Characteristics of Patients
This study included 120 patients in the esophagectomy group and 36 patients in the CRT group. Among them, 21 and 11 elderly patients were included in the esophagectomy and CRT groups, respectively (Supplementary Fig. 1). The esophagectomy and CRT groups had similar patients' characteristics, except clinical tumor depth (SM2/3: 84.2% in the esophagectomy group vs. 61.1% in the CRT group, P = 0.005) (Table 1). Synchronous stage 0 or I ESCC at diagnosis was detected in 18 patients in the esophagectomy group (15.0%) and five patients in the CRT group (13.9%). Only two patients in the esophagectomy group had history of previous treatment with endoscopic resection for pathological T1a ESCC.
Table 1
Baseline patient characteristics
| All patients (n = 156) | | Elderly patients (n = 32) |
| Esophagectomy (n = 120) n, % | CRT (n = 36) n, % | P values | Esophagectomy (n = 21) n, % | CRT (n = 11) n, % |
Age, year (median, range) | 67 (46–87) | 70 (38–85) | 0.360* | 78 (75–87) | 77 (75–85) |
Sex Male Female | 96 (79.7) 24 (20.3) | 32 (88.8) 4 (11.1) | 0.322** | 20 (95.2) 1 (4.8) | 9 (81.8) 2 (18.2) |
ECOG PS 0 1 2 | 105 (87.5) 11 (9.2) 4 (3.3) | 33 (91.7) 1 (2.8) 2 (5.6) | 0.391*** | 16 (76.1) 5 (23.8) 0 | 10 (90.9) 1 (9.1) 0 |
Tumor location Ut Mt Lt | 12 (10.0) 61 (50.8) 47 (39.2) | 4 (11.1) 26 (72.2) 6 (16.7) | 0.067*** | 3 (14.3) 10 (47.6) 8 (38.1) | 1 (9.1) 8 (72.7) 2 (18.2) |
Clinical tumor depth MM/SM1 SM2/SM3 | 19 (15.8) 101 (84.2) | 14 (38.9) 22 (61.1) | 0.005** | 2 (9.5) 19 (90.5) | 6 (54.5) 5 (45.5) |
Horizontal location ≤ 3/4 >3/4 | 74 (61.7) 46 (38.3) | 17 (47.2) 19 (52.8) | 0.129** | 15 (71.4) 6 (28.6) | 5 (45.5) 6 (54.5) |
Intramural metastasis | 3 (2.5) | 2 (5.6) | 0.326** | 1 (4.8) | 1 (9.1) |
History of treatment for ESCC | 2 (1.7) | 0 | 1.000** | 0 | 0 |
Synchronous other ESCC at diagnosis | 18 (15.0) | 5 (13.9) | 1.000** | 2 (9.5) | 0 |
Synchronous other cancer at diagnosis | 16 (13.3) | 3 (8.3) | 0.567** | 3 (14.3) | 0 |
Comorbidity Cardiovascular Respiratory Diabetes mellites Brain disease | 57 (47.5) 13 (10.8) 16 (13.3) 9 (7.5) | 13 (36.1) 2 (5.6) 5 (13.9) 2 (5.6) | 0.256** 0.523** 1.000** 1.000** | 16 (76.2) 2 (9.5) 4 (19.0) 2 (9.5) | 6 (54.5) 2 (18.2) 1 (9.1) 0 |
*Student t-test, **Fisher's exact test, ***chi-square test, Esophagectomy vs. CRT in all patients. CRT: Chemoradiotherapy; ECOG PS: Eastern Cooperative Oncology Group performance status; ESCC: esophageal squamous cell carcinoma; Lt: lower thoracic esophagus; MM: muscularis mucosae; Mt: Middle thoracic esophagus; SM: submucosa; Ut, upper thoracic esophagus. |
Table 2
Treatment details in patients with esophagectomy (A) and CRT (B)
A. Esophagectomy |
| All patients (n = 120) | Elderly patients (n = 21) | P values |
n (%) | n (%) |
Esophagectomy with a 3 FL Esophagectomy with a 2 FL Esophagectomy with 1 FL or others | 110 (91.7) 2 (1.7) 8 (6.7) | 15 (71.4) 1 (4.8) 5 (23.8) | 0.026* |
Open esophagectomy Thorascopic esophagectomy Transhiatal esophagectomy | 8 (6.7) 104 (86.7) 8 (6.7) | 0 16 (76.2) 5 (23.8) | 0.026* |
Resection margin R0 R1 | 118 (98.3) 2 (1.7) | 21 (100.0) 0 | 1.000** |
* Chi-square test, ** Fisher's exact test, All patients vs. Elderly patients. FL: field lymphasectomy |
Table 3
Complications in patients with esophagectomy (A) and CRT (B)
B. CRT |
| All patients (n = 36) | Elderly patients (n = 11) | P values* |
n (%) | n (%) |
Concurrent chemotherapy regimen 5-FU + platinum 5-FU alone | 34 (94.4) 2 (5.6) | 10 (90.9) 1 (9.1) | 0.560 |
Treatment modality X-ray Proton | 21 (58.3) 15 (41.7) | 6 (54.5) 5 (45.5) | 1.000 |
Radiation dose 50.4 Gy 60 Gy | 16 (44.4) 20 (55.6) | 5 (45.5) 6 (54.5) | 1.000 |
Response to treatment Complete remission Residual disease | 33 (91.7) 3 (8.3) | 11 (100.0) 0 | 1.000 |
* Fisher's exact test, All patients vs. Elderly patients. CRT: Chemoradiotherapy; 5-FU: 5-fluorouracil. |
A. Esophagectomy | | | |
| All patients (n = 120) | Elderly patients (n = 21) | P values* |
n (%) | n (%) |
Early complication Any RL nerve paralysis Anastomotic leakage Surgical site infection Pneumonia Lymphorrhea Chylothorax Ileus Bleeding Pneumothorax Late complication Any Esophageal stenosis Ileus Bleeding | 72 (60.0) 22 (18.3) 15 (12.5) 9 (7.5) 7 (5.8) 6 (5.0) 4 (3.3) 3 (2.5) 2 (1.7) 2 (1.7) 31 (25.8) 26 (21.7) 3 (2.5) 2 (1.7) | 14 (66.7) 4 (19.0) 1 (4.8) 4 (19.0) 3 (14.3) 1 (4.8) 0 0 0 1 (4.8) 8 (38.1) 6 (28.6) 0 0 | 0.634 1.000 0.467 0.106 0.171 1.000 1.000 1.000 1.000 0.386 0.292 0.572 1.000 1.000 |
* Fisher's exact test, All patients vs. Elderly patients. RL nerve: Recurrent laryngeal nerve |
Treatment details
Treatment details and pathological outcomes in patients who received esophagectomy are shown in Table 2A and Supplementary Table 1. Esophagectomy with three-field lymphadenectomy was performed in 110 patients (91.7%). Post-operative histological findings revealed that 86 patients (71.7%) had pathological T1N0M0 disease, and 34 patients (28.3%) had a pathological non-T1N0M0 disease. Thirty-two patients (26.7%) had LN metastasis, and six patients (5.0%) had deeper tumor depth (four patients had both LN metastasis and deeper tumor). Although most of the patients achieved complete resection (R0), two patients (1.7%) had microscopic residual disease (R1). After esophagectomy, six patients with non-T1N0M0 disease underwent adjuvant chemotherapy.
Treatment details in the CRT group are shown in Table 2B. Concurrent chemoradiotherapy was performed for all patients. Thirty-four patients (94.4%) received the 5-FU plus platinum combination regimen. In addition, 21 patients (58.3%) received X-ray therapy, and 15 patients (41.7%) received proton beam therapy. Total doses of 60 Gy or Gy equivalents and 50.4 Gy were delivered to 20 patients and 16 patients, respectively. Post-treatment endoscopic evaluation showed that 33 patients (91.7%) achieved complete remission, while three patients (8.3%) had residual disease. All three patients with residual diseases underwent additional salvage treatment (ESD in two patients and esophagectomy in one patient).
Safety
Post-operative complications in the esophagectomy group are shown in Table 3A. Seventy-two patients (60.0%) had early complications; the main common complications were recurrent laryngeal nerve paralysis (22 patients, 18.3%), anastomotic leakage (15 patients, 12.5%), and surgical site infection (9 patients, 7.5%). Esophageal stenosis was the most frequent (26 patients, 21.7%) late complication. There was no post-operative mortality within 30 days of esophagectomy.
Adverse events in the CRT group are shown in Table 3B and Supplementary Table 2. Most of the patients experienced hematologic adverse events; particularly, grade 3 or higher leucopenia and neutropenia were observed in nine patients (25.0%). Esophagitis was observed in 31 patients (86.1%); it was the most common early toxicity. Radiation-related late toxicities including pleural effusion, pericardial fluid accumulation, and irradiation pneumonitis were observed in six (16.7%), four (11.1%), and three (8.3%) patients, respectively.
Efficacy
With a median follow-up period of 71.8 months (72.8 months in esophagectomy group and 70.8 months in CRT group) with Kaplan-Meier estimate, the 5y-PFS was 77.0% in the esophagectomy group and 74.4% in the CRT group, with no significant difference between the two groups (P = 0.48) (Fig. 1A). The 5y-OS was 81.5% in the esophagectomy group and 82.6% in the CRT group, with no significant difference between the two groups (P = 0.89) (Fig. 1B). The results of univariate and multivariate analysis for PFS and OS with clinical factors are shown in supplementary table 4 and 5. Particularly, according to the clinical tumor invasion depth, which was based on clinical factors between the treatment groups, the 5y-PFS and OS in patients with cSM2/SM3 disease tend to be worse compared to those with MM/SM1 (5y-PFS, 87.9% vs. 73.4%; 5y-OS, 90.6% vs. 79.5%) (Supplementary Fig. 2). However, even in multivariate analysis, the adjusted hazard ratio of CRT was 1.299 (95%CI [0.627–2.689], p = 0.48) for PFS and 1.007 for OS (95%CI [0.438–2.315], p = 0.99), respectively; there was no significant difference in efficacy between esophagectomy and CRT. In the CRT group, the 3y- and 5y-survival rates with esophageal preservation were 80.4% and 76.9%, respectively.
Treatments after recurrence
During the follow-up period, 21 patients (17.5%) in the esophagectomy group and nine patients (25.0%) in the CRT group experienced disease recurrence. The details of recurrence sites and additional treatments are shown in Table 4 and Supplementary Table 3. The rates of local recurrence (0% vs. 2.8%), regional LN metastasis (5.8% vs. 8.3%), and distant metastasis (11.7% vs. 13.9%) were similar between the esophagectomy and CRT groups; however, bone metastasis (n = 5) was observed only in the esophagectomy group. Among the 30 patients with recurrence, salvage surgery was performed in three of 21 patients in the esophagectomy group (14.3%) and five of nine patients in the CRT group (55.5%), and their recurrence site was regional LN (n = 4), lung (n = 3), and local (n = 1) recurrence. Salvage CRT was performed in five of 21 patients in the esophagectomy group (23.8%), and all of them had regional LN recurrence. In each group, palliative chemotherapy was selected in four patients who had recurrence in distant LN, lung, and liver. Particularly, nine of 21 patients in the esophagectomy group received best supportive care (BSC) alone after recurrence due to their poor general condition. There were no significant differences in the recurrence rates between the two treatment groups; however, BSC alone was selected more frequently in the esophagectomy group (P = 0.029).
Table 4
Details about recurrence sites and additional treatments
| All patients (n = 156) | Elderly patients (n = 32) |
| Esophagectomy (n = 120) n (%) | CRT (n = 36) n (%) | Esophagectomy (n = 21) n (%) | CRT (n = 11) n (%) |
Recurrence | 21 (17.5) | 9 (24.3) | 5 (23.8) | 1 (9.1) |
Recurrence site Local recurrence Regional lymph node Distant metastasis | 0 7 (5.8) 14 (11.7) | 1 (2.8) 3 (8.3) 5 (13.9) | 0 2 (9.5) 3 (14.3) | 0 1 (9.1) 0 |
Additional treatment after recurrence Salvage surgery Salvage CRT Palliative chemotherapy BSC alone | 3 (14.3) 5 (23.8) 4 (19.0) 9 (42.9) | 5 (55.5) 0 4 (44.4) 0 | 1 (20.0) 1 (20.0) 0 3 (60.0) | 1 (100.0) 0 0 0 |
CRT: Chemoradiotherapy; BSC: best supportive care. |
Safety and efficacy in elderly patients
Among a total of 32 elderly patients, 21 patients underwent esophagectomy and 11 patients received CRT. The rate of clinical SM2/3 tumor was higher in esophagectomy group than that in CRT group (90.5% vs.45.5%, P = 0.01). In the esophagectomy group, the rate of three-field lymphadenectomy in elderly patients was lower than that in the total population (71.4% vs. 91.7%, P = 0.026) and the rate of transhiatal esophagectomy was higher (23.8% vs. 6.7%, P = 0.026) (Table 2A). On the contrary, details of treatment modality and radiation doses in the CRT group were similar between elderly patients and all patients (Table 2B). In the safety profile, there were no significant differences in the frequency of post-operative complications in the esophagectomy group (Table 3A) and the frequency of adverse events in the CRT group between all patients and elderly patients, although pleural effusion after CRT tended to be higher in elderly patients (Table 3B). The 5y-PFS was 72.3% and 81.8% (HR 0,55; 95% CI, 0.14–2.13) and the 5y-OS was 76.9% and 81.8% (HR 0,68; 95% CI, 0.16–2.81) in the esophagectomy group and the CRT group, respectively (Fig. 2). After adjusting the clinical tumor depth on Cox regression analysis, there were still no statistical differences between the esophagectomy and CRT groups in the survival outcomes; PFS, adjusted HR = 0.34, 95%CI [0.061–1.856], p = 0.211; OS, adjusted HR = 0.32, 95%CI [0.044–2.243], p = 0.249.