nil (12) | 60 (range, 50–70) | RES (43); REC (20) | SE (73% R0) | NA | 3-year OS (29.8%); 5-year OS (15.0%) |
| JCOG0909 [7] | Clinical trial (dCRT +-S) | 12 (25) | SCC (25) | FP | 50.4 | RES (13); REC (12) | SE (21 [76% R0]); lymphadenectomy (4) | NA | 1-year OS (72%); 3-year OS (33.5%); 5-year OS (22.3%); OS (2.4 yr) |
| JCOG9906 [12] | Clinical trial (dCRT +-S) | 4 (11) | SCC (11) | FP | 60 | RES (4); REC (7) | SE (10 [70% R0]); no resection (1) | 3-year OS (40%); mOS (16.7 m) | NA |
| NEEDS [11] (ongoing) | Clinical trial (nCRT +S vs. dCRT +-S) | NA (600) | SCC (600) | TC; FP; FOLFOX | 50–50.4 | RES (NA); REC (NA) | SE | NA | NA |
| Marks et al. [25] | Retrospective cohort (nCRT +S vs. dCRT +S) | 9 (65) | AC (65) | NA | 50±4 | RES (9); REC (56) | SE (90.8% R0) | NA | 3y-OS (48%); 5-year OS (32%); mOS (32 m) |
Chemotherapy regimens: FP, 5-fluorouracil + cisplatin; PFL, cisplatin + 5-fluorouracil + leucovorin; PPF, paclitaxel + cisplatin + 5-fluorouracil; TC, paclitaxel + carboplatin; TF, docetaxel + 5-fluorouracil.
SCC, squamous cell carcinoma; AC, adenocarcinoma; RES, residual; E, esophagectomy; OS, overall survival; mOS, median overall survival; RFS, recurrence-free survival; mRFS, median recurrence-free survival; dCRT, definitive chemoradiotherapy; S, surgery; SE, salvage esophagectomy; NA, not available; nCRT, neoadjuvant chemoradiation therapy; DFS, disease-free survival; REC, recurrence.
a)The numbers represent the number of patients who underwent surgery for residual tumors (all patients in the study). The numbers in bold indicate the total number of patients included in the outcome analysis. b)Salvage indications for patients assessed in the outcome analysis.
The 50.4 Gy radiation dose used here is at the higher end of neoadjuvant protocols and may enhance treatment efficacy. Emerging evidence suggests that patients achieving cCR may not require immediate surgery, supporting organ-preserving strategies. In our cohort, pCR outcomes can be compared with cCR results from other trials. In the ESOPRESSO randomized trial [8], which examined esophagectomy in cCR patients after chemoradiotherapy, the reported cCR rate (44.2%) closely matched our pCR rate. OS was similar between active surveillance and surgery groups in both intent-to-treat and as-treated analyses, but DFS showed a trend favoring surgery (2-year DFS: 66.7% surgical vs. 42.7% surveillance; p=0.262). Notably, the median DFS for cCR patients in the ESOPRESSO surveillance arm (21.7 months) was considerably shorter than the median RFS for our surgically treated pCR patients (68 months). This suggests a potential benefit of radical surgery in prolonging disease-free intervals, even among complete responders.
Findings from the SANO trial [5], which used carboplatin/paclitaxel with 41.4 Gy radiation, showed a 2-year OS of 74% in the surveillance group and 71% in the surgery group, with a median DFS of only 35 months for the surveillance arm. By comparison, our pCR cohort achieved a 3-year OS of 73.7% and a median RFS of 68 months, further supporting both the role of curative surgery and the possible benefits of a higher radiation dose during nCRT [5]. Several retrospective studies have compared active surveillance with surgery in complete CRT responders. In a multicenter study, van der Wilk et al. [9] found comparable outcomes between surgical and nonsurgical cCR patients treated with carboplatin/paclitaxel and 41.4 Gy, but their reported median progression-free survival (39.5 months) was still shorter than our pCR median RFS. Similarly, Jeong et al. [10] studied stage II–IV ESCC patients receiving dCRT (median 50 Gy) and found a 2-year DFS of 47.3% in metabolic complete responders—again lower than the 3-year RFS of 62.0% for our pCR patients (Table 3).
The 50.4 Gy dose is also widely used in dCRT protocols, where the need for salvage surgery in residual disease remains debated. The ongoing NEEDS trial is comparing dCRT with observation (surgery only upon progression) against standard nCRT followed by surgery [11]. Our non-pCR group—treated with 50.4 Gy CRT and immediate surgery—provides a benchmark for interpreting these results. Previous trials have evaluated salvage surgery after dCRT. The Japanese JCOG9906 and JCOG0909 trials, using 60 Gy and 50.4 Gy respectively for ESCC, reported cCR rates of 62.2% and 58.5%. Salvage surgery in residual/recurrent disease achieved 3-year OS rates of 40% (JCOG9906) and 33.5% (JCOG0909) [7,12]. The RTOG 0246 trial, which included both ESCC and adenocarcinoma, reported 1- and 3-year OS rates of 88.2% and 47.1% in salvage surgery patients—comparable to the 89.3% and 54.8% 3-year OS in our non-pCR group. These findings support salvage surgery as a viable option for residual disease immediately after CRT rather than deferring surgery until recurrence.
Retrospective data also support these findings. Miyata et al. [13] reported a 3-year OS of 33.7% in patients treated with 5-follow-up, cisplatin or docetaxel, and high-dose radiation (mean: 56.8±5.6 Gy), which is lower than the 49.6% seen in our non-pCR group. Likewise, Markar et al. [6] studied 234 patients treated with 5-follow-up/cisplatin and a median radiation dose of 50 Gy, reporting 3-year OS and DFS rates of 39.1% and 35.4%, which are comparable to our non-pCR 3-year RFS (33.6%) but lower than our 3-year OS (49.4%) (Table 4). Collectively, these findings indicate that salvage surgery after 50.4 Gy CRT may be an optimal strategy for selected patients with locally advanced esophageal cancer.
Concerns remain about the potential impact of high-dose radiation on postoperative morbidity. In our cohort, the overall complication rate was 70.3%, with major complications in 19.3% of patients. A comparative study by Pai et al. [14] evaluating cisplatin/5-fluorouracil CRT protocols with 45.0 Gy versus 50.4 Gy found no significant difference in surgical morbidity, suggesting modest dose escalation may not increase operative risk. In contrast, the JCOG1109 NExT trial [15], comparing neoadjuvant chemotherapy alone with chemotherapy plus 41.4 Gy radiotherapy, found that while adding radiotherapy improved pCR rates, it did not enhance OS and was associated with higher rates of pulmonary complications and non-cancer mortality. Overall, these data imply that while higher radiation doses can improve pathological response, survival benefits may be limited, and risks must be weighed carefully.
Our study also found that tumors in the lower thoracic esophagus had more favorable outcomes compared with those in the upper or middle esophagus. This advantage may be related to the use of advanced radiation techniques, including IMRT and VMAT, which allow improved dose conformity and homogeneity while reducing exposure to the heart and lungs. Kole et al. [16] demonstrated that IMRT significantly reduced heart and right coronary artery dose compared with 3-dimensional (3D)-CRT, with mean heart dose, V30Gy, and right coronary artery dose markedly lower in IMRT plans. This dosimetric advantage may translate into fewer clinical complications. Lin et al. [17] reported significantly reduced postoperative complications and shorter hospital stays for patients treated with IMRT or proton therapy compared with 3D-CRT, while other retrospective studies have linked IMRT with better OS and locoregional control [18,19]. VMAT, an advanced IMRT variant, provides comparable or superior dosimetry to IMRT [20,21], although few studies have directly compared clinical outcomes. A retrospective MD Anderson study found that VMAT improved OS, reduced nCRT-related toxicity, and lowered postoperative complication rates [22]. In our series, postoperative rates of pneumonia (9.9%), wound complications (6.2%), and anastomotic leakage (18.8%) were consistent with the literature, and the low incidence of cardiac toxicity may reflect the benefits of these advanced radiotherapy techniques.
This study has several limitations. First, its retrospective design inherently introduces selection bias. Patients who completed nCRT and proceeded to surgery may have had better baseline performance status and higher treatment compliance, potentially influencing overall outcomes. Additionally, non-pCR patients who underwent surgery may have achieved partial responses to nCRT, which could have contributed to more favorable survival results. Second, the use of pCR as the primary endpoint differs from the cCR classification commonly applied in active surveillance studies. Because cCR is determined clinically, it may include patients with microscopic residual disease who would not meet pCR criteria. This distinction in classification limits the validity of direct comparisons between studies evaluating surgical and nonsurgical management strategies.
In conclusion, in this retrospective, single-center observational study, nCRT with a 50.4 Gy radiation dose achieved a completion rate of 96.5%, with 74.4% of patients proceeding to surgery. Interval metastases occurred in 8.9% of patients. Among those who underwent esophagectomy, 45% achieved pCR. Median RFS was 68 months for pCR patients and 20 months for non-pCR patients. These results support the efficacy of 50.4 Gy neoadjuvant chemoradiotherapy in producing favorable long-term outcomes, particularly in patients with complete pathological response.
Acknowledgments
The authors acknowledge all members in the multidisciplinary esophageal cancer tumor board.
Funding Statement
Funding No financial support was received from any institution or organization for the study.
Article information
Author Contributions
Conceptualization: CSH, HSH, PKH. Data curation: CL, YPH, TYL, LIC. Formal analysis: CL. Methodology: CL, YPH, TYL, PKH. Investigation: CL, LIC. Resources: MHC, PIH, LIC, CSH, HSH. Validation: PKH. Visualization: CL. Software: CL. Funding acquisition: not applicable. Project administration: PKH. Supervision: CSH, HSH, PKH. Writing–original draft: CL. Writing–review & editing: PKH. Approval of final manuscript: all authors.
Conflict of interest
No potential conflict of interest relevant to this article was reported.
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