Abstract
Introduction
The chemotherapy and immunotherapy combination is currently the primary strategy to treat metastatic esophageal squamous cell carcinoma (ESCC). Neoadjuvant chemoimmunotherapy (NCIT) is being intensively investigated for treating locally advanced ESCC.
Objective
We compared the efficacy and safety of NCIT and neoadjuvant chemoradiotherapy (NCRT) to treat locally advanced ESCC.
Methods
We included 214 locally advanced ESCC patients who were administered neoadjuvant therapy from May 2014 to April 2022. The patients were grouped according to two neoadjuvant protocols (NCIT and NCRT) routinely used at our institution. Perioperative findings, pathological results, and survival data were compared between the two groups by conducting unmatched and 1:1 propensity score matching (PSM) analyses.
Results
Following 1:1 PSM analysis of the confounders, 66 patients were allocated to each of the two groups. Time span between neoadjuvant therapy completion and esophagectomy was significantly longer after NCRT than that after NCIT (47.1 ± 13.2 days vs. 34.7 ± 8.8 days; p < 0.001). The NCIT group exhibited significantly greater number of harvested lymph nodes than the NCRT group (33.6 ± 12.7 vs. 21.7 ± 10.2; p < 0.001). The pathological complete response and major pathological response rates were similar between the two groups [NCIT group: 25.8% (17/66) and 62.1% (41/66), respectively; NCRT group: 27.3% (18/66) and 56.1% (37/66), respectively (p > 0.05)]. The overall incidence of pneumonia, anastomotic leakage, or postoperative complications did not differ significantly between the two groups. The 2‐year cumulative overall survival rates and the 2‐year disease‐free survival rates of the NCIT and NCRT groups were 80.2% and 62.2%, respectively (p = 0.029) and 70.0% and 50.8%, respectively (p = 0.023).
Conclusion
In locally advanced ESCC patients, short‐term survival after NCIT is superior to that after NCRT, with similar perioperative and pathological outcomes.
Keywords: chemoradiotherapy, esophageal squamous cell carcinoma, immunotherapy, neoadjuvant therapy
1. INTRODUCTION
Esophageal cancer (EC), the seventh frequent malignant tumor globally, ranks sixth in cancer‐related death, and approximately 604,100 new EC cases and 544,076 deaths due to EC were reported in 2021. 1 Esophageal squamous cell carcinoma (ESCC) is often detected in Eastern Asian countries, including China, while adenocarcinoma shows a higher prevalence in North America and Europe.
In the past two decades, the treatment approach for ESCC in China has changed from single modality to multimodality, which includes preoperative chemoradiotherapy or chemotherapy; this change has significantly improved patients' survival. In the CROSS study containing 23% patients with ESCC, the 5‐ and 10‐year overall survival (OS) rates after neoadjuvant chemoradiotherapy (NCRT) were 61.0% and 46%, respectively; these rates were remarkably higher than those of patients receiving surgery alone (30% and 23%, respectively). 2 Furthermore, the median OS rates of the NCRT and surgery‐alone groups in the NEOCRTEC 5010 study were 100.1 and 66.5 months, respectively. 3 Based on these studies, the current standard therapeutic approach is NCRT with subsequent surgery for locally advanced ESCC.
Despite this established approach, locoregional and distant recurrence continues to adversely affect the survival of ESCC patients for a longer term, even after multimodality therapy. 2 The recurrence rate in the NEOCRTEC 5010 study following a median follow‐up period of 38.4 months was 33.7%, with distant metastasis and local recurrence rates of 19.6% and 9.8%, respectively, for patients receiving NCRT. 4 These high failure rates prompted our group and other research groups to assess new treatment approaches for locally advanced ESCC.
According to recent studies, compared to chemotherapy alone, the combination treatment involving immunotherapy and chemotherapy can substantially enhance the progression‐free survival and OS of advanced ESCC patients. 5 , 6 , 7 , 8 , 9 This combination is currently recommended as the primary treatment approach for metastatic and advanced ESCC. Applying chemotherapy and immunotherapy combination in the neoadjuvant chemoimmunotherapy (NCIT) is a novel and promising treatment modality. 10 Based on several phase II studies, NCIT is both effective and safe for treating locally advanced ESCC. 11 , 12 , 13 A meta‐analysis involving 815 patients in 27 clinical trials revealed the average pathological complete response (pCR) rate and the average rate of treatment‐related adverse events as 31.4% and 26.9%, respectively. 14 Despite these encouraging outcomes, this new approach requires further validation.
The present retrospective study used propensity score matching (PSM) analysis to compare the treatment efficacy and safety of NCIT and NCRT for patients with locally advanced ESCC. Moreover, the perioperative outcomes and pathological responses were compared between these two groups, together with comparison of short‐term survival by utilizing the follow‐up data.
2. PATIENTS AND METHODS
2.1. Patients and surgical procedure
The Institutional Review Board of Tianjin Medical University Cancer Institute and Hospital granted approval to the study (no. bc2023135). All patients provided their informed consent to participate in the study. The study enrolled patients treated with neoadjuvant therapy and esophagectomy from May 2014 to April 2022 at our cancer center. Prior to the start date, neoadjuvant therapy was not routinely used in our institution. The surgical procedures and preoperative evaluation are reported earlier. 15 For the present study, the inclusion criteria were (1) patients administered NCIT or NCRT, (2) patients who were diagnosed to have ESCC, and (3) patients who underwent three‐incision esophagectomy (McKeown procedure). The exclusion criteria were (1) patients with non‐SCC pathology, (2) patients receiving Ivor‐Lewis surgery due to insufficient lymph node dissection, and (3) patients who received preoperative chemotherapy alone.
For patients who underwent NCRT, radiotherapy (40–41.4 Gy, 20–23 fractions, dose: 1.8–2.0 Gy per fraction, frequency: 5 days/week) combined with chemotherapy was used. Chemotherapy regimens included the combination of a platinum agent and docetaxel, paclitaxel, or fluorouracil. The docetaxel plus cisplatin (TP) regimen included docetaxel (30 mg/m2 IV Q1W) or paclitaxel (50 mg/m2 IV Q1W) and platinum‐based drugs (nedaplatin or cisplatin: 25 mg/m2 IV Q1W; carboplatin: AUC 2 Q1W). The cisplatin plus fluorouracil regimen comprised platinum‐based drugs (75 mg/m2 IV Q3W) and 5‐fluorouracil (800 mg/m2 IV Q3W). The radiation dose was calculated based on intensity‐modulated radiotherapy validated by cone‐beam CT or image‐guided radiotherapy. Gross tumor volume (GTV) included the enlarged locoregional lymph nodes as well as the esophageal tumor. Clinical target volume (CTV) represented a 3 cm distal and proximal margin and a 6 mm radial margin around the GTV for including the subclinical involvement area. Planning target volume was estimated as a 5 mm margin around the CTV to compensate tumor movement and methodological variations. For the organs at risk, the following dose constraints were considered: lung V20 <30%, mean lung dose <18 Gy, heart V30 <40%, and spinal cord maximum dose <45 Gy.
Different immune checkpoint inhibitors inhibiting programmed cell death protein 1 (PD‐1) or PD‐1 ligand 1 (PD‐L1) were used as immunotherapeutic agents in combination with chemotherapeutic agents for the NCIT group. All patients who underwent NCIT were participating in clinical trials. 16 , 17 , 18 The surgical procedures included lymph node dissection, transthoracic esophageal dissection, construction of the gastric tube, stomach mobilization, and left cervical esophagogastric anastomosis. Open, video‐assisted, and robotic‐assisted minimally invasive esophagectomy techniques were used. The technical specifics of the surgical procedure are described previously. 15 , 19
2.2. Data collection
The following data were collected: demographic data; cT, cN, and cTNM stage; neoadjuvant treatment data: NCIT protocols, radiotherapy dose, and chemotherapy regimens; interval between neoadjuvant therapy and surgery; surgical details (modality, blood loss, and operative time); postoperative hospital stay duration; postoperative mortality and morbidity rates; pathological data; and follow‐up data. The number of harvested lymph nodes was recorded from pathological reports. Major pathological response (MPR) was estimated to be ≤10% residual viable tumor in the primary lesion. Tumor regression grade (TRG) for esophageal tumor was estimated as follows: T1, no residual tumor; T2, residual tumor ≤10%; T3, residual tumor ≤50%; T4, residual tumor <100%; and T5, no tumor regression. The duration from incision to final closure was determined as the operative time, which also included time for body repositioning during the operation. OS was estimated as the period between neoadjuvant therapy initiation date to the date of death from any cause. Those patients who survived were censored at the last follow‐up date. The period between the surgery date and disease recurrence or death date was considered disease‐free survival (DFS). Disease recurrence was outlined as locoregional (regional lymph nodes or esophageal bed) or distant (distant organs [lungs, liver, brain, and bone] or distant lymph nodes). The Esophagectomy Complication Consensus Group criteria were followed to evaluate all major complications. 20 The Tumor‐Node‐Metastasis Staging System 8th edition developed by the American Joint Committee on Cancer was used to stage all patients. 21
2.3. Study endpoint
The primary study endpoints were short‐term survival, including 2‐year DFS and OS. The secondary endpoints were perioperative and pathological outcomes, including postoperative morbidity and mortality and pathological response.
2.4. Statistical analysis
Categorical variables were expressed as frequencies (%) and assessed by Fisher's exact test or the chi‐square test. Continuous variables were represented by mean ± standard deviation and assessed by Wilcoxon rank‐sum test or unpaired student's t‐test. A balanced cohort was formed using the available explanatory factors with the PSM approach. The original sample sizes for the patient pool were 136 and 78 for the NCRT and NCIT groups, respectively. The sample size available after matching was 66 for each group. Propensity scores were estimated by the logistic regression model. PSM (a 1:1 match for the NCIT and NCRT groups) was conducted blindly with a caliper distance of 0.1 and no replacement for adjusting identifiable factors that might influence the results, including age; sex; KPS score; smoking and drinking history; comorbidities; tumor location; and clinical T, N, and M stages. The Kaplan–Meier method was utilized for plotting OS and DFS curves, and the log‐rank test was used for comparing the curves. Statistical significance was considered at a two‐sided p < 0.05. All statistical analyses were conducted with SPSS version 25 for Windows (IBM SPSS Statistics, USA).
3. RESULTS
3.1. Patient demographics
The study included 214 patients with locally advanced ESCC (Figure 1). After 1:1 PSM, 132 patients were obtained (66 per group). Table 1 shows the characteristics of unmatched and matched patients.
FIGURE 1.
Study flow chart. A total of 214 patients were included in the present study, including 78 patients who received NCIT and 136 patients who received NCRT followed by surgery.
TABLE 1.
Demographics variables.
| All patients n = 214 (%) | Before matching | After matching | |||||
|---|---|---|---|---|---|---|---|
| NCIT, n = 78 (%) | NCRT, n = 136 (%) | p * | NCIT, n = 66 (%) | NCRT, n = 66 (%) | p * | ||
| Age, years, mean ± SD | 59.7 ± 7.3 | 60.9 ± 7.3 | 59.1 ± 7.2 | 0.077 | 60.2 ± 7.3 | 58.2 ± 7.3 | 0.121 |
| Sex ratio (M:F) | 189:25 | 66:12 | 123:13 | 0.202 | 59:7 | 59:7 | 1.000 |
| Smoking (n, %) | 162 (75.7) | 55 (70.5) | 107 (78.7) | 0.180 | 48 (72.7) | 51 (77.3) | 0.546 |
| Drinking (n, %) | 160 (74.8) | 55 (70.5) | 105 (77.2) | 0.278 | 49 (74.2) | 53 (80.3) | 0.406 |
| KPS score | 88.7 ± 5.0 | 87.9 ± 5.2 | 89.1 ± 4.9 | 0.105 | 88.6 ± 4.9 | 89.4 ± 4.6 | 0.913 |
| Comorbidity | |||||||
| Hypertention | 53 (24.9) | 20 (26.0) | 33 (24.3) | 0.782 | 17 (25.8) | 17 (25.8) | 1.000 |
| Diabetes | 19 (8.9) | 9 (11.5) | 10 (7.4) | 0.300 | 8 (12.1) | 6 (9.1) | 0.572 |
| CHD | 7 (3.3) | 1 (1.3) | 6 (4.4) | 0.426 | 1 (1.5) | 1 (1.5) | 1.000 |
| Tumor location | |||||||
| 20–25 cm | 9 (4.2) | 4 (5.1) | 5 (3.7) | 0.682 | 4 (6.1) | 2 (3.0) | 0.393 |
| >25 and ≤30 cm | 92 (43.0) | 31 (39.7) | 61 (44.9) | 25 (37.9) | 32 (48.5) | ||
| >30 cm | 113 (52.8) | 43 (55.1) | 70 (51.5) | 37 (56.1) | 32 (48.5) | ||
| cT stage | |||||||
| T1 | 3 (1.4) | 3 (4.0) | 0 | <0.001 | 2 (3.0) | 0 | 0.131 |
| T2 | 3 (1.4) | 0 | 3 (2.2) | 0 | 3 (4.5) | ||
| T3 | 142 (66.4) | 68 (87.2) | 74 (54.4) | 57 (86.4) | 59 (89.4) | ||
| T4 | 66 (31.3) | 7 (9.3) | 59 (43.4) | 7 (10.6) | 4 (6.1) | ||
| cN stage | |||||||
| N0 | 30 (14.3) | 10 (13.5) | 20 (14.7) | 0.339 | 9 (13.6) | 9 (13.6) | 0.293 |
| N1 | 103 (48.1) | 36 (46.2) | 67 (49.3) | 30 (45.5) | 34 (51.5) | ||
| N2 | 70 (33.3) | 30 (40.5) | 40 (29.4) | 25 (37.9) | 17 (25.8) | ||
| N3 | 11 (5.2) | 2 (2.7) | 9 (6.6) | 2 (3.0) | 6 (9.1) | ||
| cTNM stage | |||||||
| II | 17 (7.9) | 7 (9.0) | 10 (7.4) | <0.001 | 6 (9.1) | 10 (15.2) | 0.559 |
| III | 122 (57.0) | 62 (79.5) | 60 (44.1) | 51 (77.3) | 47 (71.2) | ||
| IV | 75 (35.0) | 9 (11.5) | 66 (48.5) | 9 (13.6) | 9 (13.6) | ||
*p<0.05 was considered as statistical significance.
3.2. Neoadjuvant therapy
Sixty‐two (79.5%) patients received pembrolizumab. Most patients (62/78, 79.5%) completed three cycles of NCIT. The majority of patients underwent concurrent NCRT (100/136, 73.5%). Paclitaxel+Platinum (TP)/Docetaxel+Platinum (DP) (110/136, 80.9%) was mainly administered as the chemotherapy regimen in the NCRT group (Table 2).
TABLE 2.
Details of NCIT and NCRT.
| NCIT | n = 78 (%) | NCRT | n = 136 (%) |
|---|---|---|---|
| Immunotherapy | Radiotherapy | ||
| Pembrolizumab | 62 (79.5) | Concurrent | 100 (73.5) |
| Camrelizumab | 7 (9.0) | Sequential | 11 (8.1) |
| Sintilimab | 6 (7.7) | Concurrent/sequential | 22 (16.2) |
| Toripalimab | 1 (1.3) | Radio doze | |
| Tislelizumab | 1 (1.3) | <4000 | 4 (2.9) |
| Durvalumab | 1 (1.3) | 4000–4600 | 128 (94.1) |
| Chemotherapy | >4600 | 4 (2.9) | |
| Paclitaxel+Cisplatin, TP | 71 (91.0) | Chemotherapy | |
| Docetaxel+Cisplatin or Nedaplatin, DP | 5 (6.5) | TP/DP | 110 (80.9) |
| Docetaxel+Cisplatin+Fluorouracil, DCF | 1 (1.3) | FP | 10 (7.4) |
| Paclitaxel+Cisplatin+Fluorouracil, TCF | 1 (1.3) | Others | 16 (11.8) |
3.3. Surgery
All patients underwent lymph node dissection and 3‐incision McKeown esophagectomy. After matching for baseline characteristics, the NCIT group had more patients who underwent robot‐assisted esophagectomy than the NCRT group (83.3% vs. 18.1%, p < 0.001). The time from completion of neoadjuvant therapy to surgery was significantly longer for the NCRT group (47.1 ± 13.2 days) than for the NCIT group (34.7 ± 8.8 days) (p < 0.001). Moreover, the NCIT group had significantly higher number of harvested lymph nodes than the NCRT group (33.6 ± 12.7 vs. 21.7 ± 10.2, p < 0.001).
3.4. Postoperative complications
Table 3 shows morbidity characteristics following esophagectomy in the matched and unmatched groups. The groups did not differ significantly in the incidence of total postoperative complications, either before matching (20.5% vs. 30.1%, p = 0.125) or after matching (21.2% vs. 31.8%, p = 0.168). Anastomotic leakage occurred in 3 (3.8%) and 17 (12.5%) patients in the NCIT and NCRT groups (p = 0.036), respectively, before matching. After matching, the NCIT and NCRT groups showed 3 and 7 leakages, respectively, with no significant difference (p = 0.188).
TABLE 3.
Perioperative outcomes between NCIT and NCRT group.
| All patients n = 214 (%) | Before matching | After matching | |||||
|---|---|---|---|---|---|---|---|
| NCIT, n = 78 (%) | NCRT, n = 136 (%) | p * | NCIT, n = 66 (%) | NCRT, n = 66 (%) | p * | ||
| Surgical procedure | |||||||
| Open | 44 (20.6) | 3 (3.8) | 41 (30.1) | <0.001 | 3 (4.5) | 20 (30.3) | <0.001 |
| MIE | 75 (35.0) | 10 (12.8) | 65 (47.8) | 8 (12.1) | 34 (51.5) | ||
| Robot‐assisted MIE | 95 (44.4) | 65 (83.3) | 30 (22.1) | 55 (83.3) | 12 (18.1) | ||
| Operation time, min, mean ± SD | 313.0 ± 60.5 | 315.8 ± 60.0 | 311.4 ± 61.0 | 0.615 | 319.3 ± 63.2 | 308.9 ± 58.1 | 0.341 |
| Surgical blood loss, ml, mean ± SD | 180.3 ± 106.0 | 165.7 ± 143.2 | 189.0 ± 75.2 | 0.133 | 172.9 ± 149.7 | 185.9 ± 86.1 | 0.555 |
| Surgical interval | 43.0 ± 12.6 | 35.2 ± 9.0 | 47.6 ± 12.1 | <0.001 | 34.7 ± 8.8 | 47.1 ± 13.2 | <0.001 |
| Lymph node harvest, mean ± SD | 25.8 ± 12.6 | 34.4 ± 12.5 | 23.8 ± 21.1 | <0.001 | 33.6 ± 12.7 | 21.7 ± 10.2 | <0.001 |
| Hospital stay, days, mean ± SD | 20.5 ± 18.5 | 14.8 ± 10.7 | 23.8 ± 21.1 | 0.001 | 14.8 ± 11.0 | 24.7 ± 23.6 | 0.002 |
| ICU stay, n (%) | 13 (6.1) | 3 (3.8) | 10 (7.4) | 0.383 | 3 (4.5) | 3 (4.6) | 1.000 |
| Overall complications | 57 (26.6) | 16 (20.5) | 41 (30.1) | 0.125 | 14 (21.2) | 21 (31.8) | 0.168 |
| RLN paralysis | 5 (2.3) | 4 (5.1) | 1 (0.7) | 0.060 | 4 (6.1) | 1 (1.5) | 0.365 |
| Pulmonary complication | 18 (8.4) | 5 (6.4) | 13 (9.6) | 0.424 | 4 (6.1) | 4 (6.1) | 1.000 |
| Anastomotic leakages | 20 (9.3) | 3 (3.8) | 17 (12.5) | 0.036 | 3 (4.5) | 7 (10.6) | 0.188 |
| Chylothorax | 8 (3.7) | 2 (2.6) | 6 (4.4) | 0.713 | 1 (1.5) | 4 (6.1) | 0.365 |
| irAEs | 2 (0.9) | 2 (2.6) | 0 | – | 2 (2.9) | 0 | – |
| rrAEs | 1 (0.5) | 0 | 1 (0.7) | – | 0 | 1 (1.2) | – |
| 30‐day mortality | 2 (0.9) | 1 (1.3) | 1 (0.7) | 1.000 | 0 | 0 | – |
| 90‐day mortality | 7 (3.3) | 3 (3.9) | 4 (2.8) | 0.707 | 1 (1.5) | 1 (1.5) | 1.000 |
*p<0.05 was considered as statistical significance.
3.5. Pathological response
Among the 78 patients receiving NCIT, 47 (60.3%) and 20 (25.6%) patients exhibited MPR for primary tumor and pCR (ypT0N0), respectively. Among the 136 patients who underwent NCRT, 76 (55.9%) and 38 patients (27.9%) showed MPR and pCR, respectively. The NCIT and NCRT groups did not differ in terms of MPR, pCR, and TRG before or after PSM (p > 0.05; Table 4).
TABLE 4.
Pathological Response between NCIT and NCRT group.
| All patients n = 214 (%) | Before matching | After matching | |||||
|---|---|---|---|---|---|---|---|
| NCIT, n = 78 (%) | NCRT, n = 136 (%) | p * | NCIT, n = 66 (%) | NCRT, n = 66 (%) | p * | ||
| pT stage | |||||||
| T0 | 81 (37.9) | 31 (39.7) | 50 (36.8) | 0.093 | 26 (39.4) | 25 (37.9) | 0.202 |
| T1 | 28 (13.1) | 16 (20.5) | 12 (8.8) | 13 (19.7) | 5 (7.6) | ||
| T2 | 32 (15.0) | 10 (12.8) | 22 (16.2) | 10 (15.2) | 11 (16.7) | ||
| T3 | 55 (25.7) | 17 (21.8) | 38 (27.9) | 15 (22.7) | 19 (28.8) | ||
| T4 | 18 (8.4) | 4 (5.1) | 14 (10.3) | 2 (3.0) | 6 (9.1) | ||
| pN stage | |||||||
| N0 | 126 (58.9) | 38 (48.7) | 88 (64.7) | <0.001 | 33 (50.0) | 41 (62.1) | <0.001 |
| N1 | 59 (27.6) | 22 (28.2) | 37 (27.2) | 17 (25.8) | 21 (31.8) | ||
| N2 | 15 (7.0) | 15 (19.2) | 0 | 14 (21.2) | 0 | ||
| N3 | 14 (6.5) | 3 (3.8) | 11 (8.1) | 2 (3.0) | 4 (6.1) | ||
| ypTNM stage | |||||||
| I | 95 (44.4) | 33 (42.3) | 62 (45.6) | 0.008 | 29 (43.9) | 29 (43.9) | 0.333 |
| II | 23 (10.7) | 4 (5.1) | 19 (14.0) | 4 (6.1) | 9 (13.6) | ||
| III | 75 (35.0) | 37 (47.4) | 38 (27.9) | 30 (45.5) | 23 (34.8) | ||
| IV | 21 (9.8) | 4 (5.1) | 17 (12.5) | 3 (4.5) | 5 (7.6) | ||
| pCR (ypT0N0) | 58 (27.1) | 20 (25.6) | 38 (27.9) | 0.716 | 17 (25.8) | 18 (27.3) | 0.844 |
| MPR | 123 (57.5) | 47 (60.3) | 76 (55.9) | 0.533 | 41 (62.1) | 37 (56.1) | 0.479 |
| TRG | |||||||
| 1 | 85 (39.7) | 35 (44.9) | 50 (36.8) | 0.668 | 31 (47.0) | 25 (37.9) | 0.763 |
| 2 | 38 (17.8) | 12 (15.4) | 26 (19.1) | 10 (15.2) | 12 (18.2) | ||
| 3 | 21 (9.8) | 8 (10.3) | 13 (9.6) | 7 (10.6) | 6 (9.1) | ||
| 4 | 20 (9.3) | 5 (6.4) | 15 (11.0) | 4 (6.1) | 7 (10.6) | ||
| 5 | 50 (23.4) | 18 (23.1) | 32 (23.5) | 14 (21.2) | 16 (24.2) | ||
*p<0.05 was considered as statistical significance.
3.6. Survival
Eleven patients were lost to follow‐up (9 and 2 patients in the NCRT and NCIT groups, respectively). The median follow‐up duration was 33 months (range: 4–96 months) and 27 months (range: 3–43 months) in the NCRT and NCIT groups, respectively. Before PSM, the cumulative 1‐ and 2‐year OS rates were 85.5% and 77.5% for the NCIT group and 87.2% and 66.9% for the NCRT group, respectively (log‐rank test, p = 0.140) (Figure 2A). As shown in Figure 2B, after matching, the 1‐ and 2‐year cumulative OS rates were 86.9% and 80.2% for the NCIT group and 88.3% and 62.2% for the NCRT group, respectively (log‐rank test, p = 0.029). Seven patients died due to other causes during the follow‐up period (1 from depression, 3 from acute myocardial infarction and heart failure, 1 from intestinal obstruction due to colon cancer at 2 years after esophageal surgery, 1 from trauma, and 1 from cholangitis), the 1‐ and 2‐year disease‐specific survival was 86.9% and 81.8% in the NCIT group and 88.3% and 63.5% in the NCRT group, respectively (log‐rank test, p = 0.043).
FIGURE 2.
Overall survival (OS). (A) Before propensity score matching (PSM), the cumulative 1 and 2‐year OS rates were 85.5% and 77.5% in the NCIT group and 87.2% and 66.9% in the NCRT group, respectively (log‐rank test, p = 0.140). (B) After matching, the 1 and 2‐year cumulative OS rates were 86.9% and 80.2% in the NCIT group and 88.3% and 62.2% in the NCRT group, respectively (log‐rank test, p = 0.029).
Before matching, the 1‐ and 2‐year DFS rates were 78.9% and 68.2% in the NCIT group and 66.7% and 53.6% in the NCRT group, respectively (log‐rank test, p = 0.051) (Figure 3A). After matching, these rates were 81.3% and 70.0% in the NCIT group and 63.3% and 50.8% in the NCRT group, respectively (log‐rank test, p = 0.023) (Figure 3B).
FIGURE 3.
Disease‐free survival (DFS). (A) Before propensity score matching (PSM), the cumulative 1 and 2‐year DFS rates were 78.9% and 68.2% in the NCIT group and 66.7% and 53.6% in the NCRT group, respectively (log‐rank test, p = 0.051). (B) After matching, the 1 and 2‐year DFS rates were 81.3% and 70.0% in the NCIT group and 63.3% and 50.8% in the NCRT group, respectively (log‐rank test, p = 0.023).
Within the first year after surgery, death due to tumor occurred in 23 (18.1%) and 5 (6.6%) patients in the NCRT and NCIT groups, respectively, before PSM (p = 0.045). After PSM, the death rate from tumors was 21.7% (n = 13) and 4.6% (n = 3) in the NCRT and NCIT group, respectively (p = 0.013). The local and distant recurrence rates were 11.7% (n = 7) and 13.3% (n = 8) in the NCRT group and 6.2% (n = 4) and 1.5% (n = 1) in the NCIT group, respectively (p = 0.032). The recurrence details are shown in Table 5.
TABLE 5.
Death and disease recurrence details within 1 year after surgery.
| Before matching | After matching | |||||
|---|---|---|---|---|---|---|
| NCIT | NCRT | p * | NCIT | NCRT | p * | |
| Cause of death | n = 76 (%) | n = 127 (%) | 0.045 | n = 65 (%) | n = 60 (%) | 0.013 |
| Tumor | 5 (6.6) | 23 (18.1) | 3 (4.6) | 13 (21.7) | ||
| Treatment complications | 5 (6.6) | 4 (3.1) | 4 (6.2) | 1 (1.7) | ||
| Others | 2 (2.6) | 1 (0.8) | 2 (3.1) | 1 (1.7) | ||
| Disease recurrences | n = 76 (%) | n = 126 (%) | 0.095 | n = 65 (%) | n = 60 (%) | 0.032 |
| Local | 5 (6.6) | 15 (11.9) | 4 (6.2) | 7 (11.7) | ||
| Distant | 1 (1.3) | 11 (8.7) | 1 (1.5) | 8 (13.3) | ||
| Local + distant | 1 (1.3) | 4 (3.2) | 1 (1.5) | 3 (5.0) | ||
| Death | 9 (11.9) | 12 (9.5) | 7 (10.8) | 6 (10.0) | ||
*p<0.05 was considered as statistical significance.
4. DISCUSSION
The present retrospective case–control study clarified the efficacy of anti‐PD‐1/anti‐PD‐L1 antibody combination with chemotherapy to treat locally advanced ESCC; the pCR rate was 25.8%, identical to the rate achieved with chemoradiotherapy. More significantly, the results for short‐term survival with NCIT were superior to those with NCRT with regard to 2‐year OS (80.2% vs. 62.2%) and DFS (70.0% vs. 50.8%).
Several studies are actively investigating neoadjuvant therapy for ESCC. Although the NCRT group had a higher pCR rate in the JCOG1109 study, a higher survival benefit was not achieved. Following the beginning of the immunotherapy era, neoadjuvant immunotherapy has become the focus of research to further improve the clinical outcomes of EC patients. A recent meta‐analysis summarized the safety and efficacy of NCIT for ESCC. 22 Interestingly, Yin et al. 23 recently published their observations of a phase 1b clinical trial involving neoadjuvant monotherapy with adebrelimab (a PD‐L1 blocker) in 30 patients with resectable ESCC. Of these patients, 24% had MPR; the pCR rate and 2‐year OS were 8% and 92%, respectively. Despite these impressive results, the standard therapy for locally advanced ESCC is NCRT with subsequent surgery.
In the present study, in the NCIT group, 60.3% patients (47 of 78 patients) had MPR of the primary tumor (TRG1‐2), and 25.6% showed complete resolution of both tumor and lymph node disease (pCR); this was comparable to that of 55.9% (MPR) and 27.9% (pCR) in the NCRT group. Similar pCR and primary tumor regression rates were observed after matching. The two groups differed in lymph node and tumor regression. The downstaging of N status was substantially more after NCRT. This may be because T cells and cytotoxic T cells exhibit differences in their in situ immune patterns between metastatic lymph nodes and primary tumors, as reported for other tumors such as lung cancer. This heterogeneity might lead to varied immune responses to the type of neoadjuvant immunotherapy. 24 Further studies are warranted to clarify this difference in the immune pattern responses to neoadjuvant therapy.
The pCR rate of NCRT in our study (27.9%) was lower than that in the CROSS trial (49% for ESCC) and the 5010 study (43.2%). This may be because our study had more advanced‐stage cancer patients and used different chemoradiotherapy regimens. In the early period, because of concerns regarding the effect of NCRT on surgery, the lymph node drainage area was not included in the radiation field (pCR rate of 19.1%). With the accumulation of clinical experience, the radiotherapy fields generally included lymph node drainage areas, and the pCR rate gradually increased to 36.7%. The pCR rate of 27.9% was similar to that of the recent CMISG1701 25 study within the normal range.
We found that because of tumor regression, NCIT did not influence the surgical process and may even decrease surgical difficulty. The primary quality control standard for esophagectomy for resecting EC is radical lymph node dissection. A greater number of dissected lymph nodes led to higher OS (hazard ratio [HR] = 0.358; p < 0.001) as well as DFS (HR = 0.415; p = 0.001); moreover, the lesser number of dissected lymph nodes (<20 vs. ≥20) exhibited a significant association with total recurrence rates (41.2% vs. 25.8%, p = 0.027) and increased local recurrence (18.8% vs. 5.2%, p = 0.004) in the secondary analysis of the NEOCRTEC 5010 trial. 26 Our results showed that the NCIT group had more number of harvested lymph nodes than the NCRT group (33.6 vs. 21.7, p < 0.001). Following advances in minimally invasive techniques in recent years, an increasing number of patients have undergone minimally invasive esophagectomies. Although there is a lack of concrete evidence regarding survival benefits from techniques such as robot‐assisted surgery, their possible influence on better lymph node dissection cannot be disregarded. The therapy itself may have an influence on the dissection of lymph nodes. In this study, the same lymph node dissection technique was used for most patients. Fibrosis caused by chemoradiotherapy may increase surgical difficulty and lymph node dissection, which may lead to a decrease in the number of lymph nodes removed. A previous study reported similar results wherein NCRT was also associated with fewer dissected lymph nodes (25 vs. 19, p < 0.001). 27
Besides surgical and pathological results, mortality and postoperative complications are critical safety identifiers. It, however, remains unclear whether the incidence of mortality and postoperative complications increases following NCIT in comparison to that after NCRT. Following matching, the overall complication incidence in the NCIT and NCRT groups was 21.2% and 31.8%, respectively. No 30‐day mortality was reported in both groups. Before matching, the NCIT group showed significantly lower anastomotic leakage incidence than the NCRT group (3.8% and 12.5%, respectively; p = 0.036). After matching, the incidence of leakage was 4.5% and 10.6%, respectively, with no significant difference; this might be because each group included a smaller number of patients (p = 0.188). Local radiation, particularly including cervical esophagus and lymph node fields, is considered a risk factor for postoperative leakage due to decreased vascularity of the tissue and poor healing ability because of tissue edema and fibrosis.
The importance of pCR as the primary endpoint in neoadjuvant therapy remains debatable. A recent international cohort study showed disparities in the prognostic implication of pCR after various neoadjuvant regimens. In the study, the 5‐year RFS rate exhibited a significant decline in patients with pCR after NCRT (75.3%) as compared to those receiving neoadjuvant chemotherapy alone (87.1%, p = 0.026). This raises a doubt regarding the credibility of pCR as an oncological marker, particularly for the comparison of neoadjuvant therapy for EC. 28 , 29 In our study, the two groups showed comparable pCR rates. After the median follow‐up periods of 27 and 30 months for the NCIT and NCRT groups, respectively, these groups showed 2‐year cumulative OS rates of 80.2% and 62.2%, respectively (p = 0.029) and 2‐year DFS rates of 70.0% and 50.8%, respectively (p = 0.023). Thus, the present study confirmed that NCIT can provide remarkable short‐term survival benefits as compared to NCRT.
Death and disease recurrence within 1 year after surgery were also analyzed. The NCRT group had more deaths due to tumors than the NCIT group (21.7% vs. 4.6%, p = 0.013). The distant and local recurrence rates were 1.5% and 6.2% in the NCIT group and 13.3% and 11.7% in the NCRT group, respectively (p = 0.032).
4.1. Limitations
Because of the retrospective nature, selection bias and multiplicity must be considered in statistical analysis. PSM was utilized to reduce confounding bias and imbalance between both groups, which increased the reliability of the results. Additionally, the number of included cases was small; moreover, the duration of follow‐up was relatively short, particularly for the NCIT group. Despite this limitation, the follow‐up time covered the high‐risk recurrence period of the first 2 years after surgery. Furthermore, in this study, several immuno‐ and chemo‐regimens were adopted according to the oncologist's preference, and future clinical studies should evaluate these protocols. In recent years, an increasing number of patients have undergone minimally invasive esophagectomies. Although there is a lack of concrete evidence regarding survival benefits from techniques such as robot‐assisted surgery, these techniques might influence the dissection of lymph nodes and overall long‐term patient survival.
5. CONCLUSION
As a new treatment option for locally advanced ESCC patients who are undergoing esophagectomy, NCIT achieved superior short‐term survival outcomes as compared to NCRT, with similar perioperative complications and pathological responses. Although NCIT can achieve satisfactory short‐term survival rate, further follow‐up or prospective controlled trials are required to validate whether this short‐term survival ultimately translates into a long‐term survival benefit. 17
AUTHOR CONTRIBUTIONS
Wencheng Zhang: Data curation (supporting); writing – review and editing (supporting). Qingsong Pang: Methodology (supporting); writing – review and editing (supporting). Abbas E. Abbas: Methodology (supporting); writing – review and editing (lead). Hongjing Jiang: Conceptualization (lead); investigation (lead); project administration (lead); writing – original draft (equal); writing – review and editing (lead). Xiaobin Shang: Conceptualization (supporting); data curation (supporting); writing – review and editing (supporting). Fangdong Zhao: Data curation (equal); formal analysis (equal); writing – original draft (equal). Chen Zhang: Data curation (supporting); writing – review and editing (supporting). Jie Yue: Formal analysis (supporting); writing – review and editing (supporting). Zuoyu Chen: Formal analysis (supporting); writing – review and editing (supporting). Zhao Ma: Data curation (supporting); writing – review and editing (supporting). Chuangui Chen: Data curation (supporting); writing – review and editing (supporting). Xiaofeng Duan: Conceptualization (equal); data curation (equal); formal analysis (equal); methodology (equal); writing – original draft (equal); writing – review and editing (equal).
CONFLICT OF INTEREST STATEMENT
All authors have nothing to disclose.
Duan X, Zhao F, Shang X, et al. Neoadjuvant chemoimmunotherapy was associated with better short‐term survival of patients with locally advanced esophageal squamous cell carcinoma compared to neoadjuvant chemoradiotherapy. Cancer Med. 2024;13:e70113. doi: 10.1002/cam4.70113
Xiaofeng Duan and Fangdong Zhao contributed equally as first authors.
Contributor Information
Xiaofeng Duan, Email: xduan@tmu.edu.cn.
Hongjing Jiang, Email: jianghongjing@tmu.edu.cn.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
REFERENCES
- 1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209‐249. [DOI] [PubMed] [Google Scholar]
- 2. Eyck BM, van Lanschot JJB, Hulshof M, 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. [DOI] [PubMed] [Google Scholar]
- 3. Yang H, Liu H, Chen Y, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open‐label clinical trial. J Clin Oncol. 2018;36:2796‐2803. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Liu S, Wen J, Yang H, et al. Recurrence patterns after neoadjuvant chemoradiotherapy compared with surgery alone in oesophageal squamous cell carcinoma: results from the multicenter phase III trial NEOCRTEC5010. Eur J Cancer. 2020;138:113‐121. [DOI] [PubMed] [Google Scholar]
- 5. Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first‐line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE‐306): a global, randomised, placebo‐controlled, phase 3 study. Lancet Oncol. 2023;24:483‐495. [DOI] [PubMed] [Google Scholar]
- 6. Song Y, Zhang B, Xin D, et al. First‐line serplulimab or placebo plus chemotherapy in PD‐L1‐positive esophageal squamous cell carcinoma: a randomized, double‐blind phase 3 trial. Nat Med. 2023;29:473‐482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first‐line treatment of advanced oesophageal cancer (KEYNOTE‐590): a randomised, placebo‐controlled, phase 3 study. Lancet. 2021;398:759‐771. [DOI] [PubMed] [Google Scholar]
- 8. Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous‐cell carcinoma. N Engl J Med. 2022;386:449‐462. [DOI] [PubMed] [Google Scholar]
- 9. Lu Z, Wang J, Shu Y, et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT‐15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022;377:e068714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Hagen JA. Chemoimmunotherapy for oesophageal cancer: the next step on the path towards better outcomes. Eur J Cardiothorac Surg. 2022;62:ezac395. [DOI] [PubMed] [Google Scholar]
- 11. Liu J, Yang Y, Liu Z, 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Hong ZN, Gao L, Weng K, Huang Z, Han W, Kang M. Safety and feasibility of esophagectomy following combined immunotherapy and chemotherapy for locally advanced esophageal squamous cell carcinoma: a propensity score matching analysis. Front Immunol. 2022;13:836338. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Cheng J, Guo M, Yang Y, et al. Perioperative outcomes of minimally invasive esophagectomy after neoadjuvant immunotherapy for patients with locally advanced esophageal squamous cell carcinoma. Front Immunol. 2022;13:848881. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Ge F, Huo Z, Cai X, et al. Evaluation of clinical and safety outcomes of neoadjuvant immunotherapy combined with chemotherapy for patients with resectable esophageal cancer: a systematic review and meta‐analysis. JAMA Netw Open. 2022;5:e2239778. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Duan X, Yue J, Shang X, et al. Learning curve of robot‐assisted lymph node dissection of the left recurrent laryngeal nerve: a retrospective study of 417 patients. Ann Surg Oncol. 2023;30:3991‐4000. [DOI] [PubMed] [Google Scholar]
- 16. Shang X, Zhao G, Liang F, et al. Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage III) esophageal squamous cell carcinoma: a study protocol for a prospective, single‐arm, single‐center, open‐label, phase‐II trial (Keystone‐001). Ann Transl Med. 2022;10:229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Shang X, Zhang W, Zhao G, et al. Pembrolizumab combined with neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy followed by surgery for locally advanced oesophageal squamous cell carcinoma: protocol for a multicentre, prospective, randomized‐controlled, phase III clinical study (Keystone‐002). Front Oncol. 2022;12:831345. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Qin J, Xue L, Hao A, et al. Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT‐NEO/NCCES01 trial. Nat Med. 2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Duan X, Yue J, Chen C, et al. Lymph node dissection around left recurrent laryngeal nerve: robot‐assisted vs. video‐assisted McKeown esophagectomy for esophageal squamous cell carcinoma. Surg Endosc. 2020;35:6108‐6116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Low DE, Alderson D, Cecconello I, et al. International consensus on standardization of data collection for complications associated with esophagectomy: esophagectomy complications consensus group (ECCG). Ann Surg. 2015;262:286‐294. [DOI] [PubMed] [Google Scholar]
- 21. Rice TW, Ishwaran H, Hofstetter WL, et al. Recommendations for pathologic staging (pTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. 2016;29:897‐905. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Xu J, Yan C, Li Z, Cao Y, Duan H, Ke S. Efficacy and safety of neoadjuvant chemoimmunotherapy in resectable esophageal squamous cell carcinoma: a meta‐analysis. Ann Surg Oncol. 2023;30:1597‐1613. [DOI] [PubMed] [Google Scholar]
- 23. Yin J, Yuan J, Li Y, et al. Publisher correction: neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial. Nat Med. 2023;29:2376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Ye ZH, Long H, Zhao ZR. Different in situ immune patterns between primary tumor and lymph node in non‐small‐cell lung cancer: potential impact on neoadjuvant immunotherapy. J Immunol Res. 2022;2022:8513747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Tang H, Wang H, Fang Y, et al. Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy for locally advanced esophageal squamous cell carcinoma: a prospective multicenter randomized clinical trial. Ann Oncol. 2023;34:163‐172. [DOI] [PubMed] [Google Scholar]
- 26. Guo X, Wang Z, Yang H, et al. Impact of lymph node dissection on survival after neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: from the results of NEOCRTEC5010, a randomized multicenter study. Ann Surg. 2023;277:259‐266. [DOI] [PubMed] [Google Scholar]
- 27. Xiao X, Yang YS, Zeng XX, et al. The comparisons of neoadjuvant chemoimmunotherapy versus chemoradiotherapy for oesophageal squamous cancer. Eur J Cardiothorac Surg. 2022;62:ezac341. [DOI] [PubMed] [Google Scholar]
- 28. Cools‐Lartigue J, Markar S, Mueller C, et al. An international cohort study of prognosis associated with pathologically complete response following neoadjuvant chemotherapy versus chemoradiotherapy of surgical treated esophageal adenocarcinoma. Ann Surg. 2022;276:799‐805. [DOI] [PubMed] [Google Scholar]
- 29. Su F, Yang X, Yin J, Shen Y, Tan L. Validity of using pathological response as a surrogate for overall survival in neoadjuvant studies for esophageal cancer: a systematic review and meta‐analysis. Ann Surg Oncol. 2023;30:7461‐7471. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.