Safety and short-term outcomes of esophagectomy after neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell cancer: analysis of two phase-II clinical trials

Abstract

Background

Preoperative chemotherapy (CT) or chemoradiotherapy (CRT) show survival benefits in patients with locally advanced esophageal squamous cell carcinoma (ESCC); however, ESCC patients still have a dismal prognosis. We conducted two phase-II, single-armed clinical trials to assess the potential benefits, efficacy, feasibility, and safety of esophagectomy after combining preoperative CT or CRT and neoadjuvant programmed cell death protein 1 (PD-1) inhibitors in the treatment of ESCC.

Methods

Patients were included with histologically confirmed ESCC (clinical stage II–IVA according to the American Joint Committee on Cancer 8^th staging system) from two phase-II, single-arm trials (NCT04506138 and NCT03940001). Patients underwent two doses of intravenous PD-1 inhibitor (either camrelizumab or sintilimab) every 3 weeks, combined with two cycles of either CT or CRT. The primary endpoint of the study was the safety and short-term outcomes of esophagectomy as measured by the risk of developing complications within 30 days, after the combination of preoperative PD-1 inhibitor and CT or CRT Secondary endpoint was to evaluate the pCR rates (pT0N0), primary tumor pCR rates (pT0), operation time, postoperative stay, and 30-day mortality rate between both groups. Results between both groups were compared using a multivariable log-binomial regression model to obtain the adjusted relative risk ratios (RRs).

Results

Between May 2019 and June 2022, 55 patients were included. All patients completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group (P=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group (P=0.19). The minimally invasive surgery rates were 89.2% (33/37) in the nICT group and 94.1% (16/17) in the nICRT group. The risk of developing pulmonary, anastomotic, or other complications were similar between the two groups.

Conclusions

Esophagectomy was safe after the addition of the PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and the exploratory endpoints, including biomarkers analyses, are ongoing.

Highlight box.

Key findings

• Esophagectomy is safe and feasible following neoadjuvant immunotherapy combined with chemotherapy (nICT) and neoadjuvant immunotherapy combined with chemoradiotherapy (nICRT) for locally advanced esophageal squamous cell carcinoma (ESCC). Specifically, we found a higher primary tumor pathological complete response (pCR) rate in the nICRT group than the nICT group without significant increase in postoperative morbidity and mortality.

What is known, and what is new?

• Neoadjuvant chemoradiotherapy, or chemotherapy, improves survival in patients with locally advanced esophageal cancer.

• Our preliminary results demonstrate that esophagectomy remain safe and feasible following nICT and nICRT for locally advanced esophageal cancer. The primary tumor pCR rate was higher in the nICRT group than the nICT group. Postoperative morbidity and mortality were similar in patients treated with nICT and nICRT.

What is the implication, and what should change now?

• This is the first study to describe surgical outcomes after nICT or nICRT for locally advanced ESCC. Our results will contribute to ongoing research study design on optimal neoadjuvant immunotherapy strategies for resectable squamous esophageal cancer.

Introduction

Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth most common cause of cancer-related mortality worldwide (1). The incidence of esophageal cancer in East Asia is high, and according to the latest data, the incidence in China accounts for more than 50% of all cases worldwide (1). In China, over 90% of esophageal cancers are esophageal squamous cell carcinomas (ESCCs), and as many as 30–50% of patients have locally advanced disease when diagnosed.

Currently, neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) plus esophagectomy is recommended as the standard treatment for locally advanced, operable ESCC. However, due to the high rate of local or distant recurrence, the long-term survival of nCT or nCRT plus esophagectomy for ESCC is still unsatisfactory (2-4). Therefore, the establishment of new and effective treatment strategies is crucial to further improve the long-term survival of ESCC patients.

In recent years, immune checkpoint blockade therapy has revolutionized the treatment paradigm of multiple advanced cancers (5-10). ESCC has a very high tumor mutational burden and high programmed death-1 ligand expression (PD-L1), demonstrating its potential sensitivity to immune checkpoint inhibitors (ICIs) (11-17).

In a study of postoperative adjuvant therapy for locally advanced esophageal cancer, nivolumab was shown to improve disease-free survival after esophagectomy (18). Several other prospective clinical studies have investigated the safety and efficacy of preoperative neoadjuvant immunotherapy combined with chemotherapy (nICT) or neoadjuvant immunotherapy combined with chemoradiotherapy (nICRT) and reported satisfactory outcomes after the addition of programmed cell death protein 1 (PD-1) inhibitors to the neoadjuvant regimen (19-22). However, few studies have investigated the safety of surgery following the neoadjuvant treatment with ICIs in esophageal cancer, and to date, most such studies have only focused on the toxicity and tolerability of ICIs (23,24). Further, to date, no published studies have compared the safety and efficacy of esophagectomy after different neoadjuvant immunotherapy modalities.

In this article, we share our experience on the safety and feasibility of esophagectomy after nICT or nICRT for locally advanced ESCC. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-295/rc).

Methods

Patient selection and study design

We initiated two non-randomized, single-arm, single-center, phase-II trials to investigate the efficacy, feasibility, and safety of the combination of preoperative chemotherapy (CT) or chemoradiotherapy (CRT) and PD-1 inhibitor in the treatment of ESCC. Patients underwent esophagectomy after neoadjuvant therapy completion between May 2019 and June 2022 at the Zhejiang Cancer Hospital, China.

To be eligible for these two clinical studies, patients had to meet the following inclusion criteria: have histologically confirmed, potentially curable ESCC with cT1N1–3M0 or cT2–4aN0–3M0 (American Joint Committee on Cancer 8^th staging system); have no metastatic cervical lymph nodes; not have undergone prior therapy for any cancer; be aged 18–75 years; have normal organ function; and have adequate pulmonary and cardiac function. Patients were excluded from the study if they had an immunodeficiency disease, were receiving ongoing systemic immunosuppressive therapy with either corticosteroids (>10 mg daily prednisolone equivalent) or other immunosuppressive drugs, had an infectious disease, had a clinically significant concurrent cancer, were unable to undergo gastric tube reconstruction after esophagectomy, or were hypersensitive to albumin paclitaxel and carboplatin drugs.

These two studies were conducted in accordance with the Declaration of Helsinki (as revised in 2013). All patients provided written informed consent for their enrollment in the studies, and the studies were approved by the Ethics Committee of the Zhejiang Cancer Hospital, China (Nos. IRB-2019-38 and IRB-2020-183).

Neoadjuvant treatment protocols

nICT group

The enrolled patients received two doses of intravenous PD-1 inhibitor (camrelizumab, at a dose of 200 mg) every 3 weeks, with two cycles of CT simultaneously. The detailed regimen included albumin paclitaxel (100 mg per square meter of body-surface area) on days 1 and 8, and carboplatin targeted at an area under the curve (AUC) of 5 mg per mL per minute on day 1. Changes in tumor size were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (25). For patients who successfully received two cycles of neoadjuvant therapy, surgeons evaluated the suitability of esophagectomy. The surgery was performed 3–5 weeks after the second dose of CT.

nICRT group

Sintilimab was administered on days 1 and 22 of the neoadjuvant therapy intravenously at a dose of 200 mg. The CT regimen included carboplatin (AUC: 2 mg per mL per minute) and paclitaxel (50 mg per square meter of body-surface area), which were administered intravenously on days 1, 8, 15, 22, and 29. Radiotherapy was performed by means of external-beam radiation, and was started on day 1 of CT. A total radiation dose of 41.4 Gy was given by 23 fractions, with 5 fractions per week, and 1.8 Gy per fraction (26). Surgery was performed 6–8 weeks after the end of radiotherapy.

Surgery protocols

Minimally invasive esophagectomy (MIE), right transthoracic open esophagectomy (OE), or hybrid approaches (a combination of video-assisted thoracoscopy and laparotomy) with a total two- or three-field lymphadenectomy were performed. A gastric tube was used to reconstruct the digestive tract after esophagectomy. Transesophageal or left thoracic esophagectomy was not performed because of the limited lymph node dissection capacity of the above methods, especially for the lymph nodes along the bilateral recurrent laryngeal nerve. To ensure the success of the surgeries, all the operations were conducted by experienced attending surgeons, who had each conducted more than 100 esophagectomies.

Outcome measures

The postoperative complications were divided into the following four categories: pulmonary complications, including pneumonia, pleural effusion, respiratory failure requiring reintubation, and pulmonary embolism; anastomotic complications, including leak, dehiscence, and fistula; cardiac complications, including arrhythmia, pericardial effusion, and myocardial infarction; and other complications including chyle leak, deep venous thrombosis, wound infection, hematological toxicity, and recurrent laryngeal nerve injury. A severe surgical complication was defined as grade ≥3 toxicity, in accordance with the Clavien-Dindo classification system (27). If a patient had multiple complications in the same category of complications, the more severe complication was recorded. Operative time was measured from incision to wound closure. Postoperative hospital stay was defined as the number of hospitalized days from the day of operation to the day of leaving our hospital. Pathological complete response (pCR) was defined as no evidence of residual tumor cells. The primary endpoint was the risk of 30-day complications. The secondary endpoints included the pathological response, operation time, postoperative stay, and 30-day mortality rate.

Statistical analysis

Patient characteristics are presented as either the median and interquartile range, or the frequency and percentage. The nICT and nICRT groups were compared using either a Wilcoxon rank-sum test (continuous variables) or Fisher’s exact test (categorical variables). The relative risk ratios (RRs) of the 30-day perioperative outcomes for the nICT vs. nICRT were estimated using a multivariable log-binomial regression model, with adjustment for a set of predefined clinical factors, including age, gender, smoking, drinking status, clinical stage, and minimally invasive approach. Adjusted RRs were estimated only for outcomes with ≥8 events. A two-sided P value <0.05 was considered statistically significant. The statistical analyses were performed using SPSS Statistics (version 25, IBM, Armonk, NY, USA).

Results

Patient characteristics

The nICT group comprised 46 patients, of whom, 38 received surgery [37 underwent complete (R0) resection and one underwent exploratory surgery] (Figure 1A). The nICRT group comprised 22 patients, of whom 17 received surgery (16 underwent R0 resection and one received palliative surgery) (Figure 1B). Patient characteristics are summarized in Table 1. Interestingly, the distribution of age, gender, performance status, clinical stage, tumor location, smoking, and drinking history were similar in these two groups. In both groups, there were more male patients than female patients, and a higher percentage of patients were aged between 50 and 75 years, in clinical stage 3, and had squamous cell carcinoma.

Figure 1.

Consort diagram. (A) nICT group; (B) nICRT group. nICT, neoadjuvant immunotherapy combined with chemotherapy; nICRT, neoadjuvant immunotherapy combined with chemoradiotherapy.

Table 1. Baseline demographics and clinical characteristics of patients in nICT and nICRT groups.

Characteristics	nICT (n=38)	nICRT (n=17)	P value
Age (years), median [range]	63.3 [50–74]	62.8 [52–75]	0.79
Male, n (%)	36 (94.7)	13 (76.5)	0.07
Smoking history, n (%)	28 (73.7)	8 (47.1)	0.07
Drinking history, n (%)	30 (78.9)	9 (52.9)	0.06
Tumor location, n (%)			0.61
Proximal third	2 (5.3)	0
Middle third	14 (36.8)	6 (35.3)
Distal third	22 (57.9)	11 (64.7)
Clinical T stage, n (%)			0.04
cT2	0	2 (11.8)
cT3	37 (97.4)	13 (76.5)
cT4a	1 (2.6)	2 (11.8)
Clinical N stage, n (%)			0.08
N0	11 (28.9)	2 (11.8)
N1	20 (52.6)	7 (41.2)
N2	6 (15.8)	8 (47.1)
N3	1 (2.6)	0
Clinical stage, n (%)			0.52
II	11 (28.9)	3 (17.6)
III	25 (65.8)	12 (70.6)
IVA	2 (5.3)	2 (11.8)
Performance status (ECOG), n (%)			0.47
0	29 (76.3)	15 (88.2)
1	9 (23.7)	2 (11.8)

nICT, neoadjuvant immunotherapy combined with chemotherapy; nICRT, neoadjuvant immunotherapy combined with chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group.

Toxicities of neoadjuvant therapy

In the nICT group, 8 patients (8/46, 17.4%) did not receive surgery, 3 patients (6.5%) refused surgery, 3 patients (6.5%) were inoperable, 1 patient (2.2%) had grade 5 pneumonitis, and 1 patient (2.2%) had hematologic toxicity. In the nICRT group, 5 patients (5/22, 22.7%) did not receive surgery, 1 patient (4.5%) refused surgery, 1 patient (4.5%) was inoperable, 1 patient (4.5%) had pneumonitis, and 2 patients (9.1%) had hematologic toxicity.

The most common treatment-related adverse event (TRAE) during neoadjuvant therapy was hematological toxicity. The incidence of hematologic toxicities was 91.3% (42/46) in the nICT group and 100% (22/22) in the nICRT group. In addition to hematological toxicity, grade III or higher TRAEs included rash (1/46, 2.2%), pneumonitis (1/46, 2.2%), herpes zoster infection (1/46, 2.2%) in the nICT group, and esophagitis (4/22, 18.2%) and pneumonitis (1/22, 4.5%) in the nICRT group.

Surgical outcomes

The surgical details and pathologic outcomes are summarized in Table 2. The median operation time was 289 minutes in the nICT group and 262 minutes in the nICRT group (P=0.27). The median volume of blood loss was similar in the two groups (100 vs. 100 mL, P=0.65). All patients in the nICRT group underwent three-incision esophagectomy, and 2 (5.4%) patients in the nICT group underwent Ivor-Lewis esophagectomy. Most of the patients in the two groups underwent MIE or hybrid MIE (HMIE) (89.2% in nICT group, 94.1% in the nICRT group), 1 (5.9%) patient in the nICRT group converted to open surgery due to local invasion, and 4 (10.8%) patients in the nICT group underwent open surgery. The number of lymph nodes dissected and postoperative hospital stay were similar in the two groups. The pCR was 21.6% (8/37) in the nICT group and 41.2% (7/17) in the nICRT group (P=0.19). The primary tumor pCR was 21.6% (8/37) in the nICT group and 52.9% (9/17) in the nICRT group (P=0.03) (Figure 2). Thirty-day mortality was only observed in 1 (5.9%) patient in the nICRT group due to postoperative anastomotic leakage and pulmonary infection, which eventually led to death from septic shock on the 9^th postoperative day.

Table 2. Surgical characteristics of patients in nICT and nICRT groups.

Characteristics	nICT (n=37)†	nICRT (n=17)	P value
Surgery time (min), median	289	262	0.27
Blood loss (mL), median	100	100	0.65
Operative approaches, n (%)			0.99
MeKeown	35 (94.6)	17 (100.0)
Ivor-Lewis	2 (5.4)	0
Minimally invasive technique, n (%)			0.35
MIE	28 (75.7)	11 (64.7)
HMIE	5 (13.5)	5 (29.4)
OE	4 (10.8)	1 (5.9)
Lymph nodes removed, n	23	16	0.05
pCR, n (%)	8 (21.6)	7 (41.2)	0.19
Primary tumor pCR, n (%)	8 (21.6)	9 (52.9)	0.03*
Length of hospital stay (days)	11	14	0.16
30-day mortality, n (%)	0	1 (5.9)	0.31

^†, one patient in the nICT group underwent open-close surgery, with no resection, so it is not included in the postoperative analysis; *, P<0.05. nICT, neoadjuvant immunotherapy combined with chemotherapy; nICRT, neoadjuvant immunotherapy combined with chemoradiotherapy; MIE, minimally invasive esophagectomy; HMIE, hybrid minimally invasive esophagectomy; OE, open esophagectomy; pCR, pathological complete response.

Figure 2.

pCR rates between two groups. *, P<0.05. pCR, pathological complete response; NS, not significant; nICT, neoadjuvant immunotherapy combined with chemotherapy; nICRT, neoadjuvant immunotherapy combined with chemoradiotherapy.

Postoperative complications

The postoperative complications within 30 days are summarized in Table 3. The incidence of anastomotic and cardiac complications was similar in both groups. Anastomotic complications occurred in 6 patients (16.2%) in the nICT group and 3 patients (17.6%) in the nICRT group. All the anastomotic complications were severe, requiring further drainage or placement of a gastroscopic fistula drainage tube, as well as antibiotics. The incidence of pulmonary and other complications was numerically higher in the nICRT group than the nICT group, but the difference was not statistically significant difference (Figure 3). In terms of the pulmonary complications, two of eight in the nICT group and two of five in the nICRT group were considered severe, requiring either reintervention, critical care management, or both. After adjustment for age, gender, smoking and drinking status, clinical stage, and the minimally invasive approach, the addition of neoadjuvant radiotherapy did not significantly increase the risk of developing anastomotic [RR: 0.98; 95% confidence interval (CI): 0.757–1.277; P=0.897], pulmonary (RR: 0.90; 95% CI: 0.634–1.279; P=0.56), or other complications (RR: 0.73; 95% CI: 0.473–1.112; P=0.14) in the nICRT group. As only two patients in the nICT group and one in the nICRT group had cardiac complications, the RRs could not be calculated.

Table 3. Thirty-day complications of patients in nICT and nICRT groups.

Postoperative events	nICT (n=37)†	nICRT (n=17)	P value	Adjusted RR (95% CI)	Adjusted P value
Anastomotic leakage, n (%)	6 (16.2)	3 (17.6)	>0.99	0.98 (0.757–1.277)	0.90
Major anastomotic leakage	6 (16.2)	3 (17.6)	>0.99	0.98 (0.757–1.277)	0.90
Pulmonary, n (%)	8 (21.6)	5 (29.4)	0.78	0.90 (0.634–1.279)	0.56
Major pulmonary	2 (5.4)	2 (11.8)	0.79	–	–
Cardiac, n (%)	2 (5.4)	1 (5.9)	>0.99	–	–
Major cardiac	0 (0.0)	1 (5.9)	0.69	–	–
Other, n (%)	7 (18.9)	7 (41.2)	0.16	0.73 (0.473–1.112)	0.14
Major other	4 (10.8)	4 (23.5)	0.42	0.94 (0.794–1.112)	0.47

^†, one patient in the nICT group underwent open-close surgery, with no resection, so it is not included in the postoperative analysis. Other: other complications included chyle leak, deep venous thrombosis, wound infection, hematological toxicity and recurrent laryngeal nerve injury. nICT, neoadjuvant immunotherapy combined with chemotherapy; nICRT, neoadjuvant immunotherapy combined with chemoradiotherapy; RR, risk ratio; CI, confidence interval.

Figure 3.

Frequency of 30-day complications between two groups. NS, not significant; nICT, neoadjuvant immunotherapy combined with chemotherapy; nICRT, neoadjuvant immunotherapy combined with chemoradiotherapy.

Discussion

In this study, we assessed the feasibility and safety of esophagectomy after a combination of PD-1 inhibitor and preoperative CT or CRT in ESCC in two clinical trials. According to our preliminary data, there were no statistically significant differences between the nICT and nICRT groups in terms of the surgery-related data and postoperative complications. Immune-related adverse events were relatively infrequent and also did not significantly increase the postoperative complications. ICIs combined with CT have been proven to be safe and feasible in previous large sample-sized studies (14,28), and the addition of radiotherapy did not result in a significantly increased risk of postoperative complications or mortality.

Esophagectomy is undoubtedly the most challenging technique for surgeons. Therefore, perioperative safety and short-term outcomes after new neoadjuvant regimens in patients with esophageal cancer are primary concerns of surgeons. The median operation time and blood loss was similar in the two groups, which indicates that the addition of radiotherapy did not significantly increase surgery feasibility compared to that of the nICT group. Further, based on the experiences of the surgeons in the present study, we would like to hypothesize that tumors tended to adhere more loosely to the surrounding tissues, and were thus easier to remove after neoadjuvant therapies. This was quite different from the condition observed in patients with lung cancer after neoadjuvant ICI therapy, where the tissues surrounding the tumors were more likely to have hilar inflammation and fibrosis, as reported by a phase-I trial examining the use of neoadjuvant nivolumab in patients with resectable non-small cell lung cancer (29). However, in our study, fibrosis in the adventitia of the esophagus was rarely observed, which is similar to the findings of Sihag et al. (23). This suggests that responses to ICIs vary in different cancer types.

Another concern is the difference in the pCR rates between these two immunotherapy regimens. The pCR rate was numerically higher in the nICRT group than the nICT group (41.2% vs. 21.6%, P=0.19), but the difference was not statistically significant. When we focused on the primary tumor pCR rate, we found that the nICRT group had a higher pCR rate, and the difference was statistically significant (52.9% vs. 21.6%, P=0.03), which suggests that the addition of neoadjuvant radiotherapy better controlled the local tumor. However, the pCR rate of the nICRT group was similar with that of the nCRT group in two previous nCRT studies (26,30). Therefore, the long-term survival benefits of nICRT regimens require further investigation and we look forward to the results of phase II/III study EA2174 (No. NCT03604991) which compared patients received nCRT with or without nivolumab.

In the subgroup analysis of the NEOCRTEC 5010 study, the pCR patients had a significantly lower risk of recurrence than the non-pCR patients (15.0% vs. 48.1%, P<0.001) (3). Additionally, other studies have shown that patients with pCR have a higher survival rate, and reported a positive correlation between the response to neoadjuvant treatment and long-term survival regardless of the histology (31-35). In the current neoadjuvant treatment regimen for esophageal cancer, patients in the nICRT group had a higher pCR rate than those in the nCT group (36). However, follow-up research needs to be conducted to determine whether patients with higher pCR rates have a longer survival period.

Kamarajah et al. analyzed the National Cancer Database [2006–2015] and found that of the ESCC patients who underwent neoadjuvant therapy, those in the nCRT group had a higher pCR rate than nCT group (50.9% vs. 30.4%, P<0.001). A statistically significant overall survival (OS) benefit was evident for nCRT (hazard ratio, 0.78; 95% CI: 0.62 to 0.97). The 5-year survival rates for patients who had nCRT and nCT were 45.0% and 38.0%, respectively (P=0.026) (37). However, a study comparing the long-term results between nCRT and nCT have reported that the significantly higher pCR rate in the nCRT group did not lead to longer survival (38). A three-arm phase-III trial (JCOG1109, NExT study) (39) showed that nCRT did not significantly improve OS compared to nICT in the treatment of locally advanced ESCC; however, the nCRT group had the highest pCR rate in this three-arm trial. Considering the different immunotherapy regimens, large-sample long-term follow-up studies need to be conducted to confirm whether improving local control in the nICRT group also improves the long-term survival of patients.

To the best of our knowledge, this is the first study to compare the surgical outcomes between nICT and nICRT for locally advanced ESCC. However, our study had several limitations. First, the above two studies were only conducted at a single center with a relatively small sample size of patients. Second, the patients in the two groups were treated with two different PD-1 inhibitors produced by different companies. However, given the achievements of PD-1 inhibitors in treating advanced esophageal cancer, randomized controlled trials with larger patient sample sizes need to be conducted to determine whether either nICT or nICRT could become a new treatment mode for locally advanced esophageal cancer.

Conclusions

Our preliminary results suggest that esophagectomy may be both safe and feasible following nICT and nICRT for locally advanced esophageal cancer. The primary tumor pCR rate was higher in the nICRT group than the nICT group. Postoperative morbidity and mortality were similar in patients treated with nICT or nICRT. A longer follow-up period and more prospective comparative studies need to be conducted to confirm the long-term clinical outcomes.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. These two studies were conducted in accordance with the Declaration of Helsinki (as revised in 2013). All patients provided written informed consent for their enrollment in the studies, and the studies were approved by the Ethics Committee of the Zhejiang Cancer Hospital, China (Nos. IRB-2019-38 and IRB-2020-183).